Computationally Derived Ligand Steric Parameters Reveal Reactivity Correlations Across the Field of Nickel Catalysis

Abstract

The field of nickel catalyzed cross-coupling has grown tremendously over the past several decades due to the metal’s abundance, affordability, and versatility in organic synthesis. While affording a diversity of new reactions, the rapid growth of the field has significantly outpaced the development of new ligands, such that many modern nickel-catalyzed reactions rely on ligands originally intended for palladium. Recently, the Doyle lab has reported a unique class of phosphine ligands designed specifically for nickel that permit challenging cross-coupling reactions. Though the stereoelectronic properties of these ligands were examined in a single class of reactions, their utility in other Ni-catalyzed reactions has not been explored. The reactivity of these phosphine ligands were compared to that of commercial ligands in several classes of reactions, and their performances were correlated with steric parameters generated by computationally modeled ligand structures. The Doyle lab ligands exhibited improved reactivity in two Suzuki-Miyaura reactions, and several C – H functionalization reactions, one of which has never previously been reported with a phosphine ligand. Our computational models revealed that ligands with a large cone angle and low percent buried volume performed well, suggesting that the successful steric features identified here and in the Doyle lab’s previous report could enable improved reactivity and scope for the field of nickel-catalyzed coupling reactions.