Mechanistic imperatives for aldose-ketose isomerization in water: specific, general base- and metal ion-catalyzed isomerization of glyceraldehyde with proton and hydride transfer.

The deuterium enrichment of dihydroxyacetone obtained from the aldose-ketose isomerization of D,L-glyceraldehyde in D(2)O at 25 degrees C was determined by (1)H NMR spectroscopy from the integrated areas of the signals for the alpha-CH(2) and alpha-CHD groups of the product. One mole equivalent of deuterium is incorporated into the product when the isomerization is carried out in 150 mM pyrophosphate buffer at pD 8.4, but only 0.6 mol equiv of deuterium is incorporated into the product of isomerization in the presence of 0.01 M deuterioxide ion, so that 40% of the latter isomerization reaction proceeds by the intramolecular transfer of hydride ion. Several pathways were identified for catalysis of the isomerization of glyceraldehyde to give dihydroxyacetone. The isomerization with hydride transfer is strongly catalyzed by added Zn(2+). Deprotonation of glyceraldehyde is rate-determining for isomerization with proton transfer, and this proton-transfer reaction is catalyzed by Br?nsted bases. Proton transfer also occurs by a termolecular pathway with catalysis by the combined action of Br?nsted bases and Zn(2+). These results show that there is no large advantage to the spontaneous isomerization of glyceraldehyde in alkaline solution with either proton or hydride transfer, and that effective catalytic pathways exist to stabilize the transition states for both of these reactions in water. The existence of separate enzymes that catalyze the isomerization of sugars with hydride transfer and the isomerization of sugar phosphates with proton transfer is proposed to be a consequence of the lack of any large advantage to reaction by either of these pathways for the corresponding nonenzymatic isomerization in water.     

Frustrated Lewis Pair Mediated 1,2‐Hydrocarbation of Alkynes

Frustrated Lewis pair (FLP) chemistry enables a rare example of alkyne 1,2‐hydrocarbation with N‐methylacridinium salts as the carbon Lewis acid. This 1,2‐hydrocarbation process does not proceed through a concerted mechanism as in alkyne syn‐hydroboration, or through an intramolecular 1,3‐hydride migration as operates in the only other reported alkyne 1,2‐hydrocarbation reaction. Instead, in this study, alkyne 1,2‐hydrocarbation proceeds by a novel mechanism involving alkyne dehydrocarbation with a carbon Lewis acid based FLP to form the new C−C bond. Subsequently, intermolecular hydride transfer occurs, with the Lewis acid component of the FLP acting as a hydride shuttle that enables alkyne 1,2‐hydrocarbation.     

Cleavage of ethereal bond : IX. The reducing action of Grignard reagents on 1,3-benzoxathiole and 1,3-benzodioxole derivatives

Some reactions of 1,3-benzoxathioles and 1,3-benzodioxoles with Grignard reagents were examined in order to verify whether or not reduction products were present in addition to the substitution and elimination products previously observed. The reaction mixtures contain reduction products whenever the Grignard reagent has β-hydrogen atoms, in which case the reagent is likely to act as a hydride transfer agent. The product distribution also depends on steric hindrance by the halogen. 1,3-Benzodioxoles react with isopropylmagnesium bromide to give mixtures of alkanes and alkenes, the former arising from a double hydride ion migration, and the latter from a reduction and elimination process.     

Frustrated Lewis Pair Mediated 1,2-Hydrocarbation of Alkynes

Frustrated Lewis pair (FLP) chemistry enables a rare example of alkyne 1,2-hydrocarbation with N-methylacridinium salts as the carbon Lewis acid. This 1,2-hydrocarbation process does not proceed through a concerted mechanism as in alkyne syn-hydroboration, or through an intramolecular 1,3-hydride migration as operates in the only other reported alkyne 1,2-hydrocarbation reaction. Instead, in this study, alkyne 1,2-hydrocarbation proceeds by a novel mechanism involving alkyne dehydrocarbation with a carbon Lewis acid based FLP to form the new C−C bond. Subsequently, intermolecular hydride transfer occurs, with the Lewis acid component of the FLP acting as a hydride shuttle that enables alkyne 1,2-hydrocarbation.     

Conversion and origin of normal and abnormal temperature dependences of kinetic isotope effect in hydride transfer reactions

The effects of substituents on the temperature dependences of kinetic isotope effect (KIE) for the reactions of the hydride transfer from the substituted 5-methyl-6-phenyl-5,6-dihydrophenanthridine (G-PDH) to thioxanthylium (TX(+)) in acetonitrile were examined, and the results show that the temperature dependences of KIE for the hydride transfer reactions can be converted by adjusting the nature of the substituents in the molecule of the hydride donor. In general, electron-withdrawing groups can make the KIE to have normal temperature dependence, but electron-donating groups can make the KIE to have abnormal temperature dependence. Thermodynamic analysis on the possible pathways of the hydride transfer from G-PDH to TX(+) in acetonitrile suggests that the transfers of the hydride anion in the reactions are all carried out by the concerted one-step mechanism whether the substituent is an electron-withdrawing group or an electron-donating group. But the examination of Hammett-type free energy analysis on the hydride transfer reactions supports that the concerted one-step hydride transfer is not due to an elementary chemical reaction. The experimental values of KIE at different temperatures for the hydride transfer reactions were modeled by using a kinetic equation formed according to a multistage mechanism of the hydride transfer including a returnable charge-transfer complex as the reaction intermediate; the real mechanism of the hydride transfer and the root that why the temperature dependences of KIE can be converted as the nature of the substituents are changed were discovered.     

Theoretical studies of iridium-mediated tautomerization of substituted pyridines

Room temperature reaction of [Ir(COD)₂]BF₄ (COD = 1,5-cyclooctadiene) and amide-tethered or simple 2,3′-bipyridyls gave iridium(I) complexes bearing chelating protic pyridylidenes. This protic pyridylidene tautomer is stabilized by both chelation effect and by hydrogen bonding. The mechanistic details of this tautomerization of N-heterocycles to N-heterocyclic carbenes (NHCs) were investigated using the density functional theory (DFT). DFT studies suggested that cyclometalation of 2,3′-bipyridyls took place to give an iridium(III) hydride, which subsequently undergoes formal 1,3-hydrogen shift from the iridium to the pyridyl nitrogen atom. Two possible mechanisms of this formal 1,3-hydrogen shift process have been examined: the β-insertion of the hydride into an olefin followed by proton abstraction and the water-assisted proton transfer via a cyclic transition state. The latter mechanism is strongly favored in the presence of a catalytic amount of water, and this mechanism is applicable to the tautomerization of both amide-tethered and amide-free 2,3′-bipyridyls.     

Origin of stereoselectivity in the reduction of a planar oxacarbenium

The Kishi reduction of a planar oxacarbenium was investigated theoretically. The high diastereoselectivity for hydride transfer to the oxacarbenium intermediate is attributed to the conformation of the transition state that places the allyl side chain in an equatorial position in the major transition state and axial position in the minor. The minor transition state is destabilized by a 1,3-diaxial strain between the attacking hydride and the syn allyl side chain.     

Phosphine‐Catalyzed Interrupted Morita–Baylis–Hillman Reaction and Switchable Domino Reactions of α‐Substituted Activated Olefins with Formaldehyde and Mechanism Elucidation

3‐Olefinic oxindoles can undergo interrupted Morita‐Baylis‐Hillman reaction with formaldehyde. Apart from the previous reported dephosphoration to access reductive aldol‐type products, here we uncovered that completely different pathways were followed by tuning the substitutions of 3‐olefinic oxindoles. In combination with formalin, an unexpected domino phosphorus‐ylide formation, aldol‐type addition, hemeacetal formation and O‐substitution process was observed to produce 1,3‐dioxolane derivatives. Moreover, a switchable sequence to produce formate derivatives via a key hydride transfer process was furnished by simply replacing formalin with paraformaldehyde. Density functional theory calculations were conducted to well elucidate the catalytic reaction mechanism.     

Role of carbocation's flexibility in sesquiterpene biosynthesis: computational study of the formation mechanism of terrecyclene

Two mechanisms have been proposed in the literature to explain the formation of the skeleton of terrecyclic acid from farnesyl diphosphate. Both mechanisms satisfy the experimental data obtained using isotopic labeling, but computational results at the mPW1B95/6-31+G(d,p) level of theory allow the differentiation between them. While one of the mechanisms is basically a carbocation cascade, the other one requires several steps that imply high energetic demands. Specifically, there is a [1,3] hydride shift that requires approximately 100 kcal/mol making this mechanisms unlikely. The other mechanism is more plausible, and it suggests the participation of two secondary carbocation as intermediates, but these were not observed as minimums on the potential energy surface analyzed; they only appear as a point near the transition state in the intrinsic reaction coordinate. Both mechanisms proposed a [1,3] hydride shift, but in the less likely mechanism, the rigidity of the intermediate that undergoes the hydride shift greatly increases the energy of the corresponding transition state.     

A comparative computational investigation on the proton and hydride transfer mechanisms of monoamine oxidase using model molecules

Monoamine oxidase (MAO) enzymes regulate the level of neurotransmitters by catalyzing the oxidation of various amine neurotransmitters, such as serotonin, dopamine and norepinephrine. Therefore, they are the important targets for drugs used in the treatment of depression, Parkinson, Alzeimer and other neurodegenerative disorders. Elucidation of MAO-catalyzed amine oxidation will provide new insights into the design of more effective drugs. Various amine oxidation mechanisms have been proposed for MAO so far, such as single electron transfer mechanism, polar nucleophilic mechanism and hydride mechanism. Since amine oxidation reaction of MAO takes place between cofactor flavin and the amine substrate, we focus on the small model structures mimicking flavin and amine substrates so that three model structures were employed. Reactants, transition states and products of the polar nucleophilic (proton transfer), the water-assisted proton transfer and the hydride transfer mechanisms were fully optimized employing various semi-empirical, ab initio and new generation density functional theory (DFT) methods. Activation energy barriers related to these mechanisms revealed that hydride transfer mechanism is more feasible.     

BNAH还原质子化N—芳基芴亚胺反应的热力学及机理研究

利用热力学循环方法，通过ｐＫ和有关电化学数据的测定，首次得到了ＮＡＤ（Ｐ）Ｈ的辅酶模型物（ＢＮＡＨ）按不机理还原质子化Ｎ－芳基芴亚胺的各基元步骤的自由能变化，结合得到的同位素标纪结果，从热力学趋动力的角度区分了氢负离子的转移机理。     

Radical reduction of cyclic xanthates: Formation of alkenes and/or 1,3-oxathiolanes from 1,3-oxathiolane-2-thiones

AIBN-initiated radical reactions of 5-membered cyclic xanthates, 1,3-oxathiolane-2-thiones, with tributyltin hydride are described. Alkenes are formed at 0.025 M concentration of tributyltin hydride, whereas a higher concentration (0.25 M) gives 1,3-oxathiolanes. A mixture of alkene and 1,3-oxathiolane is obtained by use of intermediate concentrations. Reactions of cis-and trans-4,5-dialkyl-1,3-oxathiolane-2-thiones with tributyltin hydride afford E-alkenes stereoselectively. For an application of this alkene formation reaction, geraniol has been converted to linalool silyl ether in good yield.     

Stepwise Hydride Transfer in a Biological System: Insights into the Reaction Mechanism of the Light‐Dependent Protochlorophyllide Oxidoreductase

Hydride transfer plays a crucial role in a wide range of biological systems. However, its mode of action (concerted or stepwise) is still under debate. Light‐dependent NADPH: protochlorophyllide oxidoreductase (POR) catalyzes the stereospecific trans addition of a hydride anion and a proton across the C₁₇?C₁₈ double bond of protochlorophyllide. Time‐resolved absorption and emission spectroscopy were used to investigate the hydride transfer mechanism in POR. Apart from excited states of protochlorophyllide, three discrete intermediates were resolved, consistent with a stepwise mechanism that involves an initial electron transfer from NADPH. A subsequent proton‐coupled electron transfer followed by a proton transfer yield distinct different intermediates for wild type and the C226S variant, that is, initial hydride attaches to either C₁₇ or C₁₈, but ends in the same chlorophyllide stereoisomer. This work provides the first evidence of a stepwise hydride transfer in a biological system.     

Brønsted Acid Catalyzed Friedel–Crafts-Type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds

The direct Friedel–Crafts-type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal-free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α-diazo β-carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,β-unsaturated esters, β-indole-substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3- and 1,4- hydride transfer processes as well as fragmentation.     

Iridicycle‐Catalysed Imine Reduction: An Experimental and Computational Study of the Mechanism

The mechanism of imine reduction by formic acid with a single‐site iridicycle catalyst has been investigated by density functional theory (DFT), NMR spectroscopy, and kinetic measurements. The NMR and kinetic studies suggest that the transfer hydrogenation is turnover‐limited by the hydride formation step. The calculations reveal that, amongst a number of possibilities, hydride formation from the iridicycle and formate probably proceeds by an ion‐pair mechanism, whereas the hydride transfer to the imino bond occurs in an outer‐sphere manner. In the gas phase, in the most favourable pathway, the activation energies in the hydride formation and transfer steps are 26–28 and 7–8 kcal mol^?1, respectively. Introducing one explicit methanol molecule into the modelling alters the energy barrier significantly, reducing the energies to around 18 and 2 kcal mol^?1 for the two steps, respectively. The DFT investigation further shows that methanol participates in the transition state of the turnover‐limiting hydride formation step by hydrogen‐bonding to the formate anion and thereby stabilising the ion pair.     

Indium(III) acetate-catalyzed intermolecular radical addition of organic iodides to electron-deficient alkenes

In the presence of phenylsilane and a catalytic amount of indium(III) acetate, organic iodides added to electron-deficient alkenes in ethanol at room temperature. Both simple and functionalized organic iodides were applicable to this reaction. A plausible reaction mechanism involves the formation of indium hydride species by hydride transfer from silicon to indium and an indium hydride-mediated radical chain process.     

Mechanism of reduction of benzylidenemalono-nitrile by l-benzyl-1,4-dihydronicotinamide

The reduction of benzylidenemalononitrile by 1-benzyl-1,4-dihydronicotinamide undergoes via a one-step hydride transfer mechanism rather than a multistep mechanism involving initial electron transfer.     

Quantum chemical study on the mechanism of enantioselective reduction of prochiral ketones catalyzed by oxazaborolidines

The ab initio molecular orbital study on the mechanism of enantioselective reduction of 3,3-dimethyl butanone-2 with borane catalyzed by chiral oxazaborolidine is performed. As illustrated, this enantioselective reduction is exothermic and goes mainly through the formations of the catalyst-borane adduct, the catalyst-borane-3,3-dimethyl butanone-2 adduct, and the cata-lyst-alkoxyborane adduct with a B-O-B-N 4-member ring and through the decomposition of the catalyst-alkoxyborane adduct with the regeneration of the catalyst. During the hydride transfer in the catalyst-borane-3,3-dimethyl butanone-2 adduct to form the catalyst-alkoxyborane adduct, the hydride transfer and the formation of the B-O-B-N 4-member ring in the catalyst-alkoxyborane adduct happen simultaneously. The controlling step for the reduction is the transfer of hydride from the borane moiety to the carbonyl carbon of 3,3-dimethyl butanone-2. The transition state for the hydride transfer is a twisted chair structure and the reduction leads to     

Mechanism of a soluble fumarate reductase from Shewanella frigidimarina: a theoretical study

The mechanism of a unique fumarate reductase is explored using the hybrid density functional B3LYP method. The calculations show a two-step mechanism, initiated with a hydride transfer from FAD (flavin adenine dinucleotide) to fumarate, followed by a proton shift from Arg402. The rate-limiting process is assigned to the hydride transfer, and the energetics are consistent with experimental data. It is shown that the enzyme is essential to correctly position the substrate in the active site, stabilizing its extremely anionic character.     

Reduction of some polyhalogenato- and polyacetoxy- alyllic compounds with tributylin hydride in the presence or absence of a palladium catalyst: I. Reduction of dichloro- and diacetoxy-propenes

Radical-promoted tributylin hydride reduction of 3,3-dichloropropene, (Z)-1,3- dichloropropene, or (E)-1,3-dichloropropene yields a mixture of the three possible regio-stereoisomeric monochloropropenes. The palladium-catalyzed reduction yields regiospecifically the two stereoisomeric 1-chloropropenes with a Z/E ratio which remains constant whatever the starting dichloropropene but which is not the thermodynamic ratio. The results are against a radical mechanism and strongly support a polar π-allyl mechanism for the catalytic reactions.