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

The reactions of substituted 1-phenylpyrazoles (phpyz-H) at [MCl2Cp*]2 dimers (M = Rh, Ir; Cp* = C5Me5) 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 ortho-cyclometalated 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.