Twisted Cycloalkynes and Remote Activation of “Click” Reactivity

The “twisted and bent” cyclodecyne structural motif, intertwined with dormant electronic effects, opens a conceptually powerful way to control “click” reactivity. The endocyclic heteroatoms of cyclodecynes provide dual electronic activation via hyperconjugative (direct) and conjugative (remote) effects. These effects are weakened by the geometric constraints imposed by the twisted backbone, but structural reorganization in the transition state (TS) removes these constraints and unlocks the power of remote electronic effects for selective TS stabilization. Gram-scale synthesis and purification by recrystallization make this an efficient and practical approach to enantiopure cycloalkynes. Experimental kinetics confirm that these twisted cyclodecynes can be more reactive toward azides than activated cyclononynes and approach the reactivity of cyclooctynes. Furthermore, cycloalkynes with a twisted polyaromatic backbone can potentially add axial chirality to the “click” chemistry toolbox.