Inactivation path during the copper (II) catalyzed synthesis of Questiomycin A from oxidation of 2-aminophenol

Abstract

The catalytic oxidation of 2-aminophenol (OAP) to 2-amino-3H–phenoxazin-3-one (APX, Questiomycin A) was the object of numerous studies partly due to antimicrobial properties of Questiomycin A and mostly because it can be used as a model for the synthesis of the naturally occurring antineoplastic agent Actinomycin D. Several copper complexes were used as dioxygen and/or substrates activators in order to mimic the activity of phenoxazinone synthase, but the reported assays failed to provide reasonable mechanistic features in media compatible with natural conditions. The main purposes of our work were to use simple copper salts to perform oxidation of OAP in oxygenated aqueous solutions and to develop a reaction scheme able to explain the low yields in APX along with the operational inactivation of the catalyst. A 11-step kinetic model able to describe the inactivation of copper(II) catalyst during oxidation of OAP to APX in oxygenated solutions was developed, and the rate constants for both catalytic and non-catalytic branch were estimated either experimentally or using a computing program for detailed kinetic simulation. It was demonstrated that the inactivation path can be assigned to formation of the stable bis(o-iminosemiquinonato)copper(II) complex, a compound reported as a moderate antimicrobial agent.