Isotope Effects Reveal the Catalytic Mechanism of the Archetypical Suzuki-Miyaura Reaction

Abstract

Experimental and theoretical 13 C kinetic isotope effects (KIEs) are utilized to obtain atomistic insight into the catalytic mechanism of the Pd(PPh 3 ) 4 -catalyzed Suzuki-Miyaura reaction of aryl halides and aryl boronic acids. Under catalytic conditions, we establish that oxidative addition of aryl bromides occurs to a 12-electron monoligated palladium complex (Pd-(PPh 3 )). This is based on the congruence of the experimental KIE for the carbon attached to bromine (KIE C−Br = 1.020) and predicted KIE C−Br for the transition state for oxidative addition to the Pd(PPh 3 ) complex (1.021). For aryl iodides, the near-unity KIE C−I of ∼1.003 suggests that the first irreversible step in the catalytic cycle precedes oxidative addition and is likely the binding of the iodoarene to Pd(PPh 3 ). Our results suggest that the commonly proposed oxidative addition to the 14-electron Pd(PPh 3 ) 2 complex can occur only in the presence of excess added ligand or under stoichiometric conditions; in both cases, experimental KIE C−Br of 1.031 is measured, which is identical to the predicted KIE C−Br for the transition state for oxidative addition to the Pd(PPh 3 ) 2 complex (1.031). The transmetalation step, under catalytic conditions, is shown to proceed via a tetracoordinate boronate (8B4) intermediate with a Pd−O−B linkage based on the agreement between an experimental KIE for the carbon atom involved in transmetalation (KIE C-Boron = 1.035) and a predicted KIE C-Boron for the 8B4 transmetalation transition state (1.034).

Different Oxidative Addition Mechanisms for 12- and 14-Electron Palladium(0) Explain Ligand-Controlled Divergent Site Selectivity

“…On the basis of these trends, we hypothesized that sterically hindered strong σ-donor ligands favor unconventional selectivity by promoting oxidative addition at a low-coordinate species (i.e., 12e – PdL). Smaller ligands or ones that are better π-acceptors, such as PAr 3 and saturated NHCs, would be more likely to favor coordination of a second ligand. − Notably, among trialkylphosphines, selectivity switches near the % V bur (min) threshold that was previously reported to determine whether PdL or PdL 2 dominates as the active species for oxidative addition. , Nevertheless, it was unclear why 12e – PdL might react at the stronger C4–Cl bond. To evaluate this question, we used density functional theory (DFT) calculations to closely examine the mechanisms of oxidative addition at 12e – and 14e – Pd(0) using a simple model system comprising PhCl and Pd­(PMe 3 ) n ( n = 1 or 2).…”

Emerging Trends in Cross-Coupling: Twelve-Electron-Based L1Pd(0) Catalysts, Their Mechanism of Action, and Selected Applications

“…Based on Hirschi and Vetticatt's recent studies combining DFT calculations and experimental 13 C kinetic isotope effects, the proposed catalytic cycle even for Ph 3 P-based systems is shown in Scheme 5 (cf. section 2.1), where L 1 Pd(0) is the active catalytic species after the first cycle in the absence of excess Ph 3 P. 56 AI based computational and machine learning technologies have emerged as powerful tools in predicting the active ligand/ catalyst system by making use of ligand parametrization. In this context, Gensch, Sigman, Aspuru-Guzik, and co-workers very recently presented "kraken", a discovery platform for monodentate organophosphorus(III) ligands that provides comprehensive physicochemical descriptors on the basis of representative conformer sets.…”

“…However, after the first turnover and in the absence of excess ligand, the catalytically active species is the 12-electron, monoligated [Ph 3 P−Pd] (Scheme 5). 56…”

“…100 In summary, on the basis of comprehensive structural, kinetic, and computational investigations, it is clear that for both the Hiyama−Denmark and Suzuki−Miyaura cross-couplings, the transmetalation intermediate in the catalytic cycle is a monoligated L 1 Pd(II) species as opposed to the corresponding L 2 Pd(II) complex, irrespective of the size and coordination number of the palladium. The very recent study by Hirschi, Vetticatt, and co-workers 56 employing experimental and theoretical 13 C kinetic isotope effects showed that the transmetalation step likely proceeds via a tetracoordinate boronate (8-B-4) intermediate with a Pd−O−B linkage as already observed by Denmark. Having coordinatively unsaturated palladium is crucial for the rapid transfer of the organic group from silicon or boron to palladium.…”

“…Until the late 1990s, the most commonly employed ligand for cross-coupling was PPh 3 , which was thought to form a 14-electron Pd­(PPh 3 ) 2 complex as the active species during catalysis either in situ from Pd­(OAc) 2 or Pd 2 (dba) 3 or from a precatalyst. However, recent computational and experimental , studies invoke the involvement of monoligated [(Ph 3 P)­Pd­(0)] as the active species in the catalytic cycle. Based on ab initio studies, Vidossich et al have proposed solvent stabilization of the monoligated [(Ph 3 P)­Pd­(0)] under catalytic conditions …”