Kinetics and Mechanism of Azole n−π*-Catalyzed Amine Acylation

Azole anions are highly competent in the activation of weak acyl donors, but, unlike neutral (aprotic) Lewis bases, are not yet widely applied as acylation catalysts. Using a combination of in situ and stopped-flow 1H/19F NMR spectroscopy, kinetics, isotopic labeling, 1H DOSY, and electronic structure calculations, we have investigated azole-catalyzed aminolysis of p-fluorophenyl acetate. The global kinetics have been elucidated under four sets of conditions, and the key elementary steps underpinning catalysis deconvoluted using a range of intermediates and transition state probes. While all evidence points to an overarching mechanism involving n−π* catalysis via N-acylated azole intermediates, a diverse array of kinetic regimes emerges from this framework. Even seemingly minor changes to the solvent, auxiliary base, or azole catalyst can elicit profound changes in the temporal evolution, thermal sensitivity, and progressive inhibition of catalysis. These observations can only be rationalized by taking a holistic view of the mechanism and a set of limiting regimes for the kinetics. Overall, the analysis of 18 azole catalysts spanning nearly 10 orders of magnitude in acidity highlights the pitfall of pursuing ever more nucleophilic catalysts without regard for catalyst speciation.