Mechanistic studies of oxene reactions with organic substrates: Reaction paths on MNDO enthalpy surfaces—models for cytochrome P450 oxidations

Abstract

AbstractIn a systematic study, the characteristics of triplet oxene models for alkane, alkene, chloroalkane, and aryl oxidations by the cytochrome P450s have been examined using the semiempirical molecular orbital method MNDO and the formalism of statistical mechanics. Specific model substrates chosen were: methane, ethylene, propene, carbon tetrachloride, chloroform, and toluene. It was found that transition state geometries and activation entropies were reliably predicted, but that an empirical factor was necessary to correct overestimation of activation enthalpies. It was determined that both hydroxylations and epoxidation initiated by a O(3P) atom are nonconcerted; and that oxidations of CCl bonds (halosylations) occur by a two‐step mechanism similar to hydroxylation. It is shown that the radical mechanisms derived from these studies are consistent with a range of observed properties of cytochrome P450 reactions and provide reasonable explanations for secondary deuterium isotope effects and substituent effects in cytochrome P450 epoxidation of styrenes, suicide inactivation of a P450 enzyme by ethylene, and the characteristics of aerobic CCl4 and CHCl3 metabolism. A triplet oxene mechanism for the initial steps of aromatic epoxidation and hydroxylation is also discussed.