Discovery of Copper-Catalyzed Click Chemistry Reaction Intermediates in Nanoreactor by Accelerated MD

Click chemistry (Nobel Prize in Chemistry 2022) is characterized by small molecules acting as building blocks that can be joined to larger systems to build more complex molecules, with the copper-catalyzed azide-alkyne click reaction being the most prominent example. While catalysts are known to accelerate click reactions, the underlying reaction mechanisms and reaction intermediates have not been conclusively resolved. We approached this problem by constructing a first-principles based molecular dynamics simulation of the copper-catalyzed methylazide – propyne click reaction using the simulation platform Nanoreactor, which offers GPU-based capability in simulating dynamics and reaction events. Furthermore, the simulation was accelerated by an adaptive hyperdynamics algorithm to sample reactions over a larger time scale. By running the simulation at experimental conditions, we identified instances of reactions and subsequently identified species that could serve as reaction intermediates, including those not listed in literature.