Monitoring electrophilic intermediates in reactions of thiols in aqueous solution directly with 19F NMR

Abstract

Mechanistic studies of thiol reactivity can be challenging because electrophilic reaction intermediates, such as sulfenic acids (RSOH) and sulfenyl chlorides (RSCl), are generally too reactive to be observed directly. Herein we report the design and synthesis of a sterically-encumbered fluorinated triptycene thiol which enables direct observation of reaction intermediates in aqueous buffer by ¹⁹F NMR, as demonstrated in reactions with hydrogen peroxide and hypochlorous acid. Reactions with H₂O₂ resulted in the formation of a persistent RSOH species, which was subsequently converted to a sulfinic acid (RSO₂H) and then a sulfonic acid (RSO₃H), while RSCl was found to be the intermediate in reactions with HOCl. Utilizing the same scaffold, reactions of thiol with thermally and photochemically generated singlet oxygen afforded RSO₂H as the primary product. The stark difference in product profile from sterically-unencumbered thiols – which yield disulfides – implies that the reaction proceeds through a sulfenyl hydroperoxide (RSOOH) intermediate. Sulfenic acids, which were not observed in reactions of thiols with singlet oxygen, were also found to rapidly react with singlet oxygen to afford sulfinic acids, which is proposed to involve initial formation of an analogous sulfinyl hydroperoxide (RS(O)OOH). The formation and reactions of RSOOH are explored by computations. Use of the water-soluble fluorinated triptycene scaffold to probe reductive processes on RSOH (e.g., with ascorbate and/or iron) is also illustrated, wherein it was found that RSOH are surprisingly resistant to reductive heterolysis – in stark contrast with hydroperoxides – owing to their strong S–O bond.