Alkyne-Localized Strain Engineering toward Next-Generation High-Reactivity Bridged Cyclooctynes

Strain engineering is a central strategy for tuning cycloalkyne reactivity in bioorthogonal chemistry; however, the structural consequences of introducing bridges within a conserved eight-membered scaffold remain underexplored. In particular, whether bridge topology can selectively enhance alkyne-localized distortion─independent of overall ring strain or reaction thermodynamics─has not been systematically assessed. Using high-level DLPNO–CCSD(T) calculations, we examined a defined series of bridged cyclooctynes in Strain-Promoted Azide–Alkyne Cycloaddition (SPAAC), identifying architectures with reduced activation barriers relative to the parent cyclooctyne. The results show that activation barriers correlate primarily with strain localized at the alkyne rather than with total ring strain or reaction exergonicity. Propargylicly bridged systems, especially those with larger bridges, display increased alkyne distortion and correspondingly lower barriers, underscoring the critical role of bridge topology. This distortion is directly reflected in alkyne bond angles, with the average alkyne angle serving as a robust predictor of reactivity (R2 = 0.95), independent of distortion symmetry. Extension to heteroatom-substituted systems (N, O, S, P, Si) reveals that substitutions at bridgehead or main-framework sites exert stronger geometric effects than those on the bridge. These findings establish alkyne-localized distortion as the key structural determinant of SPAAC reactivity and provide a geometry-based design principle for next-generation cyclooctynes.