The reactivity of cyclooctynes is usually determined in organic solvents, while SPAAC ligations are commonly conducted in aqueous solutions. To determine the effect of solvent polarity on the rate of SPAAC, the kinetics of the reaction must be determined in mixed solvents. For this purpose, a water soluble version of the photochemical precursor to the most reactive cyclooctyne, triazole-fused dibenzocyclooctyne, has been developed. MC-DIBOT is a new photo-activatable SPAAC reagent that offers enhanced reaction rates and greater water solubility relative to some of the most common SPAAC reagents known to date. With this compound, we find that the second-order rate constant of SPAAC grows exponentially with the water content of the solvent mixture and that the reaction rate difference between wholly organic and aqueous solutions could be above 30 fold.

Solvent polarity-induced SPAAC rate enhancement of the most reactive cyclooctyne: Synthesis and photo-click kinetics of a water soluble cyclopropenone-caged triazole-fused dibenzocyclooctyne

ACS Spring 2022

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