Substrate-dependent changes of the oxidative O-dealkylation mechanism of several chemical and biological oxidizing systems

Abstract

The O-dealkylation mechanisms of a series of alkyl aryl ethers, mediated by several chemical and biological oxidizing systems, i.e. Cu²⁺–ascorbic acid–O₂, γ-radiolysis and rat liver microsomes-NADPH/O₂, were examined. In every oxidizing system, the O-dealkylation mechanisms changed dramatically depending on the nature of the substrates. In the Cu²⁺–ascorbic acid–O₂ system and γ-radiolysis, electron density at the ipso-position and the ease of H atom abstraction from the alkyl moiety of the substrates were critical to determine the O-dealkylation mechanism. In the cytochrome P450-dependent monooxygenases, the determinant was whether or not the substrate has a phenolic hydroxy group at an ortho- or para-position relative to the alkoxy group. The results have led us to propose a new O-dealkylation mechanism involving the initial formation of a phenoxyl radical.