A Mechanistic Insight into the Cu(II)‐Catalyzed C–N and C–O Coupling Reaction of Arylglyoxylic Acids with Isatins; A DFT Investigation

We carried out a DFT computational investigation on the mechanism of the copper(II) catalyzed C–N, C–O cross coupling reaction involving isatin and phenylglyoxylic acid recently reported by Gogoi. The mechanistic hypothesis proposed by this author is overall confirmed. Our computations demonstrated that the initial decarboxylation is an exergonic reaction (–15.3 kcal mol–1). This process, which can occur rather easily under the used experimental conditions (95 °C for 24 hours), triggers the catalytic cycle with the formation of the initial active organometallic complex (I1). A copper acetate ligand deprotonates the isatin nitrogen. This enhances its nucleophilic character and makes possible the attack of nitrogen on the Cu atom. A reversible transformation connects the initial encounter complex between isatin and the active intermediate I1 and the intermediate where the metal atom inserts into the amide bond. The decarbonylation step represents the rate‐determining step of the entire process (activation free energy = 23.3 kcal mol–1). Copper does not change its oxidation state (II) in the course of the catalytic reaction. The mechanism never involves directly the isatin benzene ring: this is consistent with the fact that only slight changes in the reaction yield are observed when substituents are inserted at different positions of the aromatic ring.