Clip to Click: Controlling Inverse Electron-Demand Diels–Alder Reactions with Macrocyclic Tetrazines

A universal strategy to control tetrazine reactivity in the inverse electron-demand Diels-Alder (IEDDA) reaction was developed as "Clip to Click". Incorporating a chemical bridge into 3,6-diphenyl-1,2,4,5-tetrazine (macrocyclic tetrazine) rendered it unreactive toward trans-cyclooctene. A computational study revealed that the unreactive property of macrocyclic tetrazines is mainly due to the high distortion energy of tetrazine. We demonstrated that the cleavage ("Clip") of the macrocyclic linker can activate the tetrazine moiety for the IEDDA reaction ("Click").