Part I: Biphasic Suzuki-Miyaura Coupling of Aryl Chlorides using phase-tagged Palladium-Phosphine Catalysts The Suzuki-Miyaura coupling of aryl chlorides and PhB(OH)2 under biphasic conditions (DMSO/n-heptane) can be performed in almost quantitative yields over several cycles by means of polymeric Pd catalysts with soluble polyethylene glycol phase tags. Three sterically demanding and electron-rich phosphines 1-CH2Br,4-CH2P(1-Ad)2-C6H4, 2-Cy2P-2’-OH-biphenyl and 2-tBu2P-2’-OH-biphenyl were covalently bonded to 2000 Dalton MeOPEG-OH. The catalysts, which were formed in situ from Na2[PdCl4], the respective polymeric phosphine, KF/K3PO4, and PhB(OH)2, efficiently couple aryl chlorides at 80°C at 0,5 mol% loading, resulting in a >90% yield of the respective biphenyl derivatives. The use of polar phase tags allows the efficient recovery of palladium-phosphine catalysts by simple phase separation of the catalyst-containing DMSO solution and the product containing n-heptane phase. The high activity (TOF) of the catalyst remains almost constant over more than five reaction cycles, which involve the catalytic reaction, separation of the product phase from the catalyst phase, and addition of new reactants to initiate the next cycle. The Buchwald type biphenyl phosphines form the most active Pd catalysts, which are 1.3-2.8 times more active than catalysts derived from diadamantyl-benzylphosphine, but appear to be less robust in the recycling experiments. There is no apparent leaching of the catalyst into the heptane solution (<0.05%), as evidenced by spectrophotometric measurements, and contamination of the product with Pd is avoided. Part II: Mechanistic Insights in Suzuki- and Sonogashira Cross-Coupling-Reactions via High-Throughput Kinetics We present a method for high-throughput monitoring of reaction kinetics in homogeneous catalysis, running up to 30 coupling reactions in a single reaction vessel. We demonstrate this method on the Sonogashira reaction, analyzing the kinetics for over 2000 coupling reactions. First, we analyze the one-pot reactions of phenylacetylene with a set of 30 different ortho-, meta- and para-substituted aryl bromides in the presence of 20 different Pd-phosphine complexes. Then, we study an “inverse” set, where five ArBr and ArI is reacted with eight different para-substituted phenylacetylenes. This experiment shows that the influence of substituents on the aryl halide and the phenyl acetylene on the rate of the Sonogashira coupling are comparable. As a proof for this five aryl halides are reacted simultaneously with five and eight phenyl acetylenes respectively using four different Pd-phosphine complexes. Complementing these experiments, we apply DFT calculations and extract mechanistic information from the data. Our analysis proves that both the alkyne and the aryl halide are involved in the turnover-determining step of Sonogashira reactions. We also examine temperature dependent Sonogashira reactions for 21 different ArX (X= Cl, Br, I) substrates, determining the corresponding number of activation enthalpies and entropies via Eyring plots: ArI (ΔH‡ = 48 – 62 kJ·mol-1; ΔS‡ = -71 – -39 J·mol-1·K-1; NO2 ⇒ OMe), ArBr (ΔH‡ = 54 – 82 kJ·mol-1; ΔS‡ = -55 – -11 J·mol-1·K-1) and ArCl (ΔH‡ = 95 – 144 kJ·mol-1; ΔS‡ = -6 – 100 J·mol-1·K-1). DFT calculations establish a linear correlation of ΔH‡ and the Kohn-Sham HOMO energies of ArX (X= Cl, Br, I). Despite their different C–X bond energies, aryl iodides and electrondeficient aryl bromides show similar activation parameters. This suggests that the insertion of the Pd into the C–X bond is not the turnover-limiting step. | English |
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