The Importance of Kinetic and Thermodynamic Control when Assessing Mechanisms of Carboxylate-Assisted C–H Activation

Abstract

The reactions of substituted 1-phenylpyrazoles (phpyz-H) at [MCl 2 Cp*] 2 dimers (M = Rh, Ir; Cp* = C 5 Me 5 ) in the presence of NaOAc to form cyclometalated Cp*M(phpyz)-Cl were studied experimentally and with density functional theory (DFT) calculations. At room temperature, time-course and H/D exchange experiments indicate that product formation can be reversible or irreversible depending on the metal, the substituents, and the reaction conditions. Competition experiments with both para-and meta-substituted ligands show that the kinetic selectivity favors electron-donating substituents and correlates well with the Hammett parameter giving a negative slope consistent with a cationic transition state. However, surprisingly, the thermodynamic selectivity is completely opposite, with substrates with electron-withdrawing groups being favored. These trends are reproduced with DFT calculations that show C−H activation proceeds by an AMLA/CMD mechanism. H/D exchange experiments with the meta-substituted ligands show ortho-C−H activation to be surprising facile, although (with the exception of F substituents) this does not generally lead to orthocyclometalated products. Calculations suggest that this can be attributed to the difficulty of HOAc loss after the C−H activation step due to steric effects in the 16e intermediate that would be formed. Our study highlights that the use of substituent effects to assign the mechanism of C−H activation in either stoichiometric or catalytic reactions may be misleading, unless the energetics of the C−H cleavage step and any subsequent reactions are properly taken into account. The broader implications of our study for the assignment of C−H activation mechanisms are discussed.

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

“…not be a reliable indicator of step-wise versus concerted mechanisms. [17] Ess, Periana, and Goddard later proposed a model, internal electrophilic substitution (IES), [18] to highlight the importance of an electrophilic transition metal center and an internal proton acceptor during CÀ H cleavage. The term "ambiphilic metal ligand activation" (AMLA) was also coined by Davies and Macgregor to emphasize the important roles of both an electrophilic metal and nucleophilic coordinated base in a concerted CÀ H bond heterolysis event.…”

“…[35] These computational and experimental results contrast the kinetic selectivity observed, for instance, during cyclometalation reactions by Rh(III) and Ir(III) complexes (vide infra), which favors π-basic sites. [17] Ess proposed a model to explain the kinetic site selectivity of Pd-catalyzed direct arylation, which parallels the thermodynamic driving force for the reaction. [36] While a general correlation was found between the CMD activation energy and the thermodynamic stability of the resultant organopalladium intermediate, a stronger correlation was found between the calculated energy of the developing PdÀ C bond in the CMD transition state (TS) and the overall CMD activation energy.…”

“…Analysis of selectivity in 1-arylpyrazole cyclometalations under kinetic or thermodynamic control. [17] Review Isr. J. Chem.…”

“…2020, 60, 230 -258 step in a catalytic process when drawing conclusions about CÀ H cleavage mechanism from selectivity data. [17] Depending on the substrate identity, it was found that cyclometalation at [Cp*M(OAc)(ArH)] + (C) can potentially be rate-and selectivity-determining at any of the multiple steps required to traverse the CÀ H cleavage process by an AMLA pathway ( Figure 11). A full reaction analysis for all substrates in the study suggested that a change in hapticity of coordinated acetate (k 2 in B to k 1 in C), leading to an agostic intermediate can be ratedetermining, such as when M = Ir and R = 4À NMe 2 in the reacting 1-arylpyrazole.…”

“…With consideration of the above mechanistic models (AMLA, CMD, and IES) that originated from studies of CÀ H cleavage in distinct transition metal complexes, it is pertinent to consider if these models are in fact supernumerary representations of one general mechanism, as has been postulated. [17,37] In the context of the broader utility of any one mechanistic model, Goddard, et. al has contended: "[w]hile the definition of precise language regarding mechanisms is worthwhile in its own right, the ultimate utility is whether it provides sufficient insight into the chemistry to suggest improved catalysts."…”