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

Abstract

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 13 C 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 − PdL 2 often prefers a nucleophilic displacement mechanism; (2) ligand electronics and sterics, including ligand bite angle, influence the preferred mechanism of the reaction at PdL 2 ; (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.

Mechanisms and Site Selectivity of (Het)Ar–X Oxidative Addition to Pd(0) Are Controlled by Frontier Molecular Orbital Symmetry

“…To assess this hypothesis, we have conducted a combined computational and experimental study of the oxidative addition rate and site selectivity for substituted halopyridines to L 2 Pd(0), using Pd(PCy 3 ) 2 as an exemplar . In a concurrent and complementary study, Neufeldt and co-workers further establish the interplay between Pd speciation, ligand identity, and orbital symmetry in determining the mechanism of oxidative addition for unsubstituted phenyl–X and pyridyl–X substrates (X = F, Cl, Br, I, OTf) …”

“…Hartwig’s group and Baird’s group have independently shown via kinetic analysis that both Pd(PCy 3 ) n ( n = 1, 2) species are kinetically relevant for Ph–Cl and Ph–Br OA. Neufeldt’s group has also shown that 12- and 14-electron Pd(0) species undergo different OA mechanisms depending on the substrate. , Further work is underway to improve the scope and accuracy of our oxidative addition models by expanding our data sets to better represent both FMO-based effects with a variety of substitution patterns and Pd(0) speciation with a variety of phosphine ligands.…”