Mechanistic Avenues in the Chan‐Lam‐Based Etherification Reaction: A Computational Exploration

Abstract

AbstractOngoing advances in CuII‐catalyzed aerobic oxidative coupling reactions between arylboronic esters and diverse heteroatom nucleophiles have strengthened the development of the general Chan‐Lam (CL)‐based reaction protocol, including C−O bond formation methodologies. In‐depth mechanistic understanding of CL etherification with specific emphasis on different reaction routes and their energetics are still lacking, even though the reaction has been experimentally explored. Here, we present a DFT‐guided computational study to unravel the mechanistic pathways of CL‐based etherification. The computational findings provide some interesting insights into the fundamental steps of the catalytic cycle, particularly the rate‐determining transmetalation event. An aryl boronic ester‐coordinated, methoxide‐bridged CuII intermediate that acts as resting state undergoes transmetalation with an activation barrier of 20.4 kcal mol−1. The energy spans of the remaining fundamental steps leading to the methoxylated product are relatively low. The minor p‐cresol product requires an additional 14.2 kcal mol−1 energy span to surmount in comparison to the favored route. Hammett studies for the substituted aryl boronic esters reveal higher reaction turnovers for electron‐rich aryl systems. The results agree with previously reported spectroscopic and kinetic observations. For a series of alcohol substrates, it was observed that, except for cyclohexanol, moderate to high etherification turnovers are predicted.