Remote Strain Activation in a Sulfate-Linked Dibenzocycloalkyne

Cycloalkynes and their utilization in cycloaddition reactions enable modular strategies spanning the molecular sciences. Strain─imparted by deviation from linearity─enables sufficient alkyne reactivity without the need for a catalyst (e.g., copper); however, the design and synthesis of stable reagents with suitable reactivity remains an ongoing challenge. We report the incorporation of an endocyclic sulfate within a dibenzocyclononyne scaffold to generate a cyclononyne displaying remarkable reactivity and stability. Through computational analyses, we revealed that the endocyclic sulfate group shares nearly half the total strain energy, providing an activation strategy that reduces alkyne bending. Rehybridization of alkyne carbons in the formation of the heterocyclic product relieves strain both at the reactive site and in the transannular sulfate group. This mode of remote activation enables rapid reactivity while minimizing distortion─and strain─at the reactive site (the alkyne). The result: a design strategy for a new class of cycloalkynes with increased stability and reactivity.