Resolution of the identity PBE (RI-PBE) and B3LYP density functional theory calculations are used to understand the cytochrome P450-catalyzed, Compound I-mediated oxidation of perchlorobenzenes, perfluorobenzenes, their phenols, and mixed chlorofluorobenzenes to form benzoquinones. Addition of Compound I to the chlorine-bearing carbon of perchlorobenzenes and perchlorophenols results in an apparently barrierless 1,2-shift of the chlorine atom to form hexachlorocyclohexadienones and hydroxypentachlorocyclohexadienones, respectively. Hexachlorocyclohexadienone has a significant electron affinity, and its radical anion expels chloride in a facile manner to give the pentachlorophenoxyl radical. Deprotonation of hydroxypentachlorocyclohexadienones results in the expulsion of chloride and provides a direct route to the production of tetrachloroquinones. Barrier heights for Compound I addition to fluorine-bearing carbons of hexafluorobenzene and pentafluorophenol are comparable to those computed for oxidation of benzene via an analogous reaction path. In contrast to the chlorinated cases, fluorine migration to cyclohexadienones occurs with a moderate barrier. Additionally, gas-phase elimination of fluoride from the hexafluorocyclohexadienone radical anion and deprotonated hydroxypentafluorocyclohexadienone are not facile. Rather, consideration of implicit and explicit solvent is required to achieve favorable thermochemistry for fluoride elimination and generation of the experimentally observed products. Finally, the theoretical approach described herein is predictive of the experimentally observed preferential elimination of fluorine from chloropentafluorobenzene and 1,3,5-trichloro-2,4,6-trifluorobenzene. These studies illustrate the effectiveness of P450 Compound I as an oxidant of halogenated aromatic hydrocarbons, which are persistent environmental contaminants, and the potential utility of such computational methods for predicting P450 metabolism.
