Revisiting textbook azide-clock reactions: A “propeller-crawling” mechanism explains differences in rates

An ongoing challenge to chemists is the analysis of pathways and kinetics for chemical reactions–including transient structures between the reactants and products that are difficult to resolve using laboratory experiments. Here, we enabled direct molecular dynamics simulations of a textbook series of chemical reactions on the hundreds of ns to µs timescale using the weighted ensemble (WE) path sampling strategy with hybrid quantum mechanical/molecular mechanical (QM/MM) models. We focused on azide-clock reactions involving addition of azide anion to each of three long-lived trityl cations in an acetonitrile-water solvent mixture. Azide additions are common click-chemistry reactions of great interest to synthetic chemists. Results reveal a two-step mechanism: (1) diffusional collision of reactants to form an ion-pair intermediate, (2) “activation”, or rearrangement of the intermediate to the product. Our simulations not only yield reaction rates that are within error of experiment, but also rates for individual steps, indicating the activation step as rate-limiting for all three cations. Further, the trend in reaction rates is due to differing extents of the azide anion “crawling” along the cation’s phenyl-ring “propellers” during the activation step. Our study demonstrates the power of analyzing pathways and kinetics to gain insights on reaction mechanisms, underscoring the value of including WE and other related path sampling strategies in the modern toolbox for chemists.