Hydride transfer from carbon

There are also reactions in which hydride is transferred from carbon. The carbon-hydrogen bond has little intrinsic tendency to act as a hydride donor, so especially favorable circumstances are required to promote this reactivity. Frequently these reactions proceed through a cyclic TS in which a new C—H bond is formed simultaneously with the C-H cleavage. Hydride transfer is facilitated by high electron density at the carbon atom. Aluminum alkoxides catalyze transfer of hydride from an alcohol to a ketone. This is generally an equilibrium process and the reaction can be driven to completion if the ketone is removed from the system, by, e.g., distillation, in a process known as the Meerwein-Pondorff-Verley reduction,189 The reverse reaction in which the ketone is used in excess is called the Oppenauer oxidation. 

The reaction proceeds via a cyclic TS involving coordination of both the alcohol and ketone oxygens to the aluminum. Computational (DFT) and isotope effect studies are consistent with the cyclic mechanism.190 Hydride donation usually takes place from 

Reduction of Carbon-Carbon Multiple Bonds, Carbonyl Groups, and Other Functional Groups 

Recently, enantioselective procedures involving chiral catalysts have been developed. The combination of BINOL and A1(CH3)3 can achieve 80% e.e. in the reduction of acetophenone.192 Compound J is also an effective catalyst.193 

Certain lanthanide alkoxides, such as r-BuOSmL, have also been found to catalyze hydride exchange between alcohols and ketones.194 Isopropanol can serve as the reducing agent for aldehydes and ketones that are thermodynamically better hydride acceptors than acetone. 

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Hydride transfer from carbon to a carbonyl carbon atom occurs, reversibly, in the above reaction of which the classical example is the reduction of ketones, e.g. (43), with Al(OCHMe2)3 (44) in propan-2-ol,... 

That specific hydride transfer from carbon to carbon does occur, was established by showing that use of labelled (Me2CDO)3Al led to the formation of RjCDOH. The reaction probably proceeds via a cyclic T.S. such as (47), though some cases have been observed in which two moles of alkoxide are involved—one to transfer hydride ion, while the other complexes with the carbonyl oxygen atom. The reaction has now been essentially superseded by MH reductions, but can sometimes be made to operate in the reverse direction (oxidation) by use of Al(OCMc3)3 catalyst, and with a large excess of propanone to drive the equilibrium over to the left. This reverse (oxidation) process is generally referred to as the Oppenauer reaction. 

FIGURE 24.12 The mechanism of acyl-CoA dehydrogenase. Removal of a proton from the u-C is followed by hydride transfer from the /3-carbon to FAD. 

The aldehyde or ketone, when treated with aluminum triisopropoxide in isopropanol as solvent, reacts via a six-membered cyclic transition state 4. The aluminum center of the Lewis-acidic reagent coordinates to the carbonyl oxygen, enhancing the polar character of the carbonyl group, and thus facilitating the hydride transfer from the isopropyl group to the carbonyl carbon center. The intermediate mixed aluminum alkoxide 5 presumably reacts with the solvent isopropanol to yield the product alcohol 3 and regenerated aluminum triisopropoxide 2 the latter thus acts as a catalyst in the overall process ... 

The overall stoichiometry of hydride transfer from a silicon center to an electron-deficient carbon center is quite straightforward. Almost without exception, it appears that there is simple interchange of hydride to the carbocation while the silicon center receives the elements of the carbocation s counterion (Eq. 3). 

It is well known that strong electrophiles such as carbocations are reduced by organosilicon hydrides (Eq. 1).3,70,71 On the other hand, simple mixtures of organosilicon hydrides and compounds with weakly electrophilic carbon centers such as ketones and aldehydes are normally unreactive unless the electrophilicity of the carbon center is enhanced by complexation of the carbonyl oxygen with Brpnsted acids3,70 73 or certain Lewis acids (Eq. 2).1,70,71,74,75 Using these acids, hydride transfer from the silicon center to carbon may then occur to give either alcohol-related or hydrocarbon products. 

Alternatively, unreactive mixtures of organosilicon hydrides and carbonyl compounds react by hydride transfer from the silicon center to the carbon center when certain nucleophilic species with a high affinity for silicon are added to the mixture.76 94 This outcome likely results from the formation of valence-expanded, pentacoordinate hydrosilanide anion reaction intermediates that have stronger hydride-donating capabilities than their tetravalent precursors (Eq. 6).22,95 101... 

Reduction of carbonyl compoundsThe reagent reduces aldehydes or ketones to alcohols in refluxing cyclohexane in 2-5 hours yields are 60-80%. The reduction probably involves hydride transfer from the carbon beta to the magnesium center. 

Thus, the role of zinc in the dehydrogenation reaction is to promote deprotonation of the alcohol, thereby enhancing hydride transfer from the zinc alkoxide intermediate. Conversely, in the reverse hydrogenation reaction, its role is to enhance the electrophilicity of the carbonyl carbon atom. Alcohol dehydrogenases are exquisitely stereo specific and by binding their substrate via a three-point attachment site (Figure 12.7), they can distinguish between the two-methylene protons of the prochiral ethanol molecule. 

In a collaboration between the Abelson and Hecht labs [56b], a series of noncoded amino acids were introduced into dihydrofolate reductase (DHFR) to probe substrate binding and the requirement of an aspartic acid residue for catalytic competence. When aspartic acid analogs mono- or disubstituted at the )0-carbon were substituted for the active site aspartic acid residue, the mutant DHFRs were still able to catalyze the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate at 74 - 86 % of the wild-type rate. While hydride transfer from NADPH is not the rate-limiting step for the wild-type enzyme at physiological pH, a kinetic isotope experiment with NADPD indicated that hydride transfer had likely become the rate-limiting step for the mutant containing the )0,)0-dimethylaspartic acid. 

The reaction of complex hydrides with carbonyl compounds can be exemplified by the reduction of an aldehyde with lithium aluminum hydride. The reduction is assumed to involve a hydride transfer from a nucleophile -tetrahydroaluminate ion onto the carbonyl carbon as a place of the lowest electron density. The alkoxide ion thus generated complexes the remaining aluminum hydride and forms an alkoxytrihydroaluminate ion. This intermediate reacts with a second molecule of the aldehyde and forms a dialkoxy-dihydroaluminate ion which reacts with the third molecule of the aldehyde and forms a trialkoxyhydroaluminate ion. Finally the fourth molecule of the aldehyde converts the aluminate to the ultimate stage of tetraalkoxyaluminate ion that on contact with water liberates four molecules of an alcohol, aluminum hydroxide and lithium hydroxide. Four molecules of water are needed to hydrolyze the tetraalkoxyaluminate. The individual intermediates really exist and can also be prepared by a reaction of lithium aluminum hydride... 

A key step in DNA biosynthesis, that of conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), is catalyzed by thymidylate synthetase which uses (25) as cofactor. This reaction involves both the transfer of a one carbon unit at the formaldehyde level and hydride transfer (from C-6 of (25)) to produce 7,8-dihydrofolate (27) and dTMP... 

Catalysis of glutamate dehydrogenase starts with a hydride transfer from the a carbon of the amino acid to NAD+ (fig. 22.5). The resulting a-iminoglutarate hydrolyzes to a-ketoglutarate and ammonia. 

Estimates of the kinetics of methyl loss from energy-selected CztHg" species have been made by calculation.23 The hydride transfer from alkanes to carbenium ions in the gas phase is calculated to involve a species with a symmetric potential well, which is different from the situation in superacid or zeolite media.24 A correlation between the charge on a carbon and the in-plane tensor component of its 13 C chemical shift has been observed for a number of simple cationic and anionic species.25 High-level calculations... 

Deuterium isotope effect in the hydride ion transfer from carbon-hydrogen bonds to CS ... 

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