Heteroatom Oxidation and Dealkylation

The ability of P450 enzymes to oxidize nitrogen atoms to radical cations via an initial electron abstraction is supported by a mmiber of experimental results. The finding that the 4-alkyl group of 3,5-(6/s)carbethoxy-2,6-dimethyl-4-alkyl-l, 

Differences in the deuterium isotope effects for the oxidation of carbons adjacent to nitrogen vs oxygen suggest that the two reactions are mediated by different mechanisms. The intramolecular isotope effect for O-deethylation of deuterium substituted 7-ethoxycoumarin is 13 and for O-demethylation of 4-nitroanisole with a trideuterio methyl group is lO - In contrast, an isotope effect of 2-3 is obtained for the N-dealkylation of N-methyl-N-trideuteriomethylaniline The intrinsic isotope effects for O-dealkylation thus approach those for normal carbon hydroxylation reactions, but the isotope effects for N-dealkyla-tion are much lower. 

Support for a nitrogen radical cation mechanism in P450-catalyzed A-dealkylation reactions 

It has been proposed that the isotope elFects for the P450-catalyzed oxidations of hydrocarbons and alkylamines are similar to those observed in the reactions of the same substrates with the tert-butoxyl radical The finding that the measured kinetic isotope effects for the hydrogen abstraction from benzylic methyl groups fall on the same line as those for the iV-demethylation of 

In sum, the course of heteroatom oxidation appears to be sensitive to the oxidation potential of the heteroatom, the acidity of hydrogens on the adjacent carbon, and steric factors. The bulk of the evidence suggests that oxidation of the nitrogen in amines generally involves electron abstraction followed primarily by A-dealkylation if a labile proton is present, or nitrogen oxidation if it is not. As the nitrogen oxidation potential increases, there is a shift toward direct insertion into the C-H bond, as is thought to occur in the A-dealkylation of amides. 

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Scheme 1 Typical reactions catalyzed by cytochromes P450 (a) hydroxylation of saturated hydrocarbons (b) heteroatom oxidation and dealkylation (c) olefin epoxidation (d) aromatic hydroxylation (e) desaturation (f) aldehyde deformylation.

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