Valence bond modelling and density functional theory calculations of reactivity and mechanism of cytochrome P450 enzymes: thioether sulfoxidation

Abstract

This paper introduces valence bond (VB) modelling of the mechanism and reactivity patterns of thioether sulfoxidation by cytochrome P450 enzymes (P450), as observed experimentally and as found computationally using DFT calculations on P450 sulfoxidation of para-(MeO, Me, H, NO₂) substituted thioanisoles. Thus, this study addresses the fundamental factors that cause the following two mechanistic puzzles: (a) Why do sulfoxidation reactions by P450 prefer direct oxygen atom transfer, while at the same time, the observed reaction rates exhibit correlations with electron transfer properties, e.g. the redox potentials of the thioethers? (b) Why do these reactions exhibit spin-selective chemistry and proceed on the low spin doublet state, unlike alkane hydroxylation that proceeds via two-state reactivity on both doublet and quartet states? The first puzzle is reminiscent of the classical electron transfer–polar dichotomy in physical organic chemistry, while the second one is unique to the oxidative chemistry by metal–oxo reagents. The VB modelling shows that the doublet state sulfoxidation involves bond formation coupled electron transfer (BFCET), while the quartet state process involves, in addition, a coupled d-orbital excitation, thereby generating a higher barrier. Combined with the previous VB modelling of alkane hydroxylation by P450, the VB diagram model emerges as a conceptual tool that enables understanding of mechanistic puzzles and is capable of estimating barriers in a complex reaction system.