Hydride transfer carbonyls

Approach of borohydnde to the top face of the carbonyl group is sterically hindered by one of the methyl groups The bottom face of the carbonyl group is less congested and the major product is formed by hydride transfer from this direction... 

The key step of the Cannizzaro reaction is a hydride transfer. The reaction is initiated by the nucleophilic addition of a hydroxide anion to the carbonyl group of an aldehyde molecule 1 to give the anion 4. In a strongly basic medium, the anion 4 can be deprotonated to give the dianionic species 5 ... 

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 ... 

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,... 

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack [rapid and reversible—step (1)] is by an anion—this time eCN—on the carbonyl carbon atom of one molecule, the donor (125) but instead of hydride transfer (cf. Cannizzaro, p. 216) it is now carbanion addition by (127) to the carbonyl carbon atom of the second molecule of ArCHO, the acceptor (128), that occurs. This, in common with cyanohydrin formation (p. 212) was one of the earliest reactions to have its pathway established— correctly —in 1903. The rate law commonly observed is, as might be expected,... 

On the basis of these experimental results, a possible mechanism has been proposed for the reaction of 1-215 with Sml2 (Scheme 1.52). After formation of the syn-complex A, a rearrangement occurs to give the aldehyde B, which coordinates to the added aldehyde RCHO to afford complex C. Subsequent samarium-catalyzed nucleophilic attack of the secondary alcohol to the carbonyl of RCHO generates a hemiacetal, D. There follows an irreversible intramolecular 1,5-hydride transfer via... 

Rhin(bpy)3]3+ and its derivatives are able to reduce selectively NAD+ to 1,4-NADH in aqueous buffer.48-50 It is likely that a rhodium-hydride intermediate, e.g., [Rhni(bpy)2(H20)(H)]2+, acts as a hydride transfer agent in this catalytic process. This system has been coupled internally to the enzymatic reduction of carbonyl compounds using an alcohol dehydrogenase (HLADH) as an NADH-dependent enzyme (Scheme 4). The [Rhin(bpy)3]3+ derivative containing 2,2 -bipyridine-5-sulfonic acid as ligand gave the best results in terms of turnover number (46 turnovers for the metal catalyst, 101 for the cofactor), but was handicapped by slow reaction kinetics, with a maximum of five turnovers per day.50... 

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... 

The reduction to methoxy-hydrido species (7) is thought to proceed via loss of CO from the dicarbonyl complex followed by addition of hydrogen to give the dihydrido carbonyl species (9). The next step suggested (37) is hydride transfer to the carbonyl carbon to give a formyl species in which both the carbonyl carbon and the carbonyl oxygen coordinate to the metal center, i.e., 10 ... 

In reaction (11) the metal-hydride addition suggests a protonation reaction whereas, in reaction (12) the addition appears to be a hydride transfer reaction. If the reaction is indeed a hydride transfer reaction then the introduction of p-electron donating substituents, which place more electron density at the carbonyl carbon, (the site of hydride attack) will inhibit hydride addition. The data in Table 2 show that the introduction of p-electron donating substituents reduces the turnover frequency. This is consistent with hydride attack at the benzaldehyde carbonyl carbon, (12). 

Molybdenum and tungsten carbonyl hydride complexes were shown (Eqs. (16), (17), (22), (23), (24) see Schemes 7.5 and 7.7) to function as hydride donors in the presence of acids. Tungsten dihydrides are capable of carrying out stoichiometric ionic hydrogenation of aldehydes and ketones (Eq. (28)). These stoichiometric reactions provided evidence that the proton and hydride transfer steps necessary for a catalytic cycle were viable, but closing of the cycle requires that the metal hydride bonds be regenerated from reaction with H2. 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

This system fulfills the four above-mentioned conditions, as the active species is a rhodium hydride which acts as efficient hydride transfer agent towards NAD+ and also NADP+. The regioselectivity of the NAD(P)+ reduction by these rhodium-hydride complexes to form almost exclusively the enzymatically active, 1,4-isomer has been explained in the case of the [Rh(III)H(terpy)2]2+ system by a complex formation with the cofactor[65]. The reduction potentials of the complexes mentioned here are less negative than - 900 mV vs SCE. The hydride transfer directly to the carbonyl compounds acting as substrates for the enzymes is always much slower than the transfer to the oxidized cofactors. Therefore, by proper selection of the concentrations of the mediator, the cofactor, the substrate, and the enzyme it is usually no problem to transfer the hydride to the cofactor selectively when the substrate is also present [66]. This is especially the case when the work is performed in the electrochemical enzyme membrane reactor. 

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. 

A viable iron carbonyl-mediated reduction process converts acid chlorides and bromoalkanes into aldehydes [3, 6]. Yields are high, with the exception of nitro-benzoyl chloride, and the procedure is generally applicable for the synthesis of alkyl, aryl and a,(i-unsaturated aldehydes from the acid chlorides. The reduction proceeds via the initial formation of the acyl iron complex, followed by hydride transfer and extrusion of the aldehyde (cf. Chapter 8). 

Ashby and Yu have studied the kinetics of reduction of benzophenone with TIBA in ether and showed that the overall kinetic rate expression is second order, first order in TIBA and first order in ketone (151). The observed activation parameters were AG - 18.8 kcal/mol AH = 15.8 kcal/mol and AS = - 10.1 e.u. The negative entropy of activation is consistent with a cyclic transition state for the rate-determining hydride-transfer step. A Hammett study gave a value of p = 0.362, supporting nucleophilic attack by the aluminum alkyl on the carbonyl group in the rate-determining step. 

The solvent isotope effect produces an A-ratio (HOH/DOD) of three with isotope-independent A// of 17-18 kJ/mol. This result is more difficult to interpret, because it is unknown how many isotopic sites in the enzyme or water structure contribute to the isotope effect of 2-3. If a single site should be the origin of the effect, then the site could reasonably be a solvent-derived protonic site of the enzyme involved in general-acid catalysis of the hydride transfer, most simply by protonic interaction with the carbonyl oxygen of cyclohexenone or possibly by proton transfer to an olefinic carbon of cyclohexenone. 

---