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

Area of Science:

• Organic Chemistry
• Computational Chemistry
• Catalysis

Background:

• Chan-Lam (CL) coupling reactions, particularly C-O bond formation, are crucial in organic synthesis.
• Advances in Cu(II)-catalyzed aerobic oxidative coupling have improved CL-based protocols.
• A detailed mechanistic understanding of CL etherification, including energetics, remains incomplete.

Purpose of the Study:

• To elucidate the mechanistic pathways of Chan-Lam (CL)-based etherification using DFT calculations.
• To identify the rate-determining step and key intermediates in the catalytic cycle.
• To investigate the influence of substrate electronics on reaction efficiency.

Main Methods:

• Density Functional Theory (DFT)-guided computational study.
• Analysis of catalytic cycle steps and their activation barriers.
• Hammett studies on substituted aryl boronic esters.

Main Results:

• Identified a Cu(II) intermediate as the resting state, with transmetalation as the rate-determining step (20.4 kcal/mol activation barrier).
• Subsequent steps in the catalytic cycle have lower energy spans.
• Electron-rich aryl systems exhibit higher reaction turnovers, consistent with experimental data.
• Predicted moderate to high etherification turnovers for most alcohol substrates, with cyclohexanol as an exception.

Conclusions:

• The study provides fundamental insights into the mechanism of Cu(II)-catalyzed Chan-Lam etherification.
• Computational findings clarify the energetics of key steps, particularly transmetalation.
• The results support experimental observations and offer predictive power for substrate scope and efficiency.