Metal Electronics Mediate Steric and Coordination Number Effects on Palladium (II) C–X Reductive Elimination

Reductive elimination is the key bond-forming elementary step in many transition metal catalyzed reactions relevant to the synthesis of pharmaceuticals, materials and fine chemicals. Metal electronics, ancillary ligand sterics and metal complex coordination number have been identified as the primary factors which affect the rate of reductive elimination, but their relative importance has not been quantified. We report the development of a new class of palladacycles used to study these factors in depth. Through kinetics, electrochemistry, DFT calculations and tools from causal inference, we reexamine the canonical model which describes the factors affecting the rate of reductive elimination. First, by testing the canonical model against two competing hypotheses, we find that a direct effect of coordination number on rate is unlikely, contrary to what is commonly proposed. To address this contradiction, we propose an updated understanding based on mechanistic considerations, which accounts for our findings, the canonical understanding, and other observations in literature. Our model posits that metal electronics directly affect the rate - coordination number only affects metal electronics and sterics affect all other factors. The influence of sterics on the rate has three components; the first is a direct effect on the rate, which acts through Pauli repulsion and dispersion interactions. The second effect is mediated by metal electronics and arises due to front strain, which attenuates the donating ability of ligands and, by extension, metal electronics. Finally, we propose an effect mediated by coordination number and metal electronics, wherein increasing steric demand enforces a lower coordination number, which leads to fewer donors being present, altering electronics at the metal. Path coefficients calculated using mediation analysis allow the quantification of all these effects. These show that increasing ancillary ligand sterics to the point of enforcing a coordination number change from square-planar to T-shaped accelerates reductive elimination overall, albeit to a lesser extent than decreasing electron density at the metal center. We find that for complexes of the same coordination number, the overall influence of sterics is rate-lowering, contrary to what is described in the literature. The indirect effect of sterics through front strain is the smallest effect. Overall, we find that electronics exerts the greatest influence on the rate, followed by changes in coordination number, which primarily act through altering metal electronics. Finally, using this new-found knowledge, we were able to use the structures of complexes reported in the literature to calculate appropriate DFT descriptors and predict the rate of reductive elimination for C–N, C–S and C–O bond formation with reasonable accuracy.