Entering Chemical Space with Theoretical Underpinning of the Mechanistic Pathways in the Chan-Lam Amination

Recent years have witnessed a growing interest in the development of efficient copper-based catalytic systems following the Chan-Lam (CL) reaction protocol for the C-N bond formation. Though CL amination has been widely explored experimentally, it is quite underdeveloped from a mechanistic standpoint. Extensive theoretical investigations are carried out to unravel the mechanistic pathways of the CL reaction. We report in detail the fundamental reaction steps involved in Cu-catalyzed carbon-heteroatom bond formation reactions, particularly the CL-based amination. An in-depth examination of this study provides some interesting insights into little known pathways such as the denucleation of dimeric copper acetate, the disproportionation of the Cu(II) complex, and the regeneration of Cu(II) from Cu(I) intermediates. The rate-determining step of 26.0 kcal mol(-1) involves the disproportionation and reductive elimination of the Cu(II) intermediate. The mechanism for the inhibitory effect of pinacol (BPin) esters, off-cycle reaction routes, and influence of amine substrates are elaborated in this context. For a series of heteroarene substrates, it was observed that the catalyst generation energy span correlates with the experimentally observed reaction outcome. The calculated results are in agreement with the experimental observations based on spectroscopic and kinetic studies.