Model systems for cytochrome P450 dependent mono-oxygenases. Part 2. Kinetic isotope effects for the oxidative demethylation of anisole and [Me-2H3]anisole by cytochrome P450 dependent mono-oxygenases and model systems

Abstract

Anisole, [Me-²H₃]anisole, and [¹⁸O]anisole have been used as substrates to study the mechanisms of oxidative demethylation by model systems for the cytochrome P450 dependent mono-oxygenases. The size of the kinetic isotope effect for the demethylation can be used as a sensitive probe of the oxidation mechanism and as a method for classifying the chemical systems. By this procedure 17 mono-oxygenase models and four microsomal systems have been examined. Two systems involving iron(III) prophyrins and iodosylbenzene show large kinetic isotope effects comparable with those from the microsomal oxidations and can be considered as good models for the biological process. The remaining systems exhibit smaller isotope effects, k_H/k_D 1–3.4. Alternative mechanisms for the oxidative demethylations are discussed and the major routes are shown to be either radical ipso-substitution or attack on the C–H bond of the methoxy-group.