Voltammetry of nitrobenzene with cysteine and other acids in DMSO. Implications for the biological reactivity of reduced nitroaromatics with thiols

A cyclic voltammetric investigation of nitrobenzene in DMSO in the presence of various acids including boc- and methylester-protected cysteine is reported. It has been hypothesized that the reaction of thiols with reduced nitroaromatics is at the root of the biological activity for a variety of nitroaromatics, including a number of medicinally important nitroheterocycles used to treat infections by anaerobic microorganisms. This study shows that the only reaction occurring between cysteine and the 1e− reduction product, the nitro radical anion, is proton transfer. However, by comparing the voltammetry observed in the presence of cysteine to that observed in the presence of a range of different acids in DMSO we found that further reaction occurs between cysteine and the 2e− reduction products, either the nitrogen diol or the nitroso, greatly enhancing the overall rate of the reduction. This solution reaction proceeds through a rapidly formed, oxidizably-detectable intermediate, which, by analogy to known chemistry in aqueous solution, is likely the semi-mercaptal. Thus this study shows that cyclic voltammetry in aprotic solvents is a very useful technique for studying the reactivity of nitroaromatics with thiols and confirms that the substantive reaction occurs at the 2e− stage of the reduction.