ON ISOTOPE EFFECTS FOR THE CYTOCHROME-P-450 OXIDATION OF SUBSTITUTED N,N-DIMETHYLANILINES

Isotope effects were determined for the oxidative demethylation of the substituted N-methyl-N-(trideuteriomethyl)anilines 1a-d, and the corresponding N,N-bis(dideuteriomethyl)anilines 2a-d, by microsomal cytochrome P-450. The pairs of p-cyano- and p-nitro-N,N-dimethylanilines were found to have the same intramolecular isotope effects, while the unsubstituted and p-chloro derivatives had different isotope effects. It is concluded that, in general, intramolecular isotope effects measured for the enzymatic oxidations of N-methyl-N-(trideuteriomethyl)anilines are susceptible to masking. The isotope effect for the hydrogen (deuterium) atom abstractions from PhN(CH3)2 vs PhN(CD3)2 by the tert-butoxy radical was found to be 2.5. Interestingly, this is the same as the isotope effect measured for the cytochrome P-450 oxidation of N,N-bis(dideuteriomethyl)aniline (2a). These results are discussed with respect to the use of isotope effects for distinguishing the oxidative dealkylation mechanisms of amines by cytochrome P-450 and by related enzymes.