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Sample records for electrophilic quinoids formed

  1. Screening botanical extracts for quinoid metabolites.

    PubMed

    Johnson, B M; Bolton, J L; van Breemen, R B

    2001-11-01

    Botanical dietary supplements represent a significant share of the growing market for alternative medicine in the USA, where current regulations do not require assessment of their safety. To help ensure the safety of such products, an in vitro assay using pulsed ultrafiltration and LC-MS-MS has been developed to screen botanical extracts for the formation of electrophilic and potentially toxic quinoid species upon bioactivation by hepatic cytochromes P450. Rat liver microsomes were trapped in a flow-through chamber by an ultrafiltration membrane, and samples containing botanical extracts, GSH and NADP(H), were flow-injected into the chamber. Botanical compounds that were metabolized to reactive intermediates formed stable GSH adducts mimicking a common in vivo detoxification pathway. If present in the ultrafiltrate, GSH conjugates were detected using LC-MS-MS with precursor ion scanning followed by additional characterization using product ion scanning and comparison to standard compounds. As expected, no GSH adducts of reactive metabolites were found in extracts of Trifolium pratense L. (red clover), which are under investigation as botanical dietary supplements for the management of menopause. However, extracts of Sassafras albidum (Nutt.) Nees (sassafras), Symphytum officinale L. (comfrey), and Rosmarinus officinalis L. (rosemary), all of which are known to contain compounds that are either carcinogenic or toxic to mammals, produced GSH adducts during this screening assay. Several compounds that formed GSH conjugates including novel metabolites of rosmarinic acid were identified using database searching and additional LC-MS-MS studies. This assay should be useful as a preliminary toxicity screen during the development of botanical dietary supplements. A positive test suggests that additional toxicological studies are warranted before human consumption of a botanical product.

  2. Screening botanical extracts for quinoid metabolites.

    PubMed

    Johnson, B M; Bolton, J L; van Breemen, R B

    2001-11-01

    Botanical dietary supplements represent a significant share of the growing market for alternative medicine in the USA, where current regulations do not require assessment of their safety. To help ensure the safety of such products, an in vitro assay using pulsed ultrafiltration and LC-MS-MS has been developed to screen botanical extracts for the formation of electrophilic and potentially toxic quinoid species upon bioactivation by hepatic cytochromes P450. Rat liver microsomes were trapped in a flow-through chamber by an ultrafiltration membrane, and samples containing botanical extracts, GSH and NADP(H), were flow-injected into the chamber. Botanical compounds that were metabolized to reactive intermediates formed stable GSH adducts mimicking a common in vivo detoxification pathway. If present in the ultrafiltrate, GSH conjugates were detected using LC-MS-MS with precursor ion scanning followed by additional characterization using product ion scanning and comparison to standard compounds. As expected, no GSH adducts of reactive metabolites were found in extracts of Trifolium pratense L. (red clover), which are under investigation as botanical dietary supplements for the management of menopause. However, extracts of Sassafras albidum (Nutt.) Nees (sassafras), Symphytum officinale L. (comfrey), and Rosmarinus officinalis L. (rosemary), all of which are known to contain compounds that are either carcinogenic or toxic to mammals, produced GSH adducts during this screening assay. Several compounds that formed GSH conjugates including novel metabolites of rosmarinic acid were identified using database searching and additional LC-MS-MS studies. This assay should be useful as a preliminary toxicity screen during the development of botanical dietary supplements. A positive test suggests that additional toxicological studies are warranted before human consumption of a botanical product. PMID:11712913

  3. Organosulfur compounds: electrophilic reagents in transition-metal-catalyzed carbon-carbon bond-forming reactions.

    PubMed

    Dubbaka, Srinivas Reddy; Vogel, Pierre

    2005-12-01

    Transition-metal-catalyzed carbon-carbon bond-forming reactions are among the most powerful methods in organic synthesis and play a crucial role in modern materials science and medicinal chemistry. Recent developments in the area of ligands and additives permit the cross-coupling of a large variety of reactants, including inexpensive and readily available sulfonyl chlorides. Their desulfitative carbon-carbon cross-coupling reactions (Negishi, Stille, carbonylative Stille, Suzuki-Miyaura, and Sonogashira-Hagihara-type cross-couplings and Mizoroki-Heck-type arylations) are reviewed together with carbon-carbon cross-coupling reactions with other organosulfur compounds as electrophilic reagents.

  4. Interference enhanced thermoelectricity in quinoid type structures.

    PubMed

    Strange, M; Seldenthuis, J S; Verzijl, C J O; Thijssen, J M; Solomon, G C

    2015-02-28

    Quantum interference (QI) effects in molecular junctions may be used to obtain large thermoelectric responses. We study the electrical conductance G and the thermoelectric response of a series of molecules featuring a quinoid core using density functional theory, as well as a semi-empirical interacting model Hamiltonian describing the π-system of the molecule which we treat in the GW approximation. Molecules with a quinoid type structure are shown to have two distinct destructive QI features close to the frontier orbital energies. These manifest themselves as two dips in the transmission, that remain separated, even when either electron donating or withdrawing side groups are added. We find that the position of the dips in the transmission and the frontier molecular levels can be chemically controlled by varying the electron donating or withdrawing character of the side groups as well as the conjugation length inside the molecule. This feature results in a very high thermoelectric power factor S(2)G and figure of merit ZT, where S is the Seebeck coefficient, making quinoid type molecules potential candidates for efficient thermoelectric devices. PMID:25725747

  5. Interference enhanced thermoelectricity in quinoid type structures

    SciTech Connect

    Strange, M. Solomon, G. C.; Seldenthuis, J. S.; Verzijl, C. J. O.; Thijssen, J. M.

    2015-02-28

    Quantum interference (QI) effects in molecular junctions may be used to obtain large thermoelectric responses. We study the electrical conductance G and the thermoelectric response of a series of molecules featuring a quinoid core using density functional theory, as well as a semi-empirical interacting model Hamiltonian describing the π-system of the molecule which we treat in the GW approximation. Molecules with a quinoid type structure are shown to have two distinct destructive QI features close to the frontier orbital energies. These manifest themselves as two dips in the transmission, that remain separated, even when either electron donating or withdrawing side groups are added. We find that the position of the dips in the transmission and the frontier molecular levels can be chemically controlled by varying the electron donating or withdrawing character of the side groups as well as the conjugation length inside the molecule. This feature results in a very high thermoelectric power factor S{sup 2}G and figure of merit ZT, where S is the Seebeck coefficient, making quinoid type molecules potential candidates for efficient thermoelectric devices.

  6. Detection of Electrophilic and Nucleophilic Chemical Agents

    DOEpatents

    McElhanon, James R.; Shepodd, Timothy J.

    2008-11-11

    A "real time" method for detecting electrophilic and nucleophilic species generally by employing tunable, precursor sensor materials that mimic the physiological interaction of these agents to form highly florescent berberine-type alkaloids that can be easily and rapidly detected. These novel precursor sensor materials can be tuned for reaction with both electrophilic (chemical species, toxins) and nucleophilic (proteins and other biological molecules) species.

  7. New directing groups for metal-catalyzed asymmetric carbon-carbon bond-forming processes: stereoconvergent alkyl-alkyl Suzuki cross-couplings of unactivated electrophiles.

    PubMed

    Wilsily, Ashraf; Tramutola, Francesco; Owston, Nathan A; Fu, Gregory C

    2012-04-01

    The ability of two common protected forms of amines (carbamates and sulfonamides) to serve as directing groups in Ni-catalyzed Suzuki reactions has been exploited in the development of catalytic asymmetric methods for cross-coupling unactivated alkyl electrophiles. Racemic secondary bromides and chlorides undergo C-C bond formation in a stereoconvergent process in good ee at room temperature in the presence of a commercially available Ni complex and chiral ligand. Structure-enantioselectivity studies designed to elucidate the site of binding to Ni (the oxygen of the carbamate and of the sulfonamide) led to the discovery that sulfones also serve as useful directing groups for asymmetric Suzuki cross-couplings of racemic alkyl halides. To our knowledge, this investigation provides the first examples of the use of sulfonamides or sulfones as effective directing groups in metal-catalyzed asymmetric C-C bond-forming reactions. A mechanistic study established that transmetalation occurs with retention of stereochemistry and that the resulting Ni-C bond does not undergo homolysis in subsequent stages of the catalytic cycle.

  8. Detection of electrophilic and nucleophilic chemical agents

    SciTech Connect

    McElhanon, James R.; Shepodd, Timothy J.

    2014-08-12

    A "real time" method for detecting chemical agents generally and particularly electrophilic and nucleophilic species by employing tunable, precursor sensor materials that mimic the physiological interaction of these agents to form highly florescent berberine-type alkaloids that can be easily and rapidly detected. These novel precursor sensor materials can be tuned for reaction with both electrophilic (chemical species, toxins) and nucleophilic (proteins and other biological molecules) species. By bonding or otherwise attaching these precursor molecules to a surface or substrate they can be used in numerous applications.

  9. [Decolorization of azo dyes using quinone reductase and quinoid compounds].

    PubMed

    Zhou, Mi; Liu, Guang-Fei; Zhou, Ji-Ti; Jin, Ruo-Fei; Chen, Ming-Xiang; Wang, Yan-Qing

    2009-06-15

    Using quinoid redox mediator and bacterial cellular quinone reductase, we investigated the decolorization ability of gene-engineered strain Escherichia coli YB and the effects of methylhydroquinone (MHQ) pretreatement on decolorization performance of E. coli JM109 and anaerobic sludge. The results indicate that lawsone is an effective accelerator for azo dye decolorization by E. coli YB overexpressing cellular quinone reductase AZR. In the presence of 0.2 mmol x L(-1) lawsone, 75% Amaranth (1 mmol x L(-1)) can be decolorized in 2 h. E. coli YB can also decolorize high concentration of azo dye in the presence of lawsone. Around 50% Amaranth (5 mmol x L(-1)) is decolorized in 8 h. Compared to lawsone, menadione is a less effective mediator. E. coli YB takes 12 h to reach 70% decolorization in the presence of 2.5 mmol x L(-1) menadione. Repeated decolorization studies showed that E. coli YB had stable decolorizing ability in the presence of lawsone. Four rounds of repeated decolorization can be completed in 12 h. Lawsone can also accelerate the decolorization of azo dyes with complex structures such as Acid Scarlet GR and Reactive Brilliant Red K-2BP. With the optimal LQ concentrations, 70% Acid Scarlet GR and Reactive Brilliant Red K-2BP are decolorized in 9 h and 30 h,respectively. Decolorization performances of E. coli JM109 and anaerobic sludge pretreated with MHQ are improved. After MHQ pretreatment,in the presence of lawsone, 80% Amaranth (1 mmol x L(-1)) can be decolorized in 5 h by E. coli JM109, while more than 75% Amaranth can be removed in 11 h by sludge.

  10. Electrophilic Substitution Reactions of Indoles

    NASA Astrophysics Data System (ADS)

    Sundberg, Richard J.

    The topic of this chapter is electrophilic substitution of indole and its derivatives. The indole ring is highly reactive at its 3-position toward protonation, halogenation, alkylation and acylation. Electrophilic substitution can be combined with inter- or intramolecular addition at C-2. Intramolecular alkylation by iminium ions (Pictet-Spengler reaction) is particularly useful. Enantioselectivity can be achieved in many conjugate addition reactions. These reactions have been applied to synthesis of both natural products and drugs.

  11. Dipolar Quinoidal Acene Analogues as Stable Isoelectronic Structures of Pentacene and Nonacene.

    PubMed

    Shi, Xueliang; Kueh, Weixiang; Zheng, Bin; Huang, Kuo-Wei; Chi, Chunyan

    2015-11-23

    Quinoidal thia-acene analogues, as the respective isoelectronic structures of pentacene and nonacene, were synthesized and an unusual 1,2-sulfur migration was observed during the Friedel-Crafts alkylation reaction. The analogues display a closed-shell quinoidal structure in the ground state with a distinctive dipolar character. In contrast to their acene isoelectronic structures, both compounds are stable because of the existence of more aromatic sextet rings, a dipolar character, and kinetic blocking. They exhibit unique packing in single crystals resulting from balanced dipole-dipole and [C-H⋅⋅⋅π]/[C-H⋅⋅⋅S] interactions. PMID:26447720

  12. Charge transfer emission of T-shaped π-conjugated molecules: impact of quinoid character on the excited state properties.

    PubMed

    Inouchi, Toshifumi; Nakashima, Takuya; Kawai, Tsuyoshi

    2014-04-10

    We investigate the impact of quinoid character of a π-conjugation system on the emission properties of T-shaped cross-conjugated molecules. Three π-conjugated systems with different quinoid nature including benzothiophene, 2-phenylthiophene, and 2-phenylthieno[3,2-b]thiophene were connected orthogonally to a π-conjugated bis(phenylethynyl)arylene with an acid responsive N-methylbenzimidazole junction. The enhancement of quinoid character of a vertical π-system effectively suppressed the twisted intramolecular charge transfer (TICT) emission, leading to a more planar ICT state with enhanced emission intensity as well as a shortened Stokes shift.

  13. Reactions of electrophiles with nucleophilic thiolate sites: relevance to pathophysiological mechanisms and remediation.

    PubMed

    LoPachin, Richard M; Gavin, Terrence

    2016-01-01

    Electrophiles are electron-deficient species that form covalent bonds with electron-rich nucleophiles. In biological systems, reversible electrophile-nucleophile interactions mediate basal cytophysiological functions (e.g. enzyme regulation through S-nitrosylation), whereas irreversible electrophilic adduction of cellular macromolecules is involved in pathogenic processes that underlie many disease and injury states. The nucleophiles most often targeted by electrophiles are side chains on protein amino acids (e.g. Cys, His, and Lys) and aromatic nitrogen sites on DNA bases (e.g. guanine N7). The sulfhydryl thiol (RSH) side chain of cysteine residues is a weak nucleophile that can be ionized in specific conditions to a more reactive nucleophilic thiolate (RS(-)). This review will focus on electrophile interactions with cysteine thiolates and the pathophysiological consequences that result from irreversible electrophile modification of this anionic sulfur. According to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson, electrophiles and nucleophiles can be classified as either soft or hard depending on their relative polarizability. HSAB theory suggests that electrophiles will preferentially and more rapidly form covalent adducts with nucleophiles of comparable softness or hardness. Application of HSAB principles, in conjunction with in vitro and proteomic studies, have indicated that soft electrophiles of broad chemical classes selectively form covalent Michael-type adducts with soft, highly reactive cysteine thiolate nucleophiles. Therefore, these electrophiles exhibit a common mechanism of cytotoxicity. As we will discuss, this level of detailed mechanistic understanding is a necessary prerequisite for the rational development of effective prevention and treatment strategies for electrophile-based pathogenic states.

  14. Sub-5-fs spectroscopy of a thiophene derivative with a quinoid structure

    NASA Astrophysics Data System (ADS)

    Kobayashi, Takayoshi; Wang, Haibo; Wang, Zhuan; Otsubo, Tetsuo

    2006-07-01

    Sub-5-fs spectroscopy of a thiophene derivative with an electron donative and an acceptive moieties and quinoid structure provided the experimental evidence of dynamic mode coupling. It was shown that two out-of-plane bending modes mediate the dynamic mode coupling between 1469 and 1379 cm -1 and between 1603 and 1469 cm -1. These couplings are considered to be associated with geometrical relaxation relevant to the neutral bipolaron formation in all- s- trans polyacetylene.

  15. Electrophilic addition and cyclization reactions of allenes.

    PubMed

    Ma, Shengming

    2009-10-20

    reactions results from the neighboring group participation of functional groups forming cyclic intermediates. We rationalize Z-stereoselectivity under other conditions by soft Lewis acid-base interactions and steric effects. These electrophilic reactions of allenes are efficient and useful methods for the synthesis of stereodefined alkenes and lactones, useful functionalities for synthesis.

  16. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles

    PubMed Central

    2016-01-01

    Conspectus Cross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C–H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions. Although the coupling of two different electrophiles under reducing conditions often leads primarily to symmetric dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop. A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addition to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C–C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain. Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form β-aryl alcohols, and coupling of benzyl sulfonate esters with aryl

  17. Methods and Mechanisms for Cross-Electrophile Coupling of Csp(2) Halides with Alkyl Electrophiles.

    PubMed

    Weix, Daniel J

    2015-06-16

    Cross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C-H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions. Although the coupling of two different electrophiles under reducing conditions often leads primarily to symmetric dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop. A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addition to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C-C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain. Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form β-aryl alcohols, and coupling of benzyl sulfonate esters with aryl halides to form

  18. A push-pull organic dye with a quinoidal thiophene linker: Photophysical properties and solvent effects

    NASA Astrophysics Data System (ADS)

    Climent, Clàudia; Carreras, Abel; Alemany, Pere; Casanova, David

    2016-10-01

    In the present work we perform a computational study of the properties of a push-pull organic dye with a quinoidal thiophene unit as the conjugated linker between the electron donor and acceptor groups. We investigate the photophysical properties of the dye related to its potential use as a molecular sensitizer in dye-sensitized solar cells. We rationalize the solvation effects on the absorption band of the dye in protic and aprotic solvents, identifying the interaction of alcohol solvents with the amine in the donor group as the source for the blue shift of the absorption band with respect to aprotic solvents.

  19. Theoretical studies on the quinoidal thiophene based dyes for dye sensitized solar cell and NLO applications.

    PubMed

    Nithya, R; Senthilkumar, K

    2014-10-21

    A series of quinoidal thiophene based dye molecules were designed and their optoelectronic properties were studied for dye sensitized solar cell (DSSC) applications. The efficiency of the designed dye molecules was analyzed using various parameters such as the HOMO-LUMO energy gap, absorption spectra, light harvesting efficiency (LHE), exciton biding energy (Eb) and free energy change for electron injection (ΔG(inject)). The simulated absorption spectra of the quinoidal thiophene molecules show that the electron withdrawing group substituted molecules exhibit dual band characteristics. We found that the cyano-[5'-(4″-amino benzylidene)-5H-thiophen-2'-ylidene] acetic acid based molecules, QT2B, QT4B, QT5 and QT6, are good candidates for DSSC applications. Furthermore, the study on the polarizability and hyperpolarizability of the designed molecules showed that the electron withdrawing group substituted QT2B-X molecules (X = Cl, Br, CF3, CN and NO2) are good candidates for NLO applications.

  20. Electrophilic Carbonyl Activation: Competing Condensative Cyclizations of Tryptamine Derivatives

    PubMed Central

    Liu, Fan; Movassaghi, Mohammad

    2014-01-01

    A series of tryptamine derived bisindole substrates were subject to electrophilic activation of the functional grouping at their alpha-nitrogen in the form of iminium ions to enable cyclization onto the sterically hindered indole substructure. Our observations regarding divergent cyclization outcomes using electronically distinct bisindole substrates are described. Surprising preference for Friedel-Crafts alkylation reaction and evidence for an intriguing reversible spirocyclization are discussed. PMID:26120209

  1. Phosphine Catalysis of Allenes with Electrophiles

    PubMed Central

    Wang, Zhiming; Xu, Xingzhu; Kwon, Ohyun

    2014-01-01

    Nucleophilic phosphine catalysis of allenes with electrophiles is one of the most powerful and straightforward synthetic strategies for the generation of highly functionalized carbocycle or heterocycle structural motifs, which are present in a wide range of bioactive natural products and medicinally important substances. The reaction topologies can be controlled through judicious choice of the phosphine catalyst and the structural variations of starting materials. This Tutorial Review presents selected examples of nucleophilic phosphine catalysis using allenes and electrophiles. PMID:24663290

  2. Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore

    PubMed Central

    2016-01-01

    We describe a general method to synthesize the iminium tetrahydrothiophene embedded in the dimeric Nuphar alkaloids. In contrast to prior studies, the sulfur atom of the thiaspirane pharmacophore is shown to be electrophilic. This α-thioether reacts with thiophenol or glutathione at ambient temperature to cleave the C–S bond and form a disulfide. Rates of conversion are proportional to the corresponding ammonium ion pKa and exhibit half-lives less than 5 h at a 5 mM concentration of thiol. A simple thiophane analogue of the Nuphar dimers causes apoptosis at single-digit micromolar concentration and labels reactive cysteines at similar levels as the unsaturated iminium “warhead”. Our experiments combined with prior observations suggest the sulfur of the Nuphar dimers can react as an electrophile in cellular environments and that sulfur-triggered retrodimerization can occur in the cell. PMID:27413784

  3. Potent methyl oxidation of 5-methyl-2'-deoxycytidine by halogenated quinoid carcinogens and hydrogen peroxide via a metal-independent mechanism.

    PubMed

    Shao, Jie; Huang, Chun-Hua; Kalyanaraman, Balaraman; Zhu, Ben-Zhan

    2013-07-01

    Halogenated quinones are a class of carcinogenic intermediates and are newly identified chlorination disinfection by-products in drinking water. We found recently that the highly reactive and biologically important hydroxyl radical ((•)OH) can be produced by halogenated quinones and H2O2 independent of transition metal ions. However, it is not clear whether these quinoid carcinogens and H2O2 can oxidize the nucleoside 5-methyl-2'-deoxycytidine (5mdC) to its methyl oxidation products and, if so, what the underlying molecular mechanism is. Here we show that three methyl oxidation products, 5-(hydroperoxymethyl)-, 5-(hydroxymethyl)-, and 5-formyl-2'-deoxycytidine, could be produced when 5mdC was treated with tetrachloro-1,4-benzoquinone (TCBQ) and H2O2. The formation of the oxidation products was markedly inhibited by typical (•)OH scavengers and under anaerobic conditions. Analogous effects were observed with other halogenated quinones and the classic Fenton system. Based on these data, we propose that the oxidation of 5mdC by TCBQ/H2O2 might be through the following mechanism: (•)OH produced by TCBQ/H2O2 may first abstract hydrogen from the methyl group of 5mdC, leading to the formation of 5-(2'-deoxycytidylyl)methyl radical, which may combine with O2 to form the peroxyl radical. The unstable peroxyl radical transforms into the corresponding hydroperoxide 5-(hydroperoxymethyl)-2'-deoxycytidine, which reacts with TCBQ and results in the formation of 5-(hydroxymethyl)-2'-deoxycytidine and 5-formyl-2'-deoxycytidine. This is the first report that halogenated quinoid carcinogens and H2O2 can induce potent methyl oxidation of 5mdC via a metal-independent mechanism, which may partly explain their potential carcinogenicity.

  4. Global and local reactivity indices for electrophilic/nucleophilic free radicals.

    PubMed

    Domingo, Luis R; Pérez, Patricia

    2013-07-14

    A set of five DFT reactivity indices, namely, the global electrophilicity ω° and nucleophilicity N° indices, the radical Parr function P, and the local electrophilicity ω and nucleophilicity N indices, for the study of free radicals (FRs) are proposed. Global indices have been tested for a series of 32 FRs having electrophilic and/or nucleophilic activations. As expected, no correlation between the proposed global electrophilicity ω° and global nucleophilicity N° has been found. Analysis of the local electrophilicity ω and nucleophilicity N indices for FRs, together with analysis of the local electrophilicity ωk and nucleophilicity Nk indices for alkenes, allows for an explanation of the regio- and chemoselectivity in radical additions of FRs to alkenes. Finally, an ELF bonding analysis for the C-C bond formation along the nucleophilic addition of 2-hydroxyprop-2-yl FR 28 to methyl acrylate 35 evidences that the new C-C bond is formed by C-to-C coupling of two radical centres, which are properly characterized through the use of the Parr functions. PMID:23685829

  5. Global and local reactivity indices for electrophilic/nucleophilic free radicals.

    PubMed

    Domingo, Luis R; Pérez, Patricia

    2013-07-14

    A set of five DFT reactivity indices, namely, the global electrophilicity ω° and nucleophilicity N° indices, the radical Parr function P, and the local electrophilicity ω and nucleophilicity N indices, for the study of free radicals (FRs) are proposed. Global indices have been tested for a series of 32 FRs having electrophilic and/or nucleophilic activations. As expected, no correlation between the proposed global electrophilicity ω° and global nucleophilicity N° has been found. Analysis of the local electrophilicity ω and nucleophilicity N indices for FRs, together with analysis of the local electrophilicity ωk and nucleophilicity Nk indices for alkenes, allows for an explanation of the regio- and chemoselectivity in radical additions of FRs to alkenes. Finally, an ELF bonding analysis for the C-C bond formation along the nucleophilic addition of 2-hydroxyprop-2-yl FR 28 to methyl acrylate 35 evidences that the new C-C bond is formed by C-to-C coupling of two radical centres, which are properly characterized through the use of the Parr functions.

  6. Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics.

    PubMed

    Levonen, Anna-Liisa; Hill, Bradford G; Kansanen, Emilia; Zhang, Jianhua; Darley-Usmar, Victor M

    2014-06-01

    Redox networks in the cell integrate signaling pathways that control metabolism, energetics, cell survival, and death. The physiological second messengers that modulate these pathways include nitric oxide, hydrogen peroxide, and electrophiles. Electrophiles are produced in the cell via both enzymatic and nonenzymatic lipid peroxidation and are also relatively abundant constituents of the diet. These compounds bind covalently to families of cysteine-containing, redox-sensing proteins that constitute the electrophile-responsive proteome, the subproteomes of which are found in localized intracellular domains. These include those proteins controlling responses to oxidative stress in the cytosol-notably the Keap1-Nrf2 pathway, the autophagy-lysosomal pathway, and proteins in other compartments including mitochondria and endoplasmic reticulum. The signaling pathways through which electrophiles function have unique characteristics that could be exploited for novel therapeutic interventions; however, development of such therapeutic strategies has been challenging due to a lack of basic understanding of the mechanisms controlling this form of redox signaling. In this review, we discuss current knowledge of the basic mechanisms of thiol-electrophile signaling and its potential impact on the translation of this important field of redox biology to the clinic. Emerging understanding of thiol-electrophile interactions and redox signaling suggests replacement of the oxidative stress hypothesis with a new redox biology paradigm, which provides an exciting and influential framework for guiding translational research.

  7. Relationship of electrophilic stress to aging

    PubMed Central

    Zimniak, Piotr

    2011-01-01

    This review begins with the premise that an organism's life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects, and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species (ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated to membrane peroxidizability, and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via non-targeted reactions with cellular macromolecules, and (ii) modulate signaling pathways that control longevity assurance mechanisms. PMID:21708248

  8. The Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

    PubMed Central

    Michalsen, Bradley T.; Gherezghiher, Teshome B.; Choi, Jaewoo; Esala, R.; Chandrasena, P.; Qin, Zhihui; Thatcher, Gregory R.J.; Bolton, Judy L.

    2012-01-01

    The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed Phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. 2008, 36, 1218-26) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM. PMID

  9. Selective estrogen receptor modulator (SERM) lasofoxifene forms reactive quinones similar to estradiol.

    PubMed

    Michalsen, Bradley T; Gherezghiher, Teshome B; Choi, Jaewoo; Chandrasena, R Esala P; Qin, Zhihui; Thatcher, Gregory R J; Bolton, Judy L

    2012-07-16

    The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. (2008) 36, 1218-1226) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of the total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in the formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM

  10. Electrophiles and acute toxicity to fish

    SciTech Connect

    Hermens, J.L. )

    1990-07-01

    Effect concentrations in fish LC50 tests with directly acting electrophiles are lower than those of unreactive chemicals that act by narcosis. LC50 values of more hydrophobic reactive chemicals tend to approach those of unreactive chemicals. Quantitative studies to correlate fish LC50 data to physical-chemical properties indicate that LC50 values of reactive chemicals depend on hydrophobicity as well as chemical reactivity. In this paper, several examples will be given of chemical structures that are known as direct electrophiles. This classification might be useful to identify chemicals that are more effective at lower concentrations than unreactive compounds. Chemicals that require bioactivation are not included because almost no information is available on the influence of bioactivation on acute toxic effects in aquatic organisms.32 references.

  11. Direct asymmetric dearomatization of 2-naphthols by scandium-catalyzed electrophilic amination.

    PubMed

    Nan, Jiang; Liu, Jingjing; Zheng, Huayu; Zuo, Zhijun; Hou, Lei; Hu, Huaiming; Wang, Yaoyu; Luan, Xinjun

    2015-02-16

    Catalytic asymmetric aminative dearomatization of 1-substituted 2-naphthols was successfully implemented with electrophilic azodicarboxylates under the catalysis of chiral Sc(III)/pybox complexes. This intermolecular reaction represents a hitherto unknown enantioselective C-N bond-forming process through direct dearomatization of phenolic compounds to generate chiral nitrogen-containing quaternary carbon stereocenters.

  12. Redox signaling regulated by electrophiles and reactive sulfur species.

    PubMed

    Nishida, Motohiro; Kumagai, Yoshito; Ihara, Hideshi; Fujii, Shigemoto; Motohashi, Hozumi; Akaike, Takaaki

    2016-03-01

    Redox signaling is a key modulator of oxidative stress induced by nonspecific insults of biological molecules generated by reactive oxygen species. Current redox biology is revisiting the traditional concept of oxidative stress, such that toxic effects of reactive oxygen species are protected by diverse antioxidant systems upregulated by oxidative stress responses that are physiologically mediated by redox-dependent cell signaling pathways. Redox signaling is thus precisely regulated by endogenous electrophilic substances that are generated from reactive oxygen species and nitric oxide and its derivative reactive species during stress responses. Among electrophiles formed endogenously, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) has unique cell signaling functions, and pathways for its biosynthesis, signaling mechanism, and metabolism in cells have been clarified. Reactive sulfur species such as cysteine hydropersulfides that are abundant in cells are likely involved in 8-nitro-cGMP metabolism. These new aspects of redox biology may stimulate innovative and multidisciplinary research in cell and stem cell biology; infectious diseases, cancer, metabolic syndrome, ageing, and neurodegenerative diseases; and other oxidative stress-related disorders. This review focuses on the most recent progress in the biosynthesis, cell signaling, and metabolism of 8-nitro-cGMP, which is a likely target for drug development and lead to discovery of novel therapeutics for many diseases. PMID:27013774

  13. Redox signaling regulated by electrophiles and reactive sulfur species

    PubMed Central

    Nishida, Motohiro; Kumagai, Yoshito; Ihara, Hideshi; Fujii, Shigemoto; Motohashi, Hozumi; Akaike, Takaaki

    2016-01-01

    Redox signaling is a key modulator of oxidative stress induced by nonspecific insults of biological molecules generated by reactive oxygen species. Current redox biology is revisiting the traditional concept of oxidative stress, such that toxic effects of reactive oxygen species are protected by diverse antioxidant systems upregulated by oxidative stress responses that are physiologically mediated by redox-dependent cell signaling pathways. Redox signaling is thus precisely regulated by endogenous electrophilic substances that are generated from reactive oxygen species and nitric oxide and its derivative reactive species during stress responses. Among electrophiles formed endogenously, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) has unique cell signaling functions, and pathways for its biosynthesis, signaling mechanism, and metabolism in cells have been clarified. Reactive sulfur species such as cysteine hydropersulfides that are abundant in cells are likely involved in 8-nitro-cGMP metabolism. These new aspects of redox biology may stimulate innovative and multidisciplinary research in cell and stem cell biology; infectious diseases, cancer, metabolic syndrome, ageing, and neurodegenerative diseases; and other oxidative stress-related disorders. This review focuses on the most recent progress in the biosynthesis, cell signaling, and metabolism of 8-nitro-cGMP, which is a likely target for drug development and lead to discovery of novel therapeutics for many diseases. PMID:27013774

  14. Shelf-stable electrophilic reagents for trifluoromethylthiolation.

    PubMed

    Shao, Xinxin; Xu, Chunfa; Lu, Long; Shen, Qilong

    2015-05-19

    Fluorine, which is the most electronegative element and has a small atomic radius, plays a key role in pharmaceutical, agrochemical, and materials sciences. One of the fluoroalkyl groups, the trifluoromethylthio group (CF3S-), has been well-recognized as an important structural motif in the design of lead compounds for new drug discovery because of its high lipophilicity (Hansch lipophilicity parameter π = 1.44) and strong electron-withdrawing properties, which could improve the drug molecule's cell-membrane permeability and enhance its chemical and metabolic stability. While classic methods for the preparation of trifluoromethylthiolated compounds typically involve halogen-fluorine exchange reactions of polyhalogenomethyl thioethers or trifluoromethylation of sulfur-containing compounds under harsh reaction conditions, an alternative but more attractive strategy is direct trifluoromethylthiolation of the substrate at a late stage by employing an electrophilic trifluoromethylthiolating reagent. Although several electrophilic trifluoromethylthiolating reagents have been reported previously, these reagents either require a strong Lewis acid/Brønsted acid as an activator or suffer from a toxic nature or limited substrate scope. To address these problems, in late 2011 we initiated a project with the aim to develop new, shelf-stable, and highly reactive electrophilic trifluoromethylthiolating reagents that could easily install the trifluoromethylthio group at the desired positions of the drug molecule at a late stage of drug development. Inspired by the broad reactivity of the hypervalent iodine reagent, we initially discovered a highly reactive trifluoromethylthiolating reagent, trifluoromethanesulfenate 1a. Structure-reactivity studies disclosed that the iodine atom of reagent 1a does not play an important role in this reagent's reactivity. Consequently, a simplified second-generation electrophilic reagent, trifluoromethanesulfenate 1b, was developed. In parallel

  15. Spectroscopic properties of phenolic and quinoid carotenoids: a combined theoretical and experimental study.

    PubMed

    Marian, Christel M; Kock, Sebastian C; Hundsdörfer, Claas; Martin, Hans-Dieter; Stahl, Wilhelm; Ostroumov, Evgeny; Müller, Marc G; Holzwarth, Alfred R

    2009-02-01

    For the natural carotenoid 3,3'-dihydroxyisorenieratene (DHIR) and two synthetic derivatives, 3,3'-dihydroxy-16,17,18,16',17',18'-hexanor-Phi,Phi-carotene (DHHC) and Phi,Phi-carotene-3,3'-dione (DHIRQ, isorenieratene-3,3'-dione), steady state absorption experiments and combined density functional and multi-reference configuration interaction calculations were carried out. In addition, femtosecond transient absorption spectra were recorded for DHIR. Due to their marked out-of-plane distortion in DHIR, the phenolic end groups participate only partially in the conjugation system. In the low-energy regime its absorption spectrum with the maximum at 21 700 cm(-1) in acetone solution therefore closely resembles that of beta-carotene, the same as for the T1 energy. Further similarities are also found for the decay kinetics of the optically bright 1(1)Bu+ state of these compounds. After femtosecond excitation, the 1(1)Bu+ population of DHIR decays with a lifetime of 110 fs to the vibrationally hot 2(1)Ag-,v state which in turn relaxes to the 2(1)Ag-,0 state within 500 fs. Decay of the 2(1)Ag-,0 state to the S0 state occurs at a time scale of 12 ps. Demethylation of the phenolic end groups alleviates the steric repulsion by the polyene chain and causes a small red shift (1000 cm(-1)) comparing the absorption spectra of DHHC and DHIR. Oxidation of DHIR leads to drastic changes of the electronic and geometric properties. The quinoid end groups of DHIRQ are fully integrated into the conjugation system, shifting the absorption maximum to 17 800 cm(-1) in acetone solution which thus takes a blue color. The results of the quantum chemical calculations indicate that, in addition to the 2(1)Ag-(S1) state, two dark internal charge-transfer singlet states and the 1(1)Bu- state might be located energetically below the optically bright 1(1)Bu+ (S5) state of DHIRQ. PMID:19247521

  16. Quantification of the Electrophilicity of Benzyne and Related Intermediates.

    PubMed

    Fine Nathel, Noah F; Morrill, Lucas A; Mayr, Herbert; Garg, Neil K

    2016-08-24

    The determination of reactivity parameters for short-lived intermediates provides an indispensable tool for synthetic design. Despite that electrophilicity parameters have now been established for more than 250 reactive species, the corresponding parameters for benzyne and related intermediates have not been uncovered. We report a study that has allowed for the quantification of benzyne's electrophilicity parameter. Our approach relies on the strategic use of the diffusion-clock method and also provides electrophilicity parameters E for other substituted arynes.

  17. Vibrational fingerprint of the structural tuning in push-pull organic chromophores with quinoid or proaromatic spacers.

    PubMed

    Casado, Juan; Moreno Oliva, María; Ruiz Delgado, M Carmen; López Navarrete, Juan T; Sánchez, Luis; Martín, Nazario; Andreu, Raquel; Carrasquer, Laura; Garín, Javier; Orduna, Jesús

    2007-02-21

    The Raman spectra of a series of push-pull molecules containing probenzenoid or quinoid spacers which are substituted with 1,3-dithiol-2-ylidene as donor and dicyano-methylene or barbituric acid as acceptors have been analyzed. The experimental spectra have been assigned and interpreted according to density functional theory calculations. Correlations between the Raman spectra of the isolated spacers and of the substituted molecules have been done. Raman bands in the 1620-1560 cm-1 interval provide vibrational markers of the quinoid<-->aromatic structural evolution. This finding is supported by a careful inspection of geometrical parameters, namely, bond length alteration data and particular bond distances. As a result, the peak positions and relative intensities of these Raman features can be used to evaluate the benzenoid character of the spacer as a function of the donor/acceptor substitution pattern. This paper shows that Raman spectroscopy is a powerful spectroscopic tool for the analysis of the conjugational properties (i.e., intramolecular donor-->acceptor charge transfer) of new organic materials.

  18. Electrophilic reactions of skin-sensitizing sultones.

    PubMed

    Roberts, David W; Williams, Douglas L; Bethell, Donald

    2007-01-01

    Reactions of the strong skin sensitizer hexadec-1-ene-1,3-sultone with sodium hydroxide, sodium methoxide, sodium metabisulfite, sodium butanethiolate, n-butylamine, and aniline have been investigated, and the reaction products have been identified. Most of the nucleophiles studied react by nucleophilic addition (Michael type addition) to the double bond at the 2-position, although in most cases the final products result from further reactions of the initital adducts. The findings are considered together with those reported by Meschkat, Barratt, and Lepoittevin for reactions of hex-1-ene-1,3-sultone and hexane-1,3-sultone, and the implications of the two sets of findings for the mechanism of skin-sensitizing action are discussed. It is concluded that nucleophilic attack at the 3-position of the alk-1-ene-1,3-sultones occurs only with those nucleophiles, which either have very low reactivity in nucleophilic addition or are unable to give rise to thermodynamically stable products via initial reaction at the 2-position. It is further concluded that the observed differences in electrophilic reactivity between alk-1-ene-1,3-sultones and alkane-1,3-sultones are not large enough to rationalize the differences in skin sensitization properties between the two types of sultone. It is suggested that the differences in specificity arise because the alk-1-ene-1,3-sultones act as Michael type electrophiles whereas the alkane sultones act as SN2 electrophiles. It is suggested that the reason for the greater potency of the alk-1-ene-1,3-sultones may be the ability of the initial C2 adducts with protein to undergo further reactions by substitution at C3, leading to cross-linking and consequent perturbation to the protein tertiary structure.

  19. Electrophilic surface sites as precondition for the chemisorption of pyrrole on GaAs(001) surfaces

    SciTech Connect

    Bruhn, Thomas; Fimland, Bjørn-Ove; Vogt, Patrick

    2015-03-14

    We report how the presence of electrophilic surface sites influences the adsorption mechanism of pyrrole on GaAs(001) surfaces. For this purpose, we have investigated the adsorption behavior of pyrrole on different GaAs(001) reconstructions with different stoichiometries and thus different surface chemistries. The interfaces were characterized by x-ray photoelectron spectroscopy, scanning tunneling microscopy, and by reflectance anisotropy spectroscopy in a spectral range between 1.5 and 5 eV. On the As-rich c(4 × 4) reconstruction that exhibits only nucleophilic surface sites, pyrrole was found to physisorb on the surface without any significant modification of the structural and electronic properties of the surface. On the Ga-rich GaAs(001)-(4 × 2)/(6 × 6) reconstructions which exhibit nucleophilic as well as electrophilic surface sites, pyrrole was found to form stable covalent bonds mainly to the electrophilic (charge deficient) Ga atoms of the surface. These results clearly demonstrate that the existence of electrophilic surface sites is a crucial precondition for the chemisorption of pyrrole on GaAs(001) surfaces.

  20. Electrophilicity and solvatochromic reversal of pyridinium phenolate betaine dyes

    NASA Astrophysics Data System (ADS)

    Rezende, Marcos Caroli; Aracena, Andrés

    2012-07-01

    The solvatochromic reversal of phenolate betaine dyes may be theoretically rationalized and predicted by determining the flow direction of their internal charge-transfer in media of increasing polarity, with the aid of the electrophilicities of the donor and acceptor moieties, or of the corresponding electrophilic Fukui functions. The protocol was applied to ten examples from the literature.

  1. Mechanism and Selectivity in Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl Halides

    PubMed Central

    Biswas, Soumik; Weix, Daniel J.

    2013-01-01

    The direct cross-coupling of two different electrophiles, such as an aryl halide with an alkyl halide, offers many advantages over conventional cross-coupling methods that require a carbon nucleophile. Despite its promise as a versatile synthetic strategy, a limited understanding of the mechanism and origin of cross selectivity has hindered progress in reaction development and design. Herein, we shed light on the mechanism for the nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides and demonstrate that the selectivity arises from an unusual catalytic cycle that combines both polar and radical steps to form the new C-C bond. PMID:23952217

  2. Ni-Catalyzed C-C Couplings Using Alkyl Electrophiles.

    PubMed

    Iwasaki, Takanori; Kambe, Nobuaki

    2016-10-01

    Much effort has been devoted to developing new methods using Ni catalysts for the cross-coupling reaction of alkyl electrophiles with organometallic reagents, and significant achievements in this area have emerged during the past two decades. Nickel catalysts have enabled the coupling reaction of not only primary alkyl electrophiles, but also sterically hindered secondary and tertiary alkyl electrophiles possessing β-hydrogens with various organometallic reagents to construct carbon skeletons. In addition, Ni catalysts opened a new era of asymmetric cross-coupling reaction using alkyl halides. Recent progress in nickel-catalyzed cross-coupling reaction of alkyl electrophiles with sp(3)-, sp(2)-, and sp-hybridized organometallic reagents including asymmetric variants as well as mechanistic insights of nickel catalysis are reviewed in this chapter. PMID:27580894

  3. Synthesis of quaternary α-perfluoroalkyl lactams via electrophilic perfluoroalkylation.

    PubMed

    Katayev, D; Václavík, J; Brüning, F; Commare, B; Togni, A

    2016-03-14

    Efficient protocols enabling the rapid installation of trifluoromethyl, as well as further functionalized fluoroalkyl groups by an electrophilic perfluoroalkylation of lactam-derived ketene silyl amides (KSAs) using hypervalent iodine reagents 1 and 2 have been developed. PMID:26893124

  4. Ni-Catalyzed C-C Couplings Using Alkyl Electrophiles.

    PubMed

    Iwasaki, Takanori; Kambe, Nobuaki

    2016-10-01

    Much effort has been devoted to developing new methods using Ni catalysts for the cross-coupling reaction of alkyl electrophiles with organometallic reagents, and significant achievements in this area have emerged during the past two decades. Nickel catalysts have enabled the coupling reaction of not only primary alkyl electrophiles, but also sterically hindered secondary and tertiary alkyl electrophiles possessing β-hydrogens with various organometallic reagents to construct carbon skeletons. In addition, Ni catalysts opened a new era of asymmetric cross-coupling reaction using alkyl halides. Recent progress in nickel-catalyzed cross-coupling reaction of alkyl electrophiles with sp(3)-, sp(2)-, and sp-hybridized organometallic reagents including asymmetric variants as well as mechanistic insights of nickel catalysis are reviewed in this chapter.

  5. Classification of the Electrophilic Addition Reactions of Olefins and Acetylenes

    ERIC Educational Resources Information Center

    Wilson, Michael A.

    1975-01-01

    Divides addition reactions into molecular, stepwise, or termolecular, depending on whether the reaction is synchronous or multistep; and further into nucleophilic, electrophilic, or concerted, depending on how the electrons are transferred in the initiation step. (MLH)

  6. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity

    PubMed Central

    2015-01-01

    A critical overview of the catalytic joining of two different electrophiles, cross-electrophile coupling (XEC), is presented with an emphasis on the central challenge of cross-selectivity. Recent synthetic advances and mechanistic studies have shed light on four possible methods for overcoming this challenge: (1) employing an excess of one reagent; (2) electronic differentiation of starting materials; (3) catalyst–substrate steric matching; and (4) radical chain processes. Each method is described using examples from the recent literature. PMID:24820397

  7. Mechanism of Electrophilic Fluorination with Pd(IV): Fluoride Capture and Subsequent Oxidative Fluoride Transfer†, ‡

    PubMed Central

    Brandt, Jochen R.; Lee, Eunsung; Boursalian, Gregory B.

    2013-01-01

    Electrophilic fluorinating reagents derived from fluoride are desirable for the synthesis of 18F-labeled molecules for positron emission tomography (PET). Here, we study the mechanism by which a Pd(IV)-complex captures fluoride and subsequently transfers it to nucleophiles. The intermediate Pd(IV)-F is formed with high rates even at the nano- to micromolar fluoride concentrations typical for radiosyntheses with 18F due to fast formation of an outer-sphere complex between fluoride and Pd(IV). The subsequent fluorine transfer from the Pd(IV)-F complex is proposed to proceed through an unusual SET/fluoride transfer/SET mechanism. The findings detailed in this manuscript provide a theoretical foundation suitable for addressing a more general approach for electrophilic fluorination with high specific activity 18F PET imaging. PMID:24376910

  8. A Biradical Balancing Act: Redox Amphoterism in a Diindenoanthracene Derivative Results from Quinoidal Acceptor and Aromatic Donor Motifs.

    PubMed

    Rudebusch, Gabriel E; Espejo, Guzmán L; Zafra, José L; Peña-Alvarez, Miriam; Spisak, Sarah N; Fukuda, Kotaro; Wei, Zheng; Nakano, Masayoshi; Petrukhina, Marina A; Casado, Juan; Haley, Michael M

    2016-09-28

    The reduced and oxidized states of an open-shell diindeno[b,i]anthracene (DIAn) derivative have been investigated by experimental and theoretical techniques. As a result of moderate biradical character and the ability of cyclopenta-fused scaffolds to stabilize both positive and negative charges, DIAn exhibits rich redox chemistry with four observable and isolable charged states. Structural and electronic properties of the DIAn system are brought to light by UV-vis-NIR and Raman spectroelectrochemical measurements. Aromatization of the diindeno-fused anthracene core upon successive single-electron injections is revealed through single-crystal X-ray diffraction of radical anion and dianion salts. We present a rare case where the pseudoaromatic/quinoidal ground state of a neutral biradical polycyclic hydrocarbon leads to a stable cascade of five redox states. Our detailed investigation of the transformation of molecular structure along all four redox events provides a clearer understanding of the nature of charge carriers in ambipolar organic field-effect transistors.

  9. Uncatalyzed hydroamination of electrophilic organometallic alkynes: fundamental, theoretical, and applied aspects.

    PubMed

    Wang, Yanlan; Latouche, Camille; Rapakousiou, Amalia; Lopez, Colin; Ledoux-Rak, Isabelle; Ruiz, Jaime; Saillard, Jean-Yves; Astruc, Didier

    2014-06-23

    Simple reactions of the most used functional groups allowing two molecular fragments to link under mild, sustainable conditions are among the crucial tools of molecular chemistry with multiple applications in materials science, nanomedicine, and organic synthesis as already exemplified by peptide synthesis and "click" chemistry. We are concerned with redox organometallic compounds that can potentially be used as biosensors and redox catalysts and report an uncatalyzed reaction between primary and secondary amines with organometallic electrophilic alkynes that is free of side products and fully "green". A strategy is first proposed to synthesize alkynyl organometallic precursors upon addition of electrophilic aromatic ligands of cationic complexes followed by endo hydride abstraction. Electrophilic alkynylated cyclopentadienyl or arene ligands of Fe, Ru, and Co complexes subsequently react with amines to yield trans-enamines that are conjugated with the organometallic group. The difference in reactivities of the various complexes is rationalized from the two-step reaction mechanism that was elucidated through DFT calculations. Applications are illustrated by the facile reaction of ethynylcobalticenium hexafluorophosphate with aminated silica nanoparticles. Spectroscopic, nonlinear-optical and electrochemical data, as well as DFT and TDDFT calculations, indicate a strong push-pull conjugation in these cobalticenium- and Fe- and Ru-arene-enamine complexes due to planarity or near-planarity between the organometallic and trans-enamine groups involving fulvalene iminium and cyclohexadienylidene iminium mesomeric forms.

  10. Nrf2/ARE-Mediated Antioxidant Actions of Pro-Electrophilic Drugs

    PubMed Central

    Satoh, Takumi; McKercher, Scott R.; Lipton, Stuart A.

    2013-01-01

    Living cells maintain a balance between oxidation and reduction, and perturbations of this redox balance are thought to contribute to various diseases. Recent attempts to regulate redox state have focused on electrophiles (EPs), which activate potent cellular defense systems against oxidative stress. One example of this approach is exemplified by carnosic acid (CA) and carnosol (CS), compounds that are found in the herb rosemary (Rosmarinus officinalis). Importantly, CA and CS themselves are not electrophilic, but in response to oxidation, become electrophilic, and then activate the Keap1/Nrf2/ARE (antioxidant response element) transcription pathway to synthesize endogenous anti-oxidant ‘phase 2’ enzymes. As a result of our efforts to develop these compounds as therapeutics for brain health, we have formulated two innovative criteria for drug development: the first concept is the use of Pro-Electrophilic Drugs (PEDs) that are innocuous in and of themselves; and the second concept involves the use of compounds that are Pathologically-Activated Therapeutics (PATs), i.e., these small molecules are chemically converted to their active form by the very oxidative stress that they are designed to then combat. The chemical basis for PED and PAT drugs is embodied in the ortho- and para-hydroquinone electrophilic cores of the molecules, which are oxidized by the Cu2+/Cu+ cycling system (or potentially by other transition metals). Importantly, this cycling pathway is under stringent regulation by the cell redox state. We propose that redox-dependent quinone-formation is the predominant mechanism for formation of PED and PAT drugs from their precursor compounds. In fact, redox-dependent generation of the active form of drug from the “pro-form” distinguishes this therapeutic approach from traditional EPs such as curcumin, and results in a decrease in clinical side effects at therapeutic concentrations, e.g., lack of reaction with other thiols such as glutathione (GSH

  11. A Green Starting Material for Electrophilic Aromatic Substitution for the Undergraduate Organic Laboratory

    ERIC Educational Resources Information Center

    Jones-Wilson, T. Michelle; Burtch, Elizabeth A.

    2005-01-01

    Electrophilic aromatic substitution (EAS) experiment is designed for the second-semester and undergraduate organic chemistry laboratory. In the EAS experiment, the principles of green chemistry are discussed and illustrated in conjunction with the presentation of electrophilic aromatic substitution.

  12. Reagents for Electrophilic Amination: A Quantum Monte CarloStudy

    SciTech Connect

    Amador-Bedolla, Carlos; Salomon-Ferrer, Romelia; Lester Jr.,William A.; Vazquez-Martinez, Jose A.; Aspuru-Guzik, Alan

    2006-11-01

    Electroamination is an appealing synthetic strategy toconstruct carbon-nitrogen bonds. We explore the use of the quantum MonteCarlo method and a proposed variant of the electron-pair localizationfunction--the electron-pair localization function density--as a measureof the nucleophilicity of nitrogen lone-pairs as a possible screeningprocedure for electrophilic reagents.

  13. Quantification of the electrophilic reactivities of aldehydes, imines, and enones.

    PubMed

    Appel, Roland; Mayr, Herbert

    2011-06-01

    The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale. PMID:21553901

  14. Electrophilic and Redox Properties of Diesel Exhaust Particles

    EPA Science Inventory

    The adverse health effects of air pollutants have been associated with their redox and electrophilic properties. Although the specific chemical species involved in these effects are not known, the characterization of their general physical and chemical-properties is important to ...

  15. Introducing Aliphatic Substitution with a Discovery Experiment Using Competing Electrophiles

    ERIC Educational Resources Information Center

    Curran, Timothy P.; Mostovoy, Amelia J.; Curran, Margaret E.; Berger, Clara

    2016-01-01

    A facile, discovery-based experiment is described that introduces aliphatic substitution in an introductory undergraduate organic chemistry curriculum. Unlike other discovery-based experiments that examine substitution using two competing nucleophiles with a single electrophile, this experiment compares two isomeric, competing electrophiles…

  16. Protein Damage by Reactive Electrophiles: Targets and Consequences

    PubMed Central

    Liebler, Daniel C.

    2008-01-01

    It has been sixty years since the Millers first described the covalent binding of carcinogens to tissue proteins. Protein covalent binding was gradually overshadowed by the emergence of DNA adduct formation as the dominant paradigm in chemical carcinogenesis, but re-emerged in the early 1970s as a critical mechanism of drug and chemical toxicity. Technology limitations hampered the characterization of protein adducts until the emergence of mass spectrometry-based proteomics in the late 1990s. The time since has seen rapid progress in the characterization of the protein targets of electrophiles and the consequences of protein damage. Recent integration of novel affinity chemistries for electrophile probes, shotgun proteomics methods and systems modeling tools has led to the identification of hundreds of protein targets of electrophiles in mammalian systems. The technology now exists to map the targets of damage to critical components of signaling pathways and metabolic networks and to understand mechanisms of damage at a systems level. The implementation of sensitive, specific analyses for protein adducts from both xenobiotic-derived and endogenous electrophiles offers a means to link protein damage to clinically relevant health effects of both chemical exposures and disease processes. PMID:18052106

  17. Carbocation Rearrangement in An Electrophilic Aromatic Substitution Discovery Laboratory

    ERIC Educational Resources Information Center

    Polito, Victoria; Hamann, Christian S.; Rhile, Ian J.

    2010-01-01

    In this discovery laboratory, students performed electrophilic aromatic substitution reactions between 1,4-dimethoxybenzene and either 2-methyl-2-butanol or 3-methyl-2-butanol with sulfuric acid as a catalyst. The carbocation from 3-methyl-2-butanol undergoes a hydride shift, and hence, both reactions afford…

  18. Highly Regio- and Enantioselective Formal [3 + 2]-Annulation of Indoles with Electrophilic Enol Carbene Intermediates.

    PubMed

    Jing, Changcheng; Cheng, Qing-Qing; Deng, Yongming; Arman, Hadi; Doyle, Michael P

    2016-09-16

    Chiral cyclopentane-fused indolines are synthesized with high regio- and enantiocontrol by formal [3 + 2]-annulation reactions of indoles and electrophilic enol carbenes. High enantioselectivity and exclusive regiocontrol occurred with enoldiazoacetamides using a less sterically encumbered prolinate-ligated dirhodium(II) catalyst in reactions with N-substituted indoles without substituents at the 2- or 3-positions via a selective vinylogous addition process. In this transformation, donor-acceptor cyclopropenes generated from enoldiazoacetamides serve as the carbene precursors to form metal carbene intermediates. PMID:27589203

  19. Hypobromous acid, a powerful endogenous electrophile: Experimental and theoretical studies.

    PubMed

    Ximenes, Valdecir Farias; Morgon, Nelson Henrique; de Souza, Aguinaldo Robinson

    2015-05-01

    Hypobromous acid (HOBr) is an inorganic acid produced by the oxidation of the bromide anion (Br(-)). The blood plasma level of Br(-) is more than 1,000-fold lower than that of chloride anion (Cl(-)). Consequently, the endogenous production of HOBr is also lower compared to hypochlorous acid (HOCl). Nevertheless, there is much evidence of the deleterious effects of HOBr. From these data, we hypothesized that the reactivity of HOBr could be better associated with its electrophilic strength. Our hypothesis was confirmed, since HOBr was significantly more reactive than HOCl when the oxidability of the studied compounds was not relevant. For instance: anisole (HOBr, k2=2.3×10(2)M(-1)s(-1), HOCl non-reactive); dansylglycine (HOBr, k2=7.3×10(6)M(-1)s(-1), HOCl, 5.2×10(2)M(-1)s(-1)); salicylic acid (HOBr, k2=4.0×10(4)M(-1)s(-1), non-reactive); 3-hydroxybenzoic acid (HOBr, k2=5.9×10(4)M(-1)s(-1), HOCl, k2=1.1×10(1)M(-1)s(-1)); uridine (HOBr, k2=1.3×10(3)M(-1)s(-1), HOCl non-reactive). The compounds 4-bromoanisole and 5-bromouridine were identified as the products of the reactions between HOBr and anisole or uridine, respectively, i.e. typical products of electrophilic substitutions. Together, these results show that, rather than an oxidant, HOBr is a powerful electrophilic reactant. This chemical property was theoretically confirmed by measuring the positive Mulliken and ChelpG charges upon bromine and chlorine. In conclusion, the high electrophilicity of HOBr could be behind its well-established deleterious effects. We propose that HOBr is the most powerful endogenous electrophile. PMID:25771434

  20. Analysis of protein adduction kinetics by quantitative mass spectrometry: competing adduction reactions of glutathione-S-transferase P1-1 with electrophiles.

    PubMed

    Orton, Christopher R; Liebler, Daniel C

    2007-06-30

    Defining the mechanisms and consequences of protein adduction is crucial to understanding the toxicity of reactive electrophiles. Application of tandem mass spectrometry and data analysis algorithms enables detection and mapping of chemical adducts at the level of amino acid sequence. Nevertheless, detection of adducts does not indicate relative reactivity of different sites. Here, we describe a method to measure the kinetics of competing adduction reactions at different sites on the same protein. Adducts are formed by electrophiles at Cys14 and Cys47 on the metabolic enzyme glutathione-S-transferase P1-1 and modification is accompanied by a loss of enzymatic activity. Relative quantitation of protein adducts was done by tagging N-termini of peptide digests with isotopically labeled phenyl isocyanate and tracking the ratio of light-tagged peptide adducts to heavy-tagged reference samples in liquid chromatography-tandem mass spectrometry analyses using a multiple reaction monitoring method. This approach was used to measure rate constants for adduction at both positions with two different model electrophiles, N-iodoacetyl-N-biotinylhexylenediamine and 1-biotinamido-4-(4'-[maleimidoethyl-cyclohexane]-carboxamido)butane. The results indicate that Cys47 was approximately two- to three-fold more reactive toward both electrophiles than was Cys14. This result was consistent with the relative reactivity of these electrophiles in a complex proteome system and with previously reported trends in reactivity of these sites. Kinetic analyses of protein modification reactions provide a means of evaluating the selectivity of reactive mediators of chemical toxicity.

  1. Alkyltransferase-mediated toxicity of bis-electrophiles in mammalian cells

    PubMed Central

    Kalapila, Aley G.; Pegg, Anthony E.

    2009-01-01

    The primary function of O6-alkylguanine-DNA alkyltransferase (AGT) is to maintain genomic integrity in the face of damage by both endogenous and exogenous alkylating agents. However, paradoxically, bacterial and mammalian AGTs have been shown to increase cytotoxicity and mutagenicity of dihaloalkanes and other bis-electrophiles when expressed in bacterial cells. We have extended these studies to mammalian cells using CHO cells that lack AGT expression and CHO cells stably transfected with a plasmid that expresses human AGT. The cytotoxicity of 1,2-dibromoethane, dibromomethane and epibromohydrin was significantly increased by the presence of AGT but cytotoxicity of butadiene diepoxide was not affected. Mutations caused by these agents were assessed using hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a reporter gene. There was a small (c. 2–3-fold) but statistically significant AGT-mediated increase in mutations caused by 1,2-dibromoethane, dibromomethane and epibromohydrin. Analysis of the mutation spectrum induced by 1,2-dibromoethane showed that the presence of AGT also altered the types of mutations with an increase in total base substitution mutants due to a rise in transversions at both G:C and A:T sites. AGT expression also led to mutations arising from the transcribed strand, which were not seen in cells lacking AGT. Although the frequency of deletion mutations was decreased by AGT expression, the formation of large deletions (≥3 exons) was increased. This work demonstrates that interaction of AGT with some bis-electrophiles can cause mutagenicity and diminished cell survival in mammalian cells. It is consistent with the hypothesis that DNA-AGT cross-links, which have been characterized in experiments with purified AGT protein and such bis-electrophiles, can be formed in mammalian cells. PMID:19941875

  2. Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine.

    PubMed

    Li, Jing; Lear, Martin J; Kwon, Eunsang; Hayashi, Yujiro

    2016-04-11

    Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I(+) under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.

  3. Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine.

    PubMed

    Li, Jing; Lear, Martin J; Kwon, Eunsang; Hayashi, Yujiro

    2016-04-11

    Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I(+) under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion. PMID:26938791

  4. Sequential electrophilic trifluoromethanesulfanylation-cyclization of tryptamine derivatives: synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles.

    PubMed

    Yang, Yi; Jiang, Xueliang; Qing, Feng-Ling

    2012-09-01

    A practical and efficient synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles 5 from tryptamine derivatives was described. The features of this synthesis included electrophilic activation of C(3) of tryptamine derivatives with "CF(3)S(+)" and cascade ring cyclization by carbamate nucleophile attacking at C(2). Surprisingly, when Lewis acid (BF(3)·OEt(2)) was used as activator instead of proton acid (TsOH·H(2)O) for the electrophilic trifluoromethanesulfanylation of tryptamine derivatives, the uncyclized product 6 was formed preferentially. This sequential trifluoromethanesulfanylation-cyclization protocol was used to synthesize several pyrrolidinoindolinic alkaloid analogues. The cytotoxicity activities of these trifluoromethanesulfanylated alkaloid analogues were evaluated against three cancer cell lines (K562, HeLa, L929). PMID:22889233

  5. Redox signaling regulated by an electrophilic cyclic nucleotide and reactive cysteine persulfides.

    PubMed

    Fujii, Shigemoto; Sawa, Tomohiro; Nishida, Motohiro; Ihara, Hideshi; Ida, Tomoaki; Motohashi, Hozumi; Akaike, Takaaki

    2016-04-01

    Reactive oxygen (oxidant) and free radical species are known to cause nonspecific damage of various biological molecules. The oxidant toxicology is developing an emerging concept of the physiological functions of reactive oxygen species in cell signaling regulation. Redox signaling is precisely modulated by endogenous electrophilic substances that are generated from reactive oxygen species during cellular oxidative stress responses. Among diverse electrophilic molecular species that are endogenously generated, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a unique second messenger whose formation, signaling, and metabolism in cells was recently clarified. Most important, our current studies revealed that reactive cysteine persulfides that are formed abundantly in cells are critically involved in the metabolism of 8-nitro-cGMP. Modern redox biology involves frontiers of cell research and stem cell research; medical and clinical investigations of infections, cancer, metabolic syndrome, aging, and neurodegenerative diseases; and other fields. 8-Nitro-cGMP-mediated signaling and metabolism in cells may therefore be potential targets for drug development, which may lead to discovery of new therapeutic agents for many diseases. PMID:27095231

  6. Novel palladium complex-catalyzed reaction of magnesium amides with allylic electrophiles

    SciTech Connect

    Dzhemilev, U.M.; Ibragimov, A.G.; Minsker, D.L.; Muslukhov, R.R.

    1987-08-20

    In order to develop an efficient method for the synthesis of higher order unsaturated tertiary amines, and also to explore a new method for the formation of C-N bonds, they have investigated the transition metal complex-catalyzed reaction of magnesium amides with electrophiles; the electrophiles selected for study included allyl ethers and esters, as well as sulfones, sulfides and quaternized allylamines. The effects of the nature and structure of the catalyst components, as well as of the reaction conditions, on product yield were examined in the case of the reaction of diethyl (bromomagnesium)amine with diallyl ether, and revealed that the highest yield of diethylallyl-amine (I) was achieved using Pd(acac)/sub 2/ (3-5 mole %) and Ph/sub 3/P (1:2) as catalyst in THF solution at 50/sup 0/C for 5 h. Other transition metal (Ni, Fe, Zr, Ti, Cu) compounds were also examined as catalysts, but the yield of (I) did not exceed 15% with these compounds. Bimetallic catalysts based on Zr (Cp/sub 2/ZrCl, Py/sub 2/ZrCl/sub 6/, (RO)/sub 4/Zr) and Ni (Ni(acac)/sub 2/ and NiCl/sub 2/) were successful in forming (I) from diethyl (bromomagnesium)amine and diallyl ether in 60% yield.

  7. Origin of the Regioselectivity in the Gas-Phase Aniline+CH3 (+) Electrophilic Aromatic Substitution.

    PubMed

    Kinzel, Daniel; Zilberg, Shmuel; González, Leticia

    2015-08-01

    Nonadiabatic ab initio molecular dynamics simulations are carried out to monitor the attack of CH3 (+) on aniline in the gas phase to form the corresponding σ complexes. The reaction is ultrafast and is governed by a single electron transfer within 30 fs, which involves two sequential conical intersections and finally produces a radical pair. Positive-charge allocation in the aromatic compound is found to govern the substitution pattern in ortho, meta, or para position. Although the major products in the first step of the electrophilic aromatic substitution are the ortho and para σ complexes, initially 26 % of the simulated trajectories also form meta complexes, which then undergo H shifts, mainly to the para position. PMID:26037166

  8. Origin of the Regioselectivity in the Gas-Phase Aniline+CH3 (+) Electrophilic Aromatic Substitution.

    PubMed

    Kinzel, Daniel; Zilberg, Shmuel; González, Leticia

    2015-08-01

    Nonadiabatic ab initio molecular dynamics simulations are carried out to monitor the attack of CH3 (+) on aniline in the gas phase to form the corresponding σ complexes. The reaction is ultrafast and is governed by a single electron transfer within 30 fs, which involves two sequential conical intersections and finally produces a radical pair. Positive-charge allocation in the aromatic compound is found to govern the substitution pattern in ortho, meta, or para position. Although the major products in the first step of the electrophilic aromatic substitution are the ortho and para σ complexes, initially 26 % of the simulated trajectories also form meta complexes, which then undergo H shifts, mainly to the para position.

  9. Electrophilic, Activation-Free Fluorogenic Reagent for Labeling Bioactive Amines.

    PubMed

    Sintes, Miquel; De Moliner, Fabio; Caballero-Lima, David; Denning, David W; Read, Nick D; Kielland, Nicola; Vendrell, Marc; Lavilla, Rodolfo

    2016-06-15

    Herein we report the preparation of BODIPY mesoionic acid fluorides through a short sequence involving an isocyanide multicomponent reaction as the key synthetic step. These novel BODIPY acid fluorides are water-stable electrophilic reagents that can be used for the fluorescent derivatization of amine-containing biomolecules using mild and activation-free reaction conditions. As a proof of principle, we have labeled the antifungal natamycin and generated a novel fluorogenic probe for imaging a variety of human and plant fungal pathogens, with excellent selectivity over bacterial cells. PMID:27248580

  10. Catalytic Asymmetric Synthesis of Cyclopentyl β-Amino Esters by [3+2] Cycloaddition of Enecarbamates with Electrophilic Metalloenolcarbene Intermediates.

    PubMed

    Deng, Yongming; Yglesias, Matthew V; Arman, Hadi; Doyle, Michael P

    2016-08-16

    Chiral cyclopentyl β-amino esters are formed catalytically by [3+2] cycloaddition reactions of enecarbamates with electrophilic metalloenolcarbenes in high yield with up to 98 % ee and excellent diastereocontrol. Use of β-silyl-substituted enoldiazoacetates with a chiral dirhodium catalyst and trans-β-arylvinylcarbamates are optimal for this transformation, which occurs with hydrogen-bond association between the vinylcarbamate and the intermediate metalloenolcarbene. Reductive conversion of the protected amino esters forms highly functionalized cyclopentyl β-amino acids and 3-aminocyclopentanones.

  11. Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis.

    PubMed

    Cocco, Mattia; Garella, Davide; Di Stilo, Antonella; Borretto, Emily; Stevanato, Livio; Giorgis, Marta; Marini, Elisabetta; Fantozzi, Roberto; Miglio, Gianluca; Bertinaria, Massimo

    2014-12-26

    Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure-activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.

  12. Alert-QSAR. Implications for Electrophilic Theory of Chemical Carcinogenesis

    PubMed Central

    Putz, Mihai V.; Ionaşcu, Cosmin; Putz, Ana-Maria; Ostafe, Vasile

    2011-01-01

    Given the modeling and predictive abilities of quantitative structure activity relationships (QSARs) for genotoxic carcinogens or mutagens that directly affect DNA, the present research investigates structural alert (SA) intermediate-predicted correlations ASA of electrophilic molecular structures with observed carcinogenic potencies in rats (observed activity, A = Log[1/TD50], i.e., ASA=f(X1SA,X2SA,…)). The present method includes calculation of the recently developed residual correlation of the structural alert models, i.e., ARASA=f(A−ASA,X1SA,X2SA,…). We propose a specific electrophilic ligand-receptor mechanism that combines electronegativity with chemical hardness-associated frontier principles, equality of ligand-reagent electronegativities and ligand maximum chemical hardness for highly diverse toxic molecules against specific receptors in rats. The observed carcinogenic activity is influenced by the induced SA-mutagenic intermediate effect, alongside Hansch indices such as hydrophobicity (LogP), polarizability (POL) and total energy (Etot), which account for molecular membrane diffusion, ionic deformation, and stericity, respectively. A possible QSAR mechanistic interpretation of mutagenicity as the first step in genotoxic carcinogenesis development is discussed using the structural alert chemoinformation and in full accordance with the Organization for Economic Co-operation and Development QSAR guidance principles. PMID:21954348

  13. Heteroaromatic sulfonates and phosphates as electrophiles in iron-catalyzed cross-couplings.

    PubMed

    Gøgsig, Thomas M; Lindhardt, Anders T; Skrydstrup, Troels

    2009-11-01

    Employment of heteroaromatic tosylates and phosphates as suitable electrophiles in iron-catalyzed cross-coupling reactions with alkyl Grignard reagents is reported. These reactions are performed at low temperature allowing good functional group tolerance and full conversion is achieved within minutes. In addition, an aryl-aryl cross-coupling utilizing a heteroaryl sulfamate electrophile is reported.

  14. A Green, Guided-Inquiry Based Electrophilic Aromatic Substitution for the Organic Chemistry Laboratory

    ERIC Educational Resources Information Center

    Eby, Eric; Deal, S. Todd

    2008-01-01

    We developed an alternative electrophilic aromatic substitution reaction for the organic chemistry teaching laboratory. The experiment is an electrophilic iodination reaction of salicylamide, a popular analgesic, using environmentally friendly reagents--sodium iodide and household bleach. Further, we designed the lab as a guided-inquiry…

  15. The Die Is Cast: Precision Electrophilic Modifications Contribute to Cellular Decision Making

    PubMed Central

    2016-01-01

    This perspective sets out to critically evaluate the scope of reactive electrophilic small molecules as unique chemical signal carriers in biological information transfer cascades. We consider these electrophilic cues as a new volatile cellular currency and compare them to canonical signaling circulation such as phosphate in terms of chemical properties, biological specificity, sufficiency, and necessity. The fact that nonenzymatic redox sensing properties are found in proteins undertaking varied cellular tasks suggests that electrophile signaling is a moonlighting phenomenon manifested within a privileged set of sensor proteins. The latest interrogations into these on-target electrophilic responses set forth a new horizon in the molecular mechanism of redox signal propagation wherein direct low-occupancy electrophilic modifications on a single sensor target are biologically sufficient to drive functional redox responses with precision timing. We detail how the various mechanisms through which redox signals function could contribute to their interesting phenotypic responses, including hormesis. PMID:27617777

  16. Efficient O-Functionalization of Carbohydrates with Electrophilic Reagents.

    PubMed

    Tolnai, Gergely L; Nilsson, Ulf J; Olofsson, Berit

    2016-09-01

    Novel methodology for O-functionalization of carbohydrate derivatives has been established using bench-stable and easily prepared iodonium(III) reagents. Both electron-withdrawing and electron-donating aryl groups were introduced under ambient conditions and without precautions to exclude air or moisture. Furthermore, the approach was extended both to full arylation of cyclodextrin, and to trifluoroethylation of carbohydrate derivatives. This is the first general approach to introduce traditionally non-electrophilic groups into any of the OH groups around the sugar backbone. The methodology will be useful both in synthetic organic chemistry and biochemistry, as important functional groups can be incorporated under simple and robust reaction conditions in a fast and efficient manner. PMID:27528184

  17. Amination of electrophilic aromatic compounds by vicarious nucleophilic substitution

    DOEpatents

    Mitchell, Alexander R.; Pagoria, Philip F.; Schmidt, Robert D.

    2000-01-01

    The present invention relates to a process to aminate electrophilic aromatic compounds by vicarious nucleophilic substitution of hydrogen using quaternary hydrazinium salts. The use of trialkylhydrazinium halide, e.g., trimethylhydrazinium iodide, as well as hydroxylamine, alkoxylamines, and 4-amino-1,2,4-triazole to produce aminated aromatic structures, such as 1,3-diamino-2,4,6-trinitrobenzene (DATB), 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) and 3,5-diamino-2,4,6-trinitrotoluene (DATNT), is described. DATB and TATB are useful insensitive high explosives. TATB is also used for the preparation of benzenehexamine, a starting material for the synthesis of novel materials (optical imaging devices, liquid crystals, ferromagnetic compounds).

  18. Transforming plastic surfaces with electrophilic backbones from hydrophobic to hydrophilic.

    PubMed

    Kim, Samuel; Bowen, Raffick A R; Zare, Richard N

    2015-01-28

    We demonstrate a simple nonaqueous reaction scheme for transforming the surface of plastics from hydrophobic to hydrophilic. The chemical modification is achieved by base-catalyzed trans-esterification with polyols. It is permanent, does not release contaminants, and causes no optical or mechanical distortion of the plastic. We present contact angle measurements to show successful modification of several types of plastics including poly(ethylene terephthalate) (PET) and polycarbonate (PC). Its applicability to blood analysis is explored using chemically modified PET blood collection tubes and found to be quite satisfactory. We expect this approach will reduce the cost of manufacturing plastic devices with optimized wettability and can be generalized to other types of plastic materials having an electrophilic linkage as its backbone.

  19. Amination of electrophilic aromatic compounds by vicarious nucleophilic substitution

    SciTech Connect

    Mitchell, A.R.; Pagoria, P.F.; Schmidt, R.D.

    2000-05-30

    The present invention relates to a process to aminate electrophilic aromatic compounds by vicarious nucleophilic substitution of hydrogen using quaternary hydrazinium salts. The use of trialkylhydrazinium halide, e.g., trimethylhydrazinium iodide, as well as hydroxylamine, alkoxylamines, and 4-amino-1,2,4-triazole to produce aminated aromatic structures, such as 1,3-diamino-2,4,6-trinitrobenzene (DATB), 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) and 3,5-diamino-2,4,6-trinitrotoluene (DATNT), is described. DATB and TATB are useful insensitive high explosives. TATB is also used for the preparation of benzenehexamine, a starting material for the synthesis of novel materials (optical imaging devices, liquid crystals, ferromagnetic compounds).

  20. Electrophilicity: the "dark-side" of indole chemistry.

    PubMed

    Bandini, Marco

    2013-08-28

    Indole is by far one of the most popular heterocyclic scaffolds in nature. The intriguing and challenging molecular architectures of polycyclic, naturally occurring indolyl compounds constitute a continuous stimulus for development in organic synthesis. The field had a formidable boom across the new millennium when catalysis started revolutionizing the chemistry of indole, providing always more convincing and sustainable solutions to the selective "decoration" of this pharmacophore. A common guideline of these approaches relies on the intrinsic overexpression of electron density of the indole core. Despite less diffusion, the "dark-side" of indole reactivity, electrophilicity, has been also elegantly documented with direct applications towards the realization of specific interatomic connections that would be difficult to obtain by means of conventional indole reactivity. The present Perspective article summarizes the major findings that brought the research area from the pioneering findings of the 60s to the state of the art.

  1. Modeling of Toxicity-Relevant Electrophilic Reactivity for Guanine with Epoxides: Estimating the Hard and Soft Acids and Bases (HSAB) Parameter as a Predictor.

    PubMed

    Zhang, Jing; Wang, Chenchen; Ji, Li; Liu, Weiping

    2016-05-16

    According to the electrophilic theory in toxicology, many chemical carcinogens in the environment and/or their active metabolites are electrophiles that exert their effects by forming covalent bonds with nucleophilic DNA centers. The theory of hard and soft acids and bases (HSAB), which states that a toxic electrophile reacts preferentially with a biological macromolecule that has a similar hardness or softness, clarifies the underlying chemistry involved in this critical event. Epoxides are hard electrophiles that are produced endogenously by the enzymatic oxidation of parent chemicals (e.g., alkenes and PAHs). Epoxide ring opening proceeds through a SN2-type mechanism with hard nucleophile DNA sites as the major facilitators of toxic effects. Thus, the quantitative prediction of chemical reactivity would enable a predictive assessment of the molecular potential to exert electrophile-mediated toxicity. In this study, we calculated the activation energies for reactions between epoxides and the guanine N7 site for a diverse set of epoxides, including aliphatic epoxides, substituted styrene oxides, and PAH epoxides, using a state-of-the-art density functional theory (DFT) method. It is worth noting that these activation energies for diverse epoxides can be further predicted by quantum chemically calculated nucleophilic indices from HSAB theory, which is a less computationally demanding method than the exacting procedure for locating the transition state. More importantly, the good qualitative/quantitative correlations between the chemical reactivity of epoxides and their bioactivity suggest that the developed model based on HSAB theory may aid in the predictive hazard evaluation of epoxides, enabling the early identification of mutagenicity/carcinogenicity-relevant SN2 reactivity.

  2. Aldehyde Dehydrogenases in Cellular Responses to Oxidative/electrophilic Stress

    PubMed Central

    Singh, Surendra; Brocker, Chad; Koppaka, Vindhya; Ying, Chen; Jackson, Brian; Matsumoto, Akiko; Thompson, David C.; Vasiliou, Vasilis

    2013-01-01

    Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors like dehydration and ultraviolet radiation. The ability to act as an ‘aldehyde scavenger’ during lipid peroxidation is another ostensibly universal ALDH function found across species. Up-regulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation) and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that significantly contributes to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, underscoring the fundamental importance of these enzymes in physiological and pathological processes. PMID:23195683

  3. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress.

    PubMed

    Singh, Surendra; Brocker, Chad; Koppaka, Vindhya; Chen, Ying; Jackson, Brian C; Matsumoto, Akiko; Thompson, David C; Vasiliou, Vasilis

    2013-03-01

    Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single-celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors such as dehydration and ultraviolet radiation. The ability to act as an "aldehyde scavenger" during lipid peroxidation is another ostensibly universal ALDH function found across species. Upregulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity, and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation), and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane, and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that contributes significantly to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, highlighting the fundamental importance of these enzymes in physiological and pathological processes. PMID:23195683

  4. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress.

    PubMed

    Singh, Surendra; Brocker, Chad; Koppaka, Vindhya; Chen, Ying; Jackson, Brian C; Matsumoto, Akiko; Thompson, David C; Vasiliou, Vasilis

    2013-03-01

    Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single-celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors such as dehydration and ultraviolet radiation. The ability to act as an "aldehyde scavenger" during lipid peroxidation is another ostensibly universal ALDH function found across species. Upregulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity, and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation), and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane, and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that contributes significantly to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, highlighting the fundamental importance of these enzymes in physiological and pathological processes.

  5. Diradical Character Tuning for the Third-Order Nonlinear Optical Properties of Quinoidal Oligothiophenes by Introducing Thiophene-S,S-dioxide Rings.

    PubMed

    Kishi, Ryohei; Ochi, Shoki; Izumi, Shioh; Makino, Akihiro; Nagami, Takanori; Fujiyoshi, Jun-ya; Matsushita, Naoyuki; Saito, Michika; Nakano, Masayoshi

    2016-01-22

    To create a design guideline for efficient third-order nonlinear optical (NLO) molecules, the chain-length (n) dependences of the diradical character y and the longitudinal second hyperpolarizability γ of quinoidal oligothiophenes (QTs), from monomers to octamers, involving thiophene-S,S-dioxide rings are investigated by using the density functional theory method. It turns out that the diradical character of the modified QTs is reduced as compared to those of the pristine QTs. By introducing an appropriate number of oxidized rings into the QT framework, intermediate y values can be achieved even in the systems with large values of n, in which the pristine QTs are predicted to have pure diradical character. Such intermediate diradical oligomers are shown to exhibit enhanced γ values as compared to the pristine QTs with the same value for n. From the calculation results, the introduction of the optimal number of thiophene-S,S-dioxide rings is predicted to be an efficient chemical modification for optimizing the third-order NLO properties of open-shell QTs through tuning the diradical characters. PMID:26670676

  6. Glutathione peroxidase inhibitory assay for electrophilic pollutants in diesel exhaust and tobacco smoke.

    PubMed

    Staimer, Norbert; Nguyen, Tran B; Nizkorodov, Sergey A; Delfino, Ralph J

    2012-04-01

    We developed a rapid kinetic bioassay demonstrating the inhibition of glutathione peroxidase 1 (GPx-1) by organic electrophilic pollutants, such as acrolein, crotonaldehyde, and p-benzoquinone, that are frequently found as components of tobacco smoke, diesel exhaust, and other combustion sources. In a complementary approach, we applied a high-resolution proton-transfer reaction time-of-flight mass spectrometer to monitor in real-time the generation of electrophilic volatile carbonyls in cigarette smoke. The new bioassay uses the important antioxidant selenoenzyme GPx-1, immobilized to 96-well microtiter plates, as a probe. The selenocysteine bearing subunits of the enzyme's catalytic site are viewed as cysteine analogues and are vulnerable to electrophilic attack by compounds with conjugated carbonyl systems. The immobilization of GPx-1 to microtiter plate wells enabled facile removal of excess reactive inhibitory compounds after incubation with electrophilic chemicals or aqueous extracts of air samples derived from different sources. The inhibitory response of cigarette smoke and diesel exhaust particle extracts were compared with chemical standards of a group of electrophilic carbonyls and the arylating p-benzoquinone. GPx-1 activity was directly inactivated by millimolar concentrations of highly reactive electrophilic chemicals (including acrolein, glyoxal, methylglyoxal, and p-benzoquinone) and extracts of diesel and cigarette smoke. We conclude that the potential of air pollutant components to generate oxidative stress may be, in part, a result of electrophile-derived covalent modifications of enzymes involved in the cytosolic antioxidant defense.

  7. Promiscuity and selectivity in covalent enzyme inhibition: a systematic study of electrophilic fragments.

    PubMed

    Jöst, Christian; Nitsche, Christoph; Scholz, Therese; Roux, Lionel; Klein, Christian D

    2014-09-25

    Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.

  8. Electrophilic Metal Alkyl Chemistry in New Ligand Environments

    SciTech Connect

    Jordan, Richard F.

    2013-06-30

    The goals of this project were to design new electrophilic metal alkyl complexes and to exploit these systems in fundamental studies of olefin polymerization and other important and new catalytic reactions. A key target reaction is insertion copolymerization of olefins and polar CH2=CHX vinyl monomers such as vinyl halides and vinyl ethers. During the period covered by this report we (i) investigated the properties of ortho-alkoxy-arylphosphine ligands in Ni-based olefin polymerization catalysts, (ii) studied the synthesis of double-end-capped polyethylene using group 4 metal catalysts that contain tris-pyrazolylborate ligands, (iii) explored the ethylene insertion reactivity of group 4 metal tris-pyrazolyl-borate complexes, (iv) showed that (α-diimine)PdMe{sup +} species undergo multiple insertion of silyl vinyl ethers, (v) synthesized and explored the reactivity of base-free Ni benzyl complexes that contain ortho-phosphino-arene sulfonate ligands, (vi) established the mechanism of the reaction of vinyl chloride with (α-diimine)PdMe{sup +} catalysts, (vii) explored the role of cationic polymerization and insertion chemistry in the reactions of vinyl ethers with (α-diimine)PdMe{sup +} species, (viii) discovered a new class of self-assembled tetranuclear Pd catalysts that produce high molecular weight linear polyethylene and copolymerize ethylene and vinyl fluoride, and (ix) developed model systems that enabled investigation of cis-trans isomerization of {phosphine-sulfonate}Pd(II) complexes.

  9. On the interaction between glyceraldehyde-3-phosphate dehydrogenase and airborne particles: Evidence for electrophilic species

    NASA Astrophysics Data System (ADS)

    Shinyashiki, Masaru; Rodriguez, Chester E.; Di Stefano, Emma W.; Sioutas, Constantinos; Delfino, Ralph J.; Kumagai, Yoshito; Froines, John R.; Cho, Arthur K.

    Many of the adverse health effects of airborne particulate matter (PM) have been attributed to the chemical properties of some of the large number of chemical species present in PM. Some PM component chemicals are capable of generating reactive oxygen species and eliciting a state of oxidative stress. In addition, however, PM can contain chemical species that elicit their effects through covalent bond formation with nucleophilic functions in the cell. In this manuscript, we report the presence of constituents with electrophilic properties in ambient and diesel exhaust particles, demonstrated by their ability to inhibit the thiol enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH is irreversibly inactivated by electrophiles under anaerobic conditions by covalent bond formation. This inactivation can be blocked by the prior addition of a high concentration of dithiothreitol (DTT) as an alternate nucleophile. Addition of DTT after the reaction between the electrophile and GAPDH, however, does not reverse the inactivation. This property has been utilized to develop a procedure that provides a quantitative measure of electrophiles present in samples of ambient particles collected in the Los Angeles Basin and in diesel exhaust particles. The toxicity of electrophiles is the result of irreversible changes in biological molecules; recovery is dependent on resynthesis. If the resynthesis is slow, the irreversible effects can be cumulative and manifest themselves after chronic exposure to low levels of electrophiles.

  10. 1,3,2,5-Diazadiborinine featuring nucleophilic and electrophilic boron centres.

    PubMed

    Wu, Di; Kong, Lingbing; Li, Yongxin; Ganguly, Rakesh; Kinjo, Rei

    2015-01-01

    The seminal discovery in 1865 by Kekulé that benzene nucleus exists with cyclic skeleton is considered to be the beginning of aromatic chemistry. Since then, a myriad of cyclic molecules displaying aromatic property have been synthesized. Meanwhile, borazine (B3N3H6), despite the isostructural and isoelectronic relationships with benzene, exhibits little aromaticity. Herein, we report the synthesis of a 1,3,2,5-diazadiborinine (B2C2N2R6) derivative, a hybrid inorganic/organic benzene, and we present experimental and computational evidence for its aromaticity. In marked contrast to the reactivity of benzene, borazine, and even azaborinines previously reported, 1,3,2,5-diazadiborinine readily forms the adducts with methyl trifluoromethanesulfonate and phenylacetylene without any catalysts. Moreover, 1,3,2,5-diazadiborine activates carbon dioxide giving rise to a bicycle[2,2,2] product, and the binding process was found to be reversible. These results, thus, demonstrate that 1,3,2,5-diazadiborinine features both nucleophilic and electrophilic boron centres, with a formal B(+I)/B(+III) mixed valence system, in the aromatic six-membered B2C2N2 ring. PMID:26073993

  11. 1,3,2,5-Diazadiborinine featuring nucleophilic and electrophilic boron centres

    PubMed Central

    Wu, Di; Kong, Lingbing; Li, Yongxin; Ganguly, Rakesh; Kinjo, Rei

    2015-01-01

    The seminal discovery in 1865 by Kekulé that benzene nucleus exists with cyclic skeleton is considered to be the beginning of aromatic chemistry. Since then, a myriad of cyclic molecules displaying aromatic property have been synthesized. Meanwhile, borazine (B3N3H6), despite the isostructural and isoelectronic relationships with benzene, exhibits little aromaticity. Herein, we report the synthesis of a 1,3,2,5-diazadiborinine (B2C2N2R6) derivative, a hybrid inorganic/organic benzene, and we present experimental and computational evidence for its aromaticity. In marked contrast to the reactivity of benzene, borazine, and even azaborinines previously reported, 1,3,2,5-diazadiborinine readily forms the adducts with methyl trifluoromethanesulfonate and phenylacetylene without any catalysts. Moreover, 1,3,2,5-diazadiborine activates carbon dioxide giving rise to a bicycle[2,2,2] product, and the binding process was found to be reversible. These results, thus, demonstrate that 1,3,2,5-diazadiborinine features both nucleophilic and electrophilic boron centres, with a formal B(+I)/B(+III) mixed valence system, in the aromatic six-membered B2C2N2 ring. PMID:26073993

  12. Electrochemical generation of electrophilic drug metabolites: characterization of amodiaquine quinoneimine and cysteinyl conjugates by MS, IR, and NMR.

    PubMed

    Jurva, Ulrik; Holmén, Anders; Grönberg, Gunnar; Masimirembwa, Collen; Weidolf, Lars

    2008-04-01

    The chemical reactivity of electrophilic metabolites usually prevents their detection in vivo since, by definition, they are relatively short-lived and are likely to undergo one or more structural modifications to form more stable final products. Electrochemical oxidation provides a means to generate reactive metabolites in an environment without the presence of such nucleophiles. This paper describes the results of our MS, MS/MS, NMR, IR, and computational studies on oxidation products (and conjugates) that have been generated electrochemically from the antimalarial agent amodiaquine. The electrophilic quinoneimine metabolite of amodiaquine was the major oxidation product following electrochemical oxidation at +600 mV. The absence of biological nucleophiles in the electrochemical experiment facilitated (i) the acquisition of a clean IR spectrum of the amodiaquine quinoneimine and (ii) the addition of biologically relevant nucleophiles under controlled conditions. The addition of cysteine gave four cysteinyl conjugates, while the addition of glutathione gave four glutathionyl conjugates. The product ion spectra of the conjugates formed in the electrochemical experiment were used to identify suitable fragments for selected reaction monitoring (SRM) to selectively search for these conjugates in human liver microsomal (HLM) incubations. The four cysteinyl conjugates, as well as the four glutathionyl conjugates, were also detected as metabolites in HLM. The experiment with cysteine was repeated on a preparative scale that allowed characterization of the major conjugates by (1)H NMR. Desethylamodiaquine, the major metabolite formed in human liver microsomes, was also generated electrochemically by oxidation of amodiaquine at +1200 mV followed by reduction at -800 mV. In conclusion, the EC-ESI/MS technique provides the unique opportunity to generate reactive metabolites in the absence of biological nucleophiles, which enables studies that can give insight into the nature

  13. Titanocene(III)-Catalyzed Three-Component Reaction of Secondary Amides, Aldehydes, and Electrophilic Alkenes.

    PubMed

    Zheng, Xiao; He, Jiang; Li, Heng-Hui; Wang, Ao; Dai, Xi-Jie; Wang, Ai-E; Huang, Pei-Qiang

    2015-11-01

    An umpolung Mannich-type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one-pot formation of C-N and C-C bonds by a titanocene-catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N-substituted γ-amido-acid derivatives and γ-amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α-amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.

  14. Sequential one-pot addition of excess aryl-Grignard reagents and electrophiles to O-alkyl thioformates.

    PubMed

    Murai, Toshiaki; Morikawa, Kenta; Maruyama, Toshifumi

    2013-09-23

    The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl)-1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction. PMID:23946145

  15. N-Difluoromethylthiophthalimide: A Shelf-Stable, Electrophilic Reagent for Difluoromethylthiolation.

    PubMed

    Zhu, Dianhu; Gu, Yang; Lu, Long; Shen, Qilong

    2015-08-26

    A new, electrophilic difluoromethylthiolating reagent N-difluoromethylthiophthalimide 3 was developed. Reagent 3 can be readily synthesized in four steps from easily available starting materials phthalimide and TMSCF2H. N-difluoromethylthiophthalimide 3 is a powerful electrophilic difluoromethylthiolating reagent that allows the difluoromethylthiolation of a wide range of nucleophiles including aryl/vinyl boronic acids, alkynes, amines, thiols, β-ketoesters, and oxindoles and electron-rich heteroarenes such as indole, pyrrole, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyridine, aminothiazole, isoxazole, and pyrazole under mild conditions. PMID:26178409

  16. Computational Methods to Predict the Regioselectivity of Electrophilic Aromatic Substitution Reactions of Heteroaromatic Systems.

    PubMed

    Kruszyk, Monika; Jessing, Mikkel; Kristensen, Jesper Langgaard; Jørgensen, Morten

    2016-06-17

    The validity of calculated NMR shifts to predict the outcome of electrophilic aromatic substitution reactions on different heterocyclic compounds has been examined. Based on an analysis of >130 literature examples, it was found that the lowest predicted (13)C and/or (1)H chemical shift of a heterocycle correlates qualitatively with the regiochemical outcome of halogenation reactions in >80% of the investigated cases. In the remaining cases, the site of electrophilic aromatic substitution can be explained by the calculated HOMO orbitals obtained using density functional theory. Using a combination of these two methods, the accuracy increases to >95%.

  17. Dual Neuroprotective Pathways of a Pro-Electrophilic Compound via HSF-1-activated Heat Shock Proteins and Nrf2-activated Phase 2 Antioxidant Response Enzymes

    PubMed Central

    Satoh, Takumi; Rezaie, Tayebeh; Seki, Masaaki; Sunico, Carmen R.; Tabuchi, Takahito; Kitagawa, Tomomi; Yanagitai, Mika; Senzaki, Mutsumi; Kosegawa, Chihiro; Taira, Hideharu; McKercher, Scott R.; Hoffman, Jennifer K.; Roth, Gregory P.; Lipton, Stuart A.

    2015-01-01

    Activation of the Keap1/Nrf2 pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated “pro-electrophiles.” Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) in order to analyze their protective mechanism. DNA microarray, PCR, and Western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27 and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na+-independent cystine/glutamate exchanger. Treatment with D1 resulted in activation of Nrf2 and HSF-1 transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of GRP78, an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that in it reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress

  18. Electrophile-Modified Lipoic Derivatives of PDC-E2 Elicits Anti-mitochondrial Antibody Reactivity

    PubMed Central

    Naiyanetr, Phornnop; Butler, Jeffrey D.; Meng, Liping; Pfeiff, Janice; Kenny, Thomas P.; Guggenheim, Kathryn G.; Reiger, Roman; Lam, Kit; Kurth, Mark J.; Ansari, Aftab. A.; Coppel, Ross L.; López-Hoyos, Marcos; Gershwin, M. Eric; Leung, Patrick S.C.

    2011-01-01

    Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces antimitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl1oiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC. PMID:21763105

  19. Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity.

    PubMed

    Naiyanetr, Phornnop; Butler, Jeffrey D; Meng, Liping; Pfeiff, Janice; Kenny, Thomas P; Guggenheim, Kathryn G; Reiger, Roman; Lam, Kit; Kurth, Mark J; Ansari, Aftab A; Coppel, Ross L; López-Hoyos, Marcos; Gershwin, M Eric; Leung, Patrick S C

    2011-11-01

    Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.

  20. Electrophilic addition to cyanide ligands in tungsten(II) four-electron-donor alkyne complexes

    SciTech Connect

    Frohnapfel, D.S.; Reinartz, S.; White, P.S.; Templeton, J.L.

    1998-08-17

    Extended reflux of Tp{prime}(CO)(I)W(RC{triple_bond}CR{prime}) (Tp{prime} = hydridotris(3,5-dimethylpyrazolyl)borate) complexes in ethyl acetate in the presence of silver cyanide produces Tp{prime}(CO)(CN)W(RC{triple_bond}CR{prime}) complexes in moderate to high yields. A single-crystal X-ray structure of Tp{prime}(CO)(CN)W(PhC{triple_bond}CMe) shows that the alkyne is aligned parallel to the M{single_bond}CO axis. Electrophilic attack at the nitrogen of the cyanide ligand with methyl triflate or triflic acid yields cationic isocyanide complexes, whereas attack with HBF{sub 4} results in neutral BF{sub 3} adduct complexes. Coordination of the Tp{prime}(CO)(PhC{triple_bond}CMe)W{sup +} fragment to the cyanide nitrogen of Tp{prime}(CO)(CN)W(HC{triple_bond}CBu{sup n}) to form a CN-bridged dinuclear complex has been achieved. Variable-temperature {sup 1}H NMR measurements reflect acetylene rotation barriers in the Tp{prime}(CO)(L)W(HC{triple_bond}CH){sup n+} series (L = CO, CNH, CNMe {l_brace}n = 1{r_brace}; CN{sup {minus}}, CNBF{sub 3}{sup {minus}} {l_brace}n = 0{r_brace}) and, thus, quantify {pi}-effects for the cyanide and isocyanide ligands with respect to steric considerations. Extended Hueckel molecular orbital calculations were carried out on a series of model complexes, [H{sub 3}(CO)(L)W(HC{triple_bond}CH)]{sup n{minus}} (L = CO, CNH {l_brace}n = 1{r_brace}; CN{sup {minus}}, H{sup {minus}} {l_brace}n = 2{r_brace}) to augment the experimental data.

  1. Torsional Control of Stereoselectivities in Electrophilic Additions and Cycloadditions to Alkenes

    PubMed Central

    Wang, Hao; Houk, K. N.

    2013-01-01

    Torsional effects control the π-facial stereoselectivities of a variety of synthetically important organic reactions. This review surveys theoretical calculations that have led to the understanding of the influence of the torsional effects on several types of stereoselective organic reactions, especially electrophilic additions and cycloadditions to alkenes. PMID:24409340

  2. Benzyltrifluoromethyl (or Fluoroalkyl) Selenide: Reagent for Electrophilic Trifluoromethyl (or Fluoroalkyl) Selenolation.

    PubMed

    Glenadel, Quentin; Ismalaj, Ermal; Billard, Thierry

    2016-09-16

    Trifluoromethylseleno substituent (CF3Se) is an emerging group, but its direct introduction onto organic molecules is still quite limited and mainly restricted to nucleophilic methods. Herein, we describe a new approach to easily and safely perform electrophilic trifluoromethylselenolation starting from a simple and easily accessible reagent, namely, benzyltrifluoromethyl selenide. This strategy can be generalized to various fluoroalkylselanyl groups, even functionalized ones. PMID:27571314

  3. Organic Chemistry Students' Ideas about Nucleophiles and Electrophiles: The Role of Charges and Mechanisms

    ERIC Educational Resources Information Center

    Anzovino, Mary E.; Bretz, Stacey Lowery

    2015-01-01

    Organic chemistry students struggle with reaction mechanisms and the electron-pushing formalism (EPF) used by practicing organic chemists. Faculty have identified an understanding of nucleophiles and electrophiles as one conceptual prerequisite to mastery of the EPF, but little is known about organic chemistry students' knowledge of nucleophiles…

  4. Electrophilic iodine(I) compounds induced semipinacol rearrangement via C-X bond cleavage.

    PubMed

    Tsuji, Nobuya; Kobayashi, Yusuke; Takemoto, Yoshiji

    2014-11-18

    Neutral electrophilic iodine(I) species proved to be efficient reagents for C-X bond cleavage of various cyclic and acyclic α-silyloxyhalides, and the induced desilylative semipinacol rearrangement provided the corresponding ketones in good yields. The reaction is operationally simple, and proceeds under mild conditions with good functional group compatibility. Mechanistic investigations, including computational studies, were also performed.

  5. Biochemical and cellular effects of electrophiles present in ambient air samples

    NASA Astrophysics Data System (ADS)

    Iwamoto, Noriko; Nishiyama, Akira; Eiguren-Fernandez, Arantzazu; Hinds, William; Kumagai, Yoshito; Froines, John R.; Cho, Arthur K.; Shinyashiki, Masaru

    2010-04-01

    Ambient vapor-phase samples collected in Riverside, California had shown that both redox and electrophilic activity were present, with the vapor phase containing higher levels of electrophiles than the particle phase. In this study, the biochemical effects of the vapor-phase electrophiles were examined using the purified thiol proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), protein tyrosine phosphatase 1B (PTP1B) and KELCH-1 like ECH-associated protein 1 (Keap1). The results demonstrated that the thiol proteins were inactivated by the vapor-phase samples through covalent modifications. Next, two cellular responses, epidermal growth factor receptor (EGFR)/mitogen-activated protein (MAP) kinase and NF-E2-related factor 2 (Nrf2), to the ambient vapor-phase samples were assessed in A549 and RAW 264.7 cell lines, respectively. The vapor-phase samples, at non-oxidative concentrations, increased phosphorylation of EGFR, which is negatively regulated by PTP1B, and its downstream MAP kinase, extracellular signal-regulated kinase (ERK)1/2. Activation of Nrf2, which requires Keap1 alkylation, and expression of its downstream proteins were also observed. The electrophilic compounds present in ambient vapor-phase were shown to modify cellular proteins through covalent modification and to activate diverse cellular responses that can lead to inflammatory and adaptive responses.

  6. Removal of chlorine gas by an amine functionalized metal-organic framework via electrophilic aromatic substitution.

    PubMed

    DeCoste, Jared B; Browe, Matthew A; Wagner, George W; Rossin, Joseph A; Peterson, Gregory W

    2015-08-11

    Here we report the removal of chlorine gas from air via a reaction with an amine functionalized metal-organic framework (MOF). It is found that UiO-66-NH2 has the ability to remove 1.24 g of Cl2 per g of MOF via an electrophilic aromatic substitution reaction producing HCl, which is subsequently neutralized by the MOF.

  7. 15-oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways

    PubMed Central

    Snyder, Nathaniel W.; Golin-Bisello, Franca; Gao, Yang; Blair, Ian A.; Freeman, Bruce A.; Wendell, Stacy Gelhaus

    2014-01-01

    Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic “inactivation” of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic α,β-unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15-oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2-regulated antioxidant responses (AR) and inhibits NF-κB-mediated pro-inflammatory responses via IKKβ inhibition. Inhibition of glutathione S-transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators. PMID:25450232

  8. Trifluoromethyl sulfoxides from allylic alcohols and electrophilic SCF3 donor by [2,3]-sigmatropic rearrangement.

    PubMed

    Maeno, Mayaka; Shibata, Norio; Cahard, Dominique

    2015-04-17

    An electrophilic trifluoromethylthiolation of allylic alcohols produces the corresponding allylic trifluoromethanesulfenates, which spontaneously rearrange into trifluoromethyl sulfoxides via a [2,3]-sigmatropic rearrangement. The reaction is straightforward and proceeds in good to high yields for the preparation of various allylic trifluoromethyl sulfoxides.

  9. Synthesis of Triarylmethane and Xanthene Dyes Using Electrophilic Aromatic Substitution Reactions

    ERIC Educational Resources Information Center

    McCullagh, James V.; Daggett, Kelly A.

    2007-01-01

    The synthesis of dyes has long been a popular topic in organic chemistry laboratory experiments because it allows students to see first hand that reactions learned in class can be used to make compounds with useful applications. In this experiment electrophilic aromatic substitution reactions are used to synthesize several triarylmethane and…

  10. Copper-catalyzed trifluoromethylation of alkenes with an electrophilic trifluoromethylating reagent

    PubMed Central

    Wang, Xiao-Ping; Lin, Jin-Hong; Zhang, Cheng-Pan; Zheng, Xing

    2013-01-01

    Summary An efficient method for the copper-catalyzed trifluoromethylation of terminal alkenes with an electrophilic trifluoromethylating reagent has been developed. The reactions proceeded smoothly to give trifluoromethylated alkenes in good to excellent yields. The results provided a versatile approach for the construction of Cvinyl–CF3 bonds without using prefunctionalized substrates. PMID:24367428

  11. Markers of electrophilic stress caused by chemically reactive metabolites in human hepatocytes.

    PubMed

    Takakusa, Hideo; Masumoto, Hiroshi; Mitsuru, Ayako; Okazaki, Osamu; Sudo, Kenichi

    2008-05-01

    The metabolic activation of a drug to an electrophilic reactive metabolite and its covalent binding to cellular macromolecules is considered to be involved in the occurrence of idiosyncratic drug toxicity (IDT). As a cellular defense system against oxidative and electrophilic stress, phase II enzymes are known to be induced through a Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2/antioxidant response element system. We presumed that it is important for the risk assessment of drug-induced hepatotoxicity and IDTs to observe the biological responses evoked by exposure to reactive metabolites, and then investigated the mRNA induction profiles of phase II enzymes in human hepatocytes after exposure to problematic drugs associated with IDTs, such as ticlopidine, diclofenac, clozapine, and tienilic acid, as well as safe drugs such as levofloxacin and caffeine. According to the results, the problematic drugs exhibited inductive effects on heme oxygenase 1 (HO-1), which contrasted with the safe drugs; therefore, the induction of HO-1 mRNA seems to be correlated with the occurrence of drug toxicity, including IDT caused by electrophilic reactive metabolites. Moreover, glutathione-depletion and cytochrome P450 (P450)-inhibition experiments have shown that the observed HO-1 induction was triggered by the electrophilic reactive metabolites produced from the problematic drugs through P450-mediated metabolic bioactivation. Taken together with our present study, this suggests that HO-1 induction in human hepatocytes would be a good marker of the occurrence of metabolism-based drug-induced hepatotoxicity and IDT caused by the formation of electrophilic reactive metabolites. PMID:18227147

  12. A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

    PubMed

    Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

    2015-05-20

    Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.

  13. A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

    PubMed

    Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

    2015-05-20

    Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background. PMID:25909755

  14. Thiolation of protein-bound carcinogenic aldehyde. An electrophilic acrolein-lysine adduct that covalently binds to thiols.

    PubMed

    Furuhata, Atsunori; Nakamura, Mitsuhiro; Osawa, Toshihiko; Uchida, Koji

    2002-08-01

    Acrolein, a representative carcinogenic aldehyde that could be ubiquitously generated in biological systems under oxidative stress, shows facile reactivity with the epsilon-amino group of lysine to form N(epsilon)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) as the major product (Uchida, K., Kanematsu, M., Morimitsu, Y., Osawa, T., Noguchi, N., and Niki, E. (1998) J. Biol. Chem. 273, 16058-16066). In the present study, we determined the electrophilic potential of FDP-lysine and established a novel mechanism of protein thiolation in which the FDP-lysine generated in the acrolein-modified protein reacts with sulfhydryl groups to form thioether adducts. When a sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase, was incubated with acrolein-modified bovine serum albumin in sodium phosphate buffer (pH 7.2) at 37 degrees C, a significant loss of sulfhydryl groups, which was accompanied by the loss of enzyme activity and the formation of high molecular mass protein species (>200 kDa), was observed. The FDP-lysine adduct generated in the acrolein-modified protein was suggested to represent a thiol-reactive electrophile based on the following observations. (i) N(alpha)-acetyl-FDP-lysine, prepared from the reaction of N(alpha)-acetyl lysine with acrolein, was covalently bound to glyceraldehyde-3-phosphate dehydrogenase. (ii) The FDP-lysine derivative reacted with glutathione to form a GSH conjugate. (iii) The acrolein-modified bovine serum albumin significantly reacted with GSH to form a glutathiolated protein. Furthermore, the observation that the glutathiolated acrolein-modified protein showed decreased immunoreactivity with an anti-FDP-lysine monoclonal antibody suggested that the FDP-lysine residues in the acrolein-modified protein served as the binding site of GSH. These data suggest that thiolation of the protein-bound acrolein may be involved in redox alteration under oxidative stress, whereby oxidative stress generates the increased production of

  15. Exploration of new C-O electrophiles in cross-coupling reactions.

    PubMed

    Yu, Da-Gang; Li, Bi-Jie; Shi, Zhang-Jie

    2010-12-21

    Since their development in the 1970s, cross-coupling reactions catalyzed by transition metals have become one of the most important tools for constructing both carbon-carbon and carbon-heteroatom bonds. Traditionally, organohalides were widely studied and broadly used as the electrophile, both in the laboratory and in industry. Unfortunately, the high cost, environmental toxicity, and sluggish preparation often associated with aryl halides can make them undesirable for the large-scale syntheses of industrial applications. However, with the further development of catalytic systems, and particularly of the ligands contained therein, a variety of electrophiles have now been successfully applied to cross-coupling reactions. Oxygen-based electrophiles have attracted much attention due to their ready availability from phenol and carbonyl compounds. Initially, aryl and alkenyl triflates were used in cross-coupling reactions due to their high reactivity; however, low moisture stability and high cost hampered their application. Later, with the development of highly efficient catalytic systems, the less reactive sulfonates and phosphates were successfully employed in cross-coupling reactions. Although they have higher stability and can be easily prepared, low atom economy remains an obstacle to their broader utility. Our group has worked to directly apply the abundant and readily available oxygen-containing compounds, such as phenols, alcohols, ethers, and carbonyl compounds, to cross-coupling reactions. In this Account, we describe our recent efforts in transition-metal-catalyzed cross-coupling reactions of new O-based electrophiles via C-O bond activation. We began by developing the methylation of aryl methyl ethers and benzyl methyl ethers via Ni-catalyzed selective C-O bond cleavage. With the refined Ni-based catalytic system, we further applied aryl/alkenyl carboxylates and carbamates to Suzuki-Miyaura, Negishi, and Kumada-Tamao-Corriu reactions to construct various

  16. PH-dependent forms of red wine anthocyanins as antioxidants.

    PubMed

    Lapidot, T; Harel, S; Akiri, B; Granit, R; Kanner, J

    1999-01-01

    Anthocyanins are one of the main classes of flavonoids in red wines, and they appear to contribute significantly to the powerful antioxidant properties of the flavonoids. In grapes and wines the anthocyanins are in the flavylium form. However, during digestion they may reach higher pH values, forming the carbinol pseudo-base, quinoidal-base, or the chalcone, and these compounds appear to be absorbed from the gut into the blood system. The antioxidant activity of these compounds, in several metal-catalyzed lipid oxidation model systems, was evaluated in comparison with other antioxidants. The pseudo-base and quinoidal-base malvidin 3-glucoside significantly inhibited the peroxidation of linoleate by myoglobin. Both compounds were found to work better than catechin, a well-known antioxidant. In a membrane lipid peroxidation system, the effectiveness of the antioxidant was dependent on the catalyst: In the presence of H(2)O(2)-activated myoglobin, the inhibition efficiency of the antioxidant was malvidin 3-glucoside > catechin > malvidin > resveratrol. However, in the presence of an iron redox cycle catalyzer, the order of effectiveness was resveratrol > malvidin 3-glucoside = malvidin > catechin. The pH-transformed forms of the anthocyanins remained effective antioxidants in these systems, and their I(50) values were between 0.5 and 6.2 microM. PMID:10563851

  17. PH-dependent forms of red wine anthocyanins as antioxidants.

    PubMed

    Lapidot, T; Harel, S; Akiri, B; Granit, R; Kanner, J

    1999-01-01

    Anthocyanins are one of the main classes of flavonoids in red wines, and they appear to contribute significantly to the powerful antioxidant properties of the flavonoids. In grapes and wines the anthocyanins are in the flavylium form. However, during digestion they may reach higher pH values, forming the carbinol pseudo-base, quinoidal-base, or the chalcone, and these compounds appear to be absorbed from the gut into the blood system. The antioxidant activity of these compounds, in several metal-catalyzed lipid oxidation model systems, was evaluated in comparison with other antioxidants. The pseudo-base and quinoidal-base malvidin 3-glucoside significantly inhibited the peroxidation of linoleate by myoglobin. Both compounds were found to work better than catechin, a well-known antioxidant. In a membrane lipid peroxidation system, the effectiveness of the antioxidant was dependent on the catalyst: In the presence of H(2)O(2)-activated myoglobin, the inhibition efficiency of the antioxidant was malvidin 3-glucoside > catechin > malvidin > resveratrol. However, in the presence of an iron redox cycle catalyzer, the order of effectiveness was resveratrol > malvidin 3-glucoside = malvidin > catechin. The pH-transformed forms of the anthocyanins remained effective antioxidants in these systems, and their I(50) values were between 0.5 and 6.2 microM.

  18. Synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazoles mediated by in situ generated copper(I) catalyst and electrophilic triiodide ion.

    PubMed

    Brotherton, Wendy S; Clark, Ronald J; Zhu, Lei

    2012-08-01

    Mixing copper(II) perchlorate and sodium iodide solutions results in copper(I) species and the electrophilic triiodide ions, which collectively mediate the cycloaddition reaction of organic azide and terminal alkyne to afford 5-iodo-1,4-disubstituted-1,2,3-triazoles. One molar equivalent of an amine additive is required for achieving a full conversion. Excessive addition of the amine compromises the selectivity for 5-iodo-1,2,3-triazole by promoting the formation of 5-proto-1,2,3-triazole. Based on preliminary kinetic and structural evidence, a mechanistic model is formulated in which a 5-iodo-1,2,3-triazole is formed via iodination of a copper(I) triazolide intermediate by the electrophilic triiodide ions (and possibly triethyliodoammonium ions). The experimental evidence explains the higher reactivity of the in situ generated copper(I) species and triiodide ion in the formation of 5-iodo-1,2,3-triazoles than that of the pure forms of copper(I) iodide and iodine.

  19. Olefin cis-Dihydroxylation and Aliphatic C-H Bond Oxygenation by a Dioxygen-Derived Electrophilic Iron-Oxygen Oxidant.

    PubMed

    Chatterjee, Sayanti; Paine, Tapan Kanti

    2015-08-01

    Many iron-containing enzymes involve metal-oxygen oxidants to carry out O2-dependent transformation reactions. However, the selective oxidation of C-H and C=C bonds by biomimetic complexes using O2 remains a major challenge in bioinspired catalysis. The reactivity of iron-oxygen oxidants generated from an Fe(II)-benzilate complex of a facial N3 ligand were thus investigated. The complex reacted with O2 to form a nucleophilic oxidant, whereas an electrophilic oxidant, intercepted by external substrates, was generated in the presence of a Lewis acid. Based on the mechanistic studies, a nucleophilic Fe(II)-hydroperoxo species is proposed to form from the benzilate complex, which undergoes heterolytic O-O bond cleavage in the presence of a Lewis acid to generate an Fe(IV)-oxo-hydroxo oxidant. The electrophilic iron-oxygen oxidant selectively oxidizes sulfides to sulfoxides, alkenes to cis-diols, and it hydroxylates the C-H bonds of alkanes, including that of cyclohexane.

  20. Synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazoles mediated by in situ generated copper(I) catalyst and electrophilic triiodide ion.

    PubMed

    Brotherton, Wendy S; Clark, Ronald J; Zhu, Lei

    2012-08-01

    Mixing copper(II) perchlorate and sodium iodide solutions results in copper(I) species and the electrophilic triiodide ions, which collectively mediate the cycloaddition reaction of organic azide and terminal alkyne to afford 5-iodo-1,4-disubstituted-1,2,3-triazoles. One molar equivalent of an amine additive is required for achieving a full conversion. Excessive addition of the amine compromises the selectivity for 5-iodo-1,2,3-triazole by promoting the formation of 5-proto-1,2,3-triazole. Based on preliminary kinetic and structural evidence, a mechanistic model is formulated in which a 5-iodo-1,2,3-triazole is formed via iodination of a copper(I) triazolide intermediate by the electrophilic triiodide ions (and possibly triethyliodoammonium ions). The experimental evidence explains the higher reactivity of the in situ generated copper(I) species and triiodide ion in the formation of 5-iodo-1,2,3-triazoles than that of the pure forms of copper(I) iodide and iodine. PMID:22780866

  1. Covalent functionalization of carbon nanotubes through organometallic reduction and electrophilic attack.

    PubMed

    Roubeau, Olivier; Lucas, Antoine; Pénicaud, Alain; Derré, Alain

    2007-10-01

    Organometallic reagents such as butyllithium are known to covalently functionalize the sidewalls of carbon nanotubes. The function grafted corresponds to the organic part of the alkali compound, while one negative charge is transferred to the nanotube for each function. Carbon nanotubes reduced by organolithium compounds were used here as nucleophilic reactive species through these transferred and delocalized charges. Various halogenated electrophiles in excess were reacted with them in anhydrous conditions. The grafting of the corresponding chemical function onto the carbon nanotubes through a Lewis metathetic exchange reaction was demonstrated by chemical, thermal, and spectroscopic analyses. This synthetic route applied successfully to both single-walled and multi-walled nanotubes and to a series of electrophiles. The extent of functionalization was found to depend on stoechiometries used, although a direct correlation could not be obtained. PMID:18330165

  2. Automated electrophilic radiosynthesis of [¹⁸F]FBPA using a modified nucleophilic GE TRACERlab FXFDG.

    PubMed

    Mairinger, Severin; Stanek, Johann; Wanek, Thomas; Langer, Oliver; Kuntner, Claudia

    2015-10-01

    We modified a commercially available synthesis module for nucleophilic [(18)F]fluorinations (TRACERlab(TM) FXFDG, GE Healthcare) to enable the reliable synthesis of 2-[(18)F]fluoro-4-borono-L-phenylalanine ([(18)F]FBPA) via direct electrophilic substitution of 4-borono-L-phenylalanine with [(18)F]F2 gas. [(18)F]FBPA was obtained with a RCY of 8.5±2.0% and a radiochemical purity of 98±1% in a total synthesis time of 72±7 min (n=22). The modified synthesis module might also be useful for the synthesis of other [(18)F]radiopharmaceuticals via electrophilic substitution reactions while still being suitable for nucleophilic substitution reactions.

  3. Lithium Halomethylcarbenoids: Preparation and Use in the Homologation of Carbon Electrophiles.

    PubMed

    Pace, Vittorio; Holzer, Wolfgang; De Kimpe, Norbert

    2016-08-01

    α-Halomethyllithium carbenoids are useful homologating reagents which - reacting under proper reaction conditions as carbanions - enable the installation via nucleophilic addition of a reactive halomethyl fragment onto a preformed carbon-heteroatom bond. The pronounced thermolability represented - since seminal studies by Köbrich - the Achilles' heel of these reagents: the use of Barbier-type methodologies (i.e., the electrophile should be present in the reaction mixture prior to the formation of the carbenoid) was pivotal in order to suppress decomposition through α-elimination processes. Nowadays, the use of low temperatures (-78 °C) guarantees reliable procedures and, significantly, the employment of microreactor technologies allows external trapping to be performed even at higher temperatures as reported by Luisi. We will discuss the α-halomethyllithium-mediated homologations of a series of carbon electrophiles such as carbonyl compounds, imines, esters, Weinreb amides, and isocyanates. PMID:27381551

  4. Relationships between descriptors for hydrophobicity and soft electrophilicity in predicting toxicity

    SciTech Connect

    Mekenyan, O.G.; Veith, G.D.

    1993-01-01

    The toxicity of chemicals is orthogonal with individual molecular descriptors used to quantify hydrophobicity and soft electrophilicity when considering large data sets. Estimating the toxicity of reactive chemicals requires descriptors of both passive transport and the stereoelectronic interaction, which are largely independent processes. QSARs using either log P or an electronic parameter alone are only significant for sets of chemicals that represent special, albeit some important, cases in QSAR. Chemicals were clustered according to their reactivity as soft electrophiles by defining isoelectrophilic windows along the toxicity response surface. Within these narrow windows of reactivity, the variation of toxicity was explained by the variation of log P. The authors observed that the dependence of toxicity on log P in different isoelectrophilic windows decreased as reactivity increased. The data are consistent with toxicity models where competing nucleophilic sites are distributed along the transport route of the chemicals. (Copyright (c) 1993 Gordon and Breach Science Publishers S.A.)

  5. Condensation reactions of guanidines with bis-electrophiles: Formation of highly nitrogenous heterocyclesa

    PubMed Central

    Arnold, David M.; LaPorte, Matthew G.; Anderson, Shelby M.; Wipf, Peter

    2013-01-01

    2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bi-pyrimidine, pyrimido-aminotriazine, and pyrimido-sulfonamide scaffolds. In addition, a quinazoline library was constructed using a guanidine Atwal-Biginelli reaction with 1-(quinazolin-2-yl)guanidines. The product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable additions to screening libraries for the discovery of new modulators of biological targets. PMID:23976798

  6. Electrophilic difluoro(phenylthio)methylation: generation, stability, and reactivity of α-fluorocarbocations.

    PubMed

    Betterley, Nolan M; Surawatanawong, Panida; Prabpai, Samran; Kongsaeree, Palangpon; Kuhakarn, Chutima; Pohmakotr, Manat; Reutrakul, Vichai

    2013-11-15

    Electrophilic difluoro(phenylthio)methylation of allylsilanes has been achieved using bromodifluoro(phenylthio)methane (PhSCF2Br) and silver hexafluoroantimonate (AgSbF6). The structural assignment and observation of α-fluorocarbocation were substantiated by NMR and theoretical calculations. Detailed mechanistic and electronic studies have provided a fundamental understanding of the reactivity and stability of the difluoro(phenylthio)methylium cation (PhSCF2(+)).

  7. C-C Coupling of Benzyl Fluorides Catalyzed by an Electrophilic Phosphonium Cation.

    PubMed

    Zhu, Jiangtao; Pérez, Manuel; Stephan, Douglas W

    2016-07-11

    The activation and cleavage of benzyl fluorides by the electrophilic organofluorophosphonium catalyst, [(C6 F5 )3 PF][B(C6 F5 )4 ], is reported and used for the preparation of 1,1-diarylalkanes (37 examples) and substituted aryl homoallylic alkenes (14 examples). This procedure involves mild conditions, avoids harmful waste, and is compatible with a range of substituted arenes and allylic silanes. PMID:27239806

  8. Efficient visualization of H2S via a fluorescent probe with three electrophilic centres.

    PubMed

    Asthana, Sharad Kumar; Kumar, Ajit; Neeraj; Shweta; Upadhyay, K K

    2016-04-12

    H2S is a reactive nucleophilic species with toxic effects towards human beings. Its efficient detection and marking is still a challenging job due to its similar nucleophilic character to a number of biothiols, like glutathione, cysteine, homocysteine etc. We report herein the first ever use of a chemosensor incorporating three electrophilic centres to achieve high sensitivity and very fast response time (40 s) towards H2S. PMID:27030288

  9. A Library of Fluorinated Electrophiles for Chemical Tagging and Materials Synthesis.

    PubMed

    Kasper, Jonathan J; Hitro, Jamie E; Fitzgerald, Sabrina R; Schnitter, Joseph M; Rutowski, James J; Heck, John A; Steinbacher, Jeremy L

    2016-09-01

    Various applications could benefit from new fluorinated molecules that offer chemical handles for quickly functionalizing reactive surfaces and molecules. Herein, we report the synthesis of a library of fluorinated molecules that contain nonafluoro-tert-butyl groups and electrophilic handles, mostly acrylates and acrylamides. Featuring a variety of hydrophobic and hydrophilic linkers, these molecules could find use in polymer chemistry, biomaterials, biomedical imaging, and protein tagging. PMID:27467082

  10. Copper-catalyzed electrophilic amination of sodium sulfinates at room temperature.

    PubMed

    Zhu, Haibo; Shen, Yajing; Deng, Qinyue; Tu, Tao

    2015-11-28

    By using O-benzoyl hydroxylamines as amine sources, the first convenient copper-catalyzed electrophilic amination of sodium sulfinates has been realized. Even with 2 mol% catalyst loading, the protocol provided an efficient and straightforward synthesis of a broad range of functional sulfonamides under ambient reaction conditions without an additional base and ligand. Based on the control experiments, a plausible mechanism was proposed. PMID:26419424

  11. Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action.

    PubMed

    Castro-Falcón, Gabriel; Hahn, Dongyup; Reimer, Daniela; Hughes, Chambers C

    2016-08-19

    New methods are urgently needed to find novel natural products as structural leads for the development of new drugs against emerging diseases such as cancer and multiresistant bacterial infections. Here we introduce a reactivity-guided drug discovery approach for electrophilic natural products, a therapeutically relevant class of natural products that covalently modify their cellular targets, in crude extracts. Using carefully designed halogenated aromatic reagents, the process furnishes derivatives that are UV-active and highly conspicuous via mass spectrometry by virtue of an isotopically unique bromine or chlorine tag. In addition to the identification of high-value metabolites, the process facilitates the difficult task of structure elucidation by providing derivatives that are primed for X-ray crystallographic analysis. We show that a cysteine probe efficiently and chemoselectively labels enone-, β-lactam-, and β-lactone-based electrophilic natural products (parthenolide, andrographolide, wortmannin, penicillin G, salinosporamide), while a thiophenol probe preferentially labels epoxide-based electrophilic natural products (triptolide, epoxomicin, eponemycin, cyclomarin, salinamide). Using the optimized method, we were able to detect and isolate the epoxide-bearing natural product tirandalydigin from Salinispora and thereby link an orphan gene cluster to its gene product.

  12. Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action.

    PubMed

    Castro-Falcón, Gabriel; Hahn, Dongyup; Reimer, Daniela; Hughes, Chambers C

    2016-08-19

    New methods are urgently needed to find novel natural products as structural leads for the development of new drugs against emerging diseases such as cancer and multiresistant bacterial infections. Here we introduce a reactivity-guided drug discovery approach for electrophilic natural products, a therapeutically relevant class of natural products that covalently modify their cellular targets, in crude extracts. Using carefully designed halogenated aromatic reagents, the process furnishes derivatives that are UV-active and highly conspicuous via mass spectrometry by virtue of an isotopically unique bromine or chlorine tag. In addition to the identification of high-value metabolites, the process facilitates the difficult task of structure elucidation by providing derivatives that are primed for X-ray crystallographic analysis. We show that a cysteine probe efficiently and chemoselectively labels enone-, β-lactam-, and β-lactone-based electrophilic natural products (parthenolide, andrographolide, wortmannin, penicillin G, salinosporamide), while a thiophenol probe preferentially labels epoxide-based electrophilic natural products (triptolide, epoxomicin, eponemycin, cyclomarin, salinamide). Using the optimized method, we were able to detect and isolate the epoxide-bearing natural product tirandalydigin from Salinispora and thereby link an orphan gene cluster to its gene product. PMID:27294329

  13. Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.

    PubMed

    Jain, Atul D; Potteti, Haranatha; Richardson, Benjamin G; Kingsley, Laura; Luciano, Julia P; Ryuzoji, Aya F; Lee, Hyun; Krunic, Aleksej; Mesecar, Andrew D; Reddy, Sekhar P; Moore, Terry W

    2015-10-20

    Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.

  14. Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles.

    PubMed

    Bueno, Ana B; Showalter, Aaron D; Wainscott, David B; Stutsman, Cynthia; Marín, Aranzazu; Ficorilli, James; Cabrera, Over; Willard, Francis S; Sloop, Kyle W

    2016-05-13

    Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP-1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5'-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9-36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose-dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [(3)H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and

  15. Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles*

    PubMed Central

    Showalter, Aaron D.; Wainscott, David B.; Stutsman, Cynthia; Marín, Aranzazu; Ficorilli, James; Cabrera, Over

    2016-01-01

    Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP-1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5′-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9–36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose-dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [3H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and

  16. Electrophilic Pt(II) complexes: precision instruments for the initiation of transformations mediated by the cation-olefin reaction.

    PubMed

    Felix, Ryan J; Munro-Leighton, Colleen; Gagné, Michel R

    2014-08-19

    A discontinuity exists between the importance of the cation-olefin reaction as the principal C-C bond forming reaction in terpene biosynthesis and the synthetic tools for mimicking this reaction under catalyst control; that is, having the product identity, stereochemistry, and functionality under the control of a catalyst. The main reason for this deficiency is that the cation-olefin reaction starts with a reactive intermediate (a carbocation) that reacts exothermically with an alkene to reform the reactive intermediate; not to mention that reactive intermediates can also react in nonproductive fashions. In this Account, we detail our efforts to realize catalyst control over this most fundamental of reactions and thereby access steroid like compounds. Our story is organized around our progress in each component of the cascade reaction: the metal controlled electrophilic initiation, the propagation and termination of the cyclization (the cyclase phase), and the turnover deplatinating events. Electrophilic Pt(II) complexes efficiently initiate the cation-olefin reaction by first coordinating to the alkene with selection rules that favor less substituted alkenes over more substituted alkenes. In complex substrates with multiple alkenes, this preference ensures that the least substituted alkene is always the better ligand for the Pt(II) initiator, and consequently the site at which all electrophilic chemistry is initiated. This control element is invariant. With a suitably electron deficient ligand set, the catalyst then activates the coordinated alkene to intramolecular addition by a second alkene, which initiates the cation-olefin reaction cascade and generates an organometallic Pt(II)-alkyl. Deplatination by a range of mechanisms (β-H elimination, single electron oxidation, two-electron oxidation, etc.) provides an additional level of control that ultimately enables A-ring functionalizations that are orthogonal to the cyclase cascade. We particularly focus on

  17. Reaction of delta3-unsaturated pentofuranoses with electrophilic reagents

    SciTech Connect

    Khripach, N.B.; Galitskii, N.M.

    1987-06-20

    The reaction of the 5-0-derivatives of 3-deoxy-1,2-0-isopropylidene-..cap alpha..-D-glyceropent-3-enofuranose with iodine or bromine in methanol in the presence of silver carbonate or in inert solvents in the presence of thallium fluoride leads mainly to a mixture of the cyclic product from the addition at the ..delta../sup 3/-double bond and an acyclic 3-halogeno-4-keto derivative. In some cases only one reaction product is formed. With mercuric acetate in methanol the opening of the furanose ring in the initial compound is not observed.

  18. Generation and Dietary Modulation of Anti-Inflammatory Electrophilic Omega-3 Fatty Acid Derivatives

    PubMed Central

    Cipollina, Chiara; Salvatore, Sonia R.; Muldoon, Matthew F.; Freeman, Bruce A.; Schopfer, Francisco J.

    2014-01-01

    Dietary ω-3 polyunsaturated fatty acids (PUFAs) decrease cardiovascular risk via suppression of inflammation. The generation of electrophilic α,β-unsaturated ketone derivatives of the ω-3 PUFAs docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) in activated human macrophages is catalyzed by cyclooxygenase-2 (Cox-2). These derivatives are potent pleiotropic anti-inflammatory signaling mediators that act via mechanisms including the activation of Nrf2-dependent phase 2 gene expression and suppression of pro-inflammatory NF-κB-driven gene expression. Herein, the endogenous generation of ω-3 PUFAs electrophilic ketone derivatives and their hydroxy precursors was evaluated in human neutrophils. In addition, their dietary modulation was assessed through a randomized clinical trial. Methods Endogenous generation of electrophilic omega-3 PUFAs and their hydroxy precursors was evaluated by mass spectrometry in neutrophils isolated from healthy subjects, both at baseline and upon stimulation with calcium ionophore. For the clinical trial, participants were healthy adults 30–55 years of age with a reported EPA+DHA consumption of ≤300 mg/day randomly assigned to parallel groups receiving daily oil capsule supplements for a period of 4 months containing either 1.4 g of EPA+DHA (active condition, n = 24) or identical appearing soybean oil (control condition, n = 21). Participants and laboratory technicians remained blinded to treatment assignments. Results 5-lypoxygenase-dependent endogenous generation of 7-oxo-DHA, 7-oxo-DPA and 5-oxo-EPA and their hydroxy precursors is reported in human neutrophils stimulated with calcium ionophore and phorbol 12-myristate 13-acetate (PMA). Dietary EPA+DHA supplementation significantly increased the formation of 7-oxo-DHA and 5-oxo-EPA, with no significant modulation of arachidonic acid (AA) metabolite levels. Conclusions The endogenous detection of these electrophilic ω-3 fatty acid ketone derivatives supports the

  19. Copper-mediated deoxygenative trifluoromethylation of benzylic xanthates: generation of a C-CF(3) bond from an O-based electrophile.

    PubMed

    Zhu, Lingui; Liu, Shasha; Douglas, Justin T; Altman, Ryan A

    2013-09-16

    The conversion of an alcohol-based functional group, into a trifluoromethyl analogue is a desirable transformation. However, few methods are capable of converting O-based electrophiles into trifluoromethanes. The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto's reagent as the source of CF3 to form C-CF3 bonds is described. The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the C-CF3 bond forms by reaction of the substrate with in situ generated CuCF3 and CuOTf. Further evidence suggests that the reaction could proceed via a radical cation intermediate. PMID:23922222

  20. Chemoavailability of Organic Electrophiles: Impact of Hydrophobicity and Reactivity on Their Aquatic Excess Toxicity.

    PubMed

    Böhme, Alexander; Laqua, Anja; Schüürmann, Gerrit

    2016-06-20

    Organic electrophiles have been recognized as important components of the exposome that can be characterized as cumulative totality of exposure in the organism in response to environmental perturbation. For such compounds, chemical reactivity may contribute significantly to the toxicological profile through covalent attacks at nucleophilic sites of peptides such as glutathione (GSH), proteins, lipid components, and the DNA and RNA. Employing a Michael acceptor set of 58 α,β-unsaturated carbonyls with 15 ketones, 18 aldehydes, and 25 esters, the hydrophobicity and reactivity contributions to their toxicity enhancement Te over baseline narcosis with the ciliates Tetrahymena pyriformis is analyzed through a conceptual model, featuring toxicokinetic phase transfer steps and the reactive molecular initiating event (MIE) at endogenous target sites exposed to water-rich or water-poor compartments. To this end, hydrophobicity was quantified by the octanol/water partition coefficient, Kow, electrophilic reactivity through second-order rate constants of reaction with GSH in a kinetic chemoassay, kGSH, and Te as the ratio of narcosis-level vs experimental concentration yielding 50% growth inhibition of the ciliates within 48 h of exposure. The observed decrease of log Te with increasing log Kow can be traced back to a rate-determining impact of the toxicant transfer from the membrane to the intracellular cytosol. Moreover, the recently introduced concept of chemoavailability is shown to enable, from knowledge of log Kow and log kGSH alone, a screening-level discrimination between reactive and hydrophobic MIEs triggering predominantly alone or in parallel respective adverse outcome pathways (AOPs) including the diffusion-control limit of reactive MIE saturation. As such, chemoavailability may aid in evaluating prevalent MIEs expected for a given organic electrophile and in assessing its toxicological profile within AOP schemes addressing aquatic toxicity. PMID:27096880

  1. Nickel-Catalyzed Cross-Electrophile Coupling with Organic Reductants in Non-Amide Solvents.

    PubMed

    Anka-Lufford, Lukiana L; Huihui, Kierra M M; Gower, Nicholas J; Ackerman, Laura K G; Weix, Daniel J

    2016-08-01

    Cross-electrophile coupling of aryl halides with alkyl halides has thus far been primarily conducted with stoichiometric metallic reductants in amide solvents. This report demonstrates that the use of tetrakis(dimethylamino)ethylene (TDAE) as an organic reductant enables the use of non-amide solvents, such as acetonitrile or propylene oxide, for the coupling of benzyl chlorides and alkyl iodides with aryl halides. Furthermore, these conditions work for several electron-poor heterocycles that are easily reduced by manganese. Finally, we demonstrate that TDAE addition can be used as a control element to 'hold' a reaction without diminishing yield or catalyst activity. PMID:27273457

  2. Atom-efficient metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles.

    PubMed

    Pérez, I; Sestelo, J P; Sarandeses, L A

    2001-05-01

    The novel metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles is described. Triorganoindium compounds (R(3)In) containing alkyl, vinyl, aryl, and alkynyl groups are efficiently prepared from the corresponding lithium or magnesium organometallics by reaction with indium trichloride. The cross-coupling reaction of R(3)In with aryl halides and pseudohalides (iodide 2, bromide 5, and triflate 4), vinyl triflates, benzyl bromides, and acid chlorides proceeds under palladium catalysis in excellent yields and with high chemoselectivity. Indium organometallics also react with aryl chlorides as under nickel catalysis. In the cross-coupling reaction the triorganoindium compounds transfer, in a clear example of atom economy, all three of the organic groups attached to the metal, as shown by the necessity of using only 34 mol % of indium. The feasibility of using R(3)In in reactions with different electrophiles, along with the high yields and chemoselectivities obtained, reveals indium organometallics to be useful alternatives to other organometallics in cross-coupling reactions.

  3. Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver

    SciTech Connect

    Klaassen, Curtis D.; Reisman, Scott A.

    2010-04-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes. These gene products include proteins that catalyze reduction reactions (NAD(P)H:quinone oxidoreductase 1, Nqo1), conjugation reactions (glutathione-S-transferases, Gsts and UDP-glucuronosyltransferases, Ugts), as well as the efflux of potentially toxic xenobiotics and xenobiotic conjugates (multidrug resistance-associated proteins, Mrps). The significance of Nrf2 in the liver has been established, as livers of Nrf2-null mice are more susceptible to various oxidative/electrophilic stress-induced pathologies than wild-type mice. In contrast, both pharmacological and genetic models of hepatic Nrf2 activation are protective against oxidative/electrophilic stress. Furthermore, because certain Nrf2-target genes in the liver could affect the distribution, metabolism, and excretion of xenobiotics, the effects of Nrf2 on the kinetics of drugs and other xenobiotics should also be considered, with a special emphasis on metabolism and excretion. Therefore, this review highlights the research that has contributed to the understanding of the importance of Nrf2 in toxicodynamics and toxicokinetics, especially that which pertains to the liver.

  4. Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.

    PubMed

    Kuriyan, A E; Lehmann, G M; Kulkarni, A A; Woeller, C F; Feldon, S E; Hindman, H B; Sime, P J; Huxlin, K R; Phipps, R P

    2012-01-01

    A critical component of corneal scarring is the TGFβ-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-Δ(-12,14)-prostaglandin J(2) (15d-PGJ(2)) for inhibiting TGFβ-induced myofibroblast differentiation in vitro. TGFβ was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ(2) were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFβ-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ(2)) potently inhibited TGFβ-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ(2) are strong inhibitors of TGFβ-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.

  5. Protein damage from electrophiles and oxidants in lungs of mice chronically exposed to the tumor promoter butylated hydroxytoluene.

    PubMed

    Shearn, Colin T; Fritz, Kristofer S; Thompson, John A

    2011-07-15

    The food additive butylated hydroxytoluene (BHT) promotes tumorigenesis in mouse lung. Chronic BHT exposure is accompanied by pulmonary inflammation and several studies indicate that elevated levels of reactive oxygen species (ROS) are involved in its promoting activity. The link between BHT and elevated ROS involves formation of quinone methide (QM) metabolites; these electrophiles form adducts with a variety of lung proteins including several enzymes that protect cells from oxidative stress. Studies in vitro demonstrated that QM alkylation of cytoprotective enzymes is accompanied by inactivation, so an objective of the present investigation was to determine if inactivation also occurs in vivo. Two groups of mice were exposed to BHT by intraperitoneal injection, one for 10 days and the other for 24 days, and proteins from lung cytosols were examined for damage. Analysis by Western blotting demonstrated that BHT treatment caused substantial increases in protein carbonylation, nitration and adduction by 4-hydroxynonenal, confirming the occurrence of sustained oxidative and nitrosative stress over the treatment period required for tumor promotion. Effects of BHT on the activities and/or levels of a representative group of antioxidant/protective enzymes in mouse lung also were assessed; NAD(P)H:quinone reductase and glutathione reductase were unaffected, however carbonyl reductase activity decreased 50-60%. Superoxide dismutase and glutathione peroxidase activities increased 2- and 1.5-fold, respectively, and glutamate-cysteine ligase catalytic subunit expression increased 32-39% relative to untreated mice. Glutathione S-transferase (GST) activity decreased 50-60% but concentrations of the predominant isoforms, GSTM1 and P1, were not affected. GSTP1 was substantially more susceptible than M1 to adduction and inhibition by treatment with BHT-QM in vitro, suggesting that lower GST activity in mice after BHT treatment is due to adduction of the P1 isoform. The results of

  6. Organic Chemistry Students' Fragmented Ideas about the Structure and Function of Nucleophiles and Electrophiles: A Concept Map Analysis

    ERIC Educational Resources Information Center

    Anzovino, Mary E.; Bretz, Stacey Lowery

    2016-01-01

    Organic chemistry students struggle with multiple aspects of reaction mechanisms and the curved arrow notation used by organic chemists. Many faculty believe that an understanding of nucleophiles and electrophiles, among other concepts, is required before students can develop fluency with the electronpushing formalism (EPF). An expert concept map…

  7. Electrophilic acid gas-reactive fluid, proppant, and process for enhanced fracturing and recovery of energy producing materials

    DOEpatents

    Fernandez, Carlos A.; Heldebrant, David J.; Bonneville, Alain H. R.; Jung, Hun Bok; Carroll, Kenneth

    2016-09-20

    An electrophilic acid gas-reactive fracturing and recovery fluid, proppant, and process are detailed. The fluid expands in volume to provide rapid and controlled increases in pressure that enhances fracturing in subterranean bedrock for recovery of energy-producing materials. Proppants stabilize openings in fractures and fissures following fracturing.

  8. Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper–N-Heterocyclic Carbene Complex

    PubMed Central

    Cheng, Li-Jie; Cordier, Christopher J

    2015-01-01

    A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved. PMID:26403935

  9. Charge migration in dicationic electrophiles and its application to the synthesis of aza-polycyclic aromatic compounds.

    PubMed

    Li, Ang; Kindelin, Patrick J; Klumpp, Douglas A

    2006-03-16

    [reaction: see text] Superacid-promoted reactions of dicationic electrophiles have been studied, and the positive charge centers are found to migrate apart in a predictable manner. Using isotopic labeling the charge migration is found in one system to occur through successive deprotonation-reprotonation steps. The charge migration chemistry is the basis for new general synthetic route to aza-polycyclic aromatic compounds.

  10. Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper-N-Heterocyclic Carbene Complex.

    PubMed

    Cheng, Li-Jie; Cordier, Christopher J

    2015-11-01

    A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved. PMID:26403935

  11. Converting Homogeneous to Heterogeneous in Electrophilic Catalysis using Monodisperse Metal Nanoparticles

    SciTech Connect

    Witham, Cole A.; Huang, Wenyu; Tsung, Chia-Kuang; Kuhn, John N.; Somorjai, Gabor A.; Toste, F. Dean

    2009-10-15

    A continuing goal in catalysis is the transformation of processes from homogeneous to heterogeneous. To this end, nanoparticles represent a new frontier in heterogeneous catalysis, where this conversion is supplemented by the ability to obtain new or divergent reactivity and selectivity. We report a novel method for applying heterogeneous catalysts to known homogeneous catalytic reactions through the design and synthesis of electrophilic platinum nanoparticles. These nanoparticles are selectively oxidized by the hypervalent iodine species PhICl{sub 2}, and catalyze a range of {pi}-bond activation reactions previously only homogeneously catalyzed. Multiple experimental methods are utilized to unambiguously verify the heterogeneity of the catalytic process. The discovery of treatments for nanoparticles that induce the desired homogeneous catalytic activity should lead to the further development of reactions previously inaccessible in heterogeneous catalysis. Furthermore, our size and capping agent study revealed that Pt PAMAM dendrimer-capped nanoparticles demonstrate superior activity and recyclability compared to larger, polymer-capped analogues.

  12. Diverse Reactivity of an Electrophilic Phosphasilene towards Anionic Nucleophiles: Substitution or Metal-Amino Exchange.

    PubMed

    Willmes, Philipp; Junk, Lukas; Huch, Volker; Yildiz, Cem B; Scheschkewitz, David

    2016-08-26

    The reaction of MesLi (Mes=2,4,6-trimethylphenyl) with the electrophilic phosphasilene R2 (NMe2 )Si-RSi=PNMe2 (2, R=Tip=2,4,6-triisopropylphenyl) cleanly affords R2 (NMe2 )Si-RSi=PMes and thus provides the first example of a substitution reaction at an unperturbed Si=P bond. In toluene, the reaction of 2 with lithium disilenide, R2 Si=Si(R)Li (1), apparently proceeds via an initial nucleophilic substitution step as well (as suggested by DFT calculations), but affords a saturated bicyclo[1.1.0]butane analogue as the final product, which was further characterized as its Fe(CO)4 complex. In contrast, in 1,2-dimethoxyethane the reaction of 1 with 2 results in an unprecedented metal-amino exchange reaction. PMID:27509901

  13. Asymmetric Suzuki Cross-Couplings of Activated Secondary Alkyl Electrophiles: Arylations of Racemic α-Chloroamides

    PubMed Central

    Lundin, Pamela M.; Fu, Gregory C.

    2010-01-01

    A nickel-catalyzed stereoconvergent method for the enantioselective Suzuki arylation of racemic α-chloroamides has been developed. This process represents the first example of an asymmetric arylation of an α-haloamide, of an enantioselective arylation of an α-chlorocarbonyl compound, and of an asymmetric Suzuki reaction with an activated alkyl electrophile or an arylboron reagent. The method is also applicable to the corresponding enantioselective cross-coupling of α-bromoamides. The coupling products can be transformed without racemization into useful enantioenriched α-arylcarboxylic acids and primary alcohols. An unprecedented (and modest) kinetic resolution of the α-chloroamide has been observed; a mechanistic study indicates that the selectivity likely reflects the discrimination by the chiral catalyst of the two enantiomeric α-chloroamides in an irreversible oxidative-addition process. PMID:20698665

  14. Difluoromethanesulfonyl hypervalent iodonium ylides for electrophilic difluoromethylthiolation reactions under copper catalysis

    PubMed Central

    Arimori, Sadayuki; Matsubara, Okiya; Takada, Masahiro; Shiro, Motoo; Shibata, Norio

    2016-01-01

    Difluoromethanesulfonyl hypervalent iodonium ylides 2 were developed as electrophilic difluoromethylthiolation reagents for a wide range of nucleophiles. Enamines, indoles, β-keto esters, silyl enol ethers and pyrroles were effectively reacted with 2 affording desired difluoromethylthio (SCF2H)-substituted compounds in good to high yields under copper catalysis. The reaction of allyl alcohols with 2 under the same conditions provided difluoromethylsulfinyl (S(O)CF2H) products in good yields. The difluoromethylthiolation of enamines is particularly effective with wide generality, thus the enamine method was nicely extended to the synthesis of a series of difluoromethythiolated cyclic and acyclic β-keto esters, 1,3-diketones, pyrazole and pyrimidine derivatives by a consecutive, two-step one-pot reaction using 2. PMID:27293790

  15. Difluoromethanesulfonyl hypervalent iodonium ylides for electrophilic difluoromethylthiolation reactions under copper catalysis.

    PubMed

    Arimori, Sadayuki; Matsubara, Okiya; Takada, Masahiro; Shiro, Motoo; Shibata, Norio

    2016-05-01

    Difluoromethanesulfonyl hypervalent iodonium ylides 2 were developed as electrophilic difluoromethylthiolation reagents for a wide range of nucleophiles. Enamines, indoles, β-keto esters, silyl enol ethers and pyrroles were effectively reacted with 2 affording desired difluoromethylthio (SCF2H)-substituted compounds in good to high yields under copper catalysis. The reaction of allyl alcohols with 2 under the same conditions provided difluoromethylsulfinyl (S(O)CF2H) products in good yields. The difluoromethylthiolation of enamines is particularly effective with wide generality, thus the enamine method was nicely extended to the synthesis of a series of difluoromethythiolated cyclic and acyclic β-keto esters, 1,3-diketones, pyrazole and pyrimidine derivatives by a consecutive, two-step one-pot reaction using 2. PMID:27293790

  16. A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers.

    PubMed

    Avonto, Cristina; Chittiboyina, Amar G; Rua, Diego; Khan, Ikhlas A

    2015-12-01

    Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization, integrated approaches combining different chemical, biological and in silico methods are recommended to replace conventional animal tests. Chemical methods are intended to characterize the potential of a sensitizer to induce earlier molecular initiating events. The presence of an electrophilic mechanistic domain is considered one of the essential chemical features to covalently bind to the biological target and induce further haptenation processes. Current in chemico assays rely on the quantification of unreacted model nucleophiles after incubation with the candidate sensitizer. In the current study, a new fluorescence-based method, 'HTS-DCYA assay', is proposed. The assay aims at the identification of reactive electrophiles based on their chemical reactivity toward a model fluorescent thiol. The reaction workflow enabled the development of a High Throughput Screening (HTS) method to directly quantify the reaction adducts. The reaction conditions have been optimized to minimize solubility issues, oxidative side reactions and increase the throughput of the assay while minimizing the reaction time, which are common issues with existing methods. Thirty-six chemicals previously classified with LLNA, DPRA or KeratinoSens™ were tested as a proof of concept. Preliminary results gave an estimated 82% accuracy, 78% sensitivity, 90% specificity, comparable to other in chemico methods such as Cys-DPRA. In addition to validated chemicals, six natural products were analyzed and a prediction of their sensitization potential is presented for the first time.

  17. Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

    PubMed Central

    Awwad, Khader; Steinbrink, Svenja D.; Frömel, Timo; Lill, Nicole; Isaak, Johann; Häfner, Ann-Kathrin; Roos, Jessica; Hofmann, Bettina; Heide, Heinrich; Geisslinger, Gerd; Steinhilber, Dieter; Freeman, Bruce A.; Maier, Thorsten J.; Fleming, Ingrid

    2014-01-01

    Abstract Aims: The reaction of nitric oxide and nitrite-derived species with polyunsaturated fatty acids yields electrophilic fatty acid nitroalkene derivatives (NO2-FA), which display anti-inflammatory properties. Given that the 5-lipoxygenase (5-LO, ALOX5) possesses critical nucleophilic amino acids, which are potentially sensitive to electrophilic modifications, we determined the consequences of NO2-FA on 5-LO activity in vitro and on 5-LO-mediated inflammation in vivo. Results: Stimulation of human polymorphonuclear leukocytes (PMNL) with nitro-oleic (NO2-OA) or nitro-linoleic acid (NO2-LA) (but not the parent lipids) resulted in the concentration-dependent and irreversible inhibition of 5-LO activity. Similar effects were observed in cell lysates and using the recombinant human protein, indicating a direct reaction with 5-LO. NO2-FAs did not affect the activity of the platelet-type 12-LO (ALOX12) or 15-LO-1 (ALOX15) in intact cells or the recombinant protein. The NO2-FA-induced inhibition of 5-LO was attributed to the alkylation of Cys418, and the exchange of Cys418 to serine rendered 5-LO insensitive to NO2-FA. In vivo, the systemic administration of NO2-OA to mice decreased neutrophil and monocyte mobilization in response to lipopolysaccharide (LPS), attenuated the formation of the 5-LO product 5-hydroxyeicosatetraenoic acid (5-HETE), and inhibited lung injury. The administration of NO2-OA to 5-LO knockout mice had no effect on LPS-induced neutrophil or monocyte mobilization as well as on lung injury. Innovation: Prophylactic administration of NO2-OA to septic mice inhibits inflammation and promotes its resolution by interfering in 5-LO-mediated inflammatory processes. Conclusion: NO2-FAs directly and irreversibly inhibit 5-LO and attenuate downstream acute inflammatory responses. Antioxid. Redox Signal. 20, 2667–2680. PMID:24206143

  18. A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers.

    PubMed

    Avonto, Cristina; Chittiboyina, Amar G; Rua, Diego; Khan, Ikhlas A

    2015-12-01

    Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization, integrated approaches combining different chemical, biological and in silico methods are recommended to replace conventional animal tests. Chemical methods are intended to characterize the potential of a sensitizer to induce earlier molecular initiating events. The presence of an electrophilic mechanistic domain is considered one of the essential chemical features to covalently bind to the biological target and induce further haptenation processes. Current in chemico assays rely on the quantification of unreacted model nucleophiles after incubation with the candidate sensitizer. In the current study, a new fluorescence-based method, 'HTS-DCYA assay', is proposed. The assay aims at the identification of reactive electrophiles based on their chemical reactivity toward a model fluorescent thiol. The reaction workflow enabled the development of a High Throughput Screening (HTS) method to directly quantify the reaction adducts. The reaction conditions have been optimized to minimize solubility issues, oxidative side reactions and increase the throughput of the assay while minimizing the reaction time, which are common issues with existing methods. Thirty-six chemicals previously classified with LLNA, DPRA or KeratinoSens™ were tested as a proof of concept. Preliminary results gave an estimated 82% accuracy, 78% sensitivity, 90% specificity, comparable to other in chemico methods such as Cys-DPRA. In addition to validated chemicals, six natural products were analyzed and a prediction of their sensitization potential is presented for the first time. PMID:26455772

  19. Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2

    PubMed Central

    Ma, Qiang; He, Xiaoqing

    2015-01-01

    Induction of drug-metabolizing enzymes through the antioxidant response element (ARE)-dependent transcription was initially implicated in chemoprevention against cancer by antioxidants. Recent progress in understanding the biology and mechanism of induction revealed a critical role of induction in cellular defense against electrophilic and oxidative stress. Induction is mediated through a novel signaling pathway via two regulatory proteins, the nuclear factor erythroid 2-related factor 2 (Nrf2) and the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1). Nrf2 binds to Keap1 at a two site-binding interface and is ubiquitinated by the Keap1/cullin 3/ring box protein-1-ubiquitin ligase, resulting in a rapid turnover of Nrf2 protein. Electrophiles and oxidants modify critical cysteine thiols of Keap1 and Nrf2 to inhibit Nrf2 ubiquitination, leading to Nrf2 activation and induction. Induction increases stress resistance critical for cell survival, because knockout of Nrf2 in mice increased susceptibility to a variety of toxicity and disease processes. Collateral to diverse functions of Nrf2, genome-wide search has led to the identification of a plethora of ARE-dependent genes regulated by Nrf2 in an inducer-, tissue-, and disease-dependent manner to control drug metabolism, antioxidant defense, stress response, proteasomal degradation, and cell proliferation. The protective nature of Nrf2 could also be hijacked in a number of pathological conditions by means of somatic mutation, epigenetic alteration, and accumulation of disruptor proteins, promoting drug resistance in cancer and pathologic liver features in autophagy deficiency. The repertoire of ARE inducers has expanded enormously; the therapeutic potential of the inducers has been examined beyond cancer prevention. Developing potent and specific ARE inducers and Nrf2 inhibitors holds certain new promise for the prevention and therapy against cancer, chronic disease, and toxicity

  20. Chiral fluorinated α-sulfonyl carbanions: enantioselective synthesis and electrophilic capture, racemization dynamics, and structure.

    PubMed

    Hellmann, Gunther; Hack, Achim; Thiemermann, Eric; Luche, Olaf; Raabe, Gerhard; Gais, Hans-Joachim

    2013-03-18

    Enantiomerically pure triflones R(1) CH(R(2) )SO2 CF3 have been synthesized starting from the corresponding chiral alcohols via thiols and trifluoromethylsulfanes. Key steps of the syntheses of the sulfanes are the photochemical trifluoromethylation of the thiols with CF3 Hal (Hal=halide) or substitution of alkoxyphosphinediamines with CF3 SSCF3 . The deprotonation of RCH(Me)SO2 CF3 (R=CH2 Ph, iHex) with nBuLi with the formation of salts [RC(Me)SO2 CF3 ]Li and their electrophilic capture both occurred with high enantioselectivities. Displacement of the SO2 CF3 group of (S)-MeOCH2 C(Me)(CH2 Ph)SO2 CF3 (95 % ee) by an ethyl group through the reaction with AlEt3 gave alkane MeOCH2 C(Me)(CH2 Ph)Et of 96 % ee. Racemization of salts [R(1) C(R(2) )SO2 CF3 ]Li follows first-order kinetics and is mainly an enthalpic process with small negative activation entropy as revealed by polarimetry and dynamic NMR (DNMR) spectroscopy. This is in accordance with a Cα S bond rotation as the rate-determining step. Lithium α-(S)-trifluoromethyl- and α-(S)-nonafluorobutylsulfonyl carbanion salts have a much higher racemization barrier than the corresponding α-(S)-tert-butylsulfonyl carbanion salts. Whereas [PhCH2 C(Me)SO2 tBu]Li/DMPU (DMPU = dimethylpropylurea) has a half-life of racemization at -105 °C of 2.4 h, that of [PhCH2 C(Me)SO2 CF3 ]Li at -78 °C is 30 d. DNMR spectroscopy of amides (PhCH2 )2 NSO2 CF3 and (PhCH2 )N(Ph)SO2 CF3 gave NS rotational barriers that seem to be distinctly higher than those of nonfluorinated sulfonamides. NMR spectroscopy of [PhCH2 C(Ph)SO2 R]M (M=Li, K, NBu4 ; R=CF3 , tBu) shows for both salts a confinement of the negative charge mainly to the Cα atom and a significant benzylic stabilization that is weaker in the trifluoromethylsulfonyl carbanion. According to crystal structure analyses, the carbanions of salts {[PhCH2 C(Ph)SO2 CF3 ]Li⋅L}2 (L=2 THF, tetramethylethylenediamine (TMEDA)) and [PhCH2 C(Ph)SO2 CF3 ]NBu4 have

  1. Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions.

    PubMed

    Galabov, Boris; Nalbantova, Didi; Schleyer, Paul von R; Schaefer, Henry F

    2016-06-21

    The classic SEAr mechanism of electrophilic aromatic substitution (EAS) reactions described in textbooks, monographs, and reviews comprises the obligatory formation of arenium ion intermediates (σ complexes) in a two-stage process. Our findings from several studies of EAS reactions challenge the generality of this mechanistic paradigm. This Account focuses on recent computational and experimental results for three types of EAS reactions: halogenation with molecular chlorine and bromine, nitration by mixed acid (mixture of nitric and sulfuric acids), and sulfonation with SO3. Our combined computational and experimental investigation of the chlorination of anisole with molecular chlorine in CCl4 found that addition-elimination pathways compete with the direct substitution processes. Detailed NMR investigation of the course of experimental anisole chlorination at varying temperatures revealed the formation of addition byproducts. Moreover, in the absence of Lewis acid catalysis, the direct halogenation processes do not involve arenium ion intermediates but instead proceed via concerted single transition states. We also obtained analogous results for the chlorination and bromination of several arenes in nonpolar solvents. We explored by theoretical computations and experimental spectroscopic studies the classic reaction of benzene nitration by mixed acid. The structure of the first intermediate in this process has been a subject of contradicting views. We have reported clear experimental UV/vis spectroscopic evidence for the formation of the first intermediate in this reaction. Our broader theoretical modeling of the process considers the effects of the medium as a bulk solvent but also the specific interactions of a H2SO4 solvent molecule with intermediates and transition states along the reaction path. In harmony with the obtained spectroscopic data, our computational results reveal that the structure of the initial π complex precludes the possibility of electronic

  2. Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions.

    PubMed

    Galabov, Boris; Nalbantova, Didi; Schleyer, Paul von R; Schaefer, Henry F

    2016-06-21

    The classic SEAr mechanism of electrophilic aromatic substitution (EAS) reactions described in textbooks, monographs, and reviews comprises the obligatory formation of arenium ion intermediates (σ complexes) in a two-stage process. Our findings from several studies of EAS reactions challenge the generality of this mechanistic paradigm. This Account focuses on recent computational and experimental results for three types of EAS reactions: halogenation with molecular chlorine and bromine, nitration by mixed acid (mixture of nitric and sulfuric acids), and sulfonation with SO3. Our combined computational and experimental investigation of the chlorination of anisole with molecular chlorine in CCl4 found that addition-elimination pathways compete with the direct substitution processes. Detailed NMR investigation of the course of experimental anisole chlorination at varying temperatures revealed the formation of addition byproducts. Moreover, in the absence of Lewis acid catalysis, the direct halogenation processes do not involve arenium ion intermediates but instead proceed via concerted single transition states. We also obtained analogous results for the chlorination and bromination of several arenes in nonpolar solvents. We explored by theoretical computations and experimental spectroscopic studies the classic reaction of benzene nitration by mixed acid. The structure of the first intermediate in this process has been a subject of contradicting views. We have reported clear experimental UV/vis spectroscopic evidence for the formation of the first intermediate in this reaction. Our broader theoretical modeling of the process considers the effects of the medium as a bulk solvent but also the specific interactions of a H2SO4 solvent molecule with intermediates and transition states along the reaction path. In harmony with the obtained spectroscopic data, our computational results reveal that the structure of the initial π complex precludes the possibility of electronic

  3. Environment and Primary Biliary Cirrhosis: Electrophilic Drugs and the Induction of AMA

    PubMed Central

    Leung, Patrick S.C.; Wang, Jinjun; Naiyanetr, Phornnop; Kenny, Thomas P.; Lam, Kit S.; Kurth, Mark J.; Gershwin, M. Eric

    2013-01-01

    Environmental stimulation is a major factor in the initiation and perpetuation of autoimmune diseases. We have addressed this issue and focused on primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Immunologically, PBC is distinguished by immune mediated destruction of the intra hepatic bile ducts and the presence of high titer antimitochondrial autoantibodies (AMA) directed against a highly specific epitope within the lipoic acid binding domain of the pyruvate dehydrogenase E2 subunit (PDC-E2). We submit that the uniqueness of AMA epitope specificity and the conformational changes of the PDC-E2 lipoyl domain during physiological acyl transfer could be the lynchpin to the etiology of PBC and postulate that chemical xenobiotics modification of the lipoyl domain of PDC-E2 is sufficient to break self-tolerance, with subsequent production of AMA in patients with PBC. Indeed, using quantitative structure activity relationship (QSAR) analysis on a peptide-xenobiotic conjugate microarray platform, we have demonstrated that when the lipoyl domain of PDC-E2 was modified with specific synthetic small molecule lipoyl mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native PDC-E2 molecule. Hereby, we discuss our recent QSAR analysis data on specific AMA reactivity against a focused panel of lipoic acid mimic in which the lipoyl di-sulfide bond are modified. Furthermore, data on the immunological characterization of antigen and Ig isotype specificities against one such lipoic acid mimic; 6,8-bis(acetylthio)octanoic acid (SAc), when compared with rPDC-E2, strongly support a xenobiotic etiology in PBC. This observation is of particular significance in that approximately one third of patients who have taken excessive acetaminophen (APAP) developed AMA with same specificity as patients with PBC, suggesting that the lipoic domain are a target of APAP electrophilic metabolites such as NAPQI. We submit

  4. Hydrogen-bond-driven electrophilic activation for selectivity control: scope and limitations of fluorous alcohol-promoted selective formation of 1,2-disubstituted benzimidazoles and mechanistic insight for rationale of selectivity.

    PubMed

    Chebolu, Rajesh; Kommi, Damodara N; Kumar, Dinesh; Bollineni, Narendra; Chakraborti, Asit K

    2012-11-16

    Hydrogen-bond-driven electrophilic activation for selectivity control during competitive formation of 1,2-disubstituted and 2-substituted benzimidazoles from o-phenylenediamine and aldehydes is reported. The fluorous alcohols trifluoroethanol and hexafluoro-2-propanol efficiently promote the cyclocondensation of o-phenylenediamine with aldehydes to afford selectively the 1,2-disubstituted benzimidazoles at rt in short times. A mechanistic insight is invoked by NMR, mass spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.

  5. Synthesis of α-trifluoromethyl ketones via the Cu-catalyzed trifluoromethylation of silyl enol ethers using an electrophilic trifluoromethylating agent.

    PubMed

    Li, Lun; Chen, Qing-Yun; Guo, Yong

    2014-06-01

    A method has been developed for the synthesis of α-trifluoromethyl ketones via the Cu-catalyzed trifluoromethylation of silyl enol ethers with an electrophilic trifluoromethylating agent, which produces a trifluoromethyl radical.

  6. Recent highlights in electrophilic fluorination with 1-chloromethyl-4-fluoro- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).

    PubMed

    Singh, Rajendra P; Shreeve, Jean'ne M

    2004-01-01

    Synthetic and structural aspects of organofluorine compounds continue to be the focal points of vigorous research activities, as evidenced by the appearance of a large number of publications. Among the various useful methodologies for the introduction of fluorine into organic molecules, electrophilic fluorination is a promising and exciting area of research. While a variety of electrophilic fluorinating reagents are available, currently 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) provides a remarkably straightforward and effective route. The breadth of applications realizable from this reagent in its role as a key electrophilic fluorinating reagent is highlighted here. This Account covers the literature for electrophilic fluorination reactions that employ Selectfluor during the period January 1999-January 2003.

  7. Trapping of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles: Controlling the formation of α-amino quaternary and vicinal stereocenters.

    PubMed

    Beng, Timothy K; Fox, Nathan; Bassler, Daniel P; Alwali, Amir; Sincavage, Kayla; Silaire, Ann Wens V

    2015-08-28

    The interception of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles, under HMPA-mediated conditions, has led to the diastereoselective synthesis of vicinally functionalized piperidines bearing α-amino quaternary stereocenters.

  8. Nitrated Fatty Acids Reverse Cigarette Smoke-Induced Alveolar Macrophage Activation and Inhibit Protease Activity via Electrophilic S-Alkylation

    PubMed Central

    Reddy, Aravind T.; Lakshmi, Sowmya P.; Muchumarri, Ramamohan R.; Reddy, Raju C.

    2016-01-01

    Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO-derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities. They are both reversible electrophiles and peroxisome proliferator-activated receptor γ (PPARγ) agonists, but the physiological implications of their electrophilic activity are poorly understood. We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice. NFA (10-nitro-oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-κB while upregulating those of PPARγ. It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction. Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction. NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPARγ knockout mice, pointing to a PPARγ-independent mechanism of enzyme inhibition. We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S-alkylation of Cys25 when incubated with purified Cat S. These results demonstrate that NFAs’ electrophilic activity, in addition to their role as PPARγ agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease. PMID:27119365

  9. Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)

    PubMed Central

    2015-01-01

    Undesirable side effects associated with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R negative allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochemical characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust positive allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs. PMID:26529344

  10. Electrophilic iodination: a gateway to high iodine compounds and energetic materials.

    PubMed

    Chand, Deepak; He, Chunlin; Mitchell, Lauren A; Parrish, Damon A; Shreeve, Jean'ne M

    2016-09-21

    A large number of iodine atoms can be introduced into a single molecule in a one-pot reaction using trifluoroperacetic acid-mediated electrophilic iodination methodology. The scope of this reaction was investigated extensively using several pyrazole substrates which resulted in nine polyiodo pyrazole compounds with iodine content as high as 80%. This synthetic methodology was also utilized successfully for iodination of benzimidazoles. Tetraiodobenzimidazole was nitrated with 100% nitric acid to give a high yield of 4,5,6,7-tetranitro-1H-benzimidazol-2(3H)-one (14). All of these materials were fully characterized and compounds 5, 9, 10 and 14 were confirmed further with single crystal X-ray analysis. High density, positive oxygen balance, and very good impact sensitivity values characterize 14. For the first time, two 1,2,5-oxadiazole-N-oxide rings were introduced into a benzimidazole ring (11) which remarkably improves the stability of oxadiazole-N-oxide compounds. PMID:27510578

  11. S3S63 Terminal Ynamides: Synthesis, Coupling Reactions and Additions to Common Electrophiles

    PubMed Central

    Cook, Andrea M.

    2015-01-01

    Ynamides consist of a polarized triple bond that is directly attached to a nitrogen atom carrying a sulfonyl, an alkoxycarbonyl, an acyl or another electron withdrawing group. The triple bond polarization renders ynamides broadly useful building blocks with synthetic opportunities that go far beyond traditional alkyne chemistry. The versatile reactivity of ynamides in cycloadditions, cycloisomerizations, regioselective additions with various nucleophiles or electrophiles, ring-closing metathesis, and many other reactions has been investigated in detail during the past decades. A common feature of these methods is that the triple bond is consumed and either cleaved or transformed to a new functionality. The wealth of reports on these ynamide reactions is in stark contrast to the dearth of carbon-carbon bond formations that leave the triple bond of terminal ynamides intact. The recent introduction of effective synthetic methods for the preparation of terminal ynamides has set the stage to fully explore the synthetic potential of this intriguing class of compounds. This digest letter summarizes the most effective routes to terminal ynamides and the current state of selective nucleophilic addition, substitution and coupling reactions, including the first examples of asymmetric synthesis. PMID:26085692

  12. Converting homogeneous to heterogeneous in electrophilic catalysis using monodisperse metal nanoparticles.

    PubMed

    Witham, Cole A; Huang, Wenyu; Tsung, Chia-Kuang; Kuhn, John N; Somorjai, Gabor A; Toste, F Dean

    2010-01-01

    A continuing goal in catalysis is to unite the advantages of homogeneous and heterogeneous catalytic processes. To this end, nanoparticles represent a new frontier in heterogeneous catalysis, where this unification can also be supplemented by the ability to obtain new or divergent reactivity and selectivity. We report a novel method for applying heterogeneous catalysts to known homogeneous catalytic reactions through the design and synthesis of electrophilic platinum nanoparticles. These nanoparticles are selectively oxidized by the hypervalent iodine species PhICl(2), and catalyse a range of π-bond activation reactions previously only catalysed through homogeneous processes. Multiple experimental methods are used to unambiguously verify the heterogeneity of the catalytic process. The discovery of treatments for nanoparticles that induce the desired homogeneous catalytic activity should lead to the further development of reactions previously inaccessible in heterogeneous catalysis. Furthermore, a size and capping agent study revealed that Pt PAMAM dendrimer-capped nanoparticles demonstrate superior activity and recyclability compared with larger, polymer-capped analogues.

  13. Converting homogeneous to heterogeneous in electrophilic catalysis using monodisperse metal nanoparticles

    NASA Astrophysics Data System (ADS)

    Witham, Cole A.; Huang, Wenyu; Tsung, Chia-Kuang; Kuhn, John N.; Somorjai, Gabor A.; Toste, F. Dean

    2010-01-01

    A continuing goal in catalysis is to unite the advantages of homogeneous and heterogeneous catalytic processes. To this end, nanoparticles represent a new frontier in heterogeneous catalysis, where this unification can also be supplemented by the ability to obtain new or divergent reactivity and selectivity. We report a novel method for applying heterogeneous catalysts to known homogeneous catalytic reactions through the design and synthesis of electrophilic platinum nanoparticles. These nanoparticles are selectively oxidized by the hypervalent iodine species PhICl2, and catalyse a range of π-bond activation reactions previously only catalysed through homogeneous processes. Multiple experimental methods are used to unambiguously verify the heterogeneity of the catalytic process. The discovery of treatments for nanoparticles that induce the desired homogeneous catalytic activity should lead to the further development of reactions previously inaccessible in heterogeneous catalysis. Furthermore, a size and capping agent study revealed that Pt PAMAM dendrimer-capped nanoparticles demonstrate superior activity and recyclability compared with larger, polymer-capped analogues.

  14. Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury.

    PubMed

    Cao, Zhuoxiao; Li, Yunbo

    2004-04-01

    Resveratrol is known to be protective against oxidative cardiovascular disorders. However, the underlying mechanisms remain unclear. This study was undertaken to determine if resveratrol could increase endogenous antioxidants and phase 2 enzymes in cardiomyocytes, and if such increased cellular defenses could provide protection against oxidative and electrophilic cell injury. Incubation of cardiac H9C2 cells with low micromolar resveratrol resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. To investigate the protective effects of the resveratrol-induced cellular defenses on oxidative and electrophilic cell injury, H9C2 cells were first incubated with resveratrol, and then exposed to xanthine oxidase (XO)/xanthine, 4-hydroxy-2-nonenal or doxorubicin. We observed that resveratrol pretreatment afforded a marked protection against the above agent-mediated cytotoxicity in H9C2 cells. Moreover, the resveratrol pretreatment led to a great reduction in XO/xanthine-induced intracellular accumulation of ROS. Taken together, this study demonstrates that resveratrol induces antioxidants and phase 2 enzymes in cardiomyocytes, which is accompanied by increased resistance to oxidative and electrophilic cell injury.

  15. Negatively charged Ir(iii) cyclometalated complexes containing a chelating bis-tetrazolato ligand: synthesis, photophysics and the study of reactivity with electrophiles.

    PubMed

    Fiorini, Valentina; Zacchini, Stefano; Raiteri, Paolo; Mazzoni, Rita; Zanotti, Valerio; Massi, Massimiliano; Stagni, Stefano

    2016-08-01

    The bis-tetrazolate dianion [1,2 BTB](2-), which is the deprotonated form of 1,2 bis-(1H-tetrazol-5-yl)benzene [1,2-H2BTB], is for the first time exploited as an ancillary N^N ligand for negatively charged [Ir(C^N)2(N^N)](-)-type complexes, where C^N is represented by cyclometalated 2-phenylpyridine (ppy) or 2-(2,4-difluorophenyl)pyridine (F2ppy). The new Ir(iii) complexes [Ir(ppy)2(1,2 BTB)]- and [Ir(F2ppy)2(1,2 BTB)]- have been fully characterised and the analysis of the X-ray structure of [Ir(ppy)2(1,2 BTB)]- confirmed the coordination of the [1,2 BTB](2-) dianion in a bis chelated fashion through the N-atoms adjacent to each of the tetrazolic carbons. Both of the new anionic Ir(iii) complexes displayed phosphorescence in the visible region, with intense sky-blue (λmax = 460-490 nm) or aqua (λmax = 490-520 nm) emissions originating from [Ir(F2ppy)2(1,2 BTB)]- and [Ir(ppy)2(1,2 BTB)]-, respectively. In comparison with our very recent examples of anionic Ir(iii)tetrazolate cyclometalates, the new Ir(iii) tris chelate complexes [Ir(F2ppy)2(1,2 BTB)]- and [Ir(ppy)2(1,2 BTB)]-, display an improved robustness, allowing the study of their reactivity toward the addition of electrophiles such as H(+) and CH3(+). In all cases, the electrophilic attacks occurred at the coordinated tetrazolate rings, involving the reversible - by a protonation deprotonation mechanism - or permanent - upon addition of a methyl moiety - switching of their global net charge from negative to positive and, in particular, the concomitant variation of their photoluminescence output. The combination of the anionic complexes [Ir(F2ppy)2(1,2 BTB)]- or [Ir(ppy)2(1,2 BTB)]- with a deep red emitting (λmax = 686 nm) cationic Ir(iii) tetrazole complex such as [IrTPYZ-Me]+, where TPYZ-Me is 2-(2-methyl-2H-tetrazol-5-yl)pyrazine, gave rise to two fully Ir(iii)-based soft salts capable of displaying additive and O2-sensitive emission colours, with an almost pure white light obtained by the appropriate

  16. Novel oxidative electrophilic coupling reactions of phenoxazine derivatives with MBTH and their applications to spectrophotometric determination of residual chlorine in drinking water and environmental water samples.

    PubMed

    Al-Okab, Riyad Ahmed; Syed, Akheel Ahmed

    2009-10-15

    Novel, sensitive and rapid spectrophotometric methods, using phenoxazine (PNZ), 2-chlorophe-noxazine (CPN) and 2-trifluoromethylphenoxazine (TPN) as chromogenic reagents for the determination of residual chlorine are proposed. The methods are based on the reduction of chlorine by an electrophilic coupling reagent, 3-methyl-2-benzothiazoline hydrazono hydrochloride hydrate (MBTH) in mild hydrochloric acid medium and subsequent coupling with PNZ, CPN or TPN. The blue color formed in the reaction showed maximum absorbance at 680-690 nm and obeyed Beer's law over the range 0.1-2.2 microg ml(-1). The molar absorptivity values with PNZ, CPN and TPN were 2.80 x 10(4), 2.67 x 10(4) and 1.91 x 10(4) l mol(-1)cm(-1) and Sandell's sensitivity values were 0.028, 0.027 and 0.028 microg cm(-2) respectively. The proposed methods were successfully applied in the determination of residual chlorine in drinking water and environmental water samples. The performance of proposed methods was evaluated in terms of Student's t-test and variance ratio F-test which indicated the significance of proposed methods over the standard spectrophotometric method.

  17. Where does the electron go? The nature of ortho/para and meta group directing in electrophilic aromatic substitution

    SciTech Connect

    Liu, Shubin

    2014-11-21

    Electrophilic aromatic substitution as one of the most fundamental chemical processes is affected by atoms or groups already attached to the aromatic ring. The groups that promote substitution at the ortho/para or meta positions are, respectively, called ortho/para and meta directing groups, which are often characterized by their capability to donate electrons to or withdraw electrons from the ring. Though resonance and inductive effects have been employed in textbooks to explain this phenomenon, no satisfactory quantitative interpretation is available in the literature. Here, based on the theoretical framework we recently established in density functional reactivity theory (DFRT), where electrophilicity and nucleophilicity are simultaneously quantified by the Hirshfeld charge, the nature of ortho/para and meta group directing is systematically investigated for a total of 85 systems. We find that regioselectivity of electrophilic attacks is determined by the Hirshfeld charge distribution on the aromatic ring. Ortho/para directing groups have most negative charges on the ortho/para positions, while meta directing groups often possess the largest negative charge on the meta position. Our results do not support that ortho/para directing groups are electron donors and meta directing groups are electron acceptors. Most neutral species we studied here are electron withdrawal in nature. Anionic systems are always electron donors. There are also electron donors serving as meta directing groups. We predicted ortho/para and meta group directing behaviors for a list of groups whose regioselectivity is previously unknown. In addition, strong linear correlations between the Hirshfeld charge and the highest occupied molecular orbital have been observed, providing the first link between the frontier molecular orbital theory and DFRT.

  18. Tissue sensitivity of the rat upper and lower extrapulmonary airways to the inhaled electrophilic air pollutants diacetyl and acrolein.

    PubMed

    Cichocki, Joseph A; Smith, Gregory J; Morris, John B

    2014-11-01

    The target site for inhaled vapor-induced injury often differs in mouth-breathing humans compared with nose-breathing rats, thus complicating the use of rat inhalation toxicity data for assessment of human risk. We sought to examine sensitivity of respiratory/transitional nasal (RTM) and tracheobronchial (TBM) mucosa to two electrophilic irritant vapors: diacetyl and acrolein. Computational fluid dynamic physiologically based pharmacokinetic modeling was coupled with biomarker assessment to establish delivered dose-response relationships in RTM and TBM in male F344 rats following 6 h exposure to diacetyl or acrolein. Biomarkers included glutathione status, proinflammatory and antioxidant gene mRNA levels, and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Modeling revealed that 0.0094-0.1653 μg acrolein/min-cm(2) and 3.9-21.6 μg diacetyl/min-cm(2) were deposited into RTM/TBM. Results indicate RTM and TBM were generally of similar sensitivity to diacetyl and acrolein. For instance, both tissues displayed induction of antioxidant and proinflammatory genes, and nuclear accumulation of Nrf2 after electrophile exposure. Hierarchical cellular response patterns were similar in RTM and TBM but differed between vapors. Specifically, diacetyl exposure induced proinflammatory and antioxidant genes concomitantly at low exposure levels, whereas acrolein induced antioxidant genes at much lower exposure levels than that required to induce proinflammatory genes. Generally, diacetyl was less potent than acrolein, as measured by maximal induction of transcripts. In conclusion, the upper and lower extrapulmonary airways are of similar sensitivity to inhaled electrophilic vapors. Dosimetrically based extrapolation of nasal responses in nose-breathing rodents may provide an approach to predict risk to the lower airways of humans during mouth-breathing.

  19. Tandem buildup of complexity of aromatic molecules through multiple successive electrophile generation in one pot, controlled by varying the reaction temperature.

    PubMed

    Sumita, Akinari; Otani, Yuko; Ohwada, Tomohiko

    2016-02-01

    While some sequential electrophilic aromatic substitution reactions, known as tandem/domino/cascade reactions, have been reported for the construction of aromatic single skeletons, one of the most interesting and challenging possibilities remains the one-pot build-up of a complex aromatic molecule from multiple starting components, i.e., ultimately multi-component electrophilic aromatic substitution reactions. In this work, we show how tuning of the leaving group ability of phenolate derivatives from carbamates and esters provides a way to successively generate multiple unmasked electrophiles in a controlled manner in one pot, simply by varying the temperature. Here, we demonstrate the autonomous formation of up to three bonds in one pot and formation of two bonds arising from a three-component electrophilic aromatic substitution reaction. This result provides a proof-of-concept of our strategy applicable for the self-directed construction of complex aromatic structures from multiple simple molecules, which can be a potential avenue to realize multi-component electrophilic aromatic substitution reactions.

  20. Comparison of electrophilic amination reagents for N-amination of 2-oxazolidinones and application to synthesis of chiral hydrazones.

    PubMed

    Shen, Yuehai; Friestad, Gregory K

    2002-08-23

    Comparison of several hydroxylamine-based electrophilic ammonia equivalents in the N-amination of 2-oxazolidinones revealed that O-(p-nitrobenzoyl)hydroxylamine (NbzONH(2)) and sodium hydride in dioxane is a superior reagent combination for this purpose. Practical preparations of a variety of chiral N-acylhydrazones by this method gave yields ranging from 45 to 95%. Methods for exchange or removal of the aldehyde component have been developed, making this a general route to chiral N-acylhydrazones of interest for asymmetric synthesis applications. PMID:12182669

  1. An Umpolung Strategy for the Synthesis of β-Aminoketones via Copper-Catalyzed Electrophilic Amination of Cyclopropanols.

    PubMed

    Ye, Zhishi; Dai, Mingji

    2015-05-01

    A novel copper-catalyzed electrophilic amination of cyclopropanols with O-benzoyl-N,N-dialkylhydroxylamines to synthesize various β-aminoketones via a sequence that includes C-C bond cleavage and Csp(3)-N bond formation is reported. The reaction conditions are mild and tolerate a wide range of functional groups including benzoate, tosylate, expoxide, and α,β-unsaturated carbonyls, which are incompatible in the traditional amine nucleophilic conjugate addition and the Mannich reaction conditions. Preliminary mechanistic studies and a proposed catalytic cycle of this umpolung β-aminoketone synthesis process have been described as well. PMID:25885943

  2. An Umpolung Strategy for the Synthesis of β-Aminoketones via Copper-Catalyzed Electrophilic Amination of Cyclopropanols.

    PubMed

    Ye, Zhishi; Dai, Mingji

    2015-05-01

    A novel copper-catalyzed electrophilic amination of cyclopropanols with O-benzoyl-N,N-dialkylhydroxylamines to synthesize various β-aminoketones via a sequence that includes C-C bond cleavage and Csp(3)-N bond formation is reported. The reaction conditions are mild and tolerate a wide range of functional groups including benzoate, tosylate, expoxide, and α,β-unsaturated carbonyls, which are incompatible in the traditional amine nucleophilic conjugate addition and the Mannich reaction conditions. Preliminary mechanistic studies and a proposed catalytic cycle of this umpolung β-aminoketone synthesis process have been described as well.

  3. Direct catalytic trifluoromethylthiolation of boronic acids and alkynes employing electrophilic shelf-stable N-(trifluoromethylthio)phthalimide.

    PubMed

    Pluta, Roman; Nikolaienko, Pavlo; Rueping, Magnus

    2014-02-01

    A new and safe method for the synthesis of N-(trifluoromethylthio)phthalimide, a convenient and shelf-stable reagent for the direct trifluoromethylthiolation, has been developed. N-(Trifluoromethylthio)phthalimide can be used as an electrophilic source of F3 CS(+) and reacts readily with boronic acids and alkynes under copper catalysis. The utility of CF3 S-containing molecules as biologically active agents, the mild reaction conditions employed, and the high tolerance of functional groups demonstrate the potential of this new methodology to be widely applied in organic synthesis as well as industrial pharmaceutical and agrochemical research and development. PMID:24449094

  4. Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling.

    PubMed

    Zhang, Patricia; Le, Chi Chip; MacMillan, David W C

    2016-07-01

    A strategy for cross-electrophile coupling has been developed via the merger of photoredox and transition metal catalysis. In this report, we demonstrate the use of commercially available tris(trimethylsilyl)silane with metallaphotoredox catalysis to efficiently couple alkyl bromides with aryl or heteroaryl bromides in excellent yields. We hypothesize that a photocatalytically generated silyl radical species can perform halogen-atom abstraction to activate alkyl halides as nucleophilic cross-coupling partners. This protocol allows the use of mild yet robust conditions to construct Csp(3)-Csp(2) bonds generically via a unique cross-coupling pathway. PMID:27263662

  5. Mechanism and Thermodynamics of Reductive Cleavage of Carbon-Halogen Bonds in the Polybrominated Aliphatic Electrophiles.

    PubMed

    Rosokha, Sergiy V; Lukacs, Emoke; Ritzert, Jeremy T; Wasilewski, Adam

    2016-03-17

    Quantum-mechanical computations revealed that, despite the presence of electron-withdrawing and/or π-acceptor substituents, the lowest unoccupied molecular orbitals (LUMO) of the polybromosubstituted aliphatic molecules R-Br (R-Br = C3Br2F6, CBr3NO2, CBr3CN, CBr3CONH2, CBr3CO2H, CHBr3, CFBr3, CBr4, CBr3COCBr3) are delocalized mostly over their bromine-containing fragments. The singly occupied molecular orbitals in the corresponding vertically excited anion radicals (R-Br(•-))* are characterized by essentially the same shapes and show nodes in the middle of the C-Br bonds. An injection of an electron into the antibonding LUMO results in the barrierless dissociation of the anion-radical species and the concerted reductive cleavages of C-Br bonds leading to the formation of the loosely bonded {R(•)···Br(-)} associates. The interaction energies between the fragments of these ion-radical pairs vary from ∼10 to 20 kcal mol(-1) in the gas phase and from 1 to 3 kcal mol(-1) in acetonitrile. In accord with the concerted mechanism of reductive cleavage, all R-Br molecules showed completely irreversible reduction waves in the voltammograms in the whole range of the scan rates employed (from 0.05 to 5 V s(-1)). Also, the transfer coefficients α, established from the width of these waves and dependence of reduction peak potentials Ep on the scan rates, were significantly lower than 0.5. The standard reduction potentials of the R-Br electrophiles, E(o)R-Br/R·+X(-), and the corresponding R(•) radicals, E(o)R(•)/R(-), were calculated in acetonitrile using the appropriate thermodynamic cycles. In agreement with these calculations, which indicated that the R(•) radicals resulting from the reductive cleavage of the R-Br molecules are stronger oxidants than their parents, the reduction peaks' currents in cyclic voltammograms were consistent with the two-electron transfer processes. PMID:26816138

  6. Access to novel fluorovinylidene ligands via exploitation of outer-sphere electrophilic fluorination: new insights into C-F bond formation and activation.

    PubMed

    Milner, Lucy M; Hall, Lewis M; Pridmore, Natalie E; Skeats, Matthew K; Whitwood, Adrian C; Lynam, Jason M; Slattery, John M

    2016-01-28

    Metal vinylidene complexes are widely encountered, or postulated, as intermediates in a range of important metal-mediated transformations of alkynes. However, fluorovinylidene complexes have rarely been described and their reactivity is largely unexplored. By making use of the novel outer-sphere electrophilic fluorination (OSEF) strategy we have developed a rapid, robust and convenient method for the preparation of fluorovinylidene and trifluoromethylvinylidene ruthenium complexes from non-fluorinated alkynes. Spectroscopic investigations (NMR and UV/Vis), coupled with TD-DFT studies, show that fluorine incorporation results in significant changes to the electronic structure of the vinylidene ligand. The reactivity of fluorovinylidene complexes shows many similarities to non-fluorinated analogues, but also some interesting differences, including a propensity to undergo unexpected C-F bond cleavage reactions. Heating fluorovinylidene complex [Ru(η(5)-C5H5)(PPh3)2(C[double bond, length as m-dash]C{F}R)][BF4] led to C-H activation of a PPh3 ligand to form an orthometallated fluorovinylphosphonium ligand. Reaction with pyridine led to nucleophilic attack at the metal-bound carbon atom of the vinylidene to form a vinyl pyridinium species, which undergoes both C-H and C-F activation to give a novel pyridylidene complex. Addition of water, in the presence of chloride, leads to anti-Markovnikov hydration of a fluorovinylidene complex to form an α-fluoroaldehyde, which slowly rearranges to its acyl fluoride isomer. Therefore, fluorovinylidenes ligands may be viewed as synthetic equivalents of 1-fluoroalkynes providing access to reactivity not possible by other routes. PMID:26701305

  7. Access to novel fluorovinylidene ligands via exploitation of outer-sphere electrophilic fluorination: new insights into C-F bond formation and activation.

    PubMed

    Milner, Lucy M; Hall, Lewis M; Pridmore, Natalie E; Skeats, Matthew K; Whitwood, Adrian C; Lynam, Jason M; Slattery, John M

    2016-01-28

    Metal vinylidene complexes are widely encountered, or postulated, as intermediates in a range of important metal-mediated transformations of alkynes. However, fluorovinylidene complexes have rarely been described and their reactivity is largely unexplored. By making use of the novel outer-sphere electrophilic fluorination (OSEF) strategy we have developed a rapid, robust and convenient method for the preparation of fluorovinylidene and trifluoromethylvinylidene ruthenium complexes from non-fluorinated alkynes. Spectroscopic investigations (NMR and UV/Vis), coupled with TD-DFT studies, show that fluorine incorporation results in significant changes to the electronic structure of the vinylidene ligand. The reactivity of fluorovinylidene complexes shows many similarities to non-fluorinated analogues, but also some interesting differences, including a propensity to undergo unexpected C-F bond cleavage reactions. Heating fluorovinylidene complex [Ru(η(5)-C5H5)(PPh3)2(C[double bond, length as m-dash]C{F}R)][BF4] led to C-H activation of a PPh3 ligand to form an orthometallated fluorovinylphosphonium ligand. Reaction with pyridine led to nucleophilic attack at the metal-bound carbon atom of the vinylidene to form a vinyl pyridinium species, which undergoes both C-H and C-F activation to give a novel pyridylidene complex. Addition of water, in the presence of chloride, leads to anti-Markovnikov hydration of a fluorovinylidene complex to form an α-fluoroaldehyde, which slowly rearranges to its acyl fluoride isomer. Therefore, fluorovinylidenes ligands may be viewed as synthetic equivalents of 1-fluoroalkynes providing access to reactivity not possible by other routes.

  8. 1,3-Dipolar cycloadditions of electrophilically activated benzonitrile N-oxides. Polar cycloaddition versus oxime formation.

    PubMed

    Domingo, Luis R; Picher, M Teresa; Arroyo, Pau; Saez, José A

    2006-12-01

    The reactions of electrophilically activated benzonitrile N-oxides (BNOs) toward 3-methylenephthalimidines (MPIs) have been studied using density functional theory (DFT) at the B3LYP/6-31G* level. For these reactions, two different channels allowing the formation of the [3 + 2] cycloadducts and two isomeric (E)- and (Z)-oximes have been characterized. The 1,3-dipolar cycloadditions take place along concerted but highly asynchronous transition states, while formation of the oximes is achieved through a stepwise mechanism involving zwitterionic intermediates. Both reactions are initiated by the nucleophilic attack of the methylene carbon of the MPIs to the carbon atom of the electrophilically activated BNOs. The analysis based on the natural bond orbital (NBO) and the topological analysis of the electron localization function (ELF) at the transition structures and intermediates explains correctly the polar nature of these reactions. Solvent effects considered by the PCM model allow explaining the low incidence of the solvent polarity on the rate and composition of the reactions.

  9. Reaction of bromine and chlorine with phenolic compounds and natural organic matter extracts--Electrophilic aromatic substitution and oxidation.

    PubMed

    Criquet, Justine; Rodriguez, Eva M; Allard, Sebastien; Wellauer, Sven; Salhi, Elisabeth; Joll, Cynthia A; von Gunten, Urs

    2015-11-15

    Phenolic compounds are known structural moieties of natural organic matter (NOM), and their reactivity is a key parameter for understanding the reactivity of NOM and the disinfection by-product formation during oxidative water treatment. In this study, species-specific and/or apparent second order rate constants and mechanisms for the reactions of bromine and chlorine have been determined for various phenolic compounds (phenol, resorcinol, catechol, hydroquinone, phloroglucinol, bisphenol A, p-hydroxybenzoic acid, gallic acid, hesperetin and tannic acid) and flavone. The reactivity of bromine with phenolic compounds is very high, with apparent second order rate constants at pH 7 in the range of 10(4) to 10(7) M(-1) s(-1). The highest value was recorded for the reaction between HOBr and the fully deprotonated resorcinol (k = 2.1 × 10(9) M(-1) s(-1)). The reactivity of phenolic compounds is enhanced by the activating character of the phenolic substituents, e.g. further hydroxyl groups. With the data set from this study, the ratio between the species-specific rate constants for the reactions of chlorine versus bromine with phenolic compounds was confirmed to be about 3000. Phenolic compounds react with bromine or chlorine either by oxidation (electron transfer, ET) or electrophilic aromatic substitution (EAS) processes. The dominant process mainly depends on the relative position of the hydroxyl substituents and the possibility of quinone formation. While phenol, p-hydroxybenzoic acid and bisphenol A undergo EAS, hydroquinone, catechol, gallic acid and tannic acid, with hydroxyl substituents in ortho or para positions, react with bromine by ET leading to quantitative formation of the corresponding quinones. Some compounds (e.g. phloroglucinol) show both partial oxidation and partial electrophilic aromatic substitution and the ratio observed for the pathways depends on the pH. For the reaction of six NOM extracts with bromine, electrophilic aromatic substitution

  10. Reaction of bromine and chlorine with phenolic compounds and natural organic matter extracts--Electrophilic aromatic substitution and oxidation.

    PubMed

    Criquet, Justine; Rodriguez, Eva M; Allard, Sebastien; Wellauer, Sven; Salhi, Elisabeth; Joll, Cynthia A; von Gunten, Urs

    2015-11-15

    Phenolic compounds are known structural moieties of natural organic matter (NOM), and their reactivity is a key parameter for understanding the reactivity of NOM and the disinfection by-product formation during oxidative water treatment. In this study, species-specific and/or apparent second order rate constants and mechanisms for the reactions of bromine and chlorine have been determined for various phenolic compounds (phenol, resorcinol, catechol, hydroquinone, phloroglucinol, bisphenol A, p-hydroxybenzoic acid, gallic acid, hesperetin and tannic acid) and flavone. The reactivity of bromine with phenolic compounds is very high, with apparent second order rate constants at pH 7 in the range of 10(4) to 10(7) M(-1) s(-1). The highest value was recorded for the reaction between HOBr and the fully deprotonated resorcinol (k = 2.1 × 10(9) M(-1) s(-1)). The reactivity of phenolic compounds is enhanced by the activating character of the phenolic substituents, e.g. further hydroxyl groups. With the data set from this study, the ratio between the species-specific rate constants for the reactions of chlorine versus bromine with phenolic compounds was confirmed to be about 3000. Phenolic compounds react with bromine or chlorine either by oxidation (electron transfer, ET) or electrophilic aromatic substitution (EAS) processes. The dominant process mainly depends on the relative position of the hydroxyl substituents and the possibility of quinone formation. While phenol, p-hydroxybenzoic acid and bisphenol A undergo EAS, hydroquinone, catechol, gallic acid and tannic acid, with hydroxyl substituents in ortho or para positions, react with bromine by ET leading to quantitative formation of the corresponding quinones. Some compounds (e.g. phloroglucinol) show both partial oxidation and partial electrophilic aromatic substitution and the ratio observed for the pathways depends on the pH. For the reaction of six NOM extracts with bromine, electrophilic aromatic substitution

  11. Low temperature in situ synthesis and the formation mechanism of various carbon-encapsulated nanocrystals by the electrophilic oxidation of metallocene complexes

    NASA Astrophysics Data System (ADS)

    Liu, Boyang; Fan, Chunhua; Chen, Jianwei; Wang, Junhua; Lu, Zepeng; Ren, Jiayuan; Yu, Shuaiqin; Dong, Lihua; Li, Wenge

    2016-02-01

    The core-shell nanostructures have the advantages of combining distinctive properties of varied materials and improved properties over their single-component counterparts. Synthesis approaches for this class of nanostructures have been intensively explored, generally involving multiple steps. Here, a general and convenient strategy is developed for one-step in situ synthesis of various carbon-encapsulated nanocrystals with a core-shell structure via a solid-state reaction of metallocene complexes with (NH4)2S2O8 in an autoclave at 200 °C. A variety of near-spherical and equiaxed nanocrystals with a small median size ranging from 6.5 to 50.6 nm are prepared as inner cores, including Fe7S8, Ni3S4 and NiS, CoS, TiO2, TiO2 and S8, ZrO2, (NH4)3V(SO4)3 and VO2, Fe7S8 and Fe3O4, MoS2 and MoO2. The worm-like carbon shell provides exclusive room for hundreds of nanocrystals separated from each other, preventing nanocrystal aggregation. The synergistic effect of ammonium and a strong oxidizing anion on the electrophilic oxidation of metallocene complexes containing a metal-ligand π bond contributes to the carbon formation at low temperature. It is considered that the cyclopentadienyl ligand in a metallocene complex will decompose into highly reactive straight chain olefinic pieces and the metal-olefin π interaction enables an ordered self-assembly of olefinic pieces on nanocrystals to partially form graphitizable carbon and a core-shell structure. The high capacity, good cycling behavior and rate capability of Fe7S8@C and Ni3S4 and NiS@C electrodes are attributed to the good protection and electrical conductivity of the carbon shell.

  12. Low temperature in situ synthesis and the formation mechanism of various carbon-encapsulated nanocrystals by the electrophilic oxidation of metallocene complexes.

    PubMed

    Liu, Boyang; Fan, Chunhua; Chen, Jianwei; Wang, Junhua; Lu, Zepeng; Ren, Jiayuan; Yu, Shuaiqin; Dong, Lihua; Li, Wenge

    2016-02-19

    The core-shell nanostructures have the advantages of combining distinctive properties of varied materials and improved properties over their single-component counterparts. Synthesis approaches for this class of nanostructures have been intensively explored, generally involving multiple steps. Here, a general and convenient strategy is developed for one-step in situ synthesis of various carbon-encapsulated nanocrystals with a core-shell structure via a solid-state reaction of metallocene complexes with (NH4)2S2O8 in an autoclave at 200 °C. A variety of near-spherical and equiaxed nanocrystals with a small median size ranging from 6.5 to 50.6 nm are prepared as inner cores, including Fe7S8, Ni3S4 and NiS, CoS, TiO2, TiO2 and S8, ZrO2, (NH4)3V(SO4)3 and VO2, Fe7S8 and Fe3O4, MoS2 and MoO2. The worm-like carbon shell provides exclusive room for hundreds of nanocrystals separated from each other, preventing nanocrystal aggregation. The synergistic effect of ammonium and a strong oxidizing anion on the electrophilic oxidation of metallocene complexes containing a metal-ligand π bond contributes to the carbon formation at low temperature. It is considered that the cyclopentadienyl ligand in a metallocene complex will decompose into highly reactive straight chain olefinic pieces and the metal-olefin π interaction enables an ordered self-assembly of olefinic pieces on nanocrystals to partially form graphitizable carbon and a core-shell structure. The high capacity, good cycling behavior and rate capability of Fe7S8@C and Ni3S4 and NiS@C electrodes are attributed to the good protection and electrical conductivity of the carbon shell. PMID:26783105

  13. The Role of Electrophilic Oxygen in the Viking Biology Results and in the In-situ Destruction of Organics on Mars

    NASA Astrophysics Data System (ADS)

    Quinn, R. C.; Zent, A. P.

    1999-09-01

    The return and analysis of pristine material that is relict of a putative period of chemical evolution is a fundamental goal of the exobiological exploration of Mars. In order to accomplish this objective, it is desirable to find oxidant-free regions where pristine material can be accessed at the shallowest possible depth (ideally directly from the surface). The objective of our ongoing research is to understand the spatial and temporal distribution of oxidants in the martian regolith and the redox chemistry of the soil; in effect, to understand the chemical mechanisms and kinetics relating to the in-situ destruction of organics and the formation of the reactive species responsible for the Viking biology results. Variety of electrophilic oxygen species with differing stability and chemical reactivity can form on the surface metal oxides when exposed to gaseous oxidants or irradiated by UV light. The role of these adsorbed oxygen species in the catalytic oxidation of organic compounds has been extensively explored. In addition to the potential role these types of reactions may play in the in-situ destruction of organics on Mars, we believe that the GEx oxidant may likewise be accounted for by adsorbed oxygen species. If highly reactive adsorbed oxygen species are present in the martian regolith, it likely that they may play a dominate role in both the chemical weathering of the surface material as well as the destruction of organic compounds. In this work, we report on experimental studies of oxidizing processes which may operate on either organics or soil minerals on Mars. The oxidizing processes examined include: gas-phase oxidants, UV photolysis, and UV-assisted heterogeneous catalysis. This work is supported by the NASA Research in Exobiology Program.

  14. Electrophilic Reaction of 2,2,2-Trifluorodiazoethane with the in Situ Generated N-Heterocyclic Carbenes: Access to N-Aminoguanidines.

    PubMed

    Guo, Ran; Zheng, Yan; Ma, Jun-An

    2016-09-01

    A facile and efficient electrophilic reaction of 2,2,2-trifluorodiazoethane (CF3CHN2) with the in situ generated N-heterocyclic carbenes is reported. Under basic conditions, a series of trifluoromethylated N-aminoguanidines were obtained in good to high yields. Furthermore, this protocol was applied in the synthesis of the agrochemical Imidacloprid analogue. PMID:27540867

  15. Synthesis of Functional Fluorescent BODIPY‐based Dyes through Electrophilic Aromatic Substitution: Straightforward Approach towards Customized Fluorescent Probes

    PubMed Central

    Schoenmakers, Daniël C.; Veranič, Peter; Muševič, Igor

    2016-01-01

    Abstract Fluorescent materials are widely used in biological and material applications as probes for imaging or sensing; however, their customization is usually complicated without the support of an organic chemistry laboratory. Here, we present a straightforward method for the customization of BODIPY cores, which are among the most commonly used fluorescent probes. The method is based on the formation of a new C−C bond through Friedel–Crafts electrophilic aromatic substitution carried out at room temperature. The method presented can be used to obtain completely customized fluorescent materials in one or two steps from commercially available compounds. Examples of the preparation of fluorescent materials for cell staining and functionalization of silica colloids are also presented. PMID:27777837

  16. Three-component coupling based on flash chemistry. Carbolithiation of benzyne with functionalized aryllithiums followed by reactions with electrophiles.

    PubMed

    Nagaki, Aiichiro; Ichinari, Daisuke; Yoshida, Jun-ichi

    2014-09-01

    A flow microreactor method for three-component coupling of benzyne was developed based on flash chemistry. o-Bromophenyllithium generated from 1-bromo-2-iodobenzene and a functionalized aryllithium generated from the corresponding aryl halide were mixed at -70 °C. In the subsequent reactor o-bromophenyllithium is decomposed to generate benzyne without affecting the functionalized aryllithium at -30 °C, and carbolithiation of benzyne with the aryllithium took place spontaneously. The resulting functionalized biaryllithium was reacted with an electrophile in the subsequent reactor to give the corresponding three-component coupling product. The precise optimization of reaction conditions using the temperature-residence time mapping is responsible for the success of the present transformation. The present method has been successfully applied to the synthesis of boscalid.

  17. Ubiquitin C-terminal electrophiles are activity-based probes for identification and mechanistic study of ubiquitin conjugating machinery

    PubMed Central

    Love, Kerry Routenberg; Pandya, Renuka K.; Spooner, Eric; Ploegh, Hidde L.

    2009-01-01

    Protein modification by ubiquitin (Ub) and ubiquitin-like modifiers (Ubl) requires the action of activating (E1), conjugating (E2), and ligating (E3) enzymes and is a key step in the specific destruction of proteins. Deubiquitinating enzymes (DUBs) deconjugate substrates modified with Ub/Ubls and recycle Ub inside the cell. Genome mining based on sequence homology to proteins with known function has assigned many enzymes to this pathway without confirmation of either conjugating or DUB activity. Function-dependent methodologies are still the most useful for rapid identification or assessment of biological activity of expressed proteins from cells. Activity-based protein profiling (ABPP) uses chemical probes that are active-site directed for the classification of protein activities in complex mixtures. Here we show that the design and use of an expanded set of Ub-based electrophilic probes allowed us to recover and identify members of each enzyme class in the ubiquitin-proteasome system, including E3 ligases and DUBs with previously unverified activity. We show that epitope-tagged Ub-electrophilic probes can be used as activity-based probes for E3 ligase identification by in vitro labeling and activity studies of purified enzymes identified from complex mixtures in cell lysate. Furthermore, the reactivity of our probe with the HECT domain of the E3 Ub ligase ARF-BP1 suggests that multiple cysteines may be in the vicinity of the E2-binding site and are capable of the transfer of Ub to self or to a substrate protein. PMID:19256548

  18. Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Preferences and Electrophile-Catalyst Interaction Revealed by NMR and Computational Studies.

    PubMed

    Seegerer, Andreas; Hioe, Johnny; Hammer, Michael M; Morana, Fabio; Fuchs, Patrick J W; Gschwind, Ruth M

    2016-08-10

    Catalysis with remote-stereocontrol provides special challenges in design and comprehension. One famous example is the dienamine catalysis, for which high ee values are reported despite insufficient shielding of the second double bond. Especially for dienamines with variable Z/E-ratios of the second double bond, no correlations to the ee values are found. Therefore, the structures, thermodynamics, and kinetics of dienamine intermediates in SN-type reactions are investigated. The NMR studies show that the preferred dienamine conformation provides an effective shielding if large electrophiles are used. Calculations at SCS-MP2/CBS-level of theory and experimental data of the dienamine formation show kinetic preference for the Z-isomer of the second double bond and a slow isomerization toward the thermodynamically preferred E-isomer. Modulations of the rate-determining step, by variation of the concentration of the electrophile, allow the conversion of dienamines to be observed. With electrophiles, a faster reaction of Z- than of E-isomers is observed experimentally. Calculations corroborate these results by correlating ee values of three catalysts with the kinetics of the electrophilic attack and reveal the significance of CH-π and stacking interactions in the transition states. Thus, for the first time a comprehensive understanding of the remote stereocontrol in γ-functionalization reactions of dienamines and an explanation to the "Z/E-dilemma" are presented. The combination of bulky catalyst subsystems and large electrophiles provides a shielding of one face and causes different reactivities of E/Z-dienamines in nucleophilic attacks from the other face. Kinetic preferences for the formation of Z-dienamines and their unfavorable thermodynamics support high ee values. PMID:27430865

  19. Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Preferences and Electrophile-Catalyst Interaction Revealed by NMR and Computational Studies.

    PubMed

    Seegerer, Andreas; Hioe, Johnny; Hammer, Michael M; Morana, Fabio; Fuchs, Patrick J W; Gschwind, Ruth M

    2016-08-10

    Catalysis with remote-stereocontrol provides special challenges in design and comprehension. One famous example is the dienamine catalysis, for which high ee values are reported despite insufficient shielding of the second double bond. Especially for dienamines with variable Z/E-ratios of the second double bond, no correlations to the ee values are found. Therefore, the structures, thermodynamics, and kinetics of dienamine intermediates in SN-type reactions are investigated. The NMR studies show that the preferred dienamine conformation provides an effective shielding if large electrophiles are used. Calculations at SCS-MP2/CBS-level of theory and experimental data of the dienamine formation show kinetic preference for the Z-isomer of the second double bond and a slow isomerization toward the thermodynamically preferred E-isomer. Modulations of the rate-determining step, by variation of the concentration of the electrophile, allow the conversion of dienamines to be observed. With electrophiles, a faster reaction of Z- than of E-isomers is observed experimentally. Calculations corroborate these results by correlating ee values of three catalysts with the kinetics of the electrophilic attack and reveal the significance of CH-π and stacking interactions in the transition states. Thus, for the first time a comprehensive understanding of the remote stereocontrol in γ-functionalization reactions of dienamines and an explanation to the "Z/E-dilemma" are presented. The combination of bulky catalyst subsystems and large electrophiles provides a shielding of one face and causes different reactivities of E/Z-dienamines in nucleophilic attacks from the other face. Kinetic preferences for the formation of Z-dienamines and their unfavorable thermodynamics support high ee values.

  20. Thiophene-Diketopyrrolopyrrole-Based Quinoidal Small Molecules as Solution-Processable and Air-Stable Organic Semiconductors: Tuning of the Length and Branching Position of the Alkyl Side Chain toward a High-Performance n-Channel Organic Field-Effect Transistor.

    PubMed

    Wang, Chao; Qin, Yunke; Sun, Yuanhui; Guan, Ying-Shi; Xu, Wei; Zhu, Daoben

    2015-07-29

    A series of thiophene-diketopyrrolopyrrole-based quinoidal small molecules (TDPPQ-2-TDPPQ-5) bearing branched alkyl chains with different side-chain lengths and varied branching positions are synthesized. Field-effect transistor (FET) measurement combined with thin-film characterization is utilized to systematically probe the influence of the side-chain length and branching position on the film microstructure, molecular packing, and, hence, charge-transport property. All of these TDPPQ derivatives show air-stable n-channel transporting behavior in spin-coated FET devices, which exhibit no significant decrease in mobility even after being stored in air for 2 months. Most notably, TDPPQ-3 exhibits an outstanding n-channel semiconducting property with electron mobilities up to 0.72 cm(2) V(-1) s(-1), which is an unprecedented value for spin-coated DPP-based n-type semiconducting small molecules. A balance of high crystallinity, satisfactory thickness uniformity and continuity, and strong intermolecular interaction accounts for the superior charge-transport characteristics of TDPPQ-3 films. Our study demonstrates that tuning the length and branching position of alkyl side chains of semiconducting molecules is a powerful strategy for achieving high FET performance. PMID:26134920

  1. Decarboxylative Cross-Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides.

    PubMed

    Huihui, Kierra M M; Caputo, Jill A; Melchor, Zulema; Olivares, Astrid M; Spiewak, Amanda M; Johnson, Keywan A; DiBenedetto, Tarah A; Kim, Seoyoung; Ackerman, Laura K G; Weix, Daniel J

    2016-04-20

    A new method for the decarboxylative coupling of alkyl N-hydroxyphthalimide esters (NHP esters) with aryl iodides is presented. In contrast to previous studies that form alkyl radicals from carboxylic acid derivatives, no photocatalyst, light, or arylmetal reagent is needed, only nickel and a reducing agent (Zn). Methyl, primary, and secondary alkyl groups can all be coupled in good yield (77% ave yield). One coupling with an acid chloride is also presented. Stoichiometric reactions of (dtbbpy)Ni(2-tolyl)I with an NHP ester show for the first time that arylnickel(II) complexes can directly react with NHP esters to form alkylated arenes. PMID:27029833

  2. Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

    PubMed Central

    Makia, Ngome L.; Surapureddi, Sailesh; Monostory, Katalin; Prough, Russell A.

    2014-01-01

    Cytochrome P450 (CYP)2C9 and CYP2C19 are important human enzymes that metabolize therapeutic drugs, environmental chemicals, and physiologically important endogenous compounds. Initial studies using primary human hepatocytes showed induction of both the CYP2C9 and CYP2C19 genes by tert-butylhydroquinone (tBHQ). As a pro-oxidant, tBHQ regulates the expression of cytoprotective genes by activation of redox-sensing transcription factors, such as the nuclear factor E2-related factor 2 (Nrf2) and members of the activator protein 1 (AP-1) family of proteins. The promoter region of CYP2C9 contains two putative AP-1 sites (TGAGTCA) at positions −2201 and −1930, which are also highly conserved in CYP2C19. The CYP2C9 promoter is activated by ectopic expression of cFos and JunD, whereas Nrf2 had no effect. Using specific kinase inhibitors for mitogen-activated protein kinase, we showed that extracellular signal-regulated kinase and Jun N-terminal kinase are essential for tBHQ-induced expression of CYP2C9. Electrophoretic mobility shift assays demonstrate that cFos distinctly interacts with the distal AP-1 site and JunD with the proximal site. Because cFos regulates target genes as heterodimers with Jun proteins, we hypothesized that DNA looping might be required to bring the distal and proximal AP-1 sites together to activate the CYP2C9 promoter. Chromosome conformation capture analyses confirmed the formation of a DNA loop in the CYP2C9 promoter, possibly allowing interaction between cFos at the distal site and JunD at the proximal site to activate CYP2C9 transcription in response to electrophiles. These results indicate that oxidative stress generated by exposure to electrophilic xenobiotics and metabolites induces the expression of CYP2C9 and CYP2C19 in human hepatocytes. PMID:24830941

  3. Computational Study of Chemical Reactivity Using Information-Theoretic Quantities from Density Functional Reactivity Theory for Electrophilic Aromatic Substitution Reactions.

    PubMed

    Wu, Wenjie; Wu, Zemin; Rong, Chunying; Lu, Tian; Huang, Ying; Liu, Shubin

    2015-07-23

    The electrophilic aromatic substitution for nitration, halogenation, sulfonation, and acylation is a vastly important category of chemical transformation. Its reactivity and regioselectivity is predominantly determined by nucleophilicity of carbon atoms on the aromatic ring, which in return is immensely influenced by the group that is attached to the aromatic ring a priori. In this work, taking advantage of recent developments in quantifying nucleophilicity (electrophilicity) with descriptors from the information-theoretic approach in density functional reactivity theory, we examine the reactivity properties of this reaction system from three perspectives. These include scaling patterns of information-theoretic quantities such as Shannon entropy, Fisher information, Ghosh-Berkowitz-Parr entropy and information gain at both molecular and atomic levels, quantitative predictions of the barrier height with both Hirshfeld charge and information gain, and energetic decomposition analyses of the barrier height for the reactions. To that end, we focused in this work on the identity reaction of the monosubstituted-benzene molecule reacting with hydrogen fluoride using boron trifluoride as the catalyst in the gas phase. We also considered 19 substituting groups, 9 of which are ortho/para directing and the other 9 meta directing, besides the case of R = -H. Similar scaling patterns for these information-theoretic quantities found for stable species elsewhere were disclosed for these reactions systems. We also unveiled novel scaling patterns for information gain at the atomic level. The barrier height of the reactions can reliably be predicted by using both the Hirshfeld charge and information gain at the regioselective carbon atom. The energy decomposition analysis ensued yields an unambiguous picture about the origin of the barrier height, where we showed that it is the electrostatic interaction that plays the dominant role, while the roles played by exchange-correlation and

  4. Computational Study of Chemical Reactivity Using Information-Theoretic Quantities from Density Functional Reactivity Theory for Electrophilic Aromatic Substitution Reactions.

    PubMed

    Wu, Wenjie; Wu, Zemin; Rong, Chunying; Lu, Tian; Huang, Ying; Liu, Shubin

    2015-07-23

    The electrophilic aromatic substitution for nitration, halogenation, sulfonation, and acylation is a vastly important category of chemical transformation. Its reactivity and regioselectivity is predominantly determined by nucleophilicity of carbon atoms on the aromatic ring, which in return is immensely influenced by the group that is attached to the aromatic ring a priori. In this work, taking advantage of recent developments in quantifying nucleophilicity (electrophilicity) with descriptors from the information-theoretic approach in density functional reactivity theory, we examine the reactivity properties of this reaction system from three perspectives. These include scaling patterns of information-theoretic quantities such as Shannon entropy, Fisher information, Ghosh-Berkowitz-Parr entropy and information gain at both molecular and atomic levels, quantitative predictions of the barrier height with both Hirshfeld charge and information gain, and energetic decomposition analyses of the barrier height for the reactions. To that end, we focused in this work on the identity reaction of the monosubstituted-benzene molecule reacting with hydrogen fluoride using boron trifluoride as the catalyst in the gas phase. We also considered 19 substituting groups, 9 of which are ortho/para directing and the other 9 meta directing, besides the case of R = -H. Similar scaling patterns for these information-theoretic quantities found for stable species elsewhere were disclosed for these reactions systems. We also unveiled novel scaling patterns for information gain at the atomic level. The barrier height of the reactions can reliably be predicted by using both the Hirshfeld charge and information gain at the regioselective carbon atom. The energy decomposition analysis ensued yields an unambiguous picture about the origin of the barrier height, where we showed that it is the electrostatic interaction that plays the dominant role, while the roles played by exchange-correlation and

  5. Iodine-mediated solvent-controlled selective electrophilic cyclization and oxidative esterification of o-alkynyl aldehydes: an easy access to pyranoquinolines, pyranoquinolinones, and isocumarins.

    PubMed

    Verma, Akhilesh K; Rustagi, Vineeta; Aggarwal, Trapti; Singh, Amit P

    2010-11-19

    Chemoselective behavior of iodine in different solvents in the electrophilic iodocyclization of o-alkynyl aldehydes is described. o-Alkynyl aldehydes 3a-t on reaction with I2 in CH2Cl2 with appropriate nucleophiles provides pyrano[4,3-b]quinolines 4a-f, via formation of cyclic iodonium intermediate Q; however, using alcohols as a solvent as well as nucleophile, o-alkynyl esters 5a-y were obtained selectively in good to excellent yields via formation of hypoiodide intermediate R. Subsequently, o-alkynyl esters were converted in to pyranoquinolinones 6a-i and isocoumarin 6j by electrophilic iodocyclization. This developed oxidative esterification provides a novel access for the chemoselective synthesis of esters 5q-u from aldehydes 3n-p without oxidizing primary alcohol present in the substrate.

  6. Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine.

    PubMed

    Amabili, Paolo; Amici, Adolfo; Civitavecchia, Annafelicia; Maggiore, Beatrice; Orena, Mario; Rinaldi, Samuele; Tolomelli, Alessandra

    2016-02-01

    Starting from chiral-protected 4-hydroxymethyl pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-trisubstituted isosteres of α-methyl homoserine, tethered on a γ-lactam ring, were prepared exploiting stereoselective electrophilic aminations. These reactions led to the isolation and characterization of a novel type of atropisomers, exceedingly stable at room temperature, that were directly converted to the desired products by a novel non-reductive N-N bond cleavage reaction.

  7. Adducts of Oxylipin Electrophiles to Glutathione Reflect a 13 Specificity of the Downstream Lipoxygenase Pathway in the Tobacco Hypersensitive Response

    PubMed Central

    Davoine, Céline; Falletti, Olivier; Douki, Thierry; Iacazio, Gilles; Ennar, Najla; Montillet, Jean-Luc; Triantaphylidès, Christian

    2006-01-01

    The response to reactive electrophile species (RES) is now considered as part of the plant response to pathogen and insect attacks. Thanks to a previously established high-performance liquid chromatography tandem mass spectrometry methodology, we have investigated the production of oxylipin RES adducts to glutathione (GSH) during the hypersensitive response (HR) of plants. We have observed that RES conjugation to GSH in tobacco (Nicotiana tabacum) leaves is facile and nonspecific. In cryptogein-elicited tobacco leaves, we show that the oxylipin RES adducts to GSH are produced in correlation with GSH consumption, increase in glutathione S-transferase activity, and the appearance of the cell death symptoms. In this model, the adducts arise mainly from the downstream 13 lipoxygenase (LOX) metabolism, although the induced 9 LOX pathway leads massively to the accumulation of upstream metabolites. The main adducts were obtained from 2-hexenal and 12-oxo-phytodienoic acid. They accumulate transiently as 1-hexanol-3-GSH, a reduced adduct, and 12-oxo-phytodienoic acid-GSH, respectively. RES conjugation does not initiate cell death but explains part of the GSH depletion that accompanies HR cell death. The nature of these GSH conjugates shows the key role played by the 13 LOX pathway in RES signaling in the tobacco HR. PMID:16500992

  8. Heterolytic Cleavage of H2 by Bifunctional Manganese(I) Complexes: Impact of Ligand Dynamics, Electrophilicity, and Base Positioning

    SciTech Connect

    Hulley, Elliott B.; Helm, Monte L.; Bullock, R. Morris

    2014-12-01

    We report the synthesis, characterization, and reactivity with H2 of a series of MnI complexes of the type [(P-P)Mn(L2)CO]+ (L2 = dppm, bppm, or (CO)2; P-P = PPhNMePPh or PPh2 NBn2 ) that bear pendant amine ligands designed to function as proton relays. The pendant amine was found to function as a hemilabile ligand; its binding strength is strongly affected by the ancillary ligand environment around Mn. Tuning the electrophilicity of the Mn center leads to systems capable of reversible heterolytic cleavage of the H-H bond. The strength of pendant amine binding can be balanced to protect the Mn center while still leading to facile reactivity with H2. Neutral amine-bearing MnIH species were found to react with one-electron oxidants and, after proton and electron transfer reactions, regenerate MnI cationic species. The reactivity presented herein indicate that the Mn complexes we have developed are a promising platform for Mn-based H2 oxidation electrocatalyst development. The research was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences. Pacific Northwest National Laboratory is operated by Battelle for DOE.

  9. Unprecedented Spectroscopic and Computational Evidence for Allenyl and Propargyl Titanocene(IV) Complexes: Electrophilic Quenching of Their Metallotropic Equilibrium.

    PubMed

    Ruiz-Muelle, Ana Belén; Oña-Burgos, Pascual; Ortuño, Manuel A; Oltra, J Enrique; Rodríguez-García, Ignacio; Fernández, Ignacio

    2016-02-12

    The synthesis and structural characterization of allenyl titanocene(IV) [TiClCp2 (CH=C=CH2 )] 3 and propargyl titanocene(IV) [TiClCp2 (CH2 -C≡C-(CH2 )4 CH3 )] 9 have been described for the first time. Advanced NMR methods including diffusion NMR methods (diffusion pulsed field gradient stimulated spin echo (PFG-STE) and DOSY) have been applied and established that these organometallics are monomers in THF solution with hydrodynamic radii (from the Stokes-Einstein equation) of 3.5 and 4.1 Å for 3 and 9, respectively. Full (1) H, (13) C, Δ(1) H, and Δ(13) C NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights into these derivatives are provided. In solution, they are involved in their respective metallotropic allenyl-propargyl equilibria that, after quenching experiments with aromatic and aliphatic aldehydes, ketones, and protonating agents, always give the propargyl products P (when carbonyls are employed), or allenyl products A (when a proton source is added) as the major isomers. In all the cases assayed, the ratio of products suggests that the metallotropic equilibrium should be faster than the reactions of 3 and 9 with electrophiles. Indeed, DFT calculations predict lower Gibbs energy barriers for the metallotropic equilibrium, thus confirming dynamic kinetic resolution.

  10. Unprecedented Spectroscopic and Computational Evidence for Allenyl and Propargyl Titanocene(IV) Complexes: Electrophilic Quenching of Their Metallotropic Equilibrium.

    PubMed

    Ruiz-Muelle, Ana Belén; Oña-Burgos, Pascual; Ortuño, Manuel A; Oltra, J Enrique; Rodríguez-García, Ignacio; Fernández, Ignacio

    2016-02-12

    The synthesis and structural characterization of allenyl titanocene(IV) [TiClCp2 (CH=C=CH2 )] 3 and propargyl titanocene(IV) [TiClCp2 (CH2 -C≡C-(CH2 )4 CH3 )] 9 have been described for the first time. Advanced NMR methods including diffusion NMR methods (diffusion pulsed field gradient stimulated spin echo (PFG-STE) and DOSY) have been applied and established that these organometallics are monomers in THF solution with hydrodynamic radii (from the Stokes-Einstein equation) of 3.5 and 4.1 Å for 3 and 9, respectively. Full (1) H, (13) C, Δ(1) H, and Δ(13) C NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights into these derivatives are provided. In solution, they are involved in their respective metallotropic allenyl-propargyl equilibria that, after quenching experiments with aromatic and aliphatic aldehydes, ketones, and protonating agents, always give the propargyl products P (when carbonyls are employed), or allenyl products A (when a proton source is added) as the major isomers. In all the cases assayed, the ratio of products suggests that the metallotropic equilibrium should be faster than the reactions of 3 and 9 with electrophiles. Indeed, DFT calculations predict lower Gibbs energy barriers for the metallotropic equilibrium, thus confirming dynamic kinetic resolution. PMID:26786999

  11. Steatosis-induced proteins adducts with lipid peroxidation products and nuclear electrophilic stress in hepatocytes

    PubMed Central

    Anavi, Sarit; Ni, Zhixu; Tirosh, Oren; Fedorova, Maria

    2014-01-01

    Accumulating evidence suggests that fatty livers are particularly more susceptible to several pathological conditions, including hepatic inflammation, cirrhosis and liver cancer. However the exact mechanism of such susceptibility is still largely obscure. The current study aimed to elucidate the effect of hepatocytes lipid accumulation on the nuclear electrophilic stress. Accumulation of intracellular lipids was significantly increased in HepG2 cells incubated with fatty acid (FA) complex (1 mM, 2:1 oleic and palmitic acids). In FA-treated cells, lipid droplets were localized around the nucleus and seemed to induce mechanical force, leading to the disruption of the nucleus morphology. Level of reactive oxygen species (ROS) was significantly increased in FA-loaded cells and was further augmented by treatment with moderate stressor (CoCl2). Increased ROS resulted in formation of reactive carbonyls (aldehydes and ketones, derived from lipid peroxidation) with a strong perinuclear accumulation. Mass-spectroscopy analysis indicated that lipid accumulation per-se can results in modification of nuclear protein by reactive lipid peroxidation products (oxoLPP). 235 Modified proteins involved in transcription regulation, splicing, protein synthesis and degradation, DNA repair and lipid metabolism were identified uniquely in FA-treated cells. These findings suggest that steatosis can affect nuclear redox state, and induce modifications of nuclear proteins by reactive oxoLPP accumulated in the perinuclear space upon FA-treatment. PMID:25560244

  12. ACTIVATION OF VASCULAR ENDOTHELIAL NITRIC OXIDE SYNTHASE AND HEME OXYGENASE-1 EXPRESSION BY ELECTROPHILIC NITRO-FATTY ACIDS

    PubMed Central

    Khoo, Nicholas K.H.; Rudolph, Volker; Cole, Marsha P.; Golin-Bisello, Franca; Schopfer, Francisco J.; Woodcock, Steven R.; Batthyany, Carlos; Freeman, Bruce A.

    2010-01-01

    Reactive oxygen species mediate a decrease in nitric oxide (NO) bioavailability and endothelial dysfunction, with secondary oxidized and nitrated byproducts of these reactions contributing to the pathogenesis of numerous vascular diseases. While oxidized lipids and lipoproteins exacerbate inflammatory reactions in the vasculature, in stark contrast the nitration of polyunsaturated fatty acids and complex lipids yield electrophilic products that exhibit pluripotent anti-inflammatory signaling capabilities acting via both cGMP-dependent and -independent mechanisms. Herein we report that nitro-oleic acid (OA-NO2) treatment increases expression of endothelial nitric oxide synthase (eNOS) and heme oxygenase 1 (HO-1) in the vasculature, thus transducing vascular protective effects associated with enhanced NO production. Administration of OA-NO2 via osmotic pump results in a significant increase in eNOS and HO-1 mRNA in mouse aortas. Moreover, HPLC-MS/MS analysis showed that NO2-FAs are rapidly metabolized in cultured endothelial cells (ECs) and treatment with NO2-FAs stimulated the phosphorylation of eNOS at Ser1179. These post-translational modifications of eNOS, in concert with elevated eNOS gene expression, contributed to an increase in endothelial NO production. In aggregate, OA-NO2-induced eNOS and HO-1 expression by vascular cells can induce beneficial effects on endothelial function and provide a new strategy for treating various vascular inflammatory and hypertensive disorders. PMID:19857569

  13. Induction of electrophile-responsive element (EpRE)-mediated gene expression by tomato extracts in vitro.

    PubMed

    Gijsbers, Linda; van Eekelen, Henriëtte D L M; Nguyen, Thuy H; de Haan, Laura H J; van der Burg, Bart; Aarts, Jac M M J G; Rietjens, Ivonne M C M; Bovy, Arnaud G

    2012-12-01

    The market for food products with additional health benefits is increasing rapidly and tools for identification of bio-functional characteristics of food items are essential. To facilitate the detection of beneficial effects of tomato on gene expression, methods to prepare tomato extracts suitable to test in the EpRE LUX assay and other cell-based reporter gene assays for health-related bioactivity mechanisms, were developed. An isoprenoid-containing chloroform extract of tomato fruit and most individual isoprenoids did not induce electrophile-responsive element (EpRE)-mediated gene expression. A semi-polar extract of tomato fruits, enzymatically hydrolysed to remove the glycosyl residues from the phenolic ingredients was able to induce EpRE-mediated luciferase expression at both mRNA and protein level, which might be partly due to the presence of quercetin, kaempferol, naringenin and naringenin chalcone. It was concluded that induction of EpRE-regulated genes, such as detoxifying phase II and antioxidant enzymes, may contribute to the beneficial health effects of tomato.

  14. Understanding the participation of quadricyclane as nucleophile in polar [2sigma + 2sigma + 2pi] cycloadditions toward electrophilic pi molecules.

    PubMed

    Domingo, Luis R; Saéz, José A; Zaragozá, Ramón J; Arnó, Manuel

    2008-11-21

    The formal [2sigma + 2sigma + 2pi] cycloaddition of quadricyclane, 1, with dimethyl azodicarboxylate, 2, in water has been studied using DFT methods at the B3LYP/6-31G** and MPWB1K/6-31G** levels. In the gas phase, the reaction of 1 with 2 has a two-stage mechanism with a large polar character and an activation barrier of 23.2 kcal/mol. Inclusion of water through a combined discrete-continuum model changes the mechanism to a two-step model where the first nucleophilic attack of 1 to 2 is the rate-limiting step with an activation barrier of 14.7 kcal/mol. Analysis of the electronic structure of the transition state structures points out the large zwitterionic character of these species. A DFT analysis of the global electrophilicity and nucleophilicity of the reagents provides a sound explanation about the participation of 1 as a nucleophile in these cycloadditions. This behavior is reinforced by a further study of the reaction of 1 with 1,1-dicyanoethylene.

  15. How amino and nitro substituents direct electrophilic aromatic substitution in benzene: an explanation with Kohn-Sham molecular orbital theory and Voronoi deformation density analysis.

    PubMed

    Stasyuk, O A; Szatylowicz, H; Krygowski, T M; Fonseca Guerra, C

    2016-04-28

    The substituent effect of the amino and nitro groups on the electronic system of benzene has been investigated quantum chemically using quantitative Kohn-Sham molecular orbital theory and a corresponding energy decomposition analysis (EDA). The directionality of electrophilic substitution in aniline can accurately be explained with the amount of contribution of the 2pz orbitals on the unsubstituted carbon atoms to the highest occupied π orbital. For nitrobenzene, the molecular π orbitals cannot explain the regioselectivity of electrophilic substitution as there are two almost degenerate π orbitals with nearly the same 2pz contributions on the unsubstituted carbon atoms. The Voronoi deformation density analysis has been applied to aniline and nitrobenzene to obtain an insight into the charge rearrangements due to the substituent. This analysis method identified the orbitals involved in the C-N bond formation of the π system as the cause for the π charge accumulation at the ortho and para positions in the case of the NH2 group and the largest charge depletion at these same positions for the NO2 substituent. Furthermore, we showed that it is the repulsive interaction between the πHOMO of the phenyl radical and the πHOMO of the NH2 radical that is responsible for pushing up the πHOMO of aniline and therefore activating this π orbital of the phenyl ring towards electrophilic substitution.

  16. Potential inhibitors of L-asparagine biosynthesis. 5. Electrophilic amide analogues of (S)-2,3-diaminopropionic acid.

    PubMed

    Mokotoff, M; Logue, L W

    1981-05-01

    Three electrophilic amide analogues of (S)-2,3-diaminopropionic acid (1, DAP) have been prepared as potential inhibitors of L-asparagine synthetase (ASase, from Novikoff hepatoma, EC 6.3.5.4). DAP was selectively blocked by the carbobenzoxy (Cbz) group to give 3-N-Cbz-DAP (2a). Esterification of 2a with isobutylene afforded tert-butyl 3-N-carbobenzoxy-(S)-2,3-diaminopropionate (3a), which was then blocked at the 2 position with the tert-butoxycarbonyl (Boc) group to give tert-butyl 2-[(S)-(tert-butoxycarbonyl)amino]-3-[(carbobenzoxy)amino]propionate (4). Selective cleavage of the Cbz group by H2/Pd gave the key intermediate tert-butyl 2-N-(tert-butoxycarbonyl)-(S)-2,3-diaminopropionate (5), which was acylated, via the N-hydroxysuccinimide esters, with bromoacetic acid, dichloroacetic acid, and fumaric acid monoethyl ester to give tert-butyl 2-[(S)-(tert-butoxycarbonyl)-amino]-3-(2-bromoacetamido)propionate (6a), tert-butyl 2-[(S)-(tert-butoxycarbonyl)amino]-3-(2,2-dichloroacetamido)propionate (6b), and tert-butyl 2-[(S)-(tert-butoxycarbonyl)amino]-3-(ethoxycarbonyl)acrylamido]-propionate (6c), respectively. Deblocking of 6a-c gave the corresponding amino acids (S)-2-amino-3-(2-bromoacetamido)propionic acid hydrobromide (7a), (S)-2-amino-3-(2,2-dichloroacetamido)propionic acid (7b), and ethyl N-[(S)-2-amino-2-carboxyethyl]fumarate (7c). By a slightly different procedure, 5 was converted in two steps to (S)-2-amino-3-acetamidopropionic acid hydrobromide (7d). The inhibition of ASase by 7a-c at 1 mM was 93, 19, and 37%, respectively, while 7d was without inhibition at 2 mM. Compounds 7a-c failed to increase the life span of mice infected with B16 melanoma.

  17. Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations.

    PubMed

    Mambo, Elizabeth; Gao, Xiangqun; Cohen, Yoram; Guo, Zhongmin; Talalay, Paul; Sidransky, David

    2003-02-18

    mtDNA mutations occur in a wide variety of degenerative diseases and cancer. mtDNA seems to be more susceptible to DNA damage and consequently sustains higher rates of mutation than does nuclear DNA (nDNA). Many of the somatic mtDNA mutations in human cancers are located in the displacement loop (D-loop) and in particular in a polycytidine stretch (C-tract) termed D310. The D310 region exhibits polymorphic length variation among individuals and has been described as a "hot spot" for somatic mutations in many cancer types. We used real-time quantitative PCR to analyze mtDNA integrity, damage repair, and induced mutations after exposure of human adult retinal pigment epithelial (ARPE)-19 cells to 4-nitroquinoline 1-oxide, a UV-mimetic and adduct-forming carcinogen, and tert-butyl hydroperoxide, an oxidant. The mtDNA-damage profile depended on the region. Thus, the tRNA coding for glycine (tRNA(G)) was the least affected region, whereas the D-loop, and especially its D310 region, were most sensitive to damage. The time course of repair of mutations of the D-loop and especially the D310 region after exposure to DNA-damaging agents was delayed when compared with other regions and gave rise to common D310 C-tract frame-shift mutations. The induced mutations in the D310 region were predominantly homoplasmic only 7 days after exposure to damage. Our results establish that the D-loop (especially its D310 region) is highly susceptible to mutations because of its vulnerability to DNA damage and inefficient repair mechanisms. Our findings may explain the high frequency of homoplasmic D310 somatic mutations in many tumor types.

  18. Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation.

    PubMed

    Diaz-Amarilla, Pablo; Miquel, Ernesto; Trostchansky, Andrés; Trias, Emiliano; Ferreira, Ana M; Freeman, Bruce A; Cassina, Patricia; Barbeito, Luis; Vargas, Marcelo R; Rubbo, Homero

    2016-06-01

    Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed in tissues during inflammation, which are able to induce pleiotropic cytoprotective and antioxidant pathways including up regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) responsive genes. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons associated to an inflammatory process that usually aggravates the disease progression. In ALS animal models, the activation of the transcription factor Nrf2 in astrocytes confers protection to neighboring neurons. It is currently unknown whether NO2-FA can exert protective activity in ALS through Nrf2 activation. Herein we demonstrate that nitro-arachidonic acid (NO2-AA) or nitro-oleic acid (NO2-OA) administrated to astrocytes expressing the ALS-linked hSOD1(G93A) induce antioxidant phase II enzyme expression through Nrf2 activation concomitant with increasing intracellular glutathione levels. Furthermore, treatment of hSOD1(G93A)-expressing astrocytes with NO2-FA prevented their toxicity to motor neurons. Transfection of siRNA targeted to Nrf2 mRNA supported the involvement of Nrf2 activation in NO2-FA-mediated protective effects. Our results show for the first time that NO2-FA induce a potent Nrf2-dependent antioxidant response in astrocytes capable of preventing motor neurons death in a culture model of ALS. PMID:27012417

  19. Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation.

    PubMed

    Diaz-Amarilla, Pablo; Miquel, Ernesto; Trostchansky, Andrés; Trias, Emiliano; Ferreira, Ana M; Freeman, Bruce A; Cassina, Patricia; Barbeito, Luis; Vargas, Marcelo R; Rubbo, Homero

    2016-06-01

    Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed in tissues during inflammation, which are able to induce pleiotropic cytoprotective and antioxidant pathways including up regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) responsive genes. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons associated to an inflammatory process that usually aggravates the disease progression. In ALS animal models, the activation of the transcription factor Nrf2 in astrocytes confers protection to neighboring neurons. It is currently unknown whether NO2-FA can exert protective activity in ALS through Nrf2 activation. Herein we demonstrate that nitro-arachidonic acid (NO2-AA) or nitro-oleic acid (NO2-OA) administrated to astrocytes expressing the ALS-linked hSOD1(G93A) induce antioxidant phase II enzyme expression through Nrf2 activation concomitant with increasing intracellular glutathione levels. Furthermore, treatment of hSOD1(G93A)-expressing astrocytes with NO2-FA prevented their toxicity to motor neurons. Transfection of siRNA targeted to Nrf2 mRNA supported the involvement of Nrf2 activation in NO2-FA-mediated protective effects. Our results show for the first time that NO2-FA induce a potent Nrf2-dependent antioxidant response in astrocytes capable of preventing motor neurons death in a culture model of ALS.

  20. Dechalcogenative Allylic Selenosulfide And Disulfide Rearrangements: Complementary Methods For The Formation Of Allylic Sulfides In The Absence Of Electrophiles. Scope, Limitations, And Application To The Functionalization Of Unprotected Peptides In Aqueous Media

    PubMed Central

    Crich, David; Krishnamurthy, Venkataramanan; Brebion, Franck; Karatholuvhu, Maheswaran; Subramanian, Venkataraman; Hutton, Thomas K.

    2008-01-01

    Primary allylic selenosulfates (seleno Bunte salts) and selenocyanates transfer the allylic selenide moiety to thiols giving primary allylic selenosulfides, which undergo rearrangement in the presence of PPh3 with the loss of selenium to give allylically rearranged allyl alkyl sulfides. This rearrangement may be conducted with prenyl-type selenosulfides to give isoprenyl alkyl sulfides. Alkyl secondary and tertiary allylic disulfides, formed by sulfide transfer from allylic heteroaryl disulfides to thiols, undergo desulfurative allylic rearrangement on treatment with PPh3 in methanolic acetonitrile at room temperature. With nerolidyl alkyl disulfides this rearrangement provides an electrophile-free method for the introduction of the farnesyl chain onto thiols. Both rearrangements are compatible with the full range of functionality found in the proteinogenic amino acids and it is demonstrated that the desulfurative rearrangement functions in aqueous media, enabling the derivatization of unprotected peptides. It is also demonstrated that the allylic disulfide rearrangement can be inducted in the absence of phosphine at room temperature by treatment with piperidine, or simply by refluxing in methanol. Under these latter conditions the reaction is also applicable to allyl aryl disulfides, providing allylically rearranged allyl aryl sulfides in good yields. PMID:17655306

  1. Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity.

    PubMed

    Geohagen, Brian C; Vydyanathan, Amaresh; Kosharskyy, Boleslav; Shaparin, Naum; Gavin, Terrence; LoPachin, Richard M

    2016-06-01

    Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2',4',6'-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis. PMID:27029584

  2. The role of the catecholic and the electrophilic moieties of caffeic acid in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines.

    PubMed

    Sirota, R; Gibson, D; Kohen, R

    2015-01-01

    In recent years, numerous studies have demonstrated the health benefits of polyphenols. A major portion of polyphenols in western diet are derived from coffee, which is one of the most consumed beverages in the world. It has been shown that many polyphenols gain their beneficial properties (e.g. cancer prevention) through the activation of the Nrf2/Keap1 pathway as well as their direct antioxidant activity. However, activation of Nrf2 in cancer cells might lead to resistance towards therapy through induction of phase II enzymes. In the present work we hypothesize that caffeic acid (CA), a coffee polyphenol, might act as an electrophile in addition to its nucleophilic properties and is capable of inducing the Nrf2/EpRE pathway in cancer cells. The results indicate that CA induces Nrf2 translocation into the nucleus and consequently its transcription. It has been demonstrated that generated hydrogen peroxide is involved in the induction process. It has also been found that this process is induced predominantly via the double bond in CA (Michael acceptor). However, surprisingly the presence of both nucleophilic and electrophilic moieties in CA resulted in a synergetic activation of Nrf2 and phase II enzymes. We also found that CA possesses a dual activity, although inducing GSTP1 and GSR, it inhibiting their enzymatic activity. In conclusion, the mechanism of induction of Nrf2 pathway and phase II enzymes by CA has been elucidated. The electrophilic moiety in CA is essential for the oxidation of the Keap1 protein. It should be noted that while the nucleophilic moiety (the catechol/quinone moiety) can provide scavenging ability, it cannot contribute directly to Nrf2 induction. It was found that this process may be induced by H2O2 produced by the catechol group. On the whole, it appears that CA might play a major role in the cancer cells by enhancing their resistance to treatment.

  3. Participation of covalent modification of Keap1 in the activation of Nrf2 by tert-butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole

    SciTech Connect

    Abiko, Yumi; Miura, Takashi; Phuc, Bui Hoang; Shinkai, Yasuhiro; Kumagai, Yoshito

    2011-08-15

    Butylated hydroxyanisole (BHA) is an antioxidant and class-2B carcinogen. It is biotransformed to tert-butylhydroquinone (TBHQ), which readily auto-oxidizes to the electrophilic metabolite tert-butylbenzoquinone (TBQ). BHA and TBHQ activate Nrf2, a transcription factor that is negatively regulated by Keap1 and plays a role in the initial response to chemicals causing oxidative or electrophilic stress, although, the exact mechanism of Nrf2 activation remains unclear. Here, we examined the role of TBQ in Nrf2 activation. Exposure of RAW264.7 cells to TBQ activated Nrf2 and up-regulated its downstream proteins; under these conditions, TBQ produced cellular reactive oxygen species (ROS). However, while pretreatment with catalase conjugated with polyethylene glycol (PEG-CAT) did not affect the TBQ-induced activation of Nrf2, the ROS generation caused by TBQ was entirely abolished by PEG-CAT, suggesting that ROS is not the dominant factor for TBQ-dependent Nrf2 activation. A click chemistry technique indicated that TBQ chemically modifies Keap1. Furthermore, ultrahigh performance liquid chromatography-tandem mass spectrometry analysis with purified Keap1 revealed that TBQ covalently binds to Keap1 through Cys23, Cys151, Cys226, and Cys368. These results suggest that TBQ derived from BHA activates Nrf2 through electrophilic modification of Keap1 rather than ROS formation. - Research Highlights: > tert-Butylbenzoquinone (TBQ) activates Nrf2 in RAW264.7 cells. > ROS is not essential factor for Nrf2 activation caused by TBQ. > TBQ covalently binds to Keap1 through reactive thiols, resulting in Nrf2 activation.

  4. Electrophilic Components of Diesel Exhaust Particles (DEP) Activate Transient Receptor Potential Ankyrin-1 (TRPA1): A Probable Mechanism of Acute Pulmonary Toxicity for DEP

    PubMed Central

    Deering-Rice, Cassandra E.; Romero, Erin G.; Shapiro, Darien; Hughen, Ronald W.; Light, Alan R.; Yost, Garold S.; Veranth, John M.; Reilly, Christopher A.

    2011-01-01

    Inhalation of environmental particulate matter (PM) is correlated with adverse health effects in humans, but gene products that couple detection with cellular responses, and the specific properties of PM that target different pathways, have not been fully elucidated. TRPA1 and V1 are two cation channels expressed by sensory neurons and non-neuronal cells of the respiratory tract that have been implicated as possible mediators of PM toxicity. The goals of this research were to determine if environmental PM preferentially activated TRPA1 and to elucidate the criteria responsible for selectivity. Quantification of TRPA1 activation by 4 model PM revealed that diesel exhaust PM (DEP) and coal fly ash PM (CFA1) were TRPA1 agonists at concentrations >0.077 mg/ml. DEP was more potent and approximately 97% of the activity of DEP was recovered by serial extraction of the solid DEP with ethanol and hexane:n-butyl chloride. Modification of the electrophile/agonist binding sites on TRPA1 (C621, C641, C665 and K710) to non-nucleophilic residues reduced TRPA1 activation by DEP and abolished activation by DEP extracts as well as multiple individual electrophilic chemical components of DEP. However, responses to CFA1 and DEP solids were not affected by these mutations. Activity-guided fractionation of DEP and high resolution mass spectroscopy identified several new DEP-derived TRPA1 agonists and activation of mouse dorsal root ganglion neurons demonstrated TRPA1 is a primary target for DEP in a heterogeneous population of primary sensory nerves. It is concluded that TRPA1 is a specific target for electrophilic chemical components of DEP and proposed that activation of TRPA1 in the respiratory tract is likely to be an important mechanism for DEP pneumotoxicity. PMID:21591660

  5. New methodology for the preparation of 3-hydroxy-2-pyridinone (3,2-HOPO) chelators - Reaction of amines with a novel electrophilic 3,2-HOPO precursor

    PubMed Central

    Lambert, Timothy N.; Chittamuru, Sumathi; Jacobs, Hollie K.; Gopalan, Aravamudan S.

    2012-01-01

    The preparation of the new electrophilic iminium ester mesylate salt 5 and its reaction with primary and secondary amines have been investigated. Aniline, t-butylamine, and secondary amines react with 5 via ring opening to give the corresponding HOPO derivatives in high yields. The usefulness of this methodology has been demonstrated by the preparation of two new di-HOPO derivatives 19 and 21. This method allows the introduction of the HOPO ligand onto a variety of amine platforms without the concomitant formation of an amide bond and provides access to HOPO chelators of increased water solubility. PMID:23125467

  6. Hg/Pt-catalyzed conversion of bromo alkynamines/alkynols to saturated and unsaturated γ-butyrolactams/lactones via intramolecular electrophilic cyclization.

    PubMed

    Kiran Kumar, Yalla; Ranjith Kumar, Gadi; Sridhar Reddy, Maddi

    2016-01-28

    Convenient and general Hg(ii)/Pt(iv) catalyzed syntheses of γ-butyrolactams and α,β-unsaturated γ-butyrolactones/lactams are described via intramolecular electrophilic cyclizations of bromoalkynes with tosylamino and hydroxyl tethers. The reaction features the use of wet solvents, the exclusion of any base and additive, mild conditions and practical yields. We also synthesised few chiral lactams through this pathway. Additionally, it is shown that the NHTs group distanced further from the homopropargylic position assists regioselective bromoalkyne hydration to yield useful α-bromoketones. Furthermore, Boc protected bromo homo propargyl amines undergo 6-endo-dig cyclization through Boc oxygen to give bromomethylene substituted oxazinones. PMID:26647118

  7. Emergence of electrophilic alumination as the counterpart of established nucleophilic lithiation: an academic sojourn in organometallics with William Kaska as fellow traveler.

    PubMed

    Eisch, John J

    2015-04-21

    William Kaska pursued doctoral studies with John Eisch in mechanistic organometallic chemistry, first with organolithium reactions at St. Louis University and then at the University of Michigan with organoaluminum reactions. Thereby he revealed the change in mechanism from nucleophilic lithiation and carbolithiation to that of electrophilic alumination, carboalumination and hydroalumination of organic substrates, which reactions were previously observed by Karl Ziegler in his empirical studies of organoaluminum reactions. Our findings were the first mechanistic studies attempting to set such Ziegler chemistry on a modern theoretical basis. PMID:25820225

  8. Sterically Demanding Unsymmetrical Diaryl-λ3-iodanes for Electrophilic Pentafluorophenylation and an Approach to α-Pentafluorophenyl Carbonyl Compounds with an All-Carbon Stereocenter

    PubMed Central

    Matsuzaki, Kohei; Okuyama, Kenta; Tokunaga, Etsuko; Shiro, Motoo; Shibata, Norio

    2014-01-01

    A sterically demanding unsymmetrical pentafluorophenyl-triisopropylphenyl-λ3-iodane was developed as an effective reagent for the electrophilic pentafluorophenylation of various β-keto esters and a β-keto amide. 17 examples of α-pentafluorophenylated 1,3-dicarbonyl compounds 3 having a quaternary carbon center are provided. The resulting compounds were nicely transformed into chiral α-pentafluorophenyl ketones with an all-carbon stereogenic center in high yields and high enantioselectivities using asymmetric organocatalysis (up to 98 % ee) or asymmetric metal catalysis (up to 82 % ee). PMID:25558441

  9. Emergence of electrophilic alumination as the counterpart of established nucleophilic lithiation: an academic sojourn in organometallics with William Kaska as fellow traveler.

    PubMed

    Eisch, John J

    2015-04-21

    William Kaska pursued doctoral studies with John Eisch in mechanistic organometallic chemistry, first with organolithium reactions at St. Louis University and then at the University of Michigan with organoaluminum reactions. Thereby he revealed the change in mechanism from nucleophilic lithiation and carbolithiation to that of electrophilic alumination, carboalumination and hydroalumination of organic substrates, which reactions were previously observed by Karl Ziegler in his empirical studies of organoaluminum reactions. Our findings were the first mechanistic studies attempting to set such Ziegler chemistry on a modern theoretical basis.

  10. Mass spectrometric analysis of 7-sulfoxymethyl-12-methylbenz[a]anthracene and related electrophilic polycyclic aromatic hydrocarbon metabolites.

    PubMed

    Lehner, Andreas F; Horn, Jamie; Flesher, James W

    2004-11-01

    The Meso-region theory of polycyclic aromatic hydrocarbon (PAH) carcinogenesis predicts that the development of pronounced carcinogenicity depends on the introduction of a good leaving group on alkyl side-chains attached to the exceptionally reactive meso-anthracenic or L-region positions of PAHs. Thus, the first step in carcinogenesis by methylated PAHs such as 7,12-dimethylbenz[a]anthracene (DMBA) would be the hydroxylation of the L-region methyl groups, particularly the 7-methyl group. The second would be the formation of a metabolite, e.g. a sulfate ester, which is expected to be a good leaving group capable of generating a highly reactive benzylic carbocation. 7-Hydroxymethyl-12-methylbenz[a]anthracene (7-HMBA) is a metabolite of DMBA, and sulfation of 7-HMBA to a 7-sulfoxymethyl metabolite (7-SMBA) is a known Phase II metabolic process designed to facilitate excretion, but actually enabling more destructive side-reactions. These side-reactions occur with generation of an electrophilic 7-methylene carbonium ion, and/or by in vivo halide exchange to provide neutral side-products more capable of entering cells, especially those of DMBA target tissues. Electrospray ionization mass spectrometry (MS) enabled us to visualize 7-SMBA as an intact m/z 351 conjugate anion by negative mode, and as a released m/z 255 carbonium ion by positive mode. Upon prolonged refrigeration, 7-SMBA accumulated an m/z 383 photooxide, which appeared capable of re-evolving the starting material as visualized by tandem quadrupole MS, or MS/MS. The 7-SMBA carbonium ion provided interpretable fragments when studied by fragment ion MS/MS, including those representing the loss of up to several protons. Subtle differences in this property were encountered upon perturbing 7-SMBA, either by warming it at 37 degrees C for 2 h or by substituting the initial sulfoxy group with an iodo group. Side-reactions accounting for such proton losses are proposed, and are of interest whether they occur in the

  11. Mass spectrometric analysis of 7-sulfoxymethyl-12-methylbenz[a]anthracene and related electrophilic polycyclic aromatic hydrocarbon metabolites.

    PubMed

    Lehner, Andreas F; Horn, Jamie; Flesher, James W

    2004-11-01

    The Meso-region theory of polycyclic aromatic hydrocarbon (PAH) carcinogenesis predicts that the development of pronounced carcinogenicity depends on the introduction of a good leaving group on alkyl side-chains attached to the exceptionally reactive meso-anthracenic or L-region positions of PAHs. Thus, the first step in carcinogenesis by methylated PAHs such as 7,12-dimethylbenz[a]anthracene (DMBA) would be the hydroxylation of the L-region methyl groups, particularly the 7-methyl group. The second would be the formation of a metabolite, e.g. a sulfate ester, which is expected to be a good leaving group capable of generating a highly reactive benzylic carbocation. 7-Hydroxymethyl-12-methylbenz[a]anthracene (7-HMBA) is a metabolite of DMBA, and sulfation of 7-HMBA to a 7-sulfoxymethyl metabolite (7-SMBA) is a known Phase II metabolic process designed to facilitate excretion, but actually enabling more destructive side-reactions. These side-reactions occur with generation of an electrophilic 7-methylene carbonium ion, and/or by in vivo halide exchange to provide neutral side-products more capable of entering cells, especially those of DMBA target tissues. Electrospray ionization mass spectrometry (MS) enabled us to visualize 7-SMBA as an intact m/z 351 conjugate anion by negative mode, and as a released m/z 255 carbonium ion by positive mode. Upon prolonged refrigeration, 7-SMBA accumulated an m/z 383 photooxide, which appeared capable of re-evolving the starting material as visualized by tandem quadrupole MS, or MS/MS. The 7-SMBA carbonium ion provided interpretable fragments when studied by fragment ion MS/MS, including those representing the loss of up to several protons. Subtle differences in this property were encountered upon perturbing 7-SMBA, either by warming it at 37 degrees C for 2 h or by substituting the initial sulfoxy group with an iodo group. Side-reactions accounting for such proton losses are proposed, and are of interest whether they occur in the

  12. Electrophilic addition of astatine

    SciTech Connect

    Norseev, Yu.V.; Vasaros, L.; Nhan, D.D.; Huan, N.K.

    1988-03-01

    It has been shown for the first time that astatine is capable of undergoing addition reactions to unsaturated hydrocarbons. A new compound of astatine, viz., ethylene astatohydrin, has been obtained, and its retention numbers of squalane, Apiezon, and tricresyl phosphate have been found. The influence of various factors on the formation of ethylene astatohydrin has been studied. It has been concluded on the basis of the results obtained that the univalent cations of astatine in an acidic medium is protonated hypoastatous acid.

  13. Electrophilic Addition to Alkenes: The Relation between Reactivity and Enthalpy of Hydrogenation: Regioselectivity is Determined by the Stability of the Two Conceivable Products.

    PubMed

    Schnatter, Wayne F K; Rogers, Donald W; Zavitsas, Andreas A

    2015-07-13

    Although electrophilic addition to alkenes has been well studied, some secrets still remain. Halogenations, hydrohalogenations, halohydrin formations, hydrations, epoxidations, other oxidations, carbene additions, and ozonolyses are investigated to elucidate the relation of alkene reactivities with their enthalpies of hydrogenation (ΔHhyd ). For addition of electrophiles to unconjugated hydrocarbon alkenes, ln(k) is a linear function of ΔHhyd , where k is the rate constant. Linear correlation coefficients are about 0.98 or greater. None of the many previously proposed correlations of ln(k) with the properties of alkenes or with linear free-energy relationships match the generality and accuracy of the simple linear relationship found herein. A notable exception is acid-catalyzed hydration in water or in solvents stabilizing relatively stable carbocation intermediates (e.g., tertiary, benzylic, or allylic). (13) C NMR chemical shifts of the two alkene carbons also predict regioselectivity. These effects have not been noted previously and are operative in general, including addition to heteroatom-substituted alkenes.

  14. The efficiency of the metal catalysts in the nucleophilic substitution of alcohols is dependent on the nucleophile and not on the electrophile.

    PubMed

    Biswas, Srijit; Samec, Joseph S M

    2013-05-01

    In this study, we investigate the effect of the electrophiles and the nucleophiles for eight catalysts in the catalytic SN 1 type substitution of alcohols with different degree of activation by sulfur-, carbon-, oxygen-, and nitrogen-centered nucleophiles. The catalysts do not show any general variance in efficiency or selectivity with respect to the alcohols and follow the trend of alcohol reactivity. However, when it comes to the nucleophile, the eight catalysts show general and specific variances in the efficiency and selectivity to perform the desired substitution. Interestingly, the selectivity of the alcohols to produce the desired substitution products was found to be independent of the electrophilicity of the generated carbocations but highly dependent on the ease of formation of the cation. Catalysts based on iron(III), bismuth(III), and gold(III) show higher conversions for S-, C-, and N-centered nucleophiles, and Bi(III) was the most efficient catalyst in all combinations. Catalysts based on rhenium(I) or rhenium(VII), palladium(II), and lanthanum(III) were the most efficient in performing the nucleophilic substitution on the various alcohols with the O-centered nucleophiles. These catalysts generate the symmetrical ether as a by-product from the reactions of S-, C-, and N-centered nucleophiles as well, resulting in lower chemoselectivity. PMID:23471850

  15. Isotope-Labeling Studies Support the Electrophilic Compound I Iron Active Species, FeO(3+), for the Carbon-Carbon Bond Cleavage Reaction of the Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P450 11A1.

    PubMed

    Yoshimoto, Francis K; Jung, I-Ji; Goyal, Sandeep; Gonzalez, Eric; Guengerich, F Peter

    2016-09-21

    The enzyme cytochrome P450 11A1 cleaves the C20-C22 carbon-carbon bond of cholesterol to form pregnenolone, the first 21-carbon precursor of all steroid hormones. Various reaction mechanisms are possible for the carbon-carbon bond cleavage step of P450 11A1, and most current proposals involve the oxoferryl active species, Compound I (FeO(3+)). Compound I can either (i) abstract an O-H hydrogen atom or (ii) be attacked by a nucleophilic hydroxy group of its substrate, 20R,22R-dihydroxycholesterol. The mechanism of this carbon-carbon bond cleavage step was tested using (18)O-labeled molecular oxygen and purified P450 11A1. P450 11A1 was incubated with 20R,22R-dihydroxycholesterol in the presence of molecular oxygen ((18)O2), and coupled assays were used to trap the labile (18)O atoms in the enzymatic products (i.e., isocaproaldehyde and pregnenolone). The resulting products were derivatized and the (18)O content was analyzed by high-resolution mass spectrometry. P450 11A1 showed no incorporation of an (18)O atom into either of its carbon-carbon bond cleavage products, pregnenolone and isocaproaldehyde . The positive control experiments established retention of the carbonyl oxygens in the enzymatic products during the trapping and derivatization processes. These results reveal a mechanism involving an electrophilic Compound I species that reacts with nucleophilic hydroxy groups in the 20R,22R-dihydroxycholesterol intermediate of the P450 11A1 reaction to produce the key steroid pregnenolone.

  16. Heme oxygenase (HO-1). Evidence for electrophilic oxygen addition to the porphyrin ring in the formation of alpha-meso-hydroxyheme.

    PubMed

    Wilks, A; Torpey, J; Ortiz de Montellano, P R

    1994-11-25

    Previous studies have established that reaction of the rat heme-heme oxygenase complex with H2O2 proceeds normally to give verdoheme, whereas reaction of the complex with meta-chloroperbenzoic acid yields a ferryl (FeIV = O) species and a protein radical but no verdoheme. The heme-heme oxygenase complex is shown here to react regiospecifically with ethyl hydroperoxide to give alpha-meso-ethoxyheme. Formation of this product exactly parallels the formation of alpha-meso-hydroxyheme in the normal reaction supported by cytochrome P450 reductase/NADPH or H2O2. These results rule out a nucleophilic mechanism for the alpha-meso-hydroxylation catalyzed by heme oxygenase and indicate that it involves electrophilic (or possibly radical) addition of the distal oxygen of iron-bound peroxide (FeIII-OOH) to the porphyrin ring.

  17. N-Acylsaccharins: Stable Electrophilic Amide-Based Acyl Transfer Reagents in Pd-Catalyzed Suzuki-Miyaura Coupling via N-C Cleavage.

    PubMed

    Liu, Chengwei; Meng, Guangrong; Liu, Yongmei; Liu, Ruzhang; Lalancette, Roger; Szostak, Roman; Szostak, Michal

    2016-09-01

    The development of efficient catalytic methods for N-C bond cleavage in amides remains an important synthetic challenge. The first Pd-catalyzed Suzuki-Miyaura cross-coupling of N-acylsaccharins with boronic acids by selective N-C bond activation is reported. The reaction enables preparation of a variety of functionalized diaryl and alkyl-aryl ketones with broad functional group tolerance and in good to excellent yields. Of general interest, N-acylsaccharins serve as new, highly reactive, bench-stable, economical, amide-based, electrophilic acyl transfer reagents via acyl-metal intermediates. Mechanistic studies strongly support the amide N-C(O) bond twist as the enabling feature of N-acylsaccharins in the N-C bond cleavage. PMID:27513821

  18. Nickel-Catalyzed Alkyl–Alkyl Cross-Couplings of Fluorinated Secondary Electrophiles: A General Approach to the Synthesis of Compounds that Bear a Perfluoroalkyl Substituent**

    PubMed Central

    Liang, Yufan

    2015-01-01

    Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Herein, we describe a mild, convenient, and versatile method for the synthesis of compounds that bear a perfluoroalkyl group attached to a tertiary carbon, via an alkyl–alkyl cross-coupling. Thus, a nickel catalyst derived from commercially available components (NiCl2·glyme and a pybox ligand) achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups (e.g., alkyne, aryl iodide, carbamate, furan, ketone, nitrile, phosphonate, primary alkyl bromide, and primary alkyl tosylate) are compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of TEMPO inhibits cross-coupling under these conditions and that a TEMPO–electrophile adduct can be isolated. PMID:26073669

  19. A versatile approach to Ullmann C-N couplings at room temperature: new families of nucleophiles and electrophiles for photoinduced, copper-catalyzed processes.

    PubMed

    Ziegler, Daniel T; Choi, Junwon; Muñoz-Molina, José María; Bissember, Alex C; Peters, Jonas C; Fu, Gregory C

    2013-09-01

    The use of light to facilitate copper-catalyzed cross-couplings of nitrogen nucleophiles can enable C-N bond formation to occur under unusually mild conditions. In this study, we substantially expand the scope of such processes, establishing that this approach is not limited to reactions of carbazoles with iodobenzene and alkyl halides. Specifically, we demonstrate for the first time that other nitrogen nucleophiles (e.g., common pharmacophores such as indoles, benzimidazoles, and imidazoles) as well as other electrophiles (e.g., hindered/deactivated/heterocyclic aryl iodides, an aryl bromide, an activated aryl chloride, alkenyl halides, and an alkynyl bromide) serve as suitable partners. Photoinduced C-N bond formation can be achieved at room temperature using a common procedure with an inexpensive catalyst (CuI) that does not require a ligand coadditive and is tolerant of moisture and a variety of functional groups. PMID:23968565

  20. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents

    SciTech Connect

    Higgins, Larry G.; Kelleher, Michael O.; Eggleston, Ian M.; Itoh, Ken; Yamamoto, Masayuki; Hayes, John D.

    2009-06-15

    Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2{sup -/-} MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 {mu}mol/l sulforaphane was very substantially lower in Nrf2{sup -/-} MEFs than in wild-type cells, and the rebound leading to a {approx} 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2{sup +/+} MEFs were treated with sulforaphane was not observed in Nrf2{sup -/-} fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 {mu}mol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, {alpha},{beta}-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2{sup +/+} MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2{sup -/-} MEFs were typically {approx} 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanism stimulated by sulforaphane, 5 {mu}mol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2{sup +/+} MEFs pre-treated with sulforaphane, BSO diminished intrinsic resistance and abolished inducible resistance to acrolein, CuOOH and chlorambucil, but not menadione. Thus Nrf2-dependent up-regulation of GSH is the principal mechanism by which sulforaphane pre-treatment induced resistance to acrolein, CuOOH and chlorambucil, but not menadione.

  1. Symmetrically tetrasubstituted [2.2]paracyclophanes: their systematization and regioselective synthesis of several types of bis-bifunctional derivatives by double electrophilic substitution.

    PubMed

    Vorontsova, Natalia V; Rozenberg, Valeria I; Sergeeva, Elena V; Vorontsov, Evgenii V; Starikova, Zoya A; Lyssenko, Konstantin A; Hopf, Henning

    2008-01-01

    The possible number of chiral and achiral tetrasubstituted [2.2]paracyclophanes possessing different types of symmetry (C(2), C(i), C(s), C(2v), C(2h)) is evaluated and a unified independent trivial naming descriptor system is introduced. The reactivity and regioselectivity of the electrophilic substitution of the chiral pseudo-meta- and achiral pseudo-para-disubstituted [2.2]paracyclophanes are investigated in an approach suggested to be general for the synthesis of bis-bifunctional [2.2]paracyclophanes. The mono- and diacylation of chiral pseudo-meta-dihydroxy[2.2]paracyclophane 14 with acetylchloride occur ortho-regioselectively to produce tri- 22, 23 and symmetrically 21 tetrasubstituted acyl derivatives. The same reaction with benzoylchloride is neither regio-, nor chemoselective, and gives rise to a mixture of ortho-/para-, mono-/diacylated compounds 27-31. The double acylation of pseudo-meta-dimethoxy[2.2]paracyclophane 18 is completely para-regioselective. Electrophilic substitution of pseudo-meta-bis(methoxycarbonyl)[2.2]paracyclophane 20 regioselectively generates the pseudo-gem-substitution pattern. Formylation of this substrate produces the monocarbonyl derivatives 35 only, whereas the Fe-catalyzed bromination may be directed towards mono- 36 or disubstitution 37 products chemoselectively by varying the reactions conditions. The diacylation and dibromination reactions of the respective achiral diphenol 12 and bis(methoxycarbonyl) 40 derivatives of the pseudo-para-structure retain regioselectivities which are characteristic for their pseudo-meta-regioisomers. Imino ligands 26, 25, and 39, which were obtained from monoacyl- 22 and diacyldihydroxy[2.2]paracyclophanes 21, 38, are tested as chiral ligands in stereoselective Et(2)Zn addition to benzaldehyde producing 1-phenylpropanol with ee values up to 76 %.

  2. Ynamides in Ring Forming Transformations

    PubMed Central

    WANG, XIAO-NA; YEOM, HYUN-SUK; FANG, LI-CHAO; HE, SHUZHONG; MA, ZHI-XIONG; KEDROWSKI, BRANT L.; HSUNG, RICHARD P.

    2013-01-01

    Conspectus The ynamide functional group activates carbon-carbon triple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years. This Account surveys and assesses new organic transformations involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides. This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within, or in close proximity to, a newly formed ring (or rings). Thus, ynamides have emerged

  3. Electrophilic reactions of group-VI element halides. VIII. Reactions of selenium and tellurium tetrahalides with allyl cinnamate

    SciTech Connect

    Lendel, V.G.; Sani, A.Yu.; Balog, I.M.; Migalina, Yu.V.; Kornilov, M.Yu.; Turov, A.V.

    1988-02-20

    It was shown that, as a result of two-phase selenohalogenation or tellurohalogenation of allyl cinnamate at /minus/30 C, addition took place at the C/doteq/C bond of the allyl group; the C=C bond of the cinnamoyl moiety remained uninvolved. Selenium tetrahalides were added to allyl cinnamate in accordance with the Markownikoff rule, forming adducts with 1:2 composition; tellurium tetrahalides formed products of rearrangement of the adducts with a 1:1 composition.

  4. Tracking molecular resonance forms of donor–acceptor push–pull molecules by single-molecule conductance experiments

    PubMed Central

    Lissau, Henriette; Frisenda, Riccardo; Olsen, Stine T.; Jevric, Martyn; Parker, Christian R.; Kadziola, Anders; Hansen, Thorsten; van der Zant, Herre S. J.; Brøndsted Nielsen, Mogens; Mikkelsen, Kurt V.

    2015-01-01

    The ability of molecules to change colour on account of changes in solvent polarity is known as solvatochromism and used spectroscopically to characterize charge-transfer transitions in donor–acceptor molecules. Here we report that donor–acceptor-substituted molecular wires also exhibit distinct properties in single-molecule electronics under the influence of a bias voltage, but in absence of solvent. Two oligo(phenyleneethynylene) wires with donor–acceptor substitution on the central ring (cruciform-like) exhibit remarkably broad conductance peaks measured by the mechanically controlled break-junction technique with gold contacts, in contrast to the sharp peak of simpler molecules. From a theoretical analysis, we explain this by different degrees of charge delocalization and hence cross-conjugation at the central ring. Thus, small variations in the local environment promote the quinoid resonance form (off), the linearly conjugated (on) or any form in between. This shows how the conductance of donor–acceptor cruciforms is tuned by small changes in the environment. PMID:26667583

  5. Secondary functionalization of allyl-terminated GaP(111)A surfaces via heck cross-coupling metathesis, hydrosilylation, and electrophilic addition of bromine.

    PubMed

    Peczonczyk, Sabrina L; Brown, Elizabeth S; Maldonado, Stephen

    2014-01-14

    The functionalization of single crystalline gallium phosphide (GaP) (111)A surfaces with allyl groups has been performed using a sequential chlorine-activation/Grignard reaction process. Increased hydrophobicity following reaction of a GaP(111)A surface with C3H5MgCl was observed through water contact angle measurements. Infrared spectra of GaP(111)A samples after reaction with C3H5MgCl showed the asymmetric C═C and C═C-H modes diagnostic of surface-attached allyl groups. The stability of allyl-terminated GaP(111)A surfaces under ambient and aqueous conditions was investigated. XP spectra of allyl-terminated GaP(111)A highlighted a significant resistance against interfacial oxidation both in air and in water relative to the native interface. Electrochemical impedance spectroscopy indicated a change in the flat-band potential of allyl-terminated GaP(111)A electrodes immersed in water relative to native GaP(111)A surfaces. Further, the flat-band potentials for allyl-terminated electrodes were insensitive to changes in solution pH. The utility of surface-bound allyl groups for covalent secondary functionalization of GaP(111)A interfaces was assessed through three separate reactions: Heck cross-coupling metathesis, hydrosilylation, and electrophilic addition of bromine reactions. Addition of aryl groups across the olefins on allyl-terminated GaP(111)A via Heck cross coupling was performed and confirmed through high-resolution F 1s and C 1s XP spectra and IR spectra. Control experiments with GaP(111)A surfaces functionalized with short alkanes indicated no evidence for metathesis. Hydrosilylation reactions were separately performed. Si 2s XP spectra, in conjunction with infrared spectra, similarly showed secondary evidence of surface functionalization for allyl-terminated GaP(111)A but not for CH3-terminated GaP(111)A surfaces. Similar analyses showed electrophilic addition of Br2 across the terminal olefin on an allyl-terminated GaP(111)A surface after exposure to

  6. Inflammation Modulates RLIP76/RALBP1 Electrophile-Glutathione Conjugate Transporter and Housekeeping Genes in Human Blood-Brain Barrier Endothelial Cells

    PubMed Central

    Bennani-Baiti, Barbara; Toegel, Stefan; Viernstein, Helmut; Urban, Ernst; Noe, Christian R.; Bennani-Baiti, Idriss M.

    2015-01-01

    Endothelial cells are often present at inflammation sites. This is the case of endothelial cells of the blood-brain barrier (BBB) of patients afflicted with neurodegenerative disorders such as Alzheimer's, Parkinson's, or multiple sclerosis, as well as in cases of bacterial meningitis, trauma, or tumor-associated ischemia. Inflammation is a known modulator of gene expression through the activation of transcription factors, mostly NF-κB. RLIP76 (a.k.a. RALBP1), an ATP-dependent transporter of electrophile-glutathione conjugates, modulates BBB permeability through the regulation of tight junction function, cell adhesion, and exocytosis. Genes and pathways regulated by RLIP76 are transcriptional targets of tumor necrosis factor alpha (TNF-α) pro-inflammatory molecule, suggesting that RLIP76 may also be an inflammation target. To assess the effects of TNF-α on RLIP76, we faced the problem of choosing reference genes impervious to TNF-α. Since such genes were not known in human BBB endothelial cells, we subjected these to TNF-α, and measured by quantitative RT-PCR the expression of housekeeping genes commonly used as reference genes. We find most to be modulated, and analysis of several inflammation datasets as well as a metaanalysis of more than 5000 human tissue samples encompassing more than 300 cell types and diseases show that no single housekeeping gene may be used as a reference gene. Using three different algorithms, however, we uncovered a reference geneset impervious to TNF-α, and show for the first time that RLIP76 expression is induced by TNF-α and follows the induction kinetics of inflammation markers, suggesting that inflammation can influence RLIP76 expression at the BBB. We also show that MRP1 (a.k.a. ABCC1), another electrophile-glutathione transporter, is not modulated in the same cells and conditions, indicating that RLIP76 regulation by TNF-α is not a general property of glutathione transporters. The reference geneset uncovered herein should

  7. Permission Forms

    ERIC Educational Resources Information Center

    Zirkel, Perry A.

    2005-01-01

    The prevailing practice in public schools is to routinely require permission or release forms for field trips and other activities that pose potential for liability. The legal status of such forms varies, but they are generally considered to be neither rock-solid protection nor legally valueless in terms of immunity. The following case and the…

  8. Charge-transfer mechanism for electrophilic aromatic nitration and nitrosation via the convergence of (ab initio) molecular-orbital and Marcus-Hush theories with experiments.

    PubMed

    Gwaltney, Steven R; Rosokha, Sergiy V; Head-Gordon, Martin; Kochi, Jay K

    2003-03-19

    The highly disparate rates of aromatic nitrosation and nitration, despite the very similar (electrophilic) properties of the active species: NO(+) and NO(2)(+) in Chart 1, are quantitatively reconciled. First, the thorough mappings of the potential-energy surfaces by high level (ab initio) molecular-orbital methodologies involving extensive coupled-cluster CCSD(T)/6-31G optimizations establish the intervention of two reactive intermediates in nitration (Figure 8) but only one in nitrosation (Figure 7). Second, the same distinctive topologies involving double and single potential-energy minima (Figures 6 and 5) also emerge from the semiquantitative application of the Marcus-Hush theory to the transient spectral data. Such a striking convergence from quite different theoretical approaches indicates that the molecular-orbital and Marcus-Hush (potential-energy) surfaces are conceptually interchangeable. In the resultant charge-transfer mechanism, the bimolecular interactions of arene donors with both NO(+) and NO(2)(+) spontaneously lead (barrierless) to pi-complexes in which electron transfer is concurrent with complexation. Such a pi-complex in nitration is rapidly converted to the sigma-complex, whereas this Wheland adduct in nitrosation merely represents a high energy (transition-state) structure. Marcus-Hush analysis thus demonstrates how the strongly differentiated (arene) reactivities toward NO(+) and NO(2)(+) can actually be exploited in the quantitative development of a single coherent (electron-transfer) mechanism for both aromatic nitrosation and nitration.

  9. Roles of the Yap1 transcription factor and antioxidants in Saccharomyces cerevisiae's tolerance to furfural and 5-hydroxymethylfurfural, which function as thiol-reactive electrophiles generating oxidative stress.

    PubMed

    Kim, Daehee; Hahn, Ji-Sook

    2013-08-01

    Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1(C620F), a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF.

  10. Molecular orbital studies (hardness, chemical potential, electrophilicity, and first electron excitation), vibrational investigation and theoretical NBO analysis of 2-hydroxy-5-bromobenzaldehyde by density functional method

    NASA Astrophysics Data System (ADS)

    Nataraj, A.; Balachandran, V.; Karthick, T.

    2013-01-01

    In this work, the vibrational spectral analysis was carried out using Raman and infrared spectroscopy in the range 4000-400 cm-1 and 3500-100 cm-1, respectively, for the 2-hydroxy-5-bromobenzaldehyde (HBB). The experimental spectra were recorded in the solid phase. The fundamental vibrational frequencies and intensity of vibrational bands were evaluated using density functional theory (DFT) with the standard B3LYP/6-311G++(d,p) method and basis set. Normal co-ordinate calculations were performed with the DFT force field corrected by a recommended set of scaling factors yielding fairly good agreement between observed and calculated frequencies. Simulation of infrared and Raman spectra utilizing the results of these calculations led to excellent overall agreement with the observed spectral patterns. The complete assignments were performed on the basis of the potential energy distribution (PED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. The optimized geometric parameters (bond lengths and bond angles) were compared with experimental values of related compound. The stability of the molecule arising from hyper conjugative interactions and the charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The directly calculated ionization potential (IP), electron affinity (EA), electronegativity (χ), electrophilicity index (ω), hardness (η), chemical potential (μ), and first electron excitation (τ) are all correlated with the HOMO and LUMO energies with their molecular properties. These show that charge transfer occurs within the molecule. Furthermore, molecular electrostatic potential maps (MESP) of the molecule have been calculated.

  11. A novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms.

    PubMed

    Vayalil, Praveen K; Oh, Joo-Yeun; Zhou, Fen; Diers, Anne R; Smith, M Ryan; Golzarian, Hafez; Oliver, Patsy G; Smith, Robin A J; Murphy, Michael P; Velu, Sadanandan E; Landar, Aimee

    2015-01-01

    Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration in vitro. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins.

  12. Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells

    PubMed Central

    Unoki, Takamitsu; Abiko, Yumi; Toyama, Takashi; Uehara, Takashi; Tsuboi, Koji; Nishida, Motohiro; Kaji, Toshiyuki; Kumagai, Yoshito

    2016-01-01

    Methylmercury (MeHg) modifies cellular proteins via their thiol groups in a process referred to as “S-mercuration”, potentially resulting in modulation of the cellular signal transduction pathway. We examined whether low-dose MeHg could affect Akt signaling involved in cell survival. Exposure of human neuroblastoma SH-SY5Y cells of up to 2 μM MeHg phosphorylated Akt and its downstream signal molecule CREB, presumably due to inactivation of PTEN through S-mercuration. As a result, the anti-apoptotic protein Bcl-2 was up-regulated by MeHg. The activation of Akt/CREB/Bcl-2 signaling mediated by MeHg was, at least in part, linked to cellular defence because either pretreatment with wortmannin to block PI3K/Akt signaling or knockdown of Bcl-2 enhanced MeHg-mediated cytotoxicity. In contrast, increasing concentrations of MeHg disrupted Akt/CREB/Bcl-2 signaling. This phenomenon was attributed to S-mercuration of CREB through Cys286 rather than Akt. These results suggest that although MeHg is an apoptosis-inducing toxicant, this environmental electrophile is able to activate the cell survival signal transduction pathway at lower concentrations prior to apoptotic cell death. PMID:27357941

  13. Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

    SciTech Connect

    Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi; Hiratake, Jun; Wada, Kei

    2014-02-01

    The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.

  14. Roles of the Yap1 transcription factor and antioxidants in Saccharomyces cerevisiae's tolerance to furfural and 5-hydroxymethylfurfural, which function as thiol-reactive electrophiles generating oxidative stress.

    PubMed

    Kim, Daehee; Hahn, Ji-Sook

    2013-08-01

    Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1(C620F), a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF. PMID:23793623

  15. Mutagenicity, tumorigenicity, and electrophilic reactivity of the stereoisomeric platinum(II) complexes of 1,2-diaminocyclohexane.

    PubMed

    Leopold, W R; Batzinger, R P; Miller, E C; Miller, J A; Earhart, R H

    1981-11-01

    Without external activation, cis- and trans-dichlorodiammineplatinum(II) (DDP) and the cis, trans(-), and trans(+) forms of dichloro-1,2-diaminocyclohexaneplatinum(II) (DDCP) and sulfato-1,2-diaminocyclohexaneplatinum(II) (SHP) showed a 400-fold range of mutagenicity for Salmonella typhimurium TA100 and TA98; they were 2 to 10 times more mutagenic for strain TA100 than for strain TA98. With strain TA100, trans-DDP was less than 0.5% as mutagenic as the cis isomer, which produced 180 revertants/nmol. For the diaminocyclohexane complexes, mutagenic activity was strongly dependent on the stereoisomer of the diaminocyclohexane in the complex. Thus, with strain TA100, the trans(+) forms of DDCP and SHP produced 220 and 66 revertants/nmol, respectively, while the cis and trans(-) isomers induced only 10 and 5% as many revertants as the trans(+) forms. The SHP complexes were the most reactive toward DNA and produced a greater reduction in the transforming activity of Bacillus subtilis DNA after 3-hr reaction times than did the DDP or DDCP complexes. With 20-hr reaction times, all of the platinum complexes showed similar extents of reaction with DNA and caused approximately equal losses of transforming activity. The stereoisomeric form of the diaminocyclohexane ligand of the DDCP or SHP complexes did not affect either the reactivity of the complex with DNA or its ability to reduce the transforming activity of DNA. Significant increases in the number of lung adenomas in A/J mice were induced by multiple i.p. injections of cis-DDP and each of the DDCP and SHP complexes (total doses, 21 to 108 mumol/kg body weight). Similar treatments with cis-DDP caused a significant increase in the number of skin papillomas in female CD-1 mice given promoting treatments with croton oil; the DDCP and SHP complexes had little or no activity in this system. At these levels, trans-DDP was not active for the induction of either lung adenomas or skin tumors. With the systems used for this study

  16. Good form.

    PubMed

    Sorrel, Amy Lynn

    2015-03-01

    New standardized prior authorization forms for health care services and prescription drugs released by the Texas Department of Insurance promise to alleviate administrative busy work and its related costs.

  17. Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster.

    PubMed

    Abolaji, Amos O; Kamdem, Jean P; Lugokenski, Thiago H; Farombi, Ebenezer O; Souza, Diogo O; da Silva Loreto, Élgion L; Rocha, João B T

    2015-08-01

    The compounds 4-vinylcyclohexene 1,2-monoepoxide (VCM) and 4-Vinylcyclohexene diepoxide (VCD) are the two downstream metabolites of 4-vinylcyclohexene (VCH), an ovotoxic agent in mammals. In addition, VCM and VCD may be found as by-products of VCH oxidation in the environment. Recently, we reported the involvement of oxidative stress in the toxicity of VCH in Drosophila melanogaster. However, it was not possible to determine the individual contributions of VCM and VCD in VCH toxicity. Hence, we investigated the toxicity of VCM and VCD (10-1000 µM) in flies after 5 days of exposure via the diet. Our results indicated impairments in climbing behaviour and disruptions in antioxidant balance and redox status evidenced by an increase in DCFH oxidation, decreases in total thiol content and glutathione-S-transferase (GST) activity in the flies exposed to VCM and VCD (p<0.05). These effects were accompanied by disruptions in the transcription of the genes encoding the proteins superoxide dismutase (SOD1), kelch-like erythroid-derived cap-n-collar (CNC) homology (ECH)-associated protein 1 (Keap-1), mitogen activated protein kinase 2 (MAPK-2), catalase, Cyp18a1, JAFRAC 1 (thioredoxin peroxidase 1) and thioredoxin reductase 1 (TrxR-1) (p<0.05). VCM and VCD inhibited acetylcholinesterase (AChE) and delta aminolevulinic acid dehydratase (δ-ALA D) activities in the flies (p<0.05). Indeed, here, we demonstrated that different target enzymes and genes were modified by the electrophiles VCM and VCD in the flies. Thus, D. melanogaster has provided further lessons on the toxicity of VCM and VCD which suggest that the reported toxicity of VCH may be mediated by its transformation to VCM and VCD.

  18. Kinetic Isotope Effects in Hydroxylation Reactions Effected by Cytochrome P450 Compounds I Implicate Multiple Electrophilic Oxidants for P450-Catalyzed Oxidations†

    PubMed Central

    Sheng, Xin; Zhang, Haoming; Hollenberg, Paul F.; Newcomb, Martin

    2009-01-01

    Kinetic isotope effects were measured for oxidations of (S,S)-2-(p-trifluoromethylphenyl)cyclopropylmethane containing zero, two, and three deuterium atoms on the methyl group by Compounds I from the cytochrome P450 enzymes CYP119 and CYP2B4 at 22 °C. The oxidations displayed saturation kinetics, which permitted solution of both binding constants (Kbind) and first-order oxidation rate constants (kox) for both enzymes with the three substrates. The binding constant for CYP2B4 Compound I was about one order of magnitude greater than that for CYP119 Compound I, but the oxidation rate constants were similar for the two. In oxidations of 1-d0, kox = 10.4 s−1 for CYP119 Compound I, and kox = 12.4 s−1 for CYP2B4 Compound I. Primary kinetic isotope effects (P) and secondary kinetic isotope effects (S) were obtained from the results with the three isotopomers. The primary KIEs were large, P = 9.8 and P = 8.9 for CYP119 and CYP2B4 Compounds I, respectively, and the secondary KIEs were small and normal, S = 1.07 and S = 1.05, respectively. Large intermolecular KIEs for 1-d0 and 1-d3 of kH/kD = 11.2 and 9.8 found for the two Compounds I contrast with small intermolecular KIEs obtained previously for the same substrate in P450-catalyzed oxidations; these differences suggest that a second electrophilic oxidant, presumably iron-complexed hydrogen peroxide, is important in cytochromes P450 oxidations under turnover conditions. PMID:19182902

  19. Comparative electrophilicity, mutagenicity, DNA repair induction activity, and carcinogenicity of some N- and O-acyl derivatives of N-hydroxy-2-aminoflourene.

    PubMed

    Bartsch, H; Malaveille, C; Stich, H F; Miller, E C; Miller, J A

    1977-05-01

    N-Myristoyloxy-N-acetyl-2-aminofluorene, N-acetoxy-N-myristoyl-2-aminofluorene, N-myristoyloxy-N-myristoyl-2-aminofluorene, and N-hydroxy-N-myristoyl-2-aminofluorene each yielded a high incidence of sarcomas in male rats within 5 to 7 months after s.c. injection of 64 micronmoles in divided doses. N-Acetoxy-N-acetyl-2-aminofluorene and N-hydroxy-2-acetylaminofluorene, although potent carcinogens at the s.c. site, were less active than the above derivatives with a myristoyl substituent. N-Sulfonoxy-N-acety--2-aminofluorene (purity larger than or equal to 70%) had little or no carcinogenic activity when administered in large amounts by s.c. injection to rats. The low incidence of tumors could have resulted from N-hydroxy-2-acetylaminofluorene or other decompostion products of the N-sulfonozy derivative. Each of the N-acetoxy and N-myristoyloxy derivatives of N-acetyl-2-aminofluorene and of N-myristoyl-2-aminofluorene showed electrophilic activity toward methionine; N-acetoxy-N-acetyl-2-aminofluorene was the most reactive and N-myristoyloxy-N-myristoyl-2-aminofluorine was the least reactive. Each of these esters also induced unscheduled tritiated thymidine incorportation in nondividing cultured human fibroblasts and thus appeared to induce lesions in DNA that lead to repair synthesis. EACH OF THE N-acetoxy derivatives was highly mutagenic for Salmonella typhimurium strains TA98 and TA1538 without tissue activation; neither N-myristoyloxy derivative was mutagenic under these conditions. While there was a qualitative correspondence between several of the above activities of these 2-aminofluorene derivatives, the quantitative differences and the lack of detectable mutagenicity of the 2N-myristoyloxy derivatives for S. typhimurium indicate the need for multiple short-term tests in the qualitative prediction of potential carcinogenic activity. PMID:322856

  20. Responses of tumorigenic and non-tumorigenic mouse lung epithelial cell lines to electrophilic metabolites of the tumor promoter butylated hydroxytoluene.

    PubMed

    Sun, Yude; Dwyer-Nield, Lori D; Malkinson, Alvin M; Zhang, Yan Ling; Thompson, John A

    2003-03-01

    A model system to investigate the promotion phase of pulmonary carcinogenesis involves chronic exposure of carcinogen-initiated mice to the food additive, butylated hydroxytoluene (BHT). Previous studies strongly suggested that this activity is due to the cytochrome p450-catalyzed formation of quinone methides 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM) and 6-tert-butyl-2-(1',1'-dimethyl-2'-hydroxy)ethyl-4-methylenecyclohexa-2,5-dienone (BHTOH-QM). The effects of these electrophiles on non-tumorigenic C10 and E10 epithelial cell lines derived from a normal mouse lung explant were compared with effects on their corresponding neoplastic siblings, the A5 and E9 spontaneous transformants, respectively. The tumorigenic cells were more resistant to cell killing, with LC(50) values of 165-180 microM for BHT-QM and 12-22 microM for BHTOH-QM, versus LC(50) values in the non-tumorigenic cells of 105-118 microM and 5.0-6.0 microM, respectively. Constitutive glutathione (GSH) concentrations were 12-20 nmol/10(6) cells, and BHT-QM toxicity was enhanced >2-fold by depleting GSH with buthionine sulfoximine (BSO). Formation of the GSH conjugate of BHT-QM accounted for a substantial fraction of the cellular GSH lost by quinone methide exposure. Enhanced lipid peroxidation and superoxide formation occurred in all cell lines treated with BHT-QM, but both tumorigenic lines contained higher levels of GSH S-transferase and superoxide dismutase (SOD) activities. These data suggest the possibility that BHT-derived quinone methides may exert their promoting effects by inducing oxidative stress; such stress is better tolerated by tumorigenic cells, which have higher levels of antioxidant enzymes. Normal cells are destroyed more readily which allows neoplastic cells to expand their proliferation.

  1. Carbonyl reductase inactivation may contribute to mouse lung tumor promotion by electrophilic metabolites of butylated hydroxytoluene: protein alkylation in vivo and in vitro.

    PubMed

    Shearn, Colin T; Fritz, Kristofer S; Meier, Brent W; Kirichenko, Oleg V; Thompson, John A

    2008-08-01

    Promotion of lung tumors in mice by the food additive butylated hydroxytoluene (BHT) is mediated by electrophilic metabolites produced in the target organ. Identifying the proteins alkylated by these quinone methides (QMs) is a necessary step in understanding the underlying mechanisms. Covalent adducts of the antioxidant enzymes peroxiredoxin 6 and Cu,Zn superoxide dismutase were detected previously in lung cytosols from BALB/c mice injected with BHT, and complimentary in vitro studies demonstrated that QM alkylation causes inactivation and enhances oxidative stress. In the present work, adducts of another protective enzyme, carbonyl reductase (CBR), were detected by Western blotting and mass spectrometry in mitochondria from lungs of mice one day after a single injection of BHT and throughout a 28-day period of weekly injections required to achieve tumor promotion. BHT treatment was accompanied by the accumulation of protein carbonyls in lung cytosol from sustained oxidative stress. Studies in vitro demonstrated that CBR activity in lung homogenates was susceptible to concentration- and time-dependent inhibition by QMs. Recombinant CBR underwent irreversible inhibition during QM exposure, and mass spectrometry was utilized to identify alkylation sites at Cys 51, Lys 17, Lys 189, Lys 201, His 28, and His 204. Except for Lys 17, all of these adducts were eliminated as a cause of enzyme inhibition either by chemical modification (cysteine) or site-directed mutagenesis (lysines and histidines). The data demonstrated that Lys 17 is the critical alkylation target, consistent with the role of this basic residue in NADPH binding. These data support the possibility that CBR inhibition occurs in BHT-treated mice, thereby compromising one pathway for inactivating lipid peroxidation products, particularly 4-oxo-2-nonenal. These data, in concert with previous evidence for the inactivation of antioxidant enzymes, provide a molecular basis to explain lung inflammation leading to

  2. Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster

    PubMed Central

    Abolaji, Amos O.; Kamdem, Jean P.; Lugokenski, Thiago H.; Farombi, Ebenezer O.; Souza, Diogo O.; da Silva Loreto, Élgion L.; Rocha, João B.T.

    2015-01-01

    The compounds 4-vinylcyclohexene 1,2-monoepoxide (VCM) and 4-Vinylcyclohexene diepoxide (VCD) are the two downstream metabolites of 4-vinylcyclohexene (VCH), an ovotoxic agent in mammals. In addition, VCM and VCD may be found as by-products of VCH oxidation in the environment. Recently, we reported the involvement of oxidative stress in the toxicity of VCH in Drosophila melanogaster. However, it was not possible to determine the individual contributions of VCM and VCD in VCH toxicity. Hence, we investigated the toxicity of VCM and VCD (10–1000 µM) in flies after 5 days of exposure via the diet. Our results indicated impairments in climbing behaviour and disruptions in antioxidant balance and redox status evidenced by an increase in DCFH oxidation, decreases in total thiol content and glutathione-S-transferase (GST) activity in the flies exposed to VCM and VCD (p<0.05). These effects were accompanied by disruptions in the transcription of the genes encoding the proteins superoxide dismutase (SOD1), kelch-like erythroid-derived cap-n-collar (CNC) homology (ECH)-associated protein 1 (Keap-1), mitogen activated protein kinase 2 (MAPK-2), catalase, Cyp18a1, JAFRAC 1 (thioredoxin peroxidase 1) and thioredoxin reductase 1 (TrxR-1) (p<0.05). VCM and VCD inhibited acetylcholinesterase (AChE) and delta aminolevulinic acid dehydratase (δ-ALA D) activities in the flies (p<0.05). Indeed, here, we demonstrated that different target enzymes and genes were modified by the electrophiles VCM and VCD in the flies. Thus, D. melanogaster has provided further lessons on the toxicity of VCM and VCD which suggest that the reported toxicity of VCH may be mediated by its transformation to VCM and VCD. PMID:26117601

  3. Organic Reaction Mechanisms in the Sixth Form Part 3: Reactions of Electron Pair Acceptors with Compounds Containing Multiple Bonds.

    ERIC Educational Resources Information Center

    Simpson, Peter

    1989-01-01

    The ideas behind electrophilic addition to alkenes, and electrophilic substitution in benzene derivatives are discussed. Teaching these concepts to secondary school students is stressed. Five main points useful at this age level are summarized. (Author/CW)

  4. Activation of nuclear protein binding to the antioxidant/electrophile response element in vascular smooth muscle cells by benzo(a)pyrene.

    PubMed

    Holderman, M T; Miller, K P; Ramos, K S

    2000-01-01

    This laboratory has previously shown that binding of nuclear proteins to the antioxidant/electrophile response element (ARE/EpRE) participates in deregulation of vascular gene expression by benzo(a)pyrene (BaP), a suspected atherogen. In the present study, oligonucleotides representing ARE/EpREs within the c-Ha-ras and glutathione-S-transferase (GST-Ya) promoters were employed to evaluate the role of flanking sequences in stabilizing protein:DNA interactions in BaP-treated vascular smooth muscle cells (vSMCs). We also wanted to define promoter-specific patterns of protein recognition to ARE/EpREs in this cell system. In electrophoretic mobility shift assays (EMSA), optimal protein binding to a human Ha-ras ARE/EpRE variant sequence fitted to match the extended mouse(m) GST-Ya ARE/EpRE core (5'-TMAnnRTGAYnnnGCR-3') was dependent on 5' nucleic acid sequence. Using immobilized DNA affinity chromatography (IDAC), we identified four nuclear proteins of M(r) 62, 60, 50, and 30 kDa that associated specifically with the mGSTYa ARE/EpRE. Photo crosslinking to a BrdU-substituted hHa-ras or mGST ARE/EpRE probe identified specific proteins of M(r) 80, 60, 55, 25, 23 kDa or 80, 60, 55, 27, 25, 23 kDa, respectively. Protein:DNA complexes detected using IDAC eluate overlapped with those observed in crude nuclear extracts. Chemical treatments known to modulate ARE/EpRE protein binding in vSMCs did not alter overall protein:DNA affinity and/or sequence recognition to either hHa-ras or mGST-Ya elements. We conclude that nucleotide sequences 5' to the core ARE/EpRE influence specific binding of nuclear proteins and that multiple proteins bind to ARE/EpREs in a promoter-specific manner in vSMCs.

  5. Effects of toxicologically relevant xenobiotics and the lipid-derived electrophile 4-hydroxynonenal on macrophage cholesterol efflux: silencing carboxylesterase 1 has paradoxical effects on cholesterol uptake and efflux.

    PubMed

    Ross, Matthew K; Borazjani, Abdolsamad; Mangum, Lee C; Wang, Ran; Crow, J Allen

    2014-10-20

    Cholesterol cycles between free cholesterol (unesterified) found predominantly in membranes and cholesteryl esters (CEs) stored in cytoplasmic lipid droplets. Only free cholesterol is effluxed from macrophages via ATP-binding cassette (ABC) transporters to extracellular acceptors. Carboxylesterase 1 (CES1), proposed to hydrolyze CEs, is inactivated by oxon metabolites of organophosphorus pesticides and by the lipid electrophile 4-hydroxynonenal (HNE). We assessed the ability of these compounds to reduce cholesterol efflux from foam cells. Human THP-1 macrophages were loaded with [(3)H]-cholesterol/acetylated LDL and then allowed to equilibrate to enable [(3)H]-cholesterol to distribute into its various cellular pools. The cholesterol-engorged cells were then treated with toxicants in the absence of cholesterol acceptors for 24 h, followed by a 24 h efflux period in the presence of toxicant. A concentration-dependent reduction in [(3)H]-cholesterol efflux via ABCA1 (up to 50%) was found for paraoxon (0.1-10 μM), whereas treatment with HNE had no effect. A modest reduction in [(3)H]-cholesterol efflux via ABCG1 (25%) was found after treatment with either paraoxon or chlorpyrifos oxon (10 μM each) but not HNE. No difference in efflux rates was found after treatments with either paraoxon or HNE when the universal cholesterol acceptor 10% (v/v) fetal bovine serum was used. When the re-esterification arm of the CE cycle was disabled in foam cells, paraoxon treatment increased CE levels, suggesting the neutral CE hydrolysis arm of the cycle had been inhibited by the toxicant. However, paraoxon also partially inhibited lysosomal acid lipase, which generates cholesterol for efflux, and reduced the expression of ABCA1 protein. Paradoxically, silencing CES1 expression in macrophages did not affect the percent of [(3)H]-cholesterol efflux. However, CES1 mRNA knockdown markedly reduced cholesterol uptake by macrophages, with SR-A and CD36 mRNA reduced 3- and 4-fold

  6. Hypercoordinate ketone adducts of electrophilic η3-H2SiRR' ligands on ruthenium as key intermediates for efficient and robust catalytic hydrosilation.

    PubMed

    Lipke, Mark C; Tilley, T Don

    2014-11-19

    The electrophilic η(3)-H2SiRR' σ-complexes [PhBP(Ph)3]RuH(η(3)-H2SiRR') (RR' = MePh, 1a; Ph2, 1b; [PhBP(Ph)3](-) = [PhB(CH2PPh2)3](-)) are efficient catalysts (0.01-2.5 mol % loading) for the hydrosilation of ketones with PhMeSiH2, Ph2SiH2, or EtMe2SiH. An alkoxy complex [PhBP(Ph)3]Ru-OCHPh2 (4b) was observed (by (31)P{(1)H} NMR spectroscopy) as the catalyst resting state during hydrosilation of benzophenone with EtMe2SiH. A different catalyst resting state was observed for reactions using PhMeSiH2 or Ph2SiH2, and was identified as a silane σ-complex [PhBP(Ph)3]RuH[η(2)-H-SiRR'(OCHPh2)] (RR' = MePh, 5a; Ph2, 5b) using variable temperature multinuclear NMR spectroscopy (-80 to 20 °C). The hydrosilation of benzophenone with PhMeSiH2 and 1a was examined by (1)H NMR spectroscopy at -18 °C (in CD2Cl2), and this revealed that either 1a, 5a, or both 1a and 5a could be observed as resting states of the catalytic cycle, depending on the initial [PhMeSiH2]:[benzophenone] ratio. Kinetic studies revealed two possible expressions for the rate of product formation, depending on which catalyst resting state was present (rate = kobs[PhMeSiH2][5a] and rate = k'obs[benzophenone][1a]). Computational methods (DFT, b3pw91, 6-31G(d,p)/LANL2DZ) were used to determine a model catalytic cycle for the hydrosilation of acetone with PhMeSiH2. A key step in this mechanism involves coordination of acetone to the silicon center of 1a-DFT, which leads to insertion of the carbonyl group into an Si-H bond (that is part of a Ru-H-Si 3c-2e bond). This generates an intermediate analogous to 5a (5a-i-DFT), and the final product is displaced from 5a-i-DFT by an associative process involving PhMeSiH2. PMID:25347044

  7. New ruthenium nitrosyl complexes with tris(1-pyrazolyl)methane (tpm) and 2,2'-bipyridine (bpy) coligands. Structure, spectroscopy, and electrophilic and nucleophilic reactivities of bound nitrosyl.

    PubMed

    Videla, Mariela; Jacinto, Julian S; Baggio, Ricardo; Garland, María T; Singh, Priti; Kaim, Wolfgang; Slep, Leonardo D; Olabe, José A

    2006-10-16

    The new compound [Ru(bpy)(tpm)NO](ClO4)3 [tpm = tris(1-pyrazolyl)methane; bpy = 2,2'-bipyridine] has been prepared in a stepwise procedure that involves the conversion of [Ru(bpy)(tpm)Cl]+ into the aqua and nitro intermediates, followed by acidification. The diamagnetic complex crystallizes to exhibit distorted octahedral geometry around the metal, with the Ru-N(O) bond length 1.774(12) A and the RuNO angle 179.1(12) degrees , typical for a {RuNO}6 description. The [Ru(bpy)(tpm)NO]3+ ion (I) has been characterized by 1H NMR and IR spectroscopies (nu(NO) = 1959 cm(-1)) and through density functional theory calculations. Intense electronic transitions in the 300-350-nm region are assigned through time-dependent (TD)DFT as intraligand pi --> pi for bpy and tpm. The dpi --> pi(bpy) metal-to-ligand charge-transfer transitions appear at higher energies. Aqueous cyclic voltammetric studies show a reversible wave at 0.31 V (vs Ag/AgCl, 3 M Cl-), which shifts to 0.60 V in MeCN, along with the onset of a wave of an irreversible process at -0.2 V. The waves are assigned to the one- and two-electron reductions centered at the NO ligand, leading to species with {RuNO}(7) and {RuNO}(8) configurations, respectively. Controlled potential reduction of I in MeCN led to the [Ru(bpy)(tpm)NO]2+ ion (II), revealing a significant downward shift of nu(NO) to 1660 cm(-1) as well as changes in the electronic absorption bands. II was also characterized by electron paramagnetic resonance, showing an anisotropic signal at 110 K that arises from an S = 1/2 electronic ground state; the g-matrix components and hyperfine coupling tensor resemble the behavior of related {RuNO}7 complexes. Both I and II were characterized through their main reactivity modes, electrophilic and nucleophilic, respectively. The addition of OH- into I generated the nitro complex, with k(OH) = 3.05 x 10(6) M(-1) s(-1) (25 degrees C). This value is among the highest obtained for related nitrosyl complexes and correlates

  8. Electrophilic, Ambiphilic, and Nucleophilic C-H bond Activation. Understanding the electronic continuum of C-H bond activation through transition-state and reaction pathway interaction energy decompositions

    SciTech Connect

    Ess, Daniel H.; Goddard, William A.; Periana, Roy A.

    2010-10-29

    The potential energy and interaction energy profiles for metal- and metal-ligand-mediated alkane C-H bond activation were explored using B3LYP density functional theory (DFT) and the absolutely localized molecular orbital energy decomposition analysis (ALMO-EDA). The set of complexes explored range from late transition metal group 10 (Pt and Pd) and group 11 (Au) metal centers to group 7-9 (Ir, Rh, Ru, and W) metal centers as well as a group 3 Sc complex. The coordination geometries, electron metal count (d8, d6, d4, and d0), and ligands (N-heterocycles, O-donor, phosphine, and Cp*) are also diverse. Quantitative analysis using ALMO-EDA of both directions of charge-transfer stabilization (occupied to unoccupied orbital stabilization) energies between the metal-ligand fragment and the coordinated C-H bond in the transition state for cleavage of the C-H bond allows classification of C-H activation reactions as electrophilic, ambiphilic, or nucleophilic on the basis of the net direction of charge-transfer energy stabilization. This bonding pattern transcends any specific mechanistic or bonding paradigm, such as oxidative addition, σ-bond metathesis, or substitution. Late transition metals such as Au(III), Pt(II), Pd(II), and Rh(III) metal centers with N-heterocycle, halide, or O-donor ligands show electrophilically dominated reaction profiles with forward charge-transfer from the C-H bond to the metal, leading to more stabilization than reverse charge transfer from the metal to the C-H bond. Transition states and reaction profiles for d6 Ru(II) and Ir(III) metals with Tp and acac ligands were found to have nearly equal forward and reverse charge-transfer energy stabilization. This ambiphilic region also includes the classically labeled electrophilic cationic species Cp*(PMe3)Ir(Me). Nucleophilic character, where the metal to C-H bond charge-transfer interaction is most stabilizing, was found in

  9. Synthesis of 5-iodopyrrolo[1,2-a]quinolines and indolo[1,2-a]quinolines via iodine-mediated electrophilic and regioselective 6-endo-dig ring closure.

    PubMed

    Verma, Akhilesh Kumar; Shukla, Satya Prakash; Singh, Jaspal; Rustagi, Vineeta

    2011-07-15

    The endo-cyclic ring closure of 1-(2-(substituted ethynyl)phenyl)-1H-pyrroles 3a-t and 1-(2-(substituted ethynyl)phenyl)-H-indole 4a-o mediated by Lewis acid (I(2)) under mild conditions afforded substituted 5-iodopyrrolo[1,2-a]quinolines 5a-t and 5-iodoindolo[1,2-a]quinolines 6a-o in good to excellent yields. The reaction shows selective C-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized product. Iodo derivatives of pyrrolo- and indoloquinolines allow functional group diversification on the quinoline nucleus, which proves to be highly advantageous for structural and biological activity assessments.

  10. Densified waste form and method for forming

    DOEpatents

    Garino, Terry J.; Nenoff, Tina M.; Sava Gallis, Dorina Florentina

    2016-05-17

    Materials and methods of making densified waste forms for temperature sensitive waste material, such as nuclear waste, formed with low temperature processing using metallic powder that forms the matrix that encapsulates the temperature sensitive waste material. The densified waste form includes a temperature sensitive waste material in a physically densified matrix, the matrix is a compacted metallic powder. The method for forming the densified waste form includes mixing a metallic powder and a temperature sensitive waste material to form a waste form precursor. The waste form precursor is compacted with sufficient pressure to densify the waste precursor and encapsulate the temperature sensitive waste material in a physically densified matrix.

  11. Densified waste form and method for forming

    SciTech Connect

    Garino, Terry J.; Nenoff, Tina M.; Sava Gallis, Dorina Florentina

    2015-08-25

    Materials and methods of making densified waste forms for temperature sensitive waste material, such as nuclear waste, formed with low temperature processing using metallic powder that forms the matrix that encapsulates the temperature sensitive waste material. The densified waste form includes a temperature sensitive waste material in a physically densified matrix, the matrix is a compacted metallic powder. The method for forming the densified waste form includes mixing a metallic powder and a temperature sensitive waste material to form a waste form precursor. The waste form precursor is compacted with sufficient pressure to densify the waste precursor and encapsulate the temperature sensitive waste material in a physically densified matrix.

  12. Inhibition of Mycobacterium tuberculosis PknG by non-catalytic rubredoxin domain specific modification: reaction of an electrophilic nitro-fatty acid with the Fe-S center.

    PubMed

    Gil, Magdalena; Graña, Martín; Schopfer, Francisco J; Wagner, Tristan; Denicola, Ana; Freeman, Bruce A; Alzari, Pedro M; Batthyány, Carlos; Durán, Rosario

    2013-12-01

    PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2-mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition.

  13. Initial results in the development of a reporter cell line for toxicology studies at gene expression level: activation of the electrophile-responsive element by copper and methyl parathion.

    PubMed

    Almeida, Daniela Volcan; Trindade, Gilma Santos; Geracitano, Laura A; Barros, Daniela Martí; Monserrat, José Maria; Marins, Luis Fernando

    2008-07-01

    Induction of many genes encoding detoxifying enzymes and antioxidant proteins is mediated through a common mechanism, which is controlled by electrophile-responsive elements (EpRE) within the regulatory region of those genes. Copper and methyl parathion are environmental pollutants known to induce the expression of EpRE-mediated genes. In order to evaluate the molecular response triggered by these pollutants, a stable cell line was produced, which carries a transgene comprised of the green fluorescent protein (GFP) reporter gene under transcriptional control of the mouse glutathione-S-transferase (gst1) electrophile-responsive element fused to the mouse metallothionein (mt1) minimal promoter. The rat HTC hepatoma cells were transfected with the EpREmt-GFP construct and successfully selected with G418 antibiotic. EpREmt-GFP HTC cells were treated with 0.002 mg L(-1), 0.02 mg L(-1), 0.2 mg L(-1) and 2 mg L(-1) copper sulfate and 0.001 mg L(-1), 0.01 mg L(-1), 0.1 mg L(-1) and 1 mg L(-1) methyl parathion for 48 h. GFP expression was directly quantified in living cells using a microplate fluorimeter. GFP expression was significantly increased in higher concentrations of both pollutants, showing a 1.80- and 2.58-fold induction of GFP at 2mg copper L(-1) and 1mg methyl parathion L(-1), respectively (p<0.01). The results obtained in the present study demonstrate that the EpREmt-GFP HTC cell line can be an interesting model for further development for the study of the cellular response to aquatic pollutants as well as a new tool for environmental monitoring at the molecular level. PMID:18533248

  14. A generalized operational formula based on total electronic densities to obtain 3D pictures of the dual descriptor to reveal nucleophilic and electrophilic sites accurately on closed-shell molecules.

    PubMed

    Martínez-Araya, Jorge I

    2016-09-30

    By means of the conceptual density functional theory, the so-called dual descriptor (DD) has been adapted to be used in any closed-shell molecule that presents degeneracy in its frontier molecular orbitals. The latter is of paramount importance because a correct description of local reactivity will allow to predict the most favorable sites on a molecule to undergo nucleophilic or electrophilic attacks; on the contrary, an incomplete description of local reactivity might have serio us consequences, particularly for those experimental chemists that have the need of getting an insight about reactivity of chemical reagents before using them in synthesis to obtain a new compound. In the present work, the old approach based only on electronic densities of frontier molecular orbitals is replaced by the most accurate procedure that implies the use of total electronic densities thus keeping consistency with the essential principle of the DFT in which the electronic density is the fundamental variable and not the molecular orbitals. As a result of the present work, the DD will be able to properly describe local reactivities only in terms of total electronic densities. To test the proposed operational formula, 12 very common molecules were selected as the original definition of the DD was not able to describe their local reactivities properly. The ethylene molecule was additionally used to test the capability of the proposed operational formula to reveal a correct local reactivity even in absence of degeneracy in frontier molecular orbitals. © 2016 Wiley Periodicals, Inc. PMID:27443264

  15. Induction of phase II enzymes and hsp70 genes by copper sulfate through the electrophile-responsive element (EpRE): insights obtained from a transgenic zebrafish model carrying an orthologous EpRE sequence of mammalian origin.

    PubMed

    Almeida, Daniela Volcan; Nornberg, Bruna Félix da Silva; Geracitano, Laura A; Barros, Daniela Martí; Monserrat, José Maria; Marins, Luis Fernando

    2010-09-01

    We have evaluated the homology of the electrophile-responsive element (EpRE) core sequence, a binding site for the Nrf2 transcription factor, in the proximal promoters of the mouse and zebrafish glutathione-S-transferase (gst), glutamate cysteine ligase catalytic subunit (gclc) and heat shock protein 70 (hsp70) genes. The EpRE sites identified for both species in the three analyzed genes showed a high similarity with the putative EpRE core sequence. We also produced a transgenic zebrafish model carrying a transgene comprised of the luciferase (luc) reporter gene under transcriptional control of a mouse EpRE sequence. This transgenic model was exposed to copper sulfate, and the reporter gene was significantly activated. The endogenous gst, gclc and hsp70 zebrafish genes were analyzed in the EpRE-Luc transgenic zebrafish and showed an expression pattern similar to that of the reporter transgene used. Our results demonstrate that EpRE is conserved between mouse and zebrafish for detoxification-related genes and that the development of genetically modified models using this responsive element to drive the expression of reporter genes can be an important tool in understanding the action mechanism of aquatic pollutants. PMID:19116768

  16. Bacteria form tellurium nanocrystals

    USGS Publications Warehouse

    Oremland, R.S.

    2007-01-01

    A team of researchers have found two bacterial species that produce tellurium oxyanions as respiratory electron acceptors for growth, leaving elemental tellurium in the form of nanoparticles. The crystals from the two organisms exhibit distinctively different structures. Bacillus selenitireducens initially forms nanorods that cluster together to form rosettes. Sulfurospirillum barnesii forms irregularly-shaped nanospheres that coalesce into larger composite aggregates.

  17. Handbook of Poetic Forms.

    ERIC Educational Resources Information Center

    Padgett, Ron, Ed.

    Intended for secondary teachers and student writers but useful for anyone interested in poetic forms, this book defines 74 basic poetic forms, summarizes their histories, quotes examples from noted poets, and offers professional tricks of the trade on how to use each form. The book covers the following poetic forms: abstract poem, acrostic,…

  18. CHEMICAL MODIFICATION MODULATES ESTROGENIC ACTIVITY, OXIDATIVE REACTIVITY, & METABOLIC STABILITY IN 4′F-DMA, A NEW BENZOTHIOPHENE SELECTIVE ESTROGEN RECEPTOR MODULATOR

    PubMed Central

    Liu, Hong; Bolton, Judy L.; Thatcher, Gregory R. J.

    2008-01-01

    The benzothiophene SERMs raloxifene and arzoxifene, in the clinic or clinical trials for treatment of breast cancer and postmenopausal symptoms, are highly susceptible to oxidative metabolism and formation of electrophilic metabolites. 4′F-DMA, fluoro-substituted desmethyl arzoxifene (DMA), showed attenuated oxidation to quinoids in incubation with rat hepatocytes as well as in rat and human liver microsomes. Incubations of 4′F-DMA with hepatocytes yielded only one glucuronide conjugate and no GSH conjugates; whereas DMA underwent greater metabolism giving two glucuronide conjugates, one sulfate conjugate, and two GSH conjugates. Phase I and phase II metabolism was further evaluated in human small intestine microsomes and in human intestinal Caco-2 cells. In comparison to DMA, 4′F-DMA formed significantly less glucuronide and sulfate conjugates. The formation of quinoids was futher explored in hepatocytes in which DMA was observed to give concentration and time dependent depletion of GSH accompanied by damage to DNA which showed inverse dependence on GSH; in contrast, GSH depletion and DNA damage were almost completely abrogated in incubations with 4′F-DMA. 4′F-DMA shows ligand binding affinity to ERα and ERβ with similarity to both raloxifene and to DMA. ER-mediated biological activity was measured with the ERE-luciferase reporter system in transfected MCF-7 cells and Ishikawa cells, and in MCF-7 cells proliferation was measured. In all systems, 4′F-DMA exhibited anitestrogenic acitivty of comparable potency to raloxifene, but did not manifest estrogenic properties, mirroring previous results on inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells. These results suggest that 4′F-DMA might be an improved benzothiophene SERM with similar antiestrogenic activity to raloxifene, but improved metabolic stability and attenuated toxicity; showing that simple chemical modification can abrogate oxidative bioactivation

  19. High-performance liquid chromatography of quinoidal imminium compounds derived from triphenylmethanes

    USGS Publications Warehouse

    Abidi, S.L.

    1983-01-01

    A series of eleven p-aminotriphenylmethane dyes have been studied by high-performance liquid chromatography (HPLC). The combined use of HPLC and spectrophotometry permits specific detection of these compounds in the visible range around 600 nm. As the high affinity of the imminium cations for the active sites of the hydrocarbonaceous stationary phase has presented difficulties for reversed-phase HPLC with pure solvents, organic electrolytes were added to the mobile phase to facilitate the elution of the components with improved selectivity, sensitivity (minimum detection limit, 0.1 μg/ml), and peak symmetry. The effects of chromatographic variables on the component retentivity were investigated. Retention times of the dye analytes decreased with increasing concentration of the added ionic reagent and with decreasing number of the hydrophobic alkyl substituents on the nitrogen atom. The influence of pH on the retention parameters appears to parallel that observed previously for cationic quaternary ammonium compounds. Among the acidic reagents employed, naphthalenesulfonic acid yielded the most satisfactory results. The use of binary electrolyte systems invariably improved the chromatographic behavior of the imminium solutes analyzed. Results obtained with two different octadecylsilica columns have been compared.

  20. Formation of Carbon Nanotube Based Gears: Quantum Chemistry and Molecular Mechanics Study of the Electrophilic Addition of o-Benzyne to Fullerenes, Graphene, and Nanotubes

    NASA Technical Reports Server (NTRS)

    Jaffe, Richard; Han, Jie; Globus, Al; Chancellor, Marisa K. (Technical Monitor)

    1997-01-01

    Considerable progress has been made in recent years in chemical functionalization of fullerene molecules. In some cases, the predominant reaction products are different from those obtained (using the same reactants) from polycyclic aromatic hydrocarbons (PAHs). One such example is the cycloaddition of o-benzyne to C60. It is well established that benzyne adds across one of the rings in naphthalene, anthracene and other PAHs forming the [2+4] cycloaddition product (benzobicyclo[2.2.2.]-octatriene with naphthalene and triptycene with anthracene). However, Hoke et al demonstrated that the only reaction path for o-benzyne with C60 leads to the [2+2] cycloaddition product in which benzyne adds across one of the interpentagonal bonds (forming a cyclobutene ring in the process). Either reaction product results in a loss of aromaticity and distortion of the PAH or fullerene substrate, and in a loss of strain in the benzyne. It is not clear, however, why different products are preferred in these cases. In the current paper, we consider the stability of benzyne-nanotube adducts and the ability of Brenner's potential energy model to describe the structure and stability of these adducts. The Brenner potential has been widely used for describing diamondoid and graphitic carbon. Recently it has also been used for molecular mechanics and molecular dynamics simulations of fullerenes and nanotubes. However, it has not been tested for the case of functionalized fullerenes (especially with highly strained geometries). We use the Brenner potential for our companion nanogear simulations and believe that it should be calibrated to insure that those simulations are physically reasonable. In the present work, Density Functional theory (DFT) calculations are used to determine the preferred geometric structures and energetics for this calibration. The DFT method is a kind of ab initio quantum chemistry method for determining the electronic structure of molecules. For a given basis set

  1. The generation of 4-hydroxynonenal, an electrophilic lipid peroxidation end product, in rabbit cornea organ cultures treated with UVB light and nitrogen mustard

    SciTech Connect

    Zheng, Ruijin; Po, Iris; Mishin, Vladimir; Black, Adrienne T.; Heck, Diane E.; Laskin, Debra L.; Sinko, Patrick J.; Gerecke, Donald R.; Gordon, Marion K.; Laskin, Jeffrey D.

    2013-10-15

    The cornea is highly sensitive to oxidative stress, a process that can lead to lipid peroxidation. Ultraviolet light B (UVB) and nitrogen mustard (mechlorethamine) are corneal toxicants known to induce oxidative stress. Using a rabbit air-lifted corneal organ culture model, the oxidative stress responses to these toxicants in the corneal epithelium was characterized. Treatment of the cornea with UVB (0.5 J/cm{sup 2}) or nitrogen mustard (100 nmol) resulted in the generation of 4-hydroxynonenal (4-HNE), a reactive lipid peroxidation end product. This was associated with increased expression of the antioxidant, heme oxygenase-1 (HO-1). In human corneal epithelial cells in culture, addition of 4-HNE or 9-nitrooleic acid, a reactive nitrolipid formed during nitrosative stress, caused a time-dependent induction of HO-1 mRNA and protein; maximal responses were evident after 10 h with 30 μM 4-HNE or 6 h with 10 μM 9-nitrooleic acid. 4-HNE and 9-nitrooleic acid were also found to activate Erk1/2, JNK and p38 MAP kinases, as well as phosphoinositide-3-kinase (PI3)/Akt. Inhibition of p38 blocked 4-HNE- and 9-nitrooleic acid-induced HO-1 expression. Inhibition of Erk1/2, and to a lesser extent, JNK and PI3K/Akt, suppressed only 4-HNE-induced HO-1, while inhibition of JNK and PI3K/Akt, but not Erk1/2, partly reduced 9-nitrooleic acid-induced HO-1. These data indicate that the actions of 4-HNE and 9-nitrooleic acid on corneal epithelial cells are distinct. The sensitivity of corneal epithelial cells to oxidative stress may be an important mechanism mediating tissue injury induced by UVB or nitrogen mustard. - Highlights: • UVB or nitrogen mustard causes rabbit corneal epithelial injury. • 4-Hydroxynonenal (4-HNE) was formed and heme oxygenase-1 (HO-1) was increased. • 4-HNE induced HO-1 mRNA and protein expression in human corneal epithelial cells. • The induction of HO-1 by 4-HNE was through MAP kinase activation.

  2. A novel aldo-keto reductase from Jatropha curcas L. (JcAKR) plays a crucial role in the detoxification of methylglyoxal, a potent electrophile.

    PubMed

    Mudalkar, Shalini; Sreeharsha, Rachapudi Venkata; Reddy, Attipalli Ramachandra

    2016-05-20

    Abiotic stress leads to the generation of reactive oxygen species (ROS) which further results in the production of reactive carbonyls (RCs) including methylglyoxal (MG). MG, an α, β-dicarbonyl aldehyde, is highly toxic to plants and the mechanism behind its detoxification is not well understood. Aldo-keto reductases (AKRs) play a role in detoxification of reactive aldehydes and ketones. In the present study, we cloned and characterised a putative AKR from Jatropha curcas (JcAKR). Phylogenetically, it forms a small clade with AKRs of Glycine max and Rauwolfia serpentina. JcAKR was heterologously expressed in Escherichia coli BL-21(DE3) cells and the identity of the purified protein was confirmed through MALDI-TOF analysis. The recombinant protein had high enzyme activity and catalytic efficiency in assays containing MG as the substrate. Protein modelling and docking studies revealed MG was efficiently bound to JcAKR. Under progressive drought and salinity stress, the enzyme and transcript levels of JcAKR were higher in leaves compared to roots. Further, the bacterial and yeast cells expressing JcAKR showed more tolerance towards PEG (5%), NaCl (200mM) and MG (5mM) treatments compared to controls. In conclusion, our results project JcAKR as a possible and potential target in crop improvement for abiotic stress tolerance. PMID:26995646

  3. Structure/Reactivity Relationships in the Benzo[c]phenanthrene Skeleton: Stable Ion and Electrophilic Substitution (Nitration, Bromination) Study of Substituted Analogs; Novel Carbocations and Substituted Derivatives

    PubMed Central

    Brulé, Cédric; Laali, Kenneth K.; Okazaki, Takao; Lakshman, Mahesh K.

    2008-01-01

    A series of novel carbocations were generated by low temperature protonation of substituted benzo[c]phenanthrenes B[c]Phs and their charge delocalization pathways were elucidated by NMR based on the magnitude of Δδ13C values. It has been shown that the protonation regioselectivity is strongly controlled by methoxy and hydroxyl substituents, whose directive effects override methyl substitution effects. Regiocontrol by –OMe and –OH substituents, and its stronger influence relative to methyl groups, was also observed in the nitration and bromination reactions. Charge distribution modes in the regioisomeric protonated carbocations via parent B[c]Ph as well as in the benzylic carbocation formed via fjord-region epoxide ring opening were deduced by GIAO-DFT, and from the NPA-derived changes in charges over CHs. These patterns were compared with those derived from NMR experiments in the substituted derivatives. NMR-based charge delocalization mapping provided insight into structure/activity relationships in the methylated and fluorinated B[c]Phs. Regioselectivities observed in the nitration and bromination reactions in representative cases are the same as those via protonations. Among a group of novel nitro and bromo derivatives synthesized in this study are examples where nitro group is introduced into the fjord-region, for which X-ray structure could be obtained in one case. PMID:17394355

  4. Maass Forms and Quantum Modular Forms

    NASA Astrophysics Data System (ADS)

    Rolen, Larry

    This thesis describes several new results in the theory of harmonic Maass forms and related objects. Maass forms have recently led to a flood of applications throughout number theory and combinatorics in recent years, especially following their development by the work of Bruinier and Funke the modern understanding Ramanujan's mock theta functions due to Zwegers. The first of three main theorems discussed in this thesis concerns the integrality properties of singular moduli. These are well-known to be algebraic integers, and they play a beautiful role in complex multiplication and explicit class field theory for imaginary quadratic fields. One can also study "singular moduli" for special non-holomorphic functions, which are algebraic but are not necessarily algebraic integers. Here we will explain the phenomenon of integrality properties and provide a sharp bound on denominators of symmetric functions in singular moduli. The second main theme of the thesis concerns Zagier's recent definition of a quantum modular form. Since their definition in 2010 by Zagier, quantum modular forms have been connected to numerous different topics such as strongly unimodal sequences, ranks, cranks, and asymptotics for mock theta functions. Motivated by Zagier's example of the quantum modularity of Kontsevich's "strange" function F(q), we revisit work of Andrews, Jimenez-Urroz, and Ono to construct a natural vector-valued quantum modular form whose components. The final chapter of this thesis is devoted to a study of asymptotics of mock theta functions near roots of unity. In his famous deathbed letter, Ramanujan introduced the notion of a mock theta function, and he offered some alleged examples. The theory of mock theta functions has been brought to fruition using the framework of harmonic Maass forms, thanks to Zwegers. Despite this understanding, little attention has been given to Ramanujan's original definition. Here we prove that Ramanujan's examples do indeed satisfy his

  5. DNA sequence determinants of nuclear protein binding to the c-Ha-ras antioxidant/electrophile response element in vascular smooth muscle cells: identification of Nrf2 and heat shock protein 90 beta as heterocomplex components.

    PubMed

    Miller, Kimberly P; Ramos, Kenneth S

    2005-01-01

    The antioxidant/electrophile response element (ARE/EpRE) is a cis-acting element involved in redox regulation of c-Ha-ras gene. Protein binding to the ARE/EpRE may be credited to deoxyribonucleic acid sequence; therefore, studies were conducted to evaluate the influence of internal and flanking regions to the 10-bp human c-Ha-ras ARE/EpRE core (hHaras10) on nuclear protein binding in oxidant-treated vascular smooth muscle cells. A protein doublet bound to an extended oligonucleotide comprising the ARE/EpRE core in genomic context (hHaras27), whereas a single complex bound to hHarasl0. Protein binding involved specific interactions of 25- and 23-kDa proteins with hHarasl0, and binding of 80-, 65-, and 55-kDa proteins to hHaras27. Competition assays with hNQO1 and rGSTA2 confirmed the specificity of deoxyribonucleic acid-protein interactions and indicated preferred binding of p25 and p23 to the c-Ha-ras ARE/EpRE. "NNN" sequences within the core afforded unique protein-binding profiles to the c-Ha-ras ARE/EpRE. In addition, Nrf2 and heat shock protein 90beta (p80) were identified as components of the c-Ha-ras ARE/EpRE heterocomplex. We conclude that both internal bases and flanking sequences regulate nuclear protein recruitment and complex assembly on the c-Ha-ras ARE/EpRE.

  6. Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a small-molecule positive allosteric modulator of the glucagon-like peptide-1 receptor.

    PubMed

    Eng, Heather; Sharma, Raman; McDonald, Thomas S; Edmonds, David J; Fortin, Jean-Philippe; Li, Xianping; Stevens, Benjamin D; Griffith, David A; Limberakis, Chris; Nolte, Whitney M; Price, David A; Jackson, Margaret; Kalgutkar, Amit S

    2013-08-01

    4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R. PMID:23653442

  7. Synthesis, characterization, and catalytic properties of new electrophilic iridium(III) complexes containing the (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ligand.

    PubMed

    Atesin, Abdurrahman C; Zhang, Jing; Vaidya, Tulaza; Brennessel, William W; Frontier, Alison J; Eisenberg, Richard

    2010-05-01

    The oxidative addition of MeI to the Ir(I) square-planar complex IrI(CO)((R)-(+)-BINAP) where (R)-(+)-BINAP = (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)) results in the formation of two diastereomers in a 2:1 ratio of the Ir(III) oxidative addition product IrI(2)(CO)(Me)((R)-(+)-BINAP) (4a and 4b) in a 85% overall yield. Upon iodide abstraction from the diastereomeric mixture with 2 equiv of AgSbF(6) in the presence of diethyl isopropylidene malonate (DIM), two diastereomers of the dicationic complex [Ir(CO)(Me)(DIM)((R)-(+)-BINAP)][SbF(6)](2) (5) are formed in a 90% yield with a ratio of 9:1. One diastereomer of the diiodide complex 4 and one diastereomer of the dicationic complex 5 have been characterized by X-ray diffraction. An anion exchange reaction of 5 with NaBAr(4)(f-) (BAr(4)(f-) = B(3,5-(CF(3))(2)C(6)H(3))(4)) affords [Ir(CO)(Me)(DIM)((R)-(+)-BINAP)][BAr(4)(f)](2) (6) in quantitative yield. Both 5 and 6 are active Lewis acid catalysts for the polarized Nazarov cyclization and the Diels-Alder reaction. In the Nazarov cyclization, when NaBAr(4)(f) is added as a cofactor for the reaction catalyzed by 5 or 6, the resultant oxyallyl cation intermediate from the 4pi conrotation undergoes a Wagner-Meerwein rearrangement to afford spirocyclic cyclopentenones in modest to good yields. PMID:20361755

  8. Some features of the change in the carbonyl group content of coal in the process of metamorphism

    SciTech Connect

    Kucherenko, V.A.; Kuznetsova, L.V.; Sapunov, V.A.; Osipov, A.M.

    1983-01-01

    Different forms of carbonyl groups were studied in Donbass coals and it was shown that there is a relationship between the variation in quinoidal and ketonic oxygen and the degree of metamorphism. (17 refs.)

  9. Addition of Small Electrophiles to N-Heterocyclic-Carbene-Stabilized Disilicon(0): A Revisit of the Isolobal Concept in Low-Valent Silicon Chemistry.

    PubMed

    Arz, Marius I; Straßmann, Martin; Geiß, Daniel; Schnakenburg, Gregor; Filippou, Alexander C

    2016-04-01

    Protonation and alkylation of (Idipp)Si═Si(Idipp) (1) afforded the mixed-valent disilicon(I)-borates [(Idipp)(R)Si(II)═Si(0)(Idipp)][B(Ar(F))4] (1R[B(Ar(F))4]; R = H, Me, Et; Ar(F) = C6H3-3,5-(CF3)2; Idipp = C[N(C6H3-2,6-iPr2)CH]2) as red to orange colored, highly air-sensitive solids, which were characterized by single-crystal X-ray diffraction, IR spectroscopy and multinuclear NMR spectroscopy. Dynamic NMR studies in solution revealed a degenerate isomerization (topomerization) of the "σ-bonded" tautomers of 1H[B(Ar(F))4], which proceeds according to quantum chemical calculations via a NHC-stabilized (NHC = N-heterocyclic carbene) disilahydronium ion ("π-bonded" isomer) and is reminiscent of the degenerate rearrangement of carbenium ions formed upon protonation of olefins. The topomerization of 1H[B(Ar(F))4] provides the first example of a reversible 1,2-H migration along a Si═Si bond observed in a molecular system. In contrast, 1Me[B(Ar(F))4] adopts a "rigid" structure in solution due to the higher energy required for the interconversion of the "σ-bonded" isomer into a putative NHC-stabilized disilamethonium ion. Addition of alkali metal borates to 1 afforded the alkali metal disilicon(0) borates 1M[BAr4] (M = Li, Ar = C6F5; M = Na, Ar = Ar(F)) as brown, air-sensitive solids. Single-crystal X-ray diffraction analyses and NMR spectroscopic studies of 1M[BAr4] suggest in concert with quantum chemical calculations that encapsulation of the alkali metal cations in the cavity of 1 predominantly occurs via electrostatic cation-π interactions with the Si═Si π-bond and the peripheral NHC aryl rings. Displacement of the [Si(NHC)] fragments by the isolobal fragments [PR] and [SiR](-) interrelates the cations [(NHC)(R)Si═Si(NHC)](+) to a series of familiar, multiply bonded Si and P compounds as verified by analyses of their electronic structures.

  10. Addition of Small Electrophiles to N-Heterocyclic-Carbene-Stabilized Disilicon(0): A Revisit of the Isolobal Concept in Low-Valent Silicon Chemistry.

    PubMed

    Arz, Marius I; Straßmann, Martin; Geiß, Daniel; Schnakenburg, Gregor; Filippou, Alexander C

    2016-04-01

    Protonation and alkylation of (Idipp)Si═Si(Idipp) (1) afforded the mixed-valent disilicon(I)-borates [(Idipp)(R)Si(II)═Si(0)(Idipp)][B(Ar(F))4] (1R[B(Ar(F))4]; R = H, Me, Et; Ar(F) = C6H3-3,5-(CF3)2; Idipp = C[N(C6H3-2,6-iPr2)CH]2) as red to orange colored, highly air-sensitive solids, which were characterized by single-crystal X-ray diffraction, IR spectroscopy and multinuclear NMR spectroscopy. Dynamic NMR studies in solution revealed a degenerate isomerization (topomerization) of the "σ-bonded" tautomers of 1H[B(Ar(F))4], which proceeds according to quantum chemical calculations via a NHC-stabilized (NHC = N-heterocyclic carbene) disilahydronium ion ("π-bonded" isomer) and is reminiscent of the degenerate rearrangement of carbenium ions formed upon protonation of olefins. The topomerization of 1H[B(Ar(F))4] provides the first example of a reversible 1,2-H migration along a Si═Si bond observed in a molecular system. In contrast, 1Me[B(Ar(F))4] adopts a "rigid" structure in solution due to the higher energy required for the interconversion of the "σ-bonded" isomer into a putative NHC-stabilized disilamethonium ion. Addition of alkali metal borates to 1 afforded the alkali metal disilicon(0) borates 1M[BAr4] (M = Li, Ar = C6F5; M = Na, Ar = Ar(F)) as brown, air-sensitive solids. Single-crystal X-ray diffraction analyses and NMR spectroscopic studies of 1M[BAr4] suggest in concert with quantum chemical calculations that encapsulation of the alkali metal cations in the cavity of 1 predominantly occurs via electrostatic cation-π interactions with the Si═Si π-bond and the peripheral NHC aryl rings. Displacement of the [Si(NHC)] fragments by the isolobal fragments [PR] and [SiR](-) interrelates the cations [(NHC)(R)Si═Si(NHC)](+) to a series of familiar, multiply bonded Si and P compounds as verified by analyses of their electronic structures. PMID:26978031

  11. Method for forming ammonia

    DOEpatents

    Kong, Peter C.; Pink, Robert J.; Zuck, Larry D.

    2008-08-19

    A method for forming ammonia is disclosed and which includes the steps of forming a plasma; providing a source of metal particles, and supplying the metal particles to the plasma to form metal nitride particles; and providing a substance, and reacting the metal nitride particles with the substance to produce ammonia, and an oxide byproduct.

  12. Methods of forming steel

    DOEpatents

    Branagan, Daniel J.; Burch, Joseph V.

    2001-01-01

    In one aspect, the invention encompasses a method of forming a steel. A metallic glass is formed and at least a portion of the glass is converted to a crystalline steel material having a nanocrystalline scale grain size. In another aspect, the invention encompasses another method of forming a steel. A molten alloy is formed and cooled the alloy at a rate which forms a metallic glass. The metallic glass is devitrified to convert the glass to a crystalline steel material having a nanocrystalline scale grain size. In yet another aspect, the invention encompasses another method of forming a steel. A first metallic glass steel substrate is provided, and a molten alloy is formed over the first metallic glass steel substrate to heat and devitrify at least some of the underlying metallic glass of the substrate.

  13. Forming of superplastic ceramics

    SciTech Connect

    Lesuer, D.R.; Wadsworth, J.; Nieh, T.G.

    1994-05-01

    Superplasticity in ceramics has now advanced to the stage that technologically viable superplastic deformation processing can be performed. In this paper, examples of superplastic forming and diffusion bonding of ceramic components are given. Recent work in biaxial gas-pressure forming of several ceramics is provided. These include yttria-stabilized, tetragonal zirconia (YTZP), a 20% alumina/YTZP composite, and silicon. In addition, the concurrent superplastic forming and diffusion bonding of a hybrid ceramic-metal structure are presented. These forming processes offer technological advantages of greater dimensional control and increased variety and complexity of shapes than is possible with conventional ceramic shaping technology.

  14. Profiles of antioxidant/electrophile response element (ARE/EpRE) nuclear protein binding and c-Ha-ras transactivation in vascular smooth muscle cells treated with oxidative metabolites of benzo[a]pyrene.

    PubMed

    Miller, K P; Chen, Y H; Hastings, V L; Bral, C M; Ramos, K S

    2000-11-01

    Activation of nuclear protein binding to the antioxidant/electrophile response element (ARE/EpRE) by benzo[a]pyrene (BaP) in vascular smooth muscle cells (vSMCs) is associated with transcriptional deregulation of c-Ha-ras. This response may be mediated by oxidative intermediates of BaP generated during the course of cellular metabolism. To test this hypothesis, the profile of ARE/EpRE protein binding and transactivation elicited by BaP was compared with that of 3-hydroxy BaP (3-OH BaP) (0.03 to 3.0 microM), BaP 7,8-dihydrodiol (BaP 7,8-diol) (0.03 to 3.0 microM), BaP 3,6-quinone (BaP 3,6-Q) (0.0003 to 3.0 microM), and H(2)O(2) (25 to 100 microM). Specific protein binding to the consensus c-Ha-ras ARE/EpRE was observed in vSMCs treated with all BaP metabolites at concentrations considerably lower than those required for the parent compound. H(2)O(2), a by-product of BaP 3,6-Q redox cycling, also increased binding to the ARE/EpRE. Treatment of vSMCs with oxidative BaP metabolites or H(2)O(2) transactivated the c-Ha-ras promoter in all instances, but the response was consistently half of the maximal induction elicited by BaP. Similar proteins cross-linked specifically to the consensus c-Ha-ras ARE/EpRE sequence in cells treated with BaP or its oxidative intermediates. The protein binding profile in the c-Ha-ras promoter was similar to that in the NADPH:quinone reductase gene (NQO(1)) and the glutathione S-transferase Ya gene (GSTYa) promoters, but the relative abundance of individual complexes was promoter-specific. We conclude that oxidative intermediates of BaP mediate activation of nuclear protein binding to ARE/EpRE and contribute to transcriptional de-regulation of c-Ha-ras in vSMCs.

  15. L-edge X-ray Absorption Spectroscopy and DFT Calculations on Cu2O2 Species: Direct Electrophilic Aromatic Attack by Side-on Peroxo Bridged Dicopper(II) Complexes

    PubMed Central

    Qayyum, Munzarin F.; Sarangi, Ritimukta; Fujisawa, Kiyoshi; Stack, T. Daniel P.; Karlin, Kenneth D.; Hodgson, Keith O.; Hedman, Britt; Solomon, Edward I.

    2013-01-01

    The hydroxylation of aromatic substrates catalyzed by coupled binuclear copper enzymes has been observed with side-on-peroxo-dicopper(II) (P) and bis-μ-oxo-dicopper(III) (O) model complexes. The substrate-bound-O intermediate in [Cu(II)2(DBED)2(O)2]2+ (DBED=N,N′-di-tert-butyl-ethylenediamine) was shown to perform aromatic hydroxylation. For the [Cu(II)2(NO2-XYL)(O2)]2+ complex, only a P species was spectroscopically observed. However, it was not clear whether this O-O bond cleaves to proceed through an O-type structure along the reaction coordinate for hydroxylation of the aromatic xylyl linker. Accurate evaluation of these reaction coordinates requires reasonable quantitative descriptions of the electronic structures of the P and O species. We have performed Cu L-edge XAS on two well-characterized P and O species to experimentally quantify the Cu 3d character in their ground state wavefunctions. The lower per-hole Cu character (40±6%) corresponding to higher covalency in the O species compared to the P species (52±4%) reflects a stronger bonding interaction of the bis-μ-oxo core with the Cu(III) centers. DFT calculations show that 10-20% Hartree-Fock (HF) mixing for P and ~38% for O species are required to reproduce the Cu-O bonding; for the P species this HF mixing is also required for an antiferromagnetically coupled description of the two Cu(II) centers. B3LYP (with 20% HF) was, therefore, used to calculate the hydroxylation reaction coordinate of P in [Cu(II)2(NO2-XYL)(O2)]2+. These experimentally calibrated calculations indicate that the electrophilic attack on the aromatic ring does not involve formation of a Cu(III)2(O2−)2 species. Rather, there is direct electron donation from the aromatic ring into the peroxo σ* orbital of the Cu(II)2(O22−) species, leading to concerted C-O bond formation with O-O bond cleavage. Thus, species P is capable of direct hydroxylation of aromatic substrates without the intermediacy of an O-type species. PMID:24102191

  16. Label-Free Proteomics Assisted by Affinity Enrichment for Elucidating the Chemical Reactivity of the Liver Mitochondrial Proteome toward Adduction by the Lipid Electrophile 4-hydroxy-2-nonenal (HNE).

    PubMed

    Tzeng, Shin-Cheng; Maier, Claudia S

    2016-01-01

    The analysis of oxidative stress-induced post-translational modifications remains challenging due to the chemical diversity of these modifications, the possibility of the presence of positional isomers and the low stoichiometry of the modified proteins present in a cell or tissue proteome. Alcoholic liver disease (ALD) is a multifactorial disease in which mitochondrial dysfunction and oxidative stress have been identified as being critically involved in the progression of the disease from steatosis to cirrhosis. Ethanol metabolism leads to increased levels of reactive oxygen species (ROS), glutathione depletion and lipid peroxidation. Posttranslational modification of proteins by electrophilic products of lipid peroxidation has been associated with governing redox-associated signaling mechanisms, but also as contributing to protein dysfunction leading to organelle and liver injury. In particular the prototypical α,β-unsaturated aldehyde, 4-hydroxy-2-nonenal (HNE), has been extensively studied as marker of increased oxidative stress in hepatocytes. In this study, we combined a LC-MS label-free quantification method and affinity enrichment to assess the dose-dependent insult by HNE on the proteome of rat liver mitochondria. We used a carbonyl-selective probe, the ARP probe, to label HNE-protein adducts and to perform affinity capture at the protein level. Using LC-MS to obtain protein abundance estimates, a list of protein targets was obtained with increasing concentration of HNE used in the exposure studies. In parallel, we performed affinity capture at the peptide level to acquire site-specific information. Examining the concentration-dependence of the protein modifications, we observed distinct reactivity profiles for HNE-protein adduction. Pathway analysis indicated that proteins associated with metabolic processes, including amino acid, fatty acid, and glyoxylate and dicarboxylate metabolism, bile acid synthesis and TCA cycle, showed enhanced reactivity to HNE

  17. Label-free proteomics assisted by affinity enrichment for elucidating the chemical reactivity of the liver mitochondrial proteome toward adduction by the lipid electrophile 4-hydroxy-2-nonenal (HNE)

    NASA Astrophysics Data System (ADS)

    Maier, Claudia

    2016-03-01

    The analysis of oxidative stress-induced post-translational modifications remains challenging due to the chemical diversity of these modifications, the possibility of the presence of positional isomers and the low stoichiometry of the modified proteins present in a cell or tissue proteome. Alcoholic liver disease (ALD) is a multifactorial disease in which mitochondrial dysfunction and oxidative stress have been identified as being critically involved in the progression of the disease from steatosis to cirrhosis. Ethanol metabolism leads to increased levels of reactive oxygen species (ROS), glutathione depletion and lipid peroxidation. Posttranslational modification of proteins by electrophilic products of lipid peroxidation has been associated with governing redox-associated signaling mechanisms, but also as contributing to protein dysfunction leading to organelle and liver injury. In particular the prototypical α,β-unsaturated aldehyde, 4-hydroxy-2-nonenal (HNE), has been extensively studied as marker of increased oxidative stress in hepatocytes. In this study, we combined a LC-MS label-free quantification method and affinity enrichment to assess the dose-dependent insult by HNE on the proteome of rat liver mitochondria. We used a carbonyl-selective probe, the ARP probe, to label HNE-protein adducts and to perform affinity capture at the protein level. Using LC-MS to obtain protein abundance estimates, a list of protein targets was obtained with increasing concentration of HNE used in the exposure studies. In parallel, we performed affinity capture at the peptide level to acquire site-specific information. Examining the concentration-dependence of the protein modifications, we observed distinct reactivity profiles for HNE-protein adduction. Pathway analysis indicated that proteins associated with metabolic processes, including amino acid, fatty acid and glyoxylate and dicarboxylate metabolism, bile acid synthesis and TCA cycle, showed enhanced reactivity to HNE

  18. Label-Free Proteomics Assisted by Affinity Enrichment for Elucidating the Chemical Reactivity of the Liver Mitochondrial Proteome toward Adduction by the Lipid Electrophile 4-hydroxy-2-nonenal (HNE)

    PubMed Central

    Tzeng, Shin-Cheng; Maier, Claudia S.

    2016-01-01

    The analysis of oxidative stress-induced post-translational modifications remains challenging due to the chemical diversity of these modifications, the possibility of the presence of positional isomers and the low stoichiometry of the modified proteins present in a cell or tissue proteome. Alcoholic liver disease (ALD) is a multifactorial disease in which mitochondrial dysfunction and oxidative stress have been identified as being critically involved in the progression of the disease from steatosis to cirrhosis. Ethanol metabolism leads to increased levels of reactive oxygen species (ROS), glutathione depletion and lipid peroxidation. Posttranslational modification of proteins by electrophilic products of lipid peroxidation has been associated with governing redox-associated signaling mechanisms, but also as contributing to protein dysfunction leading to organelle and liver injury. In particular the prototypical α,β-unsaturated aldehyde, 4-hydroxy-2-nonenal (HNE), has been extensively studied as marker of increased oxidative stress in hepatocytes. In this study, we combined a LC-MS label-free quantification method and affinity enrichment to assess the dose-dependent insult by HNE on the proteome of rat liver mitochondria. We used a carbonyl-selective probe, the ARP probe, to label HNE-protein adducts and to perform affinity capture at the protein level. Using LC-MS to obtain protein abundance estimates, a list of protein targets was obtained with increasing concentration of HNE used in the exposure studies. In parallel, we performed affinity capture at the peptide level to acquire site-specific information. Examining the concentration-dependence of the protein modifications, we observed distinct reactivity profiles for HNE-protein adduction. Pathway analysis indicated that proteins associated with metabolic processes, including amino acid, fatty acid, and glyoxylate and dicarboxylate metabolism, bile acid synthesis and TCA cycle, showed enhanced reactivity to HNE

  19. [Benign bone forming tumors].

    PubMed

    Caufourier, C; Leprovost, N; Guillou-Jamard, M-R; Compère, J-F; Bénateau, H

    2009-09-01

    Benign bone forming tumors typically produce dense bone (osteoma, enostosis) or osteoid tissue (osteoid osteoma, osteoblastoma). Even though these four lesions have distinct characteristics, it is sometimes difficult to tell them apart and to rule out malignant bone forming lesions such as osteosarcoma. The first line treatment is surgical exeresis.

  20. Method of forming nanodielectrics

    DOEpatents

    Tuncer, Enis [Knoxville, TN; Polyzos, Georgios [Oak Ridge, TN

    2014-01-07

    A method of making a nanoparticle filled dielectric material. The method includes mixing nanoparticle precursors with a polymer material and reacting the nanoparticle mixed with the polymer material to form nanoparticles dispersed within the polymer material to form a dielectric composite.

  1. Method for forming materials

    DOEpatents

    Tolle, Charles R.; Clark, Denis E.; Smartt, Herschel B.; Miller, Karen S.

    2009-10-06

    A material-forming tool and a method for forming a material are described including a shank portion; a shoulder portion that releasably engages the shank portion; a pin that releasably engages the shoulder portion, wherein the pin defines a passageway; and a source of a material coupled in material flowing relation relative to the pin and wherein the material-forming tool is utilized in methodology that includes providing a first material; providing a second material, and placing the second material into contact with the first material; and locally plastically deforming the first material with the material-forming tool so as mix the first material and second material together to form a resulting material having characteristics different from the respective first and second materials.

  2. Handprinted Forms and Characters

    National Institute of Standards and Technology Data Gateway

    NIST Handprinted Forms and Characters (PC database for purchase)   NIST Special Database 19 contains NIST's entire corpus of training materials for handprinted document and character recognition. It supersedes NIST Special Databases 3 and 7.

  3. Image forming apparatus

    DOEpatents

    Satoh, Hisao; Haneda, Satoshi; Ikeda, Tadayoshi; Morita, Shizuo; Fukuchi, Masakazu

    1996-01-01

    In an image forming apparatus having a detachable process cartridge in which an image carrier on which an electrostatic latent image is formed, and a developing unit which develops the electrostatic latent image so that a toner image can be formed, both integrally formed into one unit. There is provided a developer container including a discharge section which can be inserted into a supply opening of the developing unit, and a container in which a predetermined amount of developer is contained, wherein the developer container is provided to the toner supply opening of the developing unit and the developer is supplied into the developing unit housing when a toner stirring screw of the developing unit is rotated.

  4. Forms of Arthritis

    MedlinePlus

    ... It typically begins during the early-adult years. Juvenile arthritis — arthritis that is diagnosed before age 16. The most common form of juvenile arthritis, juvenile rheumatoid arthritis, affects between 30,000 and ...

  5. Electromagnetic nucleon form factors

    SciTech Connect

    Bender, A.; Roberts, C.D.; Frank, M.R.

    1995-08-01

    The Dyson-Schwinger equation framework is employed to obtain expressions for the electromagnetic nucleon form factor. In generalized impulse approximation the form factor depends on the dressed quark propagator, the dressed quark-photon vertex, which is crucial to ensuring current conservation, and the nucleon Faddeev amplitude. The approach manifestly incorporates the large space-like-q{sup 2} renormalization group properties of QCD and allows a realistic extrapolation to small space-like-q{sup 2}. This extrapolation allows one to relate experimental data to the form of the quark-quark interaction at small space-like-q{sup 2}, which is presently unknown. The approach provides a means of unifying, within a single framework, the treatment of the perturbative and nonperturbative regimes of QCD. The wealth of experimental nucleon form factor data, over a large range of q{sup 2}, ensures that this application will provide an excellent environment to test, improve and extend our approach.

  6. X-ray structure determination of new monomers to establish their polymerizability: copolymerization of two tetrasubstituted electrophilic olefins with electron-rich styrenes giving polymers with an average 1. 25 functional groups per chain carbon atom. [Tetramethyl ethylenetetracarboxylate and dimethyl dicyanofumate; gamma radiation

    SciTech Connect

    Hall, H.K. Jr.; Reineke, K.E.; Ried, J.H.; Sentman, R.C.; Miller, D.

    1982-02-01

    X-ray crystal structure determination for two tetrasubstituted electrophilic olefins, tetramethyl ethylenetetracarboxylate TMET and dimethyl dicyanofumarate DDCF, revealed two fundamentally different molecular structures. TMET is a nonplanar molecule that possesses two opposite ester groups planar and the others above and below the molecular plane. In contrast, DDCF is a molecule for which both ester groups lie in the plane of the double bond and nitrile groups. DDCF underwent thermal spontaneous copolymerization with electron-rich styrenes to give 1:1 alternating copolymers in moderate yields and molecular weights. These copolymers, which result from the first copolymerization of a tetrasubstituted olefin, possess an average functionality of 1.25 per chain carbon atom. Polymerization is made possible by low steric hindrance and the high delocalization in the propagating radical. The yields were limited by competing cycloaddition reaction. The corresponding diethyl ester also copolymerized, but not so well. Neither electrophilic olefin homopolymerized under ..gamma..-irradiation. TMET did not copolymerize at all when treated under identical conditions.

  7. Comparative waste forms study

    SciTech Connect

    Wald, J.W.; Lokken, R.O.; Shade, J.W.; Rusin, J.M.

    1980-12-01

    A number of alternative process and waste form options exist for the immobilization of nuclear wastes. Although data exists on the characterization of these alternative waste forms, a straightforward comparison of product properties is difficult, due to the lack of standardized testing procedures. The characterization study described in this report involved the application of the same volatility, mechanical strength and leach tests to ten alternative waste forms, to assess product durability. Bulk property, phase analysis and microstructural examination of the simulated products, whose waste loading varied from 5% to 100% was also conducted. The specific waste forms investigated were as follows: Cold Pressed and Sintered PW-9 Calcine; Hot Pressed PW-9 Calcine; Hot Isostatic Pressed PW-9 Calcine; Cold Pressed and Sintered SPC-5B Supercalcine; Hot Isostatic pressed SPC-5B Supercalcine; Sintered PW-9 and 50% Glass Frit; Glass 76-68; Celsian Glass Ceramic; Type II Portland Cement and 10% PW-9 Calcine; and Type II Portland Cement and 10% SPC-5B Supercalcine. Bulk property data were used to calculate and compare the relative quantities of waste form volume produced at a spent fuel processing rate of 5 metric ton uranium/day. This quantity ranged from 3173 L/day (5280 Kg/day) for 10% SPC-5B supercalcine in cement to 83 L/day (294 Kg/day) for 100% calcine. Mechanical strength, volatility, and leach resistance tests provide data related to waste form durability. Glass, glass-ceramic and supercalcine ranked high in waste form durability where as the 100% PW-9 calcine ranked low. All other materials ranked between these two groupings.

  8. Syntheses and studies of new forms of N-sulfonyloxy β-lactams as potential antibacterial agents and β-lactamase inhibitors.

    PubMed

    Carosso, Serena; Miller, Marvin J

    2015-09-15

    The synthesis of a small library of N-sulfonyloxy-2-azetidinones is reported and the preliminary results of the investigation of the biological activity of these molecules are discussed. These new multi-electrophilic β-lactams ('electrophilic bombs') display unexpected selectivity in their antibacterial activity and β-lactamase inhibitory activity. PMID:26321604

  9. Syntheses and studies of new forms of N-sulfonyloxy β-lactams as potential antibacterial agents and β-lactamase inhibitors.

    PubMed

    Carosso, Serena; Miller, Marvin J

    2015-09-15

    The synthesis of a small library of N-sulfonyloxy-2-azetidinones is reported and the preliminary results of the investigation of the biological activity of these molecules are discussed. These new multi-electrophilic β-lactams ('electrophilic bombs') display unexpected selectivity in their antibacterial activity and β-lactamase inhibitory activity.

  10. Syntheses and Studies of New Forms of N-Sulfonyloxy β-Lactams as Potential Antibacterial Agents and β-Lactamase Inhibitors

    PubMed Central

    Carosso, Serena; Miller, Marvin J.

    2015-01-01

    The synthesis of a small library of N-sulfonyloxy-2-azetidinones is reported and the preliminary results of the investigation of the biological activity of these molecules are discussed. These new multi-electrophilic β-lactams (“electrophilic bombs”) display unexpected selectivity in their antibacterial activity and β-lactamase inhibitory activity. PMID:26321604

  11. Methods for forming particles

    DOEpatents

    Fox, Robert V.; Zhang, Fengyan; Rodriguez, Rene G.; Pak, Joshua J.; Sun, Chivin

    2016-06-21

    Single source precursors or pre-copolymers of single source precursors are subjected to microwave radiation to form particles of a I-III-VI.sub.2 material. Such particles may be formed in a wurtzite phase and may be converted to a chalcopyrite phase by, for example, exposure to heat. The particles in the wurtzite phase may have a substantially hexagonal shape that enables stacking into ordered layers. The particles in the wurtzite phase may be mixed with particles in the chalcopyrite phase (i.e., chalcopyrite nanoparticles) that may fill voids within the ordered layers of the particles in the wurtzite phase thus produce films with good coverage. In some embodiments, the methods are used to form layers of semiconductor materials comprising a I-III-VI.sub.2 material. Devices such as, for example, thin-film solar cells may be fabricated using such methods.

  12. Synthesis and oxidation of 2-hydroxynevirapine, a metabolite of the HIV reverse transcriptase inhibitor nevirapine.

    PubMed

    Antunes, Alexandra M M; Novais, David A; da Silva, J L Ferreira; Santos, Pedro P; Oliveira, M Conceição; Beland, Frederick A; Marques, M Matilde

    2011-10-26

    Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, NVP) is a non-nucleoside HIV-1 reverse transcriptase inhibitor used to prevent mother-to-child transmission of the virus. However, severe hepatotoxicity and serious adverse cutaneous effects have raised concerns about the safety of NVP administration. NVP metabolism yields several phenol-type derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species that could react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As an initial step to test this hypothesis, we synthesized the phenolic metabolite, 2-hydroxy-NVP, and investigated its oxidation in vitro. Using potassium nitrosodisulfonate and sodium periodate as model oxidants, we obtained evidence for fast generation of an electrophilic quinone-imine, which readily underwent hydrolytic conversion to fully characterized spiro derivatives, 1'-cyclopropyl-4-methyl-1H,1'H-spiro[pyridine-2,2'-pyrido[2,3-d]pyrimidine]-3,4',6(3'H)-trione in aqueous media and 1'-cyclopropyl-4-methyl-1'H,2H-spiro[pyridine-3,2'-pyrido[2,3-d]pyrimidine]-2,4',6(1H,3'H)-trione in non-aqueous media. The spiro compound generated in aqueous solution underwent subsequent hydrolytic degradation of the NVP ring system, whereas the one formed in non-aqueous media was stable to hydrolysis. The product profile observed with the chemical oxidants in aqueous solution was replicated using lactoperoxidase-mediated oxidation of 2-hydroxy-NVP. These observations suggest that metabolic activation of NVP, via Phase I oxidation to 2-hydroxy-NVP and subsequent generation of a quinone-imine, could occur in vivo and play a role in NVP-induced toxicity.

  13. Method for forming targets

    DOEpatents

    Woerner, Robert L.

    1979-01-01

    Method for cryoinduced uniform deposition of cryogenic materials, such as deuterium-tritium (DT) mixtures, on the inner surface of hollow spherical members, such as inertially imploded targets. By vaporizing and quickly refreezing cryogenic materials contained within a hollow spherical member, a uniform layer of the materials is formed on the inner surface of the spherical member. Heating of the cryogenic material, located within a non-isothermal compact freezing cell, is accomplished by an electrical heat pulse, whereafter the material is quickly frozen forming a uniform layer on the inner surface of the spherical member. The method is not restricted to producing a frozen layer on only the inner surface of the innermost hollow member, but where multiple concentric hollow spheres are involved, such as in multiple shell targets for lasers, electron beams, etc., layers of cryogenic material may also be formed on the inner surface of intermediate or outer spherical members, thus providing the capability of forming targets having multiple concentric layers or shells of frozen DT.

  14. Apparatus for forming targets

    DOEpatents

    Woerner, Robert L.

    1980-01-01

    Apparatus and method for cryoinduced uniform deposition of cryogenic materials, such as deuterium-tritium (DT) mixtures, on the inner surface of hollow spherical members, such as inertially imploded targets. By vaporizing and quickly refreezing cryogenic materials contained within a hollow spherical member, a uniform layer of the materials is formed on the inner surface of the spherical member. Heating of the cryogenic material, located within a non-isothermal compact freezing cell, is accomplished by an electrical heat pulse, whereafter the material is quickly frozen forming a uniform layer on the inner surface of the spherical member. The method is not restricted to producing a frozen layer on only the inner surface of the innermost hollow member, but where multiple concentric hollow spheres are involved, such as in multiple shell targets for lasers, electron beams, etc., layers of cryogenic material may also be formed on the inner surface of intermediate or outer spherical members, thus providing the capability of forming targets having multiple concentric layers or shells of frozen DT.

  15. Many Forms of Culture

    ERIC Educational Resources Information Center

    Cohen, Adam B.

    2009-01-01

    Psychologists interested in culture have focused primarily on East-West differences in individualism-collectivism, or independent-interdependent self-construal. As important as this dimension is, there are many other forms of culture with many dimensions of cultural variability. Selecting from among the many understudied cultures in psychology,…

  16. Geodiversity and land form

    NASA Astrophysics Data System (ADS)

    Gray, Murray

    2014-05-01

    The Earth's surface has a dynamic and topographically varied natural landscape. In some cases the resulting landforms are given generic names reflecting their form and/or origin, (e.g. sand dunes, eskers, ox-bow lakes) but in many cases the land surface has a more amorphous form and is less easily categorized other than at a landscape scale (e.g. dissected plateau, Chalk downland). Across much of Europe, while the natural vegetation has been removed or radically modified, the natural land form/topography remains in tact. In this context and in terms of geoconservation we ought to be: • allowing the dynamic natural processes that create, carve and modify landscapes to continue to operate; and • retaining natural topographic character and geomorphological authenticity in the face of human actions seeking to remodel the land surface. In this presentation examples of this approach to geoconservation of land form will be given from the UK and other parts of the world. This will include examples of both appropriate and inappropriate topographic modifications.

  17. Literature: External Forms.

    ERIC Educational Resources Information Center

    Regional Curriculum Project, Atlanta, GA.

    This curriculum guide, developed as part of a total English curriculum for pre-kindergarten through grade 10, suggests that students can best understand literature by understanding its recurring external forms or genres, and includes (1) an overview describing the four literary genres of drama, narrative poetry, narrative fiction, and lyric poetry…

  18. Formed photovoltaic module busbars

    DOEpatents

    Rose, Douglas; Daroczi, Shan; Phu, Thomas

    2015-11-10

    A cell connection piece for a photovoltaic module is disclosed herein. The cell connection piece includes an interconnect bus, a plurality of bus tabs unitarily formed with the interconnect bus, and a terminal bus coupled with the interconnect bus. The plurality of bus tabs extend from the interconnect bus. The terminal bus includes a non-linear portion.

  19. Forms of Soft Sculpture

    ERIC Educational Resources Information Center

    Tucker, Dorothy

    1978-01-01

    For the past several years, students at Madison Senior High School in San Diego have responded to the tactile texture and draping quality of soft materials. They experimented enthusiastically with three-dimensional forms made out of foam rubber. Here is the result of their efforts and experimentation. (Author/RK)

  20. Inelastic Scattering Form Factors

    1992-01-01

    ATHENA-IV computes form factors for inelastic scattering calculations, using single-particle wave functions that are eigenstates of motion in either a Woods-Saxon potential well or a harmonic oscillator well. Two-body forces of Gauss, Coulomb, Yukawa, and a sum of cut-off Yukawa radial dependences are available.

  1. High energy forming facility

    NASA Technical Reports Server (NTRS)

    Ciurlionis, B.

    1967-01-01

    Watertight, high-explosive forming facility, 25 feet in diameter and 15 feet deep, withstands repeated explosions of 10 pounds of TNT equivalent. The shell is fabricated of high strength steel and allows various structural elements to deform or move elastically and independently while retaining structural integrity.

  2. Low Temperature Sheet Forming

    NASA Astrophysics Data System (ADS)

    Voges-Schwieger, Kathrin; Hübner, Sven; Behrens, Bernd-Arno

    2011-05-01

    Metastable austenitic stainless steels change their lattice during forming operations by strain-induced alpha'-martensite formation. Temperatures below T = 20° C can accelerate the phase transformation while temperatures above T = 60° C may suppress the formation of martensite during the forming operation. In past investigations, the effect of high-strength martensitic regions in an austenitic ductile lattice was used in crash relevant parts for transportation vehicles. The local martensitic regions act as reinforcements leading to an increase in crash energy absorption. Moreover, they control the folding behavior as well as the force-distance-characteristic and increase the buckling resistance. This paper deals with a concerted thermomechanical drawing process to increase the local formation of alpha'-martensite caused by low temperatures.

  3. Analytic pion form factor

    NASA Astrophysics Data System (ADS)

    Lomon, Earle L.; Pacetti, Simone

    2016-09-01

    The pion electromagnetic form factor and two-pion production in electron-positron collisions are simultaneously fitted by a vector dominance model evolving to perturbative QCD at large momentum transfer. This model was previously successful in simultaneously fitting the nucleon electromagnetic form factors (spacelike region) and the electromagnetic production of nucleon-antinucleon pairs (timelike region). For this pion case dispersion relations are used to produce the analytic connection of the spacelike and timelike regions. The fit to all the data is good, especially for the newer sets of timelike data. The description of high-q2 data, in the timelike region, requires one more meson with ρ quantum numbers than listed in the 2014 Particle Data Group review.

  4. Waste-form development

    SciTech Connect

    Neilson, R.M. Jr.; Colombo, P.

    1982-01-01

    Contemporary solidification agents are being investigated relative to their applications to major fuel cycle and non-fuel cycle low-level waste (LLW) streams. Work is being conducted to determine the range of conditions under which these solidification agents can be applied to specific LLW streams. These studies are directed primarily towards defining operating parameters for both improved solidification of problem wastes and solidification of new LLW streams generated from advanced volume reduction technologies. Work is being conducted to measure relevant waste form properties. These data will be compiled and evaluated to demonstrate compliance with waste form performance and shallow land burial acceptance criteria and transportation requirements (both as they exist and as they are modified with time).

  5. Formed HIP Can Processing

    SciTech Connect

    Clarke, Kester Diederik

    2015-07-27

    The intent of this report is to document a procedure used at LANL for HIP bonding aluminum cladding to U-10Mo fuel foils using a formed HIP can for the Domestic Reactor Conversion program in the NNSA Office of Material, Management and Minimization, and provide some details that may not have been published elsewhere. The HIP process is based on the procedures that have been used to develop the formed HIP can process, including the baseline process developed at Idaho National Laboratory (INL). The HIP bonding cladding process development is summarized in the listed references. Further iterations with Babcock & Wilcox (B&W) to refine the process to meet production and facility requirements is expected.

  6. Conjunctive visual forms.

    PubMed

    Weaver, Chris

    2009-01-01

    Visual exploration of multidimensional data is a process of isolating and extracting relationships within and between dimensions. Coordinated multiple view approaches are particularly effective for visual exploration because they support precise expression of heterogeneous multidimensional queries using simple interactions. Recent visual analytics research has made significant progress in identifying and understanding patterns of composed views and coordinations that support fast, flexible, and open-ended data exploration. What is missing is formalization of the space of expressible queries in terms of visual representation and interaction. This paper introduces the Conjunctive Visual Form model in which visual exploration consists of interactively-driven sequences of transitions between visual states that correspond to conjunctive normal forms in boolean logic. The model predicts several new and useful ways to extend the space of rapidly expressible queries through addition of simple interactive capabilities to existing compositional patterns. Two recent related visual tools offer a subset of these capabilities, providing a basis for conjecturing about such extensions.

  7. Tube-Forming Assays.

    PubMed

    Brown, Ryan M; Meah, Christopher J; Heath, Victoria L; Styles, Iain B; Bicknell, Roy

    2016-01-01

    Angiogenesis involves the generation of new blood vessels from the existing vasculature and is dependent on many growth factors and signaling events. In vivo angiogenesis is dynamic and complex, meaning assays are commonly utilized to explore specific targets for research into this area. Tube-forming assays offer an excellent overview of the molecular processes in angiogenesis. The Matrigel tube forming assay is a simple-to-implement but powerful tool for identifying biomolecules involved in angiogenesis. A detailed experimental protocol on the implementation of the assay is described in conjunction with an in-depth review of methods that can be applied to the analysis of the tube formation. In addition, an ImageJ plug-in is presented which allows automatic quantification of tube images reducing analysis times while removing user bias and subjectivity.

  8. Certification reporting forms

    SciTech Connect

    Not Available

    1981-02-18

    The required information and formats for the certification report including the cover sheet, compliance statement, and body of the report are given in this document. The body of the reports is different for each product. There are no product-to-product differences in the forms of the other parts of the reports. The products covered in this document include: furnaces, water heaters, refrigerator-freezers, central air conditioners, room air conditioners, and freezers.

  9. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Kees de Jager

    2004-08-01

    Although nucleons account for nearly all the visible mass in the universe, they have a complicated structure that is still incompletely understood. The first indication that nucleons have an internal structure, was the measurement of the proton magnetic moment by Frisch and Stern (1933) which revealed a large deviation from the value expected for a point-like Dirac particle. The investigation of the spatial structure of the nucleon, resulting in the first quantitative measurement of the proton charge radius, was initiated by the HEPL (Stanford) experiments in the 1950s, for which Hofstadter was awarded the 1961 Nobel prize. The first indication of a non-zero neutron charge distribution was obtained by scattering thermal neutrons off atomic electrons. The recent revival of its experimental study through the operational implementation of novel instrumentation has instigated a strong theoretical interest. Nucleon electro-magnetic form factors (EMFFs) are optimally studied through the exchange of a virtual photon, in elastic electron-nucleon scattering. The momentum transferred to the nucleon by the virtual photon can be selected to probe different scales of the nucleon, from integral properties such as the charge radius to scaling properties of its internal constituents. Polarization instrumentation, polarized beams and targets, and the measurement of the polarization of the recoiling nucleon have been essential in the accurate separation of the charge and magnetic form factors and in studies of the elusive neutron charge form factor.

  10. Electromagnetic pion form factor

    SciTech Connect

    Roberts, C.D.

    1995-08-01

    A phenomenological Dyson-Schwinger/Bethe-Salpeter equation approach to QCD, formalized in terms of a QCD-based model field theory, the Global Color-symmetry Model (GCM), was used to calculate the generalized impulse approximation contribution to the electromagnetic pion form factor at space-like q{sup 2} on the domain [0,10] GeV{sup 2}. In effective field theories this form factor is sometimes understood as simply being due to Vector Meson Dominance (VMD) but this does not allow for a simple connection with QCD where the VMD contribution is of higher order than that of the quark core. In the GCM the pion is treated as a composite bound state of a confined quark and antiquark interacting via the exchange of colored vector-bosons. A direct study of the quark core contribution is made, using a quark propagator that manifests the large space-like-q{sup 2} properties of QCD, parameterizes the infrared behavior and incorporates confinement. It is shown that the few parameters which characterize the infrared form of the quark propagator may be chosen so as to yield excellent agreement with the available data. In doing this one directly relates experimental observables to properties of QCD at small space-like-q{sup 2}. The incorporation of confinement eliminates endpoint and pinch singularities in the calculation of F{sub {pi}}(q{sup 2}). With asymptotic freedom manifest in the dressed quark propagator the calculation yields q{sup 4}F{sub {pi}}(q{sup 2}) = constant, up to [q{sup 2}]- corrections, for space-like-q{sup 2} {approx_gt} 35 GeV{sup 2}, which indicates that soft, nonperturbative contributions dominate the form factor at presently accessible q{sup 2}. This means that the often-used factorization Ansatz fails in this exclusive process. A paper describing this work was submitted for publication. In addition, these results formed the basis for an invited presentation at a workshop on chiral dynamics and will be published in the proceedings.

  11. 78 FR 58605 - Proposed Collection; Comment Request for Form 8453-EMP, Form 8453-F, Form 8453-FE, Form 8879-F...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-24

    ... Internal Revenue Service Proposed Collection; Comment Request for Form 8453-EMP, Form 8453-F, Form 8453-FE, Form 8879-F, and 8879-EMP. AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice and request...- file Return; Form 8453-EMP, Employment Tax Declaration for an IRS e- file Return; Form 8879-EMP, IRS...

  12. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1–NRF2 pathway, and not the BACH1–NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds

    PubMed Central

    MacLeod, A.Kenneth; McMahon, Michael; Plummer, Simon M.; Higgins, Larry G.; Penning, Trevor M.; Igarashi, Kazuhiko; Hayes, John D.

    2009-01-01

    To better understand the role of transcription factor NF-E2-related factor (NRF) 2 in the human and its contribution to cancer chemoprevention, we have knocked down its negative regulators, Kelch-like ECH-associated protein 1 (KEAP1) and broad-complex, tramtrack and bric à brac and cap'n'collar homology 1 (BACH1), in HaCaT keratinocytes. Whole-genome microarray revealed that knockdown of KEAP1 resulted in 23 messenger RNAs (mRNAs) being up-regulated ≥2.0-fold. mRNA for aldo-keto reductase (AKR) 1B10, AKR1C1, AKR1C2 and AKR1C3 were induced to the greatest extent, showing increases of between 12- and 16-fold, whereas mRNA for glutamate-cysteine ligase catalytic and modifier subunits, NAD(P)H:quinone oxidoreductase-1 and haem oxygenase-1 (HMOX1) were induced between 2.0- and 4.8-fold. Knockdown of BACH1 increased HMOX1 135-fold but induced the other genes examined to a maximum of only 2.7-fold. Activation of NRF2, by KEAP1 knockdown, caused a 75% increase in the amount of glutathione in HaCaT cells and a 1.4- to 1.6-fold increase in their resistance to the electrophiles acrolein, chlorambucil and cumene hydroperoxide (CuOOH), as well as the redox-cycling agent menadione. Inhibition of glutathione synthesis during KEAP1 knockdown, by treatment with buthionine sulfoximine, abrogated resistance to acrolein, chlorambucil and CuOOH, but not to menadione. In contrast, knockdown of BACH1 did not increase glutathione levels or resistance to xenobiotics. Knockdown of NRF2 in HaCaT cells decreased glutathione to ∼80% of normal homeostatic levels and similarly reduced their tolerance of electrophiles. Thus, the KEAP1–NRF2 pathway determines resistance to electrophiles and redox-cycling compounds in human keratinocytes through glutathione-dependent and glutathione-independent mechanisms. This study also shows that AKR1B10, AKR1C1 and AKR1C2 proteins have potential utility as biomarkers for NRF2 activation in the human. PMID:19608619

  13. [Adhesive cutaneous pharmaceutical forms].

    PubMed

    Gafiţanu, E; Matei, I; Mungiu, O C; Pavelescu, M; Mîndreci, I; Apostol, I; Ionescu, G

    1989-01-01

    The adhesive cutaneous pharmaceutical forms aimed to local action release the drug substance in view of a dermatological, traumatological, antirheumatic, cosmetic action. Two such preparations were obtained and their stability, consistency and pH were determined. The "in vitro" tests of their bioavailability revealed the dynamics of calcium ions release according to the associations of each preparation. The bioavailability determined by evaluating the pharmacological response demonstrated the antiinflammatory action obtained by the association of calcium ions with the components extracted from poplar muds. The therapeutical efficiency of the studied preparations has proved in the treatment of some sport injuries.

  14. Nucleon elastic form factors

    SciTech Connect

    D. Day

    2007-03-01

    The nucleon form factors are still the subject of active investigation even after an experimental effort spanning 50 years. This is because they are of critical importance to our understanding of the electromagnetic properties of nuclei and provide a unique testing ground for QCD motivated models of nucleon structure. Progress in polarized beams, polarized targets and recoil polarimetry have allowed an important and precise set of data to be collected over the last decade. I will review the experimental status of elastic electron scattering from the nucleon along with an outlook for future progress.

  15. GlassForm

    2011-09-16

    GlassForm is a software tool for generating preliminary waste glass formulas for a given waste stream. The software is useful because it reduces the number of verification melts required to develop a suitable additive composition. The software includes property models that calculate glass properties of interest from the chemical composition of the waste glass. The software includes property models for glass viscosity, electrical conductivity, glass transition temperature, and leach resistance as measured by the 7-daymore » product consistency test (PCT).« less

  16. Bipolar pulse forming line

    DOEpatents

    Rhodes, Mark A.

    2008-10-21

    A bipolar pulse forming transmission line module for linear induction accelerators having first, second, third, fourth, and fifth planar conductors which form an interleaved stack with dielectric layers between the conductors. Each conductor has a first end, and a second end adjacent an acceleration axis. The first and second planar conductors are connected to each other at the second ends, the fourth and fifth planar conductors are connected to each other at the second ends, and the first and fifth planar conductors are connected to each other at the first ends via a shorting plate adjacent the first ends. The third planar conductor is electrically connectable to a high voltage source, and an internal switch functions to short a high voltage from the first end of the third planar conductor to the first end of the fourth planar conductor to produce a bipolar pulse at the acceleration axis with a zero net time integral. Improved access to the switch is enabled by an aperture through the shorting plate and the proximity of the aperture to the switch.

  17. Cartilage-forming tumors.

    PubMed

    Qasem, Shadi A; DeYoung, Barry R

    2014-01-01

    Cartilage-forming tumors as a group are the most common primary bone tumors; this is largely due to the common occurrence of asymptomatic benign lesions such as osteochondroma and enchondroma. The common feature of these tumors is the presence of chondrocytic cells and the formation of cartilaginous tumor matrix. Some of these tumors are true neoplasms while others are hamartomas or developmental abnormalities. The morphologic heterogeneity of these tumors may be explained by a common multipotent mesenchymal cell differentiating along the lines of fetal-adult cartilage maturation. Recently mutations in IDH1 and IDH2 have been detected in a variety of benign and malignant cartilaginous tumors.(1-4.) PMID:24680178

  18. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Marc Vanderhaeghen; Charles Perdrisat; Vina Punjabi

    2007-10-01

    There has been much activity in the measurement of the elastic electromagnetic proton and neutron form factors in the last decade, and the quality of the data has greatly improved by performing double polarization experiments, in comparison with previous unpolarized data. Here we review the experimental data base in view of the new results for the proton, and neutron, obtained at JLab, MAMI, and MIT-Bates. The rapid evolution of phenomenological models triggered by these high-precision experiments will be discussed, including the recent progress in the determination of the valence quark generalized parton distributions of the nucleon, as well as the steady rate of improvements made in the lattice QCD calculations.

  19. Pion form factor

    SciTech Connect

    Ryong Ji, C.; Pang, A.; Szczepaniak, A.

    1994-04-01

    It is pointed out that the correct criterion to define the legal PQCD contribution to the exclusive processes in the lightcone perturbative expansion should be based on the large off-shellness of the lightcone energy in the intermediate states. In the lightcone perturbative QCD calculation of the pion form factor, the authors find that the legal PQCD contribution defined by the lightcone energy cut saturates in the smaller Q{sup 2} region compared to that defined by the gluon four-momentum square cut. This is due to the contribution by the highly off-energy-shell gluons in the end point regions of the phase space, indicating that the gluon four-momentum-square cut may have cut too much to define the legal PQCD.

  20. Weird past tense forms.

    PubMed

    Xu, F; Pinker, S

    1995-10-01

    It is often assumed that children go through a stage in which they systematically overapply irregular past tense patterns to inappropriate verbs, as in wipe-wope, bring-brang, trick-truck, walk-has walken. Such errors have been interpreted both as reflecting over-use of minor grammatical rules (e.g. 'change i to a'), and as reflecting the operation of a connectionist pattern associator network that superimposes and blends patterns of various degrees of generality. But the actual rate, time course, and nature of these errors have never been documented. We analysed 20,000 past tense and participle usages from nine children in the CHILDES database, looking for overapplications of irregular vowel-change patterns, as in brang, blends, as in branged, productive suffixations of -en, as in walken, gross distortions, as in mail-membled, and double-suffixation, as in walkeded. These errors were collectively quite rare; children made them in about two tenths of one per cent of the opportunities, and with few stable patterns: the errors were not predominantly word-substitutions, did not occur predominantly with irregular stems, showed no consistency across verbs or ages, and showed no clear age trend. Most (though not all) of the errors were based closely on existing irregular verbs; gross distortions never occurred. We suggest that both rule-theories and connectionist theories have tended to overestimate the predominance of such errors. Children master irregular forms quite accurately, presumably because irregular forms are just a special case of the arbitrary sound-meaning pairings that define words, and because children are good at learning words.

  1. Forming Spirals From Shadows

    NASA Astrophysics Data System (ADS)

    Kohler, Susanna

    2016-07-01

    What causes the large-scale spiral structures found in some protoplanetary disks? Most models assume theyre created by newly-forming planets, but a new study suggests that planets might have nothing to do with it.Perturbations from Planets?In some transition disks protoplanetary disks with gaps in their inner regions weve directly imaged large-scale spiral arms. Many theories currently attribute the formation of these structures to young planets: either the direct perturbations of a planet embedded in the disk cause the spirals, or theyre indirectly caused by the orbit of a planetary body outside of the arms.Another example of spiral arms detected in a protoplanetary disk, MWC 758. [NASA/ESA/ESO/M. Benisty et al.]But what if you could get spirals without any planets? A team of scientists led by Matas Montesinos (University of Chile) have recently published a study in which they examine what happens to a shadowed protoplanetary disk.Casting Shadows with WarpsIn the teams setup, they envision a protoplanetary disk that is warped: the inner region is slightly tilted relative to the outer region. As the central star casts light out over its protoplanetary disk, this disk warping would cause some regions of the disk to be shaded in a way that isnt axially symmetric with potentially interesting implications.Montesinos and collaborators ran 2D hydrodynamics simulations to determine what happens to the motion of particles within the disk when they pass in and out of the shadowed regions. Since the shadowed regions are significantly colder than the illuminated disk, the pressure in these regions is much lower. Particles are therefore accelerated and decelerated as they pass through these regions, and the lack of axial symmetry causes spiral density waves to form in the disk as a result.Initial profile for the stellar heating rate per unit area for one of the authors simulations. The regions shadowed as a result of the disk warp subtend 0.5 radians each (shown on the left

  2. Moon (Form-Origin)

    NASA Astrophysics Data System (ADS)

    Tsiapas, Elias

    2016-04-01

    When the Earth was formed, it was in a state of burning heat. As time went by, temperature on the planet's surface was falling due to radiation and heat transfer, and various components (crusts) began taking solid form at the Earth's poles. The formation of crusts took place at the Earth's poles, because the stirring of burning and fluid masses on the surface of the Earth was significantly slighter there than it was on the equator. Due to centrifugal force and Coriolis Effect, these solid masses headed towards the equator; those originating from the North Pole followed a south-western course, while those originating from the South Pole followed a north-western course and there they rotated from west to east at a lower speed than the underlying burning and liquid earth, because of their lower initial linear velocity, their solid state and inertia. Because inertia is proportional to mass, the initially larger solid body swept all new solid ones, incorporating them to its western side. The density of the new solid masses was higher, because the components on the surface would freeze and solidify first, before the underlying thicker components. As a result, the western side of the initial islet of solid rocks submerged, while the east side elevated. . As a result of the above, this initial islet began to spin in reverse, and after taking on the shape of a sphere, it formed the "heart" of the Moon. The Moon-sphere, rolling on the equator, would sink the solid rocks that continued to descend from the Earth's poles. The sinking rocks partially melted because of higher temperatures in the greater depths that the Moon descended to, while part of the rocks' mass bonded with the Moon and also served as a heat-insulating material, preventing the descended side of the sphere from melting. Combined with the Earth's liquid mass that covered its emerging eastern surface, new sphere-shaped shells were created, with increased density and very powerful structural cohesion. During the

  3. Moon (Form-Origin)

    NASA Astrophysics Data System (ADS)

    Tsiapas, Elias

    2014-05-01

    When the Earth was formed, it was in a state of burning heat. As time went by, temperature on the planet's surface was falling due to radiation and heat transfer, and various components (crusts) began taking solid form at the Earth's poles. The formation of crusts took place at the Earth's poles, because the stirring of burning and fluid masses on the surface of the Earth was significantly slighter there than it was on the equator. Due to centrifugal force and Coriolis Effect, these solid masses headed towards the equator; those originating from the North Pole followed a south-western course, while those originating from the South Pole followed a north-western course and there they rotated from west to east at a lower speed than the underlying burning and liquid earth, because of their lower initial linear velocity, their solid state and inertia. Because inertia is proportional to mass, the initially larger solid body swept all new solid ones, incorporating them to its western side. The density of the new solid masses was higher, because the components on the surface would freeze and solidify first, before the underlying thicker components. As a result, the western side of the initial islet of solid rocks submerged, while the east side elevated. . As a result of the above, this initial islet began to spin in reverse, and after taking on the shape of a sphere, it formed the "heart" of the Moon. The Moon-sphere, rolling on the equator, would sink the solid rocks that continued to descend from the Earth's poles. The sinking rocks partially melted because of higher temperatures in the greater depths that the Moon descended to, while part of the rocks' mass bonded with the Moon and also served as a heat-insulating material, preventing the descended side of the sphere from melting. Combined with the Earth's liquid mass that covered its emerging eastern surface, new sphere-shaped shells were created, with increased density and very powerful structural cohesion. During the

  4. Moon (Form-Origin)

    NASA Astrophysics Data System (ADS)

    Tsiapas, Elias

    2013-04-01

    When the Earth was formed, it was in a state of burning heat. As time went by, temperature on the planet's surface was falling due to radiation and heat transfer, and various components (crusts) began taking solid form at the Earth's poles. The formation of crusts took place at the Earth's poles, because the stirring of burning and fluid masses on the surface of the Earth was significantly slighter there than it was on the equator. Due to centrifugal force and Coriolis Effect, these solid masses headed towards the equator; those originating from the North Pole followed a south-western course, while those originating from the South Pole followed a north-western course and there they rotated from west to east at a lower speed than the underlying burning and liquid earth, because of their lower initial linear velocity, their solid state and inertia. Because inertia is proportional to mass, the initially larger solid body swept all new solid ones, incorporating them to its western side. The density of the new solid masses was higher, because the components on the surface would freeze and solidify first, before the underlying thicker components. As a result, the western side of the initial islet of solid rocks submerged, while the east side elevated. As a result of the above, this initial islet began to spin in reverse, and after taking on the shape of a sphere, it formed the "heart" of the Moon. The Moon-sphere, rolling on the equator, would sink the solid rocks that continued to descend from the Earth's poles. The sinking rocks partially melted because of higher temperatures in the greater depths that the Moon descended to, while part of the rocks' mass bonded with the Moon and also served as a heat-insulating material, preventing the descended side of the sphere from melting. Combined with the Earth's liquid mass that covered its emerging eastern surface, new sphere-shaped shells were created, with increased density and very powerful structural cohesion. During the

  5. Moon (Form-Origin)

    NASA Astrophysics Data System (ADS)

    Tsiapas, Elias

    2015-04-01

    When the Earth was formed, it was in a state of burning heat. As time went by, temperature on the planet's surface was falling due to radiation and heat transfer, and various components (crusts) began taking solid form at the Earth's poles. The formation of crusts took place at the Earth's poles, because the stirring of burning and fluid masses on the surface of the Earth was significantly slighter there than it was on the equator. Due to centrifugal force and Coriolis Effect, these solid masses headed towards the equator; those originating from the North Pole followed a south-western course, while those originating from the South Pole followed a north-western course and there they rotated from west to east at a lower speed than the underlying burning and liquid earth, because of their lower initial linear velocity, their solid state and inertia. Because inertia is proportional to mass, the initially larger solid body swept all new solid ones, incorporating them to its western side. The density of the new solid masses was higher, because the components on the surface would freeze and solidify first, before the underlying thicker components. As a result, the western side of the initial islet of solid rocks submerged, while the east side elevated. . As a result of the above, this initial islet began to spin in reverse, and after taking on the shape of a sphere, it formed the "heart" of the Moon. The Moon-sphere, rolling on the equator, would sink the solid rocks that continued to descend from the Earth's poles. The sinking rocks partially melted because of higher temperatures in the greater depths that the Moon descended to, while part of the rocks' mass bonded with the Moon and also served as a heat-insulating material, preventing the descended side of the sphere from melting. Combined with the Earth's liquid mass that covered its emerging eastern surface, new sphere-shaped shells were created, with increased density and very powerful structural cohesion. During the

  6. Gas Giants Form Quickly

    NASA Technical Reports Server (NTRS)

    2007-01-01

    This is an artist's concept of a hypothetical 10-million-year-old star system. The bright blur at the center is a star much like our sun. The other orb in the image is a gas-giant planet like Jupiter. Wisps of white throughout the image represent traces of gas.

    Astronomers using NASA's Spitzer Space Telescope have found evidence showing that gas-giant planets either form within the first 10 million years of a sun-like star's life, or not at all. The lifespan for sun-like stars is about 10 billion years.

    The scientists came to this conclusion after searching for traces of gas around 15 different sun-like stars, most with ages ranging from 3 million to 30 million years. With the help of Spitzer's Infrared Spectrometer instrument, they were able to search for relatively warm gas in the inner regions of these star systems, an area comparable to the zone between Earth and Jupiter in our own solar system. They also used ground-based radio telescopes to search for cooler gas in the outer regions of these systems, an area comparable to the zone around Saturn and beyond.

  7. How delusion is formed?

    PubMed

    Park, Jong Suk; Kang, Ung Gu

    2016-02-01

    Traditionally, delusions have been considered to be the products of misinterpretation and irrationality. However, some theorists have argued that delusions are normal or rational cognitive responses to abnormal experiences. That is, when a recently experienced peculiar event is more plausibly explained by an extraordinary hypothesis, confidence in the veracity of this extraordinary explanation is reinforced. As the number of such experiences, driven by the primary disease process in the perceptual domain, increases, this confidence builds and solidifies, forming a delusion. We tried to understand the formation of delusions using a simulation based on Bayesian inference. We found that (1) even if a delusional explanation is only marginally more plausible than a non-delusional one, the repetition of the same experience results in a firm belief in the delusion. (2) The same process explains the systematization of delusions. (3) If the perceived plausibility of the explanation is not consistent but varies over time, the development of a delusion is delayed. Additionally, this model may explain why delusions are not corrected by persuasion or rational explanation. This Bayesian inference perspective can be considered a way to understand delusions in terms of rational human heuristics. However, such experiences of "rationality" can lead to irrational conclusions, depending on the characteristics of the subject. PMID:26826642

  8. Can polymersomes form colloidosomes?

    PubMed

    Thompson, Kate L; Chambon, Pierre; Verber, Robert; Armes, Steven P

    2012-08-01

    Hydroxy-functionalized polymersomes (or block copolymer vesicles) were prepared via a facile one-pot RAFT aqueous dispersion polymerization protocol and evaluated as Pickering emulsifiers for the stabilization of emulsions of n-dodecane emulsion droplets in water. Linear polymersomes produced polydisperse oil droplets with diameters of ~50 μm regardless of the polymersome concentration in the aqueous phase. Introducing an oil-soluble polymeric diisocyanate cross-linker into the oil phase prior to homogenization led to block copolymer microcapsules, as expected. However, TEM inspection of these microcapsules after an alcohol challenge revealed no evidence for polymersomes, suggesting these delicate nanostructures do not survive the high-shear emulsification process. Thus the emulsion droplets are stabilized by individual diblock copolymer chains, rather than polymersomes. Cross-linked polymersomes (prepared by the addition of ethylene glycol dimethacrylate as a third comonomer) also formed stable n-dodecane-in-water Pickering emulsions, as judged by optical and fluorescence microscopy. However, in this case the droplet diameter varied from 50 to 250 μm depending on the aqueous polymersome concentration. Moreover, diisocyanate cross-linking at the oil/water interface led to the formation of well-defined colloidosomes, as judged by TEM studies. Thus polymersomes can indeed stabilize colloidosomes, provided that they are sufficiently cross-linked to survive emulsification.

  9. Tautomeric Forms of Metarhodopsin

    PubMed Central

    Matthews, Rowena G.; Hubbard, Ruth; Brown, Paul K.; Wald, George

    1963-01-01

    Light isomerizes the chromophore of rhodopsin, 11-cis retinal (formerly retinene), to the all-trans configuration. This introduces a succession of unstable intermediates—pre-lumirhodopsin, lumirhodopsin, metarhodopsin —in which all-trans retinal is still attached to the chromophoric site on opsin. Finally, retinal is hydrolyzed from opsin. The present experiments show that metarhodopsin exists in two tautomeric forms, metarhodopsins I and II, with λmax 478 and 380 mµ. Metarhodopsin I appears first, then enters into equilibrium with metarhodopsin II. In this equilibrium, the proportion of metarhodopsin II is favored by higher temperature or pH, neutral salts, and glycerol. The change from metarhodopsin I to II involves the binding of a proton by a group with pK 6.4 (imidazole?), and a large increase of entropy. Metarhodopsin II has been confused earlier with the final mixture of all-trans retinal and opsin (λmax 387 mµ), which it resembles in spectrum. These two products are, however, readily distinguished experimentally. PMID:14080814

  10. New education coalition formed

    NASA Astrophysics Data System (ADS)

    Watt Ireto, M. Frank

    The Coalition for Earth Science Education (CESE) was recently formed to promote Earth science education at all levels. Earth science is a diverse group of sciences and as a result, professional and academic organizations from the various areas, though united in their goal to stimulate student enthusiasm for the Earth sciences, have not had an effective way of reaching students or their precollege teachers. Over the past year, meetings sponsored by the National Academy of Science's Board on Earth Sciences and Resources and the National Science Foundation have paved the way for this coalition. Victor Mayer, Director of the Program for Leadership in Earth Systems Science (PLESE) project at the University of Ohio, has been the leader in initiating and promoting this effort for the last several years.The purpose of CESE is to promote communication among the member organizations and to coordinate projects in Earth science education. Individual organizations will continue to develop and run projects, but will be able to find out what types of projects others are working on or have completed through a coalition clearinghouse. The clearinghouse should aid organizations as they design projects and should afford opportunities for collaborative efforts. This will directly benefit teachers, who will be able to contact one source for information on the multitude of projects in the Earth and space sciences. The new coalition's steering committee is working on goals and guidelines, and will give a report at the next coalition meeting at the National Science Teachers Association annual convention in Boston.

  11. How desert varnish forms?

    NASA Astrophysics Data System (ADS)

    Perry, Randall S.; Kolb, Vera M.; Lynne, Bridget Y.; Sephton, Mark A.; Mcloughlin, Nicola; Engel, Michael H.; Olendzenski, Lorraine; Brasier, Martin; Staley, James T., Jr.

    2005-09-01

    Desert varnish is a black, manganese-rich rock coating that is widespread on Earth. The mechanism underlying its formation, however, has remained unresolved. We present here new data and an associated model for how desert varnish forms, which substantively challenges previously accepted models. We tested both inorganic processes (e.g. clays and oxides cementing coatings) and microbial methods of formation. Techniques used in this preliminary study include SEM-EDAX with backscatter, HRTEM of focused ion beam prepared (FIB) wafers and several other methods including XRPD, Raman spectroscopy, XPS and Tof-SIMS. The only hypothesis capable of explaining a high water content, the presence of organic compounds, an amorphous silica phase (opal-A) and lesser quantities of clays than previously reported, is a mechanism involving the mobilization and redistribution of silica. The discovery of silica in desert varnish suggests labile organics are preserved by interaction with condensing silicic acid. Organisms are not needed for desert varnish formation but Bacteria, Archaea, Eukarya, and other organic compounds are passively incorporated and preserved as organominerals. The rock coatings thus provide useful records of past environments on Earth and possibly other planets. Additionally this model also helps to explain the origin of key varnish and rock glaze features, including their hardness, the nature of the "glue" that binds heterogeneous components together, its layered botryoidal morphology, and its slow rate of formation.

  12. Symmetries of Helmholtz forms and globally variational dynamical forms

    NASA Astrophysics Data System (ADS)

    Palese, Marcella; Winterroth, Ekkehart

    2012-02-01

    Invariance properties of classes in the variational sequence suggested to Krupka et al. the idea that there should exist a close correspondence between the notions of variationality of a differential form and invariance of its exterior derivative. It was shown by them that the invariance of a closed Helmholtz form of a dynamical form is equivalent with local variationality of the Lie derivative of the dynamical form, so that the latter is locally the Euler-Lagrange form of a Lagrangian. We show that the corresponding local system of Euler-Lagrange forms is variationally equivalent to a global Euler-Lagrange form.

  13. Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide

    PubMed Central

    Song, Yang; Buettner, Garry R.

    2010-01-01

    The quinone/semiquinone/hydroquinone triad (Q/SQ•−/H2Q) represents a class of compounds that has great importance in a wide range of biological processes. The half-cell reduction potentials of these redox couples in aqueous solutions at neutral pH, E°′, provide a window to understanding the thermodynamic and kinetic characteristics of this triad and their associated chemistry and biochemistry in vivo. Substituents on the quinone ring can significantly influence the electron density “on the ring” and thus modify E°′ dramatically. E°′ of the quinone governs the reaction of semiquinone with dioxygen to form superoxide. At near-neutral pH the pKa's of the hydroquinone are outstanding indicators of the electron density in the aromatic ring of the members of these triads (electrophilicity) and thus are excellent tools to predict half-cell reduction potentials for both the one-electron and two-electron couples, which in turn allow estimates of rate constants for the reactions of these triads. For example, the higher the pKa's of H2Q, the lower the reduction potentials and the higher the rate constants for the reaction of SQ•− with dioxygen to form superoxide. However, hydroquinone autoxidation is controlled by the concentration of di-ionized hydroquinone; thus, the lower the pKa's the less stable H2Q to autoxidation. Catalysts, e.g., metals and quinone, can accelerate oxidation processes; by removing superoxide and increasing the rate of formation of quinone, superoxide dismutase can accelerate oxidation of hydroquinones and thereby increase the flux of hydrogen peroxide. The principal reactions of quinones are with nucleophiles via Michael addition, for example, with thiols and amines. The rate constants for these addition reactions are also related to E°′. Thus, pKa's of a hydroquinone and E°′ are central to the chemistry of these triads. PMID:20493944

  14. Watching How Planets Form

    NASA Astrophysics Data System (ADS)

    2006-09-01

    Anatomy of a Planet-Forming Disc around a Star More Massive than the Sun With the VISIR instrument on ESO's Very Large Telescope, astronomers have mapped the disc around a star more massive than the Sun. The very extended and flared disc most likely contains enough gas and dust to spawn planets. It appears as a precursor of debris discs such as the one around Vega-like stars and thus provides the rare opportunity to witness the conditions prevailing prior to or during planet formation. "Planets form in massive, gaseous and dusty proto-planetary discs that surround nascent stars. This process must be rather ubiquitous as more than 200 planets have now been found around stars other than the Sun," said Pierre-Olivier Lagage, from CEA Saclay (France) and leader of the team that carried out the observations. "However, very little is known about these discs, especially those around stars more massive than the Sun. Such stars are much more luminous and could have a large influence on their disc, possibly quickly destroying the inner part." The astronomers used the VISIR instrument [1] on ESO's Very Large Telescope to map in the infrared the disc surrounding the young star HD 97048. With an age of a few million years [2], HD 97048 belongs to the Chameleon I dark cloud, a stellar nursery 600 light-years away. The star is 40 times more luminous than our Sun and is 2.5 times as massive. The astronomers could only have achieved such a detailed view due to the high angular resolution offered by an 8-metre size telescope in the infrared, reaching a resolution of 0.33 arcsecond. They discovered a very large disc, at least 12 times more extended than the orbit of the farthest planet in the Solar System, Neptune. The observations suggest the disc to be flared. "This is the first time such a structure, predicted by some theoretical models, is imaged around a massive star," said Lagage. ESO PR Photo 36/06 ESO PR Photo 36/06 A Flared Proto-Planetary Disc Such a geometry can only be

  15. Waste form product characteristics

    SciTech Connect

    Taylor, L.L.; Shikashio, R.

    1995-01-01

    The Department of Energy has operated nuclear facilities at the Idaho National Engineering Laboratory (INEL) to support national interests for several decades. Since 1953, it has supported the development of technologies for the storage and reprocessing of spent nuclear fuels (SNF) and the resultant wastes. However, the 1992 decision to discontinue reprocessing of SNF has left nearly 768 MT of SNF in storage at the INEL with unspecified plans for future dispositioning. Past reprocessing of these fuels for uranium and other resource recovery has resulted in the production of 3800 M{sup 3} calcine and a total inventory of 7600 M{sup 3} of radioactive liquids (1900 M{sup 3} destined for immediate calcination and the remaining sodium-bearing waste requiring further treatment before calcination). These issues, along with increased environmental compliance within DOE and its contractors, mandate operation of current and future facilities in an environmentally responsible manner. This will require satisfactory resolution of spent fuel and waste disposal issues resulting from the past activities. A national policy which identifies requirements for the disposal of SNF and high level wastes (HLW) has been established by the Nuclear Waste Policy Act (NWPA) Sec.8,(b) para(3)) [1982]. The materials have to be conditioned or treated, then packaged for disposal while meeting US Environmental Protection Agency (EPA) and Nuclear Regulatory Commission (NRC) regulations. The spent fuel and HLW located at the INEL will have to be put into a form and package that meets these regulatory criteria. The emphasis of Idaho Chemical Processing Plant (ICPP) future operations has shifted toward investigating, testing, and selecting technologies to prepare current and future spent fuels and waste for final disposal. This preparation for disposal may include mechanical, physical and/or chemical processes, and may differ for each of the various fuels and wastes.

  16. Science Grade 7, Long Form.

    ERIC Educational Resources Information Center

    New York City Board of Education, Brooklyn, NY. Bureau of Curriculum Development.

    The Grade 7 Science course of study was prepared in two parallel forms. A short form designed for students who had achieved a high measure of success in previous science courses; the long form for those who have not been able to maintain the pace. Both forms contain similar content. The Grade 7 guide is the first in a three-year sequence for…

  17. 10. VIEW SHOWING THE ARCH FORMS. THE INTRADOS FORM IS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. VIEW SHOWING THE ARCH FORMS. THE INTRADOS FORM IS COMMONLY LIFTED 3 TO 4 DAYS AFTER POURING. REINFORCING STEEL IS THEN PLACED AND THE EXTRADOS FORM RAISED TO POSITION. THE OPERATING OF MOVING FORMS, PLACING STEEL AND CONCRETE FOR EACH ARCH LIFT REQUIRES, ON AVERAGE, EIGHT DAYS. NOTE THE TWO LINES OF WATER PIPE ON THE EXTRADOS FORM. THESE PIPES ARE FILLED WITH SPRAY NOZZLES WHICH ARE IN PRACTICALLY CONTINUOUS OPERATION EXCEPT WHEN WORK IS BEING DONE ON THE FORMS. August 9, 1938 - Bartlett Dam, Verde River, Phoenix, Maricopa County, AZ

  18. Form-definition language for an intelligent form

    SciTech Connect

    Honeyman, J.C.

    1987-01-01

    The formal specification of a form-definition language is described. A new form-based model for office automation is defined informally. The model is called the Intelligent Form System (IFS) and is composed of a knowledge base, a Synchronous Form Manager (SFM), and an Intelligent Form (IF). The IFS is designed to be a distributed system capable of being implemented using existing technology. The syntax for the form definition language (FDL) used to specify the contents and processing for an Intelligent Form is developed. The automatic processing and routing of the form based upon form content and system configuration is formally defined. A control graph describing the necessary routing to complete the form is constructed and a control process directs processing of the form using the control graph and a state table containing a history of form processing. Examples are used to illustrate the syntax of the FDL and the algorithms for construction of the control graph and control process. The end result is the informal definition of a new model and the formal definition of the form-definition language and control process.

  19. Heated die facilitates tungsten forming

    NASA Technical Reports Server (NTRS)

    Chattin, J. H.; Haystrick, J. E.; Laughlin, J. C.; Leidy, R. A.

    1966-01-01

    Tungsten forming in a press brake employs a bottom die assembly with a heating manifold between two water-cooled die sections. The manifold has hydrogen-oxygen burners spaced along its length for even heat during forming.

  20. Molecular mechanism of metal-independent decomposition of organic hydroperoxides by halogenated quinoid carcinogens and the potential biological implications.

    PubMed

    Huang, Chun-Hua; Ren, Fu-Rong; Shan, Guo-Qiang; Qin, Hao; Mao, Li; Zhu, Ben-Zhan

    2015-05-18

    Halogenated quinones (XQ) are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. Organic hydroperoxides (ROOH) can be produced both by free radical reactions and enzymatic oxidation of polyunsaturated fatty acids. ROOH have been shown to decompose to alkoxyl radicals via catalysis by transition metal ions, which may initiate lipid peroxidation or transform further to the reactive aldehydes. However, it is not clear whether XQ react with ROOH in a similar manner to generate alkoxyl radicals metal-independently. By complementary applications of ESR spin-trapping, HPLC/high resolution mass spectrometric and other analytical methods, we found that 2,5-dichloro-1,4-benzoquinone (DCBQ) could significantly enhance the decomposition of a model ROOH tert-butylhydroperoxide, resulting in the formation of t-butoxyl radicals independent of transition metals. On the basis of the above findings, we detected and identified, for the first time, an unprecedented C-centered quinone ketoxy radical. Then, we extended our study to the more physiologically relevant endogenous ROOH 13-hydroperoxy-9,11-octadecadienoic acid and found that DCBQ could also markedly enhance its decomposition to generate the reactive lipid alkyl radicals and the genotoxic 4-hydroxy-2-nonenal (HNE). Similar results were observed with other XQ. In summary, these findings demonstrated that XQ can facilitate ROOH decomposition to produce reactive alkoxyl, quinone ketoxy, lipid alkyl radicals, and genotoxic HNE via a novel metal-independent mechanism, which may explain partly their potential genotoxicity and carcinogenicity.

  1. Investigating the use of endogenous quinoid moieties on carbon fibre as means of developing micro pH sensors.

    PubMed

    Anderson, Ashleigh; Phair, Jolene; Benson, John; Meenan, Brian; Davis, James

    2014-10-01

    The redox profile obtained from electrochemically oxidised carbon fibre was exploited as a foundation from which to design a reusable pH probe. X-ray photoelectron spectroscopy of the surface after anodisation revealed an increase in the population of endogenous quinone moieties. Square wave voltammograms recorded in various buffer solutions (pH3-9) yielded a distinct and unambiguous oxidation process through which to ascribe the peak potential - with the latter found to shift in a sub-Nernstian (-0.052 V/pH) manner. The design of a discrete 2-electrode reusable probe which provides a rapid assessment of pH is described and a preliminary characterisation of the electrochemical performance is critically assessed.

  2. Warm Forming of Mg Sheets: From Incremental to Electromagnetic Forming

    NASA Astrophysics Data System (ADS)

    Ulacia, Ibai; Galdos, Lander; Esnaola, Jon Ander; Larrañaga, Jon; Arruebarrena, Gurutze; de Argandoña, Eneko Saenz; Hurtado, Iñaki

    2014-07-01

    Magnesium alloys are generating interest in the automotive and aeronautic industries due to their low density and potential to reduce gross vehicular weight. However, the formability of these alloys is poor and they are very difficult to be formed at room temperature due to their strong basal texture in rolled form. In this paper, the potential of magnesium alloy sheets to be processed at warm conditions is studied for four different forming technologies: incremental forming (IF), deep drawing (DD), hydroforming (HF), and electromagnetic forming (EMF). Forming mechanisms and process window are experimentally characterized by monitoring different process parameters. Special focus is made on the influence of the forming temperature and the strain rate. Thus, experiments at temperatures from room to 523 K (250 °C) and a wide range of strain rates, between 10-3 up to 103 s-1 according to each process nature and scope, are conducted. It is observed that, even the inherent forming rate range of each process vary considerably, increasing forming temperature increases formability for all of these forming processes. In the other hand, an opposing effect of the strain rate is observed between the quasi-static processes (IF, DD, and HF) and the high speed process (EMF). Thus, a detrimental effect on formability is observed when increasing strain rate for quasi-static processes, while a mild increase is observed for EMF.

  3. Index of NASA prefixed forms

    NASA Technical Reports Server (NTRS)

    1992-01-01

    This Handbook sets forth information for the guidance of all users of the NASA Forms Management Program System. It is issued in accordance with the Federal Information Resources Management Regulation (FIRMR), Subpart 201-9.1. This Handbook sets forth an alpha-functional index of NASA-prefixed forms by title, identifying number, and unit of issue. The automated processing two-letter code (NF) has been substituted for the spelling out of the NASA form-prefix preceding the form number. To indicate a description in lieu of a distinct title, the entire reference under the Form Title/Description column has been enclosed in parentheses. A list of current forms, shown by number and page, is included for cross-reference and to preclude the ordering of those forms which have been deleted from the system. This Handbook will be updated, as appropriate. NHB 1420.2H dated July 1986, is cancelled.

  4. Undercuts by Laser Shock Forming

    NASA Astrophysics Data System (ADS)

    Wielage, Hanna; Vollertsen, Frank

    2011-05-01

    In laser shock forming TEA-CO2-laser induced shock waves are used to form metal foils, such as aluminum or copper. The process utilizes an initiated plasma shock wave on the target surface, which leads to a forming of the foil. A challenge in forming technologies is the manufacturing of undercuts. By conventional forming methods these special forms are not feasible. In this article, it is presented that undercuts in the micro range can be produced by laser shock deep drawing. Different drawing die diameters, drawing die depths and the material aluminum in the thicknesses 20 and 50 μm were investigated. It will be presented that smaller die diameters facilitate undercuts compared to bigger die diameters. The phenomena can be explained by Barlow's formula. Furthermore, it is shown which maximum undercut depth at different die diameters can be reached. To this end, cross-sections of the different parameter combinations are displayed.

  5. The semantics of biological forms.

    PubMed

    Albertazzi, Liliana; Canal, Luisa; Dadam, James; Micciolo, Rocco

    2014-01-01

    This study analyses how certain qualitative perceptual appearances of biological forms are correlated with expressions of natural language. Making use of the Osgood semantic differential, we presented the subjects with 32 drawings of biological forms and a list of 10 pairs of connotative adjectives to be put in correlations with them merely by subjective judgments. The principal components analysis made it possible to group the semantics of forms according to two distinct axes of variability: harmony and dynamicity. Specifically, the nonspiculed, nonholed, and flat forms were perceived as harmonic and static; the rounded ones were harmonic and dynamic. The elongated forms were somewhat disharmonious and somewhat static. The results suggest the existence in the general population of a correspondence between perceptual and semantic processes, and of a nonsymbolic relation between visual forms and their adjectival expressions in natural language.

  6. Undercuts by Laser Shock Forming

    SciTech Connect

    Wielage, Hanna; Vollertsen, Frank

    2011-05-04

    In laser shock forming TEA-CO{sub 2}-laser induced shock waves are used to form metal foils, such as aluminum or copper. The process utilizes an initiated plasma shock wave on the target surface, which leads to a forming of the foil. A challenge in forming technologies is the manufacturing of undercuts. By conventional forming methods these special forms are not feasible. In this article, it is presented that undercuts in the micro range can be produced by laser shock deep drawing. Different drawing die diameters, drawing die depths and the material aluminum in the thicknesses 20 and 50 {mu}m were investigated. It will be presented that smaller die diameters facilitate undercuts compared to bigger die diameters. The phenomena can be explained by Barlow's formula. Furthermore, it is shown which maximum undercut depth at different die diameters can be reached. To this end, cross-sections of the different parameter combinations are displayed.

  7. Seal for fluid forming tools

    DOEpatents

    Golovashchenko, Sergey Fedorovich; Bonnen, John Joseph Francis

    2012-03-20

    An electro-hydraulic forming tool for forming a sheet metal blank in a one-sided die has first and second rigid rings that engage opposite sides of a sheet metal blank. The rigid rings are contained within slots on a die portion and a hydraulic force applicator portion of the forming tool. The seals are either resiliently biased by an elastomeric member or inherently resiliently biased into contact with the blank.

  8. Improving the forming capability of laser dynamic forming by using rubber as a forming medium

    NASA Astrophysics Data System (ADS)

    Shen, Zongbao; Liu, Huixia; Wang, Xiao; Wang, Cuntang

    2016-04-01

    Laser dynamic forming (LDF) is a novel high velocity forming technique, which employs laser-generated shock wave to load the sample. The forming velocity induced by the high energy laser pulse may exceed the critical forming velocity, resulting in the occurrence of premature fracture. To avoid the above premature fracture, rubber is introduced in LDF as a forming medium to prolong the loading duration in this paper. Laser induced shock wave energy is transferred to the sample in different forming stages, so the forming velocity can be kept below the critical forming velocity when the initial laser energy is high for fracture. Bulge forming experiments with and without rubber were performed to study the effect of rubber on loading duration. The experimental results show that, the shock wave energy attenuates during the propagation through the rubber layer, the rubber can avoid the premature fracture. So the plastic deformation can continue, the forming capability of LDF is improved. Due to the severe plastic deformation under rubber compression, adiabatic shear bands (ASB) occur in LDF with rubber. The material softening in ASB leads to the irregular fracture, which is different from the premature fracture pattern (regular fracture) in LDF without rubber. To better understand this deformation behavior, Johnson-Cook model is used to simulate the dynamic response and the evolution of ASB of copper sample. The simulation results also indicate the rubber can prolong the loading duration.

  9. Legal forms and reproductive norms.

    PubMed

    Fletcher, Ruth

    2003-06-01

    This article draws on Pashukanis's concept of legal form and on O'Brien's concept of synthetic value to argue that legal form plays a role in reproductive relations by constructing legal subjects as the bearers of reproductive responsibilities. Pashukanis conceived of legal form as playing a particular role in capitalist exchange relations by interpellating subjects as the bearers of property rights. O'Brien argued that reproduction's specific value is synthetic value, which represents the value of integrating nature and reason in species continuity. Synthetic value is distinct from exchange value or emotional value which may also attach to reproductive process. By working through Pashukanis's method of extracting legal form from specific social relations and by adapting it to reproductive relations, an example is provided of how legal form analysis can be extended beyond the particular context of capitalist exchange relations. Just as legal form constitutes owners and non-owners as legal subjects, so it constitutes reproducers and non-reproducers. By tracing the way in which law attributes reproductive responsibility, legal form analysis shows us how law draws a line between wanting to attribute responsibility and not to attribute it, and this contradiction is a hook which social forces such as sexuality, gender, race, class and disability can latch on to in pushing legal form to shape reproductive responsibilities in a particular way. Each legal form is also externally contradicted by other legal forms. When law negotiates a balance between the reproductive norms of responsibilities and rights, it demonstrates how particular legal forms manage the interaction of different sets of social relations, such as reproduction and exchange. PMID:15871155

  10. Automated Test-Form Generation

    ERIC Educational Resources Information Center

    van der Linden, Wim J.; Diao, Qi

    2011-01-01

    In automated test assembly (ATA), the methodology of mixed-integer programming is used to select test items from an item bank to meet the specifications for a desired test form and optimize its measurement accuracy. The same methodology can be used to automate the formatting of the set of selected items into the actual test form. Three different…

  11. When Permission Forms Work Best

    ERIC Educational Resources Information Center

    Zirkel, Perry A.

    2005-01-01

    Public schools routinely require permission or release forms for field trips and other activities of potential liability. The legal status of such forms varies, but they are generally considered neither rock-solid protection nor legally valueless in terms of immunity. This article presents a case involving a student who sustained bicycle injuries…

  12. Method of forming ceramic bricks

    DOEpatents

    Poeppel, R.B.; Claar, T.D.; Silkowski, P.

    1987-04-22

    A method for forming free standing ceramic bricks for use as tritium breeder material is disclosed. Aqueous solutions of sodium carbonate and potassium carbonate are mixed with an organic hydrocolloid dispersion and powdered lithium carbonate, spray dried, and ceramic bricks formed by molding in a die and firing.

  13. Method of forming ceramic bricks

    DOEpatents

    Poeppel, Roger B.; Claar, Terry D.; Silkowski, Peter

    1988-09-06

    A method for forming free standing ceramic bricks for use as tritium breeder material is disclosed. Aqueous solutions of sodium carbonate and potassium carbonate are mixed with an organic hydrocolloid dispersion and powdered lithium carbonate, spray dried, and ceramic bricks formed by molding in a die and firing.

  14. Method of forming ceramic bricks

    DOEpatents

    Poeppel, Roger B.; Claar, Terry D.; Silkowski, Peter

    1988-01-01

    A method for forming free standing ceramic bricks for use as tritium breeder material is disclosed. Aqueous solutions of sodium carbonate and potassium carbonate are mixed with an organic hydrocolloid dispersion and powdered lithium carbonate, spray dried, and ceramic bricks formed by molding in a die and firing.

  15. Quantum modular forms, mock modular forms, and partial theta functions

    NASA Astrophysics Data System (ADS)

    Kimport, Susanna

    Defined by Zagier in 2010, quantum modular forms have been the subject of an explosion of recent research. Many of these results are aimed at discovering examples of these functions, which are defined on the rational numbers and have "nice" modularity properties. Though the subject is in its early stages, numerous results (including Zagier's original examples) show these objects naturally arising from many areas of mathematics as limits of other modular-like functions. One such family of examples is due to Folsom, Ono, and Rhoades, who connected these new objects to partial theta functions (introduced by Rogers in 1917) and mock modular forms (about which there is a rich theory, whose origins date back to Ramanujan in 1920). In this thesis, we build off of the work of Folsom, Ono, and Rhoades by providing an infinite family of quantum modular forms of arbitrary positive half-integral weight. Further, this family of quantum modular forms "glues" mock modular forms to partial theta functions and is constructed from a so-called "universal" mock theta function by extending a method of Eichler and Zagier (originally defined for holomorphic Jacobi forms) into a non-holomorphic setting. In addition to the infinite family, we explore the weight 1/2 and 3/2 functions in more depth. For both of these weights, we are able to explicitly write down the quantum modular form, as well as the corresponding "errors to modularity," which can be shown to be Mordell integrals of specific theta functions and, as a consequence, are real-analytic functions. Finally, we turn our attention to the partial theta functions associated with these low weight examples. Berndt and Kim provide asymptotic expansions for a certain class of partial theta functions as q approaches 1 radially within the unit disk. Here, we extend this work to not only obtain asymptotic expansions for this class of functions as q approaches any root of unity, but also for a certain class of derivatives of these functions

  16. Process to form mesostructured films

    DOEpatents

    Brinker, C.J.; Anderson, M.T.; Ganguli, R.; Lu, Y.F.

    1999-01-12

    This invention comprises a method to form a family of supported films with pore size in the approximate range 0.8-20 nm exhibiting highly ordered microstructures and porosity derived from an ordered micellar or liquid-crystalline organic-inorganic precursor structure that forms during film deposition. Optically transparent, 100-500-nm thick films exhibiting a unique range of microstructures and uni-modal pore sizes are formed in seconds in a continuous coating operation. Applications of these films include sensors, membranes, low dielectric constant interlayers, anti-reflective coatings, and optical hosts. 12 figs.

  17. Process to form mesostructured films

    DOEpatents

    Brinker, C. Jeffrey; Anderson, Mark T.; Ganguli, Rahul; Lu, Yunfeng

    1999-01-01

    This invention comprises a method to form a family of supported films film with pore size in the approximate range 0.8-20 nm exhibiting highly ordered microstructures and porosity derived from an ordered micellar or liquid-crystalline organic-inorganic precursor structure that forms during film deposition. Optically transparent, 100-500-nm thick films exhibiting a unique range of microstructures and uni-modal pore sizes are formed in seconds in a continuous coating operation. Applications of these films include sensors, membranes, low dielectric constant interlayers, anti-reflective coatings, and optical hosts.

  18. Triggered pore-forming agents

    DOEpatents

    Bayley, Hagan; Walker, Barbara J.; Chang, Chung-yu; Niblack, Brett; Panchal, Rekha

    1998-01-01

    An inactive pore-forming agent which is activated to lytic function by a condition such as pH, light, heat, reducing potential, or metal ion concentration, or substance such as a protease, at the surface of a cell.

  19. Arbitrary p-form Galileons

    SciTech Connect

    Deffayet, C.; Deser, S.; Esposito-Farese, G.

    2010-09-15

    We show that scalar, 0-form, Galileon actions--models whose field equations contain only second derivatives--can be generalized to arbitrary even p-forms. More generally, they need not even depend on a single form, but may involve mixed p combinations, including equal p multiplets, where odd p fields are also permitted: We construct, for given dimension D, general actions depending on scalars, vectors, and higher p-form field strengths, whose field equations are of exactly second derivative order. We also discuss and illustrate their curved-space generalizations, especially the delicate nonminimal couplings required to maintain this order. Concrete examples of pure and mixed actions, field equations, and their curved-space extensions are presented.

  20. Differential form analysis using MACSYMA

    NASA Technical Reports Server (NTRS)

    Wahlquist, H. D.

    1977-01-01

    The MACSYMA file was written to perform these operations and discusses the improvements and additions which are needed to accomplish a complete and efficient implementation. Examples of differential form calculations are displayed.

  1. Process for forming planarized films

    DOEpatents

    Pang, Stella W.; Horn, Mark W.

    1991-01-01

    A planarization process and apparatus which employs plasma-enhanced chemical vapor deposition (PECVD) to form plarnarization films of dielectric or conductive carbonaceous material on step-like substrates.

  2. [Aspergillosis. Clinical forms and treatment].

    PubMed

    Fortún, Jesús; Meije, Yolanda; Fresco, Gema; Moreno, Santiago

    2012-04-01

    Invasive aspergillosis, chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis are the clinical forms of aspergillosis. Although there is a great number of Aspergillus species, Aspergillus fumigatus-complex is the more frequent aetiological agent, regardless of clinical form or baseline condition. The increase in immunosuppressive agents and the higher use of corticosteroids in chronic obstructive pulmonary disease have led to aspergillosis becoming more prominent in recent years. Galactomannan detection and radiological diagnostic images complement the limitations of microbiology cultures in these patients. Voriconazole and liposomal amphotericin B are the gold standard in patients requiring therapy, and posaconazole, itraconazole, caspofungin and other echinocandins are effective alternatives. The prognosis depends of clinical forms and characteristics of the host, but it is particularly poor in the disseminated invasive forms.

  3. Confectionery-based dose forms.

    PubMed

    Tangso, Kristian J; Ho, Quy Phuong; Boyd, Ben J

    2015-01-01

    Conventional dosage forms such as tablets, capsules and syrups are prescribed in the normal course of practice. However, concerns about patient preferences and market demands have given rise to the exploration of novel unconventional dosage forms. Among these, confectionery-based dose forms have strong potential to overcome compliance problems. This report will review the availability of these unconventional dose forms used in treating the oral cavity and for systemic drug delivery, with a focus on medicated chewing gums, medicated lollipops, and oral bioadhesive devices. The aim is to stimulate increased interest in the opportunities for innovative new products that are available to formulators in this field, particularly for atypical patient populations. PMID:25146440

  4. Methods of forming hardened surfaces

    DOEpatents

    Branagan, Daniel J.

    2004-07-27

    The invention encompasses a method of forming a metallic coating. A metallic glass coating is formed over a metallic substrate. After formation of the coating, at least a portion of the metallic glass can be converted into a crystalline material having a nanocrystalline grain size. The invention also encompasses metallic coatings comprising metallic glass. Additionally, the invention encompasses metallic coatings comprising crystalline metallic material, with at least some of the crystalline metallic material having a nanocrystalline grain size.

  5. Method of forming pointed structures

    NASA Technical Reports Server (NTRS)

    Pugel, Diane E. (Inventor)

    2011-01-01

    A method of forming an array of pointed structures comprises depositing a ferrofluid on a substrate, applying a magnetic field to the ferrofluid to generate an array of surface protrusions, and solidifying the surface protrusions to form the array of pointed structures. The pointed structures may have a tip radius ranging from approximately 10 nm to approximately 25 micron. Solidifying the surface protrusions may be carried out at a temperature ranging from approximately 10 degrees C. to approximately 30 degrees C.

  6. Method for forming metal contacts

    DOEpatents

    Reddington, Erik; Sutter, Thomas C; Bu, Lujia; Cannon, Alexandra; Habas, Susan E; Curtis, Calvin J; Miedaner, Alexander; Ginley, David S; Van Hest, Marinus Franciscus Antonius Maria

    2013-09-17

    Methods of forming metal contacts with metal inks in the manufacture of photovoltaic devices are disclosed. The metal inks are selectively deposited on semiconductor coatings by inkjet and aerosol apparatus. The composite is heated to selective temperatures where the metal inks burn through the coating to form an electrical contact with the semiconductor. Metal layers are then deposited on the electrical contacts by light induced or light assisted plating.

  7. Superplastic forming of alloy 718

    SciTech Connect

    Smith, G.D.; Flower, H.L. )

    1994-04-01

    Inconel Alloy 718 (UNS N07718) is now available in a fine-grained, controlled composition modification that can be super-plastically formed. The new superplastic forming (SPF) capability allows the manufacture of large, complex, and detailed parts, which improves integrity by reducing the need for joining. Furthermore, it allows designers to fabricate components having higher strength, fatigue resistance, and temperature capability than parts made of aluminum or titanium alloys.

  8. Theoretical analysis (NBO, NPA, Mulliken Population Method) and molecular orbital studies (hardness, chemical potential, electrophilicity and Fukui function analysis) of (E)-2-((4-hydroxy-2-methylphenylimino)methyl)-3-methoxyphenol

    NASA Astrophysics Data System (ADS)

    Demircioğlu, Zeynep; Kaştaş, Çiğdem Albayrak; Büyükgüngör, Orhan

    2015-07-01

    The molecular structure and spectroscopic properties of (E)-2-((4-hydroxy-2-methylphenylimino)methyl)-3-methoxyphenol, were characterized by X-ray diffraction, FT-IR and UV-Vis spectroscopy. All of theoretical calculations and optimized geometric parameters have been calculated by using density functional theory (DFT) with hybrid method B3LYP by 6-31G(d,p) basis set. The title compound of C15H15N1O3 have been analyzed according to electronic and energetics behaviors for enol-imine and keto-amine tautomers. Both these tautomers engender six-membered ring due to intramolecular hydrogen bonded interactions. Two types of intramolecular hydrogen bonds (a) strong O-H⋯N interactions in enol-imine form and (b) N-H⋯O interactions in keto-amine form are compared particularly. The theoretical vibrational frequencies have been found in good agreement with the corresponding experimental data. A study on the electronic and optical properties, absorption wavelengths, excitation energy, dipole moment, molecular electrostatic potential (MEP) and frontier molecular orbital energies are performed using DFT method. Additionally, geometry optimizations in solvent media were performed with the same level of theory by the polarizable continuum model (PCM). The effect of solvents on the tautomeric stability has been investigated. Mulliken Population Method and natural population analysis (NPA) have been studied. NBO analysis is carried out to picture the charge transfer between the localized bonds and lone pairs. The local reactivity of the molecule has been studied using the Fukui function. NLO properties related to polarizability and hyperpolarizability are also discussed.

  9. Reactions of the terminal Ni(II)-OH group in substitution and electrophilic reactions with carbon dioxide and other substrates: structural definition of binding modes in an intramolecular Ni(II)...Fe(II) bridged site.

    PubMed

    Huang, Deguang; Holm, R H

    2010-04-01

    A singular feature of the catalytic C-cluster of carbon monoxide dehydrogenase is a sulfide-bridged Ni...Fe locus where substrate is bound and transformed in the reversible reaction CO + H(2)O right harpoon over left harpoon CO(2) + 2H(+) + 2e(-). A similar structure has been sought in this work. Mononuclear planar Ni(II) complexes [Ni(pyN(2)(Me2))L](1-) (pyN(2)(Me2) = bis(2,6-dimethylphenyl)-2,6-pyridinedicarboxamidate(2-)) derived from a NNN pincer ligand have been prepared including L = OH(-) (1) and CN(-) (7). Complex 1 reacts with ethyl formate and CO(2) to form unidentate L = HCO(2)(-) (5) and HCO(3)(-) (6) products. A binucleating macrocycle was prepared which specifically binds Ni(II) at a NNN pincer site and five-coordinate Fe(II) at a triamine site. The Ni(II) macrocyle forms hydroxo (14) and cyanide complexes (15) analogous to 1 and 7. Reaction of 14 with FeCl(2) alone and with ethyl formate and 15 with FeCl(2) affords molecules with the Ni(II)-L-Fe(II) bridge unit in which L = mu(2):eta(1)-OH(-) (17) and mu(2):eta(2)-HCO(2)(-) (18) and -CN(-) (19). All bridges are nonlinear (17, 140.0 degrees ; 18, M-O-C 135.9 degrees (Ni), 120.2 degrees (Fe); 19, Ni-C-N 170.3 degrees , Fe-N-C 141.8 degrees ) with Ni...Fe separations of 3.7-4.8 A. The Ni(II)Fe(II) complexes, lacking appropriate Ni-Fe-S cluster structures, are not site analogues, but their synthesis and reactivity provide the first demonstration that molecular Ni(II)...Fe(II) sites and bridges can be attained, a necessity in the biomimetic chemistry of C-clusters. PMID:20218565

  10. INEL Spray-forming Research

    NASA Technical Reports Server (NTRS)

    Mchugh, Kevin M.; Key, James F.

    1993-01-01

    Spray forming is a near-net-shape fabrication technology in which a spray of finely atomized liquid droplets is deposited onto a suitably shaped substrate or mold to produce a coherent solid. The technology offers unique opportunities for simplifying materials processing without sacrificing, and oftentimes substantially improving, product quality. Spray forming can be performed with a wide range of metals and nonmetals, and offers property improvements resulting from rapid solidification (e.g., refined microstructures, extended solid solubilities and reduced segregation). Economic benefits result from process simplification and the elimination of unit operations. Researchers at the Idaho National Engineering Laboratory (INEL) are developing spray-forming technology for producing near-net-shape solids and coatings of a variety of metals, polymers, and composite materials. Results from several spray forming programs are presented to illustrate the range of capabilities of the technique as well as the accompanying technical and economic benefits. Low-carbon steel strip greater than 0.75 mm thick and polymer membranes for gas/gas and liquid/liquid separations that were spray formed are discussed; recent advances in spray forming molds, dies, and other tooling using low-melting-point metals are described.

  11. INEL spray-forming research

    SciTech Connect

    McHugh, K.M.; Key, J.F.

    1992-01-01

    Spray forming is a near-net-shape fabrication technology in which a spray of finely atomized liquid droplets is deposited onto a suitably shaped substrate or mold to produce a coherent solid. The technology offers unique opportunities for simplifying materials processing without sacrificing, and oftentimes substantially improving, product quality. Spray forming can be performed with a wide range of metals and nonmetals, and offers property improvements resulting from rapid solidification (e.g. refined microstructures, extended solid solubilities and reduced segregation). Economic benefits result from process simplification and the elimination of unit operations. Researchers at the Idaho National Engineering Laboratory (INEL) are developing spray-forming technology for producing near-net-shape solids and coatings of a variety of metals, polymers, and composite materials. Results from several spray-forming programs are presented to illustrate the range of capabilities of the technique as well as the accompanying technical and economic benefits. Low-carbon steel strip >0.75 mm thick and polymer membranes for gas/gas and liquid/liquid separations that were spray formed are discussed; recent advances in spray forming molds, dies, and other tooling using low-melting-point metals are described.

  12. INEL spray-forming research

    SciTech Connect

    McHugh, K.M.; Key, J.F.

    1992-12-31

    Spray forming is a near-net-shape fabrication technology in which a spray of finely atomized liquid droplets is deposited onto a suitably shaped substrate or mold to produce a coherent solid. The technology offers unique opportunities for simplifying materials processing without sacrificing, and oftentimes substantially improving, product quality. Spray forming can be performed with a wide range of metals and nonmetals, and offers property improvements resulting from rapid solidification (e.g. refined microstructures, extended solid solubilities and reduced segregation). Economic benefits result from process simplification and the elimination of unit operations. Researchers at the Idaho National Engineering Laboratory (INEL) are developing spray-forming technology for producing near-net-shape solids and coatings of a variety of metals, polymers, and composite materials. Results from several spray-forming programs are presented to illustrate the range of capabilities of the technique as well as the accompanying technical and economic benefits. Low-carbon steel strip >0.75 mm thick and polymer membranes for gas/gas and liquid/liquid separations that were spray formed are discussed; recent advances in spray forming molds, dies, and other tooling using low-melting-point metals are described.

  13. Superplastic forming of ceramic insulation

    NASA Technical Reports Server (NTRS)

    Nieh, T. G.; Wittenauer, J. P.; Wadsworth, J.

    1992-01-01

    Superplasticity has been demonstrated in many fine-grained structural ceramics and ceramic composites, including yttria-stabilized tetragonal zirconia polycrystal (YTZP), alumina, and Al2O3-reinforced zirconia (Al2O3/YTZ) duplex composites and SiC-reinforced Si3N4. These superplastic ceramics obviously offer the potential benefit of forming net shape or near net shape parts. This could be particularly useful for forming complicated shapes that are difficult to achieve using conventional forming techniques, or require elaborate, subsequent machining. In the present study, we successfully demonstrated the following: (1) superplastic 3Y-TXP and 20 percent Al2O3/YTZ composite have for the first time been successfully deformed into hemispherical caps via a biaxial gas-pressure forming technique; (2) no experimental difficulty was encountered in applying the required gas pressures and temperatures to achieve the results, thus, it is certain that higher rates of deformation than those presented in this study will be possible by using the current test apparatus at higher temperatures and pressures; and (3) an analytical model incorporating material parameters, such as variations during forming in the strain rate sensitivity exponent and grain growth-induced strain hardening, is needed to model accurately and therefore precisely control the biaxial gas-pressure forming of superplastic ceramics. Based on the results of this study, we propose to fabricate zirconia insulation tubes by superplastic extrusion of zirconia polycrystal. This would not only reduce the cost, but also improve the reliability of the tube products.

  14. Characterization of polymorphic ampicillin forms.

    PubMed

    Baraldi, C; Tinti, A; Ottani, S; Gamberini, M C

    2014-11-01

    In this work polymorphs of α-aminobenzylpenicillin (ampicillin), a β-lactamic antibiotic, were prepared and investigated by several experimental and theoretical methods. Amorphous monohydrate and three crystalline forms, the trihydrate, the crystal form I and the crystal form II, were investigated by FT-IR and micro-Raman. Also data obtained by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) and hot-stage Raman spectroscopy are reported. Finally, quantum mechanical calculations were performed by density functional theory (DFT) to assist the assignment of spectroscopic experimental bands. For the first time, the ampicillin molecule in its zwitterionic form was studied at the B3LYP/aug-cc-pVDZ level and the corresponding theoretical vibrational spectra were computed. In fact, ampicillin in the crystal is in zwitterionic form and concentrations of this same form are quite relevant in solutions at physiological pH. Experimental and theoretical results allowed identification of specific features for polymorph characterization. Bands typical of the different polymorphs are identified both in IR and Raman spectra: in particular in the NH stretching region (IR), in the amide I+δNH region (both techniques), in the 1520-1490cm(-1) region (IR), in the 1320-1300cm(-1) and 1280-1220cm(-1) (IR), in the 1200-1170cm(-1) (Raman), in the amide V region (IR), and, finally, in the 715-640cm(-1) and 220-200cm(-1) (Raman). Interconversion among different polymorphs was investigated by hot-stage Raman spectroscopy and thermal analysis, clarifying the complex pattern of transformations undergone as a function of temperature and heating rate. In particular, DSC scans show how the trihydrate crystals transform into anhydrous forms on heating. Finally, stability tests demonstrated, after a two years period, that no transformation or degradation of the polymorphs occurred.

  15. The discovery of structural form

    PubMed Central

    Kemp, Charles; Tenenbaum, Joshua B.

    2008-01-01

    Algorithms for finding structure in data have become increasingly important both as tools for scientific data analysis and as models of human learning, yet they suffer from a critical limitation. Scientists discover qualitatively new forms of structure in observed data: For instance, Linnaeus recognized the hierarchical organization of biological species, and Mendeleev recognized the periodic structure of the chemical elements. Analogous insights play a pivotal role in cognitive development: Children discover that object category labels can be organized into hierarchies, friendship networks are organized into cliques, and comparative relations (e.g., “bigger than” or “better than”) respect a transitive order. Standard algorithms, however, can only learn structures of a single form that must be specified in advance: For instance, algorithms for hierarchical clustering create tree structures, whereas algorithms for dimensionality-reduction create low-dimensional spaces. Here, we present a computational model that learns structures of many different forms and that discovers which form is best for a given dataset. The model makes probabilistic inferences over a space of graph grammars representing trees, linear orders, multidimensional spaces, rings, dominance hierarchies, cliques, and other forms and successfully discovers the underlying structure of a variety of physical, biological, and social domains. Our approach brings structure learning methods closer to human abilities and may lead to a deeper computational understanding of cognitive development. PMID:18669663

  16. The discovery of structural form.

    PubMed

    Kemp, Charles; Tenenbaum, Joshua B

    2008-08-01

    Algorithms for finding structure in data have become increasingly important both as tools for scientific data analysis and as models of human learning, yet they suffer from a critical limitation. Scientists discover qualitatively new forms of structure in observed data: For instance, Linnaeus recognized the hierarchical organization of biological species, and Mendeleev recognized the periodic structure of the chemical elements. Analogous insights play a pivotal role in cognitive development: Children discover that object category labels can be organized into hierarchies, friendship networks are organized into cliques, and comparative relations (e.g., "bigger than" or "better than") respect a transitive order. Standard algorithms, however, can only learn structures of a single form that must be specified in advance: For instance, algorithms for hierarchical clustering create tree structures, whereas algorithms for dimensionality-reduction create low-dimensional spaces. Here, we present a computational model that learns structures of many different forms and that discovers which form is best for a given dataset. The model makes probabilistic inferences over a space of graph grammars representing trees, linear orders, multidimensional spaces, rings, dominance hierarchies, cliques, and other forms and successfully discovers the underlying structure of a variety of physical, biological, and social domains. Our approach brings structure learning methods closer to human abilities and may lead to a deeper computational understanding of cognitive development.

  17. Form und Sinn: Sprachwissenschaftliche Betrachtungen (Form and Meaning: Linguistic Observations).

    ERIC Educational Resources Information Center

    Jakobson, Roman

    This collection of 14 papers and articles by Roman Jakobson contains works written and published between 1931 and 1970 which deal either with global aspects of language or with specific grammatical issues. The collection emphasizes Jakobson's concern for finding the links between form and meaning in language. The text is entirely in German with…

  18. Acceptance of Ideas of Others [Number Form and Star Form].

    ERIC Educational Resources Information Center

    Masters, James R.; Laverty, Grace E.

    As part of the instrumentation to assess the effectiveness of the Schools Without Failure (SWF) program in 10 elementary schools in the New Castle, Pa. School District, the Acceptance of Ideas of Others (Number and Star Forms) were developed to determine pupils' attitudes toward classmates. Given a list of all class members, pupils are asked to…

  19. Sixth-Form Colleges: An Endangered Organisational Form?

    ERIC Educational Resources Information Center

    Stoten, David William

    2014-01-01

    The sixth-form college sector is often marginalised in policy and academic discourse, where the much larger school and further education sectors dominate. This paper sets out to describe the sector's key features, assess its position within the wider education system and consider its future in an increasingly competitive education market. The…

  20. Substrate system for spray forming

    DOEpatents

    Chu, Men G.; Chernicoff, William P.

    2002-01-01

    A substrate system for receiving a deposit of sprayed metal droplets including a movable outer substrate on which the sprayed metal droplets are deposited. The substrate system also includes an inner substrate disposed adjacent the outer substrate where the sprayed metal droplets are deposited on the outer substrate. The inner substrate includes zones of differing thermal conductivity to resist substrate layer porosity and to resist formation of large grains and coarse constituent particles in a bulk layer of the metal droplets which have accumulated on the outer substrate. A spray forming apparatus and associated method of spray forming a molten metal to form a metal product using the substrate system of the invention is also provided.

  1. Substrate system for spray forming

    DOEpatents

    Chu, Men G.; Chernicoff, William P.

    2000-01-01

    A substrate system for receiving a deposit of sprayed metal droplets including a movable outer substrate on which the sprayed metal droplets are deposited. The substrate system also includes an inner substrate disposed adjacent the outer substrate where the sprayed metal droplets are deposited on the outer substrate. The inner substrate includes zones of differing thermal conductivity to resist substrate layer porosity and to resist formation of large grains and coarse constituent particles in a bulk layer of the metal droplets which have accumulated on the outer substrate. A spray forming apparatus and associated method of spray forming a molten metal to form a metal product using the substrate system of the invention is also provided.

  2. PROCESS OF FORMING POWDERED MATERIAL

    DOEpatents

    Glatter, J.; Schaner, B.E.

    1961-07-14

    A process of forming high-density compacts of a powdered ceramic material is described by agglomerating the powdered ceramic material with a heat- decompossble binder, adding a heat-decompossble lubricant to the agglomerated material, placing a quantity of the material into a die cavity, pressing the material to form a compact, pretreating the compacts in a nonoxidizing atmosphere to remove the binder and lubricant, and sintering the compacts. When this process is used for making nuclear reactor fuel elements, the ceramic material is an oxide powder of a fissionsble material and after forming, the compacts are placed in a cladding tube which is closed at its ends by vapor tight end caps, so that the sintered compacts are held in close contact with each other and with the interior wall of the cladding tube.

  3. Methods of forming boron nitride

    DOEpatents

    Trowbridge, Tammy L; Wertsching, Alan K; Pinhero, Patrick J; Crandall, David L

    2015-03-03

    A method of forming a boron nitride. The method comprises contacting a metal article with a monomeric boron-nitrogen compound and converting the monomeric boron-nitrogen compound to a boron nitride. The boron nitride is formed on the same or a different metal article. The monomeric boron-nitrogen compound is borazine, cycloborazane, trimethylcycloborazane, polyborazylene, B-vinylborazine, poly(B-vinylborazine), or combinations thereof. The monomeric boron-nitrogen compound is polymerized to form the boron nitride by exposure to a temperature greater than approximately 100.degree. C. The boron nitride is amorphous boron nitride, hexagonal boron nitride, rhombohedral boron nitride, turbostratic boron nitride, wurzite boron nitride, combinations thereof, or boron nitride and carbon. A method of conditioning a ballistic weapon and a metal article coated with the monomeric boron-nitrogen compound are also disclosed.

  4. Method of forming structural heliostat

    DOEpatents

    Anderson, Alfred J.

    1984-06-26

    In forming a heliostat having a main support structure and pivoting and tilting motors and gears and a mirror module for reflecting solar energy onto a collector, the improvement characterized by a method of forming the mirror module in which the mirror is laid upon a solid rigid supporting bed in one or more sections, with or without focusing; a mirror backing sheet is applied by first applying respective thin layers of silicone grease and, thereafter, progressively rolling application to eliminate air bubbles; followed by affixing of a substrate assembly to the mirror backing sheet to form a mirror module that does not curve because of thermally induced stresses and differential thermal expansion or contraction effects. The silicone grease also serves to dampen fluttering of the mirror and protect the mirror backside against adverse effects of the weather. Also disclosed are specific details of preferred embodiments.

  5. Auxin biosynthesis and storage forms

    PubMed Central

    Strader, Lucia C.

    2013-01-01

    The plant hormone auxin drives plant growth and morphogenesis. The levels and distribution of the active auxin indole-3-acetic acid (IAA) are tightly controlled through synthesis, inactivation, and transport. Many auxin precursors and modified auxin forms, used to regulate auxin homeostasis, have been identified; however, very little is known about the integration of multiple auxin biosynthesis and inactivation pathways. This review discusses the many ways auxin levels are regulated through biosynthesis, storage forms, and inactivation, and the potential roles modified auxins play in regulating the bioactive pool of auxin to affect plant growth and development. PMID:23580748

  6. FORM version 4.0

    NASA Astrophysics Data System (ADS)

    Kuipers, J.; Ueda, T.; Vermaseren, J. A. M.; Vollinga, J.

    2013-05-01

    We present version 4.0 of the symbolic manipulation system FORM. The most important new features are manipulation of rational polynomials and the factorization of expressions. Many other new functions and commands are also added; some of them are very general, while others are designed for building specific high level packages, such as one for Gröbner bases. New is also the checkpoint facility, that allows for periodic backups during long calculations. Finally, FORM 4.0 has become available as open source under the GNU General Public License version 3. Program summaryProgram title: FORM. Catalogue identifier: AEOT_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEOT_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License, version 3 No. of lines in distributed program, including test data, etc.: 151599 No. of bytes in distributed program, including test data, etc.: 1 078 748 Distribution format: tar.gz Programming language: The FORM language. FORM itself is programmed in a mixture of C and C++. Computer: All. Operating system: UNIX, LINUX, Mac OS, Windows. Classification: 5. Nature of problem: FORM defines a symbolic manipulation language in which the emphasis lies on fast processing of very large formulas. It has been used successfully for many calculations in Quantum Field Theory and mathematics. In speed and size of formulas that can be handled it outperforms other systems typically by an order of magnitude. Special in this version: The version 4.0 contains many new features. Most important are factorization and rational arithmetic. The program has also become open source under the GPL. The code in CPC is for reference. You are encouraged to upload the most recent sources from www.nikhef.nl/form/formcvs.php because of frequent bug fixes. Solution method: See "Nature of Problem", above. Additional comments: NOTE: The code in CPC is for reference. You are encouraged

  7. Auxin biosynthesis and storage forms.

    PubMed

    Korasick, David A; Enders, Tara A; Strader, Lucia C

    2013-06-01

    The plant hormone auxin drives plant growth and morphogenesis. The levels and distribution of the active auxin indole-3-acetic acid (IAA) are tightly controlled through synthesis, inactivation, and transport. Many auxin precursors and modified auxin forms, used to regulate auxin homeostasis, have been identified; however, very little is known about the integration of multiple auxin biosynthesis and inactivation pathways. This review discusses the many ways auxin levels are regulated through biosynthesis, storage forms, and inactivation, and the potential roles modified auxins play in regulating the bioactive pool of auxin to affect plant growth and development.

  8. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 6 2012-10-01 2012-10-01 false List of IAAR Forms Federal Acquisition Regulations System BROADCASTING BOARD OF GOVERNORS CLAUSES AND FORMS FORMS Illustrations of Forms The Broadcasting Board of Governors forms. List of IAAR Forms 1953.370-21The Broadcasting Board of Governors Form IA-21, Abstract...

  9. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Acquisition Regulations System BROADCASTING BOARD OF GOVERNORS CLAUSES AND FORMS FORMS Illustrations of Forms The Broadcasting Board of Governors forms. List of IAAR Forms 1953.370-21The Broadcasting Board of Governors Form IA-21, Abstract of Quotations. 1953.370-44The Broadcasting Board of Governors Form...

  10. 48 CFR 53.301 - Standard forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Standard forms. 53.301... AND FORMS FORMS Illustrations of Forms 53.301 Standard forms. This section illustrates the standard... order. The subsection numbers correspond with the standard form numbers (e.g., Standard Form 18...

  11. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true List of IAAR Forms Federal Acquisition Regulations System BROADCASTING BOARD OF GOVERNORS CLAUSES AND FORMS FORMS Illustrations of Forms The Broadcasting Board of Governors forms. List of IAAR Forms 1953.370-21The Broadcasting Board of Governors Form IA-21, Abstract...

  12. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false List of IAAR Forms Federal Acquisition Regulations System BROADCASTING BOARD OF GOVERNORS CLAUSES AND FORMS FORMS Illustrations of Forms The Broadcasting Board of Governors forms. List of IAAR Forms 1953.370-21The Broadcasting Board of Governors Form IA-21, Abstract...

  13. Triggered pore-forming agents

    DOEpatents

    Bayley, H.; Walker, B.J.; Chang, C.Y.; Niblack, B.; Panchal, R.

    1998-07-07

    An inactive pore-forming agent is revealed which is activated to lytic function by a condition such as pH, light, heat, reducing potential, or metal ion concentration, or substance such as a protease, at the surface of a cell. 30 figs.

  14. Technetium Immobilization Forms Literature Survey

    SciTech Connect

    Westsik, Joseph H.; Cantrell, Kirk J.; Serne, R. Jeffrey; Qafoku, Nikolla

    2014-05-01

    Of the many radionuclides and contaminants in the tank wastes stored at the Hanford site, technetium-99 (99Tc) is one of the most challenging to effectively immobilize in a waste form for ultimate disposal. Within the Hanford Tank Waste Treatment and Immobilization Plant (WTP), the Tc will partition between both the high-level waste (HLW) and low-activity waste (LAW) fractions of the tank waste. The HLW fraction will be converted to a glass waste form in the HLW vitrification facility and the LAW fraction will be converted to another glass waste form in the LAW vitrification facility. In both vitrification facilities, the Tc is incorporated into the glass waste form but a significant fraction of the Tc volatilizes at the high glass-melting temperatures and is captured in the off-gas treatment systems at both facilities. The aqueous off-gas condensate solution containing the volatilized Tc is recycled and is added to the LAW glass melter feed. This recycle process is effective in increasing the loading of Tc in the LAW glass but it also disproportionally increases the sulfur and halides in the LAW melter feed which increases both the amount of LAW glass and either the duration of the LAW vitrification mission or the required supplemental LAW treatment capacity.

  15. How Public Opinion is Formed

    ERIC Educational Resources Information Center

    Block, Edward M.

    1977-01-01

    Investigates the evolution of the definition of public relations by examining cultural and personal determinants of public opinion. Outlines functions of communicators and opinionmakers in forming and influencing public opinion. Available from: Public Relations Review, Ray Hiebert, Dean, College of Journalism, University of Maryland, College Park,…

  16. Acceptance of Others (Number Form).

    ERIC Educational Resources Information Center

    Masters, James R.; Laverty, Grace E.

    As part of the instrumentation to assess the effectiveness of the Schools Without Failure (SWF) program in 10 elementary schools in the New Castle, Pa. School District, the Acceptance of Others (Number Form) was prepared to determine pupil's attitudes toward classmates. Given a list of all class members, pupils are asked to circle a number from 1…

  17. Collaborating with Forms in Nature

    ERIC Educational Resources Information Center

    Castro, Aileen Pugliese

    2011-01-01

    Taking students outside is a great opportunity to make art. In this article, the author describes how her students collaborated with forms in nature to create their own visual structures to communicate ideas. This lesson can be done on the beach, in a sand box on the school playground, in grassy areas, or nature can even be brought into the…

  18. Process for forming sulfuric acid

    DOEpatents

    Lu, Wen-Tong P.

    1981-01-01

    An improved electrode is disclosed for the anode in a sulfur cycle hydrogen generation process where sulfur dioxie is oxidized to form sulfuric acid at the anode. The active compound in the electrode is palladium, palladium oxide, an alloy of palladium, or a mixture thereof. The active compound may be deposited on a porous, stable, conductive substrate.

  19. English Pidgins: Form and Function.

    ERIC Educational Resources Information Center

    Mufwene, Salikoko S.

    1988-01-01

    Highlights similarities and variation in both form and function of English pidgins the world over. It is argued that English pidgins are related more by socio-historical conditions and directions of development than by details of their formal structure. Reference list includes 68 citations. (Author/DJD)

  20. PIC Reading Readiness Test Form.

    ERIC Educational Resources Information Center

    Short, N. J.

    This rating form concerns the measurement of basic skills in connection with assessing reading readiness. Motor skills, ability to adjust to learning situations, familiarity with the alphabet, and general knowledge are assessed. See TM 001 111 for details of the Regional PIC program in which it is used. (DLG)

  1. Spin-forming Project Report

    SciTech Connect

    Switzner, Nathan; Henry, Dick

    2009-03-20

    In a second development order, spin-forming equipment was again evaluated using the test shape, a hemispherical shell. In this second development order, pure vanadium and alloy titanium (Ti-6Al-4V) were spin-formed, as well as additional copper and 21-6-9 stainless. In the first development order the following materials had been spin-formed: copper (alloy C11000 ETP), 6061 aluminum, 304L stainless steel, 21-6-9 stainless steel, and tantalum-2.5% tungsten. Significant challenges included properly adjusting the rotations-per-minute (RPM), cracking at un-beveled edges and laser marks, redressing of notches, surface cracking, non-uniform temperature evolution in the titanium, and cracking of the tailstock. Lessons learned were that 300 RPM worked better than 600 RPM for most materials (at the feed rate of 800 mm/min); beveling the edges to lower the stress reduces edge cracking; notches, laser marks, or edge defects in the preform doom the process to cracking and failure; coolant is required for vanadium spin-forming; increasing the number of passes to nine or more eliminates surface cracking for vanadium; titanium develops a hot zone in front of the rollers; and the tailstock should be redesigned to eliminate the cylindrical stress concentrator in the center.

  2. Assessing "Combining Forms" in Science.

    ERIC Educational Resources Information Center

    Floriani, Bernard P.; Cairns, Jack C.

    1982-01-01

    Since there appears to be a direct relationship between reading comprehension and vocabulary, an inventory is offered which assesses students' knowledge of the meaning of "combining forms" (automobile, aero-dynamics, etc.) and not words themselves. The inventory can serve as a model to develop additional inventories for Latin/Greek roots.…

  3. Thermolysin: a peptide forming enzyme.

    PubMed

    Reddy, A V

    1991-02-01

    Thermolysin, a thermostable endopeptidase, is recognised as a potential peptide bond forming enzyme. The importance of structural properties and its stereospecific nature towards peptide bond formation is described. Thermolysin's use in the keystep of the preparation of an artificial sweetener 'aspartame' is highlighted.

  4. Polynomial Algebra in Form 4

    NASA Astrophysics Data System (ADS)

    Kuipers, J.

    2012-06-01

    New features of the symbolic algebra package Form 4 are discussed. Most importantly, these features include polynomial factorization and polynomial gcd computation. Examples of their use are shown. One of them is an exact version of Mincer which gives answers in terms of rational polynomials and 5 master integrals.

  5. Anatomical form defines color: function, form, and aesthetics.

    PubMed

    Terry, Douglas A; Geller, Willi; Tric, Olivier; Anderson, Mark J; Tourville, Monte; Kobashigawa, Alvin

    2002-01-01

    Contemporary composite materials enable the reproduction of polychromatic effects within a tooth. A broader definition of color that incorporates the anatomy and optical properties of a tooth must be developed so the dental professional can better understand the infinite possibilities of color that exist within the tooth and restoration. This article describes a direct protocol for the development of natural restorations in the posterior dentition through the integration of function, form, and color.

  6. Electro-Hydraulic Forming of Sheet Metals: Free-forming vs. Conical-die Forming

    SciTech Connect

    Rohatgi, Aashish; Stephens, Elizabeth V.; Davies, Richard W.; Smith, Mark T.; Soulami, Ayoub; Ahzi, Said

    2012-05-01

    This work builds upon our recent advances in quantifying high-rate deformation behavior of sheet metals, during electro-hydraulic forming (EHF), using high-speed imaging and digital image correlation techniques. Following recent publication of an earlier manuscript, resulting from this project, in the Journal of Materials Processing Technology, this manuscript further details our results and compares forming behavior when the process is carried out inside an open-die or a conical die. It is anticipated that quantitative information of the sheet deformation history, made possible by the experimental technique developed in this work, will improve our understanding on the roles of strain-rate and sheet-die interactions in enhancing the sheet metal formability during high-rate forming. This knowledge will be beneficial to the automotive industry and enable them to fabricate light-weight sheet parts out of Al and advanced high strength steels.

  7. 3-(3,4-Dihydroxyphenyl)adenine, a urinary DNA adduct formed in mice exposed to high concentrations of benzene.

    PubMed

    Mikeš, Petr; Sístek, Václav; Krouželka, Jan; Králík, Antonín; Frantík, Emil; Mráz, Jaroslav; Linhart, Igor

    2013-06-01

    Metabolism of benzene, an important environmental and industrial carcinogen, produces three electrophilic intermediates, namely, benzene oxide and 1,2- and 1,4-benzoquinone, capable of reacting with the DNA. Numerous DNA adducts formed by these metabolites in vitro have been reported in the literature, but only one of them was hitherto identified in vivo. In a search for urinary DNA adducts, specific LC-ESI-MS methods have been developed for the determination in urine of six nucleobase adducts, namely, 7-phenylguanine, 3-phenyladenine, 3-hydroxy-3,N(4) -benzethenocytosine, N(2) -(4-hydroxyphenyl)guanine, 7-(3,4-dihydroxyphenyl)guanine and 3-(3,4-dihydroxyphenyl)-adenine (DHPA), with detection limits of 200, 10, 260, 50, 400 and 200 pg ml(-1) , respectively. Mice were exposed to benzene vapors at concentrations of 900 and 1800 mg m(-3) , 6 h per day for 15 consecutive days. The only adduct detected in their urine was DHPA. It was found in eight out of 30 urine samples from the high-exposure group at concentrations of 352 ± 146 pg ml(-1) (mean ± SD; n = 8), whereas urines from the low-exposure group were negative. Assuming the DHPA concentration in the negative samples to be half of the detection limit, conversion of benzene to DHPA was estimated to 2.2 × 10(-6) % of the absorbed dose. Thus, despite the known high mutagenic and carcinogenic potential of benzene, only traces of a single DNA adduct in urine were detected. In conclusion, DHPA is an easily depurinating adduct, thus allowing indication of only high recent exposure to benzene, but not long-term damage to DNA in tissues.

  8. 76 FR 61725 - Agency Information Collection Activities: Case Submission Form, Case Assistance Form; (Form DHS...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... Federal Register on July 18, 2011 at 76 FR 42129, for a 60-day public comment period. No comments were... other forms of information technology, e.g., permitting electronic submissions of responses. FOR FURTHER... to bring to the attention of the CIS Ombudsman (``trend''). For case problems, the CIS Ombudsman...

  9. Method of forming a joint

    DOEpatents

    Butt, Darryl Paul; Cutler, Raymond Ashton; Rynders, Steven Walton; Carolan, Michael Francis

    2006-08-22

    A method of joining at least two sintered bodies to form a composite structure, including providing a first multicomponent metallic oxide having a perovskitic or fluorite crystal structure; providing a second sintered body including a second multicomponent metallic oxide having a crystal structure of the same type as the first; and providing at an interface a joint material containing at least one metal oxide containing at least one metal identically contained in at least one of the first and second multicomponent metallic oxides. The joint material is free of cations of Si, Ge, Sn, Pb, P and Te and has a melting point below the sintering temperatures of both sintered bodies. The joint material is heated to a temperature above the melting point of the metal oxide(s) and below the sintering temperatures of the sintered bodies to form the joint. Structures containing such joints are also disclosed.

  10. Free-form illumination optics

    NASA Astrophysics Data System (ADS)

    Mohedano, Rubén; Chaves, Julio; Hernández, Maikel

    2016-04-01

    In many illumination problems, the beam pattern needed and/or some geometrical constraints lead to very asymmetric design conditions. These asymmetries have been solved in the past by means of arrangements of rotationally symmetric or linear lamps aimed in different directions whose patterns overlap to provide the asymmetric prescriptions or by splitting one single lamp into several sections, each one providing a part of the pattern. The development of new design methods yielding smooth continuous free-form optical surfaces to solve these challenging design problems, combined with the proper CAD modeling tools plus the development of multiple axes diamond turn machines, give birth to a new generation of optics. These are able to offer the performance and other advanced features, such as efficiency, compactness, or aesthetical advantages, and can be manufactured at low cost by injection molding. This paper presents two examples of devices with free-form optical surfaces, a camera flash, and a car headlamp.

  11. Cyclodextrin Inclusion Polymers Forming Hydrogels

    NASA Astrophysics Data System (ADS)

    Li, Jun

    This chapter reviews the advances in the developments of supramolecular hydrogels based on the polypseudorotaxanes and polyrotaxanes formed by inclusion complexes of cyclodextrins threading onto polymer chains. Both physical and chemical supramolecular hydrogels of many different types are discussed with respect to their preparation, structure, property, and gelation mechanism. A large number of physical supramolecular hydrogels were formed induced by self-assembly of densely packed cyclodextrin rings threaded on polymer or copolymer chains acting as physical crosslinking points. The thermo-reversible and thixotropic properties of these physical supramolecular hydrogels have inspired their applications as injectable drug delivery systems. Chemical supramolecular hydrogels synthesized from polypseudorotaxanes and polyrotaxanes were based on the chemical crosslinking of either the cyclodextrin molecules or the included polymer chains. The chemical supramolecular hydrogels were often made biodegradable through incorporation of hydrolyzable threading polymers, end caps, or crosslinkers, for their potential applications as biomaterials.

  12. Sphere forming method and apparatus

    NASA Technical Reports Server (NTRS)

    Youngberg, C. L.; Miller, C. G.; Stephens, J. B.; Finnerty, A. A. (Inventor)

    1983-01-01

    A system is provided for forming small accurately spherical objects. Preformed largely spherical objects are supported at the opening of a conduit on the update of hot gas emitted from the opening, so the object is in a molten state. The conduit is suddenly jerked away at a downward incline, to allow the molten object to drop in free fall, so that surface tension forms a precise sphere. The conduit portion that has the opening, lies in a moderate vacuum chamber, and the falling sphere passes through the chamber and through a briefly opened valve into a tall drop tower that contains a lower pressure, to allow the sphere to cool without deformation caused by falling through air.

  13. Unsplit bipolar pulse forming line

    DOEpatents

    Rhodes, Mark A.

    2011-05-24

    A bipolar pulse forming transmission line module and system for linear induction accelerators having first, second, third, and fourth planar conductors which form a sequentially arranged interleaved stack having opposing first and second ends, with dielectric layers between the conductors. The first and second planar conductors are connected to each other at the first end, and the first and fourth planar conductors are connected to each other at the second end via a shorting plate. The third planar conductor is electrically connectable to a high voltage source, and an internal switch functions to short at the first end a high voltage from the third planar conductor to the fourth planar conductor to produce a bipolar pulse at the acceleration axis with a zero net time integral. Improved access to the switch is enabled by an aperture through the shorting plate and the proximity of the aperture to the switch.

  14. Method for forming hermetic seals

    NASA Technical Reports Server (NTRS)

    Gallagher, Brian D.

    1987-01-01

    The firmly adherent film of bondable metal, such as silver, is applied to the surface of glass or other substrate by decomposing a layer of solution of a thermally decomposable metallo-organic deposition (MOD) compound such as silver neodecanoate in xylene. The MOD compound thermally decomposes into metal and gaseous by-products. Sealing is accomplished by depositing a layer of bonding metal, such as solder or a brazing alloy, on the metal film and then forming an assembly with another high melting point metal surface such as a layer of Kovar. When the assembly is heated above the temperature of the solder, the solder flows, wets the adjacent surfaces and forms a hermetic seal between the metal film and metal surface when the assembly cools.

  15. Method of forming calthrate ice

    DOEpatents

    Hino, T.; Gorski, A.J.

    1985-09-30

    A method of forming clathrate ice in a supercooled water-based liquid contained in a vessel is disclosed. Initially, an oscillator device is located in the liquid in the vessel. The oscillator device is then oscillated ultransonically so that small crystals are formed in the liquid. Thes small crystals serve as seed crystals for ice formation in the liquid and thereby prevent supercooling of the liquid. Preferably, the oscillating device is controlled by a thermostat which initiates operation of the oscillator device when the temperature of the liquid is lowered to the freezing point. Thereafter, the operation of the oscillator device is terminated when ice is sensed in the liquid by an ice sensor.

  16. Method of forming clathrate ice

    DOEpatents

    Hino, Toshiyuki; Gorski, Anthony J.

    1987-01-01

    A method of forming clathrate ice in a supercooled water-based liquid contained in a vessel is disclosed. Initially, an oscillator device is located in the liquid in the vessel. The oscillator device is then oscillated ultrasonically so that small crystals are formed in the liquid. These small crystals serve as seed crystals for ice formation in the liquid and thereby prevent supercooling of the liquid. Preferably, the oscillating device is controlled by a thermostat which initiates operation of the oscillator device when the temperature of the liquid is lowered to the freezing point. Thereafter, the operation of the oscillator device is terminated when ice is sensed in the liquid by an ice sensor.

  17. Rheology of hydrate forming emulsions.

    PubMed

    Peixinho, Jorge; Karanjkar, Prasad U; Lee, Jae W; Morris, Jeffrey F

    2010-07-20

    Results are reported on an experimental study of the rheology of hydrate-forming water-in-oil emulsions. Density-matched concentrated emulsions were quenched by reducing the temperature and an irreversible transition was observed where the viscosity increased dramatically. The hydrate-forming emulsions have characteristic times for abrupt viscosity change dependent only on the temperature, reflecting the importance of the effect of subcooling. Mechanical transition of hydrate-free water-in-oil emulsions may require longer times and depends on the shear rate, occurring more rapidly at higher rates but with significant scatter which is characterized through a probabilistic analysis. This rate dependence together with dependence on subcooling reflects the importance of hydrodynamic forces to bring drops or particles together.

  18. Studying how protein crystals form

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Watching molecules of the iron-storing protein apoferritin come together to form a nucleus reveals some interesting behavior. In this series of images, researchers observed clusters of four molecules at the corners of a diamond shape (top). As more molecules attach to the cluster, they arrange themselves into rods (second from top), and a raft-like configuration of molecules forms the critical nucleus (third from top), suggesting that crystal growth is much slower than it could be were the molecules arranged in a more compact formation. In the final image, a crystallite consisting of three layers containing approximately 60 to 70 molecules each is formed. Atomic force microscopy made visualizing the process of nucleation possible for the first time. The principal investigator is Peter Vekilov, of the University of Alabama in Huntsville. Vekilov's team at UAH studies protein solutions as they change phases from liquids to crystalline solids. They want to know if the molecules in the solution interact with one another, and if so, how, from the perspectives of thermodynamics and kinetics. They want to understand which forces -- electrical, electrostatic, hydrodynamic, or other kinds of forces -- are responsible for the interactions. They also study nucleation, the begirning stage of crystallization. This process is important to understand because it sets the stage for crystal growth in all kinds of solutions and liquid melts that are important in such diverse fields as agriculture, medicine, and the fabrication of metal components. Nucleation can determine the rate of crystal growth, the number of crystals that will be formed, and the quality and size of the crystals.

  19. How do atmospheric rivers form?

    NASA Astrophysics Data System (ADS)

    Dacre, Helen

    2015-04-01

    The term atmospheric river is used to describe corridors of strong water vapor transport in the troposphere. Filaments of enhanced water vapor, commonly observed in satellite imagery extending from the subtropics to the extratropics, are routinely used as a proxy for identifying these regions of strong water vapor transport. The precipitation associated with these filaments of enhanced water vapor can lead to high impact flooding events. However, there remains some debate as to how these filaments form. In this study we analyse the transport of water vapor within a climatology of wintertime North Atlantic extratropical cyclones. Results show that atmospheric rivers are formed by the cold front which sweeps up water vapor in the warm sector as it catches up with the warm front. This causes a narrow band of high water vapor content to form ahead of the cold front at the base of the warm conveyor belt airflow. Thus, water vapor in the cyclone's warm sector, and not long-distance transport of water vapor from the subtropics, is responsible for the generation of filaments of high water vapor content. A continuous cycle of evaporation and moisture convergence within the cyclone replenishes water vapor lost via precipitation. Thus, rather than representing a direct and continuous feed of moist air from the subtropics into the centre of a cyclone (as suggested by the term atmospheric river), these filaments are, in-fact, the result of water vapor exported from the cyclone and thus they represent the footprints left behind as cyclones travel polewards from subtropics.

  20. Coated particle waste form development

    SciTech Connect

    Oma, K.H.; Buckwalter, C.Q.; Chick, L.A.

    1981-12-01

    Coated particle waste forms have been developed as part of the multibarrier concept at Pacific Northwest Laboratory under the Alternative Waste Forms Program for the Department of Energy. Primary efforts were to coat simulated nuclear waste glass marbles and ceramic pellets with low-temperature pyrolytic carbon (LT-PyC) coatings via the process of chemical vapor deposition (CVD). Fluidized bed (FB) coaters, screw agitated coaters (SAC), and rotating tube coaters were used. Coating temperatures were reduced by using catalysts and plasma activation. In general, the LT-PyC coatings did not provide the expected high leach resistance as previously measured for carbon alone. The coatings were friable and often spalled off the substrate. A totally different concept, thermal spray coating, was investigated at PNL as an alternative to CVD coating. Flame spray, wire gun, and plasma gun systems were evaluated using glass, ceramic, and metallic coating materials. Metal plasma spray coatings (Al, Sn, Zn, Pb) provided a two to three orders-of-magnitude increase in chemical durability. Because the aluminum coatings were porous, the superior leach resistance must be due to either a chemical interaction or to a pH buffer effect. Because they are complex, coated waste form processes rank low in process feasibility. Of all the possible coated particle processes, plasma sprayed marbles have the best rating. Carbon coating of pellets by CVD ranked ninth when compared with ten other processes. The plasma-spray-coated marble process ranked sixth out of eleven processes.

  1. Rib forming tool for tubing

    DOEpatents

    Rowley, James P.; Lewandowski, Edward F.; Groh, Edward F.

    1976-01-01

    Three cylindrical rollers are rotatably mounted equidistant from the center of a hollow tool head on radii spaced 120.degree. apart. Each roller has a thin flange; the three flanges lie in a single plane to form an internal circumferential rib in a rotating tubular workpiece. The tool head has two complementary parts with two rollers in one part of the head and one roller in the other part; the two parts are joined by a hinge. A second hinge, located so the rollers are between the two hinges, connects one of the parts to a tool bar mounted in a lathe tool holder. The axes of rotation of both hinges and all three rollers are parallel. A hole exposing equal portions of the three roller flanges is located in the center of the tool head. The two hinges permit the tool head to be opened and rotated slightly downward, taking the roller flanges out of the path of the workpiece which is supported on both ends and rotated by the lathe. The parts of the tool head are then closed on the workpiece so that the flanges are applied to the workpiece and form the rib. The tool is then relocated for forming of the next rib.

  2. Dynamic Forms. Part 1: Functions

    NASA Technical Reports Server (NTRS)

    Meyer, George; Smith, G. Allan

    1993-01-01

    The formalism of dynamic forms is developed as a means for organizing and systematizing the design control systems. The formalism allows the designer to easily compute derivatives to various orders of large composite functions that occur in flight-control design. Such functions involve many function-of-a-function calls that may be nested to many levels. The component functions may be multiaxis, nonlinear, and they may include rotation transformations. A dynamic form is defined as a variable together with its time derivatives up to some fixed but arbitrary order. The variable may be a scalar, a vector, a matrix, a direction cosine matrix, Euler angles, or Euler parameters. Algorithms for standard elementary functions and operations of scalar dynamic forms are developed first. Then vector and matrix operations and transformations between parameterization of rotations are developed in the next level in the hierarchy. Commonly occurring algorithms in control-system design, including inversion of pure feedback systems, are developed in the third level. A large-angle, three-axis attitude servo and other examples are included to illustrate the effectiveness of the developed formalism. All algorithms were implemented in FORTRAN code. Practical experience shows that the proposed formalism may significantly improve the productivity of the design and coding process.

  3. 48 CFR 253.303 - Agency forms.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Agency forms. 253.303 Section 253.303 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CLAUSES AND FORMS FORMS Illustration of Forms 253.303 Agency forms. DoD forms...

  4. 48 CFR 253.303 - Agency forms.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Agency forms. 253.303 Section 253.303 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CLAUSES AND FORMS FORMS Illustration of Forms 253.303 Agency forms. DoD forms...

  5. 48 CFR 253.303 - Agency forms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Agency forms. 253.303 Section 253.303 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CLAUSES AND FORMS FORMS Illustration of Forms 253.303 Agency forms. DoD forms...

  6. 48 CFR 253.303 - Agency forms.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Agency forms. 253.303 Section 253.303 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CLAUSES AND FORMS FORMS Illustration of Forms 253.303 Agency forms. DoD forms...

  7. [Adult form of Pompe disease].

    PubMed

    Ziółkowska-Graca, Bozena; Kania, Aleksander; Zwolińska, Grazyna; Nizankowska-Mogilnicka, Ewa

    2008-01-01

    Pompe disease (glycogen-storage disease type II) is an autosomal recessive disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in the lysosomes primarily in muscle cells. In the adult form of the disease, proximal muscle weakness is noted and muscle volume is decreased. The infantile form is usually fatal. In the adult form of the disease the prognosis is relatively good. Muscle weakness may, however, interfere with normal daily activities, and respiratory insufficiency may be associated with obstructive sleep apnea. Death usually results from respiratory failure. Effective specific treatment is not available. Enzyme replacement therapy with recombinant human GAA (rh-GAA) still remains a research area. We report the case of a 24-year-old student admitted to the Department of Pulmonary Diseases because of severe respiratory insufficiency. Clinical symptoms such as dyspnea, muscular weakness and increased daytime sleepiness had been progressing for 2 years. Clinical examination and increased blood levels of CK suggested muscle pathology. Histopathological analysis of muscle biopsy, performed under electron microscope, confirmed the presence of vacuoles containing glycogen. Specific enzymatic activity of alpha-glucosidase was analyzed confirming Pompe disease. The only effective method to treat respiratory insufficiency was bi-level positive pressure ventilation. Respiratory rehabilitation was instituted and is still continued by the patient at home. A high-protein, low-sugar diet was proposed for the patient. Because of poliglobulia low molecular weight heparin was prescribed. The patient is eligible for experimental replacement therapy with rh-GAA. PMID:19003770

  8. Weak Energy: Form and Function

    NASA Astrophysics Data System (ADS)

    Parks, Allen D.

    The equation of motion for a time-dependent weak value of a quantum mechanical observable contains a complex valued energy factor—the weak energy of evolution. This quantity is defined by the dynamics of the pre-selected and post-selected states which specify the observable's weak value. It is shown that this energy: (i) is manifested as dynamical and geometric phases that govern the evolution of the weak value during the measurement process; (ii) satisfies the Euler-Lagrange equations when expressed in terms of Pancharatnam (P) phase and Fubini-Study (FS) metric distance; (iii) provides for a PFS stationary action principle for quantum state evolution; (iv) time translates correlation amplitudes; (v) generalizes the temporal persistence of state normalization; and (vi) obeys a time-energy uncertainty relation. A similar complex valued quantity—the pointed weak energy of an evolving quantum state—is also defined and several of its properties in PFS coordinates are discussed. It is shown that the imaginary part of the pointed weak energy governs the state's survival probability and its real part is—to within a sign—the Mukunda-Simon geometric phase for arbitrary evolutions or the Aharonov-Anandan (AA) geometric phase for cyclic evolutions. Pointed weak energy gauge transformations and the PFS 1-form are defined and discussed and the relationship between the PFS 1-form and the AA connection 1-form is established. [Editors note: for a video of the talk given by Prof. Parks at the Aharonov-80 conference in 2012 at Chapman University, see http://quantum.chapman.edu/talk-25.

  9. CERAMIC WASTE FORM DATA PACKAGE

    SciTech Connect

    Amoroso, J.; Marra, J.

    2014-06-13

    The purpose of this data package is to provide information about simulated crystalline waste forms that can be used to select an appropriate composition for a Cold Crucible Induction Melter (CCIM) proof of principle demonstration. Melt processing, viscosity, electrical conductivity, and thermal analysis information was collected to assess the ability of two potential candidate ceramic compositions to be processed in the Idaho National Laboratory (INL) CCIM and to guide processing parameters for the CCIM operation. Given uncertainties in the CCIM capabilities to reach certain temperatures throughout the system, one waste form designated 'Fe-MP' was designed towards enabling processing and another, designated 'CAF-5%TM-MP' was designed towards optimized microstructure. Melt processing studies confirmed both compositions could be poured from a crucible at 1600{degrees}C although the CAF-5%TM-MP composition froze before pouring was complete due to rapid crystallization (upon cooling). X-ray diffraction measurements confirmed the crystalline nature and phase assemblages of the compositions. The kinetics of melting and crystallization appeared to vary significantly between the compositions. Impedance spectroscopy results indicated the electrical conductivity is acceptable with respect to processing in the CCIM. The success of processing either ceramic composition will depend on the thermal profiles throughout the CCIM. In particular, the working temperature of the pour spout relative to the bulk melter which can approach 1700{degrees}C. The Fe-MP composition is recommended to demonstrate proof of principle for crystalline simulated waste forms considering the current configuration of INL's CCIM. If proposed modifications to the CCIM can maintain a nominal temperature of 1600{degrees}C throughout the melter, drain, and pour spout, then the CAF-5%TM-MP composition should be considered for a proof of principle demonstration.

  10. FORMING PROTECTIVE FILMS ON METAL

    DOEpatents

    Gurinsky, D.H.; Kammerer, O.F.; Sadofsky, J.; Weeks, J.R.

    1958-12-16

    Methods are described of inhibiting the corrosion of ferrous metal by contact with heavy liquid metals such as bismuth and gallium at temperatures above 500 icient laborato C generally by bringing nltrogen and either the metal zirconium, hafnium, or titanium into reactlve contact with the ferrous metal to form a thin adherent layer of the nitride of the metal and thereafter maintaining a fractional percentage of the metal absorbed in the heavy liquid metal in contact with the ferrous metal container. The general purpose for uslng such high boiling liquid metals in ferrous contalners would be as heat transfer agents in liquid-metal-fueled nuclear reactors.

  11. Export of newly formed LSW

    NASA Astrophysics Data System (ADS)

    Müller, Katharina; Klein, Birgit; Karstensen, Johannes; Fischer, Jürgen; Baumann, Till; Kanzow, Torsten

    2015-04-01

    The Atlantic meridional overturning circulation represents the strongest mechanism for oceanic northward heat transport. This is accomplished by moving warm water northward in the upper ocean compensated by a deep return flow of cold and dense North Atlantic Deep Water (NADW). Labrador Sea Water (LSW) constitutes the shallowest component of NADW. Since LSW is also supposed to be the most sensitive NADW component to climate change it is of particular interest. LSW is formed by deep convection not only in the centre of the Labrador Sea but also near its western boundary. Recent studies have suggested that LSW formed in the boundary region enters its export route from the Labrador Sea, the Deep Western Boundary Current, faster than LSW originating from the central Labrador Sea. In this study the spatial and temporal evolution of the export of newly formed LSW is investigated. For this purpose hydrographic mooring data from an array located at the western bounndary at 53°N starting in the late 1990s until 2014 and data from the Argo float network is used. The averaged seasonal salinity cycle at the array, particularly at the moorings further onshore, shows a pronounced freshwater signal in May indicating the arrival of newly formed LSW in the boundary current. In order to learn more about its preceding pathway and the corresponding export timescale the mooring data is complemented by data from Argo floats. Besides the annual cycles of LSW formation and export, their interannual variations are important aspects affecting the large-scale circulation. For instance, in years of relatively strong convection, as in 2008 and 2012, LSW is observed to pass the boundary current array at 53°N earlier, i.e. in February and March, respectively, than in years with weak convection, as in 2007 or 2010. Besides seasonal variations in the boundary current, a possible explanation for the earlier freshwater signal in years of enhanced convection might be a shift in convection sites

  12. 76 FR 21946 - Proposed Collection; Comment Request for Form 990-BL; Schedule A (Form 990-BL), Form 6069

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-19

    ... Internal Revenue Service Proposed Collection; Comment Request for Form 990-BL; Schedule A (Form 990-BL), Form 6069 AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice and request for comments... Form 990-BL, Schedule A (Form 990-BL), Information and Initial Excise Tax Return for Black Lung...

  13. Gravity, light and plant form.

    PubMed

    Hangarter, R P

    1997-06-01

    Plants have evolved highly sensitive and selective mechanisms that detect and respond to various aspects of their environment. As a plant develops, it integrates the environmental information perceived by all of its sensory systems and adapts its growth to the prevailing environmental conditions. Light is of critical importance because plants depend on it for energy and, thus, survival. The quantity, quality and direction of light are perceived by several different photosensory systems that together regulate nearly all stages of plant development, presumably in order to maintain photosynthetic efficiency. Gravity provides an almost constant stimulus that is the source of critical spatial information about its surroundings and provides important cues for orientating plant growth. Gravity plays a particularly important role during the early stages of seedling growth by stimulating a negative gravitropic response in the primary shoot that orientates it towards the source of light, and a positive gravitropic response in the primary root that causes it to grow down into the soil, providing support and nutrient acquisition. Gravity also influences plant form during later stages of development through its effect on lateral organs and supporting structures. Thus, the final form of a plant depends on the cumulative effects of light, gravity and other environmental sensory inputs on endogenous developmental programs. This article is focused on developmental interactions modulated by light and gravity.

  14. [Kinin forming system and ovulation].

    PubMed

    Seki, M

    1984-06-01

    The aim of the study is to clarify the role of the kinin forming system on ovulation. The results were as follows, Plasma prekallikrein of superovulated prepubertal rats was decreased to 50-60% of the normal level after PMS injection and 80-90% of the normal level after hCG injection. The lowest level was 33.8% 39 hours after PMS injection. Aprotinin suppressed the superovulation of prepubertal rats at doses of 16.7 X 10(4) KIE and 37.8 X 10(4) KIE (p less than 0.01). These results showed that the kinin production system has an effect on ovulation. As the sex steroid hormone, estradil benzoate, progesterone and testosterone propinate were used in oophorectomized mice. They had no effect on the plasma prekallikrein level. The plasma prekallikrein level during the estrus cycle of mature female mice was 85.5% of the control level in preestrus, 80.3% in estrus, 83.7% in metestrus and 89.8% in diestrus. The mean was 83.9%, which was significantly lower than that for oophorectomized mice (94.1%). It is proved that plasma prekallikrein was consumed and the kinin forming system was accelerated in the ovary with ovulation. PMID:6205107

  15. Gravity, light and plant form.

    PubMed

    Hangarter, R P

    1997-06-01

    Plants have evolved highly sensitive and selective mechanisms that detect and respond to various aspects of their environment. As a plant develops, it integrates the environmental information perceived by all of its sensory systems and adapts its growth to the prevailing environmental conditions. Light is of critical importance because plants depend on it for energy and, thus, survival. The quantity, quality and direction of light are perceived by several different photosensory systems that together regulate nearly all stages of plant development, presumably in order to maintain photosynthetic efficiency. Gravity provides an almost constant stimulus that is the source of critical spatial information about its surroundings and provides important cues for orientating plant growth. Gravity plays a particularly important role during the early stages of seedling growth by stimulating a negative gravitropic response in the primary shoot that orientates it towards the source of light, and a positive gravitropic response in the primary root that causes it to grow down into the soil, providing support and nutrient acquisition. Gravity also influences plant form during later stages of development through its effect on lateral organs and supporting structures. Thus, the final form of a plant depends on the cumulative effects of light, gravity and other environmental sensory inputs on endogenous developmental programs. This article is focused on developmental interactions modulated by light and gravity. PMID:11541207

  16. Gravity, light and plant form

    NASA Technical Reports Server (NTRS)

    Hangarter, R. P.

    1997-01-01

    Plants have evolved highly sensitive and selective mechanisms that detect and respond to various aspects of their environment. As a plant develops, it integrates the environmental information perceived by all of its sensory systems and adapts its growth to the prevailing environmental conditions. Light is of critical importance because plants depend on it for energy and, thus, survival. The quantity, quality and direction of light are perceived by several different photosensory systems that together regulate nearly all stages of plant development, presumably in order to maintain photosynthetic efficiency. Gravity provides an almost constant stimulus that is the source of critical spatial information about its surroundings and provides important cues for orientating plant growth. Gravity plays a particularly important role during the early stages of seedling growth by stimulating a negative gravitropic response in the primary shoot that orientates it towards the source of light, and a positive gravitropic response in the primary root that causes it to grow down into the soil, providing support and nutrient acquisition. Gravity also influences plant form during later stages of development through its effect on lateral organs and supporting structures. Thus, the final form of a plant depends on the cumulative effects of light, gravity and other environmental sensory inputs on endogenous developmental programs. This article is focused on developmental interactions modulated by light and gravity.

  17. Integrally formed radio frequency quadrupole

    DOEpatents

    Abbott, Steven R.

    1989-01-01

    An improved radio frequency quadrupole (10) is provided having an elongate housing (11) with an elongate central axis (12) and top, bottom and two side walls (13a-d) symmetrically disposed about the axis, and vanes (14a-d) formed integrally with the walls (13a-d), the vanes (14a-d) each having a cross-section at right angles to the central axis (12) which tapers inwardly toward the axis to form electrode tips (15a-d) spaced from each other by predetermined distances. Each of the four walls (13a-d), and the vanes (14a-d) integral therewith, is a separate structural element having a central lengthwise plane (16) passing through the tip of the vane, the walls (13a-d) having flat mounting surfaces (17, 18) at right angles to and parallel to the control plane (16), respectively, which are butted together to position the walls and vane tips relative to each other.

  18. Preventing Ice Before it Forms

    NASA Technical Reports Server (NTRS)

    2006-01-01

    In the late 1990s, a team of engineers at Ames Research Center invented an anti-icing fluid to keep ice from building up on airplane wings. Ice on wings can be a serious safety hazard, especially during takeoff, when a sheet of ice the thickness of a compact disc can reduce lift by 25 percent or more. The typical approach to clearing off the ice is to use a deicing solution once the ice has built up. The fluid created by the Ames team, though, when applied to a dry surface, prevents the ice from even forming a surface bond, which saves deicing time and money, while also preventing excessive use of chemical solvents. If, however, the solution is not applied before ice forms, it also serves as a traditional deicing formula. The formula contains propylene glycol, which has a very low freezing point, and a thickener, which helps the fluid adhere to the surface. Ice gathers on top of the formula, and then it can be wiped off with little effort. This thickening agent, a pseudo-plastic, sprays on as a liquid, like lemonade, gels like a lemon sherbet, turns back to a liquid when wiped, and then gels again into its sherbet consistency when left to solidify. The sherbet-gel stage is especially important when the formula is sprayed onto a vertical or steeped surface, as it clings better than a liquid would.

  19. Coated particle waste form development

    NASA Astrophysics Data System (ADS)

    Oma, K. H.; Buckwalter, C. Q.; Chick, L. A.

    1981-12-01

    Coated particle waste forms were developed as part of the multibarrier concept. Primary efforts were to coat simulated nuclear waste glass marbles and ceramic pellets with low temperature pyrolytic carbon (LT-PyC) coatings via the process of chemical vapor deposition (CVD). Fluidized bed coaters, screw agitated coaters, and rotating tube coaters were used. Coating temperatures were reduced by using catalysts and plasma activation. In general, the LT-PyC coatings did not provide the expected high leach resistance as previously measured for carbon alone. The coatings were friable and often spalled off the substrate. A totally different concept, thermal spray coating, was investigated as an alternative to CVD coating. Flame spray, wire gun, and plasma gun systems were evaluated using glass, ceramic, and metallic coating materials. Metal plasma spray coatings (Al, Sn, Zn, Pb) provided a two to three orders of magnitude increase in chemical durability.

  20. Frozen Film and FOSDIC Forms

    PubMed Central

    RUGGLES, STEVEN; SCHROEDER, MATTHEW; RIVERS, NATASHA; ALEXANDER, J. TRENT; GARDNER, TODD K.

    2012-01-01

    In this article, the authors describe a collaboration of the Minnesota Population Center (MPC), the U.S. Census Bureau, and the National Archives and Records Administration to restore the lost data from the 1960 Census. The data survived on refrigerated microfilm in a cave in Lenexa, Kansas. The MPC is now converting the data to usable form. Once the restored data are processed, the authors intend to develop three new data sources based on the 1960 census. These data will replace the most inadequate sample in the series of public-use census microdata spanning the years from 1850 to 2000, extend the chronological scope of the public census summary files, and provide a powerful new resource for the Census Bureau and its Research Data Centers. PMID:22544986

  1. Forming impressions from incongruent traits.

    PubMed

    Casselden, P A; Hampson, S E

    1990-08-01

    The factors that affect the ease with which impressions are formed from incongruent trait pairs are investigated. In Experiments 1 and 2, trait pairs that were both descriptively and evaluatively congruent, as well as ones that were only evaluatively congruent, were found to be more imaginable and to be perceived as more frequently co-occurring than incongruent trait pairs. In Experiment 3, response latency provided a converging measure of ease of imaginability. Experiment 4 examined written descriptions of targets described by these trait pairs, and found more attempts to integrate the congruent than the incongruent pairs. These findings are discussed in terms of the relation between laypersons' impressions of personality and formal personality assessment.

  2. Forming parts over small radii

    NASA Astrophysics Data System (ADS)

    Hazra, S. K.; Hughes, D. J.; Pereira, M. P.; Rolfe, B. F.

    2016-08-01

    Stamping simulations usually make the plane stress simplifying assumption. However, this becomes less valid when material draws around features with radius to sheet thickness ratios less than 20. Pereira, Yan & Rolfe (Wear, Vol.265, p.1687 (2008)) predicted that out-of-plane stress equivalent to material yield can occur because a line contact forms briefly at the start of the draw process. The high transient stress can cause high rates of tool wear and may cause the ‘die impact line’ cosmetic defect. In this work, we present residual strain results of a channel section that was drawn over a small radius. Using the neutron source at the Institut Laue-Langevin, in-plane and out-of-plane strains were measured in the channel part to show some support for the conclusions of Pereira et. al.

  3. Method for forming energetic nanopowders

    DOEpatents

    Lee, Kien-Yin; Asay, Blaine W.; Kennedy, James E.

    2013-10-15

    A method for the preparation of neat energetic powders, having nanometer dimensions, is described herein. For these neat powder, a solution of a chosen energetic material is prepared in an aprotic solvent and later combined with liquid hexane that is miscible with such solvent. The energetic material chosen is less soluble in the liquid hexane than in the aprotic solvent and the liquid hexane is cooled to a temperature that is below that of the solvent solution. In order to form a precipitate of said neat powders, the solvent solution is rapidly combined with the liquid hexane. When the resulting precipitate is collected, it may be dried and filtered to yield an energetic nanopowder material.

  4. [Familial form of rheumatoid nodulosis].

    PubMed

    Bosser, H; Schubert, B; Grosshans, E

    1993-01-01

    We report a familial form of rheumatoid nodulosis where the early lesions appeared in the first years of life in a young man and his son. The numerous papular and nodular skin lesions disclosed an ulcerative evolution leaving atrophic scars mainly near the limbs' joints. In both patients the evolution was characterized by the late onset of polyarthralgias and of a non-destructive seronegative polyarthritis; intra-osseous lesions were present in the metatarsal bones in the father. Rheumatoid nodulosis is a rare disease, sometimes considered as a benign variant of rheumatoid arthritis without destructive joint involvement. A serum rheumatoid factor is inconstantly present and the intra-osseous geodes have been shown to be rheumatoid nodules exhibiting the same histological structures of palisading granulomas as the subcutaneous nodules. The main symptom of the disease is the occurrence of multiple nodules followed by the delayed onset of a polyarthritis with a benign course without systemic involvement.

  5. Localization and real Jacobi forms

    NASA Astrophysics Data System (ADS)

    Ashok, Sujay K.; Doroud, Nima; Troost, Jan

    2014-04-01

    We calculate the elliptic genus of two dimensional abelian gauged linear sigma models with (2, 2) supersymmetry using supersymmetric localization. The matter sector contains charged chiral multiplets as well as Stückelberg fields coupled to the vector multiplets. These models include theories that flow in the infrared to non-linear sigma models with target spaces that are non-compact Kähler manifolds with U( N) isometry and with an asymptotically linear dilaton direction. The elliptic genera are the modular completions of mock Jacobi forms that have been proposed recently using complementary arguments. We also compute the elliptic genera of models that contain multiple Stückelberg fields from first principles.

  6. Form factors from lattice QCD

    SciTech Connect

    Dru Renner

    2012-04-01

    Precision computation of hadronic physics with lattice QCD is becoming feasible. The last decade has seen precent-level calculations of many simple properties of mesons, and the last few years have seen calculations of baryon masses, including the nucleon mass, accurate to a few percent. As computational power increases and algorithms advance, the precise calculation of a variety of more demanding hadronic properties will become realistic. With this in mind, I discuss the current lattice QCD calculations of generalized parton distributions with an emphasis on the prospects for well-controlled calculations for these observables as well. I will do this by way of several examples: the pion and nucleon form factors and moments of the nucleon parton and generalized-parton distributions.

  7. Miscellaneous Waste-Form FEPs

    SciTech Connect

    A. Schenker

    2000-12-08

    The US DOE must provide a reasonable assurance that the performance objectives for the Yucca Mountain Project (YMP) potential radioactive-waste repository can be achieved for a 10,000-year post-closure period. The guidance that mandates this direction is under the provisions of 10 CFR Part 63 and the US Department of Energy's ''Revised Interim Guidance Pending Issuance of New US Nuclear Regulatory Commission (NRC) Regulations (Revision 01, July 22, 1999), for Yucca Mountain, Nevada'' (Dyer 1999 and herein referred to as DOE's Interim Guidance). This assurance must be demonstrated in the form of a performance assessment that: (1) identifies the features, events, and processes (FEPs) that might affect the performance of the potential geologic repository; (2) examines the effects of such FEPs on the performance of the potential geologic repository; (3) estimates the expected annual dose to a specified receptor group; and (4) provides the technical basis for inclusion or exclusion of specific FEPs.

  8. Forming impressions from incongruent traits.

    PubMed

    Casselden, P A; Hampson, S E

    1990-08-01

    The factors that affect the ease with which impressions are formed from incongruent trait pairs are investigated. In Experiments 1 and 2, trait pairs that were both descriptively and evaluatively congruent, as well as ones that were only evaluatively congruent, were found to be more imaginable and to be perceived as more frequently co-occurring than incongruent trait pairs. In Experiment 3, response latency provided a converging measure of ease of imaginability. Experiment 4 examined written descriptions of targets described by these trait pairs, and found more attempts to integrate the congruent than the incongruent pairs. These findings are discussed in terms of the relation between laypersons' impressions of personality and formal personality assessment. PMID:2213498

  9. Alumina forming iron base superalloy

    DOEpatents

    Yamamoto, Yukinori; Muralidharan, Govindarajan; Brady, Michael P.

    2014-08-26

    An austenitic stainless steel alloy, consists essentially of, in weight percent 2.5 to 4 Al; 25 to 35 Ni; 12 to 19 Cr; at least 1, up to 4 total of at least one element selected from the group consisting of Nb and Ta; 0.5 to 3 Ti; less than 0.5 V; 0.1 to 1 of at least on element selected from the group consisting of Zr and Hf; 0.03 to 0.2 C; 0.005 to 0.1 B; and base Fe. The weight percent Fe is greater than the weight percent Ni. The alloy forms an external continuous scale including alumina, and contains coherent precipitates of .gamma.'-Ni.sub.3Al, and a stable essentially single phase FCC austenitic matrix microstructure. The austenitic matrix is essentially delta-ferrite-free and essentially BCC-phase-free.

  10. Nuclear waste forms for actinides

    PubMed Central

    Ewing, Rodney C.

    1999-01-01

    The disposition of actinides, most recently 239Pu from dismantled nuclear weapons, requires effective containment of waste generated by the nuclear fuel cycle. Because actinides (e.g., 239Pu and 237Np) are long-lived, they have a major impact on risk assessments of geologic repositories. Thus, demonstrable, long-term chemical and mechanical durability are essential properties of waste forms for the immobilization of actinides. Mineralogic and geologic studies provide excellent candidate phases for immobilization and a unique database that cannot be duplicated by a purely materials science approach. The “mineralogic approach” is illustrated by a discussion of zircon as a phase for the immobilization of excess weapons plutonium. PMID:10097054

  11. 48 CFR 813.307 - Forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... following forms provide a purchase or delivery order, vendor's invoice, and receiving report: (1) VA Form 90... Form 10-7078, Authorization and Invoice for Medical and Hospital Services. (2) VA Form 10-7079, Request for Outpatient Medical Services. (3) VA Form 10-2570d, Dental Record Authorization and Invoice...

  12. 48 CFR 813.307 - Forms.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... following forms provide a purchase or delivery order, vendor's invoice, and receiving report: (1) VA Form 90... Form 10-7078, Authorization and Invoice for Medical and Hospital Services. (2) VA Form 10-7079, Request for Outpatient Medical Services. (3) VA Form 10-2570d, Dental Record Authorization and Invoice...

  13. 48 CFR 2913.307 - Forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., contracting officers are encouraged to use the Standard Form (SF) SF-1449, when executing commercial acquisitions. Agencies may use forms other than the SF-1449 and may print on those forms the clauses...

  14. 48 CFR 3053.303 - Agency forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... section illustrates agency-specified forms. To access these forms go to: http://www.dhs.gov (under “Business, Acquisition Information”) or https://dhsonline.dhs.gov/portal/jhtml/general/forms.jhtml....

  15. Detection of combustion formed nanoparticles.

    PubMed

    Sgro, L A; Basile, G; Barone, A C; D'Anna, A; Minutolo, P; Borghese, A; D'Alessio, A

    2003-06-01

    UV-visible extinction and scattering and two extra situ sampling techniques: atomic force microscopy (AFM) and differential mobility analysis (DMA) are used to follow the evolution of the particles formed in flames. These particle sizing techniques were chosen because of their sensitivity to detect inception particles, which have diameters, d<5 nm, too small to be observed with typical particle measurement instrumentation. The size of the particles determined by AFM and DMA compares well with the size determined by in situ optical measurements, indicating that the interpretation of the UV-visible optical signal is quite good, and strongly showing the presence of d=2-4 nm particles. UV-visible extinction measurements are also used to determine the concentration of d=2-4 nm particles at the exhausts of practical combustion systems. A numerical model, able to reproduce the experimentally observed low coagulation rate of nanoparticles with respect to soot particles, is used to investigate the operating conditions in the combustion chamber and exhaust system for which 2-4 nm particles survive the exhaust or grow to larger sizes. Combustion generated nanoparticles are suspected to affect human and environmental health because of their affinity for water, small size, low rate of coagulation, and large surface area/weight ratio. The ability to isolate nanoparticles from soot particles in hydrosols collected from combustion may be useful for future analysis by a variety of techniques and toxicological assays.

  16. Dyadosphere formed in gravitational collapse

    SciTech Connect

    Ruffini, Remo; Xue Shesheng

    2008-10-10

    We first recall the concept of Dyadosphere (electron-positron-photon plasma around a formed black holes) and its motivation, and recall on (i) the Dirac process: annihilation of electron-positron pairs to photons; (ii) the Breit-Wheeler process: production of electron-positron pairs by photons with the energy larger than electron-positron mass threshold; the Sauter-Euler-Heisenberg effective Lagrangian and rate for the process of electron-positron production in a constant electric field. We present a general formula for the pair-production rate in the semi-classical treatment of quantum mechanical tunneling. We also present in the Quantum Electro-Dynamics framework, the calculations of the Schwinger rate and effective Lagrangian for constant electromagnetic fields. We give a review on the electron-positron plasma oscillation in constant electric fields, and its interaction with photons leading to energy and number equipartition of photons, electrons and positrons. The possibility of creating an overcritical field in astrophysical condition is pointed out. We present the discussions and calculations on (i) energy extraction from gravitational collapse; (ii) the formation of Dyadosphere in gravitational collapsing process, and (iii) its hydrodynamical expansion in Reissner Nordstroem geometry. We calculate the spectrum and flux of photon radiation at the point of transparency, and make predictions for short Gamma-Ray Bursts.

  17. Filtrating forms of soil bacteria

    NASA Astrophysics Data System (ADS)

    Van'kova, A. A.; Ivanov, P. I.; Emtsev, V. T.

    2013-03-01

    Filtrating (ultramicroscopic) forms (FF) of bacteria were studied in a soddy-podzolic soil and the root zone of alfalfa plants as part of populations of the most widespread physiological groups of soil bacteria. FF were obtained by filtering soil solutions through membrane filters with a pore diameter of 0.22 μm. It was established that the greater part of the bacteria in the soil and in the root zone of the plants has an ultramicroscopic size: the average diameter of the cells is 0.3 μm, and their length is 0.6 μm, which is significantly less than the cell size of banal bacteria. The number of FF varies within a wide range depending on the physicochemical conditions of the habitat. The FF number's dynamics in the soil is of a seasonal nature; i.e., the number of bacteria found increases in the summer and fall and decreases in the winter-spring period. In the rhizosphere of the alfalfa, over the vegetation period, the number of FF and their fraction in the total mass of the bacteria increase. A reverse tendency is observed in the rhizoplane. The morphological particularities (identified by an electron microscopy) and the nature of the FF indicate their physiological activity.

  18. Interactions of form and orientation

    NASA Technical Reports Server (NTRS)

    Mittelstaedt, Horst

    1989-01-01

    It is well known that the orientation of an optical pattern relative to egocentric or extraneous references affects its figural quality, that is, alters its perceived form and concomitantly delays or quickens its identification (Rock 1973). A square presented in the frontal plane to an upright person (S), for instance, changes from a box to a diamond when it is rotated with respect to the S's median plane by 45 deg. This angle, that is, the angle between the orientations of the pattern in which the two apparent figures (Gestalten) attain a summit of purity and distinctness, will be called the figural disparity of the pattern. If, as in this case, the S is upright, the retinal meridian and the subjective vertical (SV) are both in the viewer's median plane. The question arises with respect to which of these orientation references the two figures are identified. The answer may be found when the pattern and the S are oriented in such a way that the projections of the retinal meridian and the SV into the plane of the pattern diverge by the pattern's figural disparity or its periodic multiples: that is, in this case of a square by 45 or 135 deg, respectively. Similarly, which reference determines whether an equilateral triangle is seen as a pyramid or a traffic warning sign may be revealed at a divergence of SV and retinal meridian of 60 or 180 deg, respectively. It is generally found that for head roll tilts (Rho) and figural disparities of up to 90 deg, the figure whose axis coincides with the SV is seen. At head tilts of Rho=180 deg, however, the retinal reference dominates, as a rule independently of the figural disparity.

  19. Uniform-droplet spray forming

    SciTech Connect

    Blue, C.A.; Sikka, V.K.; Chun, Jung-Hoon; Ando, T.

    1997-04-01

    The uniform-droplet process is a new method of liquid-metal atomization that results in single droplets that can be used to produce mono-size powders or sprayed-on to substrates to produce near-net shapes with tailored microstructure. The mono-sized powder-production capability of the uniform-droplet process also has the potential of permitting engineered powder blends to produce components of controlled porosity. Metal and alloy powders are commercially produced by at least three different methods: gas atomization, water atomization, and rotating disk. All three methods produce powders of a broad range in size with a very small yield of fine powders with single-sized droplets that can be used to produce mono-size powders or sprayed-on substrates to produce near-net shapes with tailored microstructures. The economical analysis has shown the process to have the potential of reducing capital cost by 50% and operating cost by 37.5% when applied to powder making. For the spray-forming process, a 25% savings is expected in both the capital and operating costs. The project is jointly carried out at Massachusetts Institute of Technology (MIT), Tuffs University, and Oak Ridge National Laboratory (ORNL). Preliminary interactions with both finished parts and powder producers have shown a strong interest in the uniform-droplet process. Systematic studies are being conducted to optimize the process parameters, understand the solidification of droplets and spray deposits, and develop a uniform-droplet-system (UDS) apparatus appropriate for processing engineering alloys.

  20. 31 CFR 1.35 - Information forms.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Information forms. 1.35 Section 1.35... § 1.35 Information forms. (a) Review of forms. Except for forms developed and used by constituent... developed and used by the Department of the Treasury to collect information from and about individuals....

  1. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Acquisition Regulations System BROADCASTING BOARD OF GOVERNORS CLAUSES AND FORMS Reserved List of IAAR Forms 1953.370-21The Broadcasting Board of Governors Form IA-21, Abstract of Quotations. 1953.370-44The Broadcasting Board of Governors Form IA-44, Requisition-Purchase—Order-Invoice for Professional Services....

  2. Completing cremation forms: a practical guide.

    PubMed

    Proctor, Ian; Winstanley, Alison

    2013-07-01

    Before a body can be cremated doctors must complete a series of lengthy forms better known as 'crem forms'. One doctor first completes a medical certificate (Cremation Form 4, previously known as 'Part B') while a second must complete a confirmatory medical certificate (Cremation Form 5, previously 'Part C').

  3. 8 CFR 299.1 - Prescribed forms.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Prescribed forms. 299.1 Section 299.1 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS IMMIGRATION FORMS § 299.1 Prescribed forms. A listing of USCIS, ICE, and CBP approved forms referenced in chapter I can be viewed...

  4. 8 CFR 299.1 - Prescribed forms.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Prescribed forms. 299.1 Section 299.1 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS IMMIGRATION FORMS § 299.1 Prescribed forms. A listing of USCIS, ICE, and CBP approved forms referenced in chapter I can be viewed...

  5. 8 CFR 299.1 - Prescribed forms.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Prescribed forms. 299.1 Section 299.1 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS IMMIGRATION FORMS § 299.1 Prescribed forms. A listing of USCIS, ICE, and CBP approved forms referenced in chapter I can be viewed...

  6. Completing cremation forms: a practical guide.

    PubMed

    Proctor, Ian; Winstanley, Alison

    2013-07-01

    Before a body can be cremated doctors must complete a series of lengthy forms better known as 'crem forms'. One doctor first completes a medical certificate (Cremation Form 4, previously known as 'Part B') while a second must complete a confirmatory medical certificate (Cremation Form 5, previously 'Part C'). PMID:24145671

  7. Stability of polymorphic forms of ranitidine hydrochloride.

    PubMed

    Wu, V; Rades, T; Saville, D J

    2000-07-01

    Ranitidine-HCl can exist in two different polymorphic forms: form I (m.p. 134-140 degrees C) and form II (m.p. 140-144 degrees C). In the present study the stability of form I of ranitidine-HCl to a selection of powder pretreatments, to reflect conditions which might occur in manufacturing procedures, and also to a limited range of storage conditions was investigated. The original samples of form I and form II used were characterised by X-ray powder diffraction (XRPD), hot stage microscopy (HSM) and differential scanning calorimetry (DSC). A quantitative XRPD method for determining the fraction of form II in the presence of form I was used. XRPD data were analysed using regression techniques and artificial neural networks (ANN). The quantitative XRPD technique was then used to monitor the relative proportion of form II in each treated sample. Pretreatments of form I included (i) mixing with form II or with common excipients (ii) compression and grinding (iii) contact with solvents (followed by drying) before storage. Storage conditions involved three temperatures (20 degrees C, 30 degrees C, 42 degrees C) and three relative humidities (45% RH; 55% RH; 75% RH). Samples were stored for a period of 6 months. A limited factorial design was used. No increase in the form II:form I ratio was observed in the following pretreatment processes: introduction of form II nuclei into form I; introduction of excipients to form I; compression of form I powder at 5 and 15 tons; normal mixing and grinding processes; addition of isopropanol (IPA) or water/IPA mix followed by drying. In the pretreatment process where water was added to form I powder (with most or all of the powder dissolving), drying of the liquefied mass led to a mix of form I and form II. On storage at room temperature (20-30 degrees C), low relative humidity (45-55% RH), and in an air-tight container there was no increase in the form II:form I ratio. Storage of form I/form II mixes, particularly at high humidity

  8. Pre-form ceramic matrix composite cavity and method of forming and method of forming a ceramic matrix composite component

    DOEpatents

    Monaghan, Philip Harold; Delvaux, John McConnell; Taxacher, Glenn Curtis

    2015-06-09

    A pre-form CMC cavity and method of forming pre-form CMC cavity for a ceramic matrix component includes providing a mandrel, applying a base ply to the mandrel, laying-up at least one CMC ply on the base ply, removing the mandrel, and densifying the base ply and the at least one CMC ply. The remaining densified base ply and at least one CMC ply form a ceramic matrix component having a desired geometry and a cavity formed therein. Also provided is a method of forming a CMC component.

  9. Transitional Forms of Corynebacterium acnes in Disease

    PubMed Central

    Zierdt, C. H.; Wertlake, P. T.

    1969-01-01

    A clear-cut triad of sequential Corynebacterium acnes transitional forms from disease has been discovered. This entity includes three major forms which are capable of stabilization in culture, the spherical, the intermediate, and the definitive C. acnes. During conversion or reversion among the three forms, a variety of forms with mixed characteristics was observed. The spherical form was gram-negative and osmotically fragile, but it possessed a vestigial cell wall and mesosomes which excluded it from the L forms. In lieu of the L-form designation, the term “transitional” was adopted for all forms leading up to the definitive C. acnes. Culture of the spherical form was successful only on Mycoplasma-type media. The intermediate form was gram-negative, had mixed spherical and filamentous morphology, and bore a striking resemblance to Streptobacillus moniliformis. Like the spherical form, it was nutritionally exacting. The definitive form of C. acnes was preceded by gram-positive transitional forms of C. acnes morphology. It lacked, however, the carbohydrases and proteinases of C. acnes and susceptibility to C. acnes bacteriophages. Reversion was often blocked at this stage. A series of blood cultures from a patient with endocarditis was studied. Postmortem stain sections of the heart-valve lesion included intracellular masses of gram-negative spherical organisms. Indirect fluorescent antibody staining of these masses was strongly positive with antiserum to the spherical form and weakly positive with antiserum to the intermediate form. Images PMID:4886295

  10. Four new polymorphic forms of suplatast tosilate.

    PubMed

    Nagai, Keiko; Ushio, Takanori; Miura, Hidenori; Nakamura, Takashi; Moribe, Kunikazu; Yamamoto, Keiji

    2014-01-01

    We found four new polymorphic forms (γ-, ε-, ζ-, and η-forms) of suplatast tosilate (ST) by recrystallization and seeding with ST-analogous compounds; three polymorphic forms (α-, β-, and δ-forms) of ST have been previously reported. The physicochemical properties of these new forms were investigated using infrared (IR) spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry. The presence of hydrogen bonds in the new forms was assessed from the IR and solid-state NMR spectra. The crystal structures of the ε- and η-forms were determined from their powder X-ray diffraction data using the direct space approach and the Monte Carlo method, followed by Rietveld refinement. The structures determined for the ε- and η-forms supported the presence of hydrogen bonds between the ST molecules, as the IR and solid-state NMR spectra indicated. The thermodynamic characteristics of the seven polymorphic forms were evaluated by determining the solubility of each form. The α-form was the most insoluble in 2-propanol at 35°C, and was thus concluded to be the most stable form. The ε-form was the most soluble, and a polymorphic transition from the ε- to the α-form was observed during solubility testing. PMID:24211359

  11. Crystallization behavior of nuclear waste forms

    SciTech Connect

    Rusin, J.M.; Lokken, R.O.; May, R.P.; Wald, J.W.

    1981-09-01

    Several waste form options have been or are being developed for the immobilization of high-level wastes. The final selection of a waste form must take into consideration both waste form product as well as process factors. Crystallization behavior has an important role in nuclear waste form technology. For glass or vitreous waste forms, crystallization is generally controlled to a minimum by appropriate glass formulation and heat treatment schedules. With glass ceramic waste forms, crystallization is essential to convert glass products to highly crystalline waste forms with a minimum residual glass content. In the case of ceramic waste forms, additives and controlled sintering schedules are used to contain the radionuclides in specific tailored crystalline phases.

  12. Developments in GDR metal forming technology assessed

    NASA Astrophysics Data System (ADS)

    Sickel, B.

    1985-02-01

    Technological developments in the German Democratic Republic in the area of metal forming are described. Work done by the Erfurt VEB Herbert Warnke Forming Technology Combine in machine tool production is highlighted.

  13. 7 CFR 51.3747 - Well formed.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades of Honey Dew and Honey Ball Type Melons Definitions § 51.3747 Well formed. Well formed means that the melon has the normal shape characteristic of...

  14. 7 CFR 51.3747 - Well formed.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades of Honey Dew and Honey Ball Type Melons Definitions § 51.3747 Well formed. Well formed means that the melon has the normal shape characteristic of...

  15. 48 CFR 53.107 - Obtaining forms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... optional forms from the General Services Administration (GSA) by using GSA Supply Catalog - Office Products (see 41 CFR 101-26.302). Standard forms adapted for computer preparation (see 53.105) or with...

  16. 48 CFR 53.107 - Obtaining forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... optional forms from the General Services Administration (GSA) by using GSA Supply Catalog - Office Products (see 41 CFR 101-26.302). Standard forms adapted for computer preparation (see 53.105) or with...

  17. 48 CFR 53.107 - Obtaining forms.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... optional forms from the General Services Administration (GSA) by using GSA Supply Catalog - Office Products (see 41 CFR 101-26.302). Standard forms adapted for computer preparation (see 53.105) or with...

  18. 25 CFR 61.6 - Application forms.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... whether application form is for a natural child or an adopted child of the parent through whom eligibility... relationship to applicant. (3) A control number for the purpose of keeping a record of forms...

  19. 7 CFR 51.2653 - Well formed.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Standards for Grades for Sweet Cherries 1 Definitions § 51.2653 Well formed. Well formed means that the cherry has the normal shape characteristic of the variety, except that mature well developed...

  20. 7 CFR 51.2653 - Well formed.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades for Sweet Cherries 1 Definitions § 51.2653 Well formed. Well formed means that the cherry has the normal shape characteristic of the variety, except...