Which phosphines squeeze together? Phosphine ligands coordinated to palladium and nickel are essential tools for assembling the backbones of pharmaceutical compounds. For decades, descriptors that characterize spatial bulk have helped to guide phosphine optimization. However, these descriptors tend to apply to ideal geometries of a single ligand. Newman-Stonebraker et al . introduce a descriptor that considers how the ligand conformation might change in a crowded environment. Specifically, they found that the minimum percentage buried volume accurately predicts when one or two of a particular ligand will coordinate to a metal center, frequently a key determinant of successful catalysis. —JSY

The dialkyl-ortho-biaryl class of phosphines, commonly known as Buchwald-type ligands, are among the most important phosphines in Pd-catalyzed cross-coupling. These ligands have also been successfully applied to several synthetically valuable Ni-catalyzed cross-coupling methodologies and, as demonstrated in this work, are top performing ligands in Ni-catalyzed Suzuki Miyaura Coupling (SMC) and C–N coupling reactions, even outperforming commonly employed bisphosphines like dppf in many circumstances. However, little is known about their structure–reactivity relationships (SRRs) with Ni, and limited examples of well-defined, catalytically relevant Ni complexes with Buchwald-type ligands exist. In this work, we report the analysis of Buchwald-type phosphine SRRs in four representative Ni-catalyzed cross-coupling reactions. Our study was guided by data-driven classification analysis, which together with mechanistic organometallic studies of structurally characterized Ni(0), Ni(I), and Ni(II) complexes allowed us to rationalize reactivity patterns in catalysis. Overall, we expect that this study will serve as a platform for further exploration of this ligand class in organonickel chemistry as well as in the development of new Ni-catalyzed cross-coupling methodologies.

Statistical analysis of reaction data with molecular descriptors can enable chemists to identify reactivity cliffs that result from a mechanistic dependence on a specific structural feature. In this study, we develop a broadly applicable and quantitative classification workflow that identifies reactivity cliffs in eleven Ni- and Pd-catalyzed cross-coupling datasets employing monodentate phosphine ligands. A unique ligand steric descriptor, %<i>V</i>_bur (<i>min</i>), is found to divide these datasets into active and inactive regions at a similar threshold value. Organometallic studies demonstrate that this threshold corresponds to the binary outcome of bisligated versus monoligated metal and that %<i>V</i>_bur (<i>min</i>) is a physically meaningful and predictive representation of ligand structure in catalysis. Taken together, we expect that this strategy will be of broad value in mechanistic investigation of structure-reactivity relationships, while providing a means to rationally partition datasets for data-driven modeling.

Practical advances in Ni-catalyzed Suzuki−Miyaura cross-coupling (SMC) have been limited by a lack of mechanistic understanding of phosphine ligand effects. While bisphosphines are commonly used in these methodologies, we have observed instances where monophosphines can provide comparable or higher levels of reactivity. Seeking to understand the role of ligation state in catalysis, we performed a head-to-head comparison study of C(sp 2 )−C(sp 2 ) Ni SMCs catalyzed by mono-and bisphosphine precatalysts using six distinct substrate pairings. Significant variation in optimal precatalyst was observed, with the monophosphine precatalyst tending to outperform the bisphosphines with electronically deactivated and sterically hindered substrates. Mechanistic experiments revealed a role for monoligated (P 1 Ni) species in accelerating the fundamental organometallic steps of the catalytic cycle while highlighting the need for bisligated (P 2 Ni) species to avoid off-cycle reactivity and catalyst poisoning by heterocyclic motifs. These findings provide guidelines for ligand selection against challenging substrates and future ligand design tailored to the mechanistic demands of Ni-catalyzed SMCs.