Mechanism of the dealkylation of tertiary amines by hepatic oxygenases. Stable isotope studies with 1-benzyl-4-cyano-4-phenylpiperidine.

The microsomal oxidative dealkylation of 1-benzyl-4-cyano-4-phenylpiperidine has been studied and the source of oxygen shown to be molecular oxygen. The rate of debenzylation was decreased by substituting deuterium for hydrogen in the methylene portion of the benzyl group. The isotope effect was measured by comparison of the reaction rates of the d0 and d2 compounds 1a and 1b and also of the d5 and d7 compounds 1c and 1d. Determination of the reaction rates for various mixtures of labeled and unlabeled species allowed the rates for 0 (kH) and 100 mol % (kD) to be accurately obtained. A primary isotope effect of 1.46 was observed when the methylene hydrogens of benzyl were replaced by deuterium. No secondary isotope was observed when the aromatic hydrogens of benzyl were replaced by deuterium. The results of this study are consistent with a mechanism involving direct hydroxylation at the benzyl methylene position in a rate-determining step.