Transition metal-catalyzed transformations employing Pd are among the most important bond-forming reactions available to synthetic chemists. Many of the advances in versatility and practicality of Pd-catalyzed reactions over the past two decades can be attributed to rational ligand and precatalyst design, made possible by thorough mechanistic investigations into the structure-reactivity relationships (SRRs) of the ligands/complexes important in catalysis. In the same timeframe, Ni has garnered considerable attention as a more reactive and sustainable alternative to Pd. However, a similar understanding of the specific ligand features important for a reaction’s success are lacking, hindering further development and widespread adoption. Guided by a new comprehensive library of phosphine steric and electronic descriptors (Kraken) developed by the Gensch, Sigman, and Aspuru-Guzik groups, we have identified and mechanistically interrogated the specific structural features of monodentate phosphines that lead to a Ni catalyzed reaction’s success and, perhaps of equal importance, its failure. Spectroscopic and crystallographic studies revealed that a unique Kraken steric descriptor, minimum percent buried volume [%V_bur (min)], predicts and rationalizes whether a phosphine preferentially forms mono- (L₁) vs. bisligated (L₂) Ni complexes. Analysis of Ni catalyzed cross-coupling reaction data with 90 ligands, collected using High Throughput Experimentation, revealed that only ligands with %V_bur (min) values less than 32% were active. This catalytic reactivity cliff matched the ligation state cutoff observed in stoichiometric organometallic studies, with only ligands that readily formed L₂ complexes active in catalysis. Notably, our catalytic and mechanistic studies demonstrated that Tolman Cone Angle—historically the most important phosphine steric descriptor available to organometallic chemists—was incapable of rationalizing phosphine ligation state with Ni. Concurrently, a statistical classification workflow using %V_bur (min) was developed, providing a roadmap for further targeted mechanistic study of ligand SRRs by categorizing large amounts of catalytic yield data based on distinct mechanistic/structural outcome. These guided structural investigations have led to some of the first insights into the SRRs of dialkyl-ortho-biaryl (Buchwald-type) phosphine ligands with Ni, along with synthesis and characterization of novel complexes of interest in catalysis.

Samuel Newman-Stonebraker

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