Disentangling the Puzzling Regiochemistry of Thiol Addition too-Quinones

The addition of thiol compounds too-quinones, asexemplified by the biologically relevantconjugation of cysteine todopaquinone, displays an anomalous 1,6-type regiochemistry compared tothe usual 1,4-nucleophilic addition, for example, by amines, which has so fareluded intensive investigations. By means of an integrated experimental andcomputational approach, herein, we provide evidence that the addition ofglutathione, cysteine, or benzenethiol to 4-methyl-o-benzoquinone, modelingdopaquinone, proceeds by a free radical chain mechanism triggered by theaddition of thiyl radicals to theo-quinone. In support of this conclusion, DFTcalculations consistently predicted the correct regiochemistry only for theproposed thiyl radical-quinone addition pathway. These results wouldprompt a revision of the commonly accepted mechanisms for thiol-o-quinoneconjugation and stimulate further work aimed at assessing the impact of thefree radical processes in biologically relevant thiol-quinone interactions.

Automated summary

This study provides evidence for the addition mechanism of thiol compounds to quinones and discovers an anomalous 1,6-type regiochemistry compared to the usual 1,4-nucleophilic addition. These findings would prompt a revision of the commonly accepted mechanisms for thiol-quinone conjugation and stimulate further research in this field.