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Insights into Sonogashira Cross‐Coupling by High‐Throughput Kinetics and Descriptor Modeling
Author(s) -
an der Heiden Markus R.,
Plenio Herbert,
Immel Stefan,
Burello Enrico,
Rothenberg Gadi,
Hoefsloot Huub C. J.
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200701418
Subject(s) - sonogashira coupling , aryl , phenylacetylene , chemistry , kinetics , catalysis , alkyne , coupling reaction , activation energy , chemical kinetics , medicinal chemistry , computational chemistry , palladium , organic chemistry , physics , alkyl , quantum mechanics
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 (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.