Rational ligand modification maximizes turnover rate in a model Pd-catalyzed C-H arylation.

The direct cross-coupling of (hetero)aromatics without prior functionalization is a promising reaction for the chemical and pharmaceutical industries, enabling the conversion of inexpensive feedstocks in a highly step-efficient manner. However, many C-H arylations rely on high loadings of a Pd catalyst that preclude their use in low-cost applications. In this work, we have maximized the turnover rate of a Pd-catalyzed C-H arylation reaction through rational tuning of the ligands. Starting from a computational study of the catalytic mechanism, a kinetic model was derived that accurately explains the experimental time profiles. Quantitative structure-activity relationships between the substituents on the ligands and the resulting catalytic activity for various C-H arylations were obtained. This study demonstrates that, depending on the coupling partner, the C-H activation is not the sole rate-limiting step, and that the ligands can be adapted accordingly to further accelerate catalytic turnover.