Reaction kinetics of a water-soluble palladium–β-cyclodextrin catalyst for a Suzuki–Miyaura cross-coupling in continuous flow

Abstract

In the present study, a capillary microreactor experiment was designed to study the kinetics of a sample Suzuki–Miyaura coupling using a water-soluble Pd–β-cyclodextrin (Pd–β-CD) catalyst. A water–ethanol solvent system was explored as a potential reaction medium for easy separation of organic species and the metal catalyst, as well as fluid delivery in a continuous microfluidic system. The biphasic, liquid–liquid cross-coupling using the natural product as a ligand was examined for the first time in continuous flow. Mass transfer limitations were concluded to be negligible by estimation of the Hatta number ≪0.02. A catalytic cycle with a third order oxidative addition step was proposed and verified by measurement of the kinetics at different temperatures and residence times. The oxidative addition step was discovered to be the rate determining step, while the activation energy was determined to be 50.1 ± 4.7 kJ mol⁻¹, or less than previously reported values of the free energy barrier of the oxidative addition transition state in the range of 60 to 113 kJ mol⁻¹. A possible explanation is the dual site catalyst design, which may cooperate to lower the free energy barrier. The use of natural products as ligands for the Suzuki–Miyaura coupling has the potential to advance green chemistry and manufacturing of useful fine chemicals, materials, natural products, and pharmaceuticals.