Accelerated Synthesis of Pyrazoles Mediated by Water Microdroplets

Microdroplets containing water in the presence of an electric field can generate superacids/superbases at the gas–liquid interface, and this unique property drives organic reactions within milliseconds in the absence of any catalyst under ambient conditions. Considering the importance of pyrazoles in organic/inorganic synthesis, in the food industry as well as in medicinal chemistry, we introduce an environmentally friendly approach to the synthesis of pyrazoles and their derivatives in water microdroplets. While the previously reported methods require the use of either a metal catalyst or acid along with organic solvents for long duration experiments at elevated temperatures, our microdroplet-based method offers a fast (typically on the millisecond time scale), green (water as solvent), and efficient alternative for the synthesis of pyrazoles. Studies with organic solvents showed that some water is essential for the formation of substituted pyrazoles. Additionally, spray distance effects suggest that the reaction proceeds via an interfacial mechanism. Based on these results, we propose that (a) the surfaces of the aqueous microdroplets are extremely dry and (b) the inherent acidity of the microdroplet surfaces catalyzes this dehydration reaction. We synthesized eight different substituted pyrazoles by using microdroplets with moderate to excellent conversion ratios (ion yields). This reaction proceeded in a scaled-up version at a rate of 0.81 mg/min. The final products were characterized by 1H NMR and MS/MS experiments.