Insights into Sonogashira cross-coupling by high-throughput kinetics and descriptor modeling

A method is presented for the high-throughput monitoring of reaction kinetics in homogeneous catalysis, running up to 25 coupling reactions in a single reaction vessel. This method is demonstrated and validated on the Sonogashira reaction, analyzing the kinetics for almost 500 coupling reactions. First, one-pot reactions of phenylacetylene with a set of 20 different meta- and para-substituted aryl bromides were analyzed in the presence of 17 different Pd-phosphine complexes. In addition, the temperature-dependent Sonogashira reactions were examined for 21 different ArX (X = Cl, Br, I) substrates, and the corresponding activation enthalpies and entropies were determined by means of Eyring plots: ArI (ΔH^≠ = 48-62 kJ mol^-1; ΔS^≠ = -71-39 J mol^-1 K; NO₂→OMe), ArBr (ΔH^≠ = 54-82 kJ mol^-1, ΔS ^≠ = -55-11 J mol^-1 K), and ArCl (ΔH ^≠ = 95-144 kJ mol^-1, ΔS^≠ = -6-100 J mol^-1 K). DFT calculations established a linear correlation of ΔH^≠ and the Kohn-Sham HOMO energies of ArX (X = Cl, Br, I) and confirmed their involvement in the rate-limiting step. However, despite different C-X bond energies, aryl iodides and electron-deficient aryl bromides showed similar activation parameters.