Analyzing the Solvent Effects in Palladium/N‑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/N-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/N-heterocyclic carbene (Pd/NHC)-catalyzed Suzuki–Miyaura
coupling of aryl chlorides and help inform solvent selection for efficient
performance of this important coupling reaction.