Deprotonation-controlled copper-free Pd-catalyzed Sonogashira coupling

Carborane derivatives have emerged as valuable hydrophobic pharmacophores in medicinal chemistry owing to their unique electronic characteristics and rigid three-dimensional architectures. Here, density functional theory (DFT) calculations are used to dissect the copper-free Pd-catalyzed Sonogashira coupling that leads to 3-quinolylethynyl carborane alkynes and to benchmark this transformation against the Pd-catalyzed Kumada-Tamao-Corriu reaction for B-C bond formation. The Sonogashira manifold is analyzed in terms of four limiting scenarios: a carbopalladation route, cationic and anionic deprotonation pathways and an ionic pathway involving base-assisted chloride substitution at palladium. The carbopalladation route, although overall exergonic, is rendered kinetically inaccessible by a prohibitively high barrier for vinylic C-H deprotonation, whereas the cationic and ionic deprotonation mechanisms display substantially lower, but still moderate, activation free energies. In contrast, the anionic deprotonation pathway-initiated by base-promoted deprotonation of the terminal alkyne and electronic stabilization of the resulting acetylide by the 3-quinolyl group-features the lowest overall Gibbs free energy barrier and therefore emerges as the dominant mechanism under copper-free conditions. Comparison with the Kumada cycle shows that, while the latter is thermodynamically feasible, the key B-C bond-forming reductive elimination step is associated with a significantly higher barrier and delivers a less stable product than the corresponding Sonogashira outcome. Taken together with available experimental data, these results indicate that copper-free Sonogashira coupling with Pd(PPh