Switchable SuFEx linker chemistry for efficient coupling of alcohols, thiols, and selenols with O-/N-nucleophiles

Highly efficient linkage of readily available nucleophilic building blocks under mild conditions is essential for the synthesis of drug discovery and materials, yet it remains challenging due to the often unavoidable tendency of homo-coupling side reactions using traditional linkers. In this study, we present a versatile switchable SuFEx linker chemistry, exemplified by ESF, which enables highly efficient and selective coupling of thiols, alcohols, and selenols with O-/N-nucleophiles. This strategy harnesses the unique reactivity of the sulfonyl fluoride group in ESF, which can be “switched on” through noncovalent intramolecular interactions with chalcogen atoms, thereby facilitating subsequent SuFEx reactions and enabling the highly selective linkage of two distinct nucleophilic building blocks.