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

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.

Self‐assembly aryl cyclopalladated imine film supported on the silicon surface—Fabrication, formation of active PdPd/PdO sites, and catalytic properties for Sonogashira cross‐coupling reaction

“…The surface can be regarded as an infinite "pool" of the organometallic containing a little active species on the surface, 95 showing the great importance of the modification of a metallic surface by the organometallic compounds on its catalytic properties. 96,97 According to the results obtained above, the real active center is Pd/PdO in situ formed on the surface during catalysis, and the proposal catalytic mechanism was described as shown in Scheme 5, including adsorption of substrates (4-iodoanisole and phenylacetylene), intermediate Ph Pd I formation through oxidation, transmetallation between oxidative intermediate with phenylacetylene, reductive elimination to yield the crosscoupling product, and desorption of target molecular.…”

Palladium Theory of Aqueous‐Phase Heck Alkynylations for Intensification of Discovery and Manufacture

“…The coupling of 1-bromo-4-trifluoromethyl benzene and phenyl acetylene was studied (Scheme 1) in order to perform first principle calculations of the Heck alkynylation's reaction kinetics [13]. Intrinsic kinetic expressions were derived as functions of the free molecular species, i.e., the measurable species, from two previously postulated cross-coupling mechanisms: deprotonation (Eq.…”

“…Imagine reducing, by an order of magnitude, the organic solvents consumed during manufacture of fine chemicals and pharmaceuticals. Water dissolves insoluble by-products, e.g., halide salts [11,12], accelerates reaction kinetics [13], separates compounds, potentially expedites data-driven chemistry [14,15], and it can reduce organic waste by concentrating substrates. Theoretical understanding of aqueous-phase Pd-catalyzed cross-couplings, e.g., Heck alkynylations, could help to ensure a greener planet.…”

Magnetic polymer nanocomposite-supported Pd: an efficient and reusable catalyst for the Heck and Suzuki reactions in water

“…16 Amali et al 17 developed a magnetic catalyst by using highly branched polyethylenimine to entrap Pd nanoparticles onto the surface of Fe 3 O 4 . 20,21 Therefore, it is highly desirable to develop efficient catalytic systems which can work in aqueous media. These catalysts are magnetically separable and highly active for the Suzuki and Heck reactions.…”

“…Water is an attractive green reaction medium because it is nontoxic, safe and cheap. 20,21 Therefore, it is highly desirable to develop efficient catalytic systems which can work in aqueous media. On the basis of our previous studies on solid-supported catalysts, 22 we recently prepared a novel catalyst Fe 3 O 4 @PUVS-Pd from readily available monomers.…”