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Sample records for nitroalkenes vinylogous nucleophilicity

  1. Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

    PubMed Central

    Bencivenni, Giorgio; Galzerano, Patrizia; Mazzanti, Andrea; Bartoli, Giuseppe; Melchiorre, Paolo

    2010-01-01

    In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their α and β positions, little progress has been achieved in the enantioselective carbon–carbon bond formation γ to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic α,β-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of β-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete γ-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the γ and δ positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric γ-amination of cyclohexene carbaldehyde. PMID:20566884

  2. Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis.

    PubMed

    Bencivenni, Giorgio; Galzerano, Patrizia; Mazzanti, Andrea; Bartoli, Giuseppe; Melchiorre, Paolo

    2010-11-30

    In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their α and β positions, little progress has been achieved in the enantioselective carbon-carbon bond formation γ to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic α,β-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of β-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete γ-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the γ and δ positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric γ-amination of cyclohexene carbaldehyde. PMID:20566884

  3. Reaction of arynes with vinylogous amides: nucleophilic addition to the ortho-quinodimethide intermediate.

    PubMed

    Li, Ran; Wang, Xuemei; Wei, Zhibin; Wu, Chunrui; Shi, Feng

    2013-09-01

    The reaction of arynes with vinylogous amides containing no free N-H bonds proceeds in a [2 + 2] cycloaddition fashion at ambient temperature. The electronic properties of the vinylogous amides allow for the cycloadducts undergoing a facile ring-opening process, leading to electronically biased ortho-quinodimethide intermediates. Subsequent nucleophilic addition with alcohols affords 2-substituted benzaldehydes or ketones. PMID:23957502

  4. Stereoselective synthesis of 2,3-disubstituted indoline, pyrrolidine and cyclic ether-fused 1,2-dihydroquinoline derivatives using alkyne iminium ion cyclization of vinylogous carbamates: switch of regioselectivity using an internal hydroxy group as a nucleophile.

    PubMed

    Gharpure, Santosh J; Prasath, V; Kumar, Vinod

    2015-09-14

    An intramolecular, alkyne iminium ion cyclization of vinylogous carbamates derived from o-alkynyl anilines and N-protected homopropargyl amines is developed for the stereoselective construction of trans-2,3-disubstituted indolines and pyrrolidine derivatives, respectively. The regioselectivity of the alkyne iminium ion cyclization could be switched using a hydroxy group as an internal nucleophile resulting in cyclic ether-fused 1,2-dihydroquinolines. The entire process of nitrogen heterocycle formation can also be carried out in a 'one-pot' manner starting from o-iodo aniline derivatives. PMID:26226402

  5. Catalytic, enantioselective, vinylogous aldol reactions.

    PubMed

    Denmark, Scott E; Heemstra, John R; Beutner, Gregory L

    2005-07-25

    In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double-bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the pi system of a carbon-carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing "extended" dienol ethers derived from gamma-enolizable alpha,beta-unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed. PMID:15940727

  6. Enantioselective Vinylogous Organocascade Reactions.

    PubMed

    Hepburn, Hamish B; Dell'Amico, Luca; Melchiorre, Paolo

    2016-08-01

    Cascade reactions are powerful tools for rapidly assembling complex molecular architectures from readily available starting materials in a single synthetic operation. Their marriage with asymmetric organocatalysis has led to the development of novel techniques, which are now recognized as reliable strategies for the one-pot enantioselective synthesis of stereochemically dense molecules. In recent years, even more complex synthetic challenges have been addressed by applying the principle of vinylogy to the realm of organocascade catalysis. The key to the success of vinylogous organocascade reactions is the unique ability of the chiral organocatalyst to transfer reactivity to a distal position without losing control on the stereo-determining events. This approach has greatly expanded the synthetic horizons of the field by providing the possibility of forging multiple stereocenters in remote positions from the catalyst's point of action with high selectivity, while simultaneously constructing multiple new bonds. This article critically describes the developments achieved in the field of enantioselective vinylogous organocascade reactions, charting the ideas, the conceptual advances, and the milestone reactions that have been essential for reaching highly practical levels of synthetic efficiency. PMID:27256039

  7. Synthesis of β–Heteroaryl Propionates via Trapping of Carbocations with π-Nucleophiles

    PubMed Central

    Fu, Tsung-hao; Bonaparte, Amy; Martin, Stephen F.

    2009-01-01

    A variety of heterocyclic alcohols and acetates were coupled with silyl ketene acetals and other π-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted β-heteroaryl propionates, including those with contiguous quaternary centers, as well as vinylogs thereof. This reaction also proceeds with high diastereoselectivity when the π-nucleophile bears a chiral auxiliary. PMID:20161309

  8. Basic-functionalized recyclable ionic liquid catalyst: A solvent-free approach for Michael addition of 1,3-dicarbonyl compounds to nitroalkenes under ultrasound irradiation.

    PubMed

    Narayanaperumal, Senthil; da Silva, Rodrigo César; Feu, Karla Santos; de la Torre, Alexander Fernández; Corrêa, Arlene G; Paixão, Márcio Weber

    2013-05-01

    A task-specific ionic liquid (TSIL) has been introduced as a recyclable catalyst in Michael addition. A series of nitroalkenes and various C-based nucleophiles were reacted in the presence of 30mol% of recyclable basic-functionalized ionic liquid. Good to excellent yields were obtained in 30min under ultrasound irradiation. PMID:23218731

  9. Organocatalytic vinylogous Mannich reaction of trimethylsiloxyfuran with isatin-derived benzhydryl-ketimines.

    PubMed

    Rainoldi, Giulia; Sacchetti, Alessandro; Silvani, Alessandra; Lesma, Giordano

    2016-08-10

    A family of chiral quaternary 3-aminooxindole butenolides has been synthesized by BINOL-derived phosphoric acid-catalyzed addition of trimethylsiloxyfuran to isatin-derived ketimines. Such a vinylogous Mannich-type reaction was found to produce diastereoisomeric butenolides in good yields and in most cases high enantiomeric excesses. The configurational assignment of the obtained products was safely performed by chemical correlation. A computational study of the transition state allowed rationalizing the obtained stereochemical outcome, highlighting the possible binding modes of the catalyst-imine-nucleophile transition complex. PMID:27470306

  10. Direct Diastereo- and Enantioselective Vinylogous Michael Additions of Linear Enones.

    PubMed

    Guo, Qunsheng; Fraboni, Americo J; Brenner-Moyer, Stacey E

    2016-06-01

    A direct vinylogous Michael addition using linear vinylogous Michael donors has been developed. Notably, even γ-substituted Michael donors cleanly afforded γ-alkylated products in high yield and ee by this method. Moreover, control experiments revealed that, for these and related linear vinylogous Michael donors, the size of the Michael acceptor strongly influences whether α- or γ-alkylation occurs, not simply blocking effects of cocatalysts as suggested previously. PMID:27186662

  11. Enantio- and periselective nitroalkene Diels-Alder reaction.

    PubMed

    Narcis, Maurice J; Sprague, Daniel J; Captain, Burjor; Takenaka, Norito

    2012-12-14

    The periselective Diels-Alder reaction of 5-substituted pentamethylcyclopentadienes and nitroethylene has been realized by helical-chiral hydrogen bond donor catalysts. To our knowledge, this represents the first asymmetric catalytic nitroalkene Diels-Alder reaction via activation of nitroalkene, and thus establishes its proof-of-principle. PMID:23104427

  12. Thermodynamically driven, syn-selective vinylogous aldol reaction of tetronamides.

    PubMed

    Karak, Milandip; Barbosa, Luiz C A; Acosta, Jaime A M; Sarotti, Ariel M; Boukouvalas, John

    2016-06-01

    A stereoselective vinylogous aldol reaction of N-monosubstituted tetronamides with aldehydes is described. The procedure is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers (dr > 99 : 1) in high yields (70-90%). Experimental and computational studies suggest that the observed diastereoselectivity arises through anti-syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction. PMID:27163151

  13. Nucleophilic Aromatic Substitution.

    ERIC Educational Resources Information Center

    Avila, Walter B.; And Others

    1990-01-01

    Described is a microscale organic chemistry experiment which demonstrates one feasible route in preparing ortho-substituted benzoic acids and provides an example of nucleophilic aromatic substitution chemistry. Experimental procedures and instructor notes for this activity are provided. (CW)

  14. The palladium assisted transfer reduction of. alpha. ,. beta. -unsaturated nitroalkenes to oximes using ammonium formate

    SciTech Connect

    Kabalka, G.W.; Pace, R.D.; Wadgaonkar, P.P. )

    1990-01-01

    {alpha},{beta}-Unsaturated nitroalkenes are readily reduced to the corresponding oximes in good yields using ammonium formate in the presence of palladium. The reactions occur rapidly at room temperature in a solvent system of methanol and tetrahydrofuran.

  15. Definition of a nucleophilicity scale.

    PubMed

    Jaramillo, Paula; Pérez, Patricia; Contreras, Renato; Tiznado, William; Fuentealba, Patricio

    2006-07-01

    This work deals with exploring some empirical scales of nucleophilicity. We have started evaluating the experimental indices of nucleophilicity proposed by Legon and Millen on the basis of the measure of the force constants derived from vibrational frequencies using a probe dipole H-X (X = F,CN). The correlation among some theoretical parameters with this experimental scale has been evaluated. The theoretical parameters have been chosen as the minimum of the electrostatic potential V(min), the binding energy (BE) between the nucleophile and the H-X dipole, and the electrostatic potential measured at the position of the hydrogen atom V(H) when the complex nucleophile and dipole H-X is in the equilibrium geometry. All of them present good correlations with the experimental nucleophilicity scale. In addition, the BEs of the nucleophiles with two other Lewis acids (one hard, BF(3), and the other soft, BH(3)) have been evaluated. The results suggest that the Legon and Millen nucleophilicity scale and the electrostatic potential derived scales can describe in good approximation the reactivity order of the nucleophiles only when the interactions with a probe electrophile is of the hard-hard type. For a covalent interaction that is orbital controlled, a new nucleophilicity index using information of the frontier orbitals of both, the nucleophile and the electrophile has been proposed. PMID:16805506

  16. Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via N-Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes.

    PubMed

    White, Nicholas A; Ozboya, Kerem E; Flanigan, Darrin M; Rovis, Tomislav

    2014-04-01

    A concise enantioselective synthesis of (-)-paroxetine (Paxil) and (-)-femoxetine has been achieved. Key to these syntheses is a N-heterocyclic carbene catalyzed homoenolate addition to a nitroalkene followed by in situ reduction of the nitro-group to rapidly access δ-lactams. PMID:25485210

  17. Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via N-Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes

    PubMed Central

    White, Nicholas A.; Ozboya, Kerem E.; Flanigan, Darrin M.

    2014-01-01

    A concise enantioselective synthesis of (-)-paroxetine (Paxil) and (-)-femoxetine has been achieved. Key to these syntheses is a N-heterocyclic carbene catalyzed homoenolate addition to a nitroalkene followed by in situ reduction of the nitro-group to rapidly access δ-lactams. PMID:25485210

  18. Three-component synthesis of polysubstituted pyrroles from α-diazoketones, nitroalkenes, and amines.

    PubMed

    Hong, Deng; Zhu, Yuanxun; Li, Yao; Lin, Xufeng; Lu, Ping; Wang, Yanguang

    2011-09-01

    Polysubstituted pyrroles are regiospecifically synthesized via the copper-catalyzed three-component reaction of α-diazoketones, nitroalkenes, and amines under aerobic conditions. The cascade process involves an N-H insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3 + 2] cycloaddition of azomethine ylide. PMID:21830767

  19. Vinylogous chain branching catalysed by a dedicated polyketide synthase module.

    PubMed

    Bretschneider, Tom; Heim, Joel B; Heine, Daniel; Winkler, Robert; Busch, Benjamin; Kusebauch, Björn; Stehle, Thilo; Zocher, Georg; Hertweck, Christian

    2013-10-01

    Bacteria use modular polyketide synthases (PKSs) to assemble complex polyketides, many of which are leads for the development of clinical drugs, in particular anti-infectives and anti-tumoral agents. Because these multifarious compounds are notoriously difficult to synthesize, they are usually produced by microbial fermentation. During the past two decades, an impressive body of knowledge on modular PKSs has been gathered that not only provides detailed insight into the biosynthetic pathways but also allows the rational engineering of enzymatic processing lines to yield structural analogues. Notably, a hallmark of all PKS modules studied so far is the head-to-tail fusion of acyl and malonyl building blocks, which leads to linear backbones. Yet, structural diversity is limited by this uniform assembly mode. Here we demonstrate a new type of PKS module from the endofungal bacterium Burkholderia rhizoxinica that catalyses a Michael-type acetyl addition to generate a branch in the carbon chain. In vitro reconstitution of the entire PKS module, X-ray structures of a ketosynthase-branching didomain and mutagenesis experiments revealed a crucial role of the ketosynthase domain in branching the carbon chain. We present a trapped intermediary state in which acyl carrier protein and ketosynthase are covalently linked by the branched polyketide and suggest a new mechanism for chain alkylation, which is functionally distinct from terpenoid-like β-branching. For the rice seedling blight toxin rhizoxin, one of the strongest known anti-mitotic agents, the non-canonical polyketide modification is indispensable for phytotoxic and anti-tumoral activities. We propose that the formation of related pharmacophoric groups follows the same general scheme and infer a unifying vinylogous branching reaction for PKS modules with a ketosynthase-branching-acyl-carrier-protein architecture. This study unveils the structure and function of a new PKS module that broadens the biosynthetic scope of

  20. Structure-activity analysis of vinylogous urea inhibitors of human immunodeficiency virus-encoded ribonuclease H.

    PubMed

    Chung, Suhman; Wendeler, Michaela; Rausch, Jason W; Beilhartz, Greg; Gotte, Matthias; O'Keefe, Barry R; Bermingham, Alun; Beutler, John A; Liu, Shixin; Zhuang, Xiaowei; Le Grice, Stuart F J

    2010-09-01

    Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH(2)-substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane- and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH(2) or 3-CONH(2) functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH(2) and 3-CONH(2) functions were investigated. 2-NH(2)-modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH(2) and 3-CONH(2) groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis. PMID:20547794

  1. Iron-catalyzed vinylogous aldol condensation of Biginelli products and its application toward pyrido[4,3-d]pyrimidinones.

    PubMed

    Zhang, Lianqiang; Zhang, Zhiguo; Liu, Qingfeng; Liu, Tongxin; Zhang, Guisheng

    2014-03-01

    A novel iron-catalyzed vinylogous aldol condensation of Biginelli products with aryl aldehydes has been developed for the syntheses of potential bioactive (E)-6-arylvinyl-dihydropyrimidin-2(1H)-ones. These materials are valuable synthetic precursors to drug-like pyrido[4,3-d]pyrimidine derivatives. The amide group at the 5-position of the dihydropyrimidin-2(1H)-ones played an important role in the vinylogous aldol condensation reaction. PMID:24517724

  2. The application of vinylogous iminium salt derivatives to efficient formal syntheses of the marine akaloids lamellarin G trimethyl ether and ningalin B.

    PubMed

    Gupton, John T; Giglio, Benjamin C; Eaton, James E; Rieck, Elizabeth A; Smith, Kristin L; Keough, Matthew J; Barelli, Peter J; Firich, Lauren T; Hempel, Jonathan E; Smith, Timothy M; Kanters, Rene P F

    2009-05-30

    Studies directed at the synthesis of lamellarin G trimethyl ether and ningalin B via vinylogous iminium salt derivatives are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 1,2,3,4-tetrasubstituted pyrrole from a vinylogous iminium salt or vinylogous iminium salt derivative. Subsequent transformations of these highly substituted pyrroles lead to efficient and regiocontrolled formal syntheses of the respective pyrrole containing natural products. PMID:20161334

  3. Nucleophilic arylation with tetraarylphosphonium salts

    PubMed Central

    Deng, Zuyong; Lin, Jin-Hong; Xiao, Ji-Chang

    2016-01-01

    Organic phosphonium salts have served as important intermediates in synthetic chemistry. But the use of a substituent on the positive phosphorus as a nucleophile to construct C–C bond remains a significant challenge. Here we report an efficient transition-metal-free protocol for the direct nucleophilic arylation of carbonyls and imines with tetraarylphosphonium salts in the presence of caesium carbonate. The aryl nucleophile generated from phosphonium salt shows low basicity and good nucleophilicity, as evidenced by the successful conversion of enolizable aldehydes and ketones. The reaction is not particularly sensitive to water, shows wide substrate scope, and is compatible with a variety of functional groups including cyano and ester groups. Compared with the arylmetallic reagents that are usually moisture sensitive, the phosphonium salts are shelf-stable and can be easily handled. PMID:26822205

  4. Polyimidazoles Via Aromatic Nucleophilic Displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W.; Hergenrother, Paul M.

    1990-01-01

    Experiments show variety of polyimidazoles prepared by aromatic nucleophilic displacement, from reactions of bisphenol imidazoles with activated difluoro compounds. Polyimidazoles have good mechanical properties making them suitable for use as films, moldings, and adhesives.

  5. Nucleophilic Substitution by Benzodithioate Anions.

    ERIC Educational Resources Information Center

    Bonnans-Plaisance, Chantal; Gressier, Jean-Claude

    1988-01-01

    Describes a two-session experiment designed to provide a good illustration of, and to improve student knowledge of, the Grignard reaction and nucleophilic substitution. Discusses the procedure, experimental considerations, and conclusion of this experiment. (CW)

  6. Nitroalkenes and sesquiterpene hydrocarbons from the frontal gland of three prorhinotermes termite species.

    PubMed

    Piskorski, Rafal; Hanus, Robert; Vasícková, Sona; Cvacka, Josef; Sobotník, Jan; Svatos, Ales; Valterová, Irena

    2007-09-01

    Frontal gland contents of soldiers of three Prorhinotermes species, Prorhinotermes canalifrons, Prorhinotermes inopinatus, and Prorhinotermes simplex, consisted of two groups of compounds: nitroalkenes and sesquiterpene hydrocarbons. Analysis by gas chromatography-mass spectrometry revealed (E)-1-nitropentadec-1-ene as the major component of the glands with mean values of 152, 207, and 293 microg/individual for P. canalifrons, P. inopinatus, and P. simplex, respectively. Four other 1-nitroalkenes (C13, C14, C16, and C17), and two nitrodienes (C15 and C17) were also detected in the three species. The C17:1 nitroalkene was identified as (E)-1-nitroheptadec-1-ene. The sesquiterpene composition of the gland was species-specific: P. simplex contained (3Z,6E)-alpha-farnesene (mean of 39 microg/individual), while P. canalifrons and P. inopinatus contained the same compound (means of 0.5 and 1.5 microg/individual, respectively) as well as the (3E,6E) isomer (means of 1.8 and 0.7 microg/individual, respectively). Two other sesquiterpenes, trans-beta-bergamotene and (Z)-gamma-bisabolene, were also found in low quantities in the frontal gland of P. canalifrons. PMID:17665266

  7. A General Catalytic Enantioselective Transfer Hydrogenation Reaction of β,β-Disubstituted Nitroalkenes Promoted by a Simple Organocatalyst.

    PubMed

    Bernardi, Luca; Fochi, Mariafrancesca

    2016-01-01

    Given its synthetic relevance, the catalytic enantioselective reduction of β,β-disubstituted nitroalkenes has received a great deal of attention. Several bio-, metal-, and organo-catalytic methods have been developed, which however are usually applicable to single classes of nitroalkene substrates. In this paper, we present an account of our previous work on this transformation, which implemented with new disclosures and mechanistic insights results in a very general protocol for nitroalkene reductions. The proposed methodology is characterized by (i) a remarkably broad scope encompassing various nitroalkene classes; (ii) Hantzsch esters as convenient (on a preparative scale) hydrogen surrogates; (iii) a simple and commercially available thiourea as catalyst; (iv) user-friendly procedures. Overall, the proposed protocol gives a practical dimension to the catalytic enantioselective reduction of β,β-disubstituted nitroalkenes, offering a useful and general platform for the preparation of nitroalkanes bearing a stereogenic center at the β-position in a highly enantioenriched form. A transition state model derived from control kinetic experiments combined with literature data is proposed and discussed. This model accounts and justifies the observed experimental results. PMID:27483233

  8. Enantio- and periselective nitroalkene Diels-Alder reactions catalyzed by helical-chiral hydrogen bond donor catalysts.

    PubMed

    Peng, Zhili; Narcis, Maurice J; Takenaka, Norito

    2013-01-01

    Helical-chiral double hydrogen bond donor catalysts promote the nitroalkene Diels-Alder reaction in an enantio- and periselective manner. This represents the first asymmetric catalytic nitroalkene Diels-Alder reaction via LUMO-lowering catalysis. To gain an insight into this new process, the substrate scope of our catalyst was investigated by exploiting readily available 5-substituted pentamethylcyclopentadienes. The catalyst was found to tolerate dienes with different steric demands as well as dienes substituted with heteroatoms. The synthetic utility of 5-substituted pentamethylcyclopentadienes is rather limited, and thus we have developed a three-step route to 1,4,5,5-tetrasubstituted cyclopentadienes from commercially available ketones. PMID:23966083

  9. Polybenzimidazoles Via Aromatic Nucleophilic Displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W.; Hergenrother, Paul M.; Smith, Joseph G.

    1994-01-01

    Soluble polybenzimidazoles (PBI's) synthesized by nucleophilic displacement reaction of di(hydroxyphenyl)-benzimidazole monomers with activated aromatic difluoride compounds in presence of anhydrous potassium carbonate. These polymers exhibit good thermal, thermo-oxidative, and chemical stability, and high mechanical properties. Using benzimidazole monomers, more economical, and new PBI's processed more easily than commercial PBI, without loss of desirable physical properties.

  10. Chiral phosphines in nucleophilic organocatalysis

    PubMed Central

    Xiao, Yumei; Sun, Zhanhu

    2014-01-01

    Summary This review discusses the tertiary phosphines possessing various chiral skeletons that have been used in asymmetric nucleophilic organocatalytic reactions, including annulations of allenes, alkynes, and Morita–Baylis–Hillman (MBH) acetates, carbonates, and ketenes with activated alkenes and imines, allylic substitutions of MBH acetates and carbonates, Michael additions, γ-umpolung additions, and acylations of alcohols. PMID:25246969

  11. 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

  12. Nucleophilic fluorination of aromatic compounds

    DOEpatents

    Satyamurthy, Nagichettiar; Barrio, Jorge R

    2014-03-18

    Iodylbenzene derivatives substituted with electron donating as well as electron withdrawing groups on the aromatic ring are used as precursors in aromatic nucleophilic substitution reactions. The iodyl group (IO.sub.2) is regiospecifically substituted by nucleophilic fluoride to provide the corresponding fluoroaryl derivatives. No-carrier-added [F-18]fluoride ion derived from anhydrous [F-18](F/Kryptofix, [F-18]CsF or a quaternary ammonium fluoride (e.g., Me.sub.4NF, Et.sub.4NF, n-Bu.sub.4NF, (PhCH.sub.2).sub.4NF) exclusively substitutes the iodyl moiety in these derivatives and provides high specific activity F-18 labeled fluoroaryl analogs. Iodyl derivatives of a benzothiazole analog and 6-iodyl-L-dopa derivatives have been synthesized as precursors and have been used in the preparation of no-carrier-added [F-18]fluorobenzothiazole as well as 6-[F-18]fluoro-L-dopa.

  13. Polybenzimidazole via aromatic nucleophilic displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G. (Inventor)

    1994-01-01

    Di(hydroxyphenyl)benzimidazole monomers were prepared from phenyl-4-hydroxybenzoate and aromatic bis(o-diamine)s. These monomers were used in the synthesis of soluble polybenzimidazoles. The reaction involved the aromatic nucleophilic displacement of various di(hydroxyphenyl)benzimidazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds in the presence of an alkali metal base. These polymers exhibited lower glass transition temperatures, improved solubility, and better compression moldability over their commercial counterparts.

  14. Application of the intramolecular vinylogous Morita-Baylis-Hillman reaction toward the synthesis of the spinosyn A tricyclic nucleus.

    PubMed

    Mergott, Dustin J; Frank, Scott A; Roush, William R

    2002-09-01

    [reaction: see text] A concise synthesis of the spinosyn A tricyclic nucleus 27 has been developed by a route featuring a one-pot tandem intramolecular Diels-Alder reaction and intramolecular vinylogous Morita-Baylis-Hillman cyclization in which five stereocenters in tricycle 10 are set with excellent selectivity. PMID:12201741

  15. Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ-Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts.

    PubMed

    Nakamura, Shuichi; Yamaji, Ryota; Hayashi, Masashi

    2015-06-26

    A direct enantioselective vinylogous Mannich reaction of ketimines with γ-butenolide has been developed. Good yields and enantioselectivities were observed for the reaction of various ketimines by using a cinchona alkaloid amide/Zn(OTf)2 catalyst and Et3N. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. PMID:25944609

  16. Lewis base activation of Lewis acids: catalytic, enantioselective vinylogous aldol addition reactions.

    PubMed

    Denmark, Scott E; Heemstra, John R

    2007-07-20

    The generality of Lewis base catalyzed, Lewis acid mediated, enantioselective vinylogous aldol addition reactions has been investigated. The combination of silicon tetrachloride and chiral phosphoramides is a competent catalyst for highly selective additions of a variety of alpha,beta-unsaturated ketone-, 1,3-diketone-, and alpha,beta-unsaturated amide-derived dienolates to aldehydes. These reactions provided high levels of gamma-site selectivity for a variety of substitution patterns on the dienyl unit. Both ketone- and morpholine amide-derived dienol ethers afforded high enantio- and diastereoselectivity in the addition to conjugated aldehydes. Although alpha,beta-unsaturated ketone-derived dienolate did not react with aliphatic aldehydes, alpha,beta-unsaturated amide-derived dienolates underwent addition at reasonable rates affording high yields of vinylogous aldol product. The enantioselectivities achieved with the morpholine derived-dienolate in the addition to aliphatic aldehydes was the highest afforded to date with the silicon tetrachloride-chiral phosphoramide system. Furthermore, the ability to cleanly convert the morpholine amide to a methyl ketone was demonstrated. PMID:17583959

  17. Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H ▿

    PubMed Central

    Chung, Suhman; Wendeler, Michaela; Rausch, Jason W.; Beilhartz, Greg; Gotte, Matthias; O'Keefe, Barry R.; Bermingham, Alun; Beutler, John A.; Liu, Shixin; Zhuang, Xiaowei; Le Grice, Stuart F. J.

    2010-01-01

    Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH2-substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane- and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH2 or 3-CONH2 functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH2 and 3-CONH2 functions were investigated. 2-NH2-modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH2 and 3-CONH2 groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis. PMID:20547794

  18. The nucleophilicity N index in organic chemistry.

    PubMed

    Domingo, Luis R; Pérez, Patricia

    2011-10-21

    The nucleophilicity N index (J. Org. Chem. 2008, 73, 4615), the inverse of the electrophilicity, 1/ω, and the recently proposed inverse of the electrodonating power, 1/ω⁻, (J. Org. Chem. 2010, 75, 4957) have been checked toward (i) a series of single 5-substituted indoles for which rate constants are available, (ii) a series of para-substituted phenols, and for (iii) a series of 2,5-disubstituted bicyclic[2.2.1]hepta-2,5-dienes which display concurrently electrophilic and nucleophilic behaviors. While all considered indices account well for the nucleophilic behavior of organic molecules having a single substitution, the nucleophilicity N index works better for more complex molecules. Unlike, the inverse of the electrophilicity, 1/ω, (R(2) = 0.71), and the inverse of the electrodonating power, 1/ω⁻ (R(2) = 0.83), a very good correlation of the nucleophilicity N index of twelve 2-substituted-6-methoxy-bicyclic[2.2.1]hepta-2,5-dienes versus the activation energy associated with the nucleophilic attack on 1,1-dicyanoethylene is found (R(2) = 0.99). This comparative study allows to assert that the nucleophilicity N index is a measure of the nucleophilicity of complex organic molecules displaying concurrently electrophilic and nucleophilic behaviors. PMID:21842104

  19. 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.

  20. Polybenzimidazoles via aromatic nucleophilic displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

    1995-01-01

    Novel molecular weight controlled and endcapped polybenzimidazoles (PBI) are prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenyl benzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The PBI are endcapped with mono(hydroxyphenyl) benzimidazoles. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. Mono(hydroxyphenyl) benzimidazoles are synthesizedby reacting phenyl-4-hydroxybenzoate with aromatic (o-diamine)s in diphenylsulfone. Molecular weight controlled and endcapped PBI of new chemical structures are prepared that exhibit a favorable combination of physical and mechanical properties.

  1. Polybenzimidazoles Via Aromatic Nucleophilic Displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergerrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

    1997-01-01

    Novel molecular weight controlled and endcapped polybenzimidazoles (PBI) are prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenylbenzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The PBI are endcapped with mono(hydroxyphenyl)benzimidazoles. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. Mono(hydroxyphenyl)benzimidazoles are synthesized by reacting phenyl-4-hydroxybenzoate with aromatic (o-diamine)s in diphenylsulfone. Molecular weight controlled and endcapped PBI of new chemical structures are prepared that exhibit a favorable combination of physical and mechanical properties.

  2. Polyimidazoles via aromatic nucleophilic displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor)

    1991-01-01

    Polyimidazoles (Pl) are prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenyl)imidazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The reactions are carried out in polar aprotic solvents such as N,N-dimethylacetamide, sulfolane, N-methylpyrroldinone, dimethylsulfoxide, or diphenylsulfone using alkali metal bases such as potassium carbonate at elevated temperature under nitrogen. The di(hydroxyphenyl)imidazole monomers are prepared by reacting an aromatic aldehyde with a dimethoxybenzil or by reacting an aromatic dialdehyde with a methoxybenzil in the presence of ammonium acetate. The di(methoxyphenyl)imidazole is subsequently treated with aqueous hydrobromic acid to give the di(hydroxyphenyl)imidazole monomer. This synthetic route has provided high molecular weight Pl of new chemical structure, is economically and synthetically more favorable than other routes, and allows for facile chemical structure variation due to the availability of a large variety of activated aromatic dihalides and dinitro compounds.

  3. Polyimidazoles via aromatic nucleophilic displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor)

    1992-01-01

    Polyimidazoles (PI) are prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenyl) imidazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The reactions are carried out in polar aprotic solvents such as N,N-dimethyl acetamide, sulfolane, N-methylpyrrolidinone, dimethylsulfoxide, or diphenylsulfone using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. The di(hydroxyphenyl) imidazole monomers are prepared by reacting an aromatic aldehyde with a dimethoxybenzil or by reacting an aromatic dialdehyde with a methoxybenzil in the presence of ammonium acetate. The di(methoxyphenyl) imidazole is subsequently treated with aqueous hydrobromic acid to give the di(hydroxphenyl) imidazole monomer. This synthetic route has provided high molecular weight PI of new chemical structure, is economically and synthetically more favorable than other routes, and allows for facile chemical structure variation due to the availability of a large variety of activated aromatic dihalides and dinitro compounds.

  4. Tuning the Nucleophilicity in Cyclopropenylidenes

    PubMed Central

    Schoeller, Wolfgang W.; Frey, Guido D.; Bertrand, Guy

    2008-01-01

    Cyclopropenylidenes are Hückel aromatic π-systems in which one of the ring atoms is a carbene center. Quantum chemical calculations at density functional level, supplemented by coupled-cluster calculations, indicate that these species have a sizeable energy separation between the lowest energy singlet and triplet states. Amino groups considerably increase the energy difference between these two states, while electron-withdrawing substituents decrease it. The 1.1-dimerization products of cyclopropenylidenes, namely triafulvalenes, are investigated. The calculations show that, without steric hindrance and considerable electronic stabilization, cyclopropenylidenes are kinetically not stable and dimerize. Different substituents (alkyl, silyl, terphenyl, amino, and posphaneiminato) were probed to tune the energy levelling of the frontier orbitals in cyclopropenylidenes. Accordingly, it is predicted that by a suitable choice of substituents at the olefinic positions, cyclopropenylidenes can be more nucleophilic than their five-membered ring congeners, namely imidazol-2-ylidenes. PMID:18404754

  5. Oxidative nucleophilic aromatic amination of nitrobenzenes.

    PubMed

    Khutorianskyi, V V; Sonawane, M; Pošta, M; Klepetářová, B; Beier, P

    2016-06-01

    Nitrobenzenes substituted with electron-acceptor groups such as halogen, nitro, trifluoromethyl, pentafluorosulfanyl, or cyano underwent oxidative nucleophilic substitution with lithium salts of arylamines to afford N-aryl-2-nitroanilines. PMID:27152372

  6. 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.

  7. Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality.

    PubMed

    Martínez, Jose I; Uria, Uxue; Muñiz, Maria; Reyes, Efraím; Carrillo, Luisa; Vicario, Jose L

    2015-01-01

    The asymmetric and catalytic Michael reaction between α-nitroesters and nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in all cases. PMID:26734103

  8. Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

    PubMed Central

    Martínez, Jose I; Uria, Uxue; Muñiz, Maria; Reyes, Efraím

    2015-01-01

    Summary The asymmetric and catalytic Michael reaction between α-nitroesters and nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in all cases. PMID:26734103

  9. Lewis base activation of Lewis acids. Vinylogous aldol addition reactions of conjugated N,O-silyl ketene acetals to aldehydes.

    PubMed

    Denmark, Scott E; Heemstra, John R

    2006-02-01

    N,O-Silyl dienyl ketene acetals derived from unsaturated morpholine amides have been developed as highly useful reagents for vinylogous aldol addition reactions. In the presence of SiCl4 and the catalytic action of chiral phosphoramide (R,R)-3, N,O-silyl dienyl ketene acetal 8 undergoes high-yielding and highly site-selective addition to a wide variety of aldehydes with excellent enantioselectivity. Of particular note is the high yields and selectivities obtained from aliphatic aldehydes. Low catalyst loadings (2-5 mol %) can be employed. The morpholine amide serves as a useful precursor for further synthetic manipulation. PMID:16433495

  10. 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

  11. The Remarkable Reactivity of Aryl Halides with Nucleophiles

    ERIC Educational Resources Information Center

    Bunnett, Joseph F.

    1974-01-01

    Discusses the reactivity of aryl halides with nucleophilic or basic reagents, including nucleophilic attacks on carbon, hydrogen, halogen, and arynes. Suggestions are made concerning revisions of the sections on aryl halide chemistry courses and the corresponding chapters in textbooks. (CC)

  12. An asymmetric assembly of spirooxindole dihydropyranones through a direct enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles with isatins.

    PubMed

    Han, Jeng-Liang; Chang, Chia-Hao

    2016-02-01

    A highly enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles to isatins has been achieved by using bifunctional organocatalysts. The unexpected intramolecular lactonization which follows the initial aldol reaction, leading to the cleavage of the oxindole ring and generation of enantioenriched spirooxindole dihydropyranones in good to excellent yields with high enantioselectivities. PMID:26728396

  13. Study of quinones reactions with wine nucleophiles by cyclic voltammetry.

    PubMed

    Oliveira, Carla M; Barros, António S; Ferreira, António C S; Silva, Artur M S

    2016-11-15

    Quinones are electrophilic species which can react with various nucleophiles, like wine antioxidants, such as sulfur dioxide or ascorbic acid, thiols, amino acids, and numerous polyphenols. These reactions are very important in wine aging because they mediate oxygen reactions during both production and bottle aging phases. In this work, the major challenge was to determine the interaction between ortho-quinones and wine nucleophiles (amino acids, thiols, and the antioxidants SO2 and ascorbic acid), by cyclic voltammetry. Wine-model solutions with gallic acid, caffeic acid, or (+)-catechin and nucleophilic compounds were used. To understand the effect of nucleophilic addition in wine, a white wine with the same added nucleophiles was also analysed. Cyclic voltammograms were taken with glassy carbon electrode or screen-printed carbon electrodes, respectively, for wine-model and white wines solutions, in the absence and in the presence of nucleophiles. A nucleophilic order profile related to the cathodic current intensity decrease was observed. PMID:27283600

  14. Enantioselective organocatalytic reduction of β-trifluoromethyl nitroalkenes: an efficient strategy for the synthesis of chiral β-trifluoromethyl amines.

    PubMed

    Massolo, Elisabetta; Benaglia, Maurizio; Orlandi, Manuel; Rossi, Sergio; Celentano, Giuseppe

    2015-02-23

    An efficient organocatalytic stereoselective reduction of β-trifluoromethyl-substituted nitroalkenes, mediated by 3,5-dicarboxylic ester-dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea-based (S)-valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97% ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched β-trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal-free catalytic species were computationally investigated; on the basis of DFT transition-state (TS) analysis, a model of stereoselection was also proposed. PMID:25573847

  15. Palladium(ii)-catalyzed C-C and C-O bond formation for the synthesis of C1-benzoyl isoquinolines from isoquinoline N-oxides and nitroalkenes.

    PubMed

    Li, Jiu-Ling; Li, Wei-Ze; Wang, Ying-Chun; Ren, Qiu; Wang, Heng-Shan; Pan, Ying-Ming

    2016-08-01

    C1-Benzoyl isoquinolines can be generated via a palladium(ii)-catalyzed C-C and C-O coupling of isoquinoline N-oxides with aromatic nitroalkenes. The reaction proceeds through remote C-H bond activation and subsequent intramolecular oxygen atom transfer (OAT). In this reaction, the N-O bond was designed as a directing group in the C-H bond activation as well as the source of an oxygen atom. PMID:27443150

  16. Asymmetric N-heterocyclic carbene catalyzed addition of enals to nitroalkenes: controlling stereochemistry via the homoenolate reactivity pathway to access δ-lactams.

    PubMed

    White, Nicholas A; DiRocco, Daniel A; Rovis, Tomislav

    2013-06-12

    An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported syn diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams. PMID:23713683

  17. Unified Synthesis of C1-C19 Building Blocks of Halichondrins via Selective Activation/Coupling of Polyhalogenated Nucleophiles in (Ni)/Cr-Mediated Reactions.

    PubMed

    Li, Jingwei; Yan, Wuming; Kishi, Yoshito

    2015-05-20

    A unified synthesis of the C1-C19 building blocks 8-10 of halichondrins A-C was developed from the common synthetic intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized via selective activation/coupling of polyhalogenated nucleophiles 23a,b with aldehyde 11 in a (Ni)/Cr-mediated coupling reaction. Compared with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling exhibited two unique features. First, the coupling was found to proceed with a trace amount or no added Ni-catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was found to give a better yield than Zr(Cp)2Cl2. An adjustment of the oxidation state was required to transform acetylenic ketones 26a,b into C1-C19 building blocks 8 and 9 of halichondrins A and B, respectively. In the halichondrin B series, a hydroxyl-directed (Me)4NBH(OAc)3 reduction of E- and Z-β-alkoxy-enones 30 was found cleanly to achieve the required transformation, whereas a DMDO oxidation of E-vinylogous ester 27 allowed to introduce the C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4 was used to convert the double oxy-Michael product 28 into C1-C19 building block 10. PMID:25923790

  18. Nucleophilic Substitution Reactions Using Phosphine Nucleophiles: An Introduction to Phosphorus-31 NMR

    ERIC Educational Resources Information Center

    Sibbald, Paul A.

    2015-01-01

    Nuclear magnetic resonance (NMR) spectroscopy is commonly used in modern synthetic chemistry to monitor the conversion of reactants to products. Since instruction in the use of NMR spectroscopy typically does not occur until after the introduction of nucleophilic substitution reactions, organic chemistry students are not able to take advantage of…

  19. Hyperbranched Polycarbosilanes via Nucleophilic Substitution Reactions

    NASA Astrophysics Data System (ADS)

    Interrante, L.; Shen, Q.

    Nucleophilic substitution reactions involving organomagnesium (Grignard) [1] and organolithium reagents have been used extensively for many years to form Si—C bonds (see Reaction Scheme 12.1). However, their use for the construction of hyperbranched polymers whose backbone contains, as a major structural component, silicon—carbon bonds, i.e., polycarbosilanes [2] is relatively more recent. (12.1) begin{array}{l} {{R}}_3 {{SiX + MR'}} to {{R}}_3 {{SiR' + MX}} \\ left({{{R,R' = alkyl}} {{or aryl;}} {{M = Mg(X),}} {{Li,}} {{Na}};{{X = halogen, OR''}}} right) \\ This chapter focuses on the application of such nucleophilic substitution reactions toward the synthesis of hyperbranched polycarbosilanes, with particular emphasis on those preparations that have resulted in relatively well characterized products. These syntheses are organized by the type of ABn monomer unit used (see Section 1.2), where A and B refer to the (C)X and (Si)Xn, respectively, functional ends of the monomer unit and where the nature of the coupling reaction leads to entirely or primarily Si—C bond formation. In most cases, these are “one-pot” reactions that employ monomers that bear halogen or alkoxy groups on the C and Si ends of the unit. Indeed, hyperbranched polycarbosilanes have been described, in general, as “obtained in one synthetic step via a random, one-pot polymerization of multifunctional monomers of AB n type” [2]. Treatment of the ABn monomer with either elemental Mg or an organolithium reagent, ideally (but not always) forms a complexed carbanion (the nucleophile) by reaction with the C-X end of the monomer unit, resulting in an intermediate of the type, (XxM)CSiXn, where M = Mg or Li, X = halogen or alkoxy, and x = 1 (Mg) or 0 (Li). Self-coupling of this reagent via reactions of the type shown in Reaction Scheme 12.1 leads to oligomeric and polymeric products that are connected primarily through Si—C bonds and yield an inorganic MXx by-product.

  20. A Safer, Discovery-Based Nucleophilic Substitution Experiment

    ERIC Educational Resources Information Center

    Horowitz, Gail

    2009-01-01

    A discovery-based nucleophilic substitution experiment is described in which students compare the reactivity of chloride and iodide ions in an S[subscript N]2 reaction. This experiment improves upon the well-known "Competing Nucleophiles" experiment in that it does not involve the generation of hydrogen halide gas. The experiment also introduces…

  1. 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

  2. Solvent isotope effects on nucleophilic displacement reactions

    SciTech Connect

    Spiegel, G.W.

    1981-01-01

    The kinetic solvent isotope effect, KSIE, (k/sub H/sub 2/O//k/sub D/sub 2/O/), at 25.0/sup 0/C and ionic strength, I, equal to 0.20 +- 0.02 M was measured for the nucleophilic displacement of iodine ion from iodomethane, iodoacetamide, and iodoacetate ion, thiophene from S-Methylthiophenium ion, and tosylate ion from methyl tosylate by bromide ion, chloride ion, acetate ion, hydroxide ion, water, ammonia, ethylenediamine, n-butylamine, piperazine, piperidine, quinuclidine, and 1,4-Diazabicyclo(2.2.2)octane (DABCO), and the monoprotonated cations of ethylenediamine, piperazine, and DABCO. By means of solvent partition measurements at 25.0/sup 0/C and I = 0.02 M between H/sub 2/O and D/sub 2/O and a common immiscible organic solvent, the ground state activity coefficients in D/sub 2/O, the solution in H/sub 2/O being chosen as the reference state, were determined for the nitrogen-containing nucleophiles (except ammonia) and the substrates methyl tosylate, iodoacetamide, and iodoacetic acid. The solubilities at 25.0/sup 0/C of the picrate and tetraphenylborate salts of the monoprotonated cationic forms of ethylenediamine, piperazine, and DABCO were measured to determine the activity coefficients in D/sub 2/O of these ions relative to an H/sub 2/O reference state. Applying the Eyring equation, the activity coefficients of the transition states in D/sub 2/O, reference state H/sub 2/O, were calculated.

  3. Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: an organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent.

    PubMed

    Massolo, Elisabetta; Benaglia, Maurizio; Genoni, Andrea; Annunziata, Rita; Celentano, Giuseppe; Gaggero, Nicoletta

    2015-05-28

    An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-β-aryl-α-keto esters with up to 92% ee were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of a GABAB receptor agonist baclofen. PMID:25883074

  4. Copper- and Silver-Catalyzed Diastereo- and Enantioselective Conjugate Addition Reaction of 1-Pyrroline Esters to Nitroalkenes: Diastereoselectivity Switch by Chiral Metal Complexes.

    PubMed

    Koizumi, Akihiro; Kimura, Midori; Arai, Yuri; Tokoro, Yuichiro; Fukuzawa, Shin-ichi

    2015-11-01

    syn-Diastereoselective conjugate addition of 1-pyrroline esters to nitroalkenes in good yields with an excellent enantioselectivity by using CuOAc/Me-FcPHOX catalyst in the presence of pyridine. In contrast, AgOAc/tBu-ThioClickFerrophos catalyzed the anti diastereoselective conjugate addition with a high enantioselectivity without additional base. Thus, the preparation of chiral 1-pyrroline derivatives bearing diverse stereochemistry could be achieved. The diastereoselective reduction of the imine group in the conjugate adduct could afford the 2,5-cis-proline ester derivative. PMID:26426827

  5. Nucleophilic Aromatic Substitution Between Halogenated Benzene Dopants and Nucleophiles in Atmospheric Pressure Photoionization

    NASA Astrophysics Data System (ADS)

    Kauppila, Tiina J.; Haack, Alexander; Kroll, Kai; Kersten, Hendrik; Benter, Thorsten

    2016-03-01

    In a preceding work with dopant assisted-atmospheric pressure photoionization (DA-APPI), an abundant ion at [M + 77]+ was observed in the spectra of pyridine and quinoline with chlorobenzene dopant. This contribution aims to reveal the identity and route of formation of this species, and to systematically investigate structurally related analytes and dopants. Compounds containing N-, O-, and S-lone pairs were investigated with APPI in the presence of fluoro-, chloro-, bromo-, and iodobenzene dopants. Computational calculations on a density functional theory (DFT) level were carried out to study the reaction mechanism for pyridine and the different halobenzenes. The experimental and computational results indicated that the [M + 77]+ ion was formed by nucleophilic aromatic ipso-substitution between the halobenzene radical cation and nucleophilic analytes. The reaction was most efficient for N-heteroaromatic compounds, and it was weakened by sterical effects and enhanced by resonance stabilization. The reaction was most efficient with chloro-, bromo-, and iodobenzenes, whereas with fluorobenzene the reaction was scarcely observed. The calculated Gibbs free energies for the reaction between pyridine and the halobenzenes were shown to increase in the order I < Br < Cl < F. The reaction was found endergonic for fluorobenzene due to the strong C-F bonding, and exergonic for the other halobenzenes. For fluoro- and chlorobenzenes the reaction was shown to proceed through an intermediate state corresponding to [M + dopant]+, which was highly stable for fluorobenzene. For the bulkier bromine and iodine, this intermediate did not exist, but the halogens were shown to detach already during the approach by the nucleophile.

  6. Nucleophilic Aromatic Substitution Between Halogenated Benzene Dopants and Nucleophiles in Atmospheric Pressure Photoionization.

    PubMed

    Kauppila, Tiina J; Haack, Alexander; Kroll, Kai; Kersten, Hendrik; Benter, Thorsten

    2016-03-01

    In a preceding work with dopant assisted-atmospheric pressure photoionization (DA-APPI), an abundant ion at [M + 77](+) was observed in the spectra of pyridine and quinoline with chlorobenzene dopant. This contribution aims to reveal the identity and route of formation of this species, and to systematically investigate structurally related analytes and dopants. Compounds containing N-, O-, and S-lone pairs were investigated with APPI in the presence of fluoro-, chloro-, bromo-, and iodobenzene dopants. Computational calculations on a density functional theory (DFT) level were carried out to study the reaction mechanism for pyridine and the different halobenzenes. The experimental and computational results indicated that the [M + 77](+) ion was formed by nucleophilic aromatic ipso-substitution between the halobenzene radical cation and nucleophilic analytes. The reaction was most efficient for N-heteroaromatic compounds, and it was weakened by sterical effects and enhanced by resonance stabilization. The reaction was most efficient with chloro-, bromo-, and iodobenzenes, whereas with fluorobenzene the reaction was scarcely observed. The calculated Gibbs free energies for the reaction between pyridine and the halobenzenes were shown to increase in the order I < Br < Cl < F. The reaction was found endergonic for fluorobenzene due to the strong C-F bonding, and exergonic for the other halobenzenes. For fluoro- and chlorobenzenes the reaction was shown to proceed through an intermediate state corresponding to [M + dopant](+), which was highly stable for fluorobenzene. For the bulkier bromine and iodine, this intermediate did not exist, but the halogens were shown to detach already during the approach by the nucleophile. Graphical Abstract ᅟ. PMID:26637323

  7. Nucleophilic reactivity of a copper(II)-superoxide complex.

    PubMed

    Pirovano, Paolo; Magherusan, Adriana M; McGlynn, Ciara; Ure, Andrew; Lynes, Amy; McDonald, Aidan R

    2014-06-01

    Metal-bound superoxide intermediates are often implicated as electrophilic oxidants in dioxygen-activating metalloenzymes. In the nonheme iron α-ketoglutarate dependent oxygenases and pterin-dependent hydroxylases, however, Fe(III)-superoxide intermediates are postulated to react by nucleophilic attack on electrophilic carbon atoms. By reacting a Cu(II)-superoxide complex (1) with acyl chloride substrates, we have found that a metal-superoxide complex can be a very reactive nucleophile. Furthermore, 1 was found to be an efficient nucleophilic deformylating reagent, capable of Baeyer-Villiger oxidation of a number of aldehyde substrates. The observed nucleophilic chemistry represents a new domain for metal-superoxide reactivity. Our observations provide support for the postulated role of metal-superoxide intermediates in nonheme iron α-ketoglutarate dependent and pterin-dependent enzymes. PMID:24753290

  8. Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis.

    PubMed

    Isley, Nicholas A; Linstadt, Roscoe T H; Kelly, Sean M; Gallou, Fabrice; Lipshutz, Bruce H

    2015-10-01

    Given the huge dependence on dipolar, aprotic solvents such as DMF, DMSO, DMAc, and NMP in nucleophilic aromatic substitution reactions (SNAr), a simple and environmentally friendly alternative is reported. Use of a "benign-by-design" nonionic surfactant, TPGS-750-M, in water enables nitrogen, oxygen, and sulfur nucleophiles to participate in SNAr reactions. Aromatic and heteroaromatic substrates readily participate in this micellar catalysis, which takes place at or near ambient temperatures. PMID:26368348

  9. Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent.

    PubMed

    Ashtekar, Kumar Dilip; Vetticatt, Mathew; Yousefi, Roozbeh; Jackson, James E; Borhan, Babak

    2016-07-01

    Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step. Herein, we explore the modulation of alkene reactivity and halocyclization rates by nucleophile proximity and basicity, through detailed analyses of starting material spectroscopy, addition stereopreferences, isotope effects, and nucleophile-alkene interactions, all obtained in a context directly relevant to synthesis reaction conditions. The findings build on the prior work by highlighting the reactivity spectrum of halocyclizations from stepwise to concerted, and suggest strategies for design of new reactions. Alkene reactivity is seen to span the range from the often overgeneralized "sophomore textbook" image of stepwise electrophilic attack on the alkene and subsequent nucleophilic bond formation, to the nucleophile-assisted alkene activation (NAAA) cases where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack. By highlighting the factors that control reactivity across this range, this study suggests opportunities to explain and control stereo-, regio-, and organocatalytic chemistry in this important class of alkene additions. PMID:27284808

  10. Hypervalent iodine(iii)-promoted N-incorporation into N-aryl vinylogous carbamates to quinoxaline diesters: access to 1,4,5,8-tetraazaphenanthrene.

    PubMed

    Sagar, A; Vidaycharan, Shinde; Shinde, Anand H; Sharada, Duddu S

    2016-04-26

    A novel oxidative N-incorporation strategy for synthesis of quinoxaline diesters under metal-free conditions is described for the first time. The mild reaction conditions allow for this transformation via the formation of two C(sp(2))-N bonds utilizing cheaply available NaN3 as the N-atom source. N-Aryl vinylogous carbamates in this study undergo azidation at enamino C(sp(2))-H selectively. The robustness of this strategy is further demonstrated by the synthesis of a valuable 1,4,5,8-tetraazaphenanthrene derivative using a mild and convenient approach. PMID:27050385

  11. Nucleophilic Aromatic Substitution, A Guided Inquiry Laboratory Experiment.

    PubMed

    Winfield, Leyte L

    2010-01-01

    Inquiry-based learning is a unique student-centered alternative to traditional instruction. This form of active learning is ideal for the organic chemistry laboratory as it encourages critical thinking and hands on problem solving to complete an experiment. Electrophilic Aromatic Substitution is immediately associated with the undergraduate organic chemistry course. However, nucleophilic aromatic substitution is not. The N-arylation of aniline derivatives is a useful reaction for implementing nucleophilic aromatic substitution into the undergraduate curriculum. Under the framework of inquiry-based learning, a straightforward procedure has been developed for the undergraduate laboratory. This experiment explores the reaction rate of the nucleophilic aromatic substitution using various electrophiles. The reaction is conducted under microwave irradiation and the experiment is completed in one laboratory setting. PMID:21197138

  12. Highly nucleophilic acetylide, vinyl, and vinylidene complexes. Progress report

    SciTech Connect

    Not Available

    1992-06-15

    The research was divided into the following: studies of nucleophilic and chiral acetylide complex [Cp(CO)(PPh{sub 3})Mn-C{triple_bond}CR]{sup {minus}}; nucleophilic addition of carbene anions to organic ligands on electrophilic complexes; halide-promoted carbonylation of imido ligands; binuclear Fe{sub 2} complexes with bridging organonitrogen ligands; addition and cycloaddition reactions of carbyne complex [Cp(CO){sub 2}Re{triple_bond}CTol]{sup +}; addition and cycloaddition reactions of methylcarbyne complexes [Cp(CO){sub 2}M{triple_bond}CCH{sub 3}]{sup +} and vinylidene complexes Cp(CO){sub 2}M{double_bond}C{double_bond}CH{sub 2} (M=Mn, Re); studies of generation and reactivity of vinylcarbene complexes formed from reaction of manganese carbene anions and aldehydes; and addition of oxo ligands of nucleophilic oxo complexes to organic ligands on electrophilic metal centers.

  13. Selective activation/coupling of polyhalogenated nucleophiles in ni/cr-mediated reactions: synthesis of c1-c19 building block of halichondrin bs.

    PubMed

    Yan, Wuming; Li, Zhanjie; Kishi, Yoshito

    2015-05-20

    The C1-C19 building block 46 of halichondrin Bs was synthesized via a selective activation/coupling of β-bromoenone 34 with aldehyde 35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a "naked" vinylogous anion with an aldehyde. The study with the coupling of 9 + 10 → 11 revealed: (1) β-bromoenone 9b is a better nucleophile than the corresponding β-iodo- and β-chloroenones 9a,c; (2) (Me)2Phen(OMe)2·NiCl2 13b is a better Ni-catalyst than (Me)2Phen(H)2·NiCl2 13a; and (3) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of polyhalogenated nucleophiles such as 34. The competition experiment of 10 + 9b over 10 + 31a-c revealed: (1) (Me)2Phen(OMe)2·NiCl2 13b is more effective than (Me)2Phen(H)2·NiCl2 13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for discriminating β-bromoenone 9b from the three types of vinyl iodides 31a-c. The third phase of study was an application of the developed method to execute the proposed coupling of 34 + 35 → 36. For this application, a polyether-type Ni-catalyst 37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange resin-based device, the coupling product 36 was transformed to the C1-C19 building block 46 of halichondrin Bs without purification/separation of the intermediates. PMID:25923602

  14. Copper(I)-Catalyzed Allylic Substitutions with a Hydride Nucleophile.

    PubMed

    Nguyen, T N Thanh; Thiel, Niklas O; Pape, Felix; Teichert, Johannes F

    2016-05-20

    An easily accessible copper(I)/N-heterocyclic carbene (NHC) complex enables a regioselective hydride transfer to allylic bromides, an allylic reduction. The resulting aryl- and alkyl-substituted branched α-olefins, which are valuable building blocks for synthesis, are obtained in good yields and regioselectivity. A commercially available silane, (TMSO)2Si(Me)H, is employed as hydride source. This protocol offers a unified alternative to the established metal-catalyzed allylic substitutions with carbon nucleophiles, as no adaption of the catalyst to the nature of the nucleophile is required. PMID:27151495

  15. Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).

    PubMed

    Neumann, Constanze N; Hooker, Jacob M; Ritter, Tobias

    2016-06-16

    Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain (18)F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a 'leaving group' leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant (18)F-deoxyfluorination reaction of phenols, which can be used to synthesize (18)F-PET probes. Selective (18)F introduction, without the need for the common, but cumbersome, azeotropic drying of (18)F, can now be accomplished from phenols as starting materials, and provides access to (18)F-labelled compounds not accessible through conventional chemistry. PMID:27281221

  16. Concerted nucleophilic aromatic substitution with 19F‑ and 18F‑

    NASA Astrophysics Data System (ADS)

    Neumann, Constanze N.; Hooker, Jacob M.; Ritter, Tobias

    2016-06-01

    Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain 18F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a ‘leaving group’ leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant 18F-deoxyfluorination reaction of phenols, which can be used to synthesize 18F-PET probes. Selective 18F introduction, without the need for the common, but cumbersome, azeotropic drying of 18F, can now be accomplished from phenols as starting materials, and provides access to 18F-labelled compounds not accessible through conventional chemistry.

  17. Nucleophilic substitution reaction for post-functionalization of polyoxometalates

    DOE PAGESBeta

    Yin, Panchao; Li, Qiang; Zhang, Jin; Wang, Longsheng; Hao, Jian; Wei, Yongge

    2015-07-06

    In this study, a hexamolybdate-based organic inorganic hybrid molecule containing a chloralkane fragment is synthesized and its Cl atom can be substituted by iodine and nitrate through nucleophilic substitution reactions in high yields, which provide a post-functionalization protocol to bring in various additional functional groups into polyoxometalate-based hybrid materials under mild conditions.

  18. Covalent adduction of nitrogen mustards to model protein nucleophiles.

    PubMed

    Thompson, Vanessa R; DeCaprio, Anthony P

    2013-08-19

    Protein adducts have the potential to serve as unique biomarkers of exposure to compounds of interest. Many xenobiotics (or their metabolites) are electrophilic and therefore reactive with nucleophilic amino acid residues on proteins. Nitrogen mustards are reactive xenobiotics with potential use as chemical warfare agents (CWA) or agents of terrorist attack, in addition to being employed as chemotherapeutic agents. The present study utilized cysteine-, lysine-, and histidine-containing model peptides to characterize in vitro adduction of the nitrogen mustards mechloroethamine (HN-2) and tris-(2-chlorethyl)amine (HN-3) to these nucleophilic amino acid residues by means of liquid chromatography-tandem mass spectrometry. The study assessed the structure of adducts formed, the time course of adduct formation, concentration-response relationships, and temporal stability of adducts. Adduction was hypothesized to occur on all three model peptides via initial formation of a reactive aziridinium intermediate for both mechloroethamine and tris-(2-chlorethyl)amine, followed by covalent adduction to nucleophilic residues. While adduction was found to occur most readily with cysteine, it was also observed at lysine and histidine, demonstrating that adduction by mechloroethamine and tris-(2-chlorethyl)amine is possible at multiple nucleophilic sites. Following solid phase extraction cleanup, adducts formed with mechloroethamine were stable for up to three weeks. Adducts formed with tris-(2-chlorethyl)amine were less stable; however, hydrolyzed secondary adducts were observed throughout the three week period. This study demonstrates that the nitrogen mustards mechloroethamine and tris-(2-chlorethyl)amine form stable adducts with reactive protein nucleophiles other than cysteine. PMID:23859065

  19. Silyl Ketene Imines: Highly Versatile Nucleophiles for Catalytic, Asymmetric Synthesis

    PubMed Central

    Denmark, Scott E.; Wilson, Tyler W.

    2012-01-01

    This Minireview provides an overview on the development of silyl ketene imines and their recent applications in catalytic, enantioselective reactions. The unique structure of the ketene imine allows a diverse range of reactivity patterns and provides solutions to existing challenges in the enantioselective construction of quaternary stereogenic carbon centers and cross-benzoin adducts. A variety of reactions for which silyl ketene imines have been applied are presented with an overall goal of inspiring new uses for these underutilized nucleophiles. PMID:22968901

  20. HBF4-Catalysed Nucleophilic Substitutions of Propargylic Alcohols

    PubMed Central

    Barreiro, Elena; Sanz-Vidal, Alvaro; Tan, Eric; Lau, Shing-Hing; Sheppard, Tom D; Díez-González, Silvia

    2015-01-01

    The activity of HBF4 (aqueous solution) as a catalyst in propargylation reactions is presented. Diverse types of nucleophiles were employed in order to form new C–O, C–N and C–C bonds in technical acetone and in air. Good to excellent yields and good chemoselectivities were obtained using low acid loading (typically 1 mol-%) under simple reaction conditions. PMID:26693210

  1. Catalysis of Carboxypeptidase A: Promoted-water vs Nucleophilic Pathways

    PubMed Central

    Wu, Shanshan; Zhang, Chunchun; Xu, Dingguo; Guo, Hua

    2010-01-01

    The catalytic mechanism of carboxypeptidase A (CPA) for the hydrolysis of ester substrates is investigated using hybrid quantum mechanical/molecular mechanical (QM/MM) methods and high-level density functional theory. The prevailing mechanism was found to utilize an active-site water molecule assisted by Glu270 and this so-called promoted-water pathway is similar to that in the CPA catalyzed proteolytic reaction (D. Xu and H. Guo, J. Am. Chem. Soc. 131, 9780 (2009)). On the other hand, our simulations indicated the existence of an alternative pathway due to direct nucleophilic attack of Glu270 on the scissile carbonyl carbon. This so-called nucleophilic pathway, which is not viable in proteolytic reactions, leads to a stable acyl-enzyme complex. However, the nucleophilic pathway is non-productive as it is blocked by a high barrier in the deacylation step. Based on results reported here and in our earlier publication, a unified model is proposed to account for nearly all experimental observations concerning the catalysis of CPA. PMID:20583802

  2. Phosphorus-containing nitroalkenes

    SciTech Connect

    Baranov, G.M.; Perekalin, V.V.

    1987-09-20

    Dialkyl (2-nitrovinyl)phosphonates of E structure can be prepared from dialkyl (1-hydroxy-2-nitroalkyl)phosphonates by the deacylation of their acetyl derivatives and also by the denitration of dialkyl (2-nitro-1-(nitrooxy)alkyl)phosphonates. In the reactions of thionyl chloride in presence of pyridine with secondary organophosphorus nitro alcohols both dialkyl (1-chloro-2-nitroalkyl)phosphonates and dialkyl (2-nitrovinyl)phosphonates may be formed, depending on the conditions, whereas with tertiary nitro alcohols only dialkyl (2-nitroalkenyl)phosphonates are formed. The spectrum of diethyl (2-nitrovinyl)phosphonate was investigated by the method of heteronuclear double resonance /sup 1/H-//sup 31/P/. It was proved that it belongs to the ABX type (J (HHtrans) 14.5, J (PHcis) 12.2, J (Phgem) 8.9 Hz), which points unambiguously to a trans arrangement of the olefinic protons. In the PMR spectrum of diethyl (1-methyl-2-nitrovinyl)phosphonate (IVe) the signal of the proton at the double bond is a doublet of quartets on account of interaction with the /sup 31/P nucleus and with the CH/sub 3/ group (delta 7.46 ppm, J (HPcis) 15.72, J (HH) 1.78 Hz). Hence, the (nitroalkenyl)phosphonates synthesized are pure E isomers.

  3. Nucleotides as nucleophiles: reactions of nucleotides with phosphoimidazolide activated guanosine

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Rosenbach, M. T.; Hurley, T. B.

    1991-01-01

    An earlier study of the reaction of phosphoimidazolide activated nucleosides (ImpN) in aqueous phosphate buffers indicated two modes of reaction of the phosphate monoanion and dianion. The first mode is catalysis of the hydrolysis of the P-N bond in ImpN's which leads to imidazole and nucleoside 5'-monophosphate. The second represents a nucleophilic substitution of the imidazole to yield the nucleoside 5'-diphosphate. This earlier study thus served as a model for the reaction of ImpN with nucleoside monophosphates (pN) because the latter can be regarded as phosphate derivatives. In the present study we investigated the reaction of guanosine 5'-phosphate-2-methylimidazolide, 2-MeImpG, in the presence of pN (N = guanosine, adenosine and uridine) in the range 6.9 less than or equal to pH less than or equal to 7.7. We observed that pN's do act as nucleophiles to form NppG, and as general base to enhance the hydrolysis of the P-N bond in 2-MeImpG, i.e. pN show the same behavior as inorganic phosphate. The kinetic analysis yields the following rate constants for the dianion pN2-: knpN = 0.17 +/- 0.02 M-1 h-1 for nucleophilic attack and khpN = 0.11 +/- 0.07 M-1 h-1 for general base catalysis of the hydrolysis. These rate constants which are independent of the nucleobase compare with kp.2 = 0.415 M-1 h-1 and khp2. = 0.217 M-1 h-1 for the reactions of HPO4(2-). In addition, this study shows that under conditions where pN presumably form stacks, the reaction mechanism remains unchanged although in quantitative terms stacked pN are somewhat less reactive. Attack by the 2'-OH and 3'-OH groups of the ribose moiety in amounts greater than or equal to 1% is not observed; this is attributed to the large difference in nucleophilicity in the neutral pH range between the phosphate group and the ribose hydroxyls. This nucleophilicity rank is not altered by stacking.

  4. Nucleophilic addition of sulfonamides to bromoacetylenes: facile preparation of pyrroles.

    PubMed

    Yamagishi, Masahito; Nishigai, Ken; Hata, Takeshi; Urabe, Hirokazu

    2011-09-16

    Nucleophilic addition of sulfonamides to 1-bromo-1-alkynes provided (Z)-N-(1-bromo-1-alken-2-yl)-p-toluenesulfonamides in good yield and in a highly regio- and stereoselective manner. Treatment of product (Z)-N-(1-bromo-1-octen-2-yl)-N-allyl-p-toluenesulfonamide with a palladium catalyst under Heck conditions afforded 1-(p-toluenesulfonyl)-2-hexyl-4-methylpyrrole in good yield. Other pyrroles with various substituents can also be prepared in good yield by this method. PMID:21842873

  5. Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene.

    PubMed

    Ajenjo, Javier; Greenhall, Martin; Zarantonello, Camillo; Beier, Petr

    2016-01-01

    3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene. The title compound was subjected to a nucleophilic aromatic substitution of the fluorine atom with oxygen, sulfur and nitrogen nucleophiles affording novel (pentafluorosulfanyl)benzenes with 3,5-disubstitution pattern. Vicarious nucleophilic substitution of the title compound with carbon, oxygen, and nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four. PMID:26977178

  6. Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

    PubMed Central

    Ajenjo, Javier; Greenhall, Martin; Zarantonello, Camillo

    2016-01-01

    Summary 3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene. The title compound was subjected to a nucleophilic aromatic substitution of the fluorine atom with oxygen, sulfur and nitrogen nucleophiles affording novel (pentafluorosulfanyl)benzenes with 3,5-disubstitution pattern. Vicarious nucleophilic substitution of the title compound with carbon, oxygen, and nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four. PMID:26977178

  7. Catalytic generation of arynes and trapping by nucleophilic addition and iodination.

    PubMed

    Hamura, Toshiyuki; Chuda, Yu; Nakatsuji, Yuya; Suzuki, Keisuke

    2012-04-01

    A fair exchange: in the title reaction, alkynyllithium serves as an initiator for benzyne generation through an iodine-lithium exchange. When performed in the presence of stoichiometric amounts of a nucleophile, the generated benzyne undergoes attack by lithio nucleophiles to generate aryllithium, which is then iodinated by iodoalkyne to give the iodoarenes 1. PMID:22359268

  8. Lewis Acid and Fluoroalcohol Mediated Nucleophilic Addition to the C2 Position of Indoles.

    PubMed

    Morimoto, Naoki; Morioku, Kumika; Suzuki, Hideyuki; Takeuchi, Yasuo; Nishina, Yuta

    2016-05-01

    Indole readily undergoes nucleophilic substitution at the C3 site, and many indole derivatives have been functionalized using this property. Indole also forms indolium, which allows electrophilic addition in acidic conditions, but current examples have been limited to intramolecular reactions. C2 site-selective nucleophilic addition to indole derivatives using fluoroalcohol and a Lewis acid was developed. PMID:27119318

  9. Poly(N-arylenbenzimidazoles) via aromatic nucleophilic displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

    1995-01-01

    Novel poly(N-arylenebenzimidazole)s (PNABIs) are prepared by the aromatic nucleophilic displacement reaction of novel di(hydroxyphenyl-N-arylene benzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. The di(hydroxyphenyl N-arylenebenzimidazole) monomers are synthesized by reacting phenyl 4-hydroxybenzoate with bis(2-aminoanilino) arylenes in diphenylsulfone. Moderate molecular weight PNABIs of new chemical structures were prepared that exhibit a favorable combination of physical and mechanical properties. The use of the novel di(hydroxyphenyl N-arylenebenzimidazole)s permits a more economical and easier way to prepare PNABIs than previous routes.

  10. Poly(N-arylenebenzimidazole)s via aromatic nucleophilic displacement

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Jr., Joseph G. (Inventor)

    1996-01-01

    Novel poly(N-arylenebenzimidazole)s (PNABls) are prepared by the aromatic nucleophilic displacement reaction of novel di(hydroxyphenyl-N-arylene benzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. The di(hydroxyphenyl-N-arylenebenzimidazole) monomers are synthesized by reacting phenyl-4-hydroxybenzoate with bis(2-aminoanilino)arylenes in diphenylsulfone. Moderate molecular weight PNABIs of new chemical structures were prepared that exhibit a favorable combination of physical and mechanical properties. The use of the novel di(hydroxyphenyI-N-arylenebenzimidazole)s permits a more economical and easier way to prepare PNABIs than previous routes.

  11. Transetherification on Polyols by Intra- and Intermolecular Nucleophilic Substitutions

    PubMed Central

    Muraoka, Takahiro; Adachi, Kota; Chowdhury, Rainy; Kinbara, Kazushi

    2014-01-01

    Transetherification on polyols involving intra- and intermolecular nucleophilic substitutions is reported. Di- or trialkoxide formation of propane-1,3-diol or 2-(hydroxymethyl)propane-1,3-diol derivatives by NaH triggers the reaction via oxetanes formation, where the order to add NaH and a polyol significantly influences the yields of products. It was demonstrated that the protective group on the pentaerythritol skeleton is apparently transferred to the hydrophilic and hydrophobic chain molecules bearing a leaving group in one-step, and a protective group conversion from tosyl to benzyl was successful using a benzyl-appending triol to afford a desired product in 67% yield. PMID:24663293

  12. Solvolyses of Benzoyl Chlorides in Weakly Nucleophilic Media

    PubMed Central

    Bentley, Thomas William; Harris, Haldon Carl

    2011-01-01

    Rate constants and activations parameters are reported for solvolyses of p-Z-substituted benzoyl chlorides (1, Z = OMe, Me, H, and Cl) in 97% w/w hexafluoroisopropanol-water (97H). Additional kinetic data are reported for solvolyses in acetic and formic acids. Plots of log k vs. σp in 97H are consistent with previous research showing that a cationic reaction channel is dominant, even for solvolyses of 1, Z = NO2. A benzoyl cation intermediate was trapped by Friedel-Crafts reaction with 1,3,5-trimethoxybenzene in hexafluoroisopropanol. The results are explained by an SN2-SN1 spectrum of mechanisms with variations in nucleophilic solvent assistance. Ab initio calculations of heterolytic bond dissociation energies of various chloro- and fluoro-substituted and other benzoyl chlorides are correlated with log k for solvolyses. PMID:21954326

  13. 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).

  14. 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).

  15. The syn/anti-Dichotomy in the Palladium-Catalyzed Addition of Nucleophiles to Alkenes

    PubMed Central

    Kočovský, Pavel; Bäckvall, Jan-E

    2015-01-01

    In this review the stereochemistry of palladium-catalyzed addition of nucleophiles to alkenes is discussed, and examples of these reactions in organic synthesis are given. Most of the reactions discussed involve oxygen and nitrogen nucleophiles; the Wacker oxidation of ethylene has been reviewed in detail. An anti-hydroxypalladation in the Wacker oxidation has strong support from both experimental and computational studies. From the reviewed material it is clear that anti-addition of oxygen and nitrogen nucleophiles is strongly favored in intermolecular addition to olefin–palladium complexes even if the nucleophile is coordinated to the metal. On the other hand, syn-addition is common in the case of intramolecular oxy- and amidopalladation as a result of the initial coordination of the internal nucleophile to the metal. PMID:25378278

  16. Cyclic disulfide C8 iminoporfiromycin: nucleophilic activation of a porfiromycin.

    PubMed

    Lee, Sang Hyup; Kohn, Harold

    2004-04-01

    The clinical success of mitomycin C (1) and its associated toxicities and resistance have led to efforts to prepare semisynthetic analogues (i.e., KW-2149 (3), BMS-181174 (4)) that have improved pharmacological profiles. In this study, we report the preparation and evaluation of the novel 7-N-(1'-amino-4',5'-dithian-2'-yl)porfiromycin C(8) cyclized imine (6) and its reference compound, 7-N-(1'-aminocyclohex-2'-yl)porfiromycin C(8) cyclized imine (13). Porfiromycin 6 contains a disulfide unit that, upon cleavage, may provide thiol(s) that affect drug reactivity. We demonstrated that phosphines dramatically accelerated 6 activation and solvolysis in methanolic solutions ("pH 7.4") compared with 13. Porfiromycins 6 and 13 efficiently cross-linked EcoRI-linearized pBR322 DNA upon addition of Et3P. We found enhanced levels of interstrand cross-link (ISC) adducts for 6 and 13 compared with porfiromycin (7) and that 6 was more efficient than 13. The large Et3P-mediated rate enhancements for the solvolysis of 6 compared with 13 and a N(7)-substituted analogue of 1, and the increased levels of ISC adducts for 6 compared with 13 and 7 are attributed to a nucleophile-assisted disulfide cleavage process that permits porfiromycin activation and nucleophile (MeOH, DNA) adduction. The in vitro antiproliferative activities of 6 and 13 using the A549 tumor cell line (lung adenocarcinoma) were determined under aerobic and hypoxic conditions and then compared with 7. Both 6 and 13 were more cytotoxic than 7, with 13 being more potent than 6. The C(8) iminoporfiromycins 6 and 13 displayed anticancer profiles similar to 3. PMID:15053618

  17. Nucleophilic substitution at phosphorus centers (SN2@p).

    PubMed

    van Bochove, Marc A; Swart, Marcel; Bickelhaupt, F Matthias

    2007-12-01

    We have studied the characteristics of archetypal model systems for bimolecular nucleophilic substitution at phosphorus (SN2@P) and, for comparison, at carbon (SN2@C) and silicon (SN2@Si) centers. In our studies, we applied the generalized gradient approximation (GGA) of density functional theory (DFT) at the OLYP/TZ2P level. Our model systems cover nucleophilic substitution at carbon in X(-)+CH3Y (SN2@C), at silicon in X(-)+SiH3Y (SN2@Si), at tricoordinate phosphorus in X(-)+PH2Y (SN2@P3), and at tetracoordinate phosphorus in X(-)+POH2Y (SN2@P4). The main feature of going from SN2@C to SN2@P is the loss of the characteristic double-well potential energy surface (PES) involving a transition state [X--CH3--Y]- and the occurrence of a single-well PES with a stable transition complex, namely, [X--PH2--Y]- or [X--POH2--Y](-). The differences between SN2@P3 and SN2@P4 are relatively small. We explored both the symmetric and asymmetric (i.e. X, Y=Cl, OH) SN2 reactions in our model systems, the competition between backside and frontside pathways, and the dependence of the reactions on the conformation of the reactants. Furthermore, we studied the effect, on the symmetric and asymmetric SN2@P3 and S(N)2@P4 reactions, of replacing hydrogen substituents at the phosphorus centers by chlorine and fluorine in the model systems X(-)+PR2Y and X(-)+POR2Y, with R=Cl, F. An interesting phenomenon is the occurrence of a triple-well PES not only in the symmetric, but also in the asymmetric SN2@P4 reactions of X(-)+POCl2--Y. PMID:17990249

  18. Dual nucleophilic substitution at a W(ii) η(2)-coordinated diiodo acetylene leading to an amidinium carbyne complex.

    PubMed

    Helmdach, Kai; Rüger, Julia; Villinger, Alexander; Seidel, Wolfram W

    2016-02-11

    The synthesis and reactivity of a W(ii) C2I2 complex towards various nucleophiles are described. Soft, aprotic nucleophiles like 4-dimethylaminopyridine (DMAP) lead to substitution of one CO at tungsten, whereas reaction with an excess of benzylamine results in a dual nucleophilic substitution at the alkyne moiety involving the rearrangement to a novel cationic amidinium carbyne complex. PMID:26750261

  19. Crystal Structures of Apo and Liganded 4-Oxalocrotonate Decarboxylase Uncover a Structural Basis for the Metal-Assisted Decarboxylation of a Vinylogous β-Keto Acid.

    PubMed

    Guimarães, Samuel L; Coitinho, Juliana B; Costa, Débora M A; Araújo, Simara S; Whitman, Christian P; Nagem, Ronaldo A P

    2016-05-10

    The enzymes in the catechol meta-fission pathway have been studied for more than 50 years in several species of bacteria capable of degrading a number of aromatic compounds. In a related pathway, naphthalene, a toxic polycyclic aromatic hydrocarbon, is fully degraded to intermediates of the tricarboxylic acid cycle by the soil bacteria Pseudomonas putida G7. In this organism, the 83 kb NAH7 plasmid carries several genes involved in this biotransformation process. One enzyme in this route, NahK, a 4-oxalocrotonate decarboxylase (4-OD), converts 2-oxo-3-hexenedioate to 2-hydroxy-2,4-pentadienoate using Mg(2+) as a cofactor. Efforts to study how 4-OD catalyzes this decarboxylation have been hampered because 4-OD is present in a complex with vinylpyruvate hydratase (VPH), which is the next enzyme in the same pathway. For the first time, a monomeric, stable, and active 4-OD has been expressed and purified in the absence of VPH. Crystal structures for NahK in the apo form and bonded with five substrate analogues were obtained using two distinct crystallization conditions. Analysis of the crystal structures implicates a lid domain in substrate binding and suggests roles for specific residues in a proposed reaction mechanism. In addition, we assign a possible function for the NahK N-terminal domain, which differs from most of the other members of the fumarylacetoacetate hydrolase superfamily. Although the structural basis for metal-dependent β-keto acid decarboxylases has been reported, this is the first structural report for that of a vinylogous β-keto acid decarboxylase and the first crystal structure of a 4-OD. PMID:27082660

  20. 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

  1. Nucleophilic addition of nitrogen to aryl cations: mimicking Titan chemistry.

    PubMed

    Li, Anyin; Jjunju, Fred P M; Cooks, R Graham

    2013-11-01

    The reactivity of aryl cations toward molecular nitrogen is studied systematically in an ion trap mass spectrometer at 10(2) Pascal of nitrogen, the pressure of the Titan main haze layer. Nucleophilic addition of dinitrogen occurs and the nature of aryl group has a significant influence on the reactivity, through inductive effects and by changing the ground state spin multiplicity. The products of nitrogen activation, aryldiazonium ions, react with typical nitriles, aromatic amines, and alkynes (compounds that are relevant as possible Titan atmosphere constituents) to form covalently bonded heterocyclic products. Theoretical calculations at the level [DFT(B3LYP)/6-311++G(d,p)] indicate that the N2 addition reaction is exothermic for the singlet aryl cations but endothermic for their triplet spin isomers. The -OH and -NH2 substituted aryl ions are calculated to have triplet ground states, which is consistent with their decreased nitrogen addition reactivity. The energy needed for the generation of the aryl cations from their protonated precursors (ca. 340 kJ/mol starting with protonated aniline) is far less than that required to directly activate the nitrogen triple bond (the lowest energy excited state of N2 lies ca. 600 kJ/mol above the ground state). The formation of aza-aromatics via arene ionization and subsequent reactions provide a conceivable route to the genesis of nitrogen-containing organic molecules in the interstellar medium and Titan haze layers. PMID:23982933

  2. Nucleophilic Addition of Nitrogen to Aryl Cations: Mimicking Titan Chemistry

    NASA Astrophysics Data System (ADS)

    Li, Anyin; Jjunju, Fred P. M.; Cooks, R. Graham

    2013-11-01

    The reactivity of aryl cations toward molecular nitrogen is studied systematically in an ion trap mass spectrometer at 102 Pascal of nitrogen, the pressure of the Titan main haze layer. Nucleophilic addition of dinitrogen occurs and the nature of aryl group has a significant influence on the reactivity, through inductive effects and by changing the ground state spin multiplicity. The products of nitrogen activation, aryldiazonium ions, react with typical nitriles, aromatic amines, and alkynes (compounds that are relevant as possible Titan atmosphere constituents) to form covalently bonded heterocyclic products. Theoretical calculations at the level [DFT(B3LYP)/6-311++G(d,p)] indicate that the N2 addition reaction is exothermic for the singlet aryl cations but endothermic for their triplet spin isomers. The -OH and -NH2 substituted aryl ions are calculated to have triplet ground states, which is consistent with their decreased nitrogen addition reactivity. The energy needed for the generation of the aryl cations from their protonated precursors (ca. 340 kJ/mol starting with protonated aniline) is far less than that required to directly activate the nitrogen triple bond (the lowest energy excited state of N2 lies ca. 600 kJ/mol above the ground state). The formation of aza-aromatics via arene ionization and subsequent reactions provide a conceivable route to the genesis of nitrogen-containing organic molecules in the interstellar medium and Titan haze layers.

  3. Effects of electron acceptors and radical scavengers on nonchain radical nucleophilic substitution reactions

    SciTech Connect

    Xianman Zhang; Dilun Yang; Youcheng Liu )

    1993-01-01

    The yields of reaction products from thermal nucleophilic substitution reactions in dimethyl sulfoxide (DMSO) of six o- and p-nitrohalobenzenes with the sodium salt of ethyl [alpha]-cyanoacetate carbanion [Na[sup +][sup [minus

  4. REVISITING NUCLEOPHILIC SUBSTITUTION REACTIONS: MICROWAVE-ASSISTED SYNTHESIS OF AZIDES, THIOCYANATES AND SULFONES IN AQUEOUS MEDIUM

    EPA Science Inventory

    A practical, rapid and efficient microwave (MW) promoted synthesis of various azides, thiocyanates and sulfones, is described in aqueous medium. This general and expeditious MW-enhanced nucleophilic substitution approach uses easily accessible starting materials such as halides o...

  5. Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions

    PubMed Central

    Im, G-Yoon J.; Bronner, Sarah M.; Goetz, Adam E.; Paton, Robert S.; Cheong, Paul H.-Y.; Houk, K. N.; Garg, Neil K.

    2010-01-01

    Efficient syntheses of 4,5-, 5,6-, and 6,7-indolyne precursors beginning from commercially available hydroxyindole derivatives are reported. The synthetic routes are versatile and allow access to indolyne precursors that remain unsubstituted on the pyrrole ring. Indolynes can be generated under mild fluoride-mediated conditions, trapped by a variety of nucleophilic reagents, and used to access a number of novel substituted indoles. Nucleophilic addition reactions to indolynes proceed with varying degrees of regioselectivity; distortion energies control regioselectivity and provide a simple model to predict the regioselectivity in the nucleophilic additions to indolynes and other unsymmetrical arynes. This model has led to the design of a substituted 4,5-indolyne that exhibits enhanced nucleophilic regioselectivity. PMID:21114321

  6. Templated assembly of medium cyclic ethers via exo-trig nucleophilic cyclization of cyclopropenes.

    PubMed

    Alnasleh, Bassam K; Rubina, Marina; Rubin, Michael

    2016-06-14

    A novel method for the assembly of medium heterocycles via an intramolecular nucleophilic addition to cyclopropenes generated in situ from the corresponding bromocyclopropanes is described. The exo-trig nucleophilic cyclizations were shown to proceed very efficiently and in a highly diastereoselective fashion affording cis-fused bicyclic products possessing 7 to 10-membered medium rings; starting from a diastereomeric mixtures of bromocyclopropanes. PMID:27210442

  7. Regioselective nucleophilic addition of organometallic reagents to 3-geminal bis(silyl) N-acyl pyridinium.

    PubMed

    Wu, Ya; Li, Linjie; Li, Hongze; Gao, Lu; Xie, Hengmu; Zhang, Zhigao; Su, Zhishan; Hu, Changwei; Song, Zhenlei

    2014-04-01

    A regioselective nucleophilic addition to 3-geminal bis(silyl) N-acyl pyridinium has been described. Geminal bis(silane) shows contrasting roles that lead to different regioselectivities for the addition of different nucleophiles: its steric effect dominates to favor 1,6-addition of alkyl, vinyl, and aryl organometallic reagents; its directing effect dominates to favor 1,2-addition of less sterically demanding alkynyl Grignard reagents. PMID:24666415

  8. Rational design of reversible and irreversible cysteine sulfenic acid-targeted linear C-nucleophiles.

    PubMed

    Gupta, Vinayak; Carroll, Kate S

    2016-02-16

    Concerns about off-target effects has motivated the development of reversible covalent inhibition strategies for targeting cysteine. However, such strategies have not been reported for the unique cysteine oxoform, sulfenic acid. Herein, we have designed and identified linear C-nucleophiles that react selectively with cysteine sulfenic acid. The resulting thioether adducts exhibit reversibility ranging from minutes to days under reducing conditions, showing the feasibility of tuning C-nucleophile reactivity across a wide range of time scales. PMID:26878905

  9. 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

  10. Reactions of adducts of phosphorus pentachloride and oxa-containing nucleophiles with arsenic trifluoride

    SciTech Connect

    Fridland, S.V.; Miftakhov, M.N.; Arkhipov, V.P.

    1987-12-20

    Results are given on the synthesis of phosphonofluoridates by the reactions of arsenic trifluoride with adducts of phosphorus pentachloride with oxa-containing nucleophiles. The nucleophiles used were saturated ethers, dioxolanes, and vinyl ethers. Reaction products were identified by means of NMR spectroscopy using H 1, P 31, and C 13. A full analysis of chemical shift and spin-spin coupling constant behavior as well as the spectral structure is conducted.

  11. Functionally Diverse Nucleophilic Trapping of Iminium Intermediates Generated Utilizing Visible Light

    PubMed Central

    Freeman, David B.; Furst, Laura; Condie, Allison G.

    2011-01-01

    Our previous studies into visible light-mediated aza-Henry reactions demonstrated that molecular oxygen played a vital role in catalyst turnover as well as the production of base to facilitate the nucleophilic addition of nitroalkanes. Herein, improved conditions for the generation of iminium ions from tetrahydroisoquinolines that allow for versatile nucleophilic trapping are reported. The new conditions provide access to a diverse range of functionality under mild, anaerobic reaction conditions as well as mechanistic insights into the photoredox cycle. PMID:22148974

  12. Nucleophilic substitution at centers other than carbon: reaction at the chlorine of N-chloroacetanilides with triethylamine as the nucleophile

    SciTech Connect

    Underwood, G.R.; Dietze, P.E.

    1984-12-28

    The reaction between triethylamine (TEA) and a series of para-substituted N-chloroacetanilides has been studied in aqueous solution buffered to pHs between 1 and 5. The exclusive product derived from the aromatic moiety is the corresponding acetanilide. The reaction occurs via two parallel pseudo-second-order paths, one acid catalyzed (the Orton-like mechanism), the other uncatalyzed. The uncatalyzed reaction is accelerated by the presence of electron-withdrawing substituents on the aromatic ring and can best be represented as nucleophilic displacement at chlorine. It therefore appears to be the prototype of a convenient class of reactions for the study of displacement reactions at chlorine. The rho value for this reaction is 3.87, indicating substantial negative charge buildup in the aromatic ring during of the transition state. The acid-catalyzed reaction is more complex, presumable involving a protonation equilibrium for the N-chloroacetanilide prior to the rate-determining step similar to that in the Orton reaction. 15 references, 2 figures, 3 tables.

  13. Kinetic isotope effects for RNA cleavage by 2'-O- transphosphorylation: Nucleophilic activation by specific base

    PubMed Central

    Harris, Michael E; Dai, Qing; Gu, Hong; Kellerman, Dan; Piccirilli, Joseph A; Anderson, Vernon E

    2010-01-01

    To better understand the interactions between catalysts and transition states during RNA strand cleavage, primary 18O kinetic isotope effects and solvent D2O isotope effects were measured to probe the mechanism of base-catalyzed 2'-O-transphosphorylation of the RNA dinucleotide 5'-UpG-3'. The observed 18O KIEs for the nucleophilic 2'-O and in the 5'-O leaving group at pH 14 are both large relative to reactions of phosphodiesters with good leaving groups, indicating that the reaction catalyzed by hydroxide has a transition state (TS) with advanced phosphorus-oxygen bond fission to the leaving group (18kLG = 1.034 ± 0.004) and phosphorous-nucleophile bond formation (18kNUC = 0.984 ± 0.004). A breakpoint in the pH dependence of the 2'-O-transphosphorylation rate to a pH independent phase above pH 13 has been attributed to the pKa of the 2'-OH nucleophile. A smaller nucleophile KIE is observed at pH 12 (18kNUC = 0.995 ± 0.004) that is interpreted as the combined effect of the equilibrium isotope effect (~1.02) on deprotonation of the 2′-hydroxyl nucleophile and the intrinsic KIE on the nucleophilic addition step (ca. 0.981). An alternative mechanism in which the hydroxide ion acts as a general base is considered unlikely given the lack of a solvent deuterium isotope effect above the breakpoint in the pH versus rate profile. These results represent the first direct analysis of the transition state for RNA strand cleavage. The primary 18O KIE results and the lack of a kinetic solvent deuterium isotope effect together provide strong evidence for a late transition state and 2'-O nucleophile activation by specific base catalysis. PMID:20669950

  14. Nucleophilicity Parameters of Stabilized Iodonium Ylides for Characterizing Their Synthetic Potential.

    PubMed

    Chelli, Saloua; Troshin, Konstantin; Mayer, Peter; Lakhdar, Sami; Ofial, Armin R; Mayr, Herbert

    2016-08-17

    Kinetics and mechanisms of the reactions of the β-dicarbonyl-substituted iodonium ylides 1(a-d) with several π-conjugated carbenium and iminium ions have been investigated. All reactions proceed with rate-determining attack of the electrophile at the nucleophilic carbon center of the ylides to give iodonium ions, which rapidly expel iodobenzene and undergo different subsequent reactions. The second-order rate constants k2 for the reactions of the iodonium ylides with benzhydrylium ions correlate linearly with the electrophilicity parameters E of the benzhydrylium ions and thus follow the linear free energy relationship log k(20 °C) = sN(N + E) (eq 1), where electrophiles are characterized by one parameter (E), while nucleophiles are characterized by two parameters: the nucleophilicity N and the susceptibility sN. The nucleophilicity parameters 4 < N < 8 for iodonium ylides 1(a-d) derived from these correlations show that substituting hydrogen for Ph-I(+) at the carbanionic center of Meldrum's acid or dimedone, respectively, reduces the nucleophilicity by approximately 10 orders of magnitude. The iodonium ylides 1(a-d) thus have nucleophilicities similar to those of pyrroles, indoles, and silylated enol ethers and, therefore, should be suitable substrates in iminium-activated reactions. Good agreement of the measured rate constant for the cyclopropanation of the imidazolidinone-derived iminium ion 10a with the iodonium ylide 1a with the rate constant calculated by eq 1 suggests a stepwise mechanism in which the initial nucleophilic attack of the iodonium ylide at the iminium ion is rate-determining. The reaction of cinnamaldehyde with iodonium ylide 1a catalyzed by (5S)-5-benzyl-2,2,3-trimethyl-imidazolidin-4-one (11a, MacMillan's first-generation catalyst) gives the corresponding cyclopropane with an enantiomeric ratio of 70/30 and, thus, provides proof of principle that iodonium ylides are suitable substrates for iminium-activated cyclopropanations. PMID

  15. Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation.

    PubMed

    You, Hengzhi; Rideau, Emeline; Sidera, Mireia; Fletcher, Stephen P

    2015-01-15

    The development of new reactions forming asymmetric carbon-carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy--dynamic kinetic asymmetric transformation--involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods. PMID:25592541

  16. Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation

    NASA Astrophysics Data System (ADS)

    You, Hengzhi; Rideau, Emeline; Sidera, Mireia; Fletcher, Stephen P.

    2015-01-01

    The development of new reactions forming asymmetric carbon-carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy--dynamic kinetic asymmetric transformation--involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of >=50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods.

  17. Carbonylmetallates--A Special Family of Nucleophiles in Aromatic and Vinylic Substitution Reactions.

    PubMed

    Sazonov, Petr K; Beletskaya, Irina P

    2016-03-01

    Carbonylmetallates, [M(CO)(n)L](-), anionic transition-metal carbonyl complexes, represent a large family of metal-centered nucleophiles, and studying carbonylmetallates allows us to understand the differences in the behavior of the metal-centered complexes versus heteroatom-based nucleophiles. The mechanisms of carbonylmetallate reactions with aryl- and alkenyl halides have been examined by employing radical and, especially, carbanion trapping techniques. Carbonylmetallates show a marked preference for halogenophilic attack, and nucleophilic substitution with carbonylmetallates is often not a direct process, but proceeds through the initial attack at halogen with subsequent coupling of carbanion and HalM(CO)(n)L intermediates. Factors governing the competition between the halogenophilic and more common "carbophilic" reaction pathways, as well as the means of predicting the actual course of reaction are discussed. The review also considers other aspects of carbonylmetallate reactivity, including ion-pairing effects, radical-mediated nucleophilic substitution pathways, and the carbonylmetallate nucleophilicity scale in the reactions with π-electrophiles. PMID:26808811

  18. Aqueous oxidation of sulfonamide antibiotics: aromatic nucleophilic substitution of an aniline radical cation.

    PubMed

    Tentscher, Peter R; Eustis, Soren N; McNeill, Kristopher; Arey, J Samuel

    2013-08-19

    Sulfonamide antibiotics are an important class of organic micropollutants in the aquatic environment. For several, sulfur dioxide extrusion products have been previously reported upon photochemical or dark oxidation. Using quantum chemical modeling calculations and transient absorption spectroscopy, it is shown that single-electron oxidation from sulfadiazine produces the corresponding aniline radical cation. Density functional theory calculations indicate that this intermediate can exist in four protonation states. One species exhibits a low barrier for an intramolecular nucleophilic attack at the para position of the oxidized aniline ring, in which a pyrimidine nitrogen acts as a nucleophile. This attack can lead to a rearranged structure, which exhibits the same connectivity as the SO2 -extruded oxidation product that was previously observed in the aquatic environment and characterized by NMR spectroscopy. We report a detailed reaction mechanism for this intramolecular aromatic nucleophilic substitution, and we discuss the possibility of this reaction pathway for other sulfonamide drugs. PMID:23828254

  19. Alternative nucleophilic substrates for the endonuclease activities of human immunodeficiency virus type 1 integrase

    SciTech Connect

    Ealy, Julie B.; Sudol, Malgorzata; Krzeminski, Jacek; Amin, Shantu; Katzman, Michael

    2012-11-10

    Retroviral integrase can use water or some small alcohols as the attacking nucleophile to nick DNA. To characterize the range of compounds that human immunodeficiency virus type 1 integrase can accommodate for its endonuclease activities, we tested 45 potential electron donors (having varied size and number or spacing of nucleophilic groups) as substrates during site-specific nicking at viral DNA ends and during nonspecific nicking reactions. We found that integrase used 22 of the 45 compounds to nick DNA, but not all active compounds were used for both activities. In particular, 13 compounds were used for site-specific and nonspecific nicking, 5 only for site-specific nicking, and 4 only for nonspecific nicking; 23 other compounds were not used for either activity. Thus, integrase can accommodate a large number of nucleophilic substrates but has selective requirements for its different activities, underscoring its dynamic properties and providing new information for modeling and understanding integrase.

  20. Identification of the nucleophile catalytic residue of GH51 α-l-arabinofuranosidase from Pleurotus ostreatus

    DOE PAGESBeta

    Amore, Antonella; Iadonisi, Alfonso; Vincent, Florence; Faraco, Vincenza

    2015-12-21

    In this paper, the recombinant α-l-arabinofuranosidase from the fungus Pleurotus ostreatus (rPoAbf) was subjected to site-directed mutagenesis in order to identify the catalytic nucleophile residue. Based on bioinformatics and homology modelling analyses, E449 was revealed to be the potential nucleophilic residue. Thus, the mutant E449G of PoAbf was recombinantly expressed in Pichia pastoris and its recombinant expression level and reactivity were investigated in comparison to the wild-type. The design of a suitable set of hydrolysis experiments in the presence or absence of alcoholic arabinosyl acceptors and/or formate salts allowed to unambiguously identify the residue E449 as the nucleophile residue involvedmore » in the retaining mechanism of this GH51 arabinofuranosidase. 1H NMR analysis was applied for the identification of the products and the assignement of their anomeric configuration.« less

  1. Oxidative nucleophilic strategy for synthesis of thiocyanates and trifluoromethyl sulfides from thiols.

    PubMed

    Yamaguchi, Kazuya; Sakagami, Konomi; Miyamoto, Yumi; Jin, Xiongjie; Mizuno, Noritaka

    2014-12-01

    Thiocyanates and trifluoromethyl sulfides are important compounds and have classically been synthesized via multistep procedures together with the formation of significant amounts of byproducts. Herein, we demonstrate an oxidative nucleophilic strategy for the synthesis of thiocyanates and trifluoromethyl sulfides from thiol starting materials using nucleophilic reagents such as TMSCN and TMSCF3 (TMS = trimethylsilyl). In the presence of a 2 × 2 manganese oxide-based octahedral molecular sieve (OMS-2) and potassium fluoride (KF), various structurally diverse thiocyanates and trifluoromethyl sulfides could be synthesized in almost quantitative yields (typically >90%). The presented cyanation and trifluoromethylation reactions proceed through the OMS-2-catalyzed oxidative homocoupling of thiols to give disulfides followed by nucleophilic bond cleavage to produce the desired compounds and thiolate species (herein S-trimethylsilylated thiols). OMS-2 can catalyze oxidative homocoupling of the thiolate species, thus resulting formally in the quantitative production of thiocyanates and trifluoromethyl sulfides from thiols. PMID:25297894

  2. Identification of the nucleophile catalytic residue of GH51 α-L-arabinofuranosidase from Pleurotus ostreatus.

    PubMed

    Amore, Antonella; Iadonisi, Alfonso; Vincent, Florence; Faraco, Vincenza

    2015-12-01

    In this study, the recombinant α-L-arabinofuranosidase from the fungus Pleurotus ostreatus (rPoAbf) was subjected to site-directed mutagenesis in order to identify the catalytic nucleophile residue. Based on bioinformatics and homology modelling analyses, E449 was revealed to be the potential nucleophilic residue. Thus, the mutant E449G of PoAbf was recombinantly expressed in Pichia pastoris and its recombinant expression level and reactivity were investigated in comparison to the wild-type. The design of a suitable set of hydrolysis experiments in the presence or absence of alcoholic arabinosyl acceptors and/or formate salts allowed to unambiguously identify the residue E449 as the nucleophile residue involved in the retaining mechanism of this GH51 arabinofuranosidase. (1)H NMR analysis was applied for the identification of the products and the assignement of their anomeric configuration. PMID:26690659

  3. Microwaves and Aqueous Solvents Promote the Reaction of Poorly Nucleophilic Anilines with a Zincke Salt.

    PubMed

    Zeghbib, Narimane; Thelliere, Paul; Rivard, Michael; Martens, Thierry

    2016-04-15

    The Zincke reaction allows the transformation of primary amines into their respective N-alkylated or N-arylated pyridinium salts. While nucleophilic primary amines (typically, aliphatic primary amines) often lead to quantitative reactions and has been documented profusely, the use of poorly nucleophilic amines still requires an in depth account. To date, the lack of nucleophilicity of the amines is redhibitory. The subject addressed in this article is a series of primary amines deriving from aniline having been engaged in Zincke reactions. Efficient transformations were obtained, even when conducted on electronically deactivated, eventually also sterically hindered, substrates. This was achieved by the combined use of microwave activation and aqueous solvents. Under our conditions, the role of water revealed indeed crucial to avoid the self-degradation of the Zincke salt, the reagent of the reaction. PMID:26986875

  4. Advances in Nucleophilic Phosphine Catalysis of Alkenes, Allenes, Alkynes, and MBHADs

    PubMed Central

    Fan, Yi Chiao

    2014-01-01

    In nucleophilic phosphine catalysis, tertiary phosphines undergo conjugate additions to activated carbon–carbon multiple bonds to form β-phosphonium enolates, β-phosphonium dienolates, β-phosphonium enoates, and vinyl phosphonium ylides as intermediates. When these reactive zwitterionic species react with nucleophiles and electrophiles, they may generate carbo- and heterocycles with multifarious molecular architectures. This Article describes the reactivities of these phosphonium zwitterions, the applications of phosphine catalysis in the syntheses of biologically active compounds and natural products, and recent developments in the enantioselective phosphine catalysis. PMID:24196409

  5. Organocatalytic Asymmetric Nucleophilic Addition to o-Quinone Methides by Alcohols.

    PubMed

    Lai, Zengwei; Wang, Zhaobin; Sun, Jianwei

    2015-12-18

    The first catalytic asymmetric intermolecular alcohol conjugate addition to o-quinone methides (o-QMs) is disclosed. Due to reversible C-O bond formation and low nucleophilicity of alcohols, catalytic asymmetric oxa-Michael additions with simple alcohol nucleophiles to establish acyclic oxygenated carbon stereocenters remain scarce. The present reaction represents a rare example of this type. With a suitable chiral acid catalyst, the in situ formation of o-QMs and subsequent conjugate addition proceeded with high efficiency and enantioselectivity. The chiral ether products are versatile precursors to other chiral molecules. PMID:26637015

  6. Synthesis and reactivity of nitrogen nucleophiles-induced cage-rearrangement silsesquioxanes.

    PubMed

    Jaroentomeechai, Thapakorn; Yingsukkamol, Pa-Kwan; Phurat, Chuttree; Somsook, Ekasith; Osotchan, Tanakorn; Ervithayasuporn, Vuthichai

    2012-11-19

    Novel phthalimide and o-sulfobenzimide-functionalized silsesquioxanes were successfully synthesized via nucleophilic substitution reactions from octakis(3-chloropropyl)octasilsesquioxane. Surprisingly, the formation of deca- and dodecasilsesquioxanes cages was discovered during substitution with phthalimide, but only octasilsesquioxane maintained a cage in the o-sulfobenzimide substitution reaction. Moreover, we report the electronic effect of nitrogen nucleophiles to promote cage-rearrangement of inorganic silsesquioxane core for the first time. Structures of products were confirmed by (1)H, (13)C, and (29)Si NMR spectroscopy, ESI-MS analysis, and single-crystal X-ray diffraction. PMID:23134535

  7. 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

  8. Efficient copper-catalyzed direct intramolecular aminotrifluoromethylation of unactivated alkenes with diverse nitrogen-based nucleophiles.

    PubMed

    Lin, Jin-Shun; Xiong, Ya-Ping; Ma, Can-Liang; Zhao, Li-Jiao; Tan, Bin; Liu, Xin-Yuan

    2014-01-27

    A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligands, is described. Many different nitrogen-based nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulfonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction. The aminotrifluoromethylation process allows straightforward access to diversely substituted CF3-containing pyrrolidines or indolines, in good to excellent yields, through a direct difunctionalization strategy from the respective acyclic starting materials. Mechanistic studies were conducted and a plausible mechanism was proposed. PMID:24458913

  9. Synthesis of a Fluorescent Acridone Using a Grignard Addition, Oxidation, and Nucleophilic Aromatic Substitution Reaction Sequence

    ERIC Educational Resources Information Center

    Goodrich, Samuel; Patel, Miloni; Woydziak, Zachary R.

    2015-01-01

    A three-pot synthesis oriented for an undergraduate organic chemistry laboratory was developed to construct a fluorescent acridone molecule. This laboratory experiment utilizes Grignard addition to an aldehyde, alcohol oxidation, and iterative nucleophilic aromatic substitution steps to produce the final product. Each of the intermediates and the…

  10. The Element Effect Revisited: Factors Determining Leaving Group Ability in Activated Nucleophilic Aromatic Substitution Reactions

    PubMed Central

    Senger, Nicholas A.; Bo, Bo; Cheng, Qian; Keeffe, James R.; Gronert, Scott; Wu, Weiming

    2012-01-01

    The “element effect” in nucleophilic aromatic substitution reactions (SNAr) is characterized by the leaving group order, F > NO2 > Cl ≈ Br > I, in activated aryl halides. Multiple causes for this result have been proposed. Experimental evidence shows that the element effect order in the reaction of piperidine with 2,4-dinitrophenyl halides in methanol is governed by the differences in enthalpies of activation. Computational studies of the reaction of piperidine and dimethylamine with the same aryl halides using the polarizable continuum model (PCM) for solvation indicate that polar, polarizability, solvation, and negative hyperconjugative effects are all of some importance in producing the element effect in methanol. In addition, a reversal of polarity of the C–X bond from reactant to transition state in the case of ArCl and ArBr compared to ArF also contributes to their difference in reactivity. The polarity reversal, and hyperconjugative influences have received little or no attention in the past. Nor has differential solvation of the different transition states been strongly emphasized. An anionic nucleophile, thiolate, gives very early transition states and negative activation enthalpies with activated aryl halides. The element effect is not established for these reactions. We suggest that the leaving group order in the gas phase will be dependent on the exact combination of nucleophile, leaving group, and substrate framework. The geometry of the SNAr transition state permits useful, qualitative conceptual distinctions to be made between this reaction and other modes of nucleophilic attack. PMID:23057717

  11. REVISITING CLASSICAL NUCLEOPHILIC SUBSTITUTIONS IN AQUEOUS MEDIUM: MICROWAVE-ASSISTED SYNTHESIS OF ALKYL AZIDES

    EPA Science Inventory

    An efficient and clean synthesis of alkyl azides using microwave (MW) radiation is described in aqueous medium by reacting alkyl halides or tosylates with alkali azides. This general and expeditious MW-enhanced approach to nucleophilic substitution reactions is applicable to the ...

  12. 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…

  13. Benzimidazoles and benzoxazoles via the nucleophilic addition of anilines to nitroalkanes.

    PubMed

    Aksenov, Alexander V; Smirnov, Alexander N; Aksenov, Nicolai A; Bijieva, Asiyat S; Aksenova, Inna V; Rubin, Michael

    2015-04-14

    PPA-induced umpolung triggers efficient nucleophilic addition of unactivated anilines to nitroalkanes to produce N-hydroxyimidamides. The latter undergo sequential acid-promoted cyclocondensation with ortho-OH or ortho-NHR moieties to afford benzoxazoles and benzimidazoles, respectively. PMID:25758157

  14. Investigations of acidity and nucleophilicity of diphenyldithiophosphinate ligands using theory and gas-phase dissociation reactions

    SciTech Connect

    Christopher M. Leavitt; Garold L. Gresham; Michael T. Benson; Jean-Jaques Gaumet; Dean Peterman; John Klaehn; Megan Moser; Frederic Aubriet; Michael J. Van Stipdonk; Gary S. Groenewold

    2008-04-01

    Diphenyldithiophosphinate (DTP) ligands modified with electron-withdrawing trifluoromethyl (TFM) substitutents are of high interest because they have demonstrated potential for exceptional separation of Am3+ from lanthanide3+ cations. Specifically, the bis(ortho-TFM) (L1-) and (ortho-TFM)(meta-TFM) (L2-) derivatives have shown excellent separation selectivity, while the bis(meta-TFM) (L3)- and unmodified DTP (Lu-) did not. Factors responsible for selective coordination have been investigated using density functional theory (DFT) calculations in concert with competitive dissociation reactions in the gas phase. To evaluate the role of (DTP+H) acidity, density functional calculations were used to predict pKa values, which followed the trend of L3 < L2 < L1 < Lu. The order of the TFM-modified (DTP+H) acids was opposite of what would be expected based on the e--withdrawing effects of the TFM group, suggesting that secondary factors are influencing the pKa and nucleophilicity. The relative nucleophilicities of the DTP anions were evaluated by forming metal-mixed ligand complexes in a trapped ion mass spectrometer, and then fragmenting them using competitive collision induced dissociation. Relative to Na+, the unmodified Lu- anion was the strongest nucleophile. Comparing the TFM derivatives, the bis(ortho-TFM) derivative L1- was found to be the strongest nucleophile, while the bis(meta-TFM) L3- was the weakest, a trend consistent with the pKa calculations. DFT modeling of the Na+ complexes suggested that the elevated cation affinity of the L1- and L2- anions was due to donation of electron density from fluorine atoms to the metal center, which was occurring in rotational conformers where the TFM moiety was proximate to the Na+-dithiophosphinate group. Competitive dissociation experiments were performed with the dithiophosphinate anions complexed with europium nitrate species; ionic dissociation of these complexes always produced the TFM-modified dithiophosphinate anions

  15. Rhodium and copper-catalyzed asymmetric conjugate addition of alkenyl nucleophiles.

    PubMed

    Müller, Daniel; Alexakis, Alexandre

    2012-12-25

    Since the initial reports in the mid-90s, metal catalyzed asymmetric conjugate addition (ACA) reactions evolved as an important tool for the synthetic chemist. Most of the research efforts have been done in the field of rhodium and copper catalyzed ACA reactions employing aryl and alkyl nucleophiles. Despite the great synthetic value of the double bond, the addition of alkenyl nucleophiles remains insufficiently explored. In this account, an overview of the developments in the field of rhodium and copper catalyzed ACA reactions with organometallic alkenyl reagents (B, Mg, Al, Si, Zr, Sn) will be provided. The account is intended to give a comprehensive overview of all the existing methods. However, in many cases only selected examples are displayed in order to facilitate comparison of different ligands and methodologies. PMID:23096501

  16. 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

  17. A General Ligand Design for Gold Catalysis allowing Ligand-Directed Anti Nucleophilic Attack of Alkynes

    PubMed Central

    Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming

    2014-01-01

    Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803

  18. How Does Nucleophilic Aromatic Substitution Really Proceed in Nitroarenes? Computational Prediction and Experimental Verification.

    PubMed

    Błaziak, Kacper; Danikiewicz, Witold; Mąkosza, Mieczysław

    2016-06-15

    The aim of this paper is to present a correct and complete mechanistic picture of nucleophilic substitution in nitroarenes based on the results obtained by theoretical calculations and experimental observations coming from numerous publications, reviews, and monographs. This work gives the theoretical background to the very well documented experimentally yet still ignored observations that the addition of nucleophiles to halo nitroarenes resulting in the formation of σ(H) adducts, which under proper reaction conditions can be transformed into the product of the SNArH reaction, is faster than the competing process of addition to the carbon atom bearing a nucleofugal group (usually a halogen atom) resulting in the "classic" SNAr reaction. Only when the σ(H) adduct cannot be transformed into the SNArH reaction product, SNAr reaction is observed. PMID:27218876

  19. Chemoselective Boron-Catalyzed Nucleophilic Activation of Carboxylic Acids for Mannich-Type Reactions.

    PubMed

    Morita, Yuya; Yamamoto, Tomohiro; Nagai, Hideoki; Shimizu, Yohei; Kanai, Motomu

    2015-06-10

    The carboxyl group (COOH) is an omnipresent functional group in organic molecules, and its direct catalytic activation represents an attractive synthetic method. Herein, we describe the first example of a direct catalytic nucleophilic activation of carboxylic acids with BH3·SMe2, after which the acids are able to act as carbon nucleophiles, i.e. enolates, in Mannich-type reactions. This reaction proceeds with a mild organic base (DBU) and exhibits high levels of functional group tolerance. The boron catalyst is highly chemoselective toward the COOH group, even in the presence of other carbonyl moieties, such as amides, esters, or ketones. Furthermore, this catalytic method can be extended to highly enantioselective Mannich-type reactions by using a (R)-3,3'-I2-BINOL-substituted boron catalyst. PMID:26011419

  20. Control of Diastereoselectivity for Iridium-catalyzed Allylation of a Prochiral Nucleophile with a Phosphate Counterion

    PubMed Central

    Chen, Wenyong; Hartwig, John F.

    2013-01-01

    We report a highly diastereo- and enantioselective allylation of azlactones catalyzed by the combination of a metallayclic iridium complex and an optically inactive phosphate anion. The process demonstrates an approach to conduct diastereoselective reactions with prochiral nucleophiles in the presence of metallacyclic allyliridium complexes. The reaction provides access to an array of enantioenriched allylated azlactones containing adjacent tertiary and quaternary carbon centers. Preliminary mechanistic studies suggest that the phosphate and methyl carbonate anions together induce the unusually high diastereoselectivity. PMID:23286279

  1. Catalytic Chemo- and Regioselective Coupling of 1,3-Dicarbonyls with N-Heterocyclic Nucleophiles.

    PubMed

    Kenny, Miles; Kitson, Daniel J; Franckevičius, Vilius

    2016-06-17

    The development of a decarboxylative palladium-catalyzed coupling of 1,3-dicarbonyl compounds with indole, pyrrole, imidazole, and pyrazole nucleophiles via an allylic linker under neutral conditions is disclosed. This process enables the installation of an all-carbon quaternary center and new C-C and C-N bonds in a single operation. Despite the weakly acidic nature of N-heterocycles, the reactions proceed with good efficiency and complete regio- and chemoselectivity. PMID:27211875

  2. Nucleophilic reactivity and electrocatalytic reduction of halogenated organic compounds by nickel o-phenylenedioxamidate complexes.

    PubMed

    Das, Siva Prasad; Ganguly, Rakesh; Li, Yongxin; Soo, Han Sen

    2016-09-14

    A growing number of halogenated organic compounds have been identified as hazardous pollutants. Although numerous advanced oxidative processes have been developed to degrade organohalide compounds, reductive and nucleophilic molecular approaches to dehalogenate organic compounds have rarely been reported. In this manuscript, we employ nickel(ii)-ate complexes bearing the o-phenylenebis(N-methyloxamide) (Me2opba) tetraanionic ligand as nucleophilic reagents that can react with alkyl halides (methyl up to the bulky isobutyl) by O-alkylation to give their respective imidate products. Four new nickel(ii) complexes have been characterized by X-ray crystallography, and the salient structural parameters and FT-IR vibrational bands (∼1655 cm(-1)) concur with their assignment as the imidate tautomeric form. To the best of our knowledge, this is the first report on the nucleophilic reactivity of Ni(II)(Me2opba) with halogenated organic compounds. The parent nickel(ii) Me2opba complex exhibits reversible electrochemical oxidation and reduction behavior. As a proof of concept, Ni(II)(Me2opba) and its alkylated congeners were utilized for the electrocatalytic reduction of chloroform, as a representative, simple polyhalogenated organic molecule that could arise from the oxidative treatment of organic compounds by chlorination. Modest turnover numbers of up to 6 were recorded, with dichloromethane identified as one of the possible products. Future efforts are directed towards bulkier -ate complexes that possess metal-centered instead of ligand-centered nucleophilic activity to create more effective electrocatalysts for the reduction of halogenated organic compounds. PMID:27506275

  3. From carbanions to organometallic compounds: quantification of metal ion effects on nucleophilic reactivities.

    PubMed

    Corral-Bautista, Francisco; Klier, Lydia; Knochel, Paul; Mayr, Herbert

    2015-10-12

    The influence of the metal on the nucleophilic reactivities of indenyl metal compounds was quantitatively determined by kinetic investigations of their reactions with benzhydrylium ions (Ar2 CH(+) ) and structurally related quinone methides. With the correlation equation log k2 =sN (N+E), it can be derived that the ionic indenyl alkali compounds are 10(18) to 10(24) times more reactive (depending on the reference electrophile) than the corresponding indenyltrimethylsilane. PMID:25951612

  4. Transition-Metal-Free Stereospecific Cross-Coupling with Alkenylboronic Acids as Nucleophiles.

    PubMed

    Li, Chengxi; Zhang, Yuanyuan; Sun, Qi; Gu, Tongnian; Peng, Henian; Tang, Wenjun

    2016-08-31

    We herein report a transition-metal-free cross-coupling between secondary alkyl halides/mesylates and aryl/alkenylboronic acid, providing expedited access to a series of nonchiral/chiral coupling products in moderate to good yields. Stereospecific SN2-type coupling is developed for the first time with alkenylboronic acids as pure nucleophiles, offering an attractive alternative to the stereospecific transition-metal-catalyzed C(sp(2))-C(sp(3)) cross-coupling. PMID:27515390

  5. A diastereoselective, nucleophile-promoted aldol-lactonization of ketoacids leading to bicyclic-β-lactones.

    PubMed

    Liu, Gang; Shirley, Morgan E; Romo, Daniel

    2012-03-01

    An improved, tandem acid activation/aldol-lactonization process is described. This more practical protocol shortens reaction times for the construction of bicyclic β-lactones from ketoacids and implements the use of commercially available reagents p-toluenesulfonyl chloride (p-TsCl) as activator and 4-dimethylaminopyridine (4-DMAP) as nucleophilic promoter (Lewis base). Substrates with β-substituents, with respect to the carboxylic acid, consistently showed excellent levels of diastereoselectivity during the bis-cyclization event. PMID:22260519

  6. Carbazole Annulation via Cascade Nucleophilic Addition-Cyclization Involving 2-(Silyloxy)pentadienyl Cation.

    PubMed

    Stepherson, Jacob R; Ayala, Caitlan E; Tugwell, Thomas H; Henry, Jeffrey L; Fronczek, Frank R; Kartika, Rendy

    2016-06-17

    We report a new strategy toward the synthesis of highly functionalized carbazoles via 2-(silyloxy)pentadienyl cation intermediates, which were generated upon ionization of vinyl-substituted α-hydroxy silyl enol ethers under Brønsted acid catalysis. These electrophilic species were found to readily undergo cascade reactions with substituted indoles to generate carbazole molecular scaffolds in good yields via a sequence of regioselective nucleophilic addition, followed by intramolecular dehydrative cyclization. PMID:27265237

  7. Mechanistic study of secondary organic aerosol components formed from nucleophilic addition reactions of methacrylic acid epoxide

    NASA Astrophysics Data System (ADS)

    Birdsall, A. W.; Miner, C. R.; Mael, L. E.; Elrod, M. J.

    2014-08-01

    Recently, methacrylic acid epoxide (MAE) has been proposed as a precursor to an important class of isoprene-derived compounds found in secondary organic aerosol (SOA): 2-methylglyceric acid (2-MG) and a set of oligomers, nitric acid esters and sulfuric acid esters related to 2-MG. However, the specific chemical mechanisms by which MAE could form these compounds have not been previously studied. In order to determine the relevance of these processes to atmospheric aerosol, MAE and 2-MG have been synthesized and a series of bulk solution-phase experiments aimed at studying the reactivity of MAE using nuclear magnetic resonance (NMR) spectroscopy have been performed. The present results indicate that the acid-catalyzed MAE reaction is more than 600 times slower than a similar reaction of an important isoprene-derived epoxide, but is still expected to be kinetically feasible in the atmosphere on more acidic SOA. The specific mechanism by which MAE leads to oligomers was identified, and the reactions of MAE with a number of atmospherically relevant nucleophiles were also investigated. Because the nucleophilic strengths of water, sulfate, alcohols (including 2-MG), and acids (including MAE and 2-MG) in their reactions with MAE were found to be of a similar magnitude, it is expected that a diverse variety of MAE + nucleophile product species may be formed on ambient SOA. Thus, the results indicate that epoxide chain reaction oligomerization will be limited by the presence of high concentrations of non-epoxide nucleophiles (such as water); this finding is consistent with previous environmental chamber investigations of the relative humidity-dependence of 2-MG-derived oligomerization processes and suggests that extensive oligomerization may not be likely on ambient SOA because of other competitive MAE reaction mechanisms.

  8. Mechanistic study of secondary organic aerosol components formed from nucleophilic addition reactions of methacrylic acid epoxide

    NASA Astrophysics Data System (ADS)

    Birdsall, A. W.; Miner, C. R.; Mael, L. E.; Elrod, M. J.

    2014-12-01

    Recently, methacrylic acid epoxide (MAE) has been proposed as a precursor to an important class of isoprene-derived compounds found in secondary organic aerosol (SOA): 2-methylglyceric acid (2-MG) and a set of oligomers, nitric acid esters, and sulfuric acid esters related to 2-MG. However, the specific chemical mechanisms by which MAE could form these compounds have not been previously studied with experimental methods. In order to determine the relevance of these processes to atmospheric aerosol, MAE and 2-MG have been synthesized and a series of bulk solution-phase experiments aimed at studying the reactivity of MAE using nuclear magnetic resonance (NMR) spectroscopy have been performed. The present results indicate that the acid-catalyzed MAE reaction is more than 600 times slower than a similar reaction of an important isoprene-derived epoxide, but is still expected to be kinetically feasible in the atmosphere on more acidic SOA. The specific mechanism by which MAE leads to oligomers was identified, and the reactions of MAE with a number of atmospherically relevant nucleophiles were also investigated. Because the nucleophilic strengths of water, sulfate, alcohols (including 2-MG), and acids (including MAE and 2-MG) in their reactions with MAE were found to be of similar magnitudes, it is expected that a diverse variety of MAE + nucleophile product species may be formed on ambient SOA. Thus, the results indicate that epoxide chain reaction oligomerization will be limited by the presence of high concentrations of non-epoxide nucleophiles (such as water); this finding is consistent with previous environmental chamber investigations of the relative humidity dependence of 2-MG-derived oligomerization processes and suggests that extensive oligomerization may not be likely on ambient SOA because of other competitive MAE reaction mechanisms.

  9. Detoxication of sulfur half-mustards by nucleophilic scavengers: robust activity of thiopurines.

    PubMed

    Liu, Jinyun; Powell, K Leslie; Thames, Howard D; MacLeod, Michael C

    2010-03-15

    Sulfur mustard (bis-(2-chloroethyl)sulfide) has been used in chemical warfare since World War I and is well known as an acutely toxic vesicant. It has been implicated as a carcinogen after chronic low-level exposure and is known to form interstrand cross-links in DNA. Sulfur and nitrogen mustards are currently of interest as potential chemical threat agents for terrorists because of ease of synthesis. Sulfur mustard and monofunctional analogues (half-mustards, 2-[chloroethyl] alkyl sulfides) react as electrophiles, damaging cellular macromolecules, and thus are potentially subject to scavenging by nucleophilic agents. We have determined rate constants for the reaction of four purine derivatives that contain nucleophilic thiol moieties with several sulfur-half-mustards. Three of these compounds, 2,6-dithiopurine, 2,6-dithiouric acid, and 9-methyl-6-mercaptopurine, exhibit facile reaction with the electrophilic mustard compounds. At near neutral pH, these thiopurines are much better nucleophilic scavengers of mustard electrophiles than other low molecular weight thiols such as N-acetyl cysteine and glutathione. Progress curves calculated by numerical integration techniques indicate that equimolar concentrations of thiopurine provide significant reductions in the overall exposure to the episulfonium ions, which are the major reactive, electrophiles produced when sulfur mustards are dissolved in aqueous solution. PMID:20050632

  10. Hydrogen-bond promoted nucleophilic fluorination: concept, mechanism and applications in positron emission tomography.

    PubMed

    Lee, Ji-Woong; Oliveira, Maria Teresa; Jang, Hyeong Bin; Lee, Sungyul; Chi, Dae Yoon; Kim, Dong Wook; Song, Choong Eui

    2016-08-22

    Due to the tremendous interest in carbon-fluorine bond-forming reactions, research efforts in this area have been dedicated to the development of facile processes to synthesize small fluorine-containing organic molecules. Among others, PET (Positron Emission Tomography) is one of the most important applications of fluorine chemistry. Recognizing the specific requirements of PET processes, some groups have focused on fluorination reactions using alkali metal fluorides, particularly through SN2-type reactions. However, a common "misconception" about the role of protic solvents and hydrogen bonding interactions in this class of reactions has hampered the employment of these excellent promoters. Herein, we would like to review recent discoveries in this context, showing straightforward nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents. Simultaneous dual activation of reacting partners by intermolecular hydrogen bonding and the enhancement of the "effective fluoride nucleophilicity", which is Nature's biocatalytic approach with the fluorinase enzyme, are the key to this unprecedentedly successful nucleophilic fluorination. PMID:27264160

  11. Novel nucleophiles enhance the human serum paraoxonase 1 (PON1)-mediated detoxication of organophosphates.

    PubMed

    Chambers, Janice E; Chambers, Howard W; Meek, Edward C; Funck, Kristen E; Bhavaraju, Manikanthan H; Gwaltney, Steven R; Pringle, Ronald B

    2015-01-01

    Paraoxonase 1 (PON1) is a calcium-dependent hydrolase associated with serum high-density lipoprotein particles. PON1 hydrolyzes some organophosphates (OPs), including some nerve agents, through nucleophilic attack of hydroxide ion (from water) in the active site. Most OPs are hydrolyzed inefficiently. This project seeks to identify nucleophiles that can enhance PON1-mediated OP degradation. A series of novel nucleophiles, substituted phenoxyalkyl pyridinium oximes, has been synthesized which enhance the degradation of surrogates of sarin (nitrophenyl isopropyl methylphosphonate; NIMP) and VX (nitrophenyl ethyl methylphosphonate; NEMP). Two types of in vitro assays have been conducted, a direct assay using millimolar concentrations of substrate with direct spectrophotometric quantitation of a hydrolysis product (4-nitrophenol) and an indirect assay using submicromolar concentrations of substrate with quantitation by the level of inhibition of an exogenous source of acetylcholinesterase from non-hydrolyzed substrate. Neither NIMP nor NEMP is hydrolyzed effectively by PON1 if one of these novel oximes is absent. However, in the presence of eight novel oximes, PON1-mediated degradation of both surrogates occurs. Computational modeling has created a model of PON1 embedded in phospholipid and has indicated general agreement of the binding enthalpies with the relative efficacy as PON1 enhancers. PON1 enhancement of degradation of OPs could be a unique and unprecedented mechanism of antidotal action. PMID:25304213

  12. 4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions

    NASA Astrophysics Data System (ADS)

    Dong, Jinhuan; Shi, Lou; Pan, Ling; Xu, Xianxiu; Liu, Qun

    2016-06-01

    In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation.

  13. 4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions

    PubMed Central

    Dong, Jinhuan; Shi, Lou; Pan, Ling; Xu, Xianxiu; Liu, Qun

    2016-01-01

    In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation. PMID:27246540

  14. Annulation of thioimidates and vinyl carbodiimides to prepare 2-aminopyrimidines, competent nucleophiles for intramolecular alkyne hydroamination. Synthesis of (-)-crambidine.

    PubMed

    Perl, Nicholas R; Ide, Nathan D; Prajapati, Sudeep; Perfect, Hahdi H; Durón, Sergio G; Gin, David Y

    2010-02-17

    A convergent synthesis of (-)-crambidine is reported. The sequence capitalizes on two novel key transformations, including a [4+2] annulation of thioimidates with vinyl carbodiimides and an alkyne hydroamination employing 2-aminopyrimidine nucleophiles. PMID:20095555

  15. Effects of Solvent and Residual Water on Enhancing the Reactivity of Six-Membered Silyloxyallyl Cations toward Nucleophilic Addition.

    PubMed

    Malone, Joshua A; Cleveland, Alexander H; Fronczek, Frank R; Kartika, Rendy

    2016-09-01

    A new strategy for the generation of six-membered unsymmetrical silyloxyallyl cations using catalytic mild Brønsted acid is reported. These reactive intermediates were found to readily undergo direct nucleophilic addition with a broad range of nucleophiles to produce various α,α'-disubstituted silyl enol ether structural motifs. The findings also highlight the significance of the solvent effect and residual water in enhancing the reaction rate. PMID:27538538

  16. Copper-catalyzed P-arylation via direct coupling of diaryliodonium salts with phosphorus nucleophiles at room temperature.

    PubMed

    Xu, Jian; Zhang, Pengbo; Gao, Yuzhen; Chen, Yiyin; Tang, Guo; Zhao, Yufen

    2013-08-16

    A new method for copper-catalyzed P-C bond formation through reaction of phosphorus nucleophiles with diaryliodonium salts at room temperature is described. Most target products are obtained with this method in high yields within a short reaction time of 10 min. It can be easily adapted to large-scale preparations. When unsymmetrical iodonium salts are employed, nucleophilic substitution occurs preferentially on the sterically hindered aromatic ring or the more electron-deficient ring. PMID:23865378

  17. Nucleophilic Polymers and Gels in Hydrolytic Degradation of Chemical Warfare Agents.

    PubMed

    Bromberg, Lev; Creasy, William R; McGarvey, David J; Wilusz, Eugene; Hatton, T Alan

    2015-10-01

    Water- and solvent-soluble polymeric materials based on polyalkylamines modified with nucleophilic groups are introduced as catalysts of chemical warfare agent (CWA) hydrolysis. A comparative study conducted at constant pH and based on the criteria of the synthetic route simplicity, aqueous solubility, and rate of hydrolysis of CWA mimic, diisopropylfluorophosphate (DFP), indicated that 4-aminopyridine-substituted polyallylamine (PAAm-APy) and polyvinylamine substituted with 4-aminopyridine (PVAm-APy) were advantageous over 4-pyridinealdoxime-modified PVAm and PAAm, poly(butadiene-co-pyrrolidinopyridine), and PAAm modified with bipyridine and its complex with Cu(II). The synthesis of PVAm-APy and PAAm-APy involved generation of a betaine derivative of acrylamide and its covalent attachment onto the polyalkylamine chain followed by basic hydrolysis. Hydrogel particles of PAAm-APy and PVAm-APy cross-linked by epichlorohydrin exhibited pH-dependent swelling and ionization patterns that affected the rate constants of DFP nucleophilic hydrolysis. Deprotonation of the aminopyridine and amine groups increased the rates of the nucleophilic hydrolysis. The second-order rate of nucleophilic hydrolysis was 5.5- to 10-fold higher with the nucleophile-modified gels compared to those obtained by cross-linking of unmodified PAAm, throughout the pH range. Testing of VX and soman (GD) was conducted in 2.5-3.7 wt % PVAm-APy suspensions or gels swollen in water or DMSO/water mixtures. The half-lives of GD in aqueous PVAm-APy were 12 and 770 min at pH 8.5 and 5, respectively. Addition of VX into 3.5-3.7 wt % suspensions of PVAm-APy in DMSO-d6 and D2O at initial VX concentration of 0.2 vol % resulted in 100% VX degradation in less than 20 min. The unmodified PVAm and PAAm were 2 orders of magnitude less active than PVAm-APy and PAAm-APy, with VX half-lives in the range of 24 h. Furthermore, the PVAm-APy and PAAm-APy gels facilitated the dehydrochlorination reaction of sulfur mustard

  18. Nucleophilic reactions at a vinylic center. XVI. Investigation of the nucleophilic exchange of fluorine in. beta. -fluoroacrylonitriles by the MINDO/3 method

    SciTech Connect

    Shainyan, B.A.

    1986-01-10

    The potential energy surfaces of the reactions of F/sup -/ with cis- and trans-..beta..-fluoroacrylonitriles were calculated by the MINDO/3 method. It was shown that three reaction paths can be realized in the system, i.e., attack by the nucleophile at the ..beta..-carbon atom, the elimination of a proton from the ..cap alpha.. position, and the elimination of a proton from the ..beta.. position. All three reaction paths are exothermic in the gas phase, and the elimination of the proton from the ..cap alpha.. position is 70 kJ/mole more favorable than from the ..beta.. position. Allowance for the effect of the medium in terms of an unconcerted solvation model modes not lead to the appearance of an activation barrier, in contrast to the reactions of anions with ethylene.

  19. Tyrosyl-DNA phosphodiesterase I catalytic mutants reveal an alternative nucleophile that can catalyze substrate cleavage.

    PubMed

    Comeaux, Evan Q; Cuya, Selma M; Kojima, Kyoko; Jafari, Nauzanene; Wanzeck, Keith C; Mobley, James A; Bjornsti, Mary-Ann; van Waardenburg, Robert C A M

    2015-03-01

    Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes the repair of 3'-DNA adducts, such as the 3'-phosphotyrosyl linkage of DNA topoisomerase I to DNA. Tdp1 contains two conserved catalytic histidines: a nucleophilic His (His(nuc)) that attacks DNA adducts to form a covalent 3'-phosphohistidyl intermediate and a general acid/base His (His(gab)), which resolves the Tdp1-DNA linkage. A His(nuc) to Ala mutant protein is reportedly inactive, whereas the autosomal recessive neurodegenerative disease SCAN1 has been attributed to the enhanced stability of the Tdp1-DNA intermediate induced by mutation of His(gab) to Arg. However, here we report that expression of the yeast His(nuc)Ala (H182A) mutant actually induced topoisomerase I-dependent cytotoxicity and further enhanced the cytotoxicity of Tdp1 His(gab) mutants, including H432N and the SCAN1-related H432R. Moreover, the His(nuc)Ala mutant was catalytically active in vitro, albeit at levels 85-fold less than that observed with wild type Tdp1. In contrast, the His(nuc)Phe mutant was catalytically inactive and suppressed His(gab) mutant-induced toxicity. These data suggest that the activity of another nucleophile when His(nuc) is replaced with residues containing a small side chain (Ala, Asn, and Gln), but not with a bulky side chain. Indeed, genetic, biochemical, and mass spectrometry analyses show that a highly conserved His, immediately N-terminal to His(nuc), can act as a nucleophile to catalyze the formation of a covalent Tdp1-DNA intermediate. These findings suggest that the flexibility of Tdp1 active site residues may impair the resolution of mutant Tdp1 covalent phosphohistidyl intermediates and provide the rationale for developing chemotherapeutics that stabilize the covalent Tdp1-DNA intermediate. PMID:25609251

  20. Nucleophilic substitution in ionizable Fischer thiocarbene complexes: steric effect of the alkyl substituent on the heteroatom.

    PubMed

    Andrada, Diego M; Zoloff Michoff, Martin E; de Rossi, Rita H; Granados, Alejandro M

    2015-03-28

    A detailed kinetic study has been carried out for the aminolysis of ionizable Fischer thiocarbene complexes (CO)5M[double bond, length as m-dash]C(SR)CH3 (M = Cr, W; R = iPr, nBu, cHex, tBu) with five primary amines and one secondary amine in aqueous acetonitrile solutions (50% MeCN-50% water (v/v)). The observed rate constants for the reaction with primary amines showed a first-order dependence on the amine concentration, while with morpholine, the rate constant has second-order dependence. The general base catalysis process was confirmed by the variation of the rate constants with the concentration of an external catalyst and the pH. The results agree with a stepwise mechanism where the nucleophilic addition to the carbene carbon to produce a tetrahedral intermediate (T±) is the first step, followed by a rapid deprotonation of to form the anion T- which leads to the products by general-acid catalysed leaving group (-SR) expulsion. In general, it was found that the chromium complexes are less reactive than the tungsten analogues. The obtained Brønsted parameters for the nucleophilic addition (βnuc) indicate that C-N bond formation has made little progress at the transition state. By using Charton's correlation, the role that the steric factor plays throughout the mechanism has been unraveled. The nucleophilic addition to the thiocarbenes is less sensitive to steric effects than the alkoxycarbenes regardless of the nature of the metal centre. Conversely, the steric effects on the general-base catalysis can be strong depending on the volume of the catalyst and the metal centre. On the basis of the structure-reactivity coefficients β and ψ and comparison with alkoxycarbene complexes, esters and thiolesters, insights into the main factors ruling the reactivity in terms of transition state imbalances are discussed. PMID:25698135

  1. Synthesis of Allenamides by Copper-Catalyzed Coupling of Propargylic Bromides and Nitrogen Nucleophiles.

    PubMed

    Demmer, Charles S; Benoit, Emeline; Evano, Gwilherm

    2016-03-18

    An efficient and general synthesis of allenamides derived from oxazolidinones and hydantoins is reported. Upon activation with a combination of a copper catalyst and a 2,2'-bipyridine derivative in the presence of an inorganic base, propargylic bromides were found to be suitable reagents for the direct allenylation of nitrogen nucleophiles by a formal copper-catalyzed S(N)2' reaction. Besides the availability of the starting materials, notable features of this route to allenamides are its mild reaction conditions, the reaction being performed at room temperature in most cases, and its applicability to the preparation of mono-, di-, as well as trisubstituted allenamides. PMID:26936415

  2. Hydrocarbation of C≡C bonds: quantification of the nucleophilic reactivity of ynamides.

    PubMed

    Laub, Hans A; Evano, Gwilherm; Mayr, Herbert

    2014-05-01

    Donor-substituted diarylcarbenium ions Ar2 CH(+) react with ynamides to give 1-amido-substituted allyl cations (α,β-unsaturated iminium ions). Kinetic studies show that these adducts, which correspond to the addition of a CH bond across the CC bond, are formed stepwise with initial formation of keteniminium ions and subsequent 1,3-hydride shifts. The linear correlations between the second-order rate constants (lg k2 , 20 °C) with the electrophilicity parameters E of the diarylcarbenium ions allow us to include ynamides in our comprehensive nucleophilicity scale and thus predict potential electrophilic reaction partners. PMID:24715471

  3. tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions.

    PubMed

    Ramirez Hernandez, Johana; Chemla, Fabrice; Ferreira, Franck; Jackowski, Olivier; Oble, Julie; Perez-Luna, Alejandro; Poli, Giovanni

    2016-01-01

    The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon-nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions. PMID:26931222

  4. Highly nucleophilic dipropanolamine chelated boron reagents for aryl-transmetallation to iron complexes.

    PubMed

    Dunsford, Jay J; Clark, Ewan R; Ingleson, Michael J

    2015-12-21

    New aryl- and heteroarylboronate esters chelated by dipropanolamine are synthesised directly from boronic acids. The corresponding anionic borates are readily accessible by deprotonation and demonstrate an increase in hydrocarbyl nucleophilicity in comparison to other common borates. The new borates proved competent for magnesium or zinc additive-free, direct boron-to-iron hydrocarbyl transmetallations with well-defined iron(II) (pre)catalysts. The application of the new borate reagents in representative Csp(2)-Csp(3) cross-coupling led to almost exclusive homocoupling unless coupling is performed in the presence of a zinc additive. PMID:26554484

  5. Recent Developments in Metal-Catalyzed Additions of Oxygen Nucleophiles to Alkenes and Alkynes

    NASA Astrophysics Data System (ADS)

    Hintermann, Lukas

    Progress in the field of metal-catalyzed redox-neutral additions of oxygen nucleophiles (water, alcohols, carboxylic acids, and others) to alkenes, alkynes, and allenes between 2001 and 2009 is critically reviewed. Major advances in reaction chemistry include development of chiral Lewis acid catalyzed asymmetric oxa-Michael additions and Lewis-acid catalyzed hydro-alkoxylations of nonactivated olefins, as well as further development of Markovnikov-selective cationic gold complex-catalyzed additions of alcohols or water to alkynes and allenes.

  6. Covalent binding of aniline to humic substances. 2. 15N NMR studies of nucleophilic addition reactions

    USGS Publications Warehouse

    Thorn, K.A.; Pettigrew, P.J.; Goldenberg, W.S.; Weber, E.J.

    1996-01-01

    Aromatic amines are known to undergo covalent binding with humic substances in the environment. Although previous studies have examined reaction conditions and proposed mechanisms, there has been no direct spectroscopic evidence for the covalent binding of the amines to the functional groups in humic substances. In order to further elucidate the reaction mechanisms, the Suwannee River and IHSS soil fulvic and humic acids were reacted with 15N-labeled aniline at pH 6 and analyzed using 15N NMR spectrometry. Aniline underwent nucleophilic addition reactions with the quinone and other carbonyl groups in the samples and became incorporated in the form of anilinohydroquinone, anilinoquinone, anilide, imine, and heterocyclic nitrogen, the latter comprising 50% or more of the bound amine. The anilide and anilinohydroquinone nitrogens were determined to be susceptible to chemical exchange by ammonia. In the case of Suwannee River fulvic acid, reaction under anoxic conditions and pretreatment with sodium borohydride or hydroxylamine prior to reaction under oxic conditions resulted in a decrease in the proportion of anilinohydroquinone nitrogen incorporated. The relative decrease in the incorporation of anilinohydroquinone nitrogen with respect to anilinoquinone nitrogen under anoxic conditions suggested that inter- or intramolecular redox reactions accompanied the nucleophilic addition reactions.

  7. Controlling subtilisin activity and selectivity in organic media by imprinting with nucleophilic substrates

    SciTech Connect

    Rich, J.O.; Dordick, J.S.

    1997-04-09

    The activity and substrate specificity of subtilisin-catalyzed acylation of nucleosides in organic solvents can be controlled by lyophilizing the enzyme from an aqueous solution containing the substrate. This `molecular imprinting` technique was examined using thymidine as a model nucleoside, and the resulting subtilisin preparation was up to 50-fold more reactive toward thymidine acylation in nearly anhydrous tetrahydrofuran than subtilisin lyophilized from aqueous buffer in the absence of the nucleoside. Although several compounds lyophilized with subtilisin, including thymine and ribose, improved the rate of thymidine acylation, the thymidine-imprinted enzyme was the most efficient catalyst for this reaction. Furthermore, it was possible to alter the substrate selectivity of subtilisin by lyophilizing the enzyme in the presence of a different nucleophilic substrate. For example, imprinting made possible the discrimination between structurally different (i.e., sucrose versus thymidine) as well as structurally similar (i.e., thymidine versus deoxyadenosine) nucleophiles. Molecular modeling studies of the interaction of thymidine or the unrelated sucrose with subtilisin revealed that structural changes upon imprinting in the serine protease`s catalytic triad may be responsible for the observed activation and selectivity changes. 40 refs., 6 figs., 3 tabs.

  8. The second-shell metal ligands of human arginase affect coordination of the nucleophile and substrate.

    PubMed

    Stone, Everett M; Chantranupong, Lynne; Georgiou, George

    2010-12-14

    The active sites of eukaryotic arginase enzymes are strictly conserved, especially the first- and second-shell ligands that coordinate the two divalent metal cations that generate a hydroxide molecule for nucleophilic attack on the guanidinium carbon of l-arginine and the subsequent production of urea and l-ornithine. Here by using comprehensive pairwise saturation mutagenesis of the first- and second-shell metal ligands in human arginase I, we demonstrate that several metal binding ligands are actually quite tolerant to amino acid substitutions. Of >2800 double mutants of first- and second-shell residues analyzed, we found more than 80 unique amino acid substitutions, of which four were in first-shell residues. Remarkably, certain second-shell mutations could modulate the binding of both the nucleophilic water/hydroxide molecule and substrate or product ligands, resulting in activity greater than that of the wild-type enzyme. The data presented here constitute the first comprehensive saturation mutagenesis analysis of a metallohydrolase active site and reveal that the strict conservation of the second-shell metal binding residues in eukaryotic arginases does not reflect kinetic optimization of the enzyme during the course of evolution. PMID:21053939

  9. Development of Selective Colorimetric Probes for Hydrogen Sulfide Based on Nucleophilic Aromatic Substitution

    PubMed Central

    Montoya, Leticia A.; Pearce, Taylor F.; Hansen, Ryan J.; Zakharov, Lev N.; Pluth, Michael D.

    2013-01-01

    Hydrogen sulfide is an important biological signalling molecule and an important environmental target for detection. A major challenge in developing H2S detection methods is separating the often similar reactivity of thiols and other nucleophiles from H2S. To address this need, the nucleophilic aromatic substitution (SNAr) reaction of H2S with electron-poor aromatic electrophiles was developed as a strategy to separate H2S and thiol reactivity. Treatment of aqueous solutions of nitrobenzofurazan (7-nitro-1,2,3-benzoxadiazole, NBD) thioethers with H2S resulted in thiol extrusion and formation of nitrobenzofurazan thiol (λmax = 534 nm). This reactivity allows for unwanted thioether products to be converted to the desired nitrobenzofurazan thiol upon reaction with H2S. The scope of the reaction was investigated using a Hammett linear free energy relationship study, and the determined ρ = +0.34 is consistent with the proposed SN2Ar reaction mechanism. The efficacy of the developed probes was demonstrated in buffer and in serum with associated sub-micromolar detection limits as low as 190 nM (buffer) and 380 nM (serum). Furthermore, the sigmoidal response of nitrobenzofurazan electrophiles with H2S can be fit to accurately quantify H2S. The developed detection strategy offers a manifold for H2S detection that we foresee being applied in various future applications. PMID:23735055

  10. Reduced Reactivity of Amines against Nucleophilic Substitution via Reversible Reaction with Carbon Dioxide.

    PubMed

    Mohammed, Fiaz S; Kitchens, Christopher L

    2015-01-01

    The reversible reaction of carbon dioxide (CO₂) with primary amines to form alkyl-ammonium carbamates is demonstrated in this work to reduce amine reactivity against nucleophilic substitution reactions with benzophenone and phenyl isocyanate. The reversible formation of carbamates has been recently exploited for a number of unique applications including the formation of reversible ionic liquids and surfactants. For these applications, reduced reactivity of the carbamate is imperative, particularly for applications in reactions and separations. In this work, carbamate formation resulted in a 67% reduction in yield for urea synthesis and 55% reduction for imine synthesis. Furthermore, the amine reactivity can be recovered upon reversal of the carbamate reaction, demonstrating reversibility. The strong nucleophilic properties of amines often require protection/de-protection schemes during bi-functional coupling reactions. This typically requires three separate reaction steps to achieve a single transformation, which is the motivation behind Green Chemistry Principle #8: Reduce Derivatives. Based upon the reduced reactivity, there is potential to employ the reversible carbamate reaction as an alternative method for amine protection in the presence of competing reactions. For the context of this work, CO₂ is envisioned as a green protecting agent to suppress formation of n-phenyl benzophenoneimine and various n-phenyl-n-alky ureas. PMID:26703563

  11. Understanding the Origins of Nucleophilic Hydride Reactivity of a Sodium Hydride-Iodide Composite.

    PubMed

    Hong, Zonghan; Ong, Derek Yiren; Muduli, Subas Kumar; Too, Pei Chui; Chan, Guo Hao; Tnay, Ya Lin; Chiba, Shunsuke; Nishiyama, Yusuke; Hirao, Hajime; Soo, Han Sen

    2016-05-17

    Sodium hydride (NaH) has been commonly used as a Brønsted base in chemical syntheses, while it has rarely been employed to add hydride (H(-) ) to unsaturated electrophiles. We previously developed a procedure to activate NaH through the addition of a soluble iodide source and found that the new NaH-NaI composite can effect even stereoselective nucleophilic hydride reductions of nitriles, imines, and carbonyl compounds. In this work, we report that mixing NaH with NaI or LiI in tetrahydrofuran (THF) as a solvent provides a new inorganic composite, which consists of NaI interspersed with activated NaH, as revealed by powder X-ray diffraction, and both solid-state NMR and X-ray photoelectron spectroscopies. DFT calculations imply that this remarkably simple inorganic composite, which is comprised of NaH and NaI, gains nucleophilic hydridic character similar to covalent hydrides, resulting in unprecedented and unique hydride donor chemical reactivity. PMID:27038135

  12. Chloromethyl chlorosulfate: a new, catalytic method of preparation and reactions with some nucleophiles.

    PubMed

    Power, Nicholas P; Bethell, Donald; Proctor, Lee; Latham, Elliot; Dawson, Paul

    2004-05-21

    The reaction of liquid (gamma-) SO3 with CH2Cl2 at room temperature leads to SO3 insertion into the C-Cl bonds, giving the useful chloromethylating agent chloromethyl chlorosulfate (CMCS). The process is very slow but becomes rapid on addition of catalytic quantities of trimethyl borate. The product mixture consists almost entirely of CMCS and the product of further sulfation, methylene bis(chlorosulfate)(MBCS), in a ratio of ca. 2 : 1, but typical yields of CMCS, isolated by distillation, are only 30-35%. The catalysed reaction in the homogeneous liquid phase at -45 degrees C has been followed as a function of time and of reactant concentration by 1H nmr spectroscopy. It is observed that, besides CMCS and MBCS, three additional, transient products (designated A, B and C) are formed. Products A, B and C decompose slowly at -45 degrees C but much more rapidly if the reaction mixture is raised to room temperature, giving additional CMCS and MBCS. From an analysis of the SO3 balance, it is inferred that products A, B and C arise from the reaction of one molecule of CH2Cl2 with respectively two, three and four molecules of SO3; they are suggested to be chloromethyl chloropolysulfates. By measuring initial rates of CMCS formation or total CH2Cl2 consumption, it is shown that the reaction is first order in the catalyst and roughly third order in SO3. A mechanistic scheme is proposed in which SO3 forms equilibrating zwitterionic molecular complexes with CH2Cl2. of 1 : 1, 2 : 1 and higher stoichiometries. The boron-containing catalyst can activate these complexes towards nucleophilic attack at carbon by the negatively charged oxygen of another zwitterion. An analogous mechanism can be written for the conversion of CMCS into MBCS by SO3 in the presence of trimethyl borate. CMCS reacts rapidly with anionic nucleophiles, such as halide or acetate ions (X-), in homogeneous solution of their tetrabutylammonium salts in CD3CN, or in a two-phase system (CDCl3/H2O) using alkali

  13. Configurationally Stable, Enantioenriched Organometallic Nucleophiles in Stereospecific Pd-Catalyzed Cross-Coupling Reactions: An Alternative Approach to Asymmetric Synthesis

    PubMed Central

    Wang, Chao-Yuan; Derosaa, Joseph

    2015-01-01

    Several research groups have recently developed methods to employ configurationally stable, enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions. By establishing the absolute configuration of a chiral alkyltin or alkylboron nucleophile prior to its use in cross-coupling reactions, new stereogenic centers may be rapidly and reliably generated with preservation of the known initial stereochemistry. While this area of research is still in its infancy, such stereospecific cross-coupling reactions may emerge as simple, general methods to access diverse, optically active products from common enantioenriched organometallic building blocks. This minireview highlights recent progress towards the development of general, stereospecific Pd-catalyzed cross-coupling reactions using configurationally stable organometallic nucleophiles. PMID:26388985

  14. Identification of the nucleophile catalytic residue of GH51 α-l-arabinofuranosidase from Pleurotus ostreatus

    SciTech Connect

    Amore, Antonella; Iadonisi, Alfonso; Vincent, Florence; Faraco, Vincenza

    2015-12-21

    In this paper, the recombinant α-l-arabinofuranosidase from the fungus Pleurotus ostreatus (rPoAbf) was subjected to site-directed mutagenesis in order to identify the catalytic nucleophile residue. Based on bioinformatics and homology modelling analyses, E449 was revealed to be the potential nucleophilic residue. Thus, the mutant E449G of PoAbf was recombinantly expressed in Pichia pastoris and its recombinant expression level and reactivity were investigated in comparison to the wild-type. The design of a suitable set of hydrolysis experiments in the presence or absence of alcoholic arabinosyl acceptors and/or formate salts allowed to unambiguously identify the residue E449 as the nucleophile residue involved in the retaining mechanism of this GH51 arabinofuranosidase. 1H NMR analysis was applied for the identification of the products and the assignement of their anomeric configuration.

  15. Corrole and nucleophilic aromatic substitution are not incompatible: a novel route to 2,3-difunctionalized copper corrolates

    PubMed Central

    Stefanelli, M.; Mandoj, F.; Nardis, S.; Raggio, M.; Fronczek, F.R.; McCandless, G.T.; Smith, K. M.; Paolesse, R.

    2015-01-01

    The insertion of a –NO2 group onto the corrole framework represents a key step for subsequent synthetic manipulation of the macrocycle based on the chemical versatility of such a functionality. Here we report results on the investigation of a copper 3-NO2-triarylcorrolate in nucleophilic aromatic substitution reactions with “active” methylene carbanions, namely diethyl malonate and diethyl 2-chloromalonate. Although similar reactions on nitroporphyrins afford chlorin derivatives, nucleophilic attack on carbon-2 of corrole produces 2,3-difunctionalized Cu corrolates in acceptable yields (ca. 30%), evidencing once again the erratic chemistry of this contracted porphyrinoid. PMID:25986693

  16. Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides.

    PubMed

    Dumas, Aaron M; Sieradzki, Adrian J; Donnelly, Liam J

    2016-04-15

    α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp(3)-sp(2) coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals. PMID:27017848

  17. Synthesis and structural studies of flavin and alloxazine adducts with O-nucleophiles

    NASA Astrophysics Data System (ADS)

    Ménová, Petra; Eigner, Václav; Čejka, Jan; Dvořáková, Hana; Šanda, Miloslav; Cibulka, Radek

    2011-10-01

    Five flavin (isoalloxazine) and alloxazine adducts with O-nucleophiles, 5-ethyl-4a-hydroxy-3,7,8,10-tetramethyl-4a,5-dihydroisoalloxazine ( 1a-OH), 5-ethyl-4a-hydroxy-3,10-dimethyl-4a,5-dihydroisoalloxazine ( 1b-OH), 5-ethyl-4a-methoxy-3,10-dimethyl-4a,5-dihydroisoalloxazine ( 1b-OMe), 5-ethyl-4a-hydroxy-1,3-dimethyl-4a,5-dihydroalloxazine ( 2a-OH) and 5-ethyl-4a-methoxy-1,3-dimethyl-4a,5-dihydroalloxazine ( 2a-OMe) were prepared from the corresponding salts, 5-ethyl-3,7,8,10-tetramethylisoalloxazinium ( 1a), 5-ethyl-3,10-dimethylisoalloxazinium ( 1b) and 5-ethyl-1,3-dimethylalloxazinium ( 2a) perchlorates by the addition of a nucleophile (water or methanol) and triethylamine as a base. The prepared adducts represent artificial analogs of flavin cofactor derivatives which are essential for the functioning of flavoenzymes. They were characterized by 1H and 13C NMR, HR-MS and UV-VIS spectra. In the cases of 1a-OH, 1b-OH, and 2a-OMe, the crystal structures were determined by X-ray diffraction. Flavinium and alloxazinium salts are in rapid equilibria with their adducts in water or methanolic solutions without the presence of a base. It was found that the equilibrium constants for flavin adduct formation is higher by six orders of magnitude than those for alloxazine derivatives. The presence of the sp 3 hybridized C4a atom in the molecule of the adducts causes deviation from planarity. The interplanar angles between benzene and the pyrimidine ring were found to be 31.5°, 23.64° and 15.62° for 1a-OH, 1b-OH and 2a-OMe, respectively, which are much higher than those of previously published adducts of C-nucleophiles. In isoalloxazine adducts, delocalization of π electrons between the N10-C10a and C10a-N1 bonds was detected while the length of the N10-C10a and C10a-N1 bonds in the alloxazine adducts corresponds to a double and single bond, respectively.

  18. Bis-tert-Alcohol-Functionalized Crown-6-Calix[4]arene: An Organic Promoter for Nucleophilic Fluorination.

    PubMed

    Jadhav, Vinod H; Choi, Wonsil; Lee, Sung-Sik; Lee, Sungyul; Kim, Dong Wook

    2016-03-18

    A bis-tert-alcohol-functionalized crown-6-calix[4]arene (BACCA) was designed and prepared as a multifunctional organic promoter for nucleophilic fluorinations with CsF. By formation of a CsF/BACCA complex, BACCA could release a significantly active and selective fluoride source for SN2 fluorination reactions. The origin of the promoting effects of BACCA was studied by quantum chemical methods. The role of BACCA was revealed to be separation of the metal fluoride to a large distance (>8 Å), thereby producing an essentially "free" F(-). The synergistic actions of the crown-6-calix[4]arene subunit (whose O atoms coordinate the counter-cation Cs(+)) and the terminal tert-alcohol OH groups (forming controlled hydrogen bonds with F(-)) of BACCA led to tremendous efficiency in SN2 fluorination of base-sensitive substrates. PMID:26880350

  19. 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

  20. 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

  1. Taming of fluoroform: direct nucleophilic trifluoromethylation of Si, B, S, and C centers.

    PubMed

    Prakash, G K Surya; Jog, Parag V; Batamack, Patrice T D; Olah, George A

    2012-12-01

    Fluoroform (CF(3)H), a large-volume by-product of the manufacture of Teflon, refrigerants, polyvinylidene fluoride (PVDF), fire-extinguishing agents, and foams, is a potent and stable greenhouse gas that has found little practical use despite the growing importance of trifluoromethyl (CF3) functionality in more structurally elaborate pharmaceuticals, agrochemicals, and materials. Direct nucleophilic trifluoromethylation using CF(3)H has been a challenge. Here, we report on a direct trifluoromethylation protocol using close to stoichiometric amounts of CF(3)H in common organic solvents such as tetrahydrofuran (THF), diethyl ether, and toluene. The methodology is widely applicable to a variety of silicon, boron, and sulfur-based electrophiles, as well as carbon-based electrophiles. PMID:23224551

  2. Conversion of the rocket propellant UDMH to a reagent useful in vicarious nucleophilic substitution reactions

    SciTech Connect

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

    1995-11-10

    The objective of our program is to develop novel, innovative solutions for the disposal of surplus energetic materials resulting from the demilitarization of conventional and nuclear munitions. In this report we describe the use of surplus propellant (UDMH) and explosives (TNT, Explosive D) as chemical precursors for higher value products. The conversion of UDMH to 1,1,1-trimethylhydrazinium iodide (TMHI) provides a new aminating reagent for use in Vicarious Nucleophilic Substitution (VNS) reactions. When TMHI is reacted with various nitroarenes the amino functionality is introduced in good to excellent yields. Thus, 2,4,6-trinitroaniline (picramide) reacts with TMHI to give 1,3,5-triamino-2,4,6-trinitroaniline (TATB) while 2,4,6-trinitrotoluene (TNT) reacts with TMHI to give 3,5-diamino-2,4,6-trinitrotoluene (DATNT). The advantages, scope and limitations of the VNS approach and the use of TMHI are discussed.

  3. Nucleophilic addition-triggered lanthanide luminescence allows detection of amines by Eu(thenoyltrifluoroacetone)3.

    PubMed

    Zhou, Zhan; Wang, Qianming; Lin, Jintai; Chen, Yanna; Yang, Chuqin

    2012-01-01

    Herein, a novel fluorescent indicator for the real-time monitoring of amines is described. This probe contains a complex of europium-(thenoyltrifluoroacetone)(3) (Eu(TTA)(3)) that efficiently reacts with primary and secondary amines. The electron-withdrawing trifluoroacetyl undergoes a nucleophilic addition with amines, and the complex was used to selectively detect BuNH(2) and Et(2) NH (quenching concentration for BuNH(2): 10(-4) M, for Et(2)NH: 1.2 × 10(-3) M) by monitoring emission; no changes were observed in the emission spectrum of Eu(TTA)(3) in the presence of Et(3)N, [Bu(4)N]Cl, or PhNH(2) in aqueous solution (THF/H(2)O = 1:1). The ratio of emission intensity to amine concentration was linear by the least-squares fitting method. PMID:22458513

  4. Ground State Destabilization by Anionic Nucleophiles Contributes to the Activity of Phosphoryl Transfer Enzymes

    PubMed Central

    Andrews, Logan D.; Fenn, Tim D.; Herschlag, Daniel

    2013-01-01

    Enzymes stabilize transition states of reactions while limiting binding to ground states, as is generally required for any catalyst. Alkaline Phosphatase (AP) and other nonspecific phosphatases are some of Nature's most impressive catalysts, achieving preferential transition state over ground state stabilization of more than 1022-fold while utilizing interactions with only the five atoms attached to the transferred phosphorus. We tested a model that AP achieves a portion of this preference by destabilizing ground state binding via charge repulsion between the anionic active site nucleophile, Ser102, and the negatively charged phosphate monoester substrate. Removal of the Ser102 alkoxide by mutation to glycine or alanine increases the observed Pi affinity by orders of magnitude at pH 8.0. To allow precise and quantitative comparisons, the ionic form of bound Pi was determined from pH dependencies of the binding of Pi and tungstate, a Pi analog lacking titratable protons over the pH range of 5–11, and from the 31P chemical shift of bound Pi. The results show that the Pi trianion binds with an exceptionally strong femtomolar affinity in the absence of Ser102, show that its binding is destabilized by ≥108-fold by the Ser102 alkoxide, and provide direct evidence for ground state destabilization. Comparisons of X-ray crystal structures of AP with and without Ser102 reveal the same active site and Pi binding geometry upon removal of Ser102, suggesting that the destabilization does not result from a major structural rearrangement upon mutation of Ser102. Analogous Pi binding measurements with a protein tyrosine phosphatase suggest the generality of this ground state destabilization mechanism. Our results have uncovered an important contribution of anionic nucleophiles to phosphoryl transfer catalysis via ground state electrostatic destabilization and an enormous capacity of the AP active site for specific and strong recognition of the phosphoryl group in the transition

  5. Why does threonine, and not serine, function as the active site nucleophile in proteasomes?

    PubMed

    Kisselev, A F; Songyang, Z; Goldberg, A L

    2000-05-19

    Proteasomes belong to the N-terminal nucleophile group of amidases and function through a novel proteolytic mechanism, in which the hydroxyl group of the N-terminal threonines is the catalytic nucleophile. However, it is unclear why threonine has been conserved in all proteasomal active sites, because its replacement by a serine in proteasomes from the archaeon Thermoplasma acidophilum (T1S mutant) does not alter the rates of hydrolysis of Suc-LLVY-amc (Seemüller, E., Lupas, A., Stock, D., Lowe, J., Huber, R., and Baumeister, W. (1995) Science 268, 579-582) and other standard peptide amide substrates. However, we found that true peptide bonds in decapeptide libraries were cleaved by the T1S mutant 10-fold slower than by wild type (wt) proteasomes. In degrading proteins, the T1S proteasome was 3.5- to 6-fold slower than the wt, and this difference increased when proteolysis was stimulated using the proteasome-activating nucleotidase (PAN) ATPase complex. With mutant proteasomes, peptide bond cleavage appeared to be rate-limiting in protein breakdown, unlike with wt. Surprisingly, a peptide ester was hydrolyzed by both particles much faster than the corresponding amide, and the T1S mutant cleaved it faster than the wt. Moreover, the T1S mutant was inactivated by the ester inhibitor clasto-lactacystin-beta-lactone severalfold faster than the wt, but reacted with nonester irreversible inhibitors at similar rates. T1A and T1C mutants were completely inactive in all these assays. Thus, proteasomes lack additional active sites, and the N-terminal threonine evolved because it allows more efficient protein breakdown than serine. PMID:10809725

  6. The kinetics and mechanisms of aromatic nucleophilic substitution reactions in liquid ammonia.

    PubMed

    Ji, Pengju; Atherton, John H; Page, Michael I

    2011-05-01

    The rates of aromatic nucleophilic substitution reactions in liquid ammonia are much faster than those in protic solvents indicating that liquid ammonia behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions. Nitrofluorobenzenes (NFBs) readily undergo solvolysis in liquid ammonia and 2-nitrofluorobenzene is about 30 times more reactive than the 4-substituted isomer. Oxygen nucleophiles, such as alkoxide and phenoxide ions, readily displace fluorine of 4-NFB in liquid ammonia to give the corresponding substitution product with little or no competing solvolysis product. Using the pK(a) of the substituted phenols in liquid ammonia, the Brønsted β(nuc) for the reaction of 4-NFB with para-substituted phenoxides is 0.91, indicative of the removal of most of the negative charge on the oxygen anion and complete bond formation in the transition state and therefore suggests that the decomposition of the Meisenheimer σ-intermediate is rate limiting. The aminolysis of 4-NFB occurs without general base catalysis by the amine and the second-order rate constants generate a Brønsted β(nuc) of 0.36 using either the pK(a) of aminium ion in acetonitrile or in water, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer σ-intermediate. Nitrobenzene and diazene are formed as unusual products from the reaction between sodium azide and 4-NFB, which may be due to the initially formed 4-nitroazidobenzene decomposing to give a nitrene intermediate, which may then give diazene or be trapped by ammonia to give the unstable hydrazine which then yields nitrobenzene. PMID:21417418

  7. Reaction of Hydrogen Sulfide with Disulfide and Sulfenic Acid to Form the Strongly Nucleophilic Persulfide.

    PubMed

    Cuevasanta, Ernesto; Lange, Mike; Bonanata, Jenner; Coitiño, E Laura; Ferrer-Sueta, Gerardo; Filipovic, Milos R; Alvarez, Beatriz

    2015-11-01

    Hydrogen sulfide (H2S) is increasingly recognized to modulate physiological processes in mammals through mechanisms that are currently under scrutiny. H2S is not able to react with reduced thiols (RSH). However, H2S, more precisely HS(-), is able to react with oxidized thiol derivatives. We performed a systematic study of the reactivity of HS(-) toward symmetric low molecular weight disulfides (RSSR) and mixed albumin (HSA) disulfides. Correlations with thiol acidity and computational modeling showed that the reaction occurs through a concerted mechanism. Comparison with analogous reactions of thiolates indicated that the intrinsic reactivity of HS(-) is 1 order of magnitude lower than that of thiolates. In addition, H2S is able to react with sulfenic acids (RSOH). The rate constant of the reaction of H2S with the sulfenic acid formed in HSA was determined. Both reactions of H2S with disulfides and sulfenic acids yield persulfides (RSSH), recently identified post-translational modifications. The formation of this derivative in HSA was determined, and the rate constants of its reactions with a reporter disulfide and with peroxynitrite revealed that persulfides are better nucleophiles than thiols, which is consistent with the α effect. Experiments with cells in culture showed that treatment with hydrogen peroxide enhanced the formation of persulfides. Biological implications are discussed. Our results give light on the mechanisms of persulfide formation and provide quantitative evidence for the high nucleophilicity of these novel derivatives, setting the stage for understanding the contribution of the reactions of H2S with oxidized thiol derivatives to H2S effector processes. PMID:26269587

  8. Use of phosphoimidazolide-activated guanosine to investigate the nucleophilicity of spermine and spermidine

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Baird, E. E.; Smith, P. J.

    1995-01-01

    Guanosine 5'-phosphate 2-methylimidazolide (2-MeImpG), a labile phosphoimidazolide analog of guanosine triphosphate, was used to test the reactivity of the natural polyamines (PAs), spermine (spm) and spermidine (spd). The products are the guanosine 5'-phosphate-polyamine derivatives (PA-pG: spd-pG and spm-pG) which are quite stable in the range 4 < pH < 11. Our study is the first of which we are aware that reports on the nucleophilicity of these amines. The main findings are as follows. (i) HPLC analysis of the products indicates the formation of only two of the three possible spd products and only one of the two possible spm products. These results can be explained if only the primary amino groups of the two polyamines are reactive, while the secondary amino groups are rendered unreactive by a steric effect. The reactions of 2-MeImpG and other phosphoimidazolide derivatives of nucleosides (ImpNs) with primary and secondary monoamines support this interpretation (Kanavarioti et al. J. Org. Chem. 1995, 60, 632). (ii) The product ratio of the two spd-pG adducts derived from the primary amino groups varies between 2.40 and 0.71 in the range 6.1 < or equal to pH < or equal to 11.9. Such small variation in the product ratio can only be rationalized by the similar, but not identical, basicity of the two primary amino groups and provides strong support for a previously reported model for polyamine ionization (Onasch et. al. Biophys. Chem. 1984, 19, 245). (iii) On the basis of our kinetic determinations conditions at which the nucleophilicity of these amines is at a minimum and at which other interactions with ImpNs could be tested can be chosen.

  9. Mechanism of phenol oxidation by heterodinuclear Ni Cu bis(μ-oxo) complexes involving nucleophilic oxo groups

    PubMed Central

    Kundu, Subrata; Miceli, Enrico; Farquhar, Erik R.

    2014-01-01

    Oxidation of phenols by heterodinuclear CuIII(μ-O)2NiIII complexes containing nucleophilic oxo groups occurs by both proton coupled electron transfer (PCET) and hydrogen atom transfer (HAT) mechanisms; the exact mechanism depends on the nature of the phenol as well as the substitution pattern of the ligand bound to Cu. PMID:24362244

  10. 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.

  11. REACTIVITIES OF ACRYLIC AND METHACRYLIC ACIDS IN A NUCLEOPHILIC ADDITION MODEL OF THEIR BIOLOGICAL ACTIVITY (JOURNAL VERSION)

    EPA Science Inventory

    The reactivities of derivatives of acrylic and methacrylic acid (AA and MAA) in Michael reactions of nucleophilic addition that have been proposed as the underlying mechanisms for the toxicity of such compounds are evaluated from a study of the mechanism of addition of a nucleoph...

  12. Citrus Peel Additives for One-Pot Triazole Formation by Decarboxylation, Nucleophilic Substitution, and Azide-Alkyne Cycloaddition Reactions

    ERIC Educational Resources Information Center

    Mendes, Desiree E.; Schoffstall, Allen M.

    2011-01-01

    This undergraduate organic laboratory experiment consists of three different reactions occurring in the same flask: a cycloaddition reaction, preceded by decarboxylation and nucleophilic substitution reactions. The decarboxylation and cycloaddition reactions occur using identical Cu(I) catalyst and conditions. Orange, lemon, and other citrus fruit…

  13. 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

  14. 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

  15. 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

  16. A Study on the Base–Catalyzed Reverse Vinylogous Aldol Reaction of (4aβ,5β)-4,4a,5,6,7,8-Hexahydro-5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one under Robinson Annulation Conditions

    PubMed Central

    Payette, Joshua N.; Honda, Tadashi; Yoshizawa, Hidenori; Favaloro, Frank G.; Gribble, Gordon W.

    2008-01-01

    We have proposed a pathway of the base–catalyzed reverse vinylogous aldol reaction of (−)-(4aβ,5β)-4,4a,5,6,7,8-hexahydro-5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one ((−)-8) under Robinson annulation conditions. For confirmation, 4-(2,6-dimethyl-3-oxocyclohex-1-enyl)butanal (11) and 4-(2,6-dimethyl-5-oxocyclohex-1-enyl)butanal (12), both of which potentially produce enolate I, were synthesized regioselectively. Unexpectedly, 11 gave a complex mixture including only a trace amount of (±)-8 (less than 5% yield) under these basic conditions. To the contrary, 12 cleanly afforded (±)-8 in 66% yield. This result provides evidence for our proposed mechanism of the above reaction. PMID:16388674

  17. 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

  18. Liquid ammonia as a dipolar aprotic solvent for aliphatic nucleophilic substitution reactions.

    PubMed

    Ji, Pengju; Atherton, John; Page, Michael I

    2011-03-01

    The rate constants for the reactions of a variety of nucleophiles reacting with substituted benzyl chlorides in liquid ammonia (LNH(3)) have been determined. To fully interpret the associated linear free-energy relationships, the ionization constants of phenols ions in liquid ammonia were obtained using UV spectra. These equilibrium constants are the product of those for ion-pair formation and dissociation to the free ions, which can be separated by evaluating the effect of added ammonium ions. There is a linear relationship between the pK(a) of phenols in liquid ammonia and those in water of slope 1.68. Aminium ions exist in their unprotonated free base form in liquid ammonia and their ionization constants could not be determined by NMR. The rates of solvolysis of substituted benzyl chlorides in liquid ammonia at 25 °C show a Hammett ρ of zero, having little or no dependence upon ring substituents, which is in stark contrast with the hydrolysis rates of substituted benzyl halides in water, which vary 10(7) fold. The rate of substitution of benzyl chloride by substituted phenoxide ions is first order in the concentration of the nucleophile indicative of a S(N)2 process, and the dependence of the rate constants on the pK(a) of the phenol in liquid ammonia generates a Brønsted β(nuc) = 0.40. Contrary to the solvolysis reaction, the reaction of phenoxide ion with 4-substituted benzyl chlorides gives a Hammett ρ = 1.1, excluding the 4-methoxy derivative, which shows the normal positive deviation. The second order rate constants for the substitution of benzyl chlorides by neutral and anionic amines show a single Brønsted β(nuc) = 0.21 (based on the aqueous pK(a) of amine), but their dependence on the substituent in substituted benzyl chlorides varies with a Hammett ρ of 0 for neutral amines, similar to that seen for solvolysis, whereas that for amine anions is 0.93, similar to that seen for phenoxide ion. PMID:21348532

  19. Ground state destabilization by anionic nucleophiles contributes to the activity of phosphoryl transfer enzymes.

    PubMed

    Andrews, Logan D; Fenn, Tim D; Herschlag, Daniel

    2013-07-01

    Enzymes stabilize transition states of reactions while limiting binding to ground states, as is generally required for any catalyst. Alkaline Phosphatase (AP) and other nonspecific phosphatases are some of Nature's most impressive catalysts, achieving preferential transition state over ground state stabilization of more than 10²²-fold while utilizing interactions with only the five atoms attached to the transferred phosphorus. We tested a model that AP achieves a portion of this preference by destabilizing ground state binding via charge repulsion between the anionic active site nucleophile, Ser102, and the negatively charged phosphate monoester substrate. Removal of the Ser102 alkoxide by mutation to glycine or alanine increases the observed Pi affinity by orders of magnitude at pH 8.0. To allow precise and quantitative comparisons, the ionic form of bound P(i) was determined from pH dependencies of the binding of Pi and tungstate, a P(i) analog lacking titratable protons over the pH range of 5-11, and from the ³¹P chemical shift of bound P(i). The results show that the Pi trianion binds with an exceptionally strong femtomolar affinity in the absence of Ser102, show that its binding is destabilized by ≥10⁸-fold by the Ser102 alkoxide, and provide direct evidence for ground state destabilization. Comparisons of X-ray crystal structures of AP with and without Ser102 reveal the same active site and P(i) binding geometry upon removal of Ser102, suggesting that the destabilization does not result from a major structural rearrangement upon mutation of Ser102. Analogous Pi binding measurements with a protein tyrosine phosphatase suggest the generality of this ground state destabilization mechanism. Our results have uncovered an important contribution of anionic nucleophiles to phosphoryl transfer catalysis via ground state electrostatic destabilization and an enormous capacity of the AP active site for specific and strong recognition of the phosphoryl group in

  20. An immunochemical approach to detect oxidized protein tyrosine phosphatases using a selective C-nucleophile tag.

    PubMed

    Garcia, Francisco J; Carroll, Kate S

    2016-05-24

    Protein tyrosine phosphatases are crucial regulators of signal transduction and function as antagonists towards protein tyrosine kinases to control reversible tyrosine phosphorylation, thereby regulating fundamental physiological processes. Growing evidence has supported the notion that reversible oxidative inactivation of the catalytic cysteine residue in protein tyrosine phosphatases serves as an oxidative post-translational modification that regulates its activity to influence downstream signaling by promoting phosphorylation and induction of the signaling cascade. The oxidation of cysteine to the sulfenic acid is often transient and difficult to detect, thus making it problematic in understanding the role that this oxidative post-translational modification plays in redox-biology and pathogenesis. Several methods to detect cysteine oxidation in biological systems have been developed, though targeted approaches to directly detect oxidized phosphatases are still lacking. Herein we describe the development of a novel immunochemical approach to directly profile oxidized phosphatases. This immunochemical approach consists of an antibody designed to recognize the conserved sequence of the PTP active site (VHCDMDSAG) harboring the catalytic cysteine modified with dimedone (CDMD), a nucleophile that chemoselectively reacts with cysteine sulfenic acids to form a stable thioether adduct. Additionally, we provide biochemical and mass spectrometry workflows to be used in conjugation with this newly developed immunochemical approach to assist in the identification and quantification of basal and oxidized phosphatases. PMID:26757830

  1. Substituents on Quinone Methides Strongly Modulate Formation and Stability of Their Nucleophilic Adducts

    PubMed Central

    Weinert, Emily E.; Dondi, Ruggero; Colloredo-Melz, Stefano; Frankenfield, Kristen N.; Mitchell, Charles H.; Freccero, Mauro; Rokita, Steven E.

    2008-01-01

    Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 hr. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span five orders of magnitude with electron rich species reacting most slowly and electron deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application. PMID:16953635

  2. 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

  3. Fluorescent "turn-on" detecting CN- by nucleophilic addition induced Schiff-base hydrolysis

    NASA Astrophysics Data System (ADS)

    Lin, Qi; Cai, Yi; Li, Qiao; Shi, Bing-Bing; Yao, Hong; Zhang, You-Ming; Wei, Tai-Bao

    2015-04-01

    A new chemosensor Sz based on Schiff-base group as recognition site and naphthalene as the fluorescence signal group was designed and synthesised. It could fluorescent "turn-on" detect cyanide (CN-) via a novel mechanism of nucleophilic addition induced Schiff-base hydrolysis. Adding the CN- into the solution of Sz could induce Sz to emit blue fluorescence at 435 nm instantly. Moreover, Sz could also colorimetric detect CN-. Upon the addition of CN-, the Sz showed dramatic color change from yellow to colorless. These sensing procedures could not be interfered by other coexistent competitive anions such as F-, AcO-, H2PO4- and SCN-. In addition, Sz showed high sensitivity for CN-, the detection limits is 3.42 × 10-8 M of CN-, which is far lower than the WHO guideline of CN- in drinking water (less than 1.9 × 10-6 M). The CN- test strips based on Sz could act as a convenient CN- test kits.

  4. 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

  5. Routes to covalent catalysis by reactive selection for nascent protein nucleophiles.

    PubMed

    Reshetnyak, Andrey V; Armentano, Maria Francesca; Ponomarenko, Natalia A; Vizzuso, Domenica; Durova, Oxana M; Ziganshin, Rustam; Serebryakova, Marina; Govorun, Vadim; Gololobov, Gennady; Morse, Herbert C; Friboulet, Alain; Makker, Sudesh P; Gabibov, Alexander G; Tramontano, Alfonso

    2007-12-26

    Reactivity-based selection strategies have been used to enrich combinatorial libraries for encoded biocatalysts having revised substrate specificity or altered catalytic activity. This approach can also assist in artificial evolution of enzyme catalysis from protein templates without bias for predefined catalytic sites. The prevalence of covalent intermediates in enzymatic mechanisms suggests the universal utility of the covalent complex as the basis for selection. Covalent selection by phosphonate ester exchange was applied to a phage display library of antibody variable fragments (scFv) to sample the scope and mechanism of chemical reactivity in a naive molecular library. Selected scFv segregated into structurally related covalent and noncovalent binders. Clones that reacted covalently utilized tyrosine residues exclusively as the nucleophile. Two motifs were identified by structural analysis, recruiting distinct Tyr residues of the light chain. Most clones employed Tyr32 in CDR-L1, whereas a unique clone (A.17) reacted at Tyr36 in FR-L2. Enhanced phosphonylation kinetics and modest amidase activity of A.17 suggested a primitive catalytic site. Covalent selection may thus provide access to protein molecules that approximate an early apparatus for covalent catalysis. PMID:18044899

  6. Gramicidin S: a peptide model for protein glycation and reversal of glycation using nucleophilic amines.

    PubMed

    Shakkottai, V G; Sudha, R; Balaram, P

    2002-08-01

    Nonenzymatic glycation of proteins has been implicated in various diabetic complications and age-related disorders. Proteins undergo glycation at the N-terminus or at the epsilon-amino group of lysine residues. Glycation of proteins proceeds through the stages of Schiff base formation, conversion to ketoamine product and advanced glycation end products. Gramicidin S, which has two ornithine residues, was used as a model system to study the various stages of glycation of proteins using electrospray ionization mass spectrometry. The proximity of two ornithine residues in the peptide favors the glycation reaction. Formation of advanced glycation end products and diglycation on ornithine residues in gramicidin S were observed. The formation of Schiff base adduct is reversible, whereas the Amadori rearrangement to the ketoamine product is irreversible. Nucleophilic amines and hydrazines can deglycate the Schiff base adduct of glucose with peptides and proteins. Hydroxylamine, isonicotinic acid hydrazide and aminoguanidine effectively removed glucose from the Schiff base adduct of gramicidin S. Hydroxylamine is more effective in deglycating the adduct compared with isonicotinic acid hydrazide and aminoguanidine. The observation that the hydrazines are effective in deglycating the Schiff base adduct even in the presence of high concentrations of glucose, may have a possible therapeutic application in preventing complications of diabetes mellitus. Hydrazines may be used to distinguish between the Schiff base and the ketoamine products formed at the initial stages of glycation. PMID:12102724

  7. Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

    PubMed Central

    2015-01-01

    We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals. PMID:24918484

  8. sp(2)-sp(3) diboranes: astounding structural variability and mild sources of nucleophilic boron for organic synthesis.

    PubMed

    Dewhurst, Rian D; Neeve, Emily C; Braunschweig, Holger; Marder, Todd B

    2015-06-14

    Despite the widespread use of organoborane reagents in organic synthesis and catalysis, a major challenge still remains: very few boron-centered nucleophiles exist for the direct construction of B-C bonds. Perhaps the most promising emerging solution to this problem is the use of sp(2)-sp(3) diboranes, in which one boron atom of a conventional diborane(4) is quaternised by either a neutral or anionic nucleophile. These compounds, either isolated or generated in situ, serve as relatively mild and convenient sources of the boryl anion [BR2](-) for use in organic synthesis and have already proven their efficacy in metal-free as well as metal-catalysed borylation reactions. This Feature article documents the history of sp(2)-sp(3) diborane synthesis, their properties and surprising structural variability, and their burgeoning utility in organic synthesis. PMID:25912808

  9. Nucleophile-dependent regio- and stereoselective ring opening of 1-azoniabicyclo[3.1.0]hexane tosylate.

    PubMed

    Ji, Mi-Kyung; Hertsen, Dietmar; Yoon, Doo-Ha; Eum, Heesung; Goossens, Hannelore; Waroquier, Michel; Van Speybroeck, Veronique; D'hooghe, Matthias; De Kimpe, Norbert; Ha, Hyun-Joon

    2014-04-01

    1-[(1R)-(1-Phenylethyl)]-1-azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2-(3-hydroxypropyl)aziridine upon reaction with p-toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH3CN to afford either piperidines or pyrrolidines through regio- and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring-opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways. PMID:24488926

  10. Effect of Conformational Rigidity on the Stereoselectivity of Nucleophilic Additions to Five-membered Ring Bicyclic Oxocarbenium Ion Intermediates

    PubMed Central

    Lavinda, O.; Tran, Vi Tuong

    2014-01-01

    Nucleophilic substitution reactions of five-membered ring acetals bearing fused rings reveal that subtle changes in the structure of the fused ring can exert dramatic influences on selectivity. If the fused ring did not constrain the five-membered ring undergoing substitution, selectivity was comparable to what was observed for an unconstrained system (≥92% diastereoselectivity, favoring the product of inside attack on the oxocarbenium ion). If the ring were more constrained by including at least one oxygen atom in the ring, selectivity dropped considerably (to 60% diastereoselectivity in one case). Transition states of the nucleophilic addition of allyltrimethylsilane to selected oxocarbenium ions were calculated using DFT methods. These computational models reproduced the correlation between additional conformational rigidity and selectivity. PMID:25087588

  11. Catalysis of hydrolysis and nucleophilic substitution at the P-N bond of phosphoimidazolide-activated nucleotides in phosphate buffers

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Rosenbach, M. T.

    1991-01-01

    Phosphoimidazolide-activated derivatives of guanosine and cytidine 5'-monophosphates, henceforth called ImpN's, exhibit enhanced rates of degradation in the presence of aqueous inorganic phosphate in the range 4.0 < or = pH < or = 8.6. This degradation is been attributed to (i) nucleophilic substitution of the imidazolide and (ii) catalysis of the P-N bond hydrolysis by phosphate. The first reaction results in the formation of nucleoside 5'-diphosphate and the second in nucleoside 5'-monophosphate. Analysis of the observed rates as well as the product ratios as a function of pH and phosphate concentration allow distinction between various mechanistic possibilities. The results show that both H2PO4- and HPO4(2-) participate in both hydrolysis and nucleophilic substitution. Statistically corrected biomolecular rate constants indicate that the dianion is 4 times more effective as a general base than the monoanion, and 8 times more effective as nucleophile. The low Bronsted value beta = 0.15 calculated for these phosphate species, presumed to act as general bases in facilitating water attack, is consistent with the fact that catalysis of the hydrolysis of the P-N bond in ImpN's has not been detected before. The beta nuc = 0.35 calculated for water, H2PO4-, HPO4(2-), and hydroxide acting as nucleophiles indicates a more associative transition state for nucleotidyl (O2POR- with R = nucleoside) transfers than that observed for phosphoryl (PO3(2-)) transfers (beta nuc = 0.25). With respect to the stability/reactivity of ImpN's under prebiotic conditions, our study shows that these materials would not suffer additional degradation due to inorganic phosphate, assuming the concentrations of phosphate, Pi, on prebiotic Earth were similar to those in the present oceans ([Pi] approximately 2.25 micromoles).

  12. A Substrate-Assisted Mechanism of Nucleophile Activation in a Ser-His-Asp Containing C-C Bond Hydrolase

    SciTech Connect

    Ruzzini, Antonio C.; Bhowmik, Shiva; Ghosh, Subhangi; Yam, Katherine C.; Bolin, Jeffrey T.; Eltis, Lindsay D.

    2013-11-12

    The meta-cleavage product (MCP) hydrolases utilize a Ser–His–Asp triad to hydrolyze a carbon–carbon bond. Hydrolysis of the MCP substrate has been proposed to proceed via an enol-to-keto tautomerization followed by a nucleophilic mechanism of catalysis. Ketonization involves an intermediate, ESred, which possesses a remarkable bathochromically shifted absorption spectrum. We investigated the catalytic mechanism of the MCP hydrolases using DxnB2 from Sphingomonas wittichii RW1. Pre-steady-state kinetic and LC ESI/MS evaluation of the DxnB2-mediated hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid to 2-hydroxy-2,4-pentadienoic acid and benzoate support a nucleophilic mechanism catalysis. In DxnB2, the rate of ESred decay and product formation showed a solvent kinetic isotope effect of 2.5, indicating that a proton transfer reaction, assigned here to substrate ketonization, limits the rate of acylation. For a series of substituted MCPs, this rate was linearly dependent on MCP pKa2nuc ~ 1). Structural characterization of DxnB2 S105A:MCP complexes revealed that the catalytic histidine is displaced upon substrate-binding. The results provide evidence for enzyme-catalyzed ketonization in which the catalytic His–Asp pair does not play an essential role. The data further suggest that ESred represents a dianionic intermediate that acts as a general base to activate the serine nucleophile. This substrate-assisted mechanism of nucleophilic catalysis distinguishes MCP hydrolases from other serine hydrolases.

  13. Who Activates the Nucleophile in Ribozyme Catalysis? An Answer from the Splicing Mechanism of Group II Introns.

    PubMed

    Casalino, Lorenzo; Palermo, Giulia; Rothlisberger, Ursula; Magistrato, Alessandra

    2016-08-24

    Group II introns are Mg(2+)-dependent ribozymes that are considered to be the evolutionary ancestors of the eukaryotic spliceosome, thus representing an ideal model system to understand the mechanism of conversion of premature messenger RNA (mRNA) into mature mRNA. Neither in splicing nor for self-cleaving ribozymes has the role of the two Mg(2+) ions been established, and even the way the nucleophile is activated is still controversial. Here we employed hybrid quantum-classical QM(Car-Parrinello)/MM molecular dynamics simulations in combination with thermodynamic integration to characterize the molecular mechanism of the first and rate-determining step of the splicing process (i.e., the cleavage of the 5'-exon) catalyzed by group II intron ribozymes. Remarkably, our results show a new RNA-specific dissociative mechanism in which the bulk water accepts the nucleophile's proton during its attack on the scissile phosphate. The process occurs in a single step with no Mg(2+) ion activating the nucleophile, at odds with nucleases enzymes. We suggest that the novel reaction path elucidated here might be an evolutionary ancestor of the more efficient two-metal-ion mechanism found in enzymes. PMID:27309711

  14. Laboratory determination of the carbon kinetic isotope effects (KIEs) for reactions of methyl halides with various nucleophiles in solution

    USGS Publications Warehouse

    Baesman, S.M.; Miller, L.G.

    2005-01-01

    Large carbon kinetic isotope effects (KIEs) were measured for reactions of methyl bromide (MeBr), methyl chloride (MeCl), and methyl iodide (MeI) with various nucleophiles at 287 and 306 K in aqueous solutions. Rates of reaction of MeBr and MeI with H2O (neutral hydrolysis) or Cl- (halide substitution) were consistent with previous measurements. Hydrolysis rates increased with increasing temperature or pH (base hydrolysis). KIEs for hydrolysis were 51 ?? 6??? for MeBr and 38 ?? 8??? for MeI. Rates of halide substitution increased with increasing temperature and greater reactivity of the attacking nucleophile, with the fastest reaction being that of MeI with Br-. KIEs for halide substitution were independent of temperature but varied with the reactant methyl halide and the attacking nucleophile. KIEs were similar for MeBr substitution with Cl- and MeCl substitution with Br- (57 ?? 5 and 60 ?? 9??? respectively). The KIE for halide exchange of MeI was lower overall (33 ?? 8??? and was greater for substitution with Br- (46 ?? 6???) than with Cl- (29 ?? 6???). ?? Springer Science + Business Media, Inc. 2005.

  15. Mutual Cooperation in the Formal Allyl Alcohol Nucleophilic Substitution and Hydration of Alkynes for the Construction of γ-Substituted Ketones.

    PubMed

    Huang, Kaimeng; Wang, Hongkai; Liu, Lingyan; Chang, Weixing; Li, Jing

    2016-05-01

    Mutual cooperation in the formal allyl alcohol nucleophilic substitution reaction and hydration of an alkyne has been utilized in the presence of a gold catalyst to give a series of γ-functionalized ketones with high to excellent yields. This reaction actually involved an intramolecular O-H insertion cyclization of an alkyne to form the dihydrofuran intermediate, which was followed by the nucleophilic addition ring-opening of a dihydrofuran to give the target compound. PMID:26946315

  16. Selective copper(II)-mediated oxidative coupling of a nucleophilic reagent to the para-methyl group of 2,4,6-trimethylphenol.

    PubMed

    Boldron, Christophe; Ozalp-Yaman, Seniz; Gamez, Patrick; Tooke, Duncan M; Spek, Anthony L; Reedijk, Jan

    2005-11-01

    A copper(II) neocuproine system has been developed for the efficient and very selective 1,6-addition of a nucleophile to the para-methyl group of 2,4,6-trimethylphenol. Crystallographic and spectroscopic data point towards the involvement of a micro-methoxo-micro-phenoxo-bridged copper species which appears to generate a highly reactive quinone methide intermediate that can be attacked by a nucleophilic reagent. PMID:16234935

  17. Reactions of heteroatom and carbon nucleophiles with the cationic bridging methylidyne complex

    SciTech Connect

    Casey, C.P.; Crocker, M.; Vosejpka, P.C.; Fagan, P.J.; Marder, S.R.; Gohdes, M.A.

    1988-03-01

    The reaction of the ..mu..-methylidyne complex /((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CH)//sup +/PF/sub 6//sup -/ (1) with NMe/sub 3/ and (C/sub 6/H/sub 5/)/sub 2/C=NH gave the cationic 1:1 adducts /((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CHNMe/sub 3/)//sup +/PF/sub 6//sup -/ (3) and /((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CHNH=C(C/sub 6/H/sub 5/)/sub 2/)//sup +/PF/sub 6//sup -/ (9), respectively, arising from attack of nitrogen on the methylidyne carbon. The reaction of 1 with KOC(CH/sub 3/)/sub 3/ gave the neutral ..mu..-carbene complex ((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CHOC(CH/sub 3/)P/sub 3/) (4). Reaction of 1 with water afforded a 1:1 mixture of ..mu..methylene complex ((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CH/sub 2/) (2) and ((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)/sub 2/; these products are proposed to arise from disproportionation of an initially formed hydroxy carbene species. Reaction of 1 with Et/sub 4/N/sup +/Br/sup -/ gave the unstable /sup +/-carbene complex ((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CHBr) (6). Reaction of 1 with the carbon nucleophiles CH/sub 3/Li and Li(C/sub 6/H/sub 5/CuCN) gave the ..mu..-carbene complexes ((C/sub 5/H/sub 5/)(CO)Fe/sub 2/(..mu..-CO)(..mu..-CHCH/sub 3/) (11) and ((C/sub 5/H/sub 5/)(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CHC/sub 6/H/sub 5/ (12), while reaction of 1 with HFe(CO)/sub 4//sup -/ afforded 2. 1 reacted with acetone via nucleophilic addition of the enol affording the neutral ..mu..-carbene complex (C/sub 5/H/sub 5/)-(CO)Fe)/sub 2/(..mu..-CO)(..mu..-CHCH/sub 2/COCH/sub 3/)) (13). 1 also reacted with cyclohexanone, 2-butanone, 4-methyl-2-pentanone, 2,4-pentanedione, 5,5-dimethyl-1,3-cyclohexanedione, ethyl acetoacetate, and the sodium salt of diethyl malonate to give similar ..mu..-carbene products.

  18. Bifunctional reactivity of amidoximes observed upon nucleophilic addition to metal-activated nitriles.

    PubMed

    Bolotin, Dmitrii S; Demakova, Marina Ya; Novikov, Alexander S; Avdontceva, Margarita S; Kuznetsov, Maxim L; Bokach, Nadezhda A; Kukushkin, Vadim Yu

    2015-04-20

    Treatment of the aromatic nitrile complexes trans-[PtCl2(RC6H4CN)2] (R = p-CF3 NC1, H NC2, o-Cl NC3) with the aryl amidoximes p-R'C6H4C(NH2)=NOH (R' = Me AO1, H AO2, Br AO3, CF3 AO4, NO2 AO5) in all combinations, followed by addition of 1 equiv of AgOTf and then 5 equiv of Et3N, leads to the chelates [PtCl{HN=C(RC6H4)ON=C(C6H4R'-p)NC(RC6H4)═NH}] (1-15; 15 examples; yields 71-88% after column chromatography) derived from the platinum(II)-mediated coupling between metal-activated nitriles and amidoximes. The mechanism of this reaction was studied experimentally by trapping and identification of the reaction intermediates, and it was also investigated theoretically at the DFT level of theory. The combined experimental and theoretical results indicate that the coupling with the nitrile ligands involves both the HON and monodeprotonated NH2 groups of the amidoximes, whereas in the absence of the base, the NH2 functionality is inactive toward the coupling. The observed reaction represents the first example of bifunctional nucleophilic behavior of amidoximes. The complexes 1-16 were characterized by elemental analyses (C, H, N), high-resolution ESI(+)-MS, FTIR, and (1)H NMR techniques, whereas unstable 17 was characterized by HRESI(+)-MS and FTIR. In addition, 8·C4H8O2, 12, and 16·CHCl3 were studied by single-crystal X-ray diffraction. PMID:25822628

  19. Nucleophilic substitution in preparation and surface modification of hypercrosslinked stationary phases.

    PubMed

    Janků, Simona; Škeříková, Veronika; Urban, Jiří

    2015-04-01

    Four linear diaminoalkanes (1,2-diaminoethane, 1,4-diaminobutane, 1,6-diaminohexane, and 1,8-diaminooctane) have been used to hypercrosslink poly(styrene-co-vinylbenzyl chloride-co-divinylbenzene) monolithic stationary phases by nucleophilic substitution reaction. The column efficiency of polymer monoliths improved with longer diaminoalkane with 1,8-diaminoctane providing the highest efficiency. The concentration of 1,8-diaminoctane, together with hypercrosslinking time and temperature has been optimized. To improve the permeability of prepared columns, the hypercrosslinking modification has been combined with an early termination of polymerization reaction and decrease in polymerization temperature. The optimal column has been prepared by a polymerization reaction for 2h at 65°C and hypercrosslinked in the presence of 3% 1,8-diaminooctane for 2h at 95°C. The repeatability study of the presented protocol provided relative standard deviation for nine columns prepared independently out of three individual polymerization mixtures in between 2.0-12.0% for retention factors and 1.5-6.5% for plate heights, respectively. Further, we have modified residual chloromethyl groups with 2-aminoethanesulfonic acid (taurine) to prepare monolithic columns suitable for separation of small polar molecules in hydrophilic interaction chromatography. The highest retention of polar thiourea showed the column modified at 70°C for 20 h. Taurine-modified hypercrosslinked column showed the minimum of van Deemter curve of 20 μm. The prepared column provided dual-retention mechanism, including hydrophilic interaction and reversed-phase liquid chromatography that can be controlled by the composition of the mobile phase. The prepared column has been successfully used for an isocratic separation of low-molecular phenolic acids. PMID:25728663

  20. Nucleophilicity and P-C Bond Formation Reactions of a Terminal Phosphanido Iridium Complex.

    PubMed

    Serrano, Ángel L; Casado, Miguel A; Ciriano, Miguel A; de Bruin, Bas; López, José A; Tejel, Cristina

    2016-01-19

    The diiridium complex [{Ir(ABPN2)(CO)}2(μ-CO)] (1; [ABPN2](-) = [(allyl)B(Pz)2(CH2PPh2)](-)) reacts with diphenylphosphane affording [Ir(ABPN2)(CO)(H) (PPh2)] (2), the product of the oxidative addition of the P-H bond to the metal. DFT studies revealed a large contribution of the terminal phosphanido lone pair to the HOMO of 2, indicating nucleophilic character of this ligand, which is evidenced by reactions of 2 with typical electrophiles such as H(+), Me(+), and O2. Products from the reaction of 2 with methyl chloroacetate were found to be either [Ir(ABPN2)(CO)(H)(PPh2CH2CO2Me)][PF6] ([6]PF6) or [Ir(ABPN2)(CO)(Cl)(H)] (7) and the free phosphane (PPh2CH2CO2Me), both involving P-C bond formation, depending on the reaction conditions. New complexes having iridacyclophosphapentenone and iridacyclophosphapentanone moieties result from reactions of 2 with dimethyl acetylenedicarboxylate and dimethyl maleate, respectively, as a consequence of a further incorporation of the carbonyl ligand. In this line, the terminal alkyne methyl propiolate gave a mixture of a similar iridacyclophosphapentanone complex and [Ir(ABPN2){CH═C(CO2Me)-CO}{PPh2-CH═CH(CO2Me)}] (10), which bears the functionalized phosphane PPh2-CH═CH(CO2Me) and an iridacyclobutenone fragment. Related model reactions aimed to confirm mechanistic proposals are also studied. PMID:26695592

  1. Semifluorinated polymers via cycloaddition and nucleophilic addition reactions of aromatic trifluorovinyl ethers

    NASA Astrophysics Data System (ADS)

    Iacono, Scott Thomas

    This dissertation encompasses the synthesis, characterization, and properties of semifluorinated polymers derived from thermal polymerization of aryl trifluorovinyl ether (TFVE) monomers. This work is divided into two parts based on the methodology of thermal polymerization using aryl TFVE monomers. The first part of this work involves the thermal [2 + 2] cyclodimerization of aryl TFVE monomers affording perfluorocyclobutyl (PFCB) aryl ether polymers. Chapter 1 provides an overview of PFCB aryl ether polymers as a next-generation class of high performance fluoropolymers that have been successfully employed for a myriad of technologies. PFCB aryl ether polymers are highly desired because of their high thermal stability, processability, and tailorability for specific material applications. Chapter 2 introduces a general perspective of polyhedral oligomeric silsesquioxanes (POSS) that were modified with PFCB aryl ether polymer for property enhancement, specifically for low surface energy materials. Chapter 3 and 4 show the synthesis, characterization, and properties of POSS modified PFCB aryl ether polymers as blends and a variety of copolymer architectures, respectively. The second portion of this dissertation focuses on the development of a new, facile step-growth polymerization of diols/bisphenols and aryl TFVEs to afford fluoroethylene/vinylene alkyl/aryl ether (FAE) polymers. Chapter 5 is a prelude to the development of FAE polymers which entails optimizing the methodology and mechanistic rationale of nucleophile addition to aryl TFVEs. Chapter 6 details the FAE polymerization kinetics, physical properties, and strategy for functionalization. Chapter 7 illustrates the modular modification of FAE polymers for the development of tunable light emissive materials for potential use as transport layer material for organic light emitting diodes (OLEDs) and also chemical sensors. Chapter 8 introduces postfunctionaliztion of FAE polymers resulting with sulfonated biaryl

  2. Copper(I)-catalyzed enantioselective nucleophilic borylation of aldehydes: an efficient route to enantiomerically enriched α-alkoxyorganoboronate esters.

    PubMed

    Kubota, Koji; Yamamoto, Eiji; Ito, Hajime

    2015-01-14

    The first catalytic enantioselective nucleophilic borylation of a C═O double bond has been achieved. A series of aldehydes reacted with a diboron reagent in the presence of a copper(I)/DTBM-SEGPHOS complex catalyst using MeOH as a proton source to give the corresponding optically active α-alkoxyorganoboronate esters with excellent enantioselectivities. Furthermore, the products could be readily converted to the corresponding functionalized chiral alcohol derivatives through stereospecific C-C bond forming reactions involving the stereogenic C-B bond. PMID:25494834

  3. Porous coordination polymers of diverse topologies based on a twisted tetrapyridylbiaryl: application as nucleophilic catalysts for acetylation of phenols.

    PubMed

    Seth, Saona; Venugopalan, Paloth; Moorthy, Jarugu Narasimha

    2015-01-26

    Porous coordination polymers (CPs) with partially uncoordinated pyridyl rings based on rationally designed polypyridyl linkers are appealing from the point of view of their application as nucleophilic catalysts. A D2d -symmetric tetradentate organic linker L, that is, 2,2',6,6'-tetramethoxy-3,3',5,5'-tetrakis(4-pyridyl)biphenyl, was designed and synthesized for metal-assisted self-assembly aimed at porous CPs. Depending on the nature of the metal ion and the counter anion, the ligand L is found to function as a 3- or 4-connecting building block leading to porous CPs of diverse topologies. The reaction of L with Zn(NO3 )2 and Cd(NO3 )2 yields porous 2 D CPs of "fes" topology, in which the tetrapyridyl linker L serves as a 3-connecting unit with its free pyridyl rings well exposed into the pores. The functional utility of these porous CPs containing uncoordinated pyridyl rings is demonstrated by employing them as efficient heterogeneous nucleophilic catalysts for acetylation of a number of phenols with varying electronic properties and reactivities. PMID:25430673

  4. Electrochemical nucleophilic synthesis of di-tert-butyl-(4-[18F]fluoro-1,2-phenylene)-dicarbonate

    PubMed Central

    He, Qinggang; Wang, Ying; Alfeazi, Ines; Sadeghi, Saman

    2015-01-01

    An electrochemical method with the ability to conduct 18F-fluorination of aromatic molecules through direct nucleophilic fluorination of cationic intermediates is presented in this paper. The reaction was performed on a remote-controlled automatic platform. Nucleophilic electrochemical fluorination of tert-butyloxycarbonyl (Boc) protected catechol, an intermediate model molecule for the positron emission tomography (PET) probe (3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine), was performed. Fluorination was achieved under potentiostatic anodic oxidation in acetonitrile containing Et3N · 3HF and other supporting electrolytes. Radiofluorination efficiency was influenced by a number of variables, including the concentration of the precursor, concentration of Et3N · 3HF, type of supporting electrolyte, temperature and time, as well as applied potentials. Radiofluorination efficiency of 10.4 ± 0.6% (n = 4) and specific activity of up to 43 GBq/mmol was obtained after 1 h electrolysis of 0.1 M of 4-tert-butyl-diboc-catechol in the acetonitrile solution of Et3N · 3HF (0.033 M) and NBu4PF6 (0.05 M). Density functional theory (DFT) was employed to explain the tert-butyl functional group facilitation of electrochemical oxidation and subsequent fluorination. PMID:25000498

  5. Synthesis of high specific activity (+)- and (-)-6-( sup 18 F)fluoronorepinephrine via the nucleophilic aromatic substitution reaction

    SciTech Connect

    Ding, Y.S.; Fowler, J.S.; Gatley, S.J.; Dewey, S.L.; Wolf, A.P. )

    1991-02-01

    The first example of a no-carrier-added {sup 18}F-labeled catecholamine, 6-({sup 18}F)fluoronorepinephrine (6-({sup 18}F)FNE), has been synthesized via nucleophilic aromatic substitution. The racemic mixture was resolved on a chiral HPLC column to obtain pure samples of (-)-6-({sup 18}F)FNE and (+)6-({sup 18}F)FNE. Radiochemical yields of 20% at the end of bombardment (EOB) for the racemic mixture (synthesis time 93 min), 6% for each enantiomer (synthesis time 128 min) with a specific activity of 2-5 Ci/mumol at EOB were obtained. Chiral HPLC peak assignment for the resolved enantiomers was achieved by using two independent methods: polarimetric determination and reaction with dopamine beta-hydroxylase. Positron emission tomography (PET) studies with racemic 6-({sup 18}F)FNE show high uptake and retention in the baboon heart. This work demonstrates that nucleophilic aromatic substitution by ({sup 18}F)fluoride ion is applicable to systems having electron-rich aromatic rings, leading to high specific activity radiopharmaceuticals. Furthermore, the suitably protected dihydroxynitrobenzaldehyde 1 may serve as a useful synthetic precursor for the radiosynthesis of other complex {sup 18}F-labeled radiotracers.

  6. A colorimetric detection of acrylamide in potato chips based on nucleophile-initiated thiol-ene Michael addition.

    PubMed

    Hu, Qinqin; Fu, Yingchun; Xu, Xiahong; Qiao, Zhaohui; Wang, Ronghui; Zhang, Ying; Li, Yanbin

    2016-02-01

    Acrylamide (AA), a neurotoxin and a potential carcinogen, has been found in various thermally processed foods such as potato chips, biscuits, and coffee. Simple, cost-effective, and sensitive methods for the rapid detection of AA are needed to ensure food safety. Herein, a novel colorimetric method was proposed for the visual detection of AA based on a nucleophile-initiated thiol-ene Michael addition reaction. Gold nanoparticles (AuNPs) were aggregated by glutathione (GSH) because of a ligand-replacement, accompanied by a color change from red to purple. In the presence of AA, after the thiol-ene Michael addition reaction between GSH and AA with the catalysis of a nucleophile, the sulfhydryl group of GSH was consumed by AA, which hindered the subsequent ligand-replacement and the aggregation of AuNPs. Therefore, the concentration of AA could be determined by the visible color change caused by dispersion/aggregation of AuNPs. This new method showed high sensitivity with a linear range from 0.1 μmol L(-1) to 80 μmol L(-1) and a detection limit of 28.6 nmol L(-1), and especially revealed better selectivity than the fluorescence sensing method reported previously. Moreover, this new method was used to detect AA in potato chips with a satisfactory result in comparison with the standard methods based on chromatography, which indicated that the colorimetric method can be expanded for the rapid detection of AA in thermally processed foods. PMID:26699696

  7. How Do Nutritional Antioxidants Really Work: Nucleophilic Tone and Para-Hormesis Versus Free Radical Scavenging in vivo

    PubMed Central

    Forman, Henry Jay; Davies, Kelvin J. A.; Ursini, Fulvio

    2013-01-01

    We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of non-radical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of ‘Nucleophilic Tone,’ by a mechanism that can be called ‘Para-Hormesis,’ provides a means for regulating physiological non-toxic concentrations of the non-radical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health. PMID:23747930

  8. Solvent effects on kinetics of an heteroatomic nucleophilic substitution reaction in ionic liquid and molecular solvents mixtures

    NASA Astrophysics Data System (ADS)

    Salari, Hadi; Pedervand, Mohsen; Sadeghzadeh-Darabi, Faramarz; Gholami, Mohammad Reza

    2013-12-01

    Rate constants, k A, for the aromatic nucleophilic substitution reaction of 2-chloro-3,5-dinitropyridine with aniline were determined in different compositions of 2-propanol mixed with hexane, benzene, and 2-methylpropan-2-ol and 1-ethyl-3-methylimidazolium ethylsulfate ([Emim][EtSO4]) with dimethyl sulfoxide at 25°C. The obtained rate constants of the reaction in pure solvents are in the following order: 2-methylpropan-2-ol > dimethyl sulfoxide > 2-propanol > hexane > benzene > [Emim][EtSO4]. Molecularmicroscopic solvent parameters corresponding to the selected binary mixtures were utilized to study the kinetics of a nucleophilic substitution reaction in order to investigate and compare the effects of the solvents on a chemical process. The influence of solvent parameters including normalized polarity ( E {/T N }), dipolarity/polarizability (π*), hydrogen bond donor acidity (α), and hydrogen bond acceptor basicity (β) on the second-order rate constants were investigated and multiple linear regressions gave much better results with regard to single parameter regressions. The dipolarity/polarizability of media has a positive effect in all mixtures regarding zwitterionic character of the reaction intermediate and the hydrogen bond acceptor basicity of the solvent by stabilizing of activated complex increases the reaction rate.

  9. The Identity of the Nucleophile Substitution may Influence Metal Interactions with the Cleavage Site of the Minimal Hammerhead Ribozyme

    PubMed Central

    Osborne, Edith M.; Ward, W. Luke; Ruehle, Max Z.; DeRose, Victoria J.

    2010-01-01

    Potential metal interactions with the cleavage site of a minimal hammerhead ribozyme (mHHRz) were probed using 31P NMR-detected Cd2+ titration studies of HHRz constructs containing a phosphorothioate (PS) modification at the cleavage site. The mHHRz nucleophile position was replaced by either a 2′-F or a 2′-NH2 in order to block cleavage activity during the study. The 2′-F/PS cleavage site mHHRz construct, in which the 2′-F should closely imitate the atom size and electronegativity of a 2′OH, demonstrates low levels of metal ion association (<1 ppm 31P chemical shift changes). This observation indicates that having an atom size and electrostatic properties that are similar to the 2′-OH are not the governing factors in allowing metal interactions with the scissile phosphate of the mHHRz. With a 2′-NH2 substitution, a large upfield change in 31P NMR chemical shift of the phosphorothioate peak (Δ~3 ppm with 6 equivalents added Cd2+) indicates observable Cd2+ interactions with the substituted site. Since a 2′-NH2, but not a 2′-F, can serve as a metal ligand, these data suggest that a metal ion interaction with the HHRz cleavage site may include both the scissile phosphate and the 2′ nucleophile. Control samples in which the 2′-NH2/PS unit is placed either next to the mHHRz cleavage site (at U16.1), in a duplex, or in a amUPSU dinucleotide, show much weaker interactions with Cd2+. Results with these control samples indicate that simply the presence of a 2′-NH2/PS unit does not create a strong metal binding site, reinforcing the possibility that the 2′-NH2-moderated Cd-PS interaction is specific to the mHHRz cleavage site. Upfield chemical shifts of both 31P and H2′ 1H resonances in amUPSU are observed with addition of Cd2+, consistent with the predicted metal coordination to both 2′-NH2 and phosphorothioate ligands. These data suggest that metal ion association with the HHRz cleavage site may include an interaction with the 2

  10. E-H (E = B, Si, Ge) bond activation of pinacolborane, silanes, and germanes by nucleophilic palladium carbene complexes.

    PubMed

    Comanescu, Cezar C; Iluc, Vlad M

    2016-07-12

    The reactivity of two nucleophilic palladium carbenes, [PC(sp(2))P]Pd(PMe3) and [PC(sp(2))P]Pd(PPh3), where [PC(sp(2))P] = bis[2-(di-iso-propylphosphino)phenyl]methylene, toward the E-H bond activation of Ph4-nEHn (E = Si, Ge; n = 1-3) and pinacolborane (HBpin) is discussed. Unlike previous reports, both types of isomer species, hydride [PC(EHn-1Ph4-n)P]PdH or [PC(Bpin)P]PdH and silyl/germyl [PC(H)P]Pd(EHn-1Ph4-n), were observed depending on the substrate and the phosphine ligand, showing that the polarity of the Pd-C bond can be tuned by the phosphine substituents. PMID:26830660

  11. Native functionality in triple catalytic cross-coupling: sp³ C-H bonds as latent nucleophiles.

    PubMed

    Shaw, Megan H; Shurtleff, Valerie W; Terrett, Jack A; Cuthbertson, James D; MacMillan, David W C

    2016-06-10

    The use of sp(3) C-H bonds--which are ubiquitous in organic molecules--as latent nucleophile equivalents for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp(3) C-H bonds in both cyclic and acyclic systems. PMID:27127237

  12. Cationic palladium(ii)-catalyzed dehydrative nucleophilic substitutions of benzhydryl alcohols with electron-deficient benzenethiols in water.

    PubMed

    Hikawa, Hidemasa; Machino, Yumo; Toyomoto, Mariko; Kikkawa, Shoko; Azumaya, Isao

    2016-08-01

    An efficient direct nucleophilic substitution of benzhydryl alcohols with electron-deficient benzenethiols using cationic Pd(ii) catalysts as Lewis acids in water is reported. Atom economical and environmentally benign protocols afford S-benzylated products in moderate to excellent yields. Commercially available Pd(MeCN)4(OTf)2, PdCl2(MeCN)2, and Na2PdCl4 are highly efficient catalysts. Notably, this simple protocol can be achieved without any other additives such as acids, bases, or external ligands. A Hammett study on the rate constants of S-benzylation by using various substituted benzhydryl alcohols yielded negative ρ values, suggesting that there is a build-up of positive charge in the transition state. PMID:27363665

  13. Biphenyl-Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations to Form Functionalized Cyclopentenes

    PubMed Central

    Ziegler, Daniel T.; Riesgo, Lorena; Ikeda, Takuya; Fujiwara, Yuji

    2015-01-01

    Due to the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. In this report, we introduce a new family of chiral nucleophilic catalysts, biphenyl-derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation first described by Tong. A range of one-carbon coupling partners can be employed, thereby generating cyclopentenes that bear a fully substituted stereocenter (either all-carbon or heteroatom-substituted (sulfur and phosphorus)). Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four-carbon coupling partner is not the turnover-limiting step of the catalytic cycle. PMID:25287684

  14. Identification of Glu-519 as the catalytic nucleophile in beta-mannosidase 2A from Cellulomonas fimi.

    PubMed Central

    Stoll, D; He, S; Withers, S G; Warren, R A

    2000-01-01

    Incubation of the beta-mannosidase Man2A from Cellulomonas fimi with 2-deoxy-2-fluoro-beta-D-mannosyl fluoride (2FMan beta F) resulted in time-dependent inactivation of the enzyme (inactivation rate constant k(i)=0.57 min(-1), dissociation constant for the inactivator K(i)=0.41 mM) through the accumulation of a covalent 2-deoxy-2-fluoro-alpha-D-mannosyl-beta-mannosidase 2A (2FMan-Man2A) enzyme intermediate, as observed by electrospray ionization mass spectrometry. The stoichiometry of inactivation was 1:1. Removal of excess inactivator and regeneration of active enzyme by transglycosylation of the covalently attached inhibitor to gentiobiose [Glc beta(1-6)Glc] demonstrated that the covalent intermediate was catalytically competent. Comparison by MS of the peptic digests of 2FMan-Man2A with peptic digests of native Man2A revealed a peptide of m/z 1520 that was unique to 2FMan-Man2A, and one of m/z 1036.5 that was unique to a Man2A peptide. Their sequences, determined by collision-induced fragmentation, were CSEFGFQGPPTW and FGFQGPPTW, corresponding to residues 517-528 and 520-528 of Man2A respectively. The difference in mass of 483.5 between the two peptides equals the sum of the masses of the tripeptide CSE plus that of 2-fluoromannose. It was concluded that in 2FMan-Man2A, the 2-fluoromannose esterified to Glu-519 blocks hydrolysis of the Glu-519-Phe-520 peptide bond, and that Glu-519 is the catalytic nucleophile in this enzyme. This residue is conserved in all members of family 2 of the glycosyl hydrolases. This represents the first ever labelling and identification of an active-site nucleophile in a beta-mannosidase. PMID:11042141

  15. New Insights into the Detection of Sulfur Trioxide Anion Radical by Spin Trapping: Radical Trapping versus Nucleophilic Addition

    PubMed Central

    Ranguelova, Kalina; Mason, Ronald P.

    2009-01-01

    It has recently been proposed that (bi)sulfite (hydrated sulfur dioxide) reacts with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) in biological systems via a nonradical, nucleophilic reaction, implying that the radical adduct (DMPO/•SO3−) formation in these systems is an artifact and not the result of spin trapping of sulfur trioxide anion radical (•SO3−). Here, the one-electron oxidation of (bi)sulfite catalyzed by horseradish peroxidase/H2O2 has been re-investigated by ESR spin trapping with DMPO and oxygen uptake studies in order to obtain further evidence for the radical reaction mechanism. In the case of ESR experiments, the signal of DMPO/•SO3− radical adduct was detected, and the initial rate of its formation was calculated. Support for the radical pathway via •SO3− was obtained from the stoichiometry between the amount of consumed molecular oxygen and the amount of (bi)sulfite oxidized to sulfate (SO42−). When DMPO was incubated with (bi)sulfite, oxygen consumption was completely inhibited due to the efficiency of DMPO trapping. In the absence of DMPO, the initial rate of oxygen and H2O2 consumption was determined to be half of the initial rate of DMPO/•SO3− radical adduct formation as determined by ESR, demonstrating that DMPO forms the radical adduct by trapping the •SO3− exclusively. We conclude that DMPO is not susceptible to artifacts arising from nonradical chemistry (nucleophilic addition) except when both (bi)sulfite and DMPO concentrations are at nonphysiological levels of at least 0.1 M and the incubations are for longer time periods. PMID:19362142

  16. Synthesis of Aryl-Substituted 2,4-Dinitrophenylamines: Nucleophilic Aromatic Substitution as a Problem-Solving and Collaborative-Learning Approach

    ERIC Educational Resources Information Center

    Santos, Elvira Santos; Garcia, Irma Cruz Gavilan; Gomez, Eva Florencia Lejarazo; Vilchis-Reyes, Miguel Angel

    2010-01-01

    A series of experiments based on problem-solving and collaborative-learning pedagogies are described that encourage students to interpret results and draw conclusions from data. Different approaches including parallel library synthesis, solvent variation, and leaving group variation are used to study a nucleophilic aromatic substitution of…

  17. Nucleophilic index value: implication in the protection by indole-3-carbinol from N-nitrosodimethylamine cyto and genotoxicity in mouse liver.

    PubMed

    Shertzer, H G; Tabor, M W

    1988-04-01

    A novel assay system was developed in order to quantitate the nucleophilicity of pure chemicals or tissue extracts. This Nucleophilic Index Value (NIV) assay was based on the ability of putative nucleophiles to inhibit the methylation of cysteine by limiting concentrations of the electrophilic source, N-methyl-N-nitrosourea (MNU). Efficacy of model and cellular nucleophiles was quantitated as nmol cysteine protected by the nucleophile from methylation by MNU/h/mM compound. The NIVs of the pure compounds ascorbate, glutathione, 4-(4-nitrobenzyl)-pyridine (NBP) and indole-3-carbinol (I-3-C) were 2400, 1600, 3 and 0, respectively. When mice were treated with I-3-C by gavage at dosages of 0, 25, 50, 75 or 100 mg/kg body wt, the NIV for ethyl acetate extracts of the livers 1 h after treatment were 0, 33, 47, 52 and 92 nmol cysteine preserved/h/g tissue, respectively. The I-3-C enhancement of NIV was not attributable to ascorbate or glutathione, neither of which were present in the ethyl extracts of liver. When mice were treated with 10 mg N-nitrosodimethylamine (NDMA)/kg body wt 1 h after the varying dosages of I-3-C, the 24 h post-NDMA plasma alanine transaminase (ALT) values were decreased by I-3-C pretreatment in a dose-dependent fashion. Plasma ALT values were used in this study as an indicator of hepatotoxicity. The coefficient of determination, r2, computed from the linear least squares correlation coefficient between NIV and ALT values, was 0.80 (0-100 mg I-3-C/kg) and 0.97 (0-75 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3379233

  18. Enantioconvergent Nucleophilic Substitution Reaction of Racemic Alkyne-Dicobalt Complex (Nicholas Reaction) Catalyzed by Chiral Brønsted Acid.

    PubMed

    Terada, Masahiro; Ota, Yusuke; Li, Feng; Toda, Yasunori; Kondoh, Azusa

    2016-08-31

    Catalytic enantioselective syntheses enable a practical approach to enantioenriched molecules. While most of these syntheses have been accomplished by reaction at the prochiral sp(2)-hybridized carbon atom, little attention has been paid to enantioselective nucleophilic substitution at the sp(3)-hybridized carbon atom. In particular, substitution at the chiral sp(3)-hybridized carbon atom of racemic electrophiles has been rarely exploited. To establish an unprecedented enantioselective substitution reaction of racemic electrophiles, enantioconvergent Nicholas reaction of an alkyne-dicobalt complex derived from racemic propargylic alcohol was developed using a chiral phosphoric acid catalyst. In the present enantioconvergent process, both enantiomers of the racemic alcohol were transformed efficiently to a variety of thioethers with high enantioselectivity. The key to achieving success is dynamic kinetic asymmetric transformation (DYKAT) of enantiomeric cationic intermediates generated via dehydroxylation of the starting racemic alcohol under the influence of the chiral phosphoric acid catalyst. The present fascinating DYKAT involves the efficient racemization of these enantiomeric intermediates and effective resolution of these enantiomers through utilization of the chiral conjugate base of the phosphoric acid. PMID:27490239

  19. Nucleophilic substitution with two reactive centers: The CN{sup −} + CH{sub 3}I case

    SciTech Connect

    Carrascosa, E.; Bawart, M.; Stei, M.; Carelli, F.; Meyer, J.; Gianturco, F. A.; Wester, R.; Linden, F.; Geppert, W. D.

    2015-11-14

    The nucleophilic substitution reaction CN{sup −} + CH{sub 3}I allows for two possible reactive approaches of the reactant ion onto the methyl halide, which lead to two different product isomers. Stationary point calculations predict a similar shape of the potential and a dominant collinear approach for both attacks. In addition, an H-bonded pre-reaction complex is identified as a possible intermediate structure. Submerged potential energy barriers hint at a statistical formation process of both CNCH{sub 3} and NCCH{sub 3} isomers at the experimental collision energies. Experimental angle- and energy differential cross sections show dominant direct rebound dynamics and high internal excitation of the neutral product. No distinct bimodal distributions can be extracted from the velocity images, which impedes the indication of a specific preference towards any of the product isomers. A forward scattering simulation based on the experimental parameters describes accurately the experimental outcome and shows how the possibility to discriminate between the two isomers is mainly hindered by the large product internal excitation.

  20. Nucleophilic Reactivity of a Nitride-Bridged Diuranium(IV) Complex: CO2 and CS2 Functionalization.

    PubMed

    Falcone, Marta; Chatelain, Lucile; Mazzanti, Marinella

    2016-03-14

    Thermolysis of the nitride-bridged diuranium(IV) complex Cs{(μ-N)[U(OSi(O(t) Bu)3 )3 ]2 } (1) showed that the bridging nitride behaves as a strong nucleophile, promoting N-C bond formation by siloxide ligand fragmentation to yield an imido-bridged siloxide/silanediolate diuranium(IV) complex, Cs{(μ-N(t) Bu)(μ-O2 Si(O(t) Bu)2 )U2 (OSi(O(t) Bu)3 )5 }. Complex 1 displayed reactivity towards CS2 and CO2 at room temperature that is unprecedented in f-element chemistry, affording diverse N-functionalized products depending on the reaction stoichiometry. The reaction of 1 with two equivalents of CS2 yielded the thiocyanate/thiocarbonate complex Cs{(μ-NCS)(μ-CS3 )[U(OSi(O(t) Bu)3 )3 ]2 } via a putative NCS(-) /S(2-) intermediate. The reaction of 1 with one equivalent of CO2 resulted in deoxygenation and N-C bond formation, yielding the cyanate/oxo complex Cs{(μ-NCO)(μ-O)[U(OSi(O(t) Bu)3 )3 ]2 }. Addition of excess CO2 to 1 led to the unprecedented dicarbamate product Cs{(μ-NC2 O4 )[U(OSi(O(t) Bu)3 )3 ]2 }. PMID:26914732

  1. Highly nucleophilic acetylide, vinyl, and vinylidene complexes. Final progress report, 1 January 1991--31 March 1994

    SciTech Connect

    Geoffroy, G.L.

    1994-10-04

    In the course of this research the authors found that the anionic alkynyl complex [Cp{prime}(CO)(PPh{sub 3})Mn-C{triple_bond}C-CH{sub 3}]{sup {minus}} can be generated in situ by the addition of two equivalents of n-BuLi to a solution of the carbene complex Cp{prime}(CO)(PPh{sub 3})Mn{double_bond}C(OMe)CH{sub 2}CH{sub 3}. It was also found that the highly nucleophilic propynyl complex [Cp(CO)(PPh{sub 3})Mn-C{triple_bond}C-Me]{sup {minus}} reacts with a variety of aldehydes and ketones in the presence of BF{sub 3}{center_dot}Et{sub 2}O to give, after quenching with MeOH, a series of cationic vinylcarbyne complexes of the general form [Cp(CO)(PPh{sub 3})Mn{triple_bond}C-C(Me){double_bond}C(R)(R{prime})]BF{sub 4}. The cationic alkylidyne complexes [Cp(CO){sub 2}M{triple_bond}C-CH{sub 2}R]{sup +} [M = Re, R = H, M = Mn, R = H, Me, Ph] have been found to undergo facile deprotonation to give the corresponding neutral vinylidene complexes Cp(CO){sub 2}M{double_bond}C{double_bond}C(H)R. The authors have also investigated reactions relevant to the halide promoted Fe and Ru catalyzed carbonylation of nitroaromatics. The final part of this work has involved investigations of metal-oxo complexes.

  2. Surface-active ionic liquids in micellar catalysis: impact of anion selection on reaction rates in nucleophilic substitutions.

    PubMed

    Cognigni, Alice; Gaertner, Peter; Zirbs, Ronald; Peterlik, Herwig; Prochazka, Katharina; Schröder, Christian; Bica, Katharina

    2016-05-21

    A series of surface-active ionic liquids based on the 1-dodecyl-3-methylimidazolium cation and different anions such as halides and alkylsulfates was synthesized. The aggregation behavior of these ionic liquids in water was characterized by surface tension, conductivity measurements and UV-Vis spectroscopy in order to determine the critical micelle concentration (CMC) and to provide aggregation parameters. The determination of surface activity and aggregation properties of amphiphilic ionic liquids was accompanied by SAXS studies on selected surface-active ionic liquids. The application of these surface-active ionic liquids with different anions was tested in nucleophilic substitution reactions for the degradation of organophosphorus compounds. Kinetic studies via UV-Vis spectrophotometry showed a strong acceleration of the reaction in the micellar system compared to pure water. In addition, an influence of the anion was observed, resulting in a correlation between the anion binding to the micelle and the reaction rate constants, indicating that the careful choice of the surface-active ionic liquid can considerably affect the outcome of reactions. PMID:27121134

  3. Preparation and characterization of poly (arylene ether isoxazole)s by fluoride ion-mediated aromatic nucleophilic displacement reactions

    NASA Technical Reports Server (NTRS)

    Herbert, C. G.; Bass, R. G.

    1994-01-01

    As part of a continuing effort to prepare novel thermally stable high-performance polymers, poly(arylene ether isoxazole)s have been prepared by fluoride ion-catalyzed aromatic nucleophilic substitution reactions with bis(trimethylsiloxyphenyl) isoxazoles and activated bisarylhalides in diphenyl sulfone. Initial investigation involving the preparation of these materials with isoxazole bisphenols and activated bisarylhalides in the presence of potassium carbonate indicated that, under reaction conditions necessary to prepare high-molecular-weight materials, the isoxazole monomer was converted to an enamino ketone. This side reaction was avoided by using fluoride as a base. However, trimethylsilyl ether derivatives of the isoxazole bisphenols were required in these polymerizations for the preparation of high-molecular-weight materials. Moderate to high inherent viscosity eta(sub inh): 0.43-0.87 dl/g) materials with good thermal stability (air: 409-477 C, helium: 435-512 C) can be prepared by the silyl ether method. Glass transition temperatures ranged from 182 to 225 C for polymers with phenyl pendants and from 170 to 214 C for those without. Molecular weight control by 2% endcapping and the incorporation of a phenyl pendant at the 4 position of the isoxazole is necessary to yield polymers soluble in polar aprotic solvents at room temperature. There is evidence, however, indicating the existence of crosslinks between the polymer chains when the silyl ether approach is utilized.

  4. Enantioselective Nucleophile-Catalyzed Synthesis of Tertiary Alkyl Fluorides via the α-Fluorination of Ketenes: Synthetic and Mechanistic Studies

    PubMed Central

    2015-01-01

    The catalytic asymmetric synthesis of alkyl fluorides, particularly α-fluorocarbonyl compounds, has been the focus of substantial effort in recent years. While significant progress has been described in the formation of enantioenriched secondary alkyl fluorides, advances in the generation of tertiary alkyl fluorides have been more limited. Here, we describe a method for the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide (NFSI) and C6F5ONa to furnish tertiary α-fluoroesters. Mechanistic studies are consistent with the hypothesis that the addition of an external nucleophile (C6F5ONa) is critical for turnover, releasing the catalyst (PPY*) from an N-acylated intermediate. The available data can be explained by a reaction pathway wherein the enantioselectivity is determined in the turnover-limiting transfer of fluorine from NFSI to a chiral enolate derived from the addition of PPY* to the ketene. The structure and the reactivity of the product of this proposed elementary step, an α-fluoro-N-acylpyridinium salt, have been examined. PMID:24922581

  5. Oxidative group transfer to a triiron complex to form a nucleophilic μ(3)-nitride, [Fe3(μ(3)-N)]-.

    PubMed

    Powers, Tamara M; Fout, Alison R; Zheng, Shao-Liang; Betley, Theodore A

    2011-03-16

    Utilizing a hexadentate ligand platform, a high-spin trinuclear iron complex of the type ((tbs)L)Fe(3)(thf) was synthesized and characterized ([(tbs)L](6-) = [1,3,5-C(6)H(9)(NPh-o-NSi(t)BuMe(2))(3)](6-)). The silyl-amide groups only permit ligation of one solvent molecule to the tri-iron core, resulting in an asymmetric core wherein each iron ion exhibits a distinct local coordination environment. The triiron complex ((tbs)L)Fe(3)(thf) rapidly consumes inorganic azide ([N(3)]NBu(4)) to afford an anionic, trinuclear nitride complex [((tbs)L)Fe(3)(μ(3)-N)]NBu(4). The nearly C(3)-symmetric complex exhibits a highly pyramidalized nitride ligand that resides 1.205(3) Å above the mean triiron plane with short Fe-N (1.871(3) Å) distances and Fe-Fe separation (2.480(1) Å). The nucleophilic nitride can be readily alkylated via reaction with methyl iodide to afford the neutral, trinuclear methylimide complex ((tbs)L)Fe(3)(μ(3)-NCH(3)). Alkylation of the nitride maintains the approximate C(3)-symmetry in the imide complex, where the imide ligand resides 1.265(9) Å above the mean triiron plane featuring lengthened Fe-N(imide) bond distances (1.892(3) Å) with nearly equal Fe-Fe separation (2.483(1) Å). PMID:21332160

  6. Tandem Synthesis of 10-Dimethylaminobenzo[h]quinazolines from 2-Ketimino-1,8-bis(dimethylamino)naphthalenes via Nucleophilic Replacement of the Unactivated Aromatic NMe2 Group.

    PubMed

    Mikshiev, Vladimir Y; Antonov, Alexander S; Pozharskii, Alexander F

    2016-06-17

    It has been found that 2-bromo-1,8-bis(dimethylamino)naphthalene on sequential treatment with n-BuLi and 2 equiv of the same or different aryl(hetaryl) cyanide as a result of [2 + 2 + 2] nucleophilic cascade annulation produces 10-dimethylaminobenzo[h]quinazolines, as yet unknown NMe2/-N═ analogues of the proton sponge. It is even more convenient to use preliminarily prepared 2-ketimino-1,8-bis(dimethylamino)naphthalenes as starting material. The substitution of both peri-NMe2 groups furnishing quinazolino[7,8-h]quinazoline derivatives is also possible. The process is remarkable by surprisingly mild nucleophilic displacement of an unactivated aromatic NMe2 group. PMID:27258556

  7. Time-Resolved Crystallography of the Reaction Intermediate of Nitrile Hydratase: Revealing a Role for the Cysteinesulfenic Acid Ligand as a Catalytic Nucleophile.

    PubMed

    Yamanaka, Yasuaki; Kato, Yuki; Hashimoto, Koichi; Iida, Keisuke; Nagasawa, Kazuo; Nakayama, Hiroshi; Dohmae, Naoshi; Noguchi, Keiichi; Noguchi, Takumi; Yohda, Masafumi; Odaka, Masafumi

    2015-09-01

    The reaction mechanism of nitrile hydratase (NHase) was investigated using time-resolved crystallography of the mutant NHase, in which βArg56, strictly conserved and hydrogen bonded to the two post-translationally oxidized cysteine ligands, was replaced by lysine, and pivalonitrile was the substrate. The crystal structures of the reaction intermediates were determined at high resolution (1.2-1.3 Å). In combination with FTIR analyses of NHase following hydration in H2 (18) O, we propose that the metal-coordinated substrate is nucleophilically attacked by the O(SO(-) ) atom of αCys114-SO(-) , followed by nucleophilic attack of the S(SO(-) ) atom by a βArg56-activated water molecule to release the product amide and regenerate αCys114-SO(-) . PMID:26333053

  8. Nucleophilic Participation in the Solvolyses of (Arylthio)methyl Chlorides and Derivatives: Application of Simple and Extended Forms of the Grunwald-Winstein Equations.

    PubMed

    Kevill, Dennis N; Park, Young Hoon; Park, Byoung-Chun; D'Souza, Malcolm J

    2012-06-01

    The specific rates of solvolysis of chloromethyl phenyl sulfide [(phenylthio)methyl chloride] and its p-chloro-derivative have been determined at 0.0 °C in a wide range of hydroxylic solvents, including several containing a fluroalcohol. Treatment in terms of a two-term Grunwald-Winstein equation, incorporating terms based on solvent ionizing power (Y(Cl)) and solvent nucleophilicity (N(T)) suggest a mechanism similar to that for the solvolyses of tert-butyl chloride, involving in the rate-determining step a nucleophilic solvation of the incipient carbocation in an ionization process. A previous suggestion, that a third-term governed by the aromatic ring parameter (I) is required, is shown both for the new and for the previously studied related substrates to be an artifact, resulting from an appreciable degree of multicollinearity between I values and a linear combination of N(T) and Y(Cl) values. PMID:22711999

  9. 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

  10. Additional Nucleophile-Free FeCl3-Catalyzed Green Deprotection of 2,4-Dimethoxyphenylmethyl-Protected Alcohols and Carboxylic Acids.

    PubMed

    Sawama, Yoshinari; Masuda, Masahiro; Honda, Akie; Yokoyama, Hiroki; Park, Kwihwan; Yasukawa, Naoki; Monguchi, Yasunari; Sajiki, Hironao

    2016-01-01

    The deprotection of the methoxyphenylmethyl (MPM) ether and ester derivatives can be generally achieved by the combinatorial use of a catalytic Lewis acid and stoichiometric nucleophile. The deprotections of 2,4-dimethoxyphenylmethyl (DMPM)-protected alcohols and carboxylic acids were found to be effectively catalyzed by iron(III) chloride without any additional nucleophile to form the deprotected mother alcohols and carboxylic acids in excellent yields. Since the present deprotection proceeds via the self-assembling mechanism of the 2,4-DMPM protective group itself to give the hardly-soluble resorcinarene derivative as a precipitate, the rigorous purification process by silica-gel column chromatography was unnecessary and the sufficiently-pure alcohols and carboxylic acids were easily obtained in satisfactory yields after simple filtration. PMID:27373632