Concerted vs Nonconcerted Metalation–Deprotonation in Orthogonal Direct C–H Arylation of Heterocycles with Halides: A Computational Study

A computational
study on the base-assisted orthogonal C–H
arylation of azoles with halides is reported. Although concerted metalation–deprotonation
(CMD) is favored under acetate assistance at the C5 site that displays
the best balance of nucleophilic and acidic character, the most acidic
C2 site may be selectively targeted under carbonate assistance by
taking advantage of a carbanionic-type (or non-concerted) metalation–deprotonation
mechanism (nCMD). For the latter, several experimental probes including
base, ligand, and solvent effects have been collected in favor of
an outer-sphere deprotonation process after the formation of a [(Ln)­(N1-heteroaryl)­PdArX] complex. However, no
computational analysis of this fundamental elementary step has been
so far provided. We have carried out a series of density functional
theory (DFT) calculations that delineate the structural and energetic
aspects of the nCMD pathway. Starting with the oxa­(thia)­zole-4-carboxylates
selected in our group to engineer the competitive C2 vs C5 arylation
in azoles, we show that the energy barrier of the C2 anion generation
is lying unexpectedly lower than the prior heterocycle coordination
to Pd that is eventually identified as the rate-determining step.
These calculations provide satisfactory explanations for the experimental
observations of the divergence between nCMD and CMD reactivity, and
notably a lower barrier at the C2 site for the nCMD process. On the
other hand, the nCMD process is ineffective at the C5 site. Evaluation
of various azoles reveals that the nCMD mechanism at C2 is viable
from the most acidic (benzo)­oxazoles to moderately acidic (benzo)­thiazoles,
as well as weakly acidic imidazoles. In all cases, in accordance with
previously reported experimental data in orthogonal direct C–H
arylation of azoles, the nCMD route is found energetically competitive
to the CMD one at C5 for all azoles, except for imidazole which needs
stronger basic conditions than simple carbonate assistance. Additionally,
the acetate ligand, which is the base of choice for CMD, was found
inefficient for nCMD and the comparative performance of acetate vs
carbonate to assist CMD in the azole series reveals also considerable
changes from electronically close but environmentally divergent C5–H
vs C2–H bonds.