On the role of anionic ligands in the site-selectivity of oxidative C-H functionalization reactions of arenes

The replacement of an acetate ligand for carbonate leads to a reversal in site-selectivity in the Pd-mediated C-H oxidative coupling of benzo[h]quinoline with 1,3-dimethoxybenzene. This report describes Density Functional Theory studies designed to elucidate the origin of this selectivity change. These studies focused on two key mechanistic steps: C-H activation and C-C bond-forming reductive elimination. We considered monometallic and bimetallic reaction pathways for acetate and carbonate conditions. The favored C-H activation pathway proceeds via a concerted metalation deprotonation (CMD) mechanism, independent of the nature of anionic ligand (acetate versus carbonate). The predicted selectivity is ortho/para for the C-H activation for both the acetate and carbonate-ligated Pd complexes. Further, we determined that the reductive elimination step is greatly facilitated by the coordination of benzoquinone (by Delta Delta G double dagger similar to 20 kcal mol(-1)) and is predicted to be meta-meta selective with both anionic ligands. Overall, the DFT studies indicate that the anionic ligand does not induce a mechanism change at the elementary steps, and the predicted selectivity at all steps is equivalent for carbonate and acetate, no matter whether a dinuclear or mononuclear pathway is considered. These studies lead us to propose that the role of the anionic ligand is to control which step of the mechanism is overall selectivity-determining. This proposal has been tested experimentally using appropriately designed experiments. Notably, the insoluble base MgO as an acid trap under acetate conditions (with the aim of making the C-H insertion step less reversible), gave rise to predominant ortho/para selectivity in the presence of acetate, in analogy to the results previously seen under carbonate conditions.