Base-Free Copper-Catalyzed Azide-Alkyne Click Cycloadditions (CuAAc) in Natural Deep Eutectic Solvents as Green and Catalytic Reaction Media

The click cycloaddition of azides to alkynes affording 1,2,3-triazoles is a widely used and effective chemical transformation, applied to obtain relevant products in medicine, biology, and materials science. In this work, a set of natural deep eutectic solvents (NADESs) has been investigated in the copper-catalyzed azide-alkyne cycloaddition reactions (CuAAc) as green and catalytic reaction media. The use of these innovative solvents has been shown to improve the reaction effectiveness, giving excellent yields. NADESs proved to be "active" in their reducing capabilities in several cases and for the absence of added bases in all the performed reactions: DFT calculations demonstrated in fact the involvement of H-bonds between DESs and alkynes, as well as stabilization of copper catalytic intermediates. The green experimental conditions, the absence of a base, the low temperatures, the lowering of reagent amounts, and the possibility of recycling of the solvents, outline the great potential of NADESs for CuAAc.