A density functional study of the interconversion of carbonyls and alcohols in the solution: Comparison of reaction mechanisms involving NADPH, histidine, and tyrosine.

Several reaction mechanisms for the interconversion of carbonyls and alcohols in solution are examined. The model system includes acetaldehyde, 1-methyl-1,4-dihydropiridine as a hydride donor, and either 4-methyl-phenol or 4-methyl-imidazolium as a possible proton donor. This system is of relevance to understanding the catalytic mechanism of many oxidoreductase enzymes which use NADPH cofactor and tyrosine or histidine as general acids. The energetic changes are evaluated by constrained geometry optimization using density functional theory (B3LYP/6-31+G*) coupled to a Poisson-Boltzmann solvation scheme. The results show that a stepwise mechanism with an initial hydride transfer to the aldehyde is favored for both proton donors over the alternative stepwise mechanism, in which there is an initial proton transfer to the aldehyde. The: possibility of a concerted mechanism is also considered, but the corresponding activation energy exceeds those of the stepwise processes.