Transition states of strain-promoted metal-free click chemistry: 1,3-dipolar cycloadditions of phenyl azide and cyclooctynes

Density functional theory (B3LYP) calculations on the transition states for the Huisgen 1,3-dipolar cycloadditions of phenyl azide with acetylene, cyclooctyne, and difluorocyclooctyne are reported. The low activation energy of the cyclooctyne strain-promoted cycloaddition (Delta E-double dagger = 8.0) compared to the strain-free acetylene cycloaddition (Delta E-double dagger = 16.2) is due to decreased distortion energy (Delta E-d(double dagger)) of cyclooctyne (Delta Delta E-d(double dagger)= 4.6) and phenyl azide (Delta Delta E-d(double dagger) = 4.5) to achieve that cycloaddition transition state. Electronegative fluorine substituents on cyclooctyne further increase the rate of cycloaddition by increasing interaction energies.