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Ongoing advances in Cu II -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 Cu II 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., (© 2023 Wiley-VCH GmbH.)

Invited for the cover of this issue is the group of Koley and co-workers at the Indian Institute of Science Education and Research (IISER) Kolkata. The image depicts the industrial generation of the product from the available starting materials in a catalytic cycle. Read the full text of the article at 10.1002/chem.202302983., (© 2023 Wiley-VCH GmbH.)