Insights into Sonogashira Cross‐Coupling by High‐Throughput Kinetics and Descriptor Modeling

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Abstract
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.

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