Kinetic analysis of aqueous-phase Pd-catalyzed, Cu-free direct arylation of terminal alkynes using a hydrophilic ligand

Ria C. Domier, Jane N. Moore, Kevin H. Shaughnessy, Ryan Hartman

Research output: Contribution to journalArticle

Abstract

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 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-C 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.

Original languageEnglish (US)
Pages (from-to)1262-1271
Number of pages10
JournalOrganic Process Research and Development
Volume17
Issue number10
DOIs
StatePublished - Oct 18 2013

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Alkynes
alkynes
Reaction kinetics
Deprotonation
Mass transfer
Ligands
cross coupling
reaction kinetics
ligands
Kinetics
kinetics
Capillary flow
Phase control
Batch reactors
mass transfer
reactivity
Reaction rates
Density functional theory
reactors
Byproducts

ASJC Scopus subject areas

  • Organic Chemistry
  • Physical and Theoretical Chemistry

Cite this

Kinetic analysis of aqueous-phase Pd-catalyzed, Cu-free direct arylation of terminal alkynes using a hydrophilic ligand. / Domier, Ria C.; Moore, Jane N.; Shaughnessy, Kevin H.; Hartman, Ryan.

In: Organic Process Research and Development, Vol. 17, No. 10, 18.10.2013, p. 1262-1271.

Research output: Contribution to journalArticle

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