Mechanistic Insights into Active Catalyst Formation in Boronic Acid-Catalyzed Amidation

The development of catalytic methods for amide bond formation that avoid the poor atom economy of coupling reagents remains a major challenge.¹ Boronic acid-catalyzed amidation is a promising alternative due to low cost, accessibility, and sustainability of boronic acids.² Despite its broad applicability, the reaction still relies on hazardous solvents, continuous water removal, and remains poorly understood mechanistically. Previous studies suggest that the active catalyst BOB is generated only under anhydrous conditions, although its mechanism remains unclear.³ Herein, we present a computational investigation of this process. The calculated energy profiles indicate that the equilibrium between boronic acids, boroxines, and BOB plays a central role in catalytic activity, with barriers below 15.0 kcal/mol and competing pathways. Furthermore, LFER analysis suggests that reaction efficiency correlates with the thermodynamic accessibility of BOB formation, indicating that catalyst pre-equilibrium is a key descriptor of amidation performance and providing a mechanistic basis for future microkinetic models.