Twisted Cycloalkynes and Remote Activation of “Click” Reactivity

Abstract

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. Non-catalyzed alkyne/azide cycloaddition, a widely used “click” reaction in interdisciplinary scientific research, offers a modular, practical, and metal-free approach to building molecular complexity in environments where toxic and redox active species should be avoided. In this paper, we describe a fundamental concept for increasing “click” reactivity through remote interactions with the hope of leading to the development of creative technological innovations. This work also introduces axial chirality as a molecular property that can be achieved by “click” chemistry, which opens the door for the future controlled creation of chiral objects and environments from achiral small molecules, polymers, and surfaces. Interaction between donor and acceptor groups incorporated in the backbone of cycloalkynes can be partially disrupted by twisting. The additional electronic energy accumulated as a result of this disruption can be harvested in the alkyne/azide cycloaddition transition state, where an optimal conjugation pattern at a remote location is restored. The design provides electronically activated cyclodecynes that approach “click” reactivity of cyclooctynes. In addition, the twisted cyclodecynes are chiral and thus add axial chirality to the toolbox of properties introduced via “click” chemistry.