Analyzing the Solvent Effects in Palladium/ <i>N</i> -Heterocyclic Carbene (Pd/NHC)-Catalyzed Suzuki–Miyaura Coupling of Aryl Chlorides: A Computational Study of the Oxidative Addition Step with Experimental Validation

The impact of solvent effects on the oxidative addition step in the palladium/<i>N</i>-heterocyclic carbene (Pd/NHC)-catalyzed Suzuki-Miyaura coupling of aryl chlorides was studied using computational approaches and evaluated experimentally to determine which solvent properties are important when selecting a solvent for this catalyst system. Since oxidative addition is typically considered the rate-determining step of the cross-coupling with aryl chlorides, density functional theory (DFT) was employed to evaluate its energetics across 24 solvents spanning a broad range of physicochemical properties such as polarity, aromaticity, surface tension, and Abraham's hydrogen bond acidity and basicity. The activation barrier and reaction energy were found to depend primarily on the polarity of the solvent with activation barriers ranging from 10.95 kcal/mol in the most polar solvent, water, to 12.35 kcal/mol in the least polar solvent, hexane. This corresponds to a 10.6-fold variation in rate constants at room temperature based on the solvent's dielectric constant. The reaction energies were predicted to vary from -22.70 to -17.39 kcal/mol between the most and least polar solvents, respectively. The molecular origins for these findings arise predominantly from the charge transfer from the Pd(0) catalyst to the aryl chloride during the formation of the transition state for the oxidative addition step; however, this study investigated several additional solvent properties, such as the refractive index, hydrogen-bond acidity and basicity, surface tension, and aromaticity, that were not examined comprehensively in prior computational studies for this catalyst/substrate system. Some of these additional solvent properties were also found to impact the activation barriers. A series of solvents were then analyzed experimentally to determine if the yields corroborate the computational findings. These findings aid in developing a molecular understanding of the solvent properties' effects on the oxidative addition in palladium/<i>N</i>-heterocyclic carbene (Pd/NHC)-catalyzed Suzuki-Miyaura coupling of aryl chlorides and help inform solvent selection for efficient performance of this important coupling reaction.