Revealing the Hidden Complexity and Reactivity of Palladacyclic Precatalysts: The P(<i>o</i>-tolyl)₃ Ligand Enables a Cocktail of Active Species Utilizing the Pd(II)/Pd(IV) and Pd(0)/Pd(II) Pathways for Efficient Catalysis

The ligand, P(<i>o</i>-tolyl)₃, is ubiquitous in applied synthetic chemistry and catalysis, particularly in Pd-catalyzed processes, which typically include Pd(OAc)₂ (most commonly used as Pd₃(OAc)₆) as a precatalyst. The Herrmann-Beller palladacycle [Pd(C^P)(μ₂-OAc)]₂ (where C^P = monocyclopalladated P(<i>o</i>-tolyl)₃) is easily formed from reaction of Pd(OAc)₂ with P(<i>o</i>-tolyl)₃. The mechanisms by which this precatalyst system operates are inherently complex, with studies previously implicating Pd nanoparticles (PdNPs) as reservoirs for active Pd⁽⁰⁾ species in arylative cross-coupling reactions. In this study, we reveal the fascinating, complex, and nontrivial behavior of the palladacyclic group. First, in the presence of hydroxide base, [Pd(C^P)(μ₂-OAc)]₂ is readily converted into an activated form, [Pd(C^P)(μ₂-OH)]₂, which serves as a conduit for activation to catalytically relevant species. Second, palladacyclization imparts unique stability for catalytic species under reaction conditions, bringing into play a Pd^(II)/Pd^(IV) cross-coupling mechanism. For a benchmark Suzuki-Miyaura cross-coupling (SMCC) reaction, there is a shift from a mononuclear Pd catalytic pathway to a PdNP-controlled catalytic pathway during the reaction. The activation pathway of [Pd(C^P)(μ₂-OH)]₂ has been studied using an arylphosphine-stabilized boronic acid and low-temperature NMR spectroscopic analysis, which sheds light on the preactivation step, with water and/or acid being critical for the formation of active Pd⁽⁰⁾ and Pd^(II) species. <i>In situ</i> reaction monitoring has demonstrated that there is a sensitivity to the structure of the arylboron species in the presence of pinacol. This work, taken together, highlights the mechanistic complexity accompanying the use of palladacyclic precatalyst systems. It builds on recent findings involving related Pd(OAc)₂/PPh₃ precatalyst systems which readily form higher order Pd_n clusters and PdNPs under cross-coupling reaction conditions. Thus, generally, one needs to be cautious with the assumption that Pd(OAc)₂/tertiary phosphine mixtures cleanly deliver mononuclear "Pd(0)L_n" species and that any assessment of individual phosphine ligands may need to be taken on a case-by-case basis.