Ligand hardness as a key feature differentiating base- versus noble-metal mechanisms of nickel-catalyzed Suzuki-Miyaura cross-couplings

Nickel-catalyzed cross-coupling reactions that engage alkyl electrophiles provide potential routes for synthesis of molecules with high F sp3 . However, development of these reactions remains a challenge since the impact of ligand identity on competing mechanistic pathways is not yet well understood. To address this knowledge gap, we establish structure-reactivity trends across >550 Suzuki-Miyaura cross-coupling reactions with known mechanistic pathways. We evaluate reaction outcome by ligand features including heteroatom identity, hybridization, bite angle, geometry, and buried volume. The most important determinant of reactivity is heteroatom identity: nitrogen-based ligands support open-shell reactions while phosphorus-based ligands support closed-shell reactions. Here we report that experimental and calculated reduction potentials and charge density analysis correlate with catalytic activity and propose a rationale for these observations based on hard-soft acid-base theory.