Click chemistry — the subject of the 2022 Nobel Prize in Chemistry — is a powerful and efficient method for rapidly connecting chemical fragments. One highly versatile type of click chemistry involves the so-called SuFEx [sulfur(VI) fluoride exchange] reaction, which results in the formation of covalent bonds under mild conditions and can greatly simplify the synthesis of therapeutically relevant small molecules, peptides and proteins. SuFEx chemistry involves attaching a –SO2F molecular moiety, after which the F atom can easily be replaced with a range of functional molecular groups of therapeutic value. An obvious reagent for introducing the –SO2F moiety is the gaseous component sulfuryl fluoride SO2F2, but since this is mildly toxic, it requires elaborate synthetic procedures to avoid its direct use.
Now, researchers at the Flow Chemistry group of the University of Amsterdam’s Van ‘t Hoff Institute for Molecular Sciences (the Netherlands; (hims.uva.nl) have developed a modular flow-chemistry platform for a safe and efficient execution of SuFEx click chemistry. In a recent article in Nature Synthesis, they describe how their platform generates the toxic gaseous SO2F2 reagent in a safe and controlled manner, and how it facilitates the subsequent fast and selective functionalization of small molecules, peptides and proteins for therapeutic purposes.
The system consists of two interconnected flow reactors (diagram). The first generates SO2F2 in a controlled and dosed manner from inexpensive commodity chemicals sulfuryl chloride (SO2Cl2) and potassium fluoride. In the second reactor, the generated gaseous SO2F2 is mixed with other reactants, ultimately yielding the desired SuFEx product. By immediately reacting away the SO2F2, the modular system effectively eliminates the safety and practical concerns of the toxic reactant. While exploring the performance of their system, the researchers were able to obtain a diverse range of SuFEx products with excellent yields in just two minutes of residence time. They attribute this short residence time to the intimate contact between gas and liquid phase in a flow system.