Kinetic Analysis of Aqueous-Phase Pd-Catalyzed, Cu-Free Direct Arylation of Terminal Alkynes Using a Hydrophilic Ligand

The engineering of reaction mixtures that ensure the solubility of inorganic salt byproducts without compromising the reactivity is a grand challenge for continuous flow manufacturing in upstream pharmaceuticals and fine chemicals process development. Aqueous cross-coupling reactions are possible solutions. We report the study of an aqueous phase Pd-catalyzed Cu-free direct arylation of an alkyne using a hydrophilic ligand towards understanding the role of water on the cross-coupling kinetics. Kinetic analyses of theoretically estimated molar flux rates and the measured reaction kinetics reveal a transition from mass transfer to kinetically controlled deprotonation and carbopalladation mechanisms. Interfacial contact areas of immiscible aqueous–organic phases control the crossover from the mass-transfer-limited to the reaction-rate-limited regime. Highly agitated batch reactors and multiphase capillary flow reactors are needed to overcome the mass transport limitations and, thus, discover the transition f...