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

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Abstract
The rat microsomal oxidative dealkylation of 1-benzyl-4-cyano-4-phenylpiperidine was studied and the source of O2 shown to be molecular O2. The rate of debenzylation was decreased by substituting deuterium (d) for H in the methylene portion of the benzyl group. The isotope effect was measured by comparison of the reaction rates of the do 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 O (kH) [H rate constant] and 100 mol% (KD) [D rate constant] to be accurately obtained. A primary isotope effect of 1.46 was observed when the methylene H of benzyl were replaced by d. No secondary isotope was seen when the aromatic H of benzyl were replaced by d. The results of this study are consistent with a mechanism involving direct hydroxylation at the benzyl methylene position in a rate-determining step.