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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. PMID:11712913

  2. Cytochrome c adducts with PCB quinoid metabolites.

    PubMed

    Li, Miao; Teesch, Lynn M; Murry, Daryl J; Pope, R Marshal; Li, Yalan; Robertson, Larry W; Ludewig, Gabriele

    2016-02-01

    Polychlorinated biphenyls (PCBs) are a group of 209 individual congeners widely used as industrial chemicals. PCBs are found as by-products in dye and paint manufacture and are legacy, ubiquitous, and persistent as human and environmental contaminants. PCBs with fewer chlorine atoms may be metabolized to hydroxy- and dihydroxy-metabolites and further oxidized to quinoid metabolites both in vitro and in vivo. Specifically, quinoid metabolites may form adducts on nucleophilic sites within cells. We hypothesized that the PCB-quinones covalently bind to cytochrome c and, thereby, cause defects in the function of cytochrome c. In this study, synthetic PCB quinones, 2-(4'-chlorophenyl)-1,4-benzoquinone (PCB3-pQ), 4-4'-chlorophenyl)-1,2-benzoquinone (PCB3-oQ), 2-(3', 5'-dichlorophenyl)-1,4-benzoquinone, 2-(3',4', 5'-trichlorophenyl)-1,4-benzoquinone, and 2-(4'-chlorophenyl)-3,6-dichloro-1,4-benzoquinone, were incubated with cytochrome c, and adducts were detected by liquid chromatography-mass spectrometry (LC-MS) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was employed to separate the adducted proteins, while trypsin digestion and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were applied to identify the amino acid binding sites on cytochrome c. Conformation change of cytochrome c after binding with PCB3-pQ was investigated by SYBYL-X simulation and cytochrome c function was examined. We found that more than one molecule of PCB-quinone may bind to one molecule of cytochrome c. Lysine and glutamic acid were identified as the predominant binding sites. Software simulation showed conformation changes of adducted cytochrome c. Additionally, cross-linking of cytochrome c was observed on the SDS-PAGE gel. Cytochrome c was found to lose its function as electron acceptor after incubation with PCB quinones. These data provide evidence that the covalent

  3. Rhodium-Catalyzed Stitching Reaction: Convergent Synthesis of Quinoidal Fused Oligosiloles.

    PubMed

    Shintani, Ryo; Iino, Ryo; Nozaki, Kyoko

    2016-03-23

    Quinoidal fused oligosiloles, a new family of silicon-bridged π-conjugated compounds, have been synthesized for the first time based on a new synthetic strategy, a stitching reaction. Multiple carbon-carbon bonds can be formed consecutively between two oligo(silylene-ethynylene)s under rhodium catalysis in a stitching manner, and up to five siloles have been fused in a quinoidal form. Physical properties of these oligosiloles have also been investigated to find a unique trend in their LUMO levels, which become higher with longer π-conjugation. PMID:26961329

  4. 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.

  5. 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

  6. Detection of Electrophilic and Nucleophilic Chemical Agents

    SciTech Connect

    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. A quinoidal bis-phenalenyl-fused porphyrin with supramolecular organization and broad near-infrared absorption.

    PubMed

    Diev, Vyacheslav V; Femia, Denise; Zhong, Qiwen; Djurovich, Peter I; Haiges, Ralf; Thompson, Mark E

    2016-01-31

    A bis-phenalenyl-fused porphyrin has been synthesized by thermal dehydro-aromatization reaction regioselectively as a single syn-isomer. X-ray crystal structure revealed that both phenalenyl units of this porphyrin have close π-π contacts forming continuous network of interacting porphyrin rings. A broad and intense NIR absorption can be attributed to quinoidal character of bis-phenalenyl-fused porphyrin. PMID:26686757

  8. Stereoselective Electrophilic Cyclization.

    PubMed

    Sakakura, Akira; Ishihara, Kazuaki

    2015-08-01

    Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite-urea cooperative catalysts have been designed. PMID:26147781

  9. Detection of electrophilic and nucleophilic chemical agents

    DOEpatents

    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.

  10. Electronic structures of new π-conjugated cyclic polymers with quinoid structures

    NASA Astrophysics Data System (ADS)

    Hong, Sung Y.; Kwon, Si J.; Kim, Shi C.

    1995-08-01

    Geometrical and electronic structures of new π-conjugated five-membered ring polymers were theoretically investigated. These polymers are analogous to heterocyclic polymers, but adopt as bridging groups ≳CH2, ≳CF2, ≳SiH2, ≳SiF2, ≳C=CH2, ≳C=O and ≳C=S moieties instead of heteroatoms. The ground-state geometries of the polymers were predicted to be quinoid from semiempirical band calculations with AM1 Hamiltonian. The electronic properties of these systems were obtained using the modified extended Hückel method. The calculated band gaps (Eg) were analyzed in terms of geometrical relaxations and electronic effect of the bridging groups using the equation of Eg=ΔEδr+ΔE1-4+ΔEel. The effect of bond-length alternation (ΔEδr) amounts to 1.1-1.4 eV for the aromatic forms and 1.8-1.9 eV for the quinoid forms of the polymers. The interactions (ΔE1-4) between C1 and C4 atoms of the cis-PA type backbone tend to decrease the band gaps of the aromatic forms and to increase the gaps of the quinoid forms as much as 0.2-0.5 eV, depending on the size of a bridging atom. It is found that the electronic effect (ΔEel) of these bridging groups is quite small compared to that found in heterocyclic polymers such as polythiophene, polypyrrole, and polyfuran. ΔEel of ≳CF2, ≳SiH2, and ≳SiF2 bridging groups are negligible and that of the other groups amounts to 0.3-1.0 eV. Therefore, the band gaps of these systems almost correspond to the ΔEδr values which arise from the bond-length alternations, except the case of the polymers with ≳C=O and ≳C=S bridging groups whose π* orbitals strongly interact with the π system of the polymeric backbone.

  11. Effects of different quinoid redox mediators on the removal of sulphide and nitrate via denitrification.

    PubMed

    Aranda-Tamaura, Clicerio; Estrada-Alvarado, María Isabel; Texier, Anne-Claire; Cuervo, Flor; Gómez, Jorge; Cervantes, Francisco J

    2007-11-01

    The impact of different quinoid redox mediators on the simultaneous conversion of sulphide and nitrate in a denitrifying culture was evaluated. All quinones evaluated, including anthraquinone-2,6-disulphonate (AQDS), 2-hydroxy-1,4-naphthoquinone and 1,2-naphthoquinone-4-sulphonate (NQS) were reduced by sulphide under abiotic conditions. NQS showed the highest reduction rate by sulphide (132 micromol h(-1)) and promoted the maximum rate of sulphide oxidation (87 micromol h(-1)) by denitrifying sludge, which represents an increase of 44% compared to the control lacking quinones. The reduced form of AQDS (AH(2)QDS) served as an electron donor for the microbial reduction of nitrite and N(2)O, which represents the first demonstration of hydroquinones supporting the microbial reduction of denitrifying intermediates. The results taken as a whole suggest that some quinones may significantly increase the rate of removal of S and N under denitrifying conditions. PMID:17624404

  12. Developing Quinoidal Fluorophores with Unusually Strong Red/Near-Infrared Emission.

    PubMed

    Ren, Longbin; Liu, Feng; Shen, Xingxing; Zhang, Cheng; Yi, Yuanping; Zhu, Xiaozhang

    2015-09-01

    Despite the dominant position of aromatic fluorophores, we report herein the design and synthesis of quinoidal fluorophores based on rarely emissive quinoidal bithiophene. Quinoidal bitheno[3,4-b]thiophene, QBTT-C6, consisting of cruciform-fused (E)-1,2-bis(5-hexylthiophen-2-yl)ethene and quinoidal bithiophene, shows a fluorescence quantum yield of 8.5%, 25-fold higher than that of the parent quinoidal QBT chromophore, but its maximum emission is at similar wavelengths. QBTT-Ar's featuring intramolecular charge transfer can further shift the maximum emission into the near-infrared region. The intramolecular charge transfer is programmably enhanced by tuning the substituents on the aryl groups from the electron-withdrawing trifluoromethyl to the electron-donating methoxy groups. Unexpectedly, a positive relationship between intramolecular charge transfer and fluorescence quantum yield is observed; as a result, QBTT-FL gives an unprecedentedly high fluorescence quantum yield of up to 53.1% for quinoidal oligothiophenes. With detailed photophysical and theoretical investigations, we demonstrate that the nonradiative intersystem crossing (S1 → T2) is significantly restrained in QBTT-Ar's, which can be attributed to the faster reverse intersystem crossing (T2 → S1) characteristic of a small activation energy. This work reveals the possibility for developing red/near-infrared fluorophores from the less explored quinoidal molecules because of their intrinsically narrow bandgaps. PMID:26293207

  13. Electrophilicity and nucleophilicity index for radicals.

    PubMed

    De Vleeschouwer, Freija; Van Speybroeck, Veronique; Waroquier, Michel; Geerlings, Paul; De Proft, Frank

    2007-07-01

    Radicals can be regarded as electrophilic/nucleophilic, depending on their tendency to attack sites of relatively higher/lower electron density. In this paper, an electrophilicity scale, global as well as local, and a nucleophilicity scale for 35 radicals is reported. The global electrophilicity scale correlates well with the nucleophilicity scale, suggesting that these concepts are inversely related. PMID:17559221

  14. 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. PMID:26559119

  15. Carbo-quinoids: stability and reversible redox-proaromatic character towards carbo-benzenes.

    PubMed

    Cocq, Kévin; Maraval, Valérie; Saffon-Merceron, Nathalie; Saquet, Alix; Poidevin, Corentin; Lepetit, Christine; Chauvin, Remi

    2015-02-23

    The carbo-mer of the para-quinodimethane core is stable within in a bis(9-fluorenylidene) derivative. Oxidation of this carbo-quinoid with MnO2 in the presence of SnCl2 and ethanol affords the corresponding p-bis(9-ethoxy-fluoren-9-yl)-carbo-benzene. The latter can be in turn converted back into the carbo-quinoid by reduction with SnCl2 , thus evidencing a chemical reversibility of the interconversion between a pro-aromatic carbo-quinoid and an aromatic carbo-benzene, and is reminiscent of the behavior of the benzoquinone/hydroquinone redox couple (in the red-ox opposite sense). PMID:25612252

  16. High Yield Ultrafast Intramolecular Singlet Exciton Fission in a Quinoidal Bithiophene.

    PubMed

    Varnavski, Oleg; Abeyasinghe, Neranga; Aragó, Juan; Serrano-Pérez, Juan J; Ortí, Enrique; López Navarrete, Juan T; Takimiya, Kazuo; Casanova, David; Casado, Juan; Goodson, Theodore

    2015-04-16

    We report the process of singlet exciton fission with high-yield upon photoexcitation of a quinoidal thiophene molecule. Efficient ultrafast triplet photogeneration and its yield are determined by photoinduced triplet-triplet absorption, flash photolysis triplet lifetime measurements, as well as by femtosecond time-resolved transient absorption and fluorescence methods. These experiments show that optically excited quinoidal bithiophene molecule undergoes ultrafast formation of the triplet-like state with the lifetime ∼57 μs. CASPT2 and RAS-SF calculations have been performed to support the experimental findings. To date, high singlet fission rates have been reported for crystalline and polycrystalline materials, whereas for covalently linked dimers and small oligomers it was found to be relatively small. In this contribution, we show an unprecedented quantum yield of intramolecular singlet exciton fission of ∼180% for a quinoidal bithiophene system. PMID:26263138

  17. Biotinylated probes for the analysis of protein modification by electrophiles.

    PubMed

    Codreanu, Simona G; Kim, Hye-Young H; Porter, Ned A; Liebler, Daniel C

    2012-01-01

    Formation of covalent protein adducts by lipid electrophiles contributes to diseases and toxicities linked to oxidative stress, but analysis of the adducts presents a challenging analytical problem. We describe selective adduct capture using biotin affinity probes to enrich protein and peptide adducts for analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). One approach employs biotinamidohexanoic acid hydrazide to covalently label residual carbonyl groups on adducts. The other employs alkynyl analogs of lipid electrophiles, which form adducts that can be postlabeled with azidobiotin tags by Cu(+)-catalyzed cycloaddition (Click chemistry). To enhance the selectivity of adduct capture, we use an azidobiotin reagent with a photocleavable linker, which allows recovery of adducted proteins and peptides under mild conditions. This approach allows both the identification of protein targets of lipid electrophiles and sequence mapping of the adducts. PMID:22065220

  18. 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

  19. 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

  20. 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

  1. Decolorization and biogas production by an anaerobic consortium: effect of different azo dyes and quinoid redox mediators.

    PubMed

    Alvarez, L H; Valdez-Espinoza, R; García-Reyes, R B; Olivo-Alanis, D; Garza-González, M T; Meza-Escalante, E R; Gortáres-Moroyoqui, P

    2015-01-01

    The inhibitory effect of azo dyes and quinoid compounds on an anaerobic consortium was evaluated during a decolorization process and biogas production. In addition, the impact of quinoid compounds such as lawsone (LAW) and anthraquinone-2,6-disulfonate (AQDS) on the rate of decolorization of Direct Blue 71 (DB71) was assessed. The anaerobic consortium was not completely inhibited under all tested dye concentrations (0.1-2 mmol l(-1)), evidenced by an active decolorization process and biogas production. The presence of quinoid compounds at different concentrations (4, 8, and 12 mmol l(-1)) also inhibited biogas production compared to the control incubated without the quinoid compounds. In summary, the anaerobic consortium was affected to a greater extent by increasing the quantity of azo dyes or quinoid compounds. Nevertheless, at a lower concentration (1 mmol l(-1)) of quinoid compounds, the anaerobic consortium effectively decolorized 2 mmol l(-1) of DB71, increasing up to 5.2- and 20.4-fold the rate of decolorization with AQDS and LAW, respectively, compared to the control lacking quinoid compounds. PMID:26287839

  2. 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.

  3. Making the Least Reactive Electrophile the First in Class: Domino Electrophilic Activation of Amides.

    PubMed

    Kaiser, Daniel; Maulide, Nuno

    2016-06-01

    The electrophilic activation of amides, especially by the action of trifluoromethanesulfonic (triflic) anhydride, enables the formation of highly electrophilic and reactive intermediates, lending themselves to diverse reaction pathways. This synopsis sets out to highlight recent advances in the field of amide activation, focused on the use of triflic anhydride, and the myriad of transformations that can ensue upon addition of several classes of electrophiles to the intermittently generated high energy intermediates. PMID:27187724

  4. 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

  5. Theoretical model for electrophilic oxygen atom insertion into hydrocarbons

    SciTech Connect

    Bach, R.D.; Su, M.D. ); Andres, J.L. Wayne State Univ., Detroit, MI ); McDouall, J.J.W. )

    1993-06-30

    A theoretical model suggesting the mechanistic pathway for the oxidation of saturated-alkanes to their corresponding alcohols and ketones is described. Water oxide (H[sub 2]O-O) is employed as a model singlet oxygen atom donor. Molecular orbital calculations with the 6-31G basis set at the MP2, QCISD, QCISD(T), CASSCF, and MRCI levels of theory suggest that oxygen insertion by water oxide occurs by the interaction of an electrophilic oxygen atom with a doubly occupied hydrocarbon fragment orbital. The electrophilic oxygen approaches the hydrocarbon along the axis of the atomic carbon p orbital comprising a [pi]-[sub CH(2)] or [pi]-[sub CHCH(3)] fragment orbital to form a carbon-oxygen [sigma] bond. A concerted hydrogen migration to an adjacent oxygen lone pair of electrons affords the alcohol insertion product in a stereoselective fashion with predictable stereochemistry. Subsequent oxidation of the alcohol to a ketone (or aldehyde) occurs in a similar fashion and has a lower activation barrier. The calculated (MP4/6-31G*//MP2/6-31G*) activation barriers for oxygen atom insertion into the C-H bonds of methane, ethane, propane, butane, isobutane, and methanol are 10.7, 8.2, 3.9, 4.8, 4.5, and 3.3 kcal/mol, respectively. We use ab initio molecular orbital calculations in support of a frontier MO theory that provides a unique rationale for both the stereospecificity and the stereoselectivity of insertion of electrophilic oxygen and related electrophiles into the carbon-hydrogen bond. 13 refs., 7 figs., 2 tabs.

  6. 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

  7. QSAR APPROACH FOR ESTIMATING THE AQUATIC TOXICITY OF SOFT ELECTROPHILES [QSAR FOR SOFT ELECTROPHILES

    EPA Science Inventory

    This work demonstrated that descriptors of soft electrophilicity for aromatic chemicals such as average superdelocalizability and LUMO energy could be used together with the hydrophobicity descriptor, log P, to explain the variation of acute toxicity of substituted benzenes, phen...

  8. Electrophilic amination: the case of nitrenoids.

    PubMed

    Starkov, Pavel; Jamison, Timothy F; Marek, Ilan

    2015-03-27

    Among the numerous approaches and reagents employed for electrophilic amination, nitrenoids have long stayed out of the limelight. Here, we systematically review the discovery, structural features and chemical reactivity of these promising reagents. We highlight advances in applying the chemistry of nitrenoids as well as outline current limitations and future directions. PMID:25641706

  9. Fully Fused Quinoidal/Aromatic Carbazole Macrocycles with Poly-radical Characters.

    PubMed

    Das, Soumyajit; Herng, Tun Seng; Zafra, José L; Burrezo, Paula Mayorga; Kitano, Masaaki; Ishida, Masatoshi; Gopalakrishna, Tullimilli Y; Hu, Pan; Osuka, Atsuhiro; Casado, Juan; Ding, Jun; Casanova, David; Wu, Jishan

    2016-06-22

    While the chemistry of open-shell singlet diradicaloids has been successfully developed in recent years, the synthesis of π-conjugated systems with poly-radical characters (i.e., beyond diradical) in the singlet ground state has been mostly unsuccessful. In this study, we report the synthesis and isolation of two fully fused macrocycles containing four (4MC) and six (6MC) alternatingly arranged quinoidal/aromatic carbazole units. Ab initio electronic structure calculations and various experimental measurements indicate that both 4MC and 6MC have an open-shell singlet ground state with moderate tetraradical and hexaradical characters, respectively. Both compounds can be thermally populated to high-spin excited states, resulting in weak magnetization at room temperature. Our study represents the first demonstration of singlet π-conjugated molecules with poly-radical characters and also gives some insights into molecular magnetism in neutral π-conjugated polycyclic heteroarenes. PMID:27248181

  10. 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

  11. 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

  12. Electrophiles and acute toxicity to fish.

    PubMed Central

    Hermens, J L

    1990-01-01

    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. PMID:2269228

  13. 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

  14. 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

  15. 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

  16. Singlet (Phosphino)phosphinidenes are Electrophilic.

    PubMed

    Hansmann, Max M; Jazzar, Rodolphe; Bertrand, Guy

    2016-07-13

    A room-temperature stable (phosphino)-phosphinidene reacts with carbon monoxide, stable singlet carbenes, including the poor π-accepting imidazol-2-ylidene, and phosphines giving rise to the corresponding phosphaketene, phosphinidene-carbene and phosphinidene-phosphine adducts, respectively. Whereas the electronic ground-state calculations indicate a PP multiple bond character in which the terminal phosphorus is negatively charged, the observed reactivity clearly indicates that (phosphino)phosphinidenes are electrophilic as expected for an electron-deficient species. This is further demonstrated by competition experiments as well as by the results of Fukui function calculations. PMID:27340902

  17. Outer-Sphere Electrophilic Fluorination of Organometallic Complexes.

    PubMed

    Milner, Lucy M; Pridmore, Natalie E; Whitwood, Adrian C; Lynam, Jason M; Slattery, John M

    2015-08-26

    Organofluorine chemistry plays a key role in materials science, pharmaceuticals, agrochemicals, and medical imaging. However, the formation of new carbon-fluorine bonds with controlled regiochemistry and functional group tolerance is synthetically challenging. The use of metal complexes to promote fluorination reactions is of great current interest, but even state-of-the-art approaches are limited in their substrate scope, often require activated substrates, or do not allow access to desirable functionality, such as alkenyl C(sp(2))-F or chiral C(sp(3))-F centers. Here, we report the formation of new alkenyl and alkyl C-F bonds in the coordination sphere of ruthenium via an unprecedented outer-sphere electrophilic fluorination mechanism. The organometallic species involved are derived from nonactivated substrates (pyridine and terminal alkynes), and C-F bond formation occurs with full regio- and diastereoselectivity. The fluorinated ligands that are formed are retained at the metal, which allows subsequent metal-mediated reactivity. PMID:26270894

  18. 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.

  19. Electrophilicity and nucleophilicity of commonly used aldehydes.

    PubMed

    Pratihar, Sanjay

    2014-08-14

    The present approach for determining the electrophilicity (E) and nucleophilicity (N) of aldehydes includes a kinetic study of KMNO4 oxidation and NaBH4 reduction of aldehydes. A transition state analysis of the KMNO4 promoted aldehyde oxidation reaction has been performed, which shows a very good correlation with experimental results. The validity of the experimental method has been tested using the experimental activation parameters of the two reactions. The utility of the present approach is further demonstrated by the theoretical versus experimental relationship, which provides easy access to E and N values for various aldehydes and offers an at-a-glance assessment of the chemical reactivity of aldehydes in various reactions. PMID:24979574

  20. Pyridoxal 5'-Phosphate: Electrophilic Catalyst Extraordinaire

    PubMed Central

    Richard, John P.; Amyes, Tina L.; Crugeiras, Juan; Rios, Ana

    2009-01-01

    Studies of nonenzymatic electrophilic catalysis of carbon deprotonation of glycine show that pyridoxal 5'-phosphate (PLP) strongly enhances the carbon acidity of α-amino acids, but that this is not the overriding mechanistic imperative for cofactor catalysis. Although the fully protonated PLP-glycine iminium ion adduct exhibits an extraordinary low α-imino carbon acidity (pKa = 6), the more weakly acidic zwitterionic iminium ion adduct (pKa = 17) is selected for use in enzymatic reactions. The similar α-imino carbon acidities of the iminium ion adducts of glycine with 5'-deoxypyridoxal and with phenylglyoxylate shows that the cofactor pyridine nitrogen plays a relatively minor role in carbanion stabilization. The 5'-phosphodianion group of PLP likely plays an important role in catalysis by providing up to 12 kcal/mol of binding energy that may be utilized for transition state stabilization. PMID:19640775

  1. Multifaceted Regioregular Oligo(thieno[3,4-b]thiophene)s Enabled by Tunable Quinoidization and Reduced Energy Band Gap.

    PubMed

    Liu, Feng; Espejo, Guzmán L; Qiu, Shuhai; Oliva, María Moreno; Pina, João; Seixas de Melo, J Sérgio; Casado, Juan; Zhu, Xiaozhang

    2015-08-19

    Thiophene-based materials have occupied a crucial position in the development of organic electronics. However, the energy band gaps of oligo- and polythiophenes are difficult to modulate without resorting to push-pull electronic effects. We describe herein a new series of monodisperse oligo(thieno[3,4-b]thiophene) derivatives with well-defined regioregular structures synthesized efficiently by direct C-H arylation. These compounds show a unique palette of colors and amphoteric redox properties with widely tunable energy band gaps. The capacity to stabilize both cations and anions results in both anodic and cathodic electrochromism. Under excitation, these compounds can produce photoionized states able to interconvert into neutral triplet or form these through singlet exciton fission or intersystem crossing. These features arise from a progressive increase in quinoidization on a fully planar platform making the largest effective conjugation length among hetero-oligomers. Oligo(thieno[3,4-b]thiophene)s might represent the more distinctive family of oligothiophenes of this decade. PMID:26186503

  2. Computational design of small organic dyes with strong visible absorption by controlled quinoidization of the thiophene unit

    NASA Astrophysics Data System (ADS)

    Tan, Yi Yin; Tu, Wei Han; Manzhos, Sergei

    2014-02-01

    We present rational design of phenothiazine dyes by controlled quinoidization of the thiophene unit. We systematically study the effect of electron-withdrawing functional groups including pseudo- and super-halogens. We propose a new dye where a fumaronitrile unit induces an increase in the bond length alternation and a concurrent red shift in the absorption spectrum vs. the parent dye. The visible absorption peak is predicted at 520 nm, in CH2Cl2 vs. 450 nm for the parent dye. The LUMO and HOMO levels of the new dye are suitable for injection into TiO2 and regeneration by available redox shuttles, respectively.

  3. 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

  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. PMID:27580894

  5. 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

  6. 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)

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

    PubMed

    Brandt, Jochen R; Lee, Eunsung; Boursalian, Gregory B; Ritter, Tobias

    2014-01-01

    Electrophilic fluorinating reagents derived from fluoride are desirable for the synthesis of (18)F-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 (18)F 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 (18)F PET imaging. PMID:24376910

  8. 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

  9. A Furan-Thiophene-Based Quinoidal Compound: A New Class of Solution-Processable High-Performance n-Type Organic Semiconductor.

    PubMed

    Xiong, Yu; Tao, Jingwei; Wang, Ruihao; Qiao, Xiaolan; Yang, Xiaodi; Wang, Deliang; Wu, Hongzhuo; Li, Hongxiang

    2016-07-01

    The furan-thiophene-based quinoidal organic semiconductor, TFT-CN, is designed and synthesized. TFT-CN displays a high electron mobility of 7.7 cm(2) V(-1) s(-1) , two orders of magnitude higher than the corresponding thiophene-based derivative. PMID:27167524

  10. A Caged Electrophilic Probe for Global Analysis of Cysteine Reactivity in Living Cells.

    PubMed

    Abo, Masahiro; Weerapana, Eranthie

    2015-06-10

    Cysteine residues are subject to diverse modifications, such as oxidation, nitrosation, and lipidation. The resulting loss in cysteine reactivity can be measured using electrophilic chemical probes, which importantly provide the stoichiometry of modification. An iodoacetamide (IA)-based chemical probe has been used to concurrently quantify reactivity changes in hundreds of cysteines within cell lysates. However, the cytotoxicity of the IA group precludes efficient live-cell labeling, which is important for preserving transient cysteine modifications. To overcome this limitation, a caged bromomethyl ketone (BK) electrophile was developed, which shows minimal cytotoxicity and provides spatial and temporal control of electrophile activation through irradiation. The caged-BK probe was utilized to monitor cysteine reactivity changes in A431 cells upon epidermal growth factor (EGF)-stimulated release of cellular reactive oxygen species. Decreased reactivity was observed for cysteines known to form sulfenic acids and redox-active disulfides. Importantly, the caged-BK platform provided the first quantification of intracellular disulfide bond formation upon EGF stimulation. In summary, the caged-BK probe is a powerful tool to identify reactivity changes associated with diverse cysteine modifications, including oxidation, metal chelation, and inhibitor binding, within a physiologically relevant context. PMID:26020833

  11. Reprint of: Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs.

    PubMed

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

    2014-01-01

    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 antioxidant "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 Cu(2+)/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), which

  12. Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs.

    PubMed

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

    2013-12-01

    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 antioxidant "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 Cu(2+)/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), which

  13. Combined chemoassay and mass spectrometric approach to study the reactive potential of electrophiles towards deoxynucleosides as model for DNA.

    PubMed

    Schmied-Tobies, Maria I H; Paschke, Heidrun; Reemtsma, Thorsten

    2016-05-01

    The modification of DNA by adduct formation is a potential molecular initiating event of genotoxicity. A chemoassay was established to study adduct formation of electrophiles with deoxynucleosides. Liquid chromatography-mass spectrometry was used to determine the reactivity of the model electrophiles para-benzoquinone, hydroquinone, and 1,4-naphthoquinone with deoxynucleoside (deoxyadenosine (dA), deoxyguanosine (dG), deoxycytidine (dC) and thymidine (dT)) to detect formation of adducts via constant neutral loss scan of deoxyribose (116 Da), and to elucidate adduct structures using high resolution mass spectrometry. Of the four deoxynucleosides dG was most susceptible, followed by dC and para-benzoquinone was the most reactive electrophile. With this approach five dG and four dC adducts were detected, formed by Michael addition and subsequent condensation. Also oxidation occurred with reactive oxygen species (ROS). Three of the adducts formed by benzoquinone have not been reported before. This chemoassay combined with mass spectrometry offers a way (a) to screen a large number of chemicals for their genotoxic potential, (b) to determine novel adducts that may be searched for in in vitro and in vivo studies and thus (c) to better understand the reaction of electrophiles with nucleobases. PMID:26945242

  14. Highly reactive electrophilic oxidants in cytochrome P450 catalysis

    SciTech Connect

    Newcomb, Martin . E-mail: men@uic.edu; Chandrasena, R. Esala P.

    2005-12-09

    The cytochrome P450 enzymes effect a wide range of oxidations in nature including difficult hydroxylation reactions of unactivated C-H. Most of the high energy reactions of these catalysts appear to involve highly electrophilic active species. Attempts to detect the reactive transients in the enzymes have met with limited success, but evidence has accumulated that two distinct electrophilic oxidants are produced in the P450 enzymes. The consensus electrophilic oxidant termed 'iron-oxo' is usually thought to be an analogue of Compound I, an iron(IV)-oxo porphyrin radical cation species, but it is possible that a higher energy electronic isomer of Compound I is required to account for the facility of the C-H oxidation reactions. The second electrophilic oxidant of P450 is speculative; circumstantial evidence suggests that this species is iron-complexed hydrogen peroxide, but this oxidant might be a second spin state of iron-oxo. This overview discusses recent studies directed at detection of the electrophilic oxidants in P450 enzymes and the accumulated evidence for two distinct species.

  15. 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.

  16. Electrophilic metal alkyl chemistry in new ligand environments. Annual report, January 1, 1992--September 15, 1992

    SciTech Connect

    Jordan, R.F.

    1992-12-31

    Methods have been worked out for efficient synthesis of various N{sub 4}{sup 2{minus}} macrocyclic ligands, neutral group 4 metal (e.g., Zr) (N{sub 4})MR{sub 2} complexes, and cationic mono-alkyl (N{sub 4})M(R){sup +} species. Intital indications are that the latter will be highly reactive in base-free form. Objective is to develop new types of electrophilic metal alkyl complexes for study of olefin polymerization and C-H activation catalysis.

  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. 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

  19. Transduction of Redox Signaling by Electrophile-Protein Reactions

    PubMed Central

    Rudolph, Tanja K.; Freeman, Bruce A.

    2014-01-01

    Over the last 50 years, the posttranslational modification (PTM) of proteins has emerged as a central mechanism for cells to regulate metabolism, growth, differentiation, cell-cell interactions, and immune responses. By influencing protein structure and function, PTM leads to a multiplication of proteome diversity. Redox-dependent PTMs, mediated by environmental and endogenously generated reactive species, induce cell signaling responses and can have toxic effects in organisms. PTMs induced by the electrophilic by-products of redox reactions most frequently occur at protein thiols; other nucleophilic amino acids serve as less favorable targets. Advances in mass spectrometry and affinity-chemistry strategies have improved the detection of electrophile-induced protein modifications both in vitro and in vivo and have revealed a high degree of amino acid and protein selectivity of electrophilic PTM. The identification of biological targets of electrophiles has motivated further study of the functional impact of various PTM reactions on specific signaling pathways and how this might affect organisms. PMID:19797270

  20. 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…

  1. 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.

  2. 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

  3. 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 ...

  4. 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

  5. Exploring diradical chemistry: a carbon-centered radical may act as either an anion or electrophile through an orbital isomer.

    PubMed

    Gonçalves, Théo P; Mohamed, Mubina; Whitby, Richard J; Sneddon, Helen F; Harrowven, David C

    2015-04-01

    Diradical intermediates, formed by thermolysis of alkynylcyclobutenones, can display radical, anion, or electrophilic character because of the existence of an orbital isomer with zwitterionic and cyclohexatrienone character. Our realization that water, alcohols, and certain substituents can induce the switch provides new opportunities in synthesis. For example, it can be used to shut down radical pathways and to give access to aryl carbonates and tetrasubstituted quinones. PMID:25694299

  6. Electron paramagnetic resonance study of the generation of reactive oxygen species catalysed by transition metals and quinoid redox cycling by inhalable ambient particulate matter.

    PubMed

    Valavanidis, A; Fiotakis, K; Bakeas, E; Vlahogianni, T

    2005-01-01

    A range of epidemiological studies in the 1990s showed that exposure to ambient particulate matter (PM) is associated with adverse health effects in the respiratory system and increased morbidity and mortality rates. Oxidative stress has emerged as a pivotal mechanism that underlies the toxic pulmonary effects of PM. A key question from a variety of studies was whether the adverse health effects of PM are mediated by the carbonaceous particles of their reactive chemical compounds adsorbed into the particles. Experimental evidence showed that PM contains redox-active transition metals, redox cycling quinoids and polycyclic aromatic hydrocarbons (PAHs) which act synergistically to produce reactive oxygen species (ROS). Fine PM has the ability to penetrate deep into the respiratory tree where it overcomes the antioxidant defences in the fluid lining of the lungs by the oxidative action of ROS. From a previous study [Valavanidis A, Salika A, Theodoropoulou A. Generation of hydroxyl radicals by urban suspended particulate air matter. The role of iron ions. Atmospher Environ 2000; 34 : 2379-2386], we established that ferrous ions in PM play an important role in the generation of hydroxyl radicals in the presence of hydrogen peroxide (H2O2). In the present study, we investigated the synergistic effect of transition metals and persistent quinoid and semiquinone radicals for the generation of ROS without the presence of H2O2. We experimented with airborne particulate matter, such as TSPs (total suspended particulates), fresh automobile exhaust particles (diesel, DEP and gasoline, GEP) and fresh wood smoke soot. Using electron paramagnetic resonance (EPR), we examined the quantities of persistent free radicals, characteristic of a mixture of quinoid radicals with different structures and a carbonaceous core of carbon-centred radicals. We extracted, separated and analysed the quinoid compounds by EPR at alkaline solution (pH 9.5) and by TLC. Also, we studied the direct

  7. Effects of different quinoid redox mediators on the simultaneous removal of p-cresol and sulphide in a denitrifying process.

    PubMed

    Meza-Escalante, Edna R; Texier, Anne-Claire; Cuervo-López, Flor; Gómez, Jorge; Cervantes, Francisco J

    2009-01-01

    The catalytic effects of different quinoid redox mediators (RM) on the simultaneous removal of sulphide and p-cresol in a denitrifying process were evaluated in batch studies. 2-Hydroxy-1,4-naphthoquinone (LAW) and anthraquinone-2,6-disulphonate (AQDS) did not significantly affect the sulphide oxidation rate, which, in contrast, was increased 14% in the presence of 1,2-naphthoquinone-4-sulphonate (NQS). The input of NQS on the oxidation of sulphide was also favourably reflected in a 13% higher sulphate production. All RM promoted a higher (up to 34% compared to the control lacking RM) degree of mineralization of p-cresol. LAW also supported a 47% higher denitrifying yield (Y(N2)), compared to the control lacking quinones. Nevertheless, AQDS and NQS decreased the Y(N2) by 12-13%. Our results suggest that a proper scrutiny should be conducted before deciding the sort of quinone to be applied in denitrifying processes. The heterogeneous effects observed also advise to consider both the respiratory rates and the yields as important parameters for deciphering the impact of RM on denitrifying processes. PMID:19474488

  8. Quinoid radio-toxin (QRT) induced metabolic changes in mice: An ex vivo and in vivo EPR investigation

    PubMed Central

    Ibragimova, M.I.; Petukhov, V.Yu.; Zheglov, E.P.; Khan, N.; Hou, H.; Swartz, H.M.; Konjukhov, G.V.; Nizamov, R.N.

    2013-01-01

    Radio-toxins are toxic metabolites produced by ionizing irradiation and have toxic effects similar to those caused by direct irradiation. We have investigated the effect of a quinoid radio-toxin (QRT) obtained from γ-irradiated potato tuber on various organs in mice using ex vivo and in vivo EPR spectroscopy. Results indicate a decrease in the activity of ribonucleotide reductase enzyme in spleen of mice treated with 0.2 mg QRT. A dose of 2 mg QRT was fatal to mice within 45–60 min of treatment. Nitrosyl hemoglobin complexes α-(Fe2+–NO)α-(Fe2+)β-(Fe2+)2 were detected from spleen, blood, liver, kidney, heart, and lung tissue samples of mice treated with lethal doses of QRT. A significant decrease of pO2 in liver and brain was observed after administration of QRT at the lethal dose. The time of the appearance of the nitrosyl hemoglobin complex and its intensity varied with the dose of QRT and the type of tissue. These results indicate that the effect of the QRT is more prominent in spleen and to a lesser extent in liver and blood. The QRT action at the lethal doses resulted in an increased hypoxia over time with disruption of compensatory adaptive response. The results indicate similar outcome of QRT as observed with γ-irradiation. PMID:18230367

  9. 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

  10. Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench.

    PubMed

    Talk, Ruaa A; Duperray, Alexia; Li, Xiabing; Coldham, Iain

    2016-06-01

    Substituted N-tert-butoxycarbonyl (Boc)-1,2,3,4-tetrahydroisoquinolines were prepared and treated with n-butyllithium in THF at -50 °C to test the scope of the metallation and electrophilic quench. The lithiation was optimised by using in situ ReactIR spectroscopy and the rate of rotation of the carbamate was determined. The 1-lithiated intermediates could be trapped with a variety of electrophiles to give good yields of 1-substituted tetrahydroisoquinoline products. Treatment with acid or reduction with LiAlH4 allows conversion to the N-H or N-Me compound. The chemistry was applied to the efficient total syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline. PMID:27169500

  11. 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

  12. Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide.

    PubMed

    Zhu, Jiansheng; Liu, Yafei; Shen, Qilong

    2016-07-25

    A general method for the formation of alkyl difluoromethylethers under mild reaction conditions and with good functional-group tolerance was developed. The development of the method was based on the invention of a stable, electrophilic, difluoromethylating reagent, difluoromethyl-(4-nitrophenyl)-bis(carbomethoxy) methylide sulfonium ylide, which was synthesized by reaction of the easily available 4-nitrophenyl (difluoromethyl)thioether and dimethyl diazomalonate in the presence of a rhodium catalyst. PMID:27312192

  13. Electrophilic phosphonium cations catalyze hydroarylation and hydrothiolation of olefins.

    PubMed

    Pérez, Manuel; Mahdi, Tayseer; Hounjet, Lindsay J; Stephan, Douglas W

    2015-06-30

    Electrophilic phosphonium cations (EPCs) are efficient main group catalysts for the hydroarylation of olefins under mild conditions, providing a facile route to substituted aniline, bis-arylamine, phenol, furan, thiophene, pyrrole, and indole derivatives. Similarly, EPCs catalyze the hydrothiolation of aryl olefins with thiophenol affording a series of alkyl aryl thioethers. Experimental data support a mechanism for these reactions that involves initial activation of the olefin. PMID:26083901

  14. Protein Targets of Reactive Electrophiles in Human Liver Microsomes

    PubMed Central

    Shin, Nah-Young; Liu, Qinfeng; Stamer, Sheryl L.; Liebler, Daniel C.

    2008-01-01

    Liver microsomes are widely used to study xenobiotic metabolism in vitro and covalent binding to microsomal proteins serves as a surrogate marker for toxicity mediated by reactive metabolites. We have applied liquid chromatography-tandem mass spectrometry (LC-MS-MS) to identify protein targets of the biotin-tagged model electrophiles 1-biotinamido-4-(4′-[maleimidoethylcyclohexane]-carboxamido)butane (BMCC) and N-iodoacetyl-N-biotinylhexylenediamine (IAB) in human liver microsomes. The biotin-tagged peptides resulting from in-gel tryptic digestion were enriched by biotin-avidin chromatography and LC-MS-MS was used to identify 376 microsomal cysteine thiol targets of BMCC and IAB in 263 proteins. Protein adduction was selective and reproducible and only 90 specific cysteine sites in 70 proteins (approximately 25% of the total) were adducted by both electrophiles. Differences in adduction selectivity correlated with different biological effects of the compounds, as IAB, but not BMCC induced ER stress in HEK293 cells. Targeted LC-MS-MS analysis of microsomal glutathione-S-transferase cysteine 50, a target of both IAB and BMCC, detected time-dependent adduction by the reactive acetaminophen metabolite N-acetyl-p-benzoquinoneimine during microsomal incubations. The results indicate that electrophiles selectively adduct microsomal proteins, but display differing target selectivities that correlate with differences in toxicity. Analysis of selected microsomal protein adduction reactions thus could provide a more specific indication of potential toxicity than bulk covalent binding of radiolabeled compounds. PMID:17480101

  15. 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

  16. 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

  17. Electrophilic alkylation of pseudotetrahedral nickel(II) arylthiolate complexes.

    PubMed

    Deb, Tapash; Jensen, Michael P

    2015-01-01

    A kinetic study is reported for reactions of pseudotetrahedral nickel(II) arylthiolate complexes [(Tp(R,Me))Ni-SAr] (Tp(R,Me) = hydrotris{3-R-5-methyl-1-pyrazolyl}borate, R = Me, Ph, and Ar = C6H5, C6H4-4-Cl, C6H4-4-Me, C6H4-4-OMe, 2,4,6-Me3C6H2, 2,4,6-(i)Pr3C6H2) with organic electrophiles R'X (i.e., MeI, EtI, BzBr) in low-polarity organic solvents (toluene, THF, chloroform, dichloromethane, or 1,2-dichloroethane), yielding a pseudotetrahedral halide complex [(Tp(R,Me))Ni-X] (X = Cl, Br, I) and the corresponding organosulfide R'SAr. Competitive reactions with halogenated solvents and adventitious air were also examined. Akin to reactions of analogous and biomimetic zinc complexes, a pertinent mechanistic question is the nature of the reactive nucleophile, either an intact thiolate complex or a free arylthiolate resulting from a dissociative pre-equilibrium. The observed kinetics conformed to a second-order rate law, first order with respect to the complex and electrophile, and no intermediate complexes were observed. In the absence of a mechanistically diagnostic rate law, a variety of mechanistic probes were examined, including kinetic effects of varying the metal, solvent, electrophile, and temperature, as well as the 3-pyrazolyl and arylthiolate substituents. Compared to zinc analogues, the effect of Ni-SAr covalency is also of interest herein. The results are broadly interpreted with respect to the disparate mechanistic pathways. PMID:25494529

  18. 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

  19. Electrophilic activity-based RNA probes reveal a self-alkylating RNA for RNA labeling

    PubMed Central

    McDonald, Richard I.; Guilinger, John P.; Mukherji, Shankar; Curtis, Edward A.; Lee, Won I.; Liu, David R.

    2014-01-01

    Probes that form covalent bonds with RNA molecules based on their chemical reactivity would advance our ability to study the transcriptome. We developed a set of electrophilic activity-based RNA probes designed to react with unusually nucleophilic RNAs. We used these probes to identify reactive genome-encoded RNAs, resulting in the discovery of a 42-nt catalytic RNA from an archaebacterium that reacts with a 2,3-disubstituted epoxide at N7 of a specific guanosine. Detailed characterization of the catalytic RNA revealed the structural requirements for reactivity. We developed this catalytic RNA into a general tool to selectively conjugate a small molecule to an RNA of interest. This strategy enabled up to 500-fold enrichment of target RNA from total mammalian RNA or from cell lysate. We demonstrated the utility of this approach by selectively capturing proteins in yeast cell lysate that bind to the ASH1 mRNA. PMID:25306441

  20. 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

  1. The role of electrophilic species in the Fischer-Tropsch reaction.

    PubMed

    Maitlis, Peter M; Zanotti, Valerio

    2009-04-01

    The heterogeneously catalysed Fischer-Tropsch (FT) synthesis converts syngas (CO+H2) into long chain hydrocarbons and is a key step in the economically important transformation of natural gas, coal, or biomass into liquid fuels, such as diesel. Catalyst surface studies indicate that the FT reaction starts when CO is activated at imperfections on the surfaces of late transition metals (Fe, Ru, Co, or Rh) and at interfaces with "islands" of promoters (Lewis acid oxides such as alumina or titania). Activation involves CO cleavage to generate a surface carbide, C(ad), which is sequentially hydrogenated to CHx(ad) species (x=1-4). An overview of practical aspects of the FT synthesis is followed by a discussion of the chief mechanisms that have been proposed for the formation of 1-alkenes by polymerisation of surface C1 species. These mechanisms have traditionally postulated rather non-polar intermediates, such as CH2(ad) and CH3(ad). However, electrophiles and nucleophiles are well-known to play key roles in the reactions of organic and organometallic compounds, and also in many reactions homogeneously catalysed by soluble metal complexes, including olefin polymerisation. We have now extended these concepts to the Fischer-Tropsch reaction, and show that the polymerisation reactions at polarising surfaces, such as oxide-metal interfaces, can be understood if the reactive chain carrier is an electrophilic species, such as the cationic methylidyne, CH(delta+)(ad). It is proposed that the key coupling step in C-C bond formation involves the interaction of the electrophilic methylidyne with an alkylidene (RCH(ad), R=H, alkyl), followed by an H-transfer to generate the homologous alkylidene: CHdelta+(ad)+RCH(ad)-->RCHCH(ad) and RCHCH(ad)+H(ad)-->RCH2CH(ad). If the reactions occur on non-polarising surfaces, an alternative C-C bond forming reaction such as the alkenyl+methylene, RCH=CH(ad)+CH2(ad)-->RCH=CHCH2(ad), can take place. This approach explains important aspects of the

  2. 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…

  3. A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles

    PubMed Central

    Wang, Chu; Weerapana, Eranthie; Blewett, Megan; Cravatt, Benjamin F.

    2013-01-01

    Cells produce electrophilic products with the potential to modify and affect the function of proteins. Chemoproteomic methods have provided a means to qualitatively inventory proteins targeted by endogenous electrophiles; however, ascertaining the potency and specificity of these reactions to identify the most sensitive sites in the proteome to electrophilic modification requires more quantitative methods. Here, we describe a competitive activity-based profiling method for quantifying the reactivity of electrophilic compounds against 1000+ cysteines in parallel in the human proteome. Using this approach, we identify a select set of proteins that constitute “hot spots” for modification by various lipid-derived electrophiles, including the oxidative stress product 4-hydroxynonenal (HNE). We show that one of these proteins, ZAK kinase, is labeled by HNE on a conserved, active site-proximal cysteine, resulting in enzyme inhibition to create a negative feedback mechanism that can suppress the activation of JNK pathways by oxidative stress. PMID:24292485

  4. Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism*

    PubMed Central

    Kansanen, Emilia; Bonacci, Gustavo; Schopfer, Francisco J.; Kuosmanen, Suvi M.; Tong, Kit I.; Leinonen, Hanna; Woodcock, Steven R.; Yamamoto, Masayuki; Carlberg, Carsten; Ylä-Herttuala, Seppo; Freeman, Bruce A.; Levonen, Anna-Liisa

    2011-01-01

    Nitro-fatty acids (NO2-FAs) are electrophilic signaling mediators formed in vivo via nitric oxide (NO)- and nitrite (NO2−)-dependent reactions. Nitro-fatty acids modulate signaling cascades via reversible covalent post-translational modification of nucleophilic amino acids in regulatory proteins and enzymes, thus altering downstream signaling events, such as Keap1-Nrf2-antioxidant response element (ARE)-regulated gene expression. In this study, we investigate the molecular mechanisms by which 9- and 10-nitro-octadec-9-enoic acid (OA-NO2) activate the transcription factor Nrf2, focusing on the post-translational modifications of cysteines in the Nrf2 inhibitor Keap1 by nitroalkylation and its downstream responses. Of the two regioisomers, 9-nitro-octadec-9-enoic acid was a more potent ARE inducer than 10-nitro-octadec-9-enoic acid. The most OA-NO2-reactive Cys residues in Keap1 were Cys38, Cys226, Cys257, Cys273, Cys288, and Cys489. Of these, Cys273 and Cys288 accounted for ∼50% of OA-NO2 reactions in a cellular milieu. Notably, Cys151 was among the least OA-NO2-reactive of the Keap1 Cys residues, with mutation of Cys151 having no effect on net OA-NO2 reaction with Keap1 or on ARE activation. Unlike many other Nrf2-activating electrophiles, OA-NO2 enhanced rather than diminished the binding between Keap1 and the Cul3 subunit of the E3 ligase for Nrf2. OA-NO2 can therefore be categorized as a Cys151-independent Nrf2 activator, which in turn can influence the pattern of gene expression and therapeutic actions of nitroalkenes. PMID:21357422

  5. 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. PMID:26929981

  6. 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).

  7. 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. PMID:25565370

  8. 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).

  9. 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

  10. ASSESSMENT OF THE PROPENSITY FOR COVALENT BINDING OF ELECTROPHILES TO BIOLOGICAL SUBSTRATES

    EPA Science Inventory

    Electrophilic character is associated with the ability of external agents to interact with centers of electron density in biological macromolecules and to cause the interruption or alternation of normal activity. ith the observation of site specificity in mutagenic events, Pearso...

  11. RELATIONSHIPS BETWEEN DESCRIPTORS FOR HYDROPHOBICITY AND SOFT ELECTROPHILICITY IN PREDICTING TOXICITY

    EPA Science Inventory

    The toxicity of chemicals is orthogonal with individual molecular descriptors used to quantify hydrophobicity and soft electro-philicity when considering large data sets. Estimating the toxicity of reactive chemicals requires descriptors of both passive transport and the stereoel...

  12. Electrophilic activation of hydrogen peroxide: selective oxidation reactions in perfluorinated alcohol solvents.

    PubMed

    Neimann, K; Neumann, R

    2000-09-01

    [reaction; see text] The catalytic electrophilic activation of hydrogen peroxide with transition metal compounds toward reaction with nucleophiles is a matter of very significant research and practical interest. We have now found that use of perfluorinated alcoholic solvents such as 1,1, 1,3,3,3-hexafluoro-2-propanol in the absence of catalysts allowed electrophilic activation of hydrogen peroxide toward epoxidation of alkenes and the Baeyer-Villiger oxidation of ketones. PMID:10964384

  13. 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.

  14. 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.

  15. Electrophilicities and Protein Covalent Binding of Demethylation Metabolites of Colchicine.

    PubMed

    Guo, Xiucai; Lin, Dongju; Li, Weiwei; Wang, Kai; Peng, Ying; Zheng, Jiang

    2016-03-21

    Colchicine, an alkaloid existing in plants of Liliaceous colchicum, has been widely used in the treatment of gout and familial Mediterranean fever. The administration of colchicine was found to cause liver injury in humans. The mechanisms of colchicine-induced liver toxicity remain unknown. The objectives of this study were to determine the electrophilicities of demethylation metabolites of colchicine and investigate the protein adductions derived from the reactive metabolites of colchicine. Four demethylated colchicine (1-, 2-, 3-, and 10-DMCs), namely, M1-M4, were detected in colchicine-fortified microsomal incubations. Four N-acetyl cysteine (NAC) conjugates (M5-M8) derived from colchicine were detected in the microsomes in the presence of NAC. M5 and M6 were derived from 10-DMC. M7 resulted from the reaction of 2-DMC or 3-DMC with NAC, and M8 originated from 10-DMC. Microsomal protein covalent binding was observed after exposure to colchicine. Two cysteine adducts (CA-1 and CA-2) derived from 10-DMC were found in proteolytically digested microsomal protein samples after incubation with colchicine. The findings allow us to define the chemical property of demethylation metabolites of colchicine and the interaction between protein and the reactive metabolites of colchicine generated in situ. PMID:26845511

  16. Joint toxic effects of the type-2 alkene electrophiles.

    PubMed

    Zhang, Lihai; Geohagen, Brian C; Gavin, Terrence; LoPachin, Richard M

    2016-07-25

    Human populations are exposed to complex environmental mixtures of acrolein, methylvinyl ketone (MVK) and other type-2 alkenes. Many members of this chemical class are electrophiles that possess a common molecular mechanism of toxicity; i.e., protein inactivation via formation of stable cysteine adducts. Therefore, acute or chronic exposure to type-2 alkene mixtures could represent a health risk due to additive or synergistic interactions among component chemicals. Despite this risk, there is little experimental information regarding the joint effects of type-2 alkenes. In the present study we used sum of toxic units (TUsum = ∑TUi) to assess the relative toxicity of different type-2 alkene mixtures. These studies involved well characterized environmental type-2 alkene toxicants and included amide (acrylamide; ACR), ketone (methyl vinyl ketone; MVK), aldehyde (2-ethylacrolein; EA) and ester (methyl acrylate; MA) derivatives. In chemico analyses revealed that both binary and ternary mixtures could deplete thiol groups according to an additive joint effect at equitoxic and non-equitoxic ratios; i.e., TUsum = 1.0 ± 0.20. In contrast, analyses of joint effects in SNB19 cell cultures indicated that different permutations of type-2 alkene mixtures produced mostly synergistic joint effects with respect to cell lethality; i.e., TUsum < 0.80. A mixture of ACR and MA was shown to produce joint toxicity in a rat model. This mixture accelerated the onset and development of neurotoxicity relative to the effects of the individual toxicants. Synergistic effects in biological models might occur when different cellular proteomes are targeted, whereas additive effects develop when the mixtures encompasses a similar proteome. PMID:27288850

  17. 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

  18. 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

  19. Global Analysis of Protein Damage by the Lipid Electrophile 4-Hydroxy-2-nonenal*S⃞

    PubMed Central

    Codreanu, Simona G.; Zhang, Bing; Sobecki, Scott M.; Billheimer, Dean D.; Liebler, Daniel C.

    2009-01-01

    Lipid peroxidation yields a variety of electrophiles, which are thought to contribute to the molecular pathogenesis of diseases involving oxidative stress, yet little is known of the scope of protein damage caused by lipid electrophiles. We identified protein targets of the prototypical lipid electrophile 4-hydroxy-2-nonenal (HNE) in RKO cells treated with 50 or 100 μm HNE. HNE Michael adducts were biotinylated by reaction with biotinamidohexanoic acid hydrazide, captured with streptavidin, and the captured proteins were resolved by one dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, digested with trypsin, and identified by liquid chromatography-tandem mass spectrometry. Of the 1500+ proteins identified, 417 displayed a statistically significant increase in adduction with increasing HNE exposure concentration. We further identified 18 biotin hydrazide-modified, HNE-adducted peptides by specific capture using anti-biotin antibody and analysis by high resolution liquid chromatography-tandem mass spectrometry. A subset of the identified HNE targets were validated with a streptavidin capture and immunoblotting approach, which enabled detection of adducts at HNE exposures as low as 1 μm. Protein interaction network analysis indicated several subsystems impacted by endogenous electrophiles in oxidative stress, including the 26 S proteasomal and chaperonin containing TCP-1 (CCT) systems involved in protein-folding and degradation, as well as the COP9 signalosome, translation initiation complex, and a large network of ribonucleoproteins. Global analyses of protein lipid electrophile adducts provide a systems-level perspective on the mechanisms of diseases involving oxidative stress. PMID:19054759

  20. 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

  1. Vinyl carbamate epoxide, a major strong electrophilic, mutagenic and carcinogenic metabolite of vinyl carbamate and ethyl carbamate (urethane).

    PubMed

    Park, K K; Liem, A; Stewart, B C; Miller, J A

    1993-03-01

    Vinyl carbamate epoxide (VCO) was found to possess strong electrophilic, mutagenic and carcinogenic activities. It reacted with water at 37 degrees C and pH 7.4 (phosphate buffer) to form glycolaldehyde and several related reducing compounds; none of these products were mutagenic for Salmonella typhimurium TA1535. Under these conditions VCO had a half-life (determined chemically and mutagenically) of approximately 10.5 min. This half-life was progressively lowered by increasing concentrations of chloride ion (liver, serum and isotonic levels). This ion reacted with VCO to form chloroacetaldehyde. VCO also reacted with other nucleophiles such as glutathione, DNA and its constituent guanine and adenine bases. The purine adducts formed by VCO in DNA in vitro and in vivo were released by weak acid treatment and consisted of 7-(2'-oxoethyl)guanine and N2,3-ethenoguanine as major products with 1,N6-ethenoadenine as a minor product. VCO was a strong direct mutagen in Salmonella typhimurium TA1535 and TA100 but was only weakly active in the TA98 mutant. VCO was a stronger initiator of carcinogenesis in the skin of CD-1 mice and in the liver of infant male B6C3F1 mice than its metabolic precursors vinyl carbamate (VC) and ethyl carbamate (EC). Unlike VC and EC, VCO was a strong complete carcinogen in the skin of CD-1 mice and induced papillomas and carcinomas following repetitive administration of sub-ulcerogenic doses. VCO also exhibited some carcinogenic activity in the lungs of mice and in the s.c. and mammary tissue of female Sprague-Dawley rats. These data and those from other recent studies support the conclusion that VCO is a major strong electrophilic, mutagenic and carcinogenic metabolite of EC and VC in the mouse. PMID:8453720

  2. Ortho-Functionalized Aryltetrazines by Direct Palladium-Catalyzed C-H Halogenation: Application to Fast Electrophilic Fluorination Reactions.

    PubMed

    Testa, Christelle; Gigot, Élodie; Genc, Semra; Decréau, Richard; Roger, Julien; Hierso, Jean-Cyrille

    2016-04-25

    A general catalyzed direct C-H functionalization of s-tetrazines is reported. Under mild reaction conditions, N-directed ortho-C-H activation of tetrazines allows the introduction of various functional groups, thus forming carbon-heteroatom bonds: C-X (X=I, Br, Cl) and C-O. Based on this methodology, we developed electrophilic mono- and poly-ortho-fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s-aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho-functionalized aryltetrazines which are difficult to obtain by classical Pinner-like syntheses. PMID:27010438

  3. A DFT study of the formation of xanthydrol motifs during electrophilic poly(aryl ether ketone) synthesis.

    PubMed

    Melissen, Sigismund T A G; Tognetti, Vincent; Dupas, Georges; Jouanneau, Julien; Lê, Guillaume; Joubert, Laurent

    2016-01-01

    The reaction pathway of the cyclization of 2-phenoxybenzophenone into 9-phenyl-9H-xanthen-9-ol in the presence of acid and an excess of AlCl33 was studied using density functional theory. This type of reaction is known to occur during the Friedel-Crafts polycondensation of poly(aryl ether ketones) following the undesired benzoylation of nucleophilic positions ortho- to the growing polymer's ether groups. The formed defect acts as an undesired terminator of the polymer chain, causing severe problems in the polymer's melt state. A branched, multistep mechanism reminiscent of the Friedel-Crafts acylation reaction is discovered; the reaction starts with the protonation of the carbonyl oxygen, followed by intramolecular electrophilic attack on the carbonyl carbon that determines the turnover frequency of the catalytic cycle and ends by deprotonation of the Wheland intermediate. PMID:26696543

  4. Communication: Remarkable electrophilicity of the oxalic acid monomer: An anion photoelectron spectroscopy and theoretical study

    SciTech Connect

    Buonaugurio, Angela; Graham, Jacob; Buytendyk, Allyson; Bowen, Kit H. E-mail: kbowen@jhu.edu; Ryder, Matthew R. Gutowski, Maciej E-mail: kbowen@jhu.edu; Keolopile, Zibo G. E-mail: kbowen@jhu.edu; Haranczyk, Maciej

    2014-06-14

    Our experimental and computational results demonstrate an unusual electrophilicity of oxalic acid, the simplest dicarboxylic acid. The monomer is characterized by an adiabatic electron affinity and electron vertical detachment energy of 0.72 and 1.08 eV (±0.05 eV), respectively. The electrophilicity results primarily from the bonding carbon-carbon interaction in the singly occupied molecular orbital of the anion, but it is further enhanced by intramolecular hydrogen bonds. The well-resolved structure in the photoelectron spectrum is reproduced theoretically, based on Franck-Condon factors for the vibronic anion → neutral transitions.

  5. Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides.

    PubMed

    Zenzola, Marina; Doran, Robert; Degennaro, Leonardo; Luisi, Renzo; Bull, James A

    2016-06-13

    A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for metal catalysts. Mixing ammonium salts with diacetoxyiodobenzene directly converts sulfoxides into sulfoximines. This report describes the first example of using of ammonia sources with diacetoxyiodobenzene to generate an electrophilic nitrogen center. Control and mechanistic studies suggest a short-lived electrophilic intermediate, which is likely to be PhINH or PhIN(+) . PMID:27126053

  6. Pyridinium-phosphonium dications: highly electrophilic phosphorus-based Lewis acid catalysts.

    PubMed

    Bayne, Julia M; Holthausen, Michael H; Stephan, Douglas W

    2016-04-14

    Using commercially available 2-pyridyldiphenylphosphine (o-NC5H4)PPh2, a family of electrophilic phosphonium cations [(o-NC5H4)PFPh2](+) (2) and dications [(o-MeNC5H4)PRPh2](2+) (R = F (4); Me (5)) were prepared. The Lewis acidity of these pyridinium-phosphonium dications was probed in Friedel-Crafts dimerization, hydrodefluorination, hydrosilylation, dehydrocoupling and hydrodeoxygenation reactions. The influence of the counterion on the catalytic activity of the electrophilic phosphonium cations is also discussed. PMID:26666332

  7. Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides.

    PubMed

    Konev, Mikhail O; Hanna, Luke E; Jarvo, Elizabeth R

    2016-06-01

    Nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides have been developed. Both inter- and intramolecular variants proceed under mild reaction conditions. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the first example of a stereospecific cross-electrophile coupling of a secondary benzylic ester is described. PMID:27099968

  8. The exceptionally high reactivity of Cys 621 is critical for electrophilic activation of the sensory nerve ion channel TRPA1.

    PubMed

    Bahia, Parmvir K; Parks, Thomas A; Stanford, Katherine R; Mitchell, David A; Varma, Sameer; Stevens, Stanley M; Taylor-Clark, Thomas E

    2016-06-01

    Activation of the sensory nerve ion channel TRPA1 by electrophiles is the key mechanism that initiates nociceptive signaling, and leads to defensive reflexes and avoidance behaviors, during oxidative stress in mammals. TRPA1 is rapidly activated by subtoxic levels of electrophiles, but it is unclear how TRPA1 outcompetes cellular antioxidants that protect cytosolic proteins from electrophiles. Here, using physiologically relevant exposures, we demonstrate that electrophiles react with cysteine residues on mammalian TRPA1 at rates that exceed the reactivity of typical cysteines by 6,000-fold and that also exceed the reactivity of antioxidant enzymes. We show that TRPA1 possesses a complex reactive cysteine profile in which C621 is necessary for electrophile-induced binding and activation. Modeling of deprotonation energies suggests that K620 contributes to C621 reactivity and mutation of K620 alone greatly reduces the effect of electrophiles on TRPA1. Nevertheless, binding of electrophiles to C621 is not sufficient for activation, which also depends on the function of another reactive cysteine (C665). Together, our results demonstrate that TRPA1 acts as an effective electrophilic sensor because of the exceptionally high reactivity of C621. PMID:27241698

  9. Assessment of electrophile damage in a human brain endothelial cell line utilizing a clickable alkyne analog of 2-chlorohexadecanal.

    PubMed

    Nusshold, Christoph; Üllen, Andreas; Kogelnik, Nora; Bernhart, Eva; Reicher, Helga; Plastira, Ioanna; Glasnov, Toma; Zangger, Klaus; Rechberger, Gerald; Kollroser, Manfred; Fauler, Günter; Wolinski, Heimo; Weksler, Babette B; Romero, Ignacio A; Kohlwein, Sepp D; Couraud, Pierre-Olivier; Malle, Ernst; Sattler, Wolfgang

    2016-01-01

    Peripheral leukocytes aggravate brain damage by releasing cytotoxic mediators that compromise blood-brain barrier function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system. The reaction of HOCl with the endogenous plasmalogen pool of brain endothelial cells results in the generation of 2-chlorohexadecanal (2-ClHDA), a toxic, lipid-derived electrophile that induces blood-brain barrier dysfunction in vivo. Here, we synthesized an alkynyl-analog of 2-ClHDA, 2-chlorohexadec-15-yn-1-al (2-ClHDyA) to identify potential protein targets in the human brain endothelial cell line hCMEC/D3. Similar to 2-ClHDA, 2-ClHDyA administration reduced cell viability/metabolic activity, induced processing of pro-caspase-3 and PARP, and led to endothelial barrier dysfunction at low micromolar concentrations. Protein-2-ClHDyA adducts were fluorescently labeled with tetramethylrhodamine azide (N3-TAMRA) by 1,3-dipolar cycloaddition in situ, which unveiled a preferential accumulation of 2-ClHDyA adducts in mitochondria, the Golgi, endoplasmic reticulum, and endosomes. Thirty-three proteins that are subject to 2-ClHDyA-modification in hCMEC/D3 cells were identified by mass spectrometry. Identified proteins include cytoskeletal components that are central to tight junction patterning, metabolic enzymes, induction of the oxidative stress response, and electrophile damage to the caveolar/endosomal Rab machinery. A subset of the targets was validated by a combination of N3-TAMRA click chemistry and specific antibodies by fluorescence microscopy. This novel alkyne analog is a valuable chemical tool to identify cellular organelles and protein targets of 2-ClHDA-mediated damage in settings where myeloperoxidase-derived oxidants may play a disease-propagating role. PMID:26577177

  10. 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. PMID:21763105

  11. 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

  12. 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.

  13. REDOX AND ELECTROPHILIC PROPERTIES OF VAPOR- AND PARTICLE-PHASE COMPONENTS OF AMBIENT AEROSOLS

    PubMed Central

    Eiguren-Fernandez, Arantzazu; Shinyashiki, Masaru; Schmitz, Debra A.; DiStefano, Emma; Hinds, William; Kumagai, Yoshito; Cho, Arthur K.; Froines, John R.

    2010-01-01

    Particulate matter (PM) has been the primary focus of studies aiming to understand the relationship between the chemical properties of ambient aerosols and adverse health effects. Size and chemical composition of PM have been linked to their oxidative capacity which has been postulated to promote or exacerbate pulmonary and cardiovascular diseases. But in the last few years, new studies have suggested that volatile and semivolatile components may also contribute to many adverse health effects. The objectives of this study were: i) assess for the first time the redox and electrophilic potential of vapor-phase components of ambient aerosols, and ii) evaluate the relative contributions of particle- and vapor-fractions to the hazard of a given aerosol. To achieve these objectives vapor- and particle-phase samples collected in Riverside (CA) were subjected to three chemical assays to determine their redox and electrophilic capacities. The results indicate that redox active components are mainly associated with the particle-phase, while electrophilic compounds are found primarily in the vapor-phase. Vapor-phase organic extracts were also capable of inducing the stress responding protein, heme-oxygenase-1 (HO-1), in RAW264.7 murine macrophages. These results demonstrate the importance of volatile components in the overall oxidative and electrophilic capacity of aerosols, and point out the need for inclusion of vapors in future health and risk assessment studies. PMID:20152964

  14. Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation.

    PubMed

    Yan, Wen-Jing; Wang, Qi; Yuan, Cui-Hong; Wang, Fu; Ji, Yuan; Dai, Fang; Jin, Xiao-Ling; Zhou, Bo

    2016-08-01

    Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS). Considering that ROS generation depends on electrophilicity of PL, PL-CL was designed as its analog by introducing the α-substituent chlorine on the lactam ring to increase moderately its electrophilicity. In comparison with the parent molecule, this molecule was identified as a stronger ROS (O2(∙-) and H2O2) inducer and cytotoxic agent, and manifested more than 15-fold selectivity toward A549 cells over normal WI-38 cells. Mechanistic study uncovers for the first time that the selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation. Stronger intracellular TrxR inhibition and higher accumulation of ROS (O2(∙-) and H2O2) are responsible for more effective S-phase arrest and mitochondria-mediated apoptotic induction of A549 cells by PL-CL than PLvia p53-p21-cyclinA/CDK2 and ASK1-JNK/p38 signaling cascade pathways, respectively. This work provides an example of successfully designing PL-directed anticancer agent by an electrophilicity-based prooxidant (ROS-generating agent) strategy and gives added confidence for extending this strategy to other natural products. PMID:27233942

  15. Unexpected Reactivity of Trifluoromethyl Diazomethane (CF3CHN2): Electrophilicity of the Terminal N-Atom.

    PubMed

    Arkhipov, Anton V; Arkhipov, Viatcheslav V; Cossy, Janine; Kovtunenko, Volodymir O; Mykhailiuk, Pavel K

    2016-07-15

    After more than 70 years since its discovery, CF3CHN2 was found to possess a novel reactivity mode: N-terminal electrophile. With C-nucleophiles it gives hydrazones that are easily transformed into valuable CF3-heterocycles. PMID:27351064

  16. 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

  17. Phase I Metabolic Stability and Electrophilic Reactivity of 2-Phenylaminophenylacetic Acid Derived Compounds.

    PubMed

    Pang, Yi Yun; Tan, Yee Min; Chan, Eric Chun Yong; Ho, Han Kiat

    2016-07-18

    Diclofenac and lumiracoxib are two highly analogous 2-phenylaminophenylacetic acid anti-inflammatory drugs exhibiting occasional dose-limiting hepatotoxicities. Prior data indicate that bioactivation and reactive metabolite formation play roles in the observed toxicity, but the exact chemical influence of the substituents remains elusive. In order to elucidate the role of chemical influence on metabolism related toxicity, metabolic stability and electrophilic reactivity were investigated for a series of structurally related analogues and their resulting metabolites. The resulting analogues embody progressive physiochemical changes through varying halogeno- and aliphatic substituents at two positions and were subjected to in vitro human liver microsomal metabolic stability and cell-based GSH depletion assays (to measure electrophilic reactivity). LC-MS/MS analysis of the GSH trapped reactive intermediates derived from the analogues was then used to identify the putative structures of reactive metabolites. We found that chemical modifications of the structural backbone led to noticeable perturbations of metabolic stability, electrophilic reactivity, and structures and composition of reactive metabolites. With the acquired data, the relationships between stability, reactivity, and toxicity were investigated in an attempt to correlate between Phase I metabolism and in vitro toxicity. A positive correlation was identified between reactivity and in vitro toxicity, indicating that electrophilic reactivity can be an indicator for in vitro toxicity. All in all, the effect of substituents on the structures and reactivity of the metabolites, however subtle the changes, should be taken into consideration during future drug design involving similar chemical features. PMID:27245204

  18. 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…

  19. 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…

  20. 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

  1. Palladium-catalyzed intramolecular C-H arylation of arenes using tosylates and mesylates as electrophiles.

    PubMed

    Nervig, Christine S; Waller, Peter J; Kalyani, Dipannita

    2012-09-21

    This paper describes a method for the palladium catalyzed intramolecular C-H arylation using tosylates and mesylates as electrophiles. The transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally, a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented. PMID:22974229

  2. Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluoromethylthiolation.

    PubMed

    Chachignon, Hélène; Maeno, Mayaka; Kondo, Hiroya; Shibata, Norio; Cahard, Dominique

    2016-05-20

    The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF3 and a phosphine as the reducing agent. It is a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines, and enoxysilanes. PMID:27124113

  3. 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

  4. A Generalizable Platform for Interrogating Target- and Signal-Specific Consequences of Electrophilic Modifications in Redox-Dependent Cell Signaling

    PubMed Central

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

    2015-01-01

    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 & 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

  5. Unprecedented hydroxyl radical-dependent two-step chemiluminescence production by polyhalogenated quinoid carcinogens and H2O2

    PubMed Central

    Zhu, Ben-Zhan; Mao, Li; Huang, Chun-Hua; Qin, Hao; Fan, Rui-Mei; Kalyanaraman, Balaraman; Zhu, Jun-Ge

    2012-01-01

    Most chemiluminescence (CL) reactions usually generate only one-step CL, which is rarely dependent on the highly reactive and biologically/environmentally important hydroxyl radicals (•OH). Here, we show that an unprecedented two-step CL can be produced by the carcinogenic tetrachloro-1,4-benzoquinone (also known as p-chloranil) and H2O2, which was found to be well-correlated to and directly dependent on its two-step metal-independent production of •OH. We proposed that •OH-dependent formation of quinone-dioxetane and electronically excited carbonyl species might be responsible for this unusual two-step CL production by tetrachloro-1,4-benzoquinone/H2O2. This is a unique report of a previously undefined two-step CL-producing system that is dependent on intrinsically formed •OH. These findings may have potential applications in detecting and quantifying •OH and the ubiquitous polyhalogenated aromatic carcinogens, which may have broad biological and environmental implications for future research on these types of important species. PMID:22988069

  6. 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

  7. Electrophilic and free radical nitration of benzene and toluene with various nitrating agents*

    PubMed Central

    Olah, George A.; Lin, Henry C.; Olah, Judith A.; Narang, Subhash C.

    1978-01-01

    Electrophilic nitration of toluene and benzene was studied under various conditions with several nitrating systems. It was found that high orthopara regioselectivity is prevalent in all reactions and is independent of the reactivity of the nitrating agent. The methyl group of toluene is predominantly ortho-para directing under all reaction conditions. Steric factors are considered to be important but not the sole reason for the variation in the ortho/para ratio. The results reinforce our earlier views that, in electrophilic aromatic nitrations with reactive nitrating agents, substrate and positional selectivities are determined in two separate steps. The first step involves a π-aromatic-NO2+ ion complex or encounter pair, whereas the subsequent step is of arenium ion nature (separate for the ortho, meta, and para positions). The former determines substrate selectivity, whereas the latter determines regioselectivity. Thermal free radical nitration of benzene and toluene with tetranitromethane in sharp contrast gave nearly statistical product distributions. PMID:16592503

  8. 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. PMID:26159661

  9. 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

  10. 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

  11. Rhodium(III)-Catalyzed Cascade Cyclization/Electrophilic Amidation for the Synthesis of 3-Amidoindoles and 3-Amidofurans.

    PubMed

    Hu, Zhiyong; Tong, Xiaofeng; Liu, Guixia

    2016-05-01

    A rhodium(III)-catalyzed cascade cyclization/electrophilic amidation using N-pivaloyloxylamides as the electrophilic nitrogen source has been developed. This protocol provides an efficient route for the synthesis of 3-amidoindoles and 3-amidofurans under mild conditions with good functional group tolerance. The synthetic utility of this reaction has been demonstrated through the derivatization of the 3-amidoindoles to several heterocycle-fused indoles. PMID:27151555

  12. Thioredoxin reductase is required for the inactivation of tumor suppressor p53 and for apoptosis induced by endogenous electrophiles.

    PubMed

    Cassidy, Pamela B; Edes, Kornelia; Nelson, Chad C; Parsawar, Krishna; Fitzpatrick, F A; Moos, Philip J

    2006-12-01

    Previous studies demonstrate that the covalent modification of thioredoxin reductase (TrxR) by both endogenous and exogenous electrophiles results in disruption of the conformation of the tumor suppressor protein p53. Here we report that the loss of normal cellular TrxR enzymatic activity by electrophilic modification or deletion of the C-terminal catalytic selenocysteine residue has functional consequences that are distinct from those resulting from depletion of TrxR protein in human RKO colon cancer cells. A thorough kinetic analysis was performed on purified TrxR in order to characterize the mechanism of its inhibition by electrophiles. Furthermore, electrospray mass spectrometry confirmed the alkylation of TrxR by lipid electrophiles and liquid chromatography-mass spectrometry/mass spectrometry identified the C-terminus as one target for alkylation. Then the consequences of TrxR modification by electrophiles on p53 conformation, transactivation and apoptosis were compared and contrasted with the effects of depletion of TrxR protein by treatment of cells with small interfering RNA directed against TrxR1. We found that cells depleted of TrxR were actually less sensitive to electrophile-induced disruption of p53 conformation and apoptosis than were cells expressing normal levels of TrxR. When RKO cells depleted of wild-type TrxR were transfected with C-terminal mutants of TrxR lacking the catalytic selenocysteine, p53 was found to be conformationally deranged, similar to cells treated with electrophiles. These results lead us to conclude that C-terminal modification of TrxR is both necessary and sufficient for the disruption of p53 and for the induction of apoptosis. Endogenous lipid electrophiles have been our primary focus; however, metabolic activation of hormones can generate endogenous mutagens, and we demonstrate that estrone-quinone attenuates p53 function in human MCF7 cells. PMID:16777982

  13. 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

  14. 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

  15. 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

  16. 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

  17. Lewis Acid Catalyzed Synthesis of α-Trifluoromethyl Esters and Lactones by Electrophilic Trifluoromethylation.

    PubMed

    Katayev, Dmitry; Matoušek, Václav; Koller, Raffael; Togni, Antonio

    2015-12-01

    An electrophilic trifluoromethylation of ketene silyl acetals (KSAs) by hypervalent iodine reagents 1 and 2 has been developed. The reaction proceeds under very mild conditions in the presence of a catalytic amount of trimethylsilyl bis(trifluoromethanesulfonyl)imide (up to 2.5 mol %) as a Lewis acid providing a direct access to a variety of secondary, tertiary, and quaternary α-trifluoromethyl esters and lactones in high yield (up to 98%). PMID:26588788

  18. Reaction of 3,7-divinylidenebicyclo(3. 3. 1)nonane with electrophilic reagents

    SciTech Connect

    Krasutskii, P.A.; Fokin, A.A.; Kulik, N.I.; Yurchenko, A.G.

    1986-05-10

    3,7-Divinylidenebicyclo(3.3.1)nonane reacts with electrophilic reagents (strong acids, halogens) with the formation of 3-substituted 1-vinyl-2-methyleneadamantanes. In the reaction with small amounts of hydrochloric acid isomerization of the exocyclic bond to an endocyclic bond is observed in parallel with transannular cyclization. Increase in the sulfuric acid concentration leads to more extensive rearrangement to a protoadamantanone derivative.

  19. 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. PMID:26146024

  20. 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

  1. Electrophilic alkylations of vinylsilanes: a comparison of α- and β-silyl effects.

    PubMed

    Laub, Hans A; Mayr, Herbert

    2014-01-20

    Kinetics of the reactions of benzhydrylium ions (Aryl2CH(+)) with the vinylsilanes H2C=C(CH3)(SiR3), H2C=C(Ph)(SiR3), and (E)-PhCH=CHSiMe3 have been measured photometrically in dichloromethane solution at 20 °C. All reactions follow second-order kinetics, and the second-order rate constants correlate linearly with the electrophilicity parameters E of the benzhydrylium ions, thus allowing us to include vinylsilanes in the benzhydrylium-based nucleophilicity scale. The vinylsilane H2C=C(CH3)(SiMe3), which is attacked by electrophiles at the CH2 group, reacts one order of magnitude faster than propene, indicating that α-silyl-stabilization of the intermediate carbenium ion is significantly weaker than α-methyl stabilization because H2C=C(CH3)2 is 10(3)  times more reactive than propene. trans-β-(Trimethylsilyl)styrene, which is attacked by electrophiles at the silylated position, is even somewhat less reactive than styrene, showing that the hyperconjugative stabilization of the developing carbocation by the β-silyl effect is not yet effective in the transition state. As a result, replacement of vinylic hydrogen atoms by SiMe3 groups affect the nucleophilic reactivities of the corresponding C=C bonds only slightly, and vinylsilanes are significantly less nucleophilic than structurally related allylsilanes. PMID:24357501

  2. 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

  3. 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

  4. Electrophilic Pt(II) Complexes: Precision Instruments for the Initiation of Transformations Mediated by the Cation–Olefin Reaction

    PubMed Central

    2015-01-01

    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

  5. Silicon-Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling of Silicon Nucleophiles with Unactivated Secondary and Tertiary Alkyl Electrophiles.

    PubMed

    Chu, Crystal K; Liang, Yufan; Fu, Gregory C

    2016-05-25

    A wide array of cross-coupling methods for the formation of C-C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C-heteroatom bonds has lagged; for example, there have been no reports of metal-catalyzed cross-couplings of unactivated secondary or tertiary alkyl halides with silicon nucleophiles to form C-Si bonds. In this study, we address this challenge, establishing that a simple, commercially available nickel catalyst (NiBr2·diglyme) can achieve couplings of alkyl bromides with nucleophilic silicon reagents under unusually mild conditions (e.g., -20 °C); especially noteworthy is our ability to employ unactivated tertiary alkyl halides as electrophilic coupling partners, which is still relatively uncommon in the field of cross-coupling chemistry. Stereochemical, relative reactivity, and radical-trap studies are consistent with a homolytic pathway for C-X bond cleavage. PMID:27187869

  6. 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

  7. 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

  8. Compensating for the Absence of Selenocysteine in High-Molecular Weight Thioredoxin Reductases: The Electrophilic Activation Hypothesis

    PubMed Central

    2015-01-01

    Mammalian thioredoxin reductase (TR) is a pyridine disulfide oxidoreductase that uses the rare amino acid selenocysteine (Sec) in place of the more commonly used amino acid cysteine (Cys). Selenium is a Janus-faced element because it is both highly nucleophilic and highly electrophilic. Cys orthologs of Sec-containing enzymes may compensate for the absence of a Sec residue by making the active site Cys residue more (i) nucleophilic, (ii) electrophilic, or (iii) reactive by increasing both S-nucleophilicity and S-electrophilicity. It has already been shown that the Cys ortholog TR from Drosophila melanogaster (DmTR) has increased S-nucleophilicity [Gromer, S., Johansson, L., Bauer, H., Arscott, L. D., Rauch, S., Ballou, D. P., Williams, C. H., Jr., Schrimer, R. H., and Arnér, E. S (2003) Active sites of thioredoxin reductases: Why selenoproteins? Proc. Natl. Acad. Sci. U.S.A. 100, 12618–12623]. Here we present evidence that DmTR also enhances the electrophilicity of Cys490 through the use of an “electrophilic activation” mechanism. This mechanism is proposed to work by polarizing the disulfide bond that occurs between Cys489 and Cys490 in the C-terminal redox center by the placement of a positive charge near Cys489. This polarization renders the sulfur atom of Cys490 electron deficient and enhances the rate of thiol/disulfide exchange that occurs between the N- and C-terminal redox centers. Our hypothesis was developed by using a strategy of homocysteine (hCys) for Cys substitution in the Cys-Cys redox dyad of DmTR to differentiate the function of each Cys residue. The results show that hCys could substitute for Cys490 with little loss of thioredoxin reductase activity, but that substitution of hCys for Cys489 resulted in a 238-fold reduction in activity. We hypothesize that replacement of Cys489 with hCys destroys an interaction between the sulfur atom of Cys489 and His464 crucial for the proposed electrophilic activation mechanism. This electrophilic

  9. Compensating for the absence of selenocysteine in high-molecular weight thioredoxin reductases: the electrophilic activation hypothesis.

    PubMed

    Lothrop, Adam P; Snider, Gregg W; Flemer, Stevenson; Ruggles, Erik L; Davidson, Ronald S; Lamb, Audrey L; Hondal, Robert J

    2014-02-01

    Mammalian thioredoxin reductase (TR) is a pyridine disulfide oxidoreductase that uses the rare amino acid selenocysteine (Sec) in place of the more commonly used amino acid cysteine (Cys). Selenium is a Janus-faced element because it is both highly nucleophilic and highly electrophilic. Cys orthologs of Sec-containing enzymes may compensate for the absence of a Sec residue by making the active site Cys residue more (i) nucleophilic, (ii) electrophilic, or (iii) reactive by increasing both S-nucleophilicity and S-electrophilicity. It has already been shown that the Cys ortholog TR from Drosophila melanogaster (DmTR) has increased S-nucleophilicity [Gromer, S., Johansson, L., Bauer, H., Arscott, L. D., Rauch, S., Ballou, D. P., Williams, C. H., Jr., Schrimer, R. H., and Arnér, E. S (2003) Active sites of thioredoxin reductases: Why selenoproteins? Proc. Natl. Acad. Sci. U.S.A. 100, 12618-12623]. Here we present evidence that DmTR also enhances the electrophilicity of Cys490 through the use of an "electrophilic activation" mechanism. This mechanism is proposed to work by polarizing the disulfide bond that occurs between Cys489 and Cys490 in the C-terminal redox center by the placement of a positive charge near Cys489. This polarization renders the sulfur atom of Cys490 electron deficient and enhances the rate of thiol/disulfide exchange that occurs between the N- and C-terminal redox centers. Our hypothesis was developed by using a strategy of homocysteine (hCys) for Cys substitution in the Cys-Cys redox dyad of DmTR to differentiate the function of each Cys residue. The results show that hCys could substitute for Cys490 with little loss of thioredoxin reductase activity, but that substitution of hCys for Cys489 resulted in a 238-fold reduction in activity. We hypothesize that replacement of Cys489 with hCys destroys an interaction between the sulfur atom of Cys489 and His464 crucial for the proposed electrophilic activation mechanism. This electrophilic activation

  10. Synthesis of Substituted Quinolines by the Electrophilic Cyclization of N-(2-Alkynyl)anilines

    PubMed Central

    Zhang, Xiaoxia; Yao, Tuanli; Campo, Marino A.; Larock, Richard C.

    2010-01-01

    A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the 6-endo-dig electrophilic cyclization of N-(2-alkynyl)anilines by ICl, I2, Br2, PhSeBr and p-O2NC6H4SCl. The reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have been synthesized by the Hg(OTf)2-catalyzed ring closure of these same alkynylanilines. PMID:20161633

  11. 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

  12. Cytotoxicity of electrophilic iron(II)-clathrochelates in human promyelocytic leukemia cell line.

    PubMed

    Blechinger, Jenny; Varzackii, Oleg A; Kovalska, Vladyslava; Zelinskii, Genrikh E; Voloshin, Yan Z; Kinski, Elisa; Mokhir, Andriy

    2016-01-15

    We observed that electrophilic iron(II)-clathrochelates exhibit significant cytotoxicity in human promyelocytic leukemia cells (IC50=6.5±4.6μM), which correlates with the enhancement of intracellular oxidative stress (17-fold increase with respect to the cells treated with the solvent only). Based on in vitro studies we suggested that this effect is caused by alkylation of glutathione leading to inhibition of the cellular antioxidative system and by catalytic generation of reactive oxygen species by products of the alkylation reaction. PMID:26631314

  13. Microwave-induced electrophilic addition of single-walled carbon nanotubes with alkylhalides

    NASA Astrophysics Data System (ADS)

    Xu, Yang; Wang, Xianbao; Tian, Rong; Li, Shaoqing; Wan, Li; Li, Mingjian; You, Haijun; Li, Qin; Wang, Shimin

    2008-02-01

    We report the microwave-induced electrophilic addition of single-walled carbon nanotubes (SWNTs) with alkylhalides using Lewis acid as a catalyst followed by hydrolysis. The reaction results in the attachment of alkyl and hydroxyl groups to the surface of the nanotubes. This rapid and high-energy microwave radiation is found to be highly efficient for this reaction, which only needs as low as several minutes. The resulting nanotubes were characterized with FTIR, UV-vis-NIR, Raman, TGA, TEM and AFM. It demonstrates that iodo-alkanes show higher reaction activity with SWNTs than chloro- and bromo-alkanes.

  14. Reactivity, Selectivity, and Stability in Sulfenic Acid Detection: A Comparative Study of Nucleophilic and Electrophilic Probes.

    PubMed

    Gupta, Vinayak; Paritala, Hanumantharao; Carroll, Kate S

    2016-05-18

    The comparative reaction efficiencies of currently used nucleophilic and electrophilic probes toward cysteine sulfenic acid have been thoroughly evaluated in two different settings-(i) a small molecule dipeptide based model and (ii) a recombinant protein model. We further evaluated the stability of corresponding thioether and sulfoxide adducts under reducing conditions which are commonly encountered during proteomic protocols and in cell analysis. Powered by the development of new cyclic and linear C-nucleophiles, the unsurpassed efficiency in the capture of sulfenic acid under competitive conditions is achieved and thus holds great promise as highly potent tools for activity-based sulfenome profiling. PMID:27123991

  15. The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles Through the Use of P(t-Bu)3 and PCy3 as Ligands

    PubMed Central

    FU, GREGORY C.

    2009-01-01

    CONSPECTUS Metal-catalyzed coupling reactions of aryl electrophiles with organometallics and with olefins serve as unusually effective tools for forming new carbon-carbon bonds. By 1998, researchers had developed catalysts that achieved reactions of aryl iodides, bromides, and triflates. Nevertheless, many noteworthy challenges remained, among them: couplings of aryl iodides, bromides, and triflates under mild conditions (at room temperature, for example); couplings of hindered reaction partners; and, couplings of inexpensive aryl chlorides. This Account highlights some of the progress that has been made over the past decade, largely through the appropriate choice of ligand, in achieving these synthetic objectives. In particular, we have established that palladium in combination with a bulky trialkylphosphine accomplishes a broad spectrum of coupling processes, including Suzuki, Stille, Negishi, and Heck reactions. These methods have been applied in a wide array of settings, such as natural-product synthesis, materials science, and bioorganic chemistry. PMID:18947239

  16. Proteomic signatures uncover thiol-specific electrophile resistance mechanisms in Bacillus subtilis.

    PubMed

    Antelmann, Haike; Hecker, Michael; Zuber, Peter

    2008-02-01

    Proteomic and transcriptomics signatures are powerful tools for visualizing global changes in gene expression in bacterial cells after exposure to stress, starvation or toxic compounds. Based on the global expression profile and the dissection into specific regulons, this knowledge can be used to predict the mode of action for novel antimicrobial compounds. This review summarizes our recent progress of proteomic signatures in the model bacterium for low-GC Gram-positive bacteria Bacillus subtilis in response to the antimicrobial compounds phenol, catechol, salicylic acid, 2-methylhydroquinone (2-MHQ) and 6-brom-2-vinyl-chroman-4-on (chromanon). Catechol, 2-MHQ and diamide displayed a common mode of action, as revealed by the induction of the thiol-specific oxidative stress response. In addition, multiple dioxygenases/glyoxalases, azoreductases and nitroreductases were induced by thiol-reactive compounds that are regulated by two novel thiol-specific regulators, YodB and MhqR (YkvE), both of which contribute to electrophile resistance in B. subtilis. These novel thiol-stress-responsive mechanisms are highly conserved among Gram-positive bacteria and are thought to have evolved to detoxify quinone-like electrophiles. PMID:18282125

  17. Protection from oxidative and electrophilic stress in the Gsta4-null mouse heart

    PubMed Central

    Beneš, Helen; Vuong, Mai K.; Boerma, Marjan; McElhanon, Kevin E.; Siegel, Eric R.; Singh, Sharda P.

    2013-01-01

    4-hydroxynonenal (4-HNE) mediates many pathological effects of oxidative and electrophilic stress and signals to activate cytoprotective gene expression regulated by NF-E2-related factor 2 (Nrf2). By exhibiting very high levels of 4-HNE-conjugating activity, the murine glutathione transferase alpha 4 (GSTA4-4) helps regulate cellular 4-HNE levels. To examine the role of 4-HNE in vivo, we disrupted the murine Gsta4 gene. Gsta4-null mice exhibited no cardiac phenotype under normal conditions and no difference in cardiac 4-HNE level as compared to wild-type (WT) mice. We hypothesized that the Nrf2 pathway might contribute an important compensatory mechanism to remove excess cardiac 4-HNE in Gsta4-null mice. Cardiac nuclear extracts from Gsta4-null mice exhibited significantly higher Nrf2 binding to antioxidant-response elements (AREs). We also observed responses in critical Nrf2 target gene products: elevated Sod2, Cat, and Akr1b7 mRNA levels and significant increases in both cardiac anti-oxidant and anti-electrophile enzyme activities. Gsta4-null mice were less sensitive and maintained normal cardiac function following chronic doxorubicin (DOX) treatment, known to increase cardiac 4-HNE levels. Hence, in the absence of GSTA4-4 to modulate both physiological and pathological 4-HNE levels, the adaptive Nrf2 pathway may be primed to contribute to a preconditioned cardiac phenotype in the Gsta4-null mouse. PMID:23690225

  18. Tetrabutylammonium decatungstate-photosensitized alkylation of electrophilic alkenes: Convenient functionalization of aliphatic C-H bonds.

    PubMed

    Dondi, Daniele; Fagnoni, Maurizio; Albini, Angelo

    2006-05-15

    Tetrabutylammonium decatungstate (TBADT, 2 x 10(-3) m) is an effective photocatalyst for the alkylation of electrophilic alkenes (0.1 m, alpha,beta-unsaturated nitriles, esters, ketones) by alkanes, alcohols, and ethers. The products are in most cases obtained in >70 % isolated yields, through an experimentally very simple procedure. The kinetics of the radical processes following initial hydrogen abstraction by excited TBADT in deoxygenated MeCN have been studied. In the absence of a trap, back hydrogen transfer from reduced tungstate is the main pathway for alkyl radicals, while alpha-hydroxyalkyl radicals are oxidized to ketones by ground-state TBADT. With both radical types the reaction ceases at a few percent conversion. However, trapping by electrophilic alkenes is followed by reduction of the radical adduct and regeneration of the catalyst, which allows the alkylation to proceed up to complete alkene conversion with the mentioned good yields of products. With a nucleophilic (alpha-hydroxyalkyl) radical, alkylation is efficient (Phi = 0.58) and can also be carried out when degassing is omitted, the only difference being a short induction period. With a less reactive (cyclohexyl) radical, the quantum yield is lower (Phi = 0.06) and the reaction is considerably slowed in aerated solutions, but the chemical yield remains good. PMID:16521134

  19. 15-Hydroxyprostaglandin Dehydrogenase Generation of Electrophilic Lipid Signaling Mediators from Hydroxy Ω-3 Fatty Acids*

    PubMed Central

    Wendell, Stacy Gelhaus; Golin-Bisello, Franca; Wenzel, Sally; Sobol, Robert W.; Holguin, Fernando; Freeman, Bruce A.

    2015-01-01

    15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites. The oxidation of hydroxylated fatty acids, such as the conversion of prostaglandin (PG) E2 to 15-ketoPGE2, by 15PGDH is viewed to inactivate signaling responses. In contrast, the typically electrophilic products can also induce anti-inflammatory and anti-proliferative responses. This study determined that hydroxylated docosahexaenoic acid metabolites (HDoHEs) are substrates for 15PGDH. Examination of 15PGDH substrate specificity was conducted in cell culture (A549 and primary human airway epithelia and alveolar macrophages) using chemical inhibition and shRNA knockdown of 15PGDH. Substrate specificity is broad and relies on the carbon position of the acyl chain hydroxyl group. 14-HDoHE was determined to be the optimal DHA substrate for 15PGDH, resulting in the formation of its electrophilic metabolite, 14-oxoDHA. Consistent with this, 14-HDoHE was detected in bronchoalveolar lavage cells of mild to moderate asthmatics, and the exogenous addition of 14-oxoDHA to primary alveolar macrophages inhibited LPS-induced proinflammatory cytokine mRNA expression. These data reveal that 15PGDH-derived DHA metabolites are biologically active and can contribute to the salutary signaling actions of Ω-3 fatty acids. PMID:25586183

  20. 15-Hydroxyprostaglandin dehydrogenase generation of electrophilic lipid signaling mediators from hydroxy ω-3 fatty acids.

    PubMed

    Wendell, Stacy Gelhaus; Golin-Bisello, Franca; Wenzel, Sally; Sobol, Robert W; Holguin, Fernando; Freeman, Bruce A

    2015-02-27

    15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites. The oxidation of hydroxylated fatty acids, such as the conversion of prostaglandin (PG) E2 to 15-ketoPGE2, by 15PGDH is viewed to inactivate signaling responses. In contrast, the typically electrophilic products can also induce anti-inflammatory and anti-proliferative responses. This study determined that hydroxylated docosahexaenoic acid metabolites (HDoHEs) are substrates for 15PGDH. Examination of 15PGDH substrate specificity was conducted in cell culture (A549 and primary human airway epithelia and alveolar macrophages) using chemical inhibition and shRNA knockdown of 15PGDH. Substrate specificity is broad and relies on the carbon position of the acyl chain hydroxyl group. 14-HDoHE was determined to be the optimal DHA substrate for 15PGDH, resulting in the formation of its electrophilic metabolite, 14-oxoDHA. Consistent with this, 14-HDoHE was detected in bronchoalveolar lavage cells of mild to moderate asthmatics, and the exogenous addition of 14-oxoDHA to primary alveolar macrophages inhibited LPS-induced proinflammatory cytokine mRNA expression. These data reveal that 15PGDH-derived DHA metabolites are biologically active and can contribute to the salutary signaling actions of Ω-3 fatty acids. PMID:25586183

  1. 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.

  2. Cp*Rh(iii)-catalyzed electrophilic amination of arylboronic acids with azo compounds for synthesis of arylhydrazides.

    PubMed

    Lau, Yan-Fung; Chan, Chun-Ming; Zhou, Zhongyuan; Yu, Wing-Yiu

    2016-07-12

    A [Cp*Rh(iii)]-catalyzed electrophilic amination of arylboronic acids with diethyl azodicarboxylate (DEAD) was developed, and arylhydrazides were produced in excellent yields and selectivity. The analogous amination with the arylazocarboxylates afforded the corresponding N,N-diarylhydrazides. The electrophilic amination of arylboronic acids with azocarboxylates proceeds readily under mild conditions with excellent functional group tolerance. Up to 99% yields were obtained. Preliminary mechanistic studies revealed that prior formation of an arylrhodium(iii) intermediate for the azo coupling reaction can be ruled out. PMID:27339710

  3. Electrophilic Activation of α,β-Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ-Butyrolactones.

    PubMed

    Zhang, Ming; Kumagai, Naoya; Shibasaki, Masakatsu

    2016-04-11

    Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β-unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β-unsaturated 7-azaindoline amides act as reactive electrophiles to participate in catalytic diastereo- and enantioselective vinylogous conjugate addition of γ-butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner. PMID:26970428

  4. The highly electrophilic character of 4-chloro-7-nitrobenzofurazan and possible consequences for its application as a protein-labelling reagent.

    PubMed Central

    Baines, B S; Allen, G; Brocklehurst, K

    1977-01-01

    4-Chloro-7-nitrobenzofurazan possesses at least one highly electrophilic centre (C-6) that is much more reactive towards nucleophiles than position C-4, the irreversible alkylating site of this reagent. Possible consequences of the electrophilic character of 4-chloro-7-nitrobenzofurazan for its application as a protein-labelling reagent are discussed. PMID:17393

  5. α,β-Double Electrophilic Addition of Allene-1,3-Dicarboxylic Esters for the Construction of Polysubstituted Furans by KI/tert-Butyl Hydroperoxide (TBHP)-Promoted Oxidative Annulation.

    PubMed

    Li, Hong-Liang; Wang, Yu; Sun, Pei-Pei; Luo, Xiaoyan; Shen, Zhenlu; Deng, Wei-Ping

    2016-06-27

    An unprecedented KI/tert-butyl hydroperoxide promoted tandem Michael addition/oxidative annulation of allene-1,3-dicarboxylic esters and 1,3-dicarbonyl compounds has been developed. This procedure provides a new, facile, and transition-metal-free synthetic approach to afford polysubstituted furans in moderate to excellent yields (up to 93 %). This method first establishes a α,β-double electrophilic reaction mode of allene-1,3-dicarboxylic esters to form 1,3-dicarbonyl compounds. PMID:27225634

  6. Synthesis of 3,4-Disubstituted 2H-Benzopyrans Through C-C Bond Formation via Electrophilic Cyclization

    PubMed Central

    Worlikar, Shilpa A.; Kesharwani, Tanay; Yao, Tuanli; Larock, Richard C.

    2008-01-01

    The electrophilic cyclization of substituted propargylic aryl ethers by I2, ICl and PhSeBr produces 3,4-disubstituted 2H-benzopyrans in excellent yields. This methodology results in vinylic halides or selenides under mild reaction conditions, and tolerates a variety of functional groups, including methoxy, alcohol, aldehyde and nitro groups. PMID:17288382

  7. Electrophilic Activation of P-Alkynes in the Synthesis of P-Substituted and P-Centered Heterocycles.

    PubMed

    Gupta, Akhil; Flynn, Bernard L

    2016-05-20

    Electrophilic activation of alkynylphosphine oxides and phosphonates provides a novel approach to the synthesis of P-substituted and P-centered heterocycles. Iodocyclization affords a heteroaryl iodide that can, among other things, be used in reiterative alkyne coupling and iodocyclization to give cyclic phosphonates and other cyclization reactions to give π-rich P-heterocycles. PMID:27088459

  8. Determination of gas-phase nucleophilicities and electrophilicities using B⋯HX bond critical point properties of AIM analysis

    NASA Astrophysics Data System (ADS)

    Ebrahimi, Ali; Roohi, Hosein; Habibi, Mostafa; Hasannejad, Mehdi

    2006-09-01

    The values of nucleophilicity and electrophilicity have been established in gas phase for some nucleophiles (B = CH 3CN, CO, H 2O, H 2S, HCN, N 2, NH 3, PH 3) and electrophiles (HX = HF, HCl, HBr, HCN HCF 3) from properties of bond critical points of atoms in molecules (AIM) analysis. On the basis of the meaningful relationship, the recent method has been applied to electron density ( ρ), Laplacian of electron density (∇ρ2), and electronic kinetic energy density ( G), of B⋯HX bond critical point. AIM analysis has been performed on the obtained wave functions at MP2/6-311++G(d,p) level of theory. The correlation between averaged calculated values of nucleophilicity (or electrophilicity), using different properties of B⋯HX bond critical points, and complexation energies (Δ Ecomp) is satisfactory. The best correlation coefficient between nucleophilicity and Δ Ecomp is related to ρ values of bond critical points. But, the best correlation coefficient between electrophilicity and Δ Ecomp is allied to ∇ρ2 and G values of bond critical points.

  9. 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

  10. 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

  11. 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

  12. 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.

  13. Cobalt co-catalysis for cross-electrophile coupling: diarylmethanes from benzyl mesylates and aryl halides†

    PubMed Central

    2014-01-01

    The nickel-catalyzed cross-coupling of aryl halides with alkyl radicals derived from alkyl halides has recently been extended to couplings with carbon radicals generated by a co-catalyst. In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), is introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This is because Co(Pc) reacts with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction are presented. PMID:25685312

  14. Polar [3 + 2] cycloaddition of ketones with electrophilically activated carbonyl ylides. Synthesis of spirocyclic dioxolane indolinones.

    PubMed

    Bentabed-Ababsa, Ghenia; Derdour, Aicha; Roisnel, Thierry; Sáez, Jose A; Domingo, Luis R; Mongin, Florence

    2008-09-01

    The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and ketones (ethyl pyruvate, ethyl phenylglyoxylate, isatin, N-methylisatin and 5-chloroisatin) to give substituted dioxolanes and spirocyclic dioxolane indolinones was investigated. The effect of microwave irradiation on the outcome of the reaction was studied. The thermal reaction between 2,2-dicyano-3-phenyloxirane and N-methylisatin was theoretically studied using DFT methods. This reaction is a domino process that comprises two steps. The first is the thermal ring opening of the epoxide to yield a carbonyl ylide intermediate, whereas the second step is a polar [3 + 2] cycloaddition to yield the final spiro cycloadducts. The cycloaddition presents a low stereoselectivity and a large regio- and chemoselectivity. Analysis of the electrophilicity values and the Fukui functions of the reagents involved in the cycloaddition step allowed the chemical outcome to be explained. PMID:18698474

  15. 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

  16. 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

  17. Reactive force field for electrophilic substitution at an aromatic system in twin polymerization

    NASA Astrophysics Data System (ADS)

    Schönfelder, Thomas; Friedrich, Joachim; Prehl, Janett; Seeger, Steffen; Spange, Stefan; Hoffmann, Karl Heinz

    2014-08-01

    Twin polymerization is a new synthesis concept, which enables the formation of two different macromolecular structures from organic-inorganic hybrid materials in one single process step. To gain insights into formation processes we implement a first-principles-based ReaxFF reactive force field for C/H/O/Si for the initial electrophilic substitution of an aromatic system. We show that established parametrizations that have been developed to model chemical reactions of (hydro) carbon or carbon nanotubes systems successfully cannot reproduce this reaction although they include the same chemical elements and in parts same reaction mechanisms. Thus, we develop a new parametrization being capable in reproducing this aromatic reaction properly and compare it to the established ones to identify the differences.

  18. Triflic Acid-Catalyzed Enynes Cyclization: A New Strategy beyond Electrophilic π-Activation.

    PubMed

    Yu, Zhunzhun; Liu, Lu; Zhang, Junliang

    2016-06-13

    The cyclization of enynes, catalyzed by a transition metal, represents a powerful tool to construct an array of cyclic compounds through electrophilic π-activation. In this paper, we disclose a new and efficient strategy for enynes cyclization catalyzed by triflic acid. The salient features of this transformation includes a broad substrate scope, metal free synthesis, open flask and mild conditions, good yields, ease of operation, low catalyst loading, and easy scale-up to gram scale. A preliminary mechanism study demonstrated that the activation model of the reaction was σ-activation, which is different from the transition-metal-catalyzed enynes cyclization. Our strategy affords a complementary method to the traditional strategies, which use transition-metal catalysts. PMID:27124814

  19. Difluorocarbene-Derived Trifluoromethylthiolation and [(18)F]Trifluoromethylthiolation of Aliphatic Electrophiles.

    PubMed

    Zheng, Jian; Wang, Lu; Lin, Jin-Hong; Xiao, Ji-Chang; Liang, Steven H

    2015-11-01

    The first trifluoromethylthiolation and [(18)F]trifluoromethylthiolation of alkyl electrophiles with in situ generated difluorocarbene in the presence of elemental sulfur and external (radioactive) fluoride ion is described. This transition-metal-free approach is high yielding, compatible with a variety of functional groups, and operated under mild reaction conditions. The conceptual advantage of this exogenous-fluoride-mediated transformation enables unprecedented syntheses of [(18)F]CF3S-labeled molecules from most commonly used [(18)F]fluoride ions. The rapid radiochemical reaction time (≤1 min) and high functional-group tolerance allow access to a variety of aliphatic [(18)F]CF3S compounds in high yields. PMID:26387796

  20. Genetically Encoding an Electrophilic Amino Acid for Protein Stapling and Covalent Binding to Native Receptors

    PubMed Central

    2015-01-01

    Covalent bonds can be generated within and between proteins by an unnatural amino acid (Uaa) reacting with a natural residue through proximity-enabled bioreactivity. Until now, Uaas have been developed to react mainly with cysteine in proteins. Here we genetically encoded an electrophilic Uaa capable of reacting with histidine and lysine, thereby expanding the diversity of target proteins and the scope of the proximity-enabled protein cross-linking technology. In addition to efficient cross-linking of proteins inter- and intramolecularly, this Uaa permits direct stapling of a protein α-helix in a recombinant manner and covalent binding of native membrane receptors in live cells. The target diversity, recombinant stapling, and covalent targeting of endogenous proteins enabled by this versatile Uaa should prove valuable in developing novel research tools, biological diagnostics, and therapeutics by exploiting covalent protein linkages for specificity, irreversibility, and stability. PMID:25010185

  1. 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

  2. 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

  3. Electrophilic Aromatic Substitution. 13.(1) Kinetics and Spectroscopy of the Chloromethylation of Benzene and Toluene with Methoxyacetyl Chloride or Chloromethyl Methyl Ether and Aluminum Chloride in Nitromethane or Tin Tetrachloride in Dichloromethane. The Methoxymethyl Cation as a Remarkably Selective Common Electrophile.

    PubMed

    DeHaan, Franklin P.; Djaputra, Markus; Grinstaff, Mark W.; Kaufman, Craig R.; Keithly, James C.; Kumar, Amit; Kuwayama, Mark K.; Macknet, K. Dale; Na, Jim; Patel, Bimal R.; Pinkerton, Michael J.; Tidwell, Jeffrey H.; Villahermosa, Randy M.

    1997-05-01

    Vacuum line kinetics studies have been made of the reaction in nitromethane between benzene and/or toluene, methoxyacetyl chloride (MAC), and AlCl(3) to produce benzyl or xylyl chlorides, CO, and a CH(3)OH(-)AlCl(3) complex. For both arenes, the rate law appears to be R = (k(3)/[AlCl(3)](0)) [AlCl(3)](2)[MAC]. When chloromethyl methyl ether (CMME) is substituted for MAC, a similar rate law is obtained. Both chloromethylation reactions yielded similar, large k(T)()/k(B)() ratios (500-600) and similar product isomer distributions with low meta percentages ( approximately 0.4) which suggest CH(3)OCH(2)(+) or the CH(3)OCH(2)(+)Al(2)Cl(7)(-) ion pair as a common, remarkably selective, electrophile. The kinetics of MAC decomposition to CMME and CO in the presence of AlCl(3) yielded the rate law R = k(2)[AlCl(3)](0)[MAC]. Here AlCl(3) is a catalyst (no CH(3)OH is formed), and thus the rate law is equivalent to the chloromethylation rate law. All three reactions have comparable reactivities, which is consistent with rate-determining production of the electrophile. Kinetics studies of benzene or toluene with SnCl(4) and MAC or CMME in dichloromethane were also completed. With MAC and benzene the rate law is R = k(3)[SnCl(4)](0)[MAC][benzene] and with toluene R = k(2)[SnCl(4)](0)[MAC]. MAC decomposition, again followed by CO production, was unaffected by the presence of either aromatic and obeyed the rate law R = k(2)' [SnCl(4)](0)[MAC] where k(2) approximately k(2)'. Chloromethylation with CMME followed the rate law R = k(3)[SnCl(4)](0)[CMME][arene] for benzene and toluene and produced a k(T)()/k(B)() ratio and product isomer distributions very similar to those determined with AlCl(3) in nitromethane, further supporting a common electrophile. Low-temperature (13)C and (119)Sn FT-NMR and Raman spectroscopic studies suggest the existence of a weak 1:1 adduct between MAC and SnCl(4) of the type RCXO --> SnCl(4), with electron donation to the metal through carboxy oxygen

  4. 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

  5. Synthesis of 2,3-Disubstituted Benzo[b]furans by the Palladium-Catalyzed Coupling of o-Iodoanisoles and Terminal Alkynes, Followed by Electrophilic Cyclization

    PubMed Central

    Yue, Dawei; Yao, Tuanli; Larock, Richard C.

    2008-01-01

    2,3-Disubstituted benzo[b]furans are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization using I2, PhSeCl or p-O2NC6H4SCl. Aryl- and vinylic-substituted alkynes undergo electrophilic cyclization in excellent yields. Biologically important furopyridines can be prepared by this approach in high yields. PMID:16323837

  6. An unexpected 2,3-dihydrofuran derivative ring opening initiated by electrophilic bromination: scope and mechanistic study.

    PubMed

    Zhao, Yi; Wong, Ying-Chieh; Yeung, Ying-Yeung

    2015-01-01

    An unexpected 2,3-dihydrofuran ring opening process at the C(4)-C(5) bond has been developed. N-Bromosuccinimide and DABCO were used as the electrophilic halogen source and the catalyst, respectively. Mechanistic study indicates that moisture in the solvent might contribute to the reaction. The resulting brominated product could be further oxidized to yield a synthetically valuable 1,2-diketo building block. PMID:25469549

  7. 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

  8. Comprehensive Energetic Scale for Quantitatively Estimating the Fluorinating Potential of N-F Reagents in Electrophilic Fluorinations.

    PubMed

    Xue, Xiao-Song; Wang, Ya; Li, Man; Cheng, Jin-Pei

    2016-05-20

    Quantitative knowledge of the fluorinating strength of electrophilic N-F reagents is of crucial importance for rational design and optimization of novel reagents and new reactions. Herein, we report the first systematic computation of fluorinating potentials of 130 electrophilic N-F reagents in two commonly used solvents dichloromethane and acetonitrile in terms of the N-F bond heterolysis energies as expressed by the fluorine plus detachment (FPD) values. The calculated FPD scales of 130 N-F reagents cover a range from 112.3 to 290.4 kcal mol(-1) and 110.9 to 278.4 kcal mol(-1) in dichloromethane and acetonitrile, respectively. This comprehensive FPD database provides a valuable quantitative guide for studying the influence of structural variation on the fluorinating strength of the N-F reagents, opening a door to the rational design of novel reagents with appropriate fluorinating strength for specific purposes. It is demonstrated that the FPD values can reproduce the reactivity order for electrophilic N-F reagents better than other parameters. PMID:27120313

  9. 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.

  10. Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

    PubMed Central

    Haridas, Valsala; Hanausek, Margaret; Nishimura, Goshi; Soehnge, Holly; Gaikwad, Amos; Narog, Maciej; Spears, Erick; Zoltaszek, Robert; Walaszek, Zbigniew; Gutterman, Jordan U.

    2004-01-01

    Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two α,β unsaturated carbonyl groups (Michael reaction sites) in the side chain of the avicin molecule prompted us to study its effects on NF-E2–related factor 2 (Nrf2), a redox-regulated transcription factor that controls the expression of a battery of detoxification and antioxidant proteins via its binding to antioxidant response element (ARE). Avicin D–treated Hep G2 cells showed translocation of Nrf2 into the nucleus and a time-dependent increase in ARE activity. These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule. Downstream of ARE, an activation of a battery of stress-induced proteins occurred. The implications of these findings were evaluated in vivo in mouse skin exposed to an ancient stressor, UV light. Avicins inhibited epidermal hyperplasia, reduced p53 mutation, enhanced apoptosis, decreased generation of 8-hydroxy-2′-deoxyguanosine, and enhanced expression of NADPH:quinone oxidoreductase 1 and heme oxygenase-1. These data, combined with our earlier published work, demonstrate that avicins represent a new class of plant stress metabolites capable of activating stress adaptation and suppressing proinflammatory components of the innate immune system in human cells by redox regulation. The relevance for treatment of clinical diseases in which stress responses are dysfunctional or deficient is discussed. PMID:14702110

  11. 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

  12. Pyridoxylamine reactivity kinetics as an amine based nucleophile for screening electrophilic dermal sensitizers

    PubMed Central

    Chipinda, Itai; Mbiya, Wilbes; Adigun, Risikat Ajibola; Morakinyo, Moshood K.; Law, Brandon F.; Simoyi, Reuben H.; Siegel, Paul D.

    2015-01-01

    Chemical allergens bind directly, or after metabolic or abiotic activation, to endogenous proteins to become allergenic. Assessment of this initial binding has been suggested as a target for development of assays to screen chemicals for their allergenic potential. Recently we reported a nitrobenzenethiol (NBT) based method for screening thiol reactive skin sensitizers, however, amine selective sensitizers are not detected by this assay. In the present study we describe an amine (pyridoxylamine (PDA)) based kinetic assay to complement the NBT assay for identification of amine-selective and non-selective skin sensitizers. UV-Vis spectrophotometry and fluorescence were used to measure PDA reactivity for 57 chemicals including anhydrides, aldehydes, and quinones where reaction rates ranged from 116 to 6.2 × 10−6 M−1 s−1 for extreme to weak sensitizers, respectively. No reactivity towards PDA was observed with the thiol-selective sensitizers, non-sensitizers and prohaptens. The PDA rate constants correlated significantly with their respective murine local lymph node assay (LLNA) threshold EC3 values (R2 = 0.76). The use of PDA serves as a simple, inexpensive amine based method that shows promise as a preliminary screening tool for electrophilic, amine-selective skin sensitizers. PMID:24333919

  13. 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

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

    PubMed

    Kulkarni, Pushkar M; Kulkarni, Abhijit R; Korde, Anisha; Tichkule, Ritesh B; Laprairie, Robert B; Denovan-Wright, Eileen M; Zhou, Han; Janero, David R; Zvonok, Nikolai; Makriyannis, Alexandros; Cascio, Maria G; Pertwee, Roger G; Thakur, Ganesh A

    2016-01-14

    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

  15. Carborane Substituents Promote Direct Electrophilic Insertion over Reduction-Metalation Reactions.

    PubMed

    Man, Wing Y; Ellis, David; Rosair, Georgina M; Welch, Alan J

    2016-03-24

    Two-electron reduction of 1,1'-bis(o-carborane) followed by reaction with [Ru(η-mes)Cl2 ]2 affords [8-(1'-1',2'-closo-C2 B10 H11 )-4-(η-mes)-4,1,8-closo-RuC2 B10 H11 ]. Subsequent two-electron reduction of this species and treatment with [Ru(η-arene)Cl2 ]2 results in the 14-vertex/12-vertex species [1-(η-mes)-9-(1'-1',2'-closo-C2 B10 H11 )-13-(η-arene)-1,13,2,9-closo-Ru2 C2 B10 H11 ] by direct electrophilic insertion, promoted by the carborane substituent in the 13-vertex/12-vertex precursor. When arene=mesitylene (mes), the diruthenium species is fluxional in solution at room temperature in a process that makes the metal-ligand fragments equivalent. A unique mechanism for this fluxionality is proposed and is shown to be fully consistent with the observed fluxionality or nonfluxionality of a series of previously reported 14-vertex dicobaltacarboranes. PMID:26934539

  16. 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

  17. 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

  18. 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.

  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. PMID:26699842

  20. 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

  1. 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

  2. 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

  3. Electrophilic FLUORIDE-18 from AN 11 Mev Proton Cyclotron for Radiolabeling of Presynaptic Dopaminergic PET Tracers

    NASA Astrophysics Data System (ADS)

    Sunderland, John Joseph

    1990-01-01

    The reliable production of (^{18 }F) F_2 from an 11 MeV proton cyclotron has been achieved through the implementation of two accelerator targets built to exploit the copious ^{18}O(p,n)^ {18}F cross-section. Yields of electrophilic (^{18}F) F_2 from the targets reached deciCurie levels with specific activities approaching 3 Ci/mmole with 75 minute irradiations at 10 muA. Higher specific activities are expected with longer bombardments and increased beam current. The targets, one nickel, the other with a gold -plated target chamber, have been tested for (^ {18}F) F_2 production efficiency under two bombardment protocols. An economic two-step protocol cryogenically reclaims the precious enriched ^{18}O_{2 } target material following ^ {18}F production, followed by a second (^{18}F) F_2 recovery irradiation of Kr + F_2 . Studies of target performance using this protocol under variable irradiation conditions suggest a five compartment model governing the in-target kinetics. Similarly, the (^{18}F) F_2 yields have been tested using a single irradiation protocol consisting of bombardment of ^{18}O_{2} + F _2. Theoretical descriptions of beam induced phenomena in the irradiated target are also presented. The behavior of these targets cannot be judged solely on the amount of reactive ^{18 }F which elutes from the target; successful radiochemical synthesis utilizing this ^ {18}F activity in a model reaction is the true test. Synthesis of 6- (^{18 }F) fluoro-L-DOPA (6-FD) by the fluoro-demercuration method of Luxen served this purpose, testing the eletrophilic (^{18}F) F_2 gas from the two targets and two irradiation protocols. Elution of Kr + (^{18}F) F _2 from the two-step method achieved the expected 12% radiochemical yields from (^ {18}F) F_2, while experience with ^{18}F activity eluted with oxygen from the single irradiation protocol suffered lower yields. Solutions to problems associated with 6-FD studies for Positron Emission Tomography (PET) are addressed. A

  4. 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

  5. Gas-phase ion-molecule reactions: a model for the determination of biologically reactive electrophilic contaminants in the environment.

    PubMed

    Freeman, J A; Johnson, J V; Yost, R A; Kuehl, D W

    1994-06-01

    A promising instrumental technique has been investigated to rapidly screen complex environmental samples for chemical contaminants having the propensity to covalently bond to biomacromolecules such as DNA. Radical molecular ions of pyridine, a model compound for nucleophilic bases of DNA, were mass-selected and allowed to react with electrophilic environmental contaminants in the collision cell of a triple quadrupole mass spectrometer. Analytes were introduced into the collision cell via a gas chromatographic column. Reactive chemicals are then characterized by scanning Q3 to identify associative reaction products. A good qualitative correlation was observed for the gas-phase reactivity of a series of electrophilic reagents with both their alkylating reactivity in solution (4-(4-nitrobenzyl)pyridine) and AMES test mutagenicity which had been previously published. Femtomole limits of detection for specific associative reaction products were demonstrated. Gas-phase reactions of ions of environmental contaminants (introduced into the source) with neutral pyridine (in the collision cell) were also investigated. Reactions of the radical molecular ion of the allyl reagents with neutral pyridine were similar to results from the mass-selected reaction of the pyridine radical molecular ion with neutral allylic reagents. PMID:8030792

  6. Reactivity of endohedral metallofullerene la2@c80 in nucleophilic and electrophilic attacks: vibronic coupling density approach.

    PubMed

    Haruta, Naoki; Sato, Tohru; Tanaka, Kazuyoshi

    2015-01-01

    The regioselectivities of La2@C80 in thermal nucleophilic and electrophilic attacks were theoretically investigated using vibronic coupling density (VCD) analysis. Nucleophilic and electrophilic cycloadditions to La2@C80 were experimentally reported to yield [6,6] and [6,5] adducts, respectively, as major products. VCD analysis provided a clear explanation for these experimental results. For nucleophilic reactions, it was found that the reactive [6,6] bonds did not have a large lowest unoccupied molecular orbital (LUMO) density and Fukui function but a large potential derivative with respect to a reaction mode. The VCD illustrates the origin of the interaction between the electronic and vibrational states. On the other hand, conventional reactivity indices such as frontier orbital density take only the electronic state into account. The result suggested that the stabilization due to vibronic couplings plays an important role in the regioselectivity of nucleophilic cycloadditions. The VCD with respect to the effective mode could provide a picture of the functional groups, which are the double bonds of ethylene moieties. VCD analysis with respect to hypothetical localized modes enabled the quantitative prediction of regioselectivities. PMID:25389657

  7. Reaction of a 2,4,6-triphenylphosphinine ferrate anion with electrophiles: a new route to phosphacyclohexadienyl complexes.

    PubMed

    Hoidn, Christian M; Wolf, Robert

    2016-06-01

    A novel, versatile route to phosphorus- and carbon-substituted η(5)-phosphacyclohexadienyl complexes was developed. Reaction of the anionic 2,4,6-triphenylphosphinine iron complex [K([18]crown-6)(thf)2][Cp*Fe(PC5Ph3H2)] (1) with selected main group element electrophiles afforded the new complexes [Cp*Fe(2-endo-H-PC5Ph3H2)] (endo-3), [Cp*Fe(2-exo-H-PC5Ph3H2)] (exo-3), [Cp*Fe(1-Me-PC5Ph3H2)] (4), [Cp*Fe(1-Me3Si-PC5Ph3H2)] (5), [Cp*Fe(1-PPh2-PC5Ph3H2)] (6) and [Cp*Fe(2-BCat-PC5Ph3H2)] (7, BCat = 2-benzo[d][1,3,2]dioxaborol-2-yl). Initial attack of the electrophile at phosphorus was observed, leading to a P-substitued phosphinine ligand. A subsequent rearragement occured in some cases, resulting in C-substituted phosphinine complexes endo-3, exo-3 and 7. The new complexes were characterized by (1)H, (31)P{(1)H}, and (13)C{(1)H} NMR spectroscopy, UV-vis spectroscopy and elemental analysis; their molecular structures were determined by X-ray crystallography. PMID:27150955

  8. Reactivity of molybdenum and rhenium hydroxo-carbonyl complexes toward organic electrophiles.

    PubMed

    Cuesta, Luciano; Gerbino, Darío C; Hevia, Eva; Morales, Dolores; Navarro Clemente, M Elena; Pérez, Julio; Riera, Lucía; Riera, Víctor; Miguel, Daniel; del Río, Ignacio; García-Granda, Santiago

    2004-04-01

    The hydroxo compounds [Re(OH)(CO)(3)(N-N)] (N-N=bipy, 2 a; Me(2)-bipy, 2 b) were prepared in a biphasic H(2)O/CH(2)Cl(2) medium by reaction of [Re(OTf)(CO)(3)(N-N)] with KOH. In contrast, when anhydrous CH(2)Cl(2) was used, the binuclear hydroxo-bridged compound [[Re(CO)(3)(bipy)](2)(mu-OH)]OTf (3-OTf) was obtained. Compound [Re(OH)(CO)(3)(Me(2)-bipy)] (2 b) reacted with phenyl acetate or vinyl acetate to afford [Re(OAc)(CO)(3)(Me(2)-bipy)] (4) and phenol or acetaldehyde, respectively. The reactions of [Mo(OH)(eta(3)-C(3)H(4)-Me-2)(CO)(2)(phen)] (1), 2 a, and 2 b toward several unsaturated organic electrophiles were studied. The reaction of 1 with (p-tolyl)isocyanate afforded an adduct of N,N'-di(p-tolyl)urea and the carbonato-bridged compound [[Mo(eta(3)-C(3)H(4)-Me-2)(CO)(2)(phen)](2)(mu-eta(1)(O),eta(1)(O)-CO(3))] (5). In contrast, the reaction of 2 a with phenylisocyanate afforded [Re(OC(O)NHPh)(CO)(3)(bipy)] (6); this results from formal PhNCO insertion into the O-H bond. On the other hand, compounds [Mo[SC(O)NH(p-tolyl)](eta(3)-C(3)H(4)-Me-2)(CO)(2)(phen)] (7), [Re[SC(O)NH(p-tolyl)](CO)(3)(Me(2)-bipy)] (8 a), and [Re[SC(O)NHEt](CO)(3)(Me(2)-bipy)] (8 b) were obtained by reaction of 1 or 2 b with the corresponding alkyl or aryl isothiocyanates. In those cases, RNCS was inserted into the M-O bond. The reactions of 1, 2 a, and 2 b with dimethylacetylenedicarboxylate (DMAD) gave the complexes [Mo[C(OH)-C(CO(2)Me)C(CO(2)Me)-O](eta(3)-C(3)H(4)-Me-2)(CO)(phen)] (9) and [Re[C(OH)C(CO(2)Me)C(CO(2)Me)O](CO)(2)(N-N)] (N-N=bipy, 10 a; Me(2)-bipy, 10 b). The molecules of these compounds contain five-membered metallacycles that are the result of coupling between the hydroxo ligand, DMAD, and one of the CO ligands. The new compounds were characterized by a combination of IR and NMR spectroscopy, and for [[Re(CO)(3)(bipy)(2)(mu-OH)]BF(4) (3-BF(4)), 4, 5, 6, 7, 8 b, 9, and 10 b, also by means of single-crystal X-ray diffraction. PMID:15054764

  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. 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.

  11. 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

  12. 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

  13. The stereochemical outcome of electrophilic addition reactions on the 5,6-double bond in the spinosyns.

    PubMed

    De Amicis, C V; Graupner, P R; Erickson, J A; Paschal, J W; Kirst, H A; Creemer, L C; Fanwick, P E

    2001-12-14

    The electrophilic addition of reagents to the 5,6-double bond in spinosyn A and spinosyn D systems occurred with high pi-diastereofacial selectivity. Addition occurred preferentially from the beta face of the molecule with selectivities ranging from 5:1 to better than 30:1. Various NMR properties were investigated in order to distinguish the beta and alpha isomers with the help of theoretical models of the products. These NMR properties include a (13)C gamma effect to C-11 and vicinal coupling between H-4 and H-5. To help rationalize the selectivity, computational studies on the transition states for epoxidation were calculated using density functional theory. The results indicate that beta epoxidation is favored and that the geometries of the transition structures are consistent with torsional steering being the source of the selectivity. PMID:11735521

  14. Electrophilic arene hydroxylation and phenol O-H oxidations performed by an unsymmetric μ-η(1):η(1)-O2-peroxo dicopper(II) complex.

    PubMed

    Garcia-Bosch, Isaac; Ribas, Xavi; Costas, Miquel

    2012-02-13

    Reactions of the unsymmetric dicopper(II) peroxide complex [Cu(II)(2)(μ-η(1):η(1)-O(2))(m-XYL(N3N4))](2+) (1 O(2), where m-XYL is a heptadentate N-based ligand), with phenolates and phenols are described. Complex 1 O(2) reacts with p-X-PhONa (X = MeO, Cl, H, or Me) at -90 °C performing tyrosinase-like ortho-hydroxylation of the aromatic ring to afford the corresponding catechol products. Mechanistic studies demonstrate that reactions occur through initial reversible formation of metastable association complexes [Cu(II)(2)(μ-η(1):η(1)-O(2))(p-X-PhO)(m-XYL(N3N4))](+) (1 O(2)⋅X-PhO) that then undergo ortho-hydroxylation of the aromatic ring by the peroxide moiety. Complex 1 O(2) also reacts with 4-X-substituted phenols p-X-PhOH (X = MeO, Me, F, H, or Cl) and with 2,4-di-tert-butylphenol at -90 °C causing rapid decay of 1 O(2) and affording biphenol coupling products, which is indicative that reactions occur through formation of phenoxyl radicals that then undergo radical C-C coupling. Spectroscopic UV/Vis monitoring and kinetic analysis show that reactions take place through reversible formation of ground-state association complexes [Cu(II)(2)(μ-η(1):η(1)-O(2))(X-PhOH)(m-XYL(N3N4))](2+) (1 O(2)⋅X-PhOH) that then evolve through an irreversible rate-determining step. Mechanistic studies indicate that 1 O(2) reacts with phenols through initial phenol binding to the Cu(2)O(2) core, followed by a proton-coupled electron transfer (PCET) at the rate-determining step. Results disclosed in this work provide experimental evidence that the unsymmetric 1 O(2) complex can mediate electrophilic arene hydroxylation and PCET reactions commonly associated with electrophilic Cu(2)O(2) cores, and strongly suggest that the ability to form substrate⋅Cu(2)O(2) association complexes may provide paths to overcome the inherent reactivity of the O(2)-binding mode. This work provides experimental evidence that the presence of a H(+) completely determines the

  15. Protonation of azines and purines as a model for the electrophilic aromatic substitution - rationalization by triadic formula.

    PubMed

    Vianello, Robert

    2011-09-01

    First gas-phase carbon proton affinities of eleven azines and purines (pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, bicyclic purine, pyridine-N-oxide, 2-aminopyrimidine and uracil) were calculated by a composite G3B3 methodology and used to probe their susceptibility to undergo electrophilic aromatic substitution (EAS), taking benzene as a reference molecule. The results revealed excellent agreement with the available experimental data and were interpreted using the triadic approach. We found out that pyrroles, which are more reactive towards EAS reaction than benzene, are stronger carbon bases than the latter compound, whereas pyridines exhibit lower carbon basicity, being at the same time less reactive toward substitution by electrophiles than benzene. In all of the investigated molecules the frontier orbital describing the corresponding p-electron density at the carbon atom to be protonated is HOMO as calculated by the HF/G3large//B3LYP/6-31G(d) level of theory. Our results are in a disagreement with the work by D'Auria (M. D'Auria, Tetrahedron Lett. 2005, 46, 6333-6336; Lett. Org. Chem. 2005, 2, 659-661), who at B3LYP/6-311+G(d, p) level found out that in some of systems investigated here the HOMO orbital is not of -symmetry, which was used to rationalize the lower reactivity of these systems towards EAS. It turned out that energies of HOMO orbitals alone correlate very poorly with carbon proton affinities, unlike the difference in proton affinities between the most basic carbon atom and thermodynamically the most favourable site of protonation, which performs much better. Triadic analysis demonstrated the importance of considering a complete picture of the protonation process and all three terms appearing in the triadic scheme individually when discussing trends in basicity/nucleophilicity of closely related molecules. PMID:24062111

  16. 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

  17. Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products.

    PubMed Central

    Levonen, Anna-Liisa; Landar, Aimee; Ramachandran, Anup; Ceaser, Erin K; Dickinson, Dale A; Zanoni, Giuseppe; Morrow, Jason D; Darley-Usmar, Victor M

    2004-01-01

    The molecular mechanisms through which oxidized lipids and their electrophilic decomposition products mediate redox cell signalling is not well understood and may involve direct modification of signal-transduction proteins or the secondary production of reactive oxygen or nitrogen species in the cell. Critical in the adaptation of cells to oxidative stress, including exposure to subtoxic concentrations of oxidized lipids, is the transcriptional regulation of antioxidant enzymes, many of which are controlled by antioxidant-responsive elements (AREs), also known as electrophile-responsive elements. The central regulator of the ARE response is the transcription factor Nrf2 (NF-E2-related factor 2), which on stimulation dissociates from its cytoplasmic inhibitor Keap1, translocates to the nucleus and transactivates ARE-dependent genes. We hypothesized that electrophilic lipids are capable of activating ARE through thiol modification of Keap1 and we have tested this concept in an intact cell system using induction of glutathione synthesis by the cyclopentenone prostaglandin, 15-deoxy-Delta12,14-prostaglandin J2. On exposure to 15-deoxy-Delta12,14-prostaglandin J2, the dissociation of Nrf2 from Keap1 occurred and this was dependent on the modification of thiols in Keap1. This mechanism appears to encompass other electrophilic lipids, since 15-A(2t)-isoprostane and the lipid aldehyde 4-hydroxynonenal were also shown to modify Keap1 and activate ARE. We propose that activation of ARE through this mechanism will have a major impact on inflammatory situations such as atherosclerosis, in which both enzymic as well as non-enzymic formation of electrophilic lipid oxidation products are increased. PMID:14616092

  18. Kinetic glutathione chemoassay to quantify thiol reactivity of organic electrophiles--application to alpha,beta-unsaturated ketones, acrylates, and propiolates.

    PubMed

    Böhme, Alexander; Thaens, Diana; Paschke, Albrecht; Schüürmann, Gerrit

    2009-04-01

    Glutathione (GSH) is a soft nucleophile and, as such, can be used to sense the reactivity of electrophilic agents toward the thiol group and other electron-rich sites of molecular structures. A new kinetic GSH chemoassay is introduced that employs a photometric method to quantify GSH loss and enables an efficient determination of second-order rate constants, k(GSH), of the reaction between electrophilic substances and GSH. Comparison with an existing 2 h static assay shows that the new kinetic variant is superior with respect to the detectable range of electrophilic reactivity and to confounding factors such as additional GSH loss due to oxidation. Analysis of the chemoassay degradation kinetics provides insight into the characteristic reaction times and the contributions of GSH-electrophile Michael addition and GSH oxidation to the overall GSH loss. For 15 alpha,beta-unsaturated ketones, nine acrylates, and two propiolates acting as Michael acceptors, the measured k(GSH) values span ca. 5 orders of magnitude. Moreover, log k(GSH) correlates with the compounds' toxicity toward the ciliates Tetrahymena pyriformis in terms of 48 h log EC(50) (50% growth inhibition) values, yielding a squared correlation coefficient (r(2)) of 0.91 and a root-mean-square error of 0.30 log units. It shows that for these and related compounds, aquatic toxicity is driven by electrophilic reactivity. The findings demonstrate that the kinetic GSH chemoassay can be used as an efficient tool to analyze, interpret, and predict correspondingly reactive toxicity in the context of qualitative and quantitative structure-activity relationship studies and as a nonanimal tool of integrated testing strategies for REACH to screen compounds for excess toxicity. PMID:19317512

  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. PMID:27430865

  20. Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and DNA looping.

    PubMed

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

    2014-08-01

    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

  1. 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

  2. Structural reevaluation of the electrophilic hypervalent iodine reagent for trifluoromethylthiolation supported by the crystalline sponge method for X-ray analysis

    PubMed Central

    Vinogradova, Ekaterina V.; Müller, Peter; Buchwald, Stephen L.

    2014-01-01

    Hypervalent iodine λ3-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Herein we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate), resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), which was previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state. PMID:24677728

  3. An Energetic Guide for Estimating Trifluoromethyl Cation Donor Abilities of Electrophilic Trifluoromethylating Reagents: Computations of X-CF3 Bond Heterolytic Dissociation Enthalpies.

    PubMed

    Li, Man; Xue, Xiao-Song; Guo, Jinping; Wang, Ya; Cheng, Jin-Pei

    2016-04-15

    This work established an energetic guide for estimating the trifluoromethyl cation-donating abilities (TC(+)DA) of electrophilic trifluoromethylating reagents through computing X-CF3 bond (X = O, S, Se, Te, and I) heterolytic dissociation enthalpies. TC(+)DA values for a wide range of popular reagents were derived on the basis of density functional calculations (M06-2X). A good correspondence has been identified between the computed TC(+)DA values and the experimentally observed relative trifluoromethylating capabilities of the reagents. Substituent effects hold good linear free energy relationships on the TC(+)DAs of the most widely used reagents including Umemoto reagent, Yagupolskii-Umemoto reagent, and Togni reagents, which allow their trifluoromethylating capabilities to be rationally tuned by substituents and thus extend their synthetic utility. All the information disclosed in this work would contribute to future rational exploration of the electrophilic trifluoromethylation chemistry. PMID:26999452

  4. N-heterocyclic carbene-catalyzed homoenolate additions with N-aryl ketimines as electrophiles: efficient synthesis of spirocyclic γ-lactam oxindoles.

    PubMed

    Zhang, Bo; Feng, Peng; Sun, Li-Hui; Cui, Yuxin; Ye, Song; Jiao, Ning

    2012-07-23

    In pole position: A simple and efficient approach to spirocyclic γ-lactam oxindoles by the N-heterocyclic carbene catalyzed addition of homoenloate equivalents to N-aryl isatinimines has been developed (see scheme). The use of N-aryl isatinimines as electrophiles in the NHC-catalyzed umpolung reaction of α,β-unsaturated aldehydes is demonstrated for the first time. PMID:22736551

  5. 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. PMID:26800159

  6. 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

  7. Assessment of the extended Koopmans' theorem for the chemical reactivity: Accurate computations of chemical potentials, chemical hardnesses, and electrophilicity indices.

    PubMed

    Yildiz, Dilan; Bozkaya, Uğur

    2016-01-30

    The extended Koopmans' theorem (EKT) provides a straightforward way to compute ionization potentials and electron affinities from any level of theory. Although it is widely applied to ionization potentials, the EKT approach has not been applied to evaluation of the chemical reactivity. We present the first benchmarking study to investigate the performance of the EKT methods for predictions of chemical potentials (μ) (hence electronegativities), chemical hardnesses (η), and electrophilicity indices (ω). We assess the performance of the EKT approaches for post-Hartree-Fock methods, such as Møller-Plesset perturbation theory, the coupled-electron pair theory, and their orbital-optimized counterparts for the evaluation of the chemical reactivity. Especially, results of the orbital-optimized coupled-electron pair theory method (with the aug-cc-pVQZ basis set) for predictions of the chemical reactivity are very promising; the corresponding mean absolute errors are 0.16, 0.28, and 0.09 eV for μ, η, and ω, respectively. PMID:26458329

  8. 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

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

    PubMed

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

    2015-01-01

    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 (1mM, 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

  10. 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.

  11. Arenediazonium salts as electrophiles for the oxidative addition of gold(i).

    PubMed

    Asomoza-Solís, Eric Omar; Rojas-Ocampo, Jonathan; Toscano, Rubén Alfredo; Porcel, Susana

    2016-06-01

    Arenediazonium salts generated in situ from anilines have been found for the first time to efficiently oxidize [AuCl(L)] (L = SMe2, PPh3) complexes in DMSO as a solvent, under thermal conditions. The structure of the [AuArCl2(L)] complexes formed has been confirmed by X-ray diffraction analyses. These complexes have been used as intermediates, in a one pot cross-coupling reaction of anilines with silver acetylides. PMID:27181520

  12. A novel application of DDQ as electrophile in the Nenitzescu reaction.

    PubMed

    Kucklaender, U; Bollig, R; Frank, W; Gratz, A; Jose, J

    2011-04-15

    Reaction of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) with secondary enaminones yields surprisingly 2-aza-spiro[4,5]decatrienes. The reaction occurs via cyclisation of the primary Michael-adduct with the nitrile group. Reaction of DDQ with tertiary and also certain secondary enamines leads to 3-amino-benzo[b]furan derivatives. This is formed not by Michael-addition, but via geminate radical ion pair formation with subsequent generation of an oxygen-carbon bond to yield benzofurans. The new products are investigated with regards to inhibition of purified human proteinkinase CK2 and their general cytostatic activity. It turned out, that the most active compound is the 3-amino-5-hydroxy-benzofuran derivative 11s with an IC(50) value of 0,2μM for CK2. PMID:21459578

  13. 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

  14. Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant.

    PubMed

    Deng, Yijun; Haimowitz, Thomas; LaPorte, Matthew G; Rippin, Susan R; Alexander, Matthew D; Kumar, Pavan Tirunahari; Hendi, Mukta S; Lee, Yu-Hua; Condon, Stephen M

    2016-03-10

    Birinapant/TL32711 (1) is a bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins and was designed to mimic AVPI, the N-terminal tetrapeptide of the second mitochondria-derived activator of caspases (Smac/DIABLO). Birinapant bound to the BIR3 domains of cIAP1, cIAP2, and XIAP with K i values of 1, 36, and 45 nM, respectively. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-κB activation, induction of tumor cell death in vitro, and tumor regression in vivo. Birinapant is being evaluated in Phase 1/2 trials for the treatment of cancer and hepatitis B virus (HBV) infection. After one year at accelerated storage conditions, a formulation of 1 afforded four degradants in >0.1% abundance by HPLC analysis. The primary degradants (2 and 3) were formed via oxidation of the biindole core, while the secondary degradants (5 and 6) arose via [1,2]-rearrangement of 3 and 2, respectively. Forced degradation conditions were developed, which allowed the isolation of 2 and 3 in multigram quantities. Novel deuterated analogues of 1 were prepared to determine the site of oxidation, and NMR experiments confirmed the chemical structures of 5 and 6. The de novo synthesis of 2, 3, 5, and 6 confirmed these experimental findings. PMID:26985322

  15. Triosephosphate isomerase: removal of a putatively electrophilic histidine residue results in a subtle change in catalytic mechanism

    SciTech Connect

    Nickbarg, E.B.; Davenport, R.C.; Petsko, G.A.; Knowles, J.R.

    1988-08-09

    An important active-site residue in the glycolytic enzyme triosephosphate isomerase is His-95, which appears to act as an electrophilic component in catalyzing the enolization of the substrates. With the techniques of site-directed mutagenesis, His-95 has been replaced by Gln in the isomerase from Saccharomyces cerevisiae. The mutant isomerase has been expressed in Escherichia coli strain DF502 and purified to homogeneity. The specific catalytic activity of the mutant enzyme is less than that of wild type by a factor of nearly 400. The mutant enzyme can be resolved from the wild-type isomerase on nondenaturing isoelectric focusing gels, and an isomerase activity stain shows that the observed catalytic activity indeed derives from the mutant protein. The mutant enzyme shows the same stereospecificity of proton transfer as the wild type. Tritium exchange experiments similar to those used to define the free energy profile for the wild-type yeast isomerase, together with a new method of analysis involving /sup 14/C and /sup 3/H doubly labeled substrates, have been used to investigate the energetics of the mutant enzyme catalyzed reaction. The deuterium kinetic isotope effects observed with the mutant isomerase using (1(R)-/sup 2/H)dihydroxyacetone phosphate and (2-/sup 2/H)glyceraldehyde 3-phosphate are 2.15 +/- 0.04 and 2.4 +/- 0.1, respectively. These results lead to the conclusion that substitution of Gln for His-95 so impairs the ability of the enzyme to stabilize the reaction intermediate that there is a change in the pathways of proton transfer mediated by the mutant enzyme.

  16. Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)-Resistant CML Lines While Circumventing Pharmacokinetic Liabilities.

    PubMed

    Ali, Ahmed M; Gómez-Biagi, Rodolfo F; Rosa, David A; Lai, Ping-Shan; Heaton, William L; Park, Ji Sung; Eiring, Anna M; Vellore, Nadeem A; de Araujo, Elvin D; Ball, Dan P; Shouksmith, Andrew E; Patel, Ami B; Deininger, Michael W; O'Hare, Thomas; Gunning, Patrick T

    2016-04-19

    Pharmacologic blockade of the activation of signal transducer and activator of transcription 3 (STAT3) in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) cell lines characterized by kinase-independent resistance was shown to re-sensitize CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. Benzoic acid- and hydroxamic acid-based STAT3 inhibitors SH-4-054 and SH-5-007, developed previously in our laboratory, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD-1 mice) revealed that both SH-4-054 and SH-5-007 are susceptible to glutathione conjugation at the para position of the pentafluorophenyl group via nucleophilic aromatic substitution (SN Ar). To determine whether the electrophilicity of the pentafluorophenyl sulfonamide could be tempered, an in-depth structure-activity relationship (SAR) study of the SH-4-054 scaffold was conducted. These studies revealed that AM-1-124, possessing a 2,3,5,6-tetrafluorophenylsulfonamide group, retained STAT3 protein affinity (Ki =15 μm), as well as selectivity over STAT1 (Ki >250 μm). Moreover, in both hepatocytes and in in vivo pharmacokinetic studies (CD-1 mice), AM-1-124 was found to be dramatically more stable than SH-4-054 (t1/2 =1.42 h cf. 10 min, respectively). AM-1-124 is a promising STAT3-targeting inhibitor with demonstrated bioavailability, suitable for evaluation in preclinical cancer models. PMID:27028877

  17. Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts

    PubMed Central

    Villacorta, Luis; Chang, Lin; Salvatore, Sonia R.; Ichikawa, Tomonaga; Zhang, Jifeng; Petrovic-Djergovic, Danica; Jia, Lingyun; Carlsen, Harald; Schopfer, Francisco J.; Freeman, Bruce A.; Chen, Y. Eugene

    2013-01-01

    Aims Electrophilic fatty acid nitroalkene derivatives, products of unsaturated fatty acid nitration, exert long-term cardiovascular protection in experimental models of metabolic and cardiovascular diseases. The goal of this study is to examine the effects of nitro-fatty acids in the regulation of upstream signalling events in nuclear factor-κB (NF-κB) activation and determine whether low-dose acute administration of nitro-fatty acids reduces vascular inflammation in vivo. Methods and results Using NF-κB-luciferase transgenic mice, it was determined that pre-emptive treatment with nitro-oleic acid (OA-NO2), but not oleic acid (OA) inhibits lipopolysaccharide (LPS)-induced NF-κB activation both in vivo and in isolated macrophages. Acute intravenous administration of OA-NO2 was equally effective to inhibit leukocyte recruitment to the vascular endothelium assessed by intravital microscopy and significantly reduces aortic expression of adhesion molecules. An acute treatment with OA-NO2 in vivo yielding nanomolar concentrations in plasma, is sufficient to inhibit LPS-induced Toll-like receptor 4 (TLR4)-induced cell surface expression in leukocytes and NF-κB activation. In vitro experiments reveal that OA-NO2 suppresses LPS-induced TLR4 signalling, inhibitor of κB (IκBα) phosphorylation and ubiquitination, phosphorylation of the IκB kinase (IKK), impairing the recruitment of the TLR4 and TNF receptor associated factor 6 (TRAF6) to the lipid rafts compartments. Conclusion These studies demonstrate that acute administration of nitro-fatty acids is effective to reduce vascular inflammation in vivo. These findings reveal a direct role of nitro-fatty acids in the disruption of the TLR4 signalling complex in lipid rafts, upstream events of the NF-κB pathway, leading to resolution of pro-inflammatory activation of NF-κB in the vasculature. PMID:23334216

  18. Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles.

    PubMed

    Aluise, Christopher D; Rose, Kristie; Boiani, Mariana; Reyzer, Michelle L; Manna, Joseph D; Tallman, Keri; Porter, Ned A; Marnett, Lawrence J

    2013-02-18

    Oxidation of membrane phospholipids is associated with inflammation, neurodegenerative disease, and cancer. Oxyradical damage to phospholipids results in the production of reactive aldehydes that adduct proteins and modulate their function. 4-Hydroxynonenal (HNE), a common product of oxidative damage to lipids, adducts proteins at exposed Cys, His, or Lys residues. Here, we demonstrate that peptidyl-prolyl cis/trans-isomerase A1 (Pin1), an enzyme that catalyzes the conversion of the peptide bond of pSer/pThr-Pro moieties in signaling proteins from cis to trans, is highly susceptible to HNE modification. Incubation of purified Pin1 with HNE followed by MALDI-TOF/TOF mass spectrometry resulted in detection of Michael adducts at the active site residues His-157 and Cys-113. Time and concentration dependencies indicate that Cys-113 is the primary site of HNE modification. Pin1 was adducted in MDA-MB-231 breast cancer cells treated with 8-alkynyl-HNE as judged by click chemistry conjugation with biotin followed by streptavidin-based pulldown and Western blotting with anti-Pin1 antibody. Furthermore, orbitrap MS data support the adduction of Cys-113 in the Pin1 active site upon HNE treatment of MDA-MB-231 cells. siRNA knockdown of Pin1 in MDA-MB-231 cells partially protected the cells from HNE-induced toxicity. Recent studies indicate that Pin1 is an important molecular target for the chemopreventive effects of green tea polyphenols. The present study establishes that it is also a target for electrophilic modification by products of lipid peroxidation. PMID:23231502

  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. PMID:27012417

  20. Substituent effects and charge delocalization mode in chrysenium, benzo[c]phenanthrenium, and benzo[g]chrysenium cations: a stable ion and electrophilic substitution study.

    PubMed

    Laali, K K; Okazaki, T; Kumar, S; Galembeck, S E

    2001-02-01

    The first series of persistent carbocations derived from mono- and disubstituted chrysenes Ch (5- methyl- 3, 2-methoxy- 19, 2-methoxy-11-methyl- 20, 2-methoxy-5-methyl- 21, and 9-methyl-4H-cyclopenta[def]chrysene 22), monosubstituted benzo[c]phenanthrenes BcPh (3-methoxy- 23, 3-hydroxy- 24), and monosubstituted benzo[g]chrysenes BgCh (12-methoxy- 25; 12-hydroxy- 26) were generated in FSO3H/SO2ClF or FSO3H-SbF5 (4:1)/SO2ClF and studied by low-temperature NMR at 500 MHz. The methoxy and methyl substituents direct the protonation to their respective ortho positions. Whereas parent Ch 1 is protonated at C-6/C-12, 3 is protonated at C-6 (3aH+) and at C-12 (3bH+) with the latter being the thermodynamic cation. The 2-methoxy-Ch 19 is protonated at C-1 to give two conformationally distinct carboxonium ions (19aH+/19bH+). In the disubstituted Ch derivatives 20 and 21, the 2-methoxy overrides the 5-methyl and the predominant carbocations formed are via attack ortho to methoxy. For the methano derivative 22 (Me at C-9), a 3:1 mixture of 22aH+/22bH+ is formed. For parent BcPh 13, nitration and benzoylation are directed to C-5. With 3-methoxy-BcPh 23, the site of attack moves to C-4, thus producing two conformationally distinct carboxonium ions (23aH+/23bH+), whereas conventional nitration gave a 2:1 mixture of 23aNO2 and 23bNO2. In 3-hydroxy-BcPh 24, the carboxonium ion 24H+ is exclusively formed. For parent BgCh 16, protonation, nitration, and benzoylation are all directed to C-10 (16H+, 16NO2, 16COPh), but presence of OMe or OH substituent at C-12 changes the site of attack to C-11. Charge delocalization mode is probed based on magnitude of delta delta 13Cs and conformational aspects via NOED experiments. Complete NMR data are also reported for several benzoylation/nitration products. Using ab initio/GIAO (and NICS), the NMR chemical shifts (and aromaticity) in model carbocations A-D were evaluated. This work represents the first direct study of the carbocations derived from

  1. 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

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

    PubMed Central

    Sirota, R.; Gibson, D.; Kohen, R.

    2014-01-01

    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. PMID:25498967

  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. 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

  5. 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

  6. Gills as a glutathione-dependent metabolic barrier in Pacific oysters Crassostrea gigas: Absorption, metabolism and excretion of a model electrophile.

    PubMed

    Trevisan, Rafael; Mello, Danielle F; Delapedra, Gabriel; Silva, Danilo G H; Arl, Miriam; Danielli, Naissa M; Metian, Marc; Almeida, Eduardo A; Dafre, Alcir L

    2016-04-01

    The mercapturic acid pathway (MAP) is a major phase II detoxification route, comprising the conjugation of electrophilic substances to glutathione (GSH) in a reaction catalyzed by glutathione S-transferase (GST) enzymes. In mammals, GSH-conjugates are exported from cells, and the GSH-constituent amino acids (Glu/Gly) are subsequently removed by ectopeptidases. The resulting Cys-conjugates are reabsorbed and, finally, a mercapturic acid is generated through N-acetylation. This pathway, though very well characterized in mammals, is poorly studied in non-mammalian biological models, such as bivalve mollusks, which are key organisms in aquatic ecosystems, aquaculture activities and environmental studies. In the present work, the compound 1-chloro-2,4-dinitrobenzene (CDNB) was used as a model electrophile to study the MAP in Pacific oysters Crassostrea gigas. Animals were exposed to 10μM CDNB and MAP metabolites were followed over 24h in the seawater and in oyster tissues (gills, digestive gland and hemolymph). A rapid decay was detected for CDNB in the seawater (half-life 1.7h), and MAP metabolites peaked in oyster tissues as soon as 15min for the GSH-conjugate, 1h for the Cys-conjugate, and 4h for the final metabolite (mercapturic acid). Biokinetic modeling of the MAP supports the fast CDNB uptake and metabolism, and indicated that while gills are a key organ for absorption, initial biotransformation, and likely metabolite excretion, hemolymph is a possible milieu for metabolite transport along different tissues. CDNB-induced GSH depletion (4h) was followed by increased GST activity (24h) in the gills, but not in the digestive gland. Furthermore, the transcript levels of glutamate-cysteine ligase, coding for the rate limiting enzyme in GSH synthesis, and two phase II biotransformation genes (GSTpi and GSTo), presented a fast (4h) and robust (∼6-70 fold) increase in the gills. Waterborne exposure to electrophilic compounds affected gills, but not digestive gland

  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. Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile.

    PubMed

    Liu, Yen-Chin; Hsieh, Chia-Wen; Wu, Chun-Ching; Wung, Being-Sun

    2007-03-20

    Chalcone, an alpha,beta-unsaturated flavonoid, possesses anti-inflammatory properties. In our present study, we have demonstrated chalcone inhibited IL-6- and LPS-induced ICAM-1 gene expression. In adhesion assay, chalcone reduced the LPS-induced adhesion of THP-1 cells to endothelial cells (ECs). Chalcone was found to abrogate the activation of STAT3 and NF-kappaB in a dose- and time-dependent manner, in IL-6- and LPS-treated ECs. Other flavonoids, quercetin and cyanidin, which lack alpha,beta-unsaturated carbonyl group, showed weaker or no inhibitory effect on both IL-6-induced STAT3 phosphorylation and LPS-induced p65 translocation. However, the electrophilic compounds curcumin and crotonaldehyde, which also contain an alpha,beta-unsaturated carbonyl moiety, mimic the inhibitory effects of chalcone with different efficiencies. In addition, N-acetyl-L-cysteine (NAC) could reverse the inhibition of STAT3 phosphorylation when preincubated with chalcone. The use of buthionine sulfoximine (BSO) to decrease intracellular GSH levels further enhanced the effects of chalcone. On the other hand, in ECs treated with BSO only no abrogation of IL-6-induced STAT3 phosphorylation was observed. We also found that chalcone could reduce the GSH level in vitro. Furthermore, the cellular GSH levels were rapidly reduced after 25 microM chalcone treatment. Following 6 h exposure, however, chalcone treatment rescued the GSH levels in ECs, coincident with the inhibition of STAT3 and NF-kappaB activation. In contrast, chalcone induced expression of thioredoxin reductase and heme-oxygenase genes after prolonged treatment. Furthermore, chalcone upregulated the levels of the transcription factor Nrf2 in nuclear extracts and increased antioxidant response element (ARE)-luciferase activity and thioredoxin reductase promoter activity. Hence, our present findings indicate that chalcone suppresses both IL-6- and LPS-induced signaling pathways through the thiol-dependent intracellular redox

  9. Method for Derivatization and Detection of Chemical Weapons Convention Related Sulfur Chlorides via Electrophilic Addition with 3-Hexyne.

    PubMed

    Goud, D Raghavender; Pardasani, Deepak; Purohit, Ajay Kumar; Tak, Vijay; Dubey, Devendra Kumar

    2015-07-01

    Sulfur monochloride (S2Cl2) and sulfur dichloride (SCl2) are important precursors of the extremely toxic chemical warfare agent sulfur mustard and classified, respectively, into schedule 3.B.12 and 3.B.13 of the Chemical Weapons Convention (CWC). Hence, their detection and identification is of vital importance for verification of CWC. These chemicals are difficult to detect directly using chromatographic techniques as they decompose and do not elute. Until now, the use of gas chromatographic approaches to follow the derivatized sulfur chlorides is not reported in the literature. The electrophilic addition reaction of sulfur monochloride and sulfur dichloride toward 3-hexyne was explored for the development of a novel derivatization protocol, and the products were subjected to gas chromatography-mass spectrometric (GC-MS) analysis. Among various unsaturated reagents like alkenes and alkynes, symmetrical alkyne 3-hexyne was optimized to be the suitable derivatizing agent for these analytes. Acetonitrile was found to be the suitable solvent for the derivatization reaction. The sample preparation protocol for the identification of these analytes from hexane spiked with petrol matrix was also optimized. Liquid-liquid extraction followed by derivatization was employed for the identification of these analytes from petrol matrix. Under the established conditions, the detection and quantification limits are 2.6 μg/mL, 8.6 μg/mL for S2Cl2 and 2.3 μg/mL, 7.7 μg/mL for SCl2, respectively, in selected ion monitoring (SIM) mode. The calibration curve had a linear relationship with y = 0.022x - 0.331 and r(2) = 0.992 for the working range of 10 to 500 μg/mL for S2Cl2 and y = 0.007x - 0.064 and r(2) = 0.991 for the working range of 10 to 100 μg/mL for SCl2, respectively. The intraday RSDs were between 4.80 to 6.41%, 2.73 to 6.44% and interday RSDs were between 2.20 to 7.25% and 2.34 to 5.95% for S2Cl2 and SCl2, respectively. PMID:26054007

  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. 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.

  12. 4-Hydroxy-2-nonenal upregulates endogenous antioxidants and phase 2 enzymes in rat H9c2 myocardiac cells: protection against overt oxidative and electrophilic injury.

    PubMed

    Zhu, Hong; Zhang, Li; Xi, Xiaoqing; Zweier, Jay L; Li, Yunbo

    2006-08-01

    This study was undertaken to determine if 4-hydroxy-2-nonenal (HNE) could upregulate antioxidants and phase 2 enzymes in rat H9c2 myocardiac cells, and if the upregulated defenses led to cytoprotection against oxidative and electrophilic injury. Incubation of H9c2 cells with HNE at noncytotoxic concentrations resulted in significant induction of cellular catalase, glutathione (GSH), GSH S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1), as determined by enzyme activity and/or protein expression. HNE treatment caused increased mRNA expression of catalase, gamma-glutamylcysteine ligase, GST-A1, and NQO1. Pretreatment of H9c2 cells with HNE led to significant protection against cytotoxicity induced by reactive oxygen and nitrogen species. HNE-pretreated cells also exhibited increased resistance to injury elicited by subsequent cytotoxic concentrations of HNE. Taken together, this study demonstrates that several antioxidants and phase 2 enzymes in H9c2 cells are upregulated by HNE and that the increased defenses afford protection against overt oxidative and electrophilic cardiac cell injury. PMID:17015266

  13. Zero-flux surfaces of the electrostatic potential: the border of influence zones of nucleophilic and electrophilic sites in crystalline environment.

    PubMed

    Mata, Ignasi; Molins, Elies; Espinosa, Enrique

    2007-10-01

    The topology of the electrostatic potential varphi(r) has been studied for single molecules using geometries and electron distributions rho(r) determined from high-resolution single-crystal X-ray diffraction data. The electrostatic potential gradient nablavarphi(r), which is the negative of the electric field E = -nablavarphi, has been represented, revealing the position of zero-flux surfaces and critical points. Local maxima and minima of the electrostatic potential are interpreted in terms of electrophilic and nucleophilic sites, which present influence zones delimited by zero-flux surfaces containing saddle points. The influence zones of the nucleophilic and electrophilic sites define two alternative partitions of the space in disjoint volumes, the completeness of these partitions depending on either the neutral or ionic character of the molecule. The results obtained by using this methodology are useful for the interpretation of the saddle points of the electrostatic potential, which are related to the limits of the influence zones and reveal the path for preferred attack on reactive sites with finite influence zones. PMID:17727276

  14. An amphoteric reactivity of a mixed-valent bis(μ-oxo)dimanganese(III,IV) complex acting as an electrophile and a nucleophile.

    PubMed

    Sankaralingam, Muniyandi; Jeon, So Hyun; Lee, Yong-Min; Seo, Mi Sook; Ohkubo, Kei; Fukuzumi, Shunichi; Nam, Wonwoo

    2016-01-01

    A mixed-valent bis(μ-oxo)dimanganese(III,IV) complex, [(dpaq)Mn(III)(O)2Mn(IV)(dpaq)](+) (1), was prepared by reacting a hydroxomanganese(III) complex, [(dpaq)Mn(III)(OH)](+), with hydrogen peroxide in the presence of triethylamine. The mixed-valent bis(μ-oxo)dimanganese(III,IV) complex (1) was well characterised by UV-vis, EPR and CSI-MS techniques. The electrophilic reactivity of 1 was investigated in the oxidation of 2,6-di-tert-butylphenol derivatives by 1, in which the relative rate afforded a good Hammett correlation with a ρ value of -1.0. The nucleophilic character of 1 was then investigated in aldehyde deformylation reactions, using 2-phenylpropionaldehyde (2-PPA) and benzaldehyde derivatives as substrates. In contrast to the case of the reaction of 1 with 2,6-di-tert-butylphenol derivatives, a positive ρ value of 0.89 was obtained in the Hammett plot, demonstrating that the bis(μ-oxo)-dimanganese(III,IV) complex is an active nucleophilic oxidant. Thus, 1 exhibited an amphoteric reactivity in both electrophilic and nucleophilic oxidative reactions. PMID:26620273

  15. A Cool Way to Form High-Conductivity Two-Dimensional Polymers Using Ice

    NASA Astrophysics Data System (ADS)

    Park, Moon Jeong

    Ice surfaces are used as removable hard templates to form two-dimensional polyaniline (PANI) nanosheets. Distinctly high current flows of 5.5 mA at 1 V and a high electrical conductivity of 35 S/cm were obtained for the PANI nanosheets, which marked a significant improvement from the literature values on other PANIs reported over the past decades. These improved electrical properties of ice-templated PANI nanosheets were attributed to the long-range ordered edge-on p-stacking of the quinoid ring, ascribed to the ice surface-assisted vertical growth of PANI. The unprecedented advantages of the ice-templated PANI nanosheets are two-fold. First, the PANI nanosheet can be easily transferred onto various types of substrates via ``float off'' from the ice surfaces. Second, PANI can be patterned into any shape using predetermined masks, and this is expected to facilitate the eventual convenient and inexpensive application of conducting polymers in versatile electronic device forms.

  16. 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

  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. Synthesis of 3-iodoindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization.

    PubMed

    Yue, Dawei; Yao, Tuanli; Larock, Richard C

    2006-01-01

    [reaction: see text] 3-Iodoindoles have been prepared in excellent yields by coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. Aryl-, vinylic-, alkyl-, and silyl-substituted terminal acetylenes undergo this process to produce excellent yields of 3-iodoindoles. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows the following order: Me > n-Bu, Me > Ph, and cyclohexyl > Me. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting 3-iodoindoles proceed smoothly in good yields. PMID:16388618

  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. Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress.

    PubMed

    Li, Yunbo; Cao, Zhuoxiao; Zhu, Hong

    2006-01-01

    Resveratrol (3,4',5-trihydroxystilbene), a polyphenolic compound found in mulberries, grapes and red wine has been demonstrated to be capable of protecting against oxidative cardiovascular pathophysiology. However, the underlying cellular and biochemical mechanisms remain to be elucidated. This study was undertaken to determine if resveratrol could upregulate endogenous antioxidants and phase 2 enzymes in cultured aortic smooth muscle cells (ASMCs), and if such increased cellular defenses could provide protection against oxidative and electrophilic vascular cell injury. Incubation of rat ASMCs with resveratrol at low micromolar concentrations resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. These cytoprotective factors include superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1). Notably, induction of catalase, GST, and NOQ1 was most remarkable among the above resveratrol-inducible antioxidants and phase 2 enzymes. Moreover, resveratrol treatment also significantly increased the mRNA expression of catalase, GSTA1, and NQO1 in a time-dependent manner. Pretreatment of ASMCs with resveratrol afforded a remarkable protection against xanthine oxidase (XO)/xanthine- or 4-hydroxy-2-nonenal-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Resveratrol pretreatment also led to a marked reduction in intracellular accumulation of reactive oxygen species in ASMCs after incubation with XO/xanthine. Taken together, this study demonstrates that a scope of key endogenous antioxidants and phase 2 enzymes in cultured ASMCs can be upregulated by resveratrol at low micromolar concentrations, and that such chemically-elevated cellular defenses rendered cells increased resistance to oxidative and electrophilic

  1. Oxygen-Atom Transfer Reactivity of Axially Ligated Mn(V)–Oxo Complexes: Evidence for Enhanced Electrophilic and Nucleophilic Pathways

    PubMed Central

    2015-01-01

    Addition of anionic donors to the manganese(V)–oxo corrolazine complex MnV(O)(TBP8Cz) has a dramatic influence on oxygen-atom transfer (OAT) reactivity with thioether substrates. The six-coordinate anionic [MnV(O)(TBP8Cz)(X)]− complexes (X = F–, N3–, OCN–) exhibit a ∼5 cm–1 downshift of the Mn–O vibrational mode relative to the parent MnV(O)(TBP8Cz) complex as seen by resonance Raman spectroscopy. Product analysis shows that the oxidation of thioether substrates gives sulfoxide product, consistent with single OAT. A wide range of OAT reactivity is seen for the different axial ligands, with the following trend determined from a comparison of their second-order rate constants for sulfoxidation: five-coordinate ≈ thiocyanate ≈ nitrate < cyanate < azide < fluoride ≪ cyanide. This trend correlates with DFT calculations on the binding of the axial donors to the parent MnV(O)(TBP8Cz) complex. A Hammett study was performed with p-X-C6H4SCH3 derivatives and [MnV(O)(TBP8Cz)(X)]− (X = CN– or F–) as the oxidant, and unusual “V-shaped” Hammett plots were obtained. These results are rationalized based upon a change in mechanism that hinges on the ability of the [MnV(O)(TBP8Cz)(X)]− complexes to function as either an electrophilic or weak nucleophilic oxidant depending upon the nature of the para-X substituents. For comparison, the one-electron-oxidized cationic MnV(O)(TBP8Cz•+) complex yielded a linear Hammett relationship for all substrates (ρ = −1.40), consistent with a straightforward electrophilic mechanism. This study provides new, fundamental insights regarding the influence of axial donors on high-valent MnV(O) porphyrinoid complexes. PMID:25238495

  2. 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.

  3. Form classification

    NASA Astrophysics Data System (ADS)

    Reddy, K. V. Umamaheswara; Govindaraju, Venu

    2008-01-01

    The problem of form classification is to assign a single-page form image to one of a set of predefined form types or classes. We classify the form images using low level pixel density information from the binary images of the documents. In this paper, we solve the form classification problem with a classifier based on the k-means algorithm, supported by adaptive boosting. Our classification method is tested on the NIST scanned tax forms data bases (special forms databases 2 and 6) which include machine-typed and handwritten documents. Our method improves the performance over published results on the same databases, while still using a simple set of image features.

  4. Structure-activity relationships for degradation reaction of 1-beta-o-acyl glucuronides: kinetic description and prediction of intrinsic electrophilic reactivity under physiological conditions.

    PubMed

    Baba, Akiko; Yoshioka, Tadao

    2009-01-01

    1-beta-O-Acyl glucuronides (betaGAs) are potentially reactive metabolites capable of binding to proteins, and they have been implicated in adverse drug reactions of the carboxylic acid drugs. To explore their electrophilic reactivity, we studied structure-activity relationships (SARs) to characterize the factors affecting the degradation rate constants (k values) of betaGAs and ultimately to predict k values of structurally diverse betaGAs. Twenty-seven betaGAs and four related compounds were synthesized, and their k values were determined under physiological conditions (pH 7.4 and 37 degrees C). 1-beta-O-Benzoyl glucuronide (BAGA) and glucopyranoside (BAG) showed almost the same k values, whereas their 1-alpha-O-benzoyl isomers degraded approximately 40-fold faster than BAGA and BAG. BAGA methyl ester showed almost the same rate constant as BAGA in the cleavage of their 1-beta-O-benzoyl linkages. A pH-log k profile obtained indicated kinetics catalyzed by both specific and general bases. The log k of betaGAs derived from m- and p-substituted benzoic acids correlated with Hammett's sigma constants. A similar correlation was observed with delta(COOH), (1)H NMR chemical shifts of the parent benzoic acids including ones with less sterically bulky o-substituents. Alternative descriptors of delta(CO) and delta((CO)OH), (13)C chemical shifts for ester carbonyl carbons of betaGAs and for carbonyl carbons of the parent benzoic acids, respectively, correlated well with the log k of all 16 betaGAs derived from benzoic acids including ones with bulkier o-substituents. Of the betaGA isomers derived from (2R)- and (2S)-alpha-methyl-4-biphenylylacetic acid, the (2R)-isomer degraded approximately 2-fold faster than the (2S)-isomer. The alpha-methyl group in the (2S)-isomer would encumber the intramolecular acyl migration. The log k of betaGAs derived from n-aralkyl carboxylic acids and of the (2R)-isomer correlated with their delta(COOH). However, the log k of betaGAs derived

  5. 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

  6. Synthesis of 3-Sulfenyl- and 3-Selenylindoles by the Pd/Cu-Catalyzed Coupling of N,N-Dialkyl-2-iodoanilines and Terminal Alkynes, Followed by n-Bu4NI-Induced Electrophilic Cyclization

    PubMed Central

    Chen, Yu; Cho, Chul-Hee; Shi, Feng; Larock, Richard C.

    2009-01-01

    3-Sulfenyl- and 3-selenylindoles are readily synthesized by a two-step process involving the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-ortho-iodoanilines and terminal alkynes and subsequent electrophilic cyclization of the resulting N,N-dialkyl-ortho-(1-alkynyl)anilines with arylsulfenyl chlorides or arylselenyl chlorides. The presence of a stoichiometric amount of n-Bu4NI is crucial to the success of the electrophilic cyclization. A variety of 3-sulfenyl- and 3-selenylindole derivatives bearing alkyl, vinylic, aryl, and heteroaryl substituents have been prepared in good to excellent yields (up to 99%). By employing N,N-dibenzyl-ortho-iodoanilines, a 3-sulfenyl-N-H-indole has been successfully prepared. In addition, 3-sulfonyl- and 3-sulfinylindoles have also been successfully prepared by facile oxidation of the corresponding 3-sulfenylindoles. PMID:19663396

  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. 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

  9. Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1'-sulfoöxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1'-hydroxysafrole in mouse liver.

    PubMed

    Boberg, E W; Miller, E C; Miller, J A; Poland, A; Liem, A

    1983-11-01

    The role of sulfation of 1'-hydroxysafrole in the formation of hepatic macromolecular adducts and in hepatic tumor formation in mice given 1'-hydroxysafrole was investigated by the use of: (a) mice treated with the specific sulfotransferase inhibitor pentachlorophenol; and (b) brachymorphic mice, which are characterized by a deficiency in the hepatic synthesis of 3'-phosphoadenosine 5'-phosphosulfate. Cytosolic sulfotransferase activity for 1'-hydroxysafrole in both mouse and rat liver was significantly inhibited by 10 microM pentachlorophenol, usually by greater than 90%. Prior administration of nontoxic amounts of pentachlorophenol, either in the diet of adult female CD-1 mice or by i.p. injection of 12-day-old male C57BL/6 X C3H F1 (hereafter called B6C3F1) mice, resulted in an 85% decrease in the level of adducts formed from 1'-hydroxysafrole in hepatic DNA and RNA as compared to those of non-pentachlorophenol-treated animals. Likewise, the chronic administration of a nontoxic level of pentachlorophenol in the diet of adult female CD-1 mice strongly inhibited hepatic tumor induction by long-term dietary administration of either safrole or 1'-hydroxysafrole. Initiation of hepatic tumors by a single i.p. injection of 1'-hydroxysafrole to 12-day-old male B6C3F1 mice was strongly inhibited by prior treatment with pentachlorophenol. Under these conditions, the hepatocarcinogenicity of diethylnitrosamine was not inhibited by pentachlorophenol. Supplementation with adenosine triphosphate and sulfate of hepatic cytosols from adult female or 12-day-old brachymorphic progeny of a B6C3 background outbred to B6C3F1 mice (B6C3F2), of either sex, resulted in 5- to 10-fold less binding of 1'-hydroxysafrole to added RNA than when cytosols from phenotypically normal B6C3F2 mice were used. On administration of [3H]-1'-hydroxysafrole to adult female or 12-day-old brachymorphic B6C3F2 mice of either sex, the levels of hepatic DNA and RNA adducts were 7- to 12-fold lower than those

  10. 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

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

    PubMed

    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

  12. Site-Specific, Intramolecular Cross-Linking of Pin1 Active Site Residues by the Lipid Electrophile 4-Oxo-2-nonenal

    PubMed Central

    2016-01-01

    Products of oxidative damage to lipids include 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE), both of which are cytotoxic electrophiles. ONE reacts more rapidly with nucleophilic amino acid side chains, resulting in covalent protein adducts, including residue–residue cross-links. Previously, we demonstrated that peptidylprolyl cis/trans isomerase A1 (Pin1) was highly susceptible to adduction by HNE and that the catalytic cysteine (Cys113) was the preferential site of modification. Here, we show that ONE also preferentially adducts Pin1 at the catalytic Cys but results in a profoundly different modification. Results from experiments using purified Pin1 incubated with ONE revealed the principal product to be a Cys-Lys pyrrole-containing cross-link between the side chains of Cys113 and Lys117. In vitro competition assays between HNE and ONE demonstrate that ONE reacts more rapidly than HNE with Cys113. Exposure of RKO cells to alkynyl-ONE (aONE) followed by copper-mediated click chemistry and streptavidin purification revealed that Pin1 is also modified by ONE in cells. Analysis of the Pin1 crystal structure reveals that Cys113 and Lys117 are oriented toward each other in the active site, facilitating formation of an ONE cross-link. PMID:25739016

  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. 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)

  15. The activation of electrophile, nucleophile and leaving group during the reaction catalysed by pI258 arsenate reductase.

    PubMed

    Roos, Goedele; Loverix, Stefan; Brosens, Elke; Van Belle, Karolien; Wyns, Lode; Geerlings, Paul; Messens, Joris

    2006-06-01

    The reduction of arsenate to arsenite by pI258 arsenate reductase (ArsC) combines a nucleophilic displacement reaction with a unique intramolecular disulfide cascade. Within this reaction mechanism, the oxidative equivalents are translocated from the active site to the surface of ArsC. The first reaction step in the reduction of arsenate by pI258 ArsC consists of a nucleophilic displacement reaction carried out by Cys10 on dianionic arsenate. The second step involves the nucleophilic attack of Cys82 on the Cys10-arseno intermediate formed during the first reaction step. The onset of the second step is studied here by using quantum chemical calculations in a density functional theory context. The optimised geometry of the Cys10-arseno adduct in the ArsC catalytic site (sequence motif: Cys10-Thr11-Gly12-Asn13-Ser14-Cys15-Arg16-Ser17) forms the starting point for all subsequent calculations. Thermodynamic data and a hard and soft acids and bases (HSAB) reactivity analysis show a preferential nucleophilic attack on a monoanionic Cys10-arseno adduct, which is stabilised by Ser17. The P-loop active site of pI258 ArsC activates first a hydroxy group and subsequently arsenite as the leaving group, as is clear from an increase in the calculated nucleofugality of these groups upon going from the gas phase to the solvent phase to the enzymatic environment. Furthermore, the enzymatic environment stabilises the thiolate form of the nucleophile Cys82 by 3.3 pH units through the presence of the eight-residue alpha helix flanked by Cys82 and Cys89 (redox helix) and through a hydrogen bond with Thr11. The importance of Thr11 in the pKa regulation of Cys82 was confirmed by the observed decrease in the kcat value of the Thr11Ala mutant as compared to that of wild-type ArsC. During the final reaction step, Cys89 is activated as a nucleophile by structural alterations of the redox helix that functions as a pKa control switch for Cys89; this final step is necessary to expose a Cys82-Cys

  16. Trigonal pyramidal carbon geometry as model for electrophilic addition-substitution and elimination reactions and its significance in enzymatic processes

    NASA Astrophysics Data System (ADS)

    Buck, Henk M.

    Various examples are given in which compounds are characterized as products or intermediates in a (distorted) trigonal pyramidal (TP) geometry. These observations have taken place mainly in the field of carbocation chemistry. Special attention is given to carbenium ions formed by halogen addition to 1,1-diarylsubstituted ethylenes focused on the electronic effects of the C-halogen bond as axial bond in a TP geometry with regard to the ?-distribution in the rest of the molecular system. The experimental verification is accompanied by quantum chemical calculations. We also used the TP structure as a reactive model for specific enzymatic reactions. The relevance of this geometry is shown for the dehalogenation reaction of the nucleophilic displacement in dichloroethane catalyzed by haloalkane dehalogenase and for the decarboxylation of L-ornithine with ornithine decarboxylase under loss of carbon dioxide.

  17. Variation of isomer distribution in electrophilic nitration of toluene, anisole, and o-xylene: Independence of high regioselectivity from reactivity of reagent*

    PubMed Central

    Olah, George A.; Lin, Henry C.; Olah, Judith A.; Narang, Subhash C.

    1978-01-01

    The nitration of toluene and anisole was studied with nitrating systems of varying reactivity. High regioselectivity of ortho-para over meta substitution was maintained in all nitrations, regardless of the reactivity of the nitrating system. At the same time, the amount of meta substitution stayed low (3% or less), even when the fast reactions may have reached the encounter-controlled limit. Because the nitration of o-xylene, in which both ring positions are activated by the effect of a methyl group, also does not show any diminishing of regioselectivity, the possibility of a dual mechanistic pathway, in which the activated position would react by a fast, encounter-controlled path, whereas the nonactivated meta position by a slower σ-type path, can be ruled out. The data unambiguously prove that the high regioselectivity of electrophilic aromatic nitration is independent of the reactivity of the reagent, because no significant increase of meta substitution of toluene or anisole was observed, regardless of the activity of the nitrating system. No selectivity-reactivity relationship is thus evident and the ortho-para directing effect of primary substituents over meta substitution is always maintained. The variation in the amount of the meta isomer, up to the observed limit of about 3% in the case of toluene and <2% for anisole, is probably significant but, at the present time, cannot be quantitatively evaluated with the ±0.5% overall reproducible accuracy of the nitrations. Steric factors, such as increasing bulkiness of the nitrating agent, also can affect the ortho-para isomer ratios but are not considered to be the only reason for the observed variations, which reflect the specific nitrating systems, affecting the nature and position of the transition state of highest energy on the reaction pathway. PMID:16592489

  18. 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

  19. Electrophilic adduction of ubiquitin activating enzyme E1 by N,N-diethyldithiocarbamate inhibits ubiquitin activation and is accompanied by striatal injury in the rat.

    PubMed

    Viquez, Olga M; Caito, Samuel W; McDonald, W Hayes; Friedman, David B; Valentine, William M

    2012-11-19

    Previous studies have shown ubiquitin activating enzyme E1 to be sensitive to adduction through both Michael addition and SN(2) chemistry in vitro. E1 presents a biologically important putative protein target for adduction due to its role in initiating ubiquitin based protein processing and the involvement of impaired ubiquitin protein processing in two types of familial Parkinson's disease. We tested whether E1 is susceptible to xenobiotic-mediated electrophilic adduction in vivo and explored the potential contribution of E1 adduction to neurodegenerative events in an animal model. N,N-Diethyldithiocarbamate (DEDC) was administered to rats using a protocol that produces covalent cysteine modifications in vivo, and brain E1 protein adducts were characterized and mapped using shotgun LC-MS/MS. E1 activity, global and specific protein expression, and protein carbonyls were used to characterize cellular responses and injury in whole brain and dorsal striatal samples. The data demonstrate that DEDC treatment produced S-(ethylaminocarbonyl) adducts on Cys234 and Cys179 residues of E1 and decreased the levels of activated E1 and total ubiquitinated proteins. Proteomic analysis of whole brain samples identified expression changes for proteins involved in myelin structure, antioxidant response, and catechol metabolism, systems often disrupted in neurodegenerative disease. Our studies also delineated localized injury within the striatum as indicated by decreased levels of tyrosine hydroxylase, elevated protein carbonyl content, increased antioxidant enzyme and α-synuclein expression, and enhanced phosphorylation of tau and tyrosine hydroxylase. These data are consistent with E1 having similar susceptibility to adduction in vivo as previously reported in vitro and support further investigation into environmental agent adduction of E1 as a potential contributing factor to neurodegenerative disease. Additionally, this study supports the predictive value of in vitro screens

  20. 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

  1. 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. PMID:26117601

  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. Tidal Forms

    NASA Astrophysics Data System (ADS)

    Bolla Pittaluga, M.; Seminara, G.; Tambroni, N.

    2003-04-01

    We give an overview of some recent investigations on the mechanics of the processes whereby forms develop in tidal environments. The viewpoint taken here is mechanistic. Some of the questions which deserve an answer may be summarised as follows: i) do tidal channels tend to some altimetric long term equilibrium? ii) why are they typically convergent and weakly meandering? iii) how is such equilibrium affected by the hydrodynamics and morphodynamics of tidal inlets? iv) what is the hydrodynamic and morphodynamic role played by tidal flats adjacent to the channels? Some of the above questions have received a considerable attention in the last few years. Schuttelaars and de Swart (1996), Lanzoni and Seminara (2002) and, more recently, Bolla Pittaluga (2003) have investigated the first problem. In particular, the latter two contributions have shown that a straight tidal channel connected to a tidal sea at one end and closed at the other end tends to reach a long term equilibrium profile, which is slightly concave seaward and convex landward where a beach forms. The equilibrium profile is strongly sensitive to the harmonic content of the tidal forcing as well as to the value of sediment concentration established by the coastal hydrodynamics in the far field of the inlet region. Less important are the effect of channel convergence and the role of settling lag in the transport of suspended load. Insufficient attention has been devoted to the understanding of what mechanisms control channel convergence and meandering, though some similarities and differences between tidal and fluvial channels have emerged from some recent works. In particular, free bars form in tidal channels due to an instability mechanism essentially similar to that occurring under steady conditions though the oscillatory character of the flow field makes the bar pattern non migrating (Seminara and Tubino, 2001). Similarly, forced bars in curved tidal channels are driven by the development of

  4. 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

  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 Central

    2015-01-01

    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 [3H]-cholesterol/acetylated LDL and then allowed to equilibrate to enable [3H]-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 [3H]-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 [3H]-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 [3H]-cholesterol efflux. However, CES1 mRNA knockdown markedly reduced cholesterol uptake by macrophages, with SR-A and CD36 mRNA reduced 3- and 4-fold, respectively

  6. Substituent Effects on Electrophilic Catalysis by the Carbonyl Group: Anatomy of the Rate Acceleration for PLP-Catalyzed Deprotonation of Glycine

    PubMed Central

    Crugeiras, Juan; Rios, Ana; Riveiros, Enrique; Richard, John P.

    2011-01-01

    First-order rate constants, determined by 1H NMR, are reported for deuterium exchange between solvent D2O and the α-amino carbon of glycine in the presence of increasing concentrations of carbonyl compounds (acetone, benzaldehyde and salicylaldehyde) and at different pD and buffer concentrations. These rate data were combined with 1H NMR data that define the position of the equilibrium for formation of imines/iminium ions from addition of glycine to the respective carbonyl compounds, to give second-order rate constants kDO for deprotonation of α-imino carbon by DO−. The assumption that these second-order rate constants lie on linear structure-reactivity correlations between log kOL and pKa was made in estimating the following pKas for deprotonation of α-imino carbon: pKa = 22, glycine–acetone iminium ion; pKa = 27, glycine–benzaldehyde imine; pKa ≈ 23, glycine–benzaldehyde iminium ion; and, pKa = 25, glycine–salicylaldehyde iminium ion. The much lower pKa of 17 [Toth, K.; Richard, J. P. J. Am. Chem. Soc. 2007, 129, 3013–3021] for carbon deprotonation of the adduct between 5′-deoxypyridoxal (DPL) and glycine shows that the strongly electron-withdrawing pyridinium ion is unique in driving the extended delocalization of negative charge from the α-iminium to the α-pyridinium carbon. This favors carbanion protonation at the α–pyridinium carbon, and catalysis of the 1,3-aza-allylic isomerization reaction that is a step in enzyme-catalyzed transamination reactions. An analysis of the effect of incremental changes in structure on the activity of benzaldehyde in catalysis of deprotonation of glycine shows the carbonyl group electrophile, the 2-O− ring substituent and the cation pyridinium nitrogen of DPL each make a significant contribution to the catalytic activity of this cofactor analog. The extraordinary activity of DPL in catalysis of deprotonation of α–amino carbon results from the summation of these three smaller effects. PMID:21323335

  7. Catabolism of 4-Hydroxy-2-trans-Nonenal by THP1 Monocytes/Macrophages and Inactivation of Carboxylesterases by this Lipid Electrophile

    PubMed Central

    Borazjani, Abdolsamad; Edelmann, Mariola J.; Hardin, Katelyn L.; Herring, Katye L.; Crow, J. Allen; Ross, Matthew K.

    2011-01-01

    Oxidative stress in cells and tissues leads to the formation of an assortment of lipid electrophiles, such as the quantitatively important 4-hydroxy-2-trans-nonenal (HNE). Although this cytotoxic aldehyde is atherogenic the mechanisms involved are unclear. We hypothesize that elevated HNE levels can directly inactivate esterase and lipase activities in macrophages via protein adduction, thus generating a biochemical lesion that accelerates foam cell formation and subsequent atherosclerosis. In the present study we examined the effects of HNE treatment on esterase and lipase activities in human THP1 monocytes/macrophages at various physiological scales (i.e., pure recombinant enzymes, cell lysate, and intact living cells). The hydrolytic activities of bacterial and human carboxylesterase enzymes (pnbCE and CES1, respectively) were inactivated by HNE in vitro in a time- and concentration-dependent manner. In addition, so were the hydrolytic activities of THP1 cell lysates and intact THP1 monocytes and macrophages. A single lysine residue (Lys105) in recombinant CES1 was modified by HNE via a Michael addition reaction, whereas the lone reduced cysteine residue (Cys389) was found unmodified. The lipolytic activity of cell lysates and intact cells was more sensitive to the inhibitory effects of HNE than the esterolytic activity. Moreover, immunoblotting analysis using HNE antibodies confirmed that several cellular proteins were adducted by HNE following treatment of intact THP1 monocytes, albeit at relatively high HNE concentrations (>50 µM). Unexpectedly, in contrast to CES1, the treatment of a recombinant human CES2 with HNE enhanced its enzymatic activity ~3-fold compared to untreated enzyme. In addition, THP1 monocytes/macrophages can efficiently metabolize HNE, and glutathione conjugation of HNE is responsible for ~43% of its catabolism. The functional importance of HNE-mediated inactivation of cellular hydrolytic enzymes with respect to atherogenesis remains

  8. 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

  9. 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.

  10. 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.

  11. 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

  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 Central

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

    2014-01-01

    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. PMID:23792274

  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. Prototype Systems Containing Human Cytochrome P450 for High-Throughput Real-Time Detection of DNA Damage by Compounds That Form DNA-Reactive Metabolites.

    PubMed

    Brito Palma, Bernardo; Fisher, Charles W; Rueff, José; Kranendonk, Michel

    2016-05-16

    The formation of reactive metabolites through biotransformation is the suspected cause of many adverse drug reactions. Testing for the propensity of a drug to form reactive metabolites has increasingly become an integral part of lead-optimization strategy in drug discovery. DNA reactivity is one undesirable facet of a drug or its metabolites and can lead to increased risk of cancer and reproductive toxicity. Many drugs are metabolized by cytochromes P450 in the liver and other tissues, and these reactions can generate hard electrophiles. These hard electrophilic reactive metabolites may react with DNA and may be detected in standard in vitro genotoxicity assays; however, the majority of these assays fall short due to the use of animal-derived organ extracts that inadequately represent human metabolism. The current study describes the development of bacterial systems that efficiently detect DNA-damaging electrophilic reactive metabolites generated by human P450 biotransformation. These assays use a GFP reporter system that detects DNA damage through induction of the SOS response and a GFP reporter to control for cytotoxicity. Two human CYP1A2-competent prototypes presented here have appropriate characteristics for the detection of DNA-damaging reactive metabolites in a high-throughput manner. The advantages of this approach include a short assay time (120-180 min) with real-time measurement, sensitivity to small amounts of compound, and adaptability to a microplate format. These systems are suitable for high-throughput assays and can serve as prototypes for the development of future enhanced versions. PMID:27031942

  15. Careers (A Course of Study). Unit V: Forms, Forms, Forms.

    ERIC Educational Resources Information Center

    Turley, Kay

    Designed to enable special needs students to understand and complete various job-related forms, this set of activities devoted to forms encountered before and after one obtains a job is the fifth in a nine-unit secondary level careers course intended to provide handicapped students with the knowledge and tools necessary to succeed in the world of…

  16. The "FORM" Approach to Reading Forms.

    ERIC Educational Resources Information Center

    Sandel, Lenore

    The FORM approach is designed to help persons in the senior population with the task of filling out the forms or applications required for a myriad of societal and human needs. The acronym represents a four-part approach consisting of: Facing the issue; applying Overview; Rewriting headings as questions; and Matching information as appropriate…

  17. 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

  18. Molecular orbital studies (hardness, chemical potential and electrophilicity), vibrational investigation and theoretical NBO analysis of 4-4'-(1H-1,2,4-triazol-1-yl methylene) dibenzonitrile based on abinitio and DFT methods.

    PubMed

    Sheela, N R; Muthu, S; Sampathkrishnan, S

    2014-01-01

    The Fourier transform infrared (FTIR) and FT Raman (FTR) of 4-4'-(1H-1, 2, 4-triazol-1-yl methylene) dibenzonitrile (4-HTMDBN) have been recorded and analyzed. The equilibrium geometry harmonic vibrational frequencies have been investigated with the help of standard HF and DFT methods with 6-31G(d,p) as basis set. The assignments of the vibrational spectra have been carried out with the help of normal co-ordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMFF). Theoretical simulations of the FTIR and FTR spectra of the title compound have been calculated. The (1)H and (13)C Nuclear Magnetic Resonance (NMR) chemical shifts of the molecule were calculated by the Gauge including atomic orbital (GIAO) method. The stability of the molecule has been analyzed using natural bond orbital (NBO) analysis. The linear polarizability (α) and the first order hyperpolarizability (β) values of the investigated molecule have been computed using HF/DFT/6-31G(d,p) methods on the finite field approach. UV-Vis spectrum of the compound is recorded and the electronic properties such as HOMO and LUMO energies, are performed. The directly calculated ionization potential (IP), electron affinity (EA), electronegativity (χ), electrophilicity index (ω), hardness (η) and chemical potential (ρ) are all correlated with the HOMO and LUMO energies with their molecular properties. Mulliken population analysis on atomic charges, molecular electrostatic potential maps (MEP) and thermodynamical properties of title compound at different temperature have been calculated. PMID:24184626

  19. 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

  20. In Vivo Roles of Conjugation with Glutathione and O6-Alkylguanine DNA-Alkyltransferase in the Mutagenicity of the bis-Electrophiles 1,2-Dibromoethane and 1,2,3,4-Diepoxybutane in Mice

    PubMed Central

    Cho, Sung-Hee; Guengerich, F. Peter

    2013-01-01

    Several studies with bacteria and in vitro mammalian systems have provided evidence for the roles of two thiol-based conjugation systems, glutathione (GSH) transferase and O6-alkylguanine DNA-alkyltransferase (AGT), in the bioactivation of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane (DEB), the latter an oxidation product of 1,3-butadiene. The in vivo relevance of these conjugation reactions to biological activity in mammals has not been addressed, particularly with DEB. In the present work we used transgenic Big Blue® mice, utilizing the cII gene, to examine the effects of manipulation of conjugation pathways on liver mutations arising from dibromoethane and DEB in vivo. Treatment of the mice with butathionine sulfoxime (BSO) prior to dibromoethane lowered hepatic GSH levels, dibromoethane-GSH DNA adducts (N7-guanyl), and cII mutation frequency. Administration of O6-benzylguanine (O6-BzGua), an inhibitor of AGT, did not change the mutation frequency. Depletion of GSH (BSO) and AGT (O6-BzGua) both lowered the mutation frequency induced by DEB, and BSO lowered the levels of GSH-DEB N7-guanyl and N6-adenyl DNA adducts. Our results provide evidence that the GSH conjugation pathway is a major in vivo factor in dibromoethane genotoxicity; both GSH and AGT conjugation are major factors in the genotoxicity of DEB. The latter findings are considered to be of relevance to the carcinogenicity of 1,3-butadiene. PMID:24191644

  1. In vivo roles of conjugation with glutathione and O6-alkylguanine DNA-alkyltransferase in the mutagenicity of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane in mice.

    PubMed

    Cho, Sung-Hee; Guengerich, F Peter

    2013-11-18

    Several studies with bacteria and in vitro mammalian systems have provided evidence of the roles of two thiol-based conjugation systems, glutathione (GSH) transferase and O(6)-alkylguanine DNA-alkyltransferase (AGT), in the bioactivation of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane (DEB), the latter an oxidation product of 1,3-butadiene. The in vivo relevance of these conjugation reactions to biological activity in mammals has not been addressed, particularly with DEB. In this work, we used transgenic Big Blue mice, utilizing the cII gene, to examine the effects of manipulation of conjugation pathways on liver mutations arising from dibromoethane and DEB in vivo. Treatment of the mice with butathionine sulfoxime (BSO) prior to dibromoethane lowered hepatic GSH levels, dibromoethane-GSH DNA adduct levels (N(7)-guanyl), and the cII mutation frequency. Administration of O(6)-benzylguanine (O(6)-BzGua), an inhibitor of AGT, did not change the mutation frequency. Depletion of GSH (BSO) and AGT (O(6)-BzGua) lowered the mutation frequency induced by DEB, and BSO lowered the levels of GSH-DEB N(7)-guanyl and N(6)-adenyl DNA adducts. Our results provide evidence that the GSH conjugation pathway is a major in vivo factor in dibromoethane genotoxicity; both GSH conjugation and AGT conjugation are major factors in the genotoxicity of DEB. The latter findings are considered to be relevant to the carcinogenicity of 1,3-butadiene. PMID:24191644

  2. Form 5-Mining venture agreement model form

    SciTech Connect

    Not Available

    1984-01-01

    This text acts as a reference of the basic terms and conditions for a negotiated mining venture agreement. Alternative clauses and provisions, along with extensive commentary, are supplied. The model form contains many articles which define and detail the process.

  3. 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,…

  4. 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.

  5. High electrophilicity at silicon in η3-silane σ-complexes: Lewis base adducts of a silane ligand, featuring octahedral silicon and three Ru-H-Si interactions.

    PubMed

    Lipke, Mark C; Tilley, T Don

    2011-10-19

    New η(3)-silane σ-complexes [PhBP(Ph)(3)]RuH(η(3)-H(2)SiRR') (RR' = PhMe, Ph(2)) were synthesized. Lewis bases [THF, 4-(dimethylamino)pyridine, and PMe(3)] coordinate to the silicon centers of these complexes to form stable adducts. The base adducts, [PhBP(Ph)(3)]Ru(μ-H)(3)SiRR'(base), feature three nonclassical Ru-H-Si interactions and hexacoordinate silicon centers, as determined by multinuclear NMR spectroscopy, X-ray crystallography, and computational investigations. PMID:21936540

  6. Forms of Arthritis

    MedlinePlus

    ... this page please turn Javascript on. Forms of Arthritis Past Issues / Fall 2006 Table of Contents Today, ... of Linda Saisselin Osteoarthritis (OA) — the form of arthritis typically occurring during middle or old age, this ...

  7. Forms of Arthritis

    MedlinePlus

    ... stiffness, inflammation, swelling and, sometimes, destruction of joints. Gout — a form of arthritis that occurs when uric ... the joints. Some 2.1 million Americans have gout. Lupus — a form of arthritis, like rheumatoid arthritis, ...

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. Mesonic Form Factors

    SciTech Connect

    Frederic D. R. Bonnet; Robert G. Edwards; George T. Fleming; Randal Lewis; David Richards

    2003-07-22

    We have started a program to compute the electromagnetic form factors of mesons. We discuss the techniques used to compute the pion form factor and present preliminary results computed with domain wall valence fermions on MILC asqtad lattices, as well as Wilson fermions on quenched lattices. These methods can easily be extended to rho-to-gamma-pi transition form factors.

  14. 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.

  15. Forms in Space.

    ERIC Educational Resources Information Center

    Moore, Paula

    1998-01-01

    Uses the work of M. C. Escher to instruct upper elementary students in the transformation of flat shape into three-dimensional form. Outlines the lesson as a series of sections: (1) reviewing form drawing; (2) creating three-dimensional effects; (3) imagining the forms in an inhabited world; and (4) using color and shading. (DSK)

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

    PubMed Central

    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.

    2013-01-01

    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/cm2) 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 hr with 30 μM 4-HNE or 6 hr 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. PMID:23845594

  17. 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.

  18. 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

  19. Mixture Toxicity of SN2-Reactive Soft Electrophiles: 3. Evaluation of Ethyl α-Halogenated Acetates with α-Halogenated Acetonitriles

    PubMed Central

    Pöch, G.; Schultz, T. W.

    2014-01-01

    Mixture toxicity for each of four ethyl α-halogenated acetates (ExACs) with each of three α-halogenated acetonitriles (xANs) was assessed. Inhibition of bioluminescence in Vibrio fischeri was measured after 15, 30 and 45-min of exposure. Concentration-response curves were developed for each chemical at each exposure duration and used to develop predicted concentration-response curves for the dose-addition and independence models of combined effect. Concentration-response curves for each mixture and each exposure duration were then evaluated against the predicted curves, using three metrics per model: 1) EC50-based additivity quotient (AQ) or independence quotient (IQ) values, 2) mean AQ (mAQ) or mean IQ (mIQ) values, calculated by averaging the EC25, EC50 and EC75 AQ or IQ values, and 3) deviation values from additivity (DV-A) or independence (DV-I). Mixture toxicity for ethyl iodoacetate (EIAC) was dose-additive with each of the xANs at all exposure durations and was often consistent with independence as well. The same was true for mixture toxicity of ethyl bromoacetate (EBAC) with each xAN. However, for the two more slowly reactive chemicals ethyl chloroacetate (ECAC) and ethyl fluoroacetate (EFAC) mixture toxicity with each xAN only became consistent with dose-addition upon increasing exposure duration. Consistency with independence for both ECAC and EFAC with the xANs was essentially limited to the EC50-IQ metric; thereby demonstrating the utility of calculating the mean quotient (mAQ, mIQ) and deviation value (DV-A, DV-I) metrics. Upon review of these findings with those from the first two papers in the series, the results suggest that instances in which mixture toxicity was not consistent with dose-addition relate: 1) to differences in the capability of the chemicals to form strong H-bonds with water and 2) to differences in relative reactivity and time-dependent toxicity levels of the chemicals. PMID:24368709

  20. 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.)

  1. Accounting Forms. Instructor's Handbook.

    ERIC Educational Resources Information Center

    Itter, Pat

    Supporting performance objective of the 16 V-TECS (Vocational-Technical Education Consortium of States) Bookkeeper Catalog, this instructor's manual contains copies of accounting forms which can be used to make spirit masters or transparencies. (This module is the first in a set of ten on bookkeeping [CE 019 480-489].) Twenty forms grouped under…

  2. 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.

  3. 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.

  4. 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

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

    2013-11-20

    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 wave functions. 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(O(2-))2 species. Rather, there is direct electron donation from the aromatic ring into the peroxo σ* orbital of the Cu(II)2(O2(2-)) 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

  5. 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

  6. 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

  7. 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

  8. Spin forming development

    SciTech Connect

    Gates, W.G.

    1982-05-01

    Bendix product applications require the capability of fabricating heavy gage, high strength materials. Five commercial sources have been identified that have the capability of spin forming metal thicknesses greater than 9.5 mm and four equiment manufacturers produce machines with this capability. Twelve assemblies selected as candidates for spin forming applications require spin forming of titanium, 250 maraging steel, 17-4 pH stainless steel, Nitronic 40 steel, 304 L stainless steel, and 6061 aluminum. Twelve parts have been cold spin formed from a 250 maraging steel 8.1 mm wall thickness machine preform, and six have been hot spin formed directly from 31.8-mm-thick flat plate. Thirty-three Ti-6Al-4V titanium alloy parts and 26 17-4 pH stainless steel parts have been hot spin formed directly from 31.8-mm-thick plate. Hot spin forming directly from plate has demonstrated the feasibility and favorable economics of this fabrication technique for Bendix applications.

  9. 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.

  10. 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.

  11. 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.

  12. Shell forming system

    NASA Technical Reports Server (NTRS)

    Kendall, Jr., James M. (Inventor); Wang, Taylor G. (Inventor); Elleman, Daniel D. (Inventor)

    1990-01-01

    Hollow shells of high uniformity are formed by emitting liquid through an outer nozzle and gas through an inner nozzle, to form a hollow extrusion, by flowing the gas at a velocity between about 1.3 and 10 times the liquid velocity. The natural breakup rate of the extrusion can be increased to decrease shell size by applying periodic perturbations to one of the materials prior to exiting the nozzles, to a nozzle, or to the extrusion.

  13. Mild electrophilic trifluoromethylthiolation of ketones with trifluoromethanesulfanamide.

    PubMed

    Wu, Wei; Zhang, Xuxue; Liang, Fang; Cao, Song

    2015-07-01

    A straightforward and convenient approach for trifluoromethylthiolation of various acyclic and cyclic ketones with PhNHSCF3 is described. The reaction proceeds smoothly in the presence of acetyl chloride at room temperature and affords α-trifluoromethylthiolated ketones in fair to good yields. PMID:26030292

  14. Composite hot drape forming

    NASA Astrophysics Data System (ADS)

    Ott, Thomas

    1994-02-01

    This program was initiated to replace labor-intensive ply-by-ply layup of composite I-beam posts and angle stiffeners used in the Space Station Freedom (SSF) rack structure. Hot drape forming (HDF) has been successfully implemented by BCAG for 777 composite I-stringers and by Bell Helicopter/Textron for the V-22 I-stingers. The two companies utilize two vastly different approaches to the I-beam fabrication process. A drape down process is used by Bell Helicopter where the compacted ply charge is placed on top of a forming mandrel and heated. When the heated ply charge reached a set temperature, vacuum pressure is applied and the plies are formed over the mandrel. The BCAG 777 process utilizes an inverted forming process where the ply stack is placed on a forming table and the mandrel is inverted and placed upon the ply stack. A heating and vacuum bladder underneath the ply stack form the play stack up onto the mandrels after reaching the temperature setpoint. Both methods have their advantages, but the drape down process was selected for SSF because it was more versatile and could be fabricated from readily available components.

  15. Composite hot drape forming

    NASA Technical Reports Server (NTRS)

    Ott, Thomas

    1994-01-01

    This program was initiated to replace labor-intensive ply-by-ply layup of composite I-beam posts and angle stiffeners used in the Space Station Freedom (SSF) rack structure. Hot drape forming (HDF) has been successfully implemented by BCAG for 777 composite I-stringers and by Bell Helicopter/Textron for the V-22 I-stingers. The two companies utilize two vastly different approaches to the I-beam fabrication process. A drape down process is used by Bell Helicopter where the compacted ply charge is placed on top of a forming mandrel and heated. When the heated ply charge reached a set temperature, vacuum pressure is applied and the plies are formed over the mandrel. The BCAG 777 process utilizes an inverted forming process where the ply stack is placed on a forming table and the mandrel is inverted and placed upon the ply stack. A heating and vacuum bladder underneath the ply stack form the play stack up onto the mandrels after reaching the temperature setpoint. Both methods have their advantages, but the drape down process was selected for SSF because it was more versatile and could be fabricated from readily available components.

  16. 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

  17. Laser forming process development

    SciTech Connect

    Blake, R.J.

    1996-12-31

    This paper is a summary of the activities performed for the process development of laser thermal forming sheet metal parts in support of rapid prototyping. A 400 watt pulsed Nd:YAG laser and 50 watt desktop CO{sub 2} laser were used during initial process development. Several tool-assisted laser forming approaches were conceived during the development of the process, and simple fixtures for process development/understanding were used throughout all testing. Much of the actual forming was performed with the base material in an unfixtured state. CRES (304) was used for baseline development, but the effort was directed toward forming titanium (e.g., 6Al-4V, 15V-3Cr-3Sn-3Al). Several DOE (i.e., Design of Experiment) techniques were employed during development and a Neural Net Computer Model was conceived for process control. This program was a joint effort in cooperation with the American Welding Society under contract with the Defense Advanced Research Projects Agency (DARPA). A synopsis of the laser forming process development, future opportunities, and applications are presented.

  18. 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.

  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. Synthesis, Absorption, and Electrochemical Properties of Quinoid-Type Bisboron Complexes with Highly Symmetrical Structures.

    PubMed

    Kubota, Yasuhiro; Niwa, Takahiro; Jin, Jiye; Funabiki, Kazumasa; Matsui, Masaki

    2015-06-19

    Novel bisboron complexes of bidentate ligands consisting of 1,4-benzoquinone and two pyrrole rings were synthesized by using a simple two-step reaction. In solution, the bisboron complexes showed absorption maxima at ∼620 and 800 nm, which were attributed to the allowed S0 → S2 and forbidden S0 → S1 transitions, respectively. The bisboron complexes did not show any fluorescence, probably because of their highly symmetrical structure which forbids the S0 → S1 transition. Bisboron complexes underwent a two-electron reduction to yield the corresponding aromatic dianion, which showed absorption maxima at ∼410 nm. PMID:26067338

  1. Literature: Internal Forms.

    ERIC Educational Resources Information Center

    Regional Curriculum Project, Atlanta, GA.

    This curriculum guide in literature, developed as part of a total English curriculum for pre-kindergarten through grade 10, suggests that students can best understand literature by recognizing its internal forms (i.e., characteristics that recur in settings, characters, and narrative patterns). Materials cover (1) an overview for teachers on the…

  2. 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.

  3. 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.

  4. 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…

  5. 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.

  6. 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.

  7. 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,…

  8. 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.

  9. Inelastic Scattering Form Factors

    Energy Science and Technology Software Center (ESTSC)

    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.

  10. 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)

  11. Changing Organizational Forms.

    ERIC Educational Resources Information Center

    1997

    This document contains three papers from a symposium on changing organizational forms. "Goal Integration in a Multi-divisional Organization" (Richard J. Torraco, Mary Finnegan), reports on a study that examined how goals are integrated into organizational activities once they have been identified, proposes a model of goal integration, and develops…

  12. 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).

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Space form of motionsickness

    NASA Technical Reports Server (NTRS)

    Komendantov, G. L.; Kopanev, V. I.

    1975-01-01

    Spacesickness under weightlessness conditions is explained mainly by disruption of the activity of the functional system perceiving space and participating in carrying out the balancing function, consisting, in particular, of the vestibular, proprioceptive, interoceptive, visual and cutaneomechanical analyzers. It can be assumed that, under specific conditions, Coriolis acceleration also is a cause of spacesickness. Adaptation is possible by formation of a new functional system which is adequate to the new mechanical conditions of weightlessness. Selection, training, creation of optimum conditions in the spacecraft cabin, medicinal, and technical improvement of spacecraft play an important role in prophylaxis of the space form of seasickness.

  18. GlassForm

    Energy Science and Technology Software Center (ESTSC)

    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

  19. Spun Almost Normal Form

    NASA Astrophysics Data System (ADS)

    Paullin, Katherine L.

    Many of a 3-manifold's properties are determined by the surfaces they contain, and this knowledge leads to the foundation of decision algorithms for 3- manifolds. Popular work influencing the work of 3-manifold algorithms has it's roots in normal surface theory. In a triangulated 3-manifold, Haken and Kneser showed that we could put any incompressible surface into normal form. Expanding on those techniques, Rubinstein and Stocking later showed we could put any strongly irreducible surface into almost normal form. Walsh has more recently shown that in an ideal triangulation of a hyperbolic manifold many surfaces can be spun normalized. One unsolved problem in 3-manifold algorithms is studying the complexity of Lens Space Recognition. Spun almost normalization appears to be a part of solving this larger problem. In this dissertation, I will first discuss a nontraditional technique using graphs of equivalence classes of compressing disks that allows us to take a combinatorial approach to generalize the result of Walsh's to nonhyperbolic manifolds. Using that method, I'll also explore the conditions needed to show that a surface can be spun almost normalized.

  20. MLKL forms cation channels

    PubMed Central

    Xia, Bingqing; Fang, Sui; Chen, Xueqin; Hu, Hong; Chen, Peiyuan; Wang, Huayi; Gao, Zhaobing

    2016-01-01

    The mixed lineage kinase domain-like (MLKL) protein is a key factor in tumor necrosis factor-induced necroptosis. Recent studies on necroptosis execution revealed a commitment role of MLKL in membrane disruption. However, our knowledge of how MLKL functions on membrane remains very limited. Here we demonstrate that MLKL forms cation channels that are permeable preferentially to Mg2+ rather than Ca2+ in the presence of Na+ and K+. Moreover, the N-terminal domain containing six helices (H1-H6) is sufficient to form channels. Using the substituted cysteine accessibility method, we further determine that helix H1, H2, H3, H5 and H6 are transmembrane segments, while H4 is located in the cytoplasm. Finally, MLKL-induced membrane depolarization and cell death exhibit a positive correlation to its channel activity. The Mg2+-preferred permeability and five transmembrane segment topology distinguish MLKL from previously identified Mg2+-permeable channels and thus establish MLKL as a novel class of cation channels. PMID:27033670

  1. 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.

  2. 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

    ... 8879-F, IRS e-file Signature Authorization for Form 1041. DATES: Written comments should be received on... (Form 1041). Title: U.S. Estate or Trust Declaration and Signature for an IRS e- File Return. OMB Number... Electronic Filing. This form will only be used as a signature letter to Form 1041. This new form...

  3. Shell forming system

    NASA Technical Reports Server (NTRS)

    Kendall, Jr., James M. (Inventor); Wang, Taylor G. (Inventor); Elleman, Daniel D. (Inventor)

    1987-01-01

    An apparatus is provided for forming gas-filled spheres of metal, glass or other material, which produces spheres (12) of uniform size and wall thickness in a relatively simple system. The system includes concentric nozzles, including an inner nozzle (18) through which gas flows and and an outer nozzle (20), which jointly define an annular passageway (50) through which a liquid flows. The flow rates are adjusted so that the gas flows at greater velocity than does the liquid, out of their respective nozzles, e.g. three times as great, in order to produce an extrusion (30) which undergoes axisymmetric oscillations resulting in the pinch off into hollow spheres with very uniform spacing. The system is useful not only where gas-filled spheres are required, but also is useful to accurately control the dispensing of solid, liquid, or gaseous materials.

  4. Shell forming apparatus

    NASA Technical Reports Server (NTRS)

    Wang, Taylor G. (Inventor); Granett, Dan (Inventor); Akutagawa, Wesley M. (Inventor)

    1987-01-01

    A nozzle assembly is described for use in a system that forms small gas-filled shells, which avoids the need for holding a miniature inner nozzle precisely concentric with a miniature outer nozzle. The outer nozzle has a diameter which is less than about 0.7 millimeter, which results in fluid passing through the nozzle having a progressively greater velocity at locations progressively further from the walls of the outer nozzle across most of the nozzle. This highly variable velocity profile automatically forces gas to the center of the outer nozzle. The end of the inner nozzle, which emits gas, is spaced upstream from the tip of the outer nozzle, to provide a distance along which to center the gas. This self-centering characteristic permits the inner nozzle to be positioned so its axis is not concentric with the axis of the outer nozzle.

  5. 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.

  6. 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.

  7. Spray-formed tooling

    NASA Astrophysics Data System (ADS)

    McHugh, K. M.; Key, J. F.

    The United States Council for Automotive Research (USCAR) has formed a partnership with the Idaho National Engineering Laboratory (INEL) to develop a process for the rapid production of low-cost tooling based on spray forming technology developed at the INEL. Phase 1 of the program will involve bench-scale system development, materials characterization, and process optimization. In Phase 2, prototype systems will be designed, constructed, evaluated, and optimized. Process control and other issues that influence commercialization will be addressed during this phase of the project. Technology transfer to USCAR, or a tooling vendor selected by USCAR, will be accomplished during Phase 3. The approach INEL is using to produce tooling, such as plastic injection molds and stamping dies, combines rapid solidification processing and net-shape materials processing into a single step. A bulk liquid metal is pressure-fed into a de Laval spray nozzle transporting a high velocity, high temperature inert gas. The gas jet disintegrates the metal into fine droplets and deposits them onto a tool pattern made from materials such as plastic, wax, clay, ceramics, and metals. The approach is compatible with solid freeform fabrication techniques such as stereolithography, selective laser sintering, and laminated object manufacturing. Heat is extracted rapidly, in-flight, by convection as the spray jet entrains cool inert gas to produce undercooled and semi-solid droplets. At the pattern, the droplets weld together while replicating the shape and surface features of the pattern. Tool formation is rapid; deposition rates in excess of 1 ton/h have been demonstrated for bench-scale nozzles.

  8. Spray-formed tooling

    SciTech Connect

    McHugh, K.M.; Key, J.F.

    1994-12-31

    The United States Council for Automotive Research (USCAR) has formed a partnership with the Idaho National Engineering Laboratory (INEL) to develop a process for the rapid production of low-cost tooling based on spray forming technology developed at the INEL. Phase 1 of the program will involve bench-scale system development, materials characterization, and process optimization. In Phase 2, prototype systems will be de signed, constructed, evaluated, and optimized. Process control and other issues that influence commercialization will be addressed during this phase of the project. Technology transfer to USCAR, or a tooling vendor selected by USCAR, will be accomplished during Phase 3. The approach INEL is using to produce tooling, such as plastic injection molds and stamping dies, combines rapid solidification processing and net-shape materials processing into a single step. A bulk liquid metal is pressure-fed into a de Laval spray nozzle transporting a high velocity, high temperature inert gas. The gas jet disintegrates the metal into fine droplets and deposits them onto a tool pattern made from materials such as plastic, wax, clay, ceramics, and metals. The approach is compatible with solid freeform fabrication techniques such as stereolithography, selective laser sintering, and laminated object manufacturing. Heat is extracted rapidly, in-flight, by convection as the spray jet entrains cool inert gas to produce undercooled and semi-solid droplets. At the pattern, the droplets weld together while replicating the shape and surface features of the pattern. Tool formation is rapid; deposition rates in excess of 1 ton/h have been demonstrated for bench-scale nozzles.

  9. 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

  10. 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

  11. 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

  12. 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

  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. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. Reaction of N-arylsulfonylquinonimines and quinones with N-chloramides

    SciTech Connect

    Bezverkhii, N.P.; Protashchuk, S.I.; Borodavko, N.D.

    1987-11-10

    N-chloro derivatives of formamide, chloroacetamide and N-substituted ureas in the presence of triethylamine or potassium acetate amidate N-arylsulfonylquinonimines. Quantum chemical calculations of the electronic structure of anions of N-chloramides of carboxylic and sulfonic acids show that the amidation of quinoid systems by N-chloramides is subject to orbital control. In the framework of the frontier molecular orbital theory, the inactivity of benzoquinones and naphthoquinones and N,N/sup 1/-bis(benzoyl)-1,4-benzoquinonediimine in the amidation reaction is attributed to the level of the lowest unoccupied molecular orbital, which is higher than that in N-arylsulfonylquinonimines. The quantum chemical calculations showed that the major contribution to the reaction of quinonimines with N-chloramide anions is made by an orbital interaction. Thus, the electrophilic reactivity of quinoid compounds should depend on the level of their LUMO, whose energy is approximately equal to the electron affinity of the molecule.

  20. Doing Focus-on-Form.

    ERIC Educational Resources Information Center

    Ellis, Rod; Basturkmen, Helen; Loewen, Shawn

    2002-01-01

    Considers the rationale for using a focus on form approach to teaching form as opposed to the more traditional focus on forms approach where linguistic features are treated sequentially. Describes methodological options for attending to form in communication. (Author/VWL)

  1. 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…

  2. 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.

  3. Investigating Form-Focused Instruction.

    ERIC Educational Resources Information Center

    Ellis, Rod

    2001-01-01

    Provides an historical sketch of form-focused instruction research, defines what is meant by form-focused instruction, and discusses the main research methods that have been used to investigate form-focused instruction in terms of a broad distinction between confirmatory and interpretive research. (Author/VWL)

  4. 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.

  5. 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.

  6. 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. PMID:25669053

  7. 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.

  8. 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.

  9. System for forming janus particles

    DOEpatents

    Hong, Liang; Jiang, Shan; Granick, Steve

    2011-01-25

    The invention is a method of forming Janus particles, that includes forming an emulsion that contains initial particles, a first liquid, and a second liquid; solidifying the first liquid to form a solid that contains at least a portion of the initial particles on a surface of the solid; and treating the exposed particle sides with a first surface modifying agent, to form the Janus particles. Each of the initial particles on the surface has an exposed particle side and a blocked particle side.

  10. L Form of Neisseria gonorrhoeae

    PubMed Central

    Roberts, Richard B.

    1966-01-01

    Roberts, Richard B. (Walter Reed Army Institute of Research, Washington, D.C.). L form of Neisseria gonorrhoeae. J. Bacteriol. 92:1609–1614. 1966.—L forms were produced by the penicillin gradient plate technique from a recently isolated strain of Neisseria gonorrhoeae. To date, these L forms have had 30 serial passages on medium containing penicillin. Stabilized L forms developed on penicillin-free medium after 10 or more passages in the presence of penicillin. Morphological characteristics of these organisms were identical to L forms of meningococci. Medium and environmental conditions necessary for optimal growth included: Brain Heart Infusion of pH 7.2 to 7.4, 1.1 to 1.3% agar, 10 to 20% sucrose, 10 to 20% horse serum, temperature at 35 to 36 C, and increased CO2 tension (candle jar). L forms were more resistant than the parent gonococcus to penicillin, ampicillin, methicillin, cycloserine, and cephalothin, whereas both organisms had similar sensitivities to bacitracin, vancomycin, ristocetin, novobiocin, tetracycline, and erythromycin. Revertant gonococci were produced on penicillin-free medium from L forms which had had 1, 5, and 10 serial passages. Morphology and fermentative reactions of revertant strains were identical to those of the parent gonococcus. Revertant strains produced L forms more readily than the parent organism; in fact, L forms from certain revertants did not require penicillin, but only serum and sucrose for their production and propagation on artificial medium. Images PMID:4959715

  11. 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.

  12. 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

  13. 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…

  14. 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…

  15. 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.

  16. 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.

  17. 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.

  18. Cutting Costs on Computer Forms.

    ERIC Educational Resources Information Center

    Rupp, Robert V., Jr.

    1989-01-01

    Using the experience of Ford Motor Company, Oscar Meyer, and IBM, this article shows that companies are enjoying high quality product performance and substantially lower costs by converting from premium white bond computer stock forms to blended bond forms. School administrators are advised to do likewise. (MLH)

  19. Organic forms of soil nitrogen

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chemical forms of soil organic nitrogen (N) are thought to influence the cycling rates of soil N. Limited evidence for this relationship is available, though, because until recently technical constraints have not allowed adequate elucidation of the chemical forms. Recent developments in spectros...

  20. 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

  1. Canonical forms for nonlinear systems

    NASA Technical Reports Server (NTRS)

    Su, R.; Hunt, L. R.; Meyer, G.

    1983-01-01

    Necessary and sufficient conditions for transforming a nonlinear system to a controllable linear system have been established, and this theory has been applied to the automatic flight control of aircraft. These transformations show that the nonlinearities in a system are often not intrinsic, but are the result of unfortunate choices of coordinates in both state and control variables. Given a nonlinear system (that may not be transformable to a linear system), we construct a canonical form in which much of the nonlinearity is removed from the system. If a system is not transformable to a linear one, then the obstructions to the transformation are obvious in canonical form. If the system can be transformed (it is called a linear equivalent), then the canonical form is a usual one for a controllable linear system. Thus our theory of canonical forms generalizes the earlier transformation (to linear systems) results. Our canonical form is not unique, except up to solutions of certain partial differential equations we discuss. In fact, the important aspect of this paper is the constructive procedure we introduce to reach the canonical form. As is the case in many areas of mathematics, it is often easier to work with the canonical form than in arbitrary coordinate variables.

  2. Colloidal thermoresponsive gel forming hybrids.

    PubMed

    Liu, Ruixue; Tirelli, Nicola; Cellesi, Francesco; Saunders, Brian R

    2010-09-15

    Colloidal hybrids comprise organic and inorganic components and are attracting considerable attention in the literature. Recently, we reported hybrid anisotropic microsheets that formed thermoresponsive gels in polymer solutions [Liu et al., Langmuir, 25, 490, 2009]. Here, we investigate the composition and properties of these hybrid colloids themselves in detail for the first time. Three different cationic PNIPAm (N-isopropylacrylamide) graft copolymers and two inorganic nanoparticle types (laponite and Ludox silica) were used to prepare a range of hybrids. Anisotropic microsheets only formed when laponite particles were added to the copolymer implying directed self-assembly. Aqueous dispersions of the microsheets spontaneously formed gels at room temperature and these gels were thermoresponsive. They represent a new class of gel forming colloid and are termed thermoresponsive gel forming hybrids. The compositions of the hybrids were determined from thermogravimetric analysis and those that gave gel forming behaviour identified. Variable-temperature rheology experiments showed that the elasticity of the gels increased linearly with temperature. The reversibility of the thermally-triggered changes in gel elasticity was investigated. The concentration dependence of the rheology data was well described by elastic percolation scaling theory and the data could be collapsed onto a master curve. The concentration exponent for the elastic modulus was 2.5. The strong attractive interactions that exist between the dispersed gel forming hybrids was demonstrated by the formation of stable thermoresponsive hybrid hydrogels through casting of hybrid dispersions. PMID:20561633

  3. 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.

  4. 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.

  5. Supergravity actions with integral forms

    NASA Astrophysics Data System (ADS)

    Castellani, L.; Catenacci, R.; Grassi, P. A.

    2014-12-01

    Integral forms provide a natural and powerful tool for the construction of supergravity actions. They are generalizations of usual differential forms and are needed for a consistent theory of integration on supermanifolds. The group geometrical approach to supergravity and its variational principle are reformulated and clarified in this language. Central in our analysis is the Poincaré dual of a bosonic manifold embedded into a supermanifold. Finally, using integral forms we provide a proof of Gates' so-called "Ectoplasmic Integration Theorem", relating superfield actions to component actions.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. Method for forming metal contacts

    SciTech Connect

    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.

  14. Form 6 - gas balancing agreement

    SciTech Connect

    Not Available

    1990-01-01

    In 1988, a special Committee of the Rocky Mountain Mineral Law Foundation undertook a project to draft a model from gas balancing agreement. This project was initiated at the request of a number of Foundation members who felt that a model form gas balancing agreement would facilitate the negotiation of operating agreement, since gas balancing issues had become sticking points in the process. The Committee was composed of attorneys representing a wide cross-section of the oil and gas industry including both major and independent oil companies, production companies with interstate pipeline affiliates, and private practitioners. The Committee attempted to address the more controversial issues in gas balancing with optional provisions in the Form. To facilitate the negotiation process, the number of optional provisions was minimized. This form may be used as an Appendix to the new A.A.P.L. Form 610-1989 Model Form Operating Agreement. This book includes provision of this Form which are: Ownership of gas production; Balancing of production accounts; Cash balancing upon depletion; Deliverability tests; Nominations; Statements; Payment of taxes; Operating expenses; Overproducing allowable; Payment of leasehold burdens; Operator's liability; Successors and assigns; Audits; Arbitration; and Operator's fees.

  15. 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.

  16. 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.

  17. 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.

  18. Conjoint Forming - Technologies for Simultaneous Forming and Joining

    NASA Astrophysics Data System (ADS)

    Groche, P.; Wohletz, S.; Mann, A.; Krech, M.; Monnerjahn, V.

    2016-03-01

    The market demand for new products optimized for e. g. lightweight applications or smart components leads to new challenges in production engineering. Hybrid structures represent one promising approach. They aim at higher product performance by using a suitable combination of different materials. The developments of hybrid structures stimulate the research on joining of dissimilar materials. Since they allow for joining dissimilar materials without external heating technologies based on joining by plastic deformation seem to be of special attractiveness. The paper at hand discusses the conjoint forming approach. This approach combines forming and joining in one process. Two or more workpieces are joined while at least one workpiece is plastically deformed. After presenting the fundamental joining mechanisms, the conjoint forming approach is discussed comprehensively. Examples of conjoint processes demonstrate the effectiveness and reveal the underlying phenomena.

  19. 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…

  20. 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…

  1. 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…

  2. Reactions of the Terminal NiII–OH Group in Substitution and Electrophilic Reactions with Carbon Dioxide and Other Substrates: Structural Definition of Binding Modes in an Intramolecular NiII…FeII Bridged Site

    PubMed Central

    Huang, Deguang; Holm, R. H.

    2010-01-01

    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 + H2O ⇌ CO2 + 2H+ + 2e−. A similar structure has been sought in this work. Mononuclear planar NiII complexes [Ni(pyN2Me2)L]1− (pyN2Me2 = 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 CO2 to form unidentate L = HCO2− (5) and HCO3− (6) products. A binucleating macrocycle was prepared which specifically binds NiII at a NNN pincer site and five-coordinate FeII at a triamine site. The NiII macrocyle forms hydroxo (14) and cyanide complexes (15) analogous to 1 and 7. Reaction of 14 with FeCl2 alone and with ethyl formate and 15 with FeCl2 affords molecules with the NiII-L-FeII bridge unit in which L = µ2:η1-OH− (17) and µ2:η2-HCO2− (18) and -CN− (19). All bridges are non-linear (17, 140.0°; 18, M-O-C 135.9° (Ni), 120.2° (Fe); 19, Ni-C-N 170.3°, Fe-N-C 141.8°) with Ni⋯Fe separations of 3.7–4.8 Å. The NiIIFeII complexes, lacking appropriate Ni-Fe-S cluster structures, are not site analogues but their synthesis and reactivity provide the first demonstration that molecular NiII…FeII sites and bridges can be attained, a necessity in the biomimetic chemistry of C-clusters. PMID:20218565

  3. 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.

  4. Modeling Production Plant Forming Processes

    SciTech Connect

    Rhee, M; Becker, R; Couch, R; Li, M

    2004-09-22

    Engineering has simulation tools and experience in modeling forming processes. Y-12 personnel have expressed interest in validating our tools and experience against their manufacturing process activities such as rolling, casting, and forging etc. We have demonstrated numerical capabilities in a collaborative DOE/OIT project with ALCOA that is nearing successful completion. The goal was to use ALE3D to model Alcoa's slab rolling process in order to demonstrate a computational tool that would allow Alcoa to define a rolling schedule that would minimize the probability of ingot fracture, thus reducing waste and energy consumption. It is intended to lead to long-term collaboration with Y-12 and perhaps involvement with other components of the weapons production complex. Using simulations to aid in design of forming processes can: decrease time to production; reduce forming trials and associated expenses; and guide development of products with greater uniformity and less scrap.

  5. Glasses formed by hypervelocity impact

    NASA Technical Reports Server (NTRS)

    Stoeffler, D.

    1984-01-01

    This paper presents description, classification, and geological setting of impact glasses, which are formed as a result of meteorite impacts with the planetary surface, and discusses the impact-glass formation process in the context of cratering mechanics. Impact glasses can be classified as belonging to two major groups: (1) mineral glasses, which are identical in composition to a mineral, and (2) rock glasses, which have the composition of a rock or a mixture of various rocks. Rock glasses may be (1) melt ejecta, (2) parts of a coherent melt layer inside the crater cavity, or (3) dikes or veins. The composition of rock glasses at a particular crater can be matched by that of the target. In nonporous rocks, the formation of rock glasses requires peak pressures in excess of 60-80 GPa, while mineral glasses are formed in the pressure range of about 25 to 55 GPa; in porous rocks, interstitial glass forms at pressures as low as 5 GPa.

  6. Methods of forming boron nitride

    SciTech Connect

    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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 6 2013-10-01 2013-10-01 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...

  14. 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...

  15. 48 CFR 53.301 - Standard forms.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 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...

  16. 48 CFR 53.301 - Standard forms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 2 2012-10-01 2012-10-01 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...

  17. 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...

  18. 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...

  19. 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...

  20. Emerging Forms of School Organization.

    ERIC Educational Resources Information Center

    Rufo-Lignos, Patricia; Richards, Craig E.

    2003-01-01

    Examines new forms of school organization that do not fit traditional definitions of public and private schools. Three case studies explore critical features of the public-private distinction, highlighting the fuzzy boundaries between schools that are clearly public and schools that are clearly private, and contending that their shared…

  1. 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.

  2. Synthesis Can Take Many Forms

    ERIC Educational Resources Information Center

    Darrow, Rob

    2005-01-01

    Synthesis can take many forms at the high school level and from a Big6 perspective. Synthesis means purposeful, valuable and interesting assignments. It is very important for a classroom teacher to recognize that students can synthesize information several times during a project and that there are many different ways to present information.

  3. 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…

  4. TEAM TEACHING HAS MANY FORMS.

    ERIC Educational Resources Information Center

    DIESMAN, FLORENCE M.

    COMMENTS ARE MADE ON VARIOUS FORMS OF TEAM TEACHING. AT FERRIS HIGH SCHOOL, SPOKANE, A TEAM OF FOUR INSTRUCTORS TAUGHT ENGLISH TO 526 SOPHOMORES, IN LECTURE GROUPS OF ABOUT 250 EACH. THE DAY WAS DIVIDED INTO 26 15-MINUTE MODULES. CLASS LECTURES, SEMINARS, STUDY PERIODS, LABORATORIES WERE ALL COMPOSED OF VARIOUS COMBINATIONS OF THESE MODULES.…

  5. Intersections: Form, Feeling, and Isomorphism

    ERIC Educational Resources Information Center

    Reichling, Mary J.

    2004-01-01

    In this article, the author examines the intersections of three concepts, form, feeling, and isomorphism, in the work of Susanne Langer, as they are fundamental to an understanding of her aesthetic theory and to the construction of a philosophy of music and music education. These three concepts hold meanings that differ among musicians and…

  6. 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.

  7. 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.

  8. 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.

  9. Researching New Forms of Literacy.

    ERIC Educational Resources Information Center

    Mackey, Margaret

    2003-01-01

    Proposes that reading researchers and teachers must acknowledge that contemporary new readers have no other way of learning about reading except within the context of a background of vast textual experience across many media and through multiple forms of address. Suggests educators need to take a broad view of the complex context in which texts…

  10. 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.…

  11. Cheaper Hydride-Forming Cathodes

    NASA Technical Reports Server (NTRS)

    Jones, Jack A.; Blue, Gary

    1990-01-01

    Hydride-forming cathodes for electrochemical experiments made of materials or combinations of materials cheaper and more abundant than pure palladium, according to proposal. Concept prompted by needs of experimenters in now-discredited concept of electrochemical nuclear fusion, cathodes useful in other electrochemical applications involving generation or storage of hydrogen, deuterium, or tritium.

  12. Quantitative comparison of carcinogenicity, mutagenicity and electrophilicity of 10 direct-acting alkylating agents and of the initial O6:7-alkylguanine ratio in DNA with carcinogenic potency in rodents.

    PubMed

    Bartsch, H; Terracini, B; Malaveille, C; Tomatis, L; Wahrendorf, J; Brun, G; Dodet, B

    1983-08-01

    The quantitative relationship between carcinogenicity in rodents and mutagenicity in Salmonella typhimurium was examined, by using 10 monofunctional alkylating agents, including N-nitrosamides, alkyl methanesulfonates, epoxides, beta-propiolactone and 1,3-propane sultone. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535 and TA100) and in plate and liquid assays. The mutagenic activity of the agents was compared with their alkylating activity towards 4-(4'-nitrobenzyl)pyridine and with their half-lives (solvolysis constants) in an aqueous medium. No correlations between these variables were found, nor was mutagenic activity correlated with estimates of carcinogenicity in rodents. There was a positive relationship between carcinogenicity and the initial ratios of 7-:O6-alkylguanine formed or expected after their reaction with double-stranded DNA in vitro. The results suggest that alkylation of guanine at position O6 (or at other O atoms of DNA bases) may be a critical DNA-base modification that determines the overall carcinogenicity of these alkylating agents in rodents. PMID:6348521

  13. 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.

  14. 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... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HOMELAND...-7001), Online Ombudsman Form DHS-7001 AGENCY: Office of the Citizenship and Immigration...

  15. Terra firma-forme dermatosis.

    PubMed

    Oztürk, Ferdi; Kocabaş, Engin; Ertan, Pelin; Ermertcan, Aylin Türel

    2010-12-01

    Terra firma-forme dermatosis (TFFD) is an uncommon disorder of keratinization with an unknown etiology in which patients present with dirt-like lesions that are resistant to washing. A 6-year old girl presented with the complaint of an asymptomatic brownish black dirt-like eruption on her body. Her parents reported no response to washing with soap and water. Dermatologic examination revealed brown hyperpigmented patches on the trunk and abdominal region. TFFD was suspected, and isopropyl alcohol was applied to the patient's lesions. All lesions completely disappeared after rubbing with alcohol. Terra firma-forme dermatosis is a relatively recently described entity that is much more common than might be expected when surveying the medical literature. With the very few reports found in the literature about TFFD, we believe that an increased awareness of this entity among primary care physicians would help decrease unnecessary worries or medical procedures, since TFFD lesions simply resolve by rubbing with isopropyl alcohol. PMID:20684734

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Form development sample test matrix

    SciTech Connect

    Ebbinghaus, B B

    1999-10-15

    This document summarizes the status of sample fabrication and analysis in the Form Development Sample Test Matrix. Since its publication in the ''Baseline Formulation'' report (UCRL-ID- 133089, PIP-99-O 12) and in the ''Complete Single-Phase Sample Fabrications that Support the Licensing Application and Complete Process and Compositional Extreme Sample Fabrications that Support the Licensing Application'' report (PIP-99-078), the Sample Test Matrix has been updated and expanded. This version is current though September 30, 1999.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Fuzzy logic of Aristotelian forms

    SciTech Connect

    Perlovsky, L.I.

    1996-12-31

    Model-based approaches to pattern recognition and machine vision have been proposed to overcome the exorbitant training requirements of earlier computational paradigms. However, uncertainties in data were found to lead to a combinatorial explosion of the computational complexity. This issue is related here to the roles of a priori knowledge vs. adaptive learning. What is the a-priori knowledge representation that supports learning? I introduce Modeling Field Theory (MFT), a model-based neural network whose adaptive learning is based on a priori models. These models combine deterministic, fuzzy, and statistical aspects to account for a priori knowledge, its fuzzy nature, and data uncertainties. In the process of learning, a priori fuzzy concepts converge to crisp or probabilistic concepts. The MFT is a convergent dynamical system of only linear computational complexity. Fuzzy logic turns out to be essential for reducing the combinatorial complexity to linear one. I will discuss the relationship of the new computational paradigm to two theories due to Aristotle: theory of Forms and logic. While theory of Forms argued that the mind cannot be based on ready-made a priori concepts, Aristotelian logic operated with just such concepts. I discuss an interpretation of MFT suggesting that its fuzzy logic, combining a-priority and adaptivity, implements Aristotelian theory of Forms (theory of mind). Thus, 2300 years after Aristotle, a logic is developed suitable for his theory of mind.

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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.

  14. 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.

  15. 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.

  16. Friction-formed liquid droplets

    NASA Astrophysics Data System (ADS)

    Lockwood, A. J.; Anantheshwara, K.; Bobji, M. S.; Inkson, B. J.

    2011-03-01

    The formation of nanoscale liquid droplets by friction of a solid is observed in real-time. This is achieved using a newly developed in situ transmission electron microscope (TEM) triboprobe capable of applying multiple reciprocating wear cycles to a nanoscale surface. Dynamical imaging of the nanoscale cyclic rubbing of a focused-ion-beam (FIB) processed Al alloy by diamond shows that the generation of nanoscale wear particles is followed by a phase separation to form liquid Ga nanodroplets and liquid bridges. The transformation of a two-body system to a four-body solid-liquid system within the reciprocating wear track significantly alters the local dynamical friction and wear processes. Moving liquid bridges are observed in situ to play a key role at the sliding nanocontact, interacting strongly with the highly mobile nanoparticle debris. In situ imaging demonstrates that both static and moving liquid droplets exhibit asymmetric menisci due to nanoscale surface roughness. Nanodroplet kinetics are furthermore dependent on local frictional temperature, with solid-like surface nanofilaments forming on cooling. TEM nanotribology opens up new avenues for the real-time quantification of cyclic friction, wear and dynamic solid-liquid nanomechanics, which will have widespread applications in many areas of nanoscience and nanotechnology.

  17. 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.

  18. 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.

  19. 75 FR 26782 - Agency Information Collection Activities: Form I-864, Form I-864A, Form I-864EZ, and Form I-864W...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-12

    ... SECURITY U.S. Citizenship and Immigration Services Agency Information Collection Activities: Form I-864, Form I- 864A, Form I-864EZ, and Form I-864W; Extension of an Existing Information Collection; Comment Request ACTION: 60-Day Notice of Information Collection Under Review; Form I- 864, Affidavit of...

  20. 49 CFR 225.21 - Forms.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... following forms and copies of the “FRA Guide for Preparing Accident/Incident Reports” may be obtained from... the form and in the current “FRA Guide for Preparing Accident/Incident Reports.” The form shall be... Inquiry Form.—Form FRA F 6180.150 shall be sent to every potentially injured highway user, or...

  1. 49 CFR 225.21 - Forms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... following forms and copies of the “FRA Guide for Preparing Accident/Incident Reports” may be obtained from... the form and in the current “FRA Guide for Preparing Accident/Incident Reports.” The form shall be... Inquiry Form.—Form FRA F 6180.150 shall be sent to every potentially injured highway user, or...

  2. 48 CFR Appendix - List of IAAR Forms

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 6 2014-10-01 2014-10-01 false List of IAAR Forms Federal 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...

  3. 16 CFR 455.3 - Window form.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Window form. 455.3 Section 455.3 Commercial... Window form. (a) Form given to buyer. Give the buyer of a used vehicle sold by you the window form...) Incorporated into contract. The information on the final version of the window form is incorporated into...

  4. 48 CFR 570.701 - Standard forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Forms 570.701 Standard forms. Use Standard Form 2, U.S. Government Lease for Real Property, to award leases unless you use GSA Form 3626 (see 570.702). Delete the reference to the Standard Form 2-A in paragraph 7....

  5. 48 CFR 570.702 - GSA forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Forms 570.702 GSA forms. (a) You may use GSA Form 3626, U.S. Government Lease for Real Property (Short Form), to award leases if you use the simplified leasing procedures in 570.2 or if you determine it advantageous to use. (b) You may use GSA Form...

  6. 48 CFR 813.307 - Forms.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... following forms provide a purchase or delivery order, vendor's invoice, and receiving report: (1) VA Form 90-2138, Order for Supplies or Services. (2) VA Form 90-2139, Order for Supplies or Services (Continuation). (3) VA Form 90-2138-ADP, Purchase Order for Supplies or Services. (4) VA Form 2139-ADP, Order...

  7. 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 90-2138, Order for Supplies or Services. (2) VA Form 90-2139, Order for Supplies or Services (Continuation). (3) VA Form 90-2138-ADP, Purchase Order for Supplies or Services. (4) VA Form 2139-ADP, Order...

  8. 48 CFR 813.307 - Forms.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... following forms provide a purchase or delivery order, vendor's invoice, and receiving report: (1) VA Form 90-2138, Order for Supplies or Services. (2) VA Form 90-2139, Order for Supplies or Services (Continuation). (3) VA Form 90-2138-ADP, Purchase Order for Supplies or Services. (4) VA Form 2139-ADP, Order...

  9. 48 CFR 813.307 - Forms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... following forms provide a purchase or delivery order, vendor's invoice, and receiving report: (1) VA Form 90-2138, Order for Supplies or Services. (2) VA Form 90-2139, Order for Supplies or Services (Continuation). (3) VA Form 90-2138-ADP, Purchase Order for Supplies or Services. (4) VA Form 2139-ADP, Order...

  10. 48 CFR 1353.107 - Obtaining forms.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Obtaining forms. 1353.107 Section 1353.107 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CLAUSES AND FORMS FORMS General 1353.107 Obtaining forms. The DOC forms may be obtained from any DOC contracting office....

  11. 48 CFR 1353.107 - Obtaining forms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Obtaining forms. 1353.107 Section 1353.107 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CLAUSES AND FORMS FORMS General 1353.107 Obtaining forms. The DOC forms may be obtained from any DOC contracting office....

  12. 48 CFR 1353.107 - Obtaining forms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Obtaining forms. 1353.107 Section 1353.107 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CLAUSES AND FORMS FORMS General 1353.107 Obtaining forms. The DOC forms may be obtained from any DOC contracting office....

  13. 48 CFR 1353.107 - Obtaining forms.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Obtaining forms. 1353.107 Section 1353.107 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CLAUSES AND FORMS FORMS General 1353.107 Obtaining forms. The DOC forms may be obtained from any DOC contracting office....

  14. 48 CFR 1353.107 - Obtaining forms.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Obtaining forms. 1353.107 Section 1353.107 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CLAUSES AND FORMS FORMS General 1353.107 Obtaining forms. The DOC forms may be obtained from any DOC contracting office....

  15. 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.

  16. 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.

  17. Alumina forming iron base superalloy

    SciTech Connect

    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.

  18. Coalition forms to support NEHRP

    NASA Astrophysics Data System (ADS)

    A group of professional associations, including the Seismological Society of America and the Earthquake Engineering Research Institute, has formed a coalition to support the National Earthquake Hazards Reduction Program (NEHRP). Meeting in met on February 20, the group plans to actively support the research necessary to mitigate earthquake losses and to seek continued federal funding of the program.NEHRP was established by President Carter following the Earthquake Hazards Reduction Act of 1977. Funding was originally authorized for 3 years and has been reauthorized by Congress each year. The program is funded through four federal agencies—the U.S. Geological Survey, National Science Foundation, Federal Emergency Management Agency, and the National Institute of Stan dards and Technology. Its purpose is to address the nation's earthquake threat by reducing earthquake hazards.

  19. Eight salt forms of sulfadiazine.

    PubMed

    Buist, Amanda R; Dennany, Lynn; Kennedy, Alan R; Manzie, Craig; McPhie, Katherine; Walker, Brandon

    2014-09-01

    Proton transfer to the sulfa drug sulfadiazine [systematic name: 4-amino-N-(pyrimidin-2-yl)benzenesulfonamide] gave eight salt forms. These are the monohydrate and methanol hemisolvate forms of the chloride (2-{[(4-azaniumylphenyl)sulfonyl]azanidyl}pyrimidin-1-ium chloride monohydrate, C(10)H(11)N(4)O(2)S(+) · Cl(-) · H2O, (I), and 2-{[(4-azaniumylphenyl)sulfonyl]azanidyl}pyrimidin-1-ium chloride methanol hemisolvate, C(10)H(11)N(4)O(2)S(+) · Cl(-) · (0.5)CH(3)OH, (II)); a bromide monohydrate (2-{[(4-azaniumylphenyl)sulfonyl]azanidyl}pyrimidin-1-ium bromide monohydrate, C(10)H(11)N(4)O(2)S(+) · Br(-) · H2O, (III)), which has a disordered water channel; a species containing the unusual tetraiodide dianion [bis(2-{[(4-azaniumylphenyl)sulfonyl]azanidyl}pyrimidin-1-ium) tetraiodide, 2C(10)H(11)N(4)O(2)S(+) · I4(2-), (IV)], where the [I4](2-) ion is located at a crystallographic inversion centre; a tetrafluoroborate monohydrate (2-{[(4-azaniumylphenyl)sulfonyl]azanidyl}pyrimidin-1-ium tetrafluoroborate monohydrate, C(10)H(11)N(4)O(2)S(+) · BF(4)(-) · H2O, (V)); a nitrate (2-{[(4-azaniumylphenyl)sulfonyl]azanidyl}pyrimidin-1-ium nitrate, C(10)H(11)N(4)O(2)S(+) · NO(3)(-), (VI)); an ethanesulfonate {4-[(pyrimidin-2-yl)sulfamoyl]anilinium ethanesulfonate, C(10)H(11)N(4)O(2)S(+) · C(2)H(5)SO(3)(-), (VII)}; and a dihydrate of the 4-hydroxybenzenesulfonate {4-[(pyrimidin-2-yl)sulfamoyl]anilinium 4-hydroxybenzenesulfonate dihydrate, C(10)H(11)N(4)O(2)S(+) · HOC(6)H(4)SO(3)(-) · 2H2O, (VIII)}. All these structures feature alternate layers of cations and of anions where any solvent is associated with the anion layers. The two sulfonate salts are protonated at the aniline N atom and the amide N atom of sulfadiazine, a tautomeric form of the sulfadiazine cation that has not been crystallographically described before. All the other salt forms are instead protonated at the aniline group and on one N atom of the pyrimidine ring. Whilst all eight species are based upon

  20. 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