The reaction mechanism of the azide-alkyne Huisgen cycloaddition

The azide-alkyne Huisgen cycloaddition has a key role in click chemistry and is configured as a powerful tool in pharmaceutical and medicinal chemistry. Although this reaction has already been largely studied, there is an ongoing debate about its mechanism. In this work we study the dynamical aspects of the process using metadynamics computer simulations. We focus on the conformational aspects that determine the course of the reaction and characterize its free energy landscape. To properly capture the thermodynamics of the process we select optimal collective variables using harmonic linear discriminant analysis. The results qualitatively confirm and explain the experimental evidence and give insights into the role of the substituents and the possible transition mechanisms.