Boric Acid Promoted Base-Free Chan-Lam Amination Reaction: A Computationally Inspired Mechanistic Investigation

Area of Science:

• Organic Chemistry
• Catalysis
• Computational Chemistry

Background:

• Copper-II catalyzed Chan-Lam (CL) reactions are vital for forming carbon-nitrogen/heteroatom bonds.
• Despite widespread use, the precise mechanism of CL amination remains incompletely understood.
• Existing knowledge gaps hinder further optimization and industrial application of this methodology.

Purpose of the Study:

• To elucidate the mechanism of base-free Chan-Lam amination using theoretical calculations.
• To investigate the role of boric acid (B(OH)3) as a promoter in the catalytic cycle.
• To explore the influence of substrate stoichiometry and electronic effects on reaction kinetics.

Main Methods:

• Theoretical investigation employing computational chemistry methods.
• Analysis of reaction pathways, transition states, and energy barriers.
• Comparison with experimental kinetic and Hammett studies.

Main Results:

• Identified a rate-determining transmetalation step with an energy span of 26.4 kcal mol⁻¹.
• Observed a unique six-membered transition state for aryl migration.
• Demonstrated that boric acid stabilizes copper intermediates, facilitating Cu(I)→Cu(II) regeneration and lowering overall energy barriers.

Conclusions:

• Boric acid acts as a promoter, stabilizing intermediates and enabling base-free Chan-Lam amination.
• The study provides the first mechanistic insight into the effect of organoboron:amine stoichiometry.
• Electron-rich aryl boronic acids exhibit lower transmetalation barriers, consistent with Hammett studies.