The Role of AQ in the Regioselectivity of Strong Alkyl C–O Bond Activation Catalyzed by Pd(OAc)2: A Density Functional Theory Mechanistic Study

A density functional theory method was employed to investigate the mechanism of C-O bond activation of butanoic acid substrates bearing the 8-aminoquinoline (AQ) group catalyzed by Pd(OAc)2. The whole reaction consists of five fundamental steps: the chelation of substrate A1, the C-H activation step, the C-N coupling step, the protodepalladation step, and the release of the final product. The calculated results indicated that the protodepalladation step is the rate-determining step with a free energy barrier of 24.3 kcal/mol. This theoretical study pointed out that the energy barriers of C-H activation in the presence and absence of AQ are 11.3 and 26.6 kcal/mol, respectively. This is to say that the installation of the AQ directing group is critical to the regioselectivity of C-H activation and the β-O elimination steps, and this reason enables selective activation of the γ C-O bond. Furthermore, this chelating functionality facilitated the protodepalladation step because the energy barrier of the protodepalladation step was decreased with the coordination of the AQ directing group with a Pd center, and that was 39.3 kcal/mol in the absence of AQ. This also explains why no product formation was observed in the experiment upon changing the directing AQ group to a phenylamino group. Finally, other substrates bearing the phenol leaving group at the β- and δ-positions of carbonyl were investigated in order to expand the applicability of the AQ directing strategy. This work could provide new theoretical insights into the activation of strong alkyl C(sp3) covalent bonds via the AQ directing strategy.