Cavity Click Chemistry: Cavity-Catalyzed Azide-Alkyne Cycloaddition.

Click chemistry, which refers to chemical reactions that are fast and selective with high product yields, has become a powerful approach in organic synthesis and chemical biology. Due to the cytotoxicity of the transition metals employed in click chemistry reactions, a search for novel metal-free alternatives continues. Herein, we demonstrate that an optical cavity can be utilized as a metal-free alternative in the click chemistry cycloaddition reaction between cyanoacetylene and formylazide using the quantum electrodynamics coupled cluster method. We show that by changing the molecular orientation with respect to the polarization of the cavity mode(s), the reaction can be selectively catalyzed to form a major 1,4-disubstituted or 1,5-disubstituted product. This work highlights that a cavity has the same effect on the investigated cycloaddition as the transition metal catalysts traditionally employed in click chemistry reactions. We expect our findings to further stimulate research on cavity-assisted click chemistry reactions.