Elucidating Ligand‐Dependent Selectivities in Pd‐Catalyzed C–H Activations

Abstract Achieving regioselectivity in C–H activation remains a major challenge. Controlling or even reversing the regioisomeric outcome through the choice of ligand is even harder to achieve, let alone to predict. In this study, we investigated ligand effects in the regioselective Pd‐catalyzed alkynylation of thiophenes using multivariate linear regression to build predictive models that offer deeper insight into the structural factors driving regioselectivity and enabled the discovery of a more selective ligand. Combining experimental and DFT studies, we propose a Curtin–Hammett scenario between the C–H activation and migratory insertion as the origin of the ligand‐controlled selectivities. A detailed investigation of solvent effects uncovered an inadequate description of solvent‐solute dispersion interactions by implicit solvation models. The crucial role of the solvent in substrate coordination is further evidenced by an inverse solvent kinetic isotope effect. Additionally, the often poorly understood role of silver was scrutinized, showing that it serves to mitigate a detrimental side reaction. This study provides generalizable insights for the computational description of challenging regio‐ and stereoselectivities and is expected to aid future mechanistic investigations in Pd‐catalyzed C–H activation that holistically consider the role of all reaction components.