A hybrid computational approach to the benzoin synthesis in different media

Abstract

Benzoin derivatives are widely used in organic chemistry, mainly as starting materials in drug synthesis and photoinitiators in polymer chemistry, due to their bifunctionality, the presence of the asymmetric center, and the photolabile benzoyl group. In this study, the synthesis of benzoin has been modeled in two different media in the presence of two different catalysts. In the first part of the study, the reactions of benzil derivatives (donor aldehydes) with benzaldehyde derivatives (acceptor aldehydes) have been modeled with PM3 and B3LYP/6-31G*. The reaction mechanism and the effect of ortho substitutions on the aromatic phenyl rings have been discussed. The rate determining steps have been rationalized based on the effect of the substituents. Among the substituted benzaldehydes o-fluoro benzaldehyde has been found to decrease the activation barrier of the reaction. In the second part of the reaction, the enantioselective benzoin synthesis in benzoylformate decarboxylase (BFD) environment has been investigated with molecular dynamics. The effect of the surrounding residues in the vicinity of the active center has been elucidated. Ten models with various protonation states of the amino acids and their mutated counterparts near the active center have been devised, modeled and analysed. Our studies indicate that H70, S26 and H281 are the catalytically important amino acids besides E47 cited in the literature. The role of these residues in the catalytic function of the enzyme has been rationalized. Furthermore, the experimentally observed enantioselectivity was explained on the basis of the face selectivity of the enamine/carbanion produced during the reaction.