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.