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 (Δ H ≠ =48–62 kJ mol −1 ; Δ S ≠ =−71–−39 J mol −1  K; NO 2 →OMe), ArBr (Δ H ≠ =54–82 kJ mol −1 , Δ S ≠ =−55–11 J mol −1  K), and ArCl (Δ H ≠ =95–144 kJ mol −1 , Δ S ≠ =−6–100 J mol −1  K). DFT calculations established a linear correlation of Δ H ≠ and the Kohn–Sham HOMO energies of ArX (X=Cl, Br, I) and confirmed their involvement in the rate‐limiting step. However, despite different CX bond energies, aryl iodides and electron‐deficient aryl bromides showed similar activation parameters.