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

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• 作者：Ria C. Domier ; Jane N. Moore ; Kevin H. Shaughnessy ; Ryan L. Hartman
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：October 18, 2013
• 年：2013
• 卷：17
• 期：10
• 页码：1262-1271
• 全文大小：397K
• 年卷期：v.17,no.10(October 18, 2013)
• ISSN：1520-586X

文摘

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鈥搊rganic 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 from the apparent reaction kinetics to the true reaction kinetics. Comparison of previously reported Density Functional Theory calculations with experimentally measured activation energies, ranging from 14.8 to 20.0 kcal/mol, elucidates the theoretical possibility of designing the aqueous phase C鈥揅 cross-coupling reaction with similar reactivity as purely organic reactions. Although ambiguity remains concerning which reaction step is rate-determining in either the deprotonation or the carbopalladation mechanism, our discovery undergirds that one mechanism or the other could dominate in aqueous designed direct arylations.