Noncovalent Interactions in Palladium(II)-Catalyzed Meta-Selective C-H Functionalization: Mechanistic Insights and Origins of Regioselectivity.

The use of noncovalent interactions to control the regioselectivity of transition metal-catalyzed C-H functionalization of arenes has received significant attention in recent years. Herein, we present a mechanistic study based on Density Functional Theory (DFT) of palladium(II)-catalyzed meta-selective C-H olefination employing a noncovalent directing template. We analyze the key steps of the mechanism and discuss the origins of reaction selectivity. The role of the directing template was elucidated, demonstrating its essential function in lowering reaction barriers and controlling selectivity. Our results reveal a competition in activation between ortho- and meta-C-H bonds. Contrary to the previous proposal in the literature, hydrogen bonds between the N-H bonds of the urea moiety and the carbonyl oxygen of the substrate predominantly favor ortho-selectivity over meta-selectivity. DFT results, alongside Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction Index analysis, suggest that secondary interactions between the R group linked to the urea moiety and the catalyst exert a more pronounced influence compared to the aforementioned hydrogen bonds, directing the selectivity towards the meta C-H bond.

Palladium(II)-catalyzed annulation of N-methoxy amides and arynes: computational mechanistic insights and substituents effects.

CONTEXT: The combined use of transition metal-catalyzed C-H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C-H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C-H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd-C bond formation and a late C-H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. METHODS: All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent.