Unveiling the mechanistic pathways of the Chan-Lam C-N arylation reaction: A computational exploration

The copper-catalyzed Chan-Lam (CL) reaction has emerged as a powerful tool for the synthesis of diverse and valuable heteroatom-containing compounds. It offers a direct method for C-heteroatom coupling between aryl boronic acid with heteroatom-containing nucleophiles (Scheme 1), bypassing traditional and often less efficient coupling reactions. Though it is highly efficient in mild reaction conditions, chemists are concerned about its high dependencies on substrate and other reaction conditions. Understanding the mechanistic intricacies of the Chan-Lam reaction is crucial for efficient rational catalyst design as well as optimization of the reaction condition.
The chemists are concern about the “capricious nature” of the CL reactions, particularly in its dependencies on substrate and other reaction conditions. Therefore, we cannot formulate a general set of reaction conditions, which largely differ for closely related nucleophiles and other substrates. Here, we present comprehensive mechanistic details of the CL based C-N coupling reaction employing copper diamine complex [Cu(OH).TMEDA]₂Cl₂ as a catalyst using DFT calculations based on Collman’s protocol. The studied mechanistic aspects of the Chan-Lam reaction, provide insights into the key intermediates, transition states, reaction pathways, and factors influencing its efficiency. We will briefly compare our calculated pathways with the previously studied C-heteroatom coupling reactions based on the experimental protocols of Watson and Collman.
In addition, we will explain the relative stabilities of the catalytic key intermediates and the reactivities for each of each fundamental catalytic step. We have also studied the role of different ligands on the yield of catalytic reactions as well as the energetic origin of regioselectivity.

This work will conclude with a discussion of the potential challenges and future directions in the mechanistic study of the CL reaction, highlighting its importance in the development of sustainable and efficient synthetic methodologies for the synthesis of complex heteroatom-containing organic molecules. Overall, a deeper understanding of the Chan-Lam reaction's mechanistic underpinnings will contribute to its continued advancement and broad applicability in the field of synthetic organic chemistry.