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The unimolecular nucleophilic substitution (S.sub.N1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via S.sub.N1 pathways. Here we report asymmetric catalysis of an S.sub.N1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres. Cooperation between a chiral hydrogen-bond-donor catalyst and a strong Lewis-acid promoter in an S.sub.N1-type reaction mediates the formation of tertiary carbocations and enables control over enantioselectivity and product distribution., Author(s): Alison E. Wendlandt [sup.1] , Prithvi Vangal [sup.1] , Eric N. Jacobsen [sup.1] Author Affiliations: (1) Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA Main Quaternary stereogenic [...]

For a theoretical model study on the cyclic reaction of 4-hydroxybutanal (4-OH-BL), we have examined five assumed reaction pathways (I-V) by performing the B3LYP calculations in the gas phase and self-consistent isodensity polarized continuum model (SCIPCM)-B3LYP calculations in aqueous solution. Pathways II (4-OH-BL + [H.sup.+]), III (4-OH-BL + [H.sub.3][O.sup.+]), and IV (4-OH-BL + [H.sub.3][O.sup.+] + [H.sub.2]O) represent three models for the cyclic reaction catalyzed by Bronsted acids. The present study leads to the following conclusions concerning the five pathways (mainly on the basis of the calculation results in the solution). The high barrier along pathway I (with no catalyst) implies that the reaction does not occur without a catalyst, and the extremely large stabilization energy of the intermediate implies that pathway II is not a realistic model for the reaction catalyzed by Bronsted acid. Along pathway III, there are two intermediates and a transition state in between, and they are 10-16 kcal/mol lower in energy than the reactants (4-OH-BL + [H.sub.3][O.sup.+]). Along pathway IV, there is only one intermediate, and it is 20.6 kcal/mol lower in energy than the reactants (4-OH-BL + [H.sub.3][O.sup.+] + [H.sub.2]O). Pathways III and IV are predicted to be feasible. Energetically, pathway IV is more favourable than pathway III and it is considered as a rational model for the cyclic reaction of 4-OH-BL catalyzed by Bronsted acid. Our calculations for pathway V (catalyzed by [H.sub.2]O) indicate that the water molecule may also serve as a catalyst for the cyclic reaction. The transition state along pathway V is 20.0 kcal/mol higher in energy than the reactants (4-OH-BL + [H.sub.2]O), and one can clearly see the 'proton wire' in its structure. Our calculations show strong solvent effects on energetics of the charged intermediates along pathways II, III, and IV. Key words: cyclic reaction of 4-hydroxybutanal, catalyzed by Bronsted acid, B3LYP, self-consistent isodensity polarized continuum model (SCIPCM), model study. Comme modele theorique pour une etude de la reaction cyclique du 4-hydroxybutanal (4-OH-BL), on a etudie cinq presumees voies reactionnelles (I-V) en effectuant des calculs B3LYP en phase gazeuse et des calculs SCIPCM-B3LYP en solution et les voies reactionnelles II (4-OH-BL + [H.sup.+]), III (4-OH-BL + [H.sub.3][O.sup.+]) et IV (4-OH-BL + [H.sub.3][O.sup.+] + [H.sub.2]O) representent trois modeles pour la reaction cyclique catalysee par les acides de Bronsted. La presente etude conduit aux conclusions suivantes concernant les cinq voies reactionnelles (principalement sur la base des resultats de calculs en solution). La barriere elevee le long de la voie I (sans catalyseur) implique que la reaction ne se produit pas sans catalyseur et l'energie de stabilisation extremement grande de l'intermediaire implique que la voie reactionnelle II n'est pas un modele realiste pour la reaction catalysee par un acide de Bronsted. Le long de la voie III, on rencontre deux intermediaires et un etat de transition entre les deux et leurs energies sont de 10 a 16 kcal/mol inferieures a celles des reactifs (4-OH-BL + [H.sub.3][O.sup.+]). Le long de la voie IV, il n'existe qu'un intermediaire et son energie est de 20,6 kcal/mol inferieure a l'energie des reactifs (4-OH-BL + [H.sub.3][O.sup.+] + [H.sub.2]O). Les voies reactionnelles III et IV sont donc toutes les deux possibles. D'un point de vue energetique, la voie IV est plus favorable que la voie III et on la considere comme un modele rationnel pour la reaction du 4-OH-BL catalysee par un acide de Bronsted. Les calculs pour la voie V (catalysee par l'eau) indiquent que la molecule d'eau peut aussi servir de catalyseur pour la reaction cyclique. L'energie de transition de l'etat de transition le long de la voie V est de 20,0 kcal/mol plus elevee que celles des reactifs (4-OH-BL + [H.sub.2]O) et on peut voir le << treillis de proton >> dans sa structure. Les calculs montrent l'existence d'importants effets de solvant sur les energies des intermediaires charges le long des voies reactionnelles II, III et IV. Mots-cles : reaction cyclique du 4-hydroxybutanal, catalyse par un acide de Bronsted, B3LYP, SCIPCM, etude modele. [Traduit par la Redaction], Introduction Nucleophilic reactions are very important reactions in organic chemistry. (1) There are numerous theoretical studies (2-9) on nucleophilic substitution reactions ([S.sub.N]2 reactions), but less theoretical studies on nucleophilic addition [...]

Abstract: 3-, 5-, 6-, 7-and 8-Nitroquinolines react with 4-amino-1,2,4-triazole in basic medium (potassium tertbutoxide-dimethyl sulfoxide) giving amino products of the vicarious nucleophilic substitution (VNS) of hydrogen, predominantly at ortho position [...]

Abstract: Additional specific rates of solvolysis have been determined for acetyl chloride and diphenylacetyl chloride. These are combined with literature values to carry out correlation analyses, using the extended Grunwald--Winstein [...]

Abstract: For protonation of a base B to give [BH.sup.+] and for reaction of carbocations [R.sup.+] with water to give ROH in a range of sulfuric acid--water mixtures, slopes of [...]

The rearrangement and nucleophilic substitution of cyclo-propylcarbinyl and cyclobutyl halides over NaY zeolite has succeeded in the formation of [C.sub.4][H.sub.7.sup.} cations as discrete intermediates inside the zeolite cavity. The results have shown that zeolites have acted as solid solvents, thus permitting ionization and solvation of ionic species.

The synthesis, phase-transfer catalysis and the recycling of the several Perfluoroalkylated 4,13-diaza-18-crown-6 ethers, having two different side arms are studied. The analysis reveals that the perfluoroalkylated macrocycles can be widely used as the phase-transfer catalysts, giving extremely high catalytic activities under solid-liquid phase transfer conditions.

The kinetics of the reactions of various primary and secondary amines with the benzhydrylium ions in water are investigated, demonstrating their nucleophilcites. The results show a poor correlation between the nucleophilicities values, as the secondary alkyl amines and anilines are more nucleophilicdue to the difference in their pH values.

The reactions of N-chlorotaurine with several nucleophilic reagents, the protonation at nitrogen during the transfer of chlorine from N-chlorotaurine to a nucleophile and its mechanisms of transfer reactions are studied. The results have provided evidence against an electron-transfer mechanism for chlorination of the nuclophiles by protonated N-chlorotaurine.

A short, two-step approach based on a Ugi multicomponent reaction (MCR) followed by a subsequent intramolecular [S.sub.N]2 reaction is described for the synthesis of diazepane or diazocane systems. The results have shown the power of coupling Ugi MCRs with post-condensation transformations for obtaining relatively complex heterocyclic scaffolds in few steps.

A series of archetypal [S.sub.N]2@C and [S.sub.N]2@Si reactions are analyzed by using the ADF program. The results have shown that by simple increasing the steric demand of the substituents R around the silicon atom, the [S.sub.N]2@Si mechanisms changes from its regular single-well potential energy surfaces (PES), via a triple-well PES, to a double-well PES, which is normally encountered for [S.sub.N]2@C reactions.

Various ab initio calculations are used to study the chemoselective nucleophilic fluorination of several alkyl halides by a selective solvation of the [S.sub.N]2 transition state, which leads to a combination of elimination and nucleophilic substitution in the dipolar solvents. The results show that the strong hydrogen bond between the catalyst and the fluoride ions leads to a lower stabilization of the nucleophile, which in turn leads to a high reaction rate.

A study focuses on the enolpyruvylshikimate-3-phosphate synthase, EPSP (AroA), which is a carboxyvinyl transferase that helps in the biosynthesis of aromatic amino acid by using shikimate 3-phosphate and phosphoenolpyruvate. The analysis reveals that a large amount of catalytic power is used up by AroA for the formation of an EPSP cation, an intermediate which is a very easy target motif for inhibitor design.

A study conducted reports that triflyl azide rapidly reacts with a series of amine-functionalized solid supports to generate azide-coated supports. The results show that the so-formed azide coat could be used to load leader nucleoside monomers on solid supports using click chemistry under benign experimental conditions.

Elimination of nonnutritional and insoluble compounds is a critical task for any living organism. Flavin-containing monooxygenases (FMOs) attach an oxygen atom to the insoluble nucleophilic compounds to increase solubility and thereby increase excretion. Here we analyze the functional mechanism of FMO from Schizosaccharomyces pombe using the crystal structures of the wild type and protein-cofactor and protein-substrate complexes. The structure of the wild-type FMO revealed that the prosthetic group FAD is an integral part of the protein. FMO needs NADPH as a cofactor in addition to the prosthetic group for its catalytic activity. Structures of the protein-cofactor and protein-substrate complexes provide insights into mechanism of action. We propose that FMOs exist in the cell as a complex with a reduced form of the prosthetic group and NADPH cofactor, readying them to act on substrates. The 4[alpha]-hydroperoxyflavin form of the prosthetic group represents a transient intermediate of the monooxygenation process. The oxygenated and reduced forms of the prosthetic group help stabilize interactions with cofactor and substrate alternately to permit continuous enzyme turnover. three-dimensional structure | xenobiotics | methimazole

The nucleophilic addition of beta-lactam-4-ylidenes, a type of ambiphilic cyclic amidocarbene, to aryl isocyanates is studied and their application in organic syntheis is demonstrated. It is reported that beta-lactam-4-ylidenes, actually behave as good nucleophiles as bisheteroatom-substituted carbenes in the addition reaction to isocyanates to form both N- and O-lactam substituted spiro(azetidine-2-one-4,3'-indole-2'-one) derivatives.

The results from a thorough natural bond orbital analysis of several transition states (TSs) for nucleophilic additions to carbonyl function are discussed. It is demonstrated that the absence or presence of the Cieplax type [sigma]->[sigma.sup.*#] interaction depends on whether the TS in question is of early or late character.

Infrared and electronic spectroscopy was applied to the benzene-ammonia cluster cation in the gas phase, and the observed spectra revealed the formation of a new C-N valence bond between the benzene and ammonia moieties, which is predicted by the quantum chemical calculations. This cluster cation is regarded as a model for the cyclohexadienyl type intermediate in nucleophilic substitution reactions.

The nucleophilic pentafluoroethylation reagent generated by reduction of pentafluoroethyl iodide by tetrakis(dimethylamino)ethylene (TDAE) is useful in their nucleophilic reactions with aldehydes, ketones, imines, disulfides and diselenides. Irradiation has proved to be very useful in the aldehyde and ketone reactions.

The reactivity of (2-azaallyl)nitriles toward double nucleophilic addition and the double allylation reactions of (2-azaallyl)stannanes are reported. The conversion of the N,N-bis(3-butenyl)amines obtained as products from the double allylation reactions to 2,3,6,7-tetrahydroazepines through ring-closing metathesis is described.

The crystal structures of the yeast 20S proteasome core particle (CP) in complex with Salinosporamides A (NPI-0052; 1) and B(4) that were solved at

A comprehensive pH-rate study is undertaken using spectral global fitting and chloride nucleophile trapping of CC-1065's A-ring bearing the 2-substituents, and spectral global fitting is developed to study intermediates in complex photochemical reactions. The results imply that the general-acid-catalyzed alkylation of DNA minor groove by the A-ring is possible, but the 2-substituent does not affect the pKa of the protonated carbonyl of the A-ring and has little effect on the rate of nucleophile trapping.

Full details of the theoretical study are reported on the lithium--halogen reaction of 1,1-dihaloalkenes with methyllithium and the nucleophilic substitution reaction of the resulting alpha-halo alkenyllithium compounds. The thermodynamic preferences were predicted correctly by the energy differences of the products.

Reactive studies are performed of the iron-hydroperoxo species in nucleophilic and electrophilic reactions with in situ-generated mononuclear non-heme iron(III)-hydroperoxo complexes that are well characterized with various spectroscopic techniques. Results demonstrate that non-heme iron(III)- hydroperoxo species are sluggish oxidants and that the oxidizing power of the intermediates cannot compete with that of high-valent iron(IV)-oxo complexes.

Bowman's adiabatic rotation approximation is employed to describe reactive systems that have symmetric-top geometries during the entire collision progress. The results are compared with the approach of shifting the total energy by a characteristic rotational energy.

1,3-Dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one, prepared by intramolecular displacement of nitro group in N-(2-hydroxyphenyl)-2,4,6-trinitrobenzamide, reacts with O- and S-nucleophiles to yield the products of mono-or bis-substitution of the nitro group. N-Alkylation of the nitro substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones yields analogues of a known antidepressant drug Sintamil.

Ab calculations are used to study the S(sub N)2 reactions of the CH3OCH2I with a methoxide ion (CH(sub 3)O(super -) and a methanol molecule by systematically building the reaction system with explicit incorporation of the methanol solvent molecules. The result suggest that molecule S(sub N)2 reaction could be very fast in methanol solutions through reaction with the methanol tetramer.

Conformationally restrained substituted pregnane-20-one derivatives are obtained by an intramolecular nitrene and dition onto a C-5/C-6 double bond involving a tethered C-19 sulfamoyl moiety. The resulting aziridine underwent regioselective nucleophilic ring opening at C-5 at room temperature with cyanide, fluoride, and acetate.

4-(dimethylaminopyridine) (DMAP) immobilized mesporous silica catalyst is successfully synthesized and characterized which showed high recyclability and high turnover number for Baylis-Hillman, acylation, and silylation reaction. DMAP-functionalized mesoporous silica material can serve as an efficient heterogenous catalyst for many other catalytic nucleophilic reactions.

A series of gas-phase nucleophilic substitution reactions at sulfur of methanesulfinyl derivatives by small anions is examined by Hartree-Fock, MP2, and DFT computations. In most cases, substitution is found to follow an addition-elimination mechanism, resulting in a triple-well potential energy surface with small barriers of activation on either side of the central, tetracoordinate-sulfur minimum.

A study of the denitrosation mechanism of N(super 1)-nitrosomelatonin (NOMe1) as a model for N(super 1)-nitrosoindoles is presented. The results revealed that NOMe1 slowly decomposes spontaneously in aqueous solution, generating melatonin as the main organic product.

The extension of carbocyclizations of C-tethered N-acyloxyiminium ions with substituted alkene, alkyne and allene tethers to give novel azacyclic ring systems is reported. It is shown that the carbocyclization of mixed allene/alkene/alkyne tethers favors reaction of the allene, leading to the preferential formation of relatively strained hydrooxazinones rather than the corresponding hydroindoles.

The scope and limitations of the CF3I/TDAE reagent in nucleophilic trifluoromethylation chemistry is studied. It is demonstrated that a two-electron transfer from TDAE to CF3I generates a stabilized TDAE dication/trifluoromethyl anion 'complex'.

The m-chloroperoxybenzoate (m-CPBA) anion is highly efficient nucleophilic epoxidating reagent for strongly deactivated olefins containing two electron-withdrawing groups at the same carbon, under mild conditions. It is observed that the combined use of m-CPBA with catalytic or stoichiometric amounts of KOH or K2CO3 allows the selection formation of oxirans only from strongly gem-disubstituted olefines by electron withdrawing agents.

The site-directed mutagenesis studies of the three conserved active site residues, namely, His292, Arg237, Glu266, as well as Lys76 are reported. The versatility of nature's catalytic scaffolds is highlighted, as a common framework with modest changes allows phosphite dehydrogenase to catalyze its unusual nucleophilic displacement reaction and D-hydroxy acid dehyrogenases to oxidize alcohols to ketones.

A variety of key precursors to the intramolecular Diels-Alder reaction of furan diene (IMDAF) are prepared via a very facile 1,4-addition of O-, S-, N-, and C-entered nucleophiles possessing unsaturated tether to beta-furyl nitroethylene. Subsequent IMDAF reaction of the 1,4-adducts, carried out under thermal conditions, provided five- and six-membered carbocycles and heterocycles fused to an easily cleavable oxabicycloheptane moiety.

The viability of hydroxylamines as nucleophiles in transition-metal-catalyzed allylic substitution was examined. It was found that the oxygen atom of hydroxylamines having an N-electron-withdrawing substituent acts as a reactive nucleophile.

The EXAFS measurements have been interpreted as the cation (dppe)Pd[H2-CC(H)CMe(sub 2)](super +) has different structures in the solid phase and in THF solution. This structural alteration was suggested to play a role in governing the regioselectivity of the nucleophilic addition to the allyl carbons.

The seven serotypes of botulinum neurotoxins (A-G) produced by clostridium botulinum share significant sequence homology and structural similarity. The study reveals the role of the nucleophilic water and the charge on the catalytic activity.

The nucleophilic substitution of hydrogen in heterocyclic chemistry is discussed. The study shows that the formal total synthesis of D, L-physostigmine, the key intermediate is obtained in the reaction of 4-nitroanisole with 3-pheylpyrrolidin-2-one derivative following the fluoride-assisted ONSH protocol.

The reaction cross-sections and the speed of product distribution are specified for the bimolecular gas phase nucleophilic substitution (SN2) reaction as a function of collided force. The outcome indicates that the exothermic SN2 reaction is not sufficient in comparison to the phasespace theory along with the ion dipole capture models.

The ability of a carbanion to displace the leaving group in a barrierless process is examined. It is found that the concerted nature of the reaction depends on the conditions used to generate the carbanion.

Density functional studies, based on the local density approximation including nonlocal correction for correlation and exchange self consistently, are carried out for the equilibrium structures of the phosphinidene transition metal complex MLn=PH. The calculated geometries indicate that the length of the metal-phosphorus bond for all studied complexes, depend solely on the atomic size of the transition metal and not on the nature of its ligands.

The nucleophilic solvent participation in the solvolysis of tert-butyl chloride, and the development of solvent N values which appears to ignore the ground-state destabilization and the importance of hydrogen bond donating solvents to stabilize developing anion in the transition state are described. The solvent N values that were generated to characterize solvent nucleophilicity are not correlated by measures of solvent basicity but rather by the negative of measures of solvent hydrogen bond donor ability.

The synthesis of cis- and trans-3-(benzyloxymethyl)-1, 2-epoxycyclohexanes allows the study of their nucleophilic addition reactions. In the presence of a metallic salt catalyst, the cis-epoxide forms chelate intermediates which invite a nucleophilic attack on the C-1 oxirane carbon, resulting in ring cleavage. Its preference for chelation thus sterically directs the site of cleavage. The trans-epoxide, on the other hand, is prevented from undergoing chelation reactions due to its conformation. Its ring opening reactions are based on steric factors alone.

A unimolecular nucleophilic substitution (SN1) mechanism characterizes the reaction of N-(sulfonatooxy)-2-(acetylamino)fluorene with the aromatic amines, aniline and N,N-dimythelaniline. The observations on the kinetics and products of the reaction reveal the occurrence of an insubstantial overall rate effect and independent product yields. The study shows that the steric hindrance caused by the nitrogen in the fluorene compound apparently facilitates the alteration of the SN2 process leading to the development of the SN1 process.

The type of metal determines the synthetic route to be taken in nucleophilic organometallic reactions with 2-(1-naphthyl)- and 2-cinnamyl-1,3-oxazolidines. Organomagnesium reagents promote 1,4-conjugate addition while lithium, cerium and copper organometallic reagents facilitate 1,2-addition. Furthermore, the results have shown that organocerium reagents provide the most efficient 1, 2-addition to 2-substituted 1,3-oxazolidines. In addition, two 1,2-addition amino alcohol intermediates have been successfully converted to alpha-(1-naphthyl)alkylamines.

The highly reactive 2,3-dihalo-1-(phenylsulfonyl)-1-propenes can serve as precursors for the formation of different (phenylsulfonyl)methyl-substituted and annulated furans. The beta-dicarbonyl anions and the solvent that are introduced in the reaction influence the initial alkylation reaction's regiochemistry and the type of furan nucleus produced. Furthermore, the presence of 1,3-dicarbonyls at the C2-position completely reverses the manner of ring closure. The method can also be used in the preparation of functionalized cyclopentenones through the addition of beta-diketone and -keto ester anions to the dihalo propene.

The reaction of 1-(phenylsulfonyl)-1,2-propadiene with either bromine or iodine results in the formation of a highly reactive 2,3-dihalo-1-(phenylsulfonyl)-1-propene which features allyl halide, vinyl halide and vinyl sulfone functionalities at a three-carbon array. The nature and condition of the nucleophilic reactions determine the reactivity of the dihalo propene. Amines, thiophenols, sodium hydrides and ambident nucleophiles such as beta-dicarbonyls, silyl enol ethers and thioamides react with the dihalo propene to efficiently synthesize different arylsulfonyl-substituted heterocycles and furans.