SO2F2 mediated click chemistry enables modular disulfide formation in diverse reaction media
Hengzhao Li, Mengqi Peng, Junyu Li, Lijun Wang, Hainam Do, Ke Ni, Minlong Wang, Zhankui Yuan, Tianxiao Zhao, Xiaohe Zhang, Xiaoxu Zhang, Zhaonong Hu, Fazheng Ren, Jie An
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.