Base‐Assisted C−H Bond Cleavage in Cross‐Coupling: Recent Insights into Mechanism, Speciation, and Cooperativity

Abstract

This review analyzes recent mechanistic studies that have provided new insights into how the structure of a metal complex influences the rate and selectivity of baseassisted CÀ H cleavage. Partitioning a broader mechanistic continuum into classes delimited by the polarization between catalyst and substrate during CÀ H cleavage is postulated as a method to identify catalysts favoring electrophilic or nucleophilic reactivity patterns, which may be predictive based on structural features of the metal complex (i. e., oxidation state, d-electron count, charge). Multi-metallic cooperativity and polynuclear speciation also provide new avenues to affect energy barriers for CÀ H cleavage and site selectivity beyond the limitations of single metal catalysts. An improved understanding of mechanistic nuances and structure-activity relationships on this important bond activation step carries important implications for efficiency and controllable site selectivity in non-directed CÀ H functionalization. Figure 1. Early reports on alkenylation of organopalladium intermediates generated through (a) transmetalation, (b) oxidative addition, or (c) CÀ H bond cleavage.

Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium

“…We began by focusing our attention on the key C-H activation step. As documented in literature, four classes of mechanistic pathways are known for the metal-mediated C-H activation: 1) Concerted C-H activations with base assistance spanning the whole spectrum from concerted metalation/deprotonation (CMD)/amphiphilic metal-ligand activations (AMLA), which are used to describe processes that preferentially activate C-H acidic sites, to electrophilicity-driven mechanisms typically denoted as base-assisted internal electrophilic substitution (BIES) or electrophilic CMD (eCMD); [14,17,[18][19][20] 2) σ-bond metathesis; [21,22] 3) oxidative addition; [23] 4) electrophilic metalation. [22,24] Based on detailed mechanistic studies on Pd-catalysis using N-acetyl amino acids as single ligands and the regioselectivities observed in our synthetic methods, we began our studies with the working hypothesis that the C-H activation step proceeds via a concerted C-H activation with base assistance, likely in the BIES/eCMD regime.…”

“…To avoid hydrogen bonding to the solvent as a potential source of error in our DOSY measurements, six fluorinated molecules without hydrogen bond-acceptors were selected as internal standards. The MW calculated from the diffusion constants of the pyridinecontaining palladium complexes by internal standard reference 19 F-DOSY are slightly above the ones of simple mononuclear complexes, but at the same time drastically too low for analogous dinuclear species ( Figure 5). We hypothesized that the overestimation of the MW could be explained by unspecific hydrogen bonding between the palladium complexes and HFIP.…”

“…Diffusion ordered NMR spectroscopy (DOSY) has emerged as a powerful tool to determine the molecular weight of complexes in solution since the diffusion constant (D) depends on the size and is proportional to the MW using the relationship log MW ∝ log D. [27,38] While 1 H-DOSY has been used extensively for absolute diffusion information to estimate the size of molecules and aggregates, the catalyst shown in Scheme 2 proved to be too complex for a determination of diffusion constants (D) by 1 H-NMR. We envisaged that applying heteronuclear 19 F-DOSY with a 19 Flabeled pyridine ligand would allow us to analyze the different catalytic species in solution separately due to the large chemical shift dispersion of 19 F compared to 1 H and the reduced overall number of peaks. 19 F-DOSY has been applied to determine monomer/dimer equilibria and molecular weights (MW) of complexes in solution.…”

“…We envisaged that applying heteronuclear 19 F-DOSY with a 19 Flabeled pyridine ligand would allow us to analyze the different catalytic species in solution separately due to the large chemical shift dispersion of 19 F compared to 1 H and the reduced overall number of peaks. 19 F-DOSY has been applied to determine monomer/dimer equilibria and molecular weights (MW) of complexes in solution. [39] In order to introduce fluorine into the catalyst, 3,5-difluoropyridine was used instead of ligand 2 or 3.…”

“…This can also be rationalized considering the bond orders in the transition states, which are consistent with a highly synchronous yet somewhat electrophilic concerted C-H activation mechanism (BIES/eCMD, for further discussion, see the Supporting Information). [20], [19] Proposed Catalytic Cycle. Based on the kinetic investigation, spectroscopic and spectrometric data, and the theoretical analysis presented above, as well as analogies to related literature reports, we propose the catalytic cycle shown in Scheme 8.…”