Model and Mechanism: N-Hydroxylation of Primary Aromatic Amines by Cytochrome P450

摘要

Primary aromatic amines (PAA) are used for the synthesis of various products including pesticides, pharmaceuticals, rubber, azo dyes, epoxy polymers, and aromatic polyurethane materials, and are thus of considerable industrial interest. Their potential mutagenicity and carcinogenicity have been recognized to be initiated through N-hydroxylation by cytochrome P450 enzymes (P450). The underlying reaction mechanism, however, is still a matter of debate. So far, four pathways involving the active-site ferryl oxo species Fe~(IV)O called Compound I (Cpd I) and one route catalyzed by the ferric peroxo dianion Fe~(III)OO have been discussed (Scheme 1 a-e): a) H-atom transfer (HAT), involving H- atom abstraction from the amine N by the FeO oxygen center and a subsequent radical rebound step to yield the aromatic hydroxylamine ArNHOH; b) oxygen addition rearrangement (OAR), wherein the FeO oxygen atom adds at the N lone pair with subsequent rearrangement to the hydroxyl- amine; c) single-electron transfer (SET) from the amine to FeO with subsequent proton transfer and a final rebound step between the intermediate aminyl radical and FeOH; d) two-electron transfer (TET), of which only the variant with the maximum number of elementary steps . (SET + proton transfer + SET + rebound) is shown in the scheme; and e) proton transfer (PT) to FeOO~(2-)to form the ferric hydroperoxide anion FeOOH~- (Cpd 0) and ArNH", thus eventually leading to ArNHOH upon protonation.