Theory-guided design of Pd-catalysts for nondirected C-H functionalization governed by noncovalent interactions

The development of selective catalysts for nondirected C-H functionalization remains a critical challenge in organic synthesis. In this study, we present a computational framework for designing PdIV-based catalysts for nondirected meta-selective C-H activation of anisole, with a focus on ligand design for the Pd complex. Among the ligands surveyed, the pyrazolo naphthyridine (PzNPy) ligand was predicted to exhibit both higher reactivity and selectivity for meta-C-H activation compared to other ligands, as evidenced by its lower overall and relative (meta vs. para) Gibbs free energy barriers, respectively. Energy decomposition analysis (EDA) highlighted the importance of noncovalent interactions, particularly the frozen interaction components (permanent electrostatics, Pauli repulsion, and dispersion), in determining the selectivity trends. Systematic modification of the PzNPy ligand in silico by introducing various electron-donating or electron-withdrawing substituents revealed that while changes to substituents do not significantly affect the selectivity of the catalyst, they do have a pronounced effect on its reactivity. Furthermore, we observed a strong correlation between the Hammett sigma meta (σm) constant of the substituents and the enthalpic contributions to the free energy barrier (∆H‡meta), highlighting how the electronic effects of substituents influence reactivity. Further analysis also revealed a strong correlation between ∆H‡meta and the strength of electrostatic interaction evaluated at the intermediate reactant complex that forms prior to the transition state, providing insights into the enhanced reactivity associated with electron-withdrawing substituents on the PzNPy ligand. Our results demonstrate the potential to enhance both the reactivity and selectivity of catalysts for non-directed C-H functionalization through rational ligand design.