Revisiting the classic azide-clock reaction: Direct simulation of pathways reveals a rate-limiting activation step

An ongoing challenge to chemists is the analysis of kinetics and pathways for chem- ical reactions–including all the transient structures between the reactants and products that are typically difficult for experiments to resolve. Here, we applied the weighted ensemble (WE) path sampling strategy with hybrid quantum mechanical molecular me- chanical (QM/MM) models to enable the simulation of the classic azide-clock reaction for three short-lived trimethylphenyl cations with explicit solvent. While this reaction has long been assumed to be diffusion-controlled for certain cations, our simulations reveal that the rate-limiting step is an activation step: the rearrangement of an ion- pair intermediate that is formed via diffusional collision of the reactants. Importantly, our calculated reaction rate constants are in reasonable agreement with experiment. To analyze reaction pathways, we have clustered pathways into distinct classes using a pattern matching algorithm that has been employed for plagiarism detection. Our results demonstrate the power of analyzing path ensembles and kinetics, underscoring the value of including WE and other path sampling strategies in the modern toolbox for chemists.