Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms

Two limiting mechanisms are possible for oxidative addition
of
(hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and
a nucleophilic displacement mechanism. Until now, there has been little
understanding about when each mechanism is relevant. Prior investigations
to distinguish between these pathways were limited to a few specific
combinations of the substrate and ligand. Here, we computationally
evaluated over 180 transition structures for oxidative addition in
order to determine mechanistic trends based on substrate, ligand(s),
and coordination number. Natural abundance 13C kinetic
isotope effects provide experimental results consistent with computational
predictions. Key findings include that (1) differences in highest
occupied molecular orbital (HOMO) symmetries dictate that, although
12e– PdL is strongly biased toward a 3-centered
concerted mechanism, 14e– PdL2 often
prefers a nucleophilic displacement mechanism; (2) ligand electronics
and sterics, including ligand bite angle, influence the preferred
mechanism of the reaction at PdL2; (3) phenyl triflate
always reacts through a displacement mechanism regardless of the catalyst
structure due to the stability of a triflate anion and the inability
of oxygen to effectively donate electron density to Pd; and (4) the
high reactivity of C–X bonds adjacent to nitrogen in pyridine
substrates relates to stereoelectronic stabilization of a nucleophilic
displacement transition state. This work has implications for controlling
rate and selectivity in catalytic couplings, and we demonstrate application
of the mechanistic insight toward chemodivergent cross-couplings of
bromochloroheteroarenes.