SO2F2 mediated click chemistry enables modular disulfide formation in diverse reaction media

Abstract

The dynamic disulfide linkage plays a vital role in various biological processes as well as drugs and biomaterials. The conversion of thiols to their corresponding disulfides is a hallmark of sulfur chemistry, but notoriously difficult to control. Achieving optimal reactivity and selectivity continues to pose significant challenges. Here, we describe a click chemistry for disulfide formation from thiols in both batch and flow-mode using SO2F2, which display exceptional selectivity toward disulfide formation through an effective nucleophilic substitution cascade. This reaction’s unique characteristics satisfy the stringent click-criteria with its high thermodynamic driving force, straightforward conditions, wide scope, quantitative yields, exceptional chemoselectivity, and non-chromatographic purification process. The modular synthesis of symmetrical, unsymmetrical, cyclic and polydisulfides is demonstrated, along with the formation of disulfide cross-linked hydrogels. Disulfide bonds are widely found in nature and are prevalent in therapeutic contexts due to their dynamic nature. Here, the authors disclose a click chemistry protocol to convert thiols to disulfides using SO2F2, and show its application in aqueous contexts, in flow, and for polymerizations.