An Explicit Interpretation of the Directing Group Effect for the Pd(OAc)₂-Catalyzed Aromatic C–H Activations

Abstract

A comprehensive DFT investigation has been performed for a series of the Pd(OAc)2-catalyzed C-H activations, updating and extending the understanding of directing group effect. In the beginning, the directed and undirected C-H activation mechanisms, based on 10 model reactions, have been discussed comparatively, which disclosed that directing group can exert a thermodynamic driving force, not necessarily a kinetic promotion, on the C-H activation process. Formation of the open palladation species via the undirected pathway is thermodynamically unspontaneous (ΔG = 4-9 kcal/mol), in sharp contrast to that of the cyclopalladation species via the directed pathway (ΔG < 0). Further calculations revealed that the free-energy barriers of proton-transfer are in fact not so high on the undirected pathway (17-24 kcal/mol), while mediation of some O-center groups in the directed pathway would increase the free-energy barriers of proton-transfer. For pyridine N-oxide systems, the undirected mechanism was estimated to be more plausible than the 4-member-directed one both thermodynamically and kinetically. In addition, the uncommon 7-membered cyclopalladation has been tentatively explored using two current examples, predicting that electron-rich directing groups can help to stabilize the 7-membered palladacycles formed.

Dehydrogenative (Hetero)arene Alkoxylations Triggered by PdII‐Catalyzed C(sp2)–H Activation and Coordinating Substituent: PdII,III or PdIV Complex as Key Intermediate?

“…A heteroaromatic substituent able to coordinate to the palladium atom is required for intermolecular DAA . The coordination leads to a cyclopalladated intermediate, and governs the regioselectivity of the alkoxylation . Thus, this review is organized according to the type of the coordinating substituent and, mostly, the chronological order of the reports.…”

Pd-catalyzed Intermolecular Dehydrogenative Heck Reactions of Six-membered Heteroarenes

“…To the best of our knowledge, no Pd-catalyzed DHR of pyridine N-oxides was published since 2010 [73] 4 . The mechanism of the Pd(OAc) 2 -mediated C-H activation of pyridine N-oxide has however been investigated by Fang and Zhang through density functional theory (DFT) calculations [75]. While coordination of the catalyst to the N-oxide was previously proposed as the step directing the regioselectivity of the C-Pd bond formation [76], DFT calculations indicated that the undirected mechanism is more plausible than the 4-memberdirected one both thermodynamically and kinetically [75].…”

Preferred C2−H Activation of Quinoline N‐Oxides Catalyzed by Palladium Acetate: DFT Study on the Plausible Mechanism and Regioselectivity

“…Detailed analysis on the C2‐selectivity of quinoline N‐oxides has been deficient in the literature. For example, it was not very clear whether C2−H activation would be assisted by the directing group center, considering that the formation of four‐member palladacycles might be quite unusual; otherwise, it would proceed via the undirected mechanism involving open (i. e., acyclic) palladated species . In this study, we present a series of density functional theory (DFT) calculations to locate the plausible reaction mechanisms leading to the preferred C2−H activation.…”

“…The electron‐rich oxygen atom appears to be the directing group center of quinoline N‐oxides, in which C2−H activation would afford four‐member palladacycles as possible intermediates. Considering five‐member palladacycles should be more common than the four‐member counterparts, C8−H activation might be thought as a competitive reaction path. However, experimental results demonstrated that C2−H activation was strongly preferred and functionalizations on the other positions were incompetitive…”