  The azide-alkyne Huisgen cycloaddition has a key role in click chemistry and
configures as 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 simulation. We focus on the conformational aspects
that determine the course of the reaction and characterize the free energy
landscape of the process. To properly capture the thermodynamics of the process
we select optimal collective variables using harmonic linear discriminant
analysis. The results confirm the experimental evidence qualitatively and give
insight on the role of the substituents and the possible transition mechanisms.
