A detailed theoretical investigation to unravel the molecular mechanism of the ligand-free copper-catalyzed Suzuki cross-coupling reaction

• Published in: Organic & biomolecular chemistry 2022-06, Vol.2 (22), p.4539-4552
• Main Authors: Rajalakshmi, C, Krishnan, Anandhu, Saranya, Salim, Anilkumar, Gopinathan, Thomas, Vibin Ipe
• Format: Article
• Language: English
• Subjects: Chemical reactions; Conductors; Continuum modeling; Copper; Coupling (molecular); Covalent bonds; Cross coupling; Density functional theory; Halides; High temperature; Ligands; Palladium; Species; Substitution reactions; Substrates; Temperature requirements
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d2ob00371f

The Suzuki-Miyaura coupling (SMC) represents a very efficacious method for constructing C-C bonds in organic synthesis. The ligand-free variants of SMC have been grabbing attention these days. Despite this momentousness, the mechanistic details of the ligand-free variants are scant in the literature. Herein, we have carried out a detailed mechanistic investigation into the ligand-free Cu-catalyzed SMC of unsaturated organic halides with aryl boronic acid with the aid of density functional theory (DFT) calculations employing the conductor-like polarizable continuum model (CPCM) method. The present study elucidates that in the absence of ancillary ligands on the metal, the substrates, base, and solvent molecules could act as pseudo-ancillary ligands to facilitate the cross-coupling reaction. The investigation further revealed that unsaturated halides like alkynyl halides/vinyl halides could act as good ancillary ligands for copper by forming a Cu-π intermediate and promoting a facile transmetalation process. However, regarding the oxidative addition and reductive elimination steps, a concerted pathway is observed contrary to Pd catalyzed Suzuki coupling, owing to the instability of Cu( iii ) species and the favourability of Csp 2 -Csp bond formation. In the whole set of mechanisms explored, oxidative addition/oxidative nucleophilic substitution was the rate-determining step in all the cases. A thermodynamically stable π-coordinated intermediate species where the substrate and base molecule are coordinated to the metal center is identified as the rate-determining species for the ligand-free Suzuki cross-coupling reaction. The presence of the aforesaid intermediate increases the energy span and consequently the activation barrier for the rate-determining step. This study unveiled a theoretical rationale for the high-temperature requirement in the ligand-free Cu-catalyzed SMC reaction. A DFT study into the mechanism of ligand-free Cu catalyzed Suzuki cross-coupling reactions of unsaturated halides with aryl boronic acid that portrays the effect of substrate molecules on reaction feasibility by acting as pseudo-ancillary ligands.