Role of Explicit Solvents in Palladium(II)-Catalyzed Alkoxylation of Arenes: An Interesting Paradigm for Preferred Outer-Sphere Reductive Elimination over Inner-Sphere Pathway

The mechanism of palladium acetate catalyzed directed C(sp(2)) H functionalization of N-methoxybenzamide in methanol leading to an ortho-alkoxylated product is examined using density functional theory (M06, M06-2X, and B3LYP) computations. The cluster-continuum solvation model is employed to account for both specific and long-range interactions with the methanolic medium. A large number of mechanistic scenarios consisting of microsolvated transition states inclusive of explicit methanol molecules have been considered to unravel the role of methanol in the crucial cyclometalation deprotonation (C H activation) as well as in the reductive elimination steps besides that in the other steps of the reaction. A cooperative C H activation, assisted by both methanol and palladium-bound acetate, involving a relay proton transfer has been identified as a vital mechanistic event. Most importantly, the generally proposed inner-sphere reductive elimination (ISRE) transition states are found to be more than 6 (CCSD(T)) to 9 (DFT, M06) kcal/mol higher than the corresponding outer-sphere (OSRE) equivalent. The methoxide bound to palladium is introduced to the ortho aryl carbon in the case of ISRE, while a hydrogen-bonded methanol is deprotonated by the palladium-bound acetate ligand as it gets simultaneously attached to the ortho carbon in the OSRE mechanism. In most of these steps, a relay proton transfer facilitated by the explicitly bound methanol molecules is identified as responsible for the additional stabilization of the crucial transition states in the mechanistic course. These results underscore the importance of specific interactions with the polar protic solvent molecules in reactions such as the title reaction while attempting to derive meaningful mechanistic insights.