Chemoselective cyclodesulfurization <i>vs.</i> dehydration enabled by aqueous microdroplet chemistry

Dehydration reactions are typically favored in microdroplets due to the relatively dry environment at the air-water interface. However, we demonstrate that cyclodesulfurization may outcompete dehydration under these conditions. We report on a catalyst-free method for inducing a two-step cyclodesulfurization in microdroplets under ambient conditions by reacting benzhydrazide with phenyl isothiocyanate. The reaction involves the formation of benzhydrazine-1-carbothioamide, a compound that contains two nucleophilic centers. During competing nucleophilic attacks by hydroxyl and thiol groups, reactive oxygen species at the droplet interface oxidize the thiol, forming the sulfoxylic and then the sulfurous acid. These transient reactive intermediates are detected using online mass spectrometry. The interfacial oxidation reduces thiol nucleophilicity, favoring hydroxyl-mediated nucleophilic attack to form 1,3,4-oxadiazole, a structural motif prevalent in pharmaceuticals. The reaction kinetics are influenced by reagent concentration and the droplet travel distance. The absence of dehydration (commonly found in microdroplet reactions) is a key finding of this work. Our findings also highlight the unique potential of charged microdroplets to promote chemoselective transformations, driven by the distinctive properties of the air-water interface.