Origins of halogen effects in bioorthogonal sydnone cycloadditions.

Halogen substituents increase sydnone cycloaddition reactivities substantially. Fluoro-sydnones are superior to bromo- and chloro-sydnones, and can achieve extremely high second-order rate constants with strained alkynes. Computational studies have revealed the fluorine substituent increases the reactivity of sydnone mainly by lowering its distortion energy.