Electronic Effects versus Distortion Energies During Strain-Promoted Alkyne-Azide Cycloadditions: A Theoretical Tool to Predict Reaction Kinetics

Second-order reaction kinetics of known strain-promoted azide-alkyne cycloaddition (SPAAC) reactions were compared with theoretical data from a range of ab initio methods. This produced both detailed insights into the factors determining the reaction rates and two straightforward theoretical tools that can be used to predict a priori the reaction kinetics of novel cyclooctynes for strain-promoted cycloaddition reactions. Multiple structural and electronic effects contribute to the reactivity of various cyclooctynes. It is therefore hard to relate a physical or electronic property directly and independently to the reactivity of the cyclooctyne. However, we show that Hartree-Fock LUMO energies, which were acquired while calculating activation energies at the MP2 level of theory, correlate with second-order kinetic rate data and are therefore usable for reactivity predictions of cyclooctynes towards azides. Using this correlation, we developed a simple theoretical tool that can be used to predict the reaction kinetics of (novel) cyclooctynes for SPAAC reactions.