Kinetic Analysis of Aqueous-Phase Pd-Catalyzed, Cu-Free Direct

Article pubs.acs.org/OPRD

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,*,‡ and Ryan L. Hartman*,† †

Department of Chemical and Biological Engineering, The University of Alabama, Box 870203, Tuscaloosa, Alabama 35401, United States ‡ Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, Alabama 35401, United States S Supporting Information *

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 Cufree 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.

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chemicals.7 Significant advances have been made in the design of ligand-promoted, palladium-catalyzed cross-coupling reactions that provide high activities with a range of substrates including inexpensive, widely available, but challenging, organic chloride and sulfonate substrates.8 Despite the advances, largescale application of these methods is still limited by undesirably low TON or TOF values. Separation of the homogeneous palladium catalyst from the organic product stream, particularly to the levels required for pharmaceutical applications, also presents a major challenge.2 Palladium-catalyzed cross-coupling in aqueous-biphasic solvents has a long history dating back to the initial development of the Suzuki coupling of aryl halides and organoboronic acids.9 Casalnuovo pioneered the use of water-soluble phosphine ligands to constrain the palladium catalyst in the aqueous phase of a water/organic reaction mixture.10 Since this initial report, catalysts derived from a wide range of water-soluble ligands have been used to promote palladium catalyzed couplings in water/organic solvent mixtures.1c By using a water-soluble catalyst species, the catalyst containing an aqueous phase can be readily separated from the hydrophobic product phase. Furthermore, the catalyst solution can potentially be recycled for use in subsequent reaction cycles. In addition to the

INTRODUCTION Water as a reaction solvent is potentially a transformative approach to greener and safer synthetic chemistry,1 both in the laboratory and in production scenarios. Water is an attractive solvent because it is cheap, nonflammable, and environmentally benign. In addition, the use of water-soluble catalysts in aqueous-biphasic systems presents the opportunity for catalyst recovery.1c Catalyst recovery and its reuse are important because of the cost and the scarcity of the most catalytically useful metals (Pd, Pt, Rh, Ru). Residual trace metal impurities are stringently regulated in pharmaceuticals. Separation of homogeneous catalysts from organic product streams can prove challenging.2 Water can, in some cases, provide new or improved reactivity in catalytic processes due to its unique solvent properties.3 Furthermore, the precipitation of insoluble inorganic salt byproducts, problematic in continuous flow reactions in organic solvents,4 could potentially be dealt with using water as a reaction solvent. Palladium-catalyzed cross-coupling reactions of organic halides with organoboron compounds (Suzuki coupling), organostannanes (Stille coupling), alkenes (Heck coupling), and alkynes (Sonogashira coupling), as well as the many variations on these reactions, are indispensible methods to construct carbon−carbon bonds.5 The generality and functional group tolerance of these reactions allow them be utilized in the synthesis of complex natural product targets.6 Their operational simplicity and wide scope have led to their adoption in the fine chemical industry in both development- and process-level synthesis of active pharmaceutical ingredients and other fine © 2013 American Chemical Society

Special Issue: Engineering Contributions to Chemical Process Development Received: May 21, 2013 Published: September 3, 2013 1262

dx.doi.org/10.1021/op4001274 | Org. Process Res. Dev. 2013, 17, 1262−1271

Organic Process Research & Development

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separation advantages offered by water, the unique properties of water compared to organic solvents can result in enhancements in reaction rates or changes in reactivity trends. Breslow first noted the ability of water to accelerate reactions of hydrophobic molecules.11 Recently, there has been a resurgence of interest in the role of water in accelerating organic reactions.3,12 The design of aqueous phase catalyzed cross-couplings with process design in mind motivates a closer look at the laboratory techniques commonly employed for their discovery. Classical batch syntheses mediated by hydrophilic ligands rely on efficiency in heterogeneous reaction mixtures where molecular diffusion potentially influences the reaction rates. The extent of mass transfer limitations must be considered to properly evaluate intrinsic kinetics when reactions occur at liquid−liquid interfaces. It is readily known that molecular flux to and from bulk fluids in gas−liquid and liquid−liquid systems influences the reaction kinetics with the interfacial contact areas being principally important.13 The same principles hold true for batch and continuous flow reactors with the characteristic diffusion length scales being of utmost importance. Extensive knowledge is available on mesoscale to full production batch mixing principles,14 and numerous elegant works outline the mixing principles in continuous laminar flow reactors.14h,15 In either case, properly assessing the role of mass transport limitations on the experimentally measured kinetics requires analyses of reaction time scales relative to molecular diffusion time scales,16 which is made possible through first principle calculations. The existence of mass transport limitations does not necessarily constrain synthetic methodology discovery. However, process chemistry requires intrinsic knowledge to accurately scale-up from the laboratory to production.17 Flow chemistry has been a topic of intense research4b,c,5u,17c,f,18 for these reasons and many other benefits related to green chemistry and engineering.19 Aqueous derived synthetic methodologies1,5j,18j,20 have the potential to expand the scope of continuous process intensification. However, a first principle understanding of laboratory-scale mass transport phenomena must accompany the synthesis techniques to ensure the accurate estimation of kinetics. In the present work, we examine the palladium-catalyzed synthesis of diarylacetylenes using hydrophilic ligand with the goal of evaluating the influence of mass transfer on the kinetics. Molar flux and interfacial contact areas potentially control the kinetics in multiphase aqueous−organic reactions instead of intrinsic mechanisms. Capillary flow reactors are applied to estimate the molar flux rates in multiphase classical batch reactors, and in turn the reaction space necessary for our laboratory-scale kinetics discovery is identified. We report that highly agitated batch reactors and multiphase capillary flow reactors provide sufficient interfacial contact areas to identify the crossover from the mass-transfer-limited to the reactionrate-limited regime (i.e., the transition from the apparent reaction kinetics to the true kinetics). The subsequent comparison of mass transfer limited models to intrinsic kinetic models, derived from first principles and based on the deprotonation and the carbopalladation catalytic cycles, reveals the transformative approach of engineering water as a reaction solvent in fine chemicals synthesis and manufacturing. Our study using capillary flow and batch reactors establishes the groundwork for the innovation of reactors and hydrophilic ligands for aqueous phase catalyzed cross-couplings.

Article

REACTION MECHANISM AND KINETICS

The Pd-catalyzed copper-free direct arylation of phenylacetylene with 4-bromobenzotrifluoride is shown in Scheme 1. Water-soluble alkylphosphines, such as DTBPPS (3-(di-(tertbutyl)phosphonium)propylsulfonate), are effective ligands in the aqueous-phase Pd-catalyzed Suzuki, Sonogashira, and Heck coupling reactions.5e−k,m,v,21 Sterically demanding and strongly electron donating ligands have been shown to provide the most effective catalysts for a wide range of Pd- and Rh-catalyzed cross-coupling reactions. In addition, they have similar steric and electronic properties to the ligands commonly used in the direct arylation of C−H bonds. Scheme 1. Pd-catalyzed copper-free cross-coupling between terminal alkyne and 4-bromobenzotrifluoride using watersoluble DTBPPS

Two different mechanisms, deprotonation and carbopalladation,5s,22 have been proposed for the palladium-catalyzed copper-free cross-coupling between a terminal alkyne and an aryl halide. The two catalytic cycles, shown in Figures 1a and b, both undergo the reversible oxidative addition of the aryl halide to the catalytically active Pd0LX species 1. Large concentrations of aryl halide and alkyne relative to other free species drive either catalytic cycle in the forward direction, which establishes reaction conditions far from equilibrium. The resulting

Figure 1. Proposed deprotonation (a) and carbopalladation (b) mechanisms for the palladium-catalyzed copper-free cross-coupling between a terminal alkyne and an aryl halide. 1263



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liquid−liquid segmented flow was established, and the reactions were quenched with 1.0 M HCl to ensure accurate analyses offline with gas chromatography. In batch, samples were acquired using syringes and immediately diluted with ethyl acetate followed by their analyses with gas chromatography. Batch experiments at 50, 70, and 80 °C were conducted over a range of stirrer rates (from 176 to 1100 rpm). Analyses of aliquots taken at 1 to 5 min intervals over 30 min in batch reactors and aliquots collected for 1, 3, and 5 min residence times yielded the substrate concentrations as a function of the reaction time (i.e., molar flow rates of less than 25.0 μmol/ min). Monitoring the substrate concentrations as functions of the reaction times yielded interesting kinetic observations. One observes in Figures 3, S1a, and S1b that increasing the reaction

oxidative addition adduct, species 2, then undergoes reversible coordination to the alkyne, forming alkyne−PdII complex 3. In the deprotonation mechanism, the base then removes a proton from the alkyne−PdII complex 3, and as a result forms the vinyl−PdII complex 4. The cross-coupled product R−Ar then undergoes dissociation, restoring the catalytically active Pd0LX species 1. Reversible cationic and anionic alternatives for the deprotonation mechanism have been proposed. In the carbopalladation mechanism, however, the intramolecular rearrangement (5) of the alkyne−PdII complex 3 takes place through migratory insertion of the aryl group Ar to the terminal alkyne. The product R−Ar is then expelled from the vinyl−PdII complex, complex 4′, via reductive elimination to restore the catalytically active Pd0LX species 1. The concentration of the base in either mechanism will have a larger impact on reductive elimination when the base is strong. Cationic and ionic versions of the deprotonation mechanism rely on the solution ionic strength, which makes aqueous reaction mixtures interestingly complex. The mechanisms postulated in Figure 1 further support that base-to-ligand interactions could influence the catalytic cycles, which motivates an even deeper molecular understanding of hydrophilic ligand design. Although significant contributions have been published, there remains ambiguity in the literature towards understanding which of the two catalytic cycles controls the copper-free Sonogashira reaction.5s,22 Both theoretical and experimental works summarize the mechanistic studies on the deprotonation and the carbopalladation mechanisms.5s,22 Density Functional Theory (DFT) calculations by Garcia-Melchor et al.22a conclude a high-energy barrier for the carbopalladation mechanism, indicating that the deprotonation mechanism operates under the reaction space they investigated. However, the mechanistic complexity necessitates understanding specific reaction scenarios, as the multiple reaction pathways exhibit competitive rates as functions of the solvent, ligands, substrates, base, and, as our results will demonstrate, the reactor design.

Figure 3. Aryl bromide concentrations as functions of their reaction times at 50, 70, and 80 °C and 1100 rpm. Aryl alkyne (Figure S1a) and base (Figure S1b) concentrations are available in the Supporting Information.

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temperatures from 50 to 80 °C at 1100 rpm increased the rates of disappearance of the aryl bromide, alkyne, and the base. However, Figures 4, S2a, and S2b illustrate that the stirring rate and the nature of the reactor (batch or continuous) each have a

RESULTS AND DISCUSSION Diaryl Alkyne Synthesis. Direct arylations of a terminal alkyne were performed in batch reactors (4.0 mL vials) and in 0.1 mL continuous flow capillary reactors (PFA tubing 1/16″ O.D., 1.0 mm I.D.). In either case, a heated oil bath was used to establish isothermal reaction conditions. Batch reactors were agitated via magnetic stirrers (dimp/dflask = 0.77) whereas a Harvard Apparatus PHD2000 syringe pump was used to inject reagents as shown schematically in Figure 2. In flow, multiphase

Figure 4. Aryl bromide concentrations as functions of their reaction times (at 80 °C) in 4.0 mL vials mixed at 176, 522, and 1100 rpm. The concentrations exiting a capillary flow reactor (at 80 °C) were measured at residence times, τ, of 1, 3, and 5 min. Aryl alkyne (Figure S2a) and base (Figure S2b) concentrations are available in the Supporting Information.

Figure 2. Continuous flow capillary reactor apparatus consisting of 1.0 mm I.D. PFA tubing (0.1 mL). Batch reactor experiments were performed by replacing the capillary reactor system with a 4.0 mL vial sealed via septum and agitated with magnetic stirrers. 1264



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profound impact on the reaction. Batch experiments (at 80 °C) carried out at 176, 522, and 1100 rpm demonstrate that increasing the stirrer rate increases the rate of disappearance of the substrate. Stirrer rates of 1100 rpm represent the maximum agitation achievable using a conventional magnetic stirrer plate. The general observation is a preliminary indication of inadequate shear between the immiscible aqueous and organic fluids (i.e., the existence of mixing limitations) at lower stirring rates of 176 and 522 rpm. The mixing of two immiscible liquids in batch is complex with both convective and diffusive terms being challenging to characterize. Low Reynolds number (Re < 10) flow, however, is well characterized, and it offers a ubiquitous reactor platform to evaluate either mass transfer limited or reaction rate limited synthesis.15h,i,16,23 Examination of the substrate concentrations measured in the capillary flow reactor demonstrates results comparable to batch experiments at 1100 rpm, as shown in Figures 4, S2a, and S2b. Table 1 Table 1. Experimentally calculated diaryl alkyne yields for batch and flow experiments entry

reaction time (min)

1 2 3 4 5 6 7 8 9 10 11 12

1.0 5.0 10 1.0 5.0 10 1.0 5.0 10 1.0 3.0 5.0

reactora T (°C) batch batch batch batch batch batch batch batch batch flow flow flow

50 50 50 70 70 70 80 80 80 80 80 80

diaryl alkyne yield (%)b

std. dev.b

7 37 64 13 70 87 12 81 90 5.5 17 36

5 7 10 2 10 4 6 10 2 0.3 0.4 4

Figure 5. Linearized aryl bromide mass transfer rates, given by expressions (S3) and (S4), for the instantaneous reaction via either mechanism, deprotonation, or carbopalladation. The data illustrate the potential for mass transfer influences on either mechanism (a) for varying fluid mechanics and (b) at different reaction temperatures.

a Batch experiments performed at 1100 rpm. bAll yields calculated from product concentrations measured in three samples. No byproducts were measured.

On the other hand, the flow results of Figure 5a motivate a more in-depth analysis that reveals the role of mass transfer. Figure 5a approximates the measured value, kca = 0.1 min−1, using expression (S4) for flow. Theoretically calculated kca values are available, using expression (S2), by substituting the liquid−liquid interfacial contact area in the milliscale flow reactor, a = 90 cm2/cm3, for liquid slugs having equivalent droplet diameters,24 di = 0.21 cm. Theoretical and experimental values of the substrate diffusivity, predicted by the Wilke− Chang correlation24 and Valencia and Gonzalez,25 are 2.3 × 10−3 and 6.2 × 10−3 cm2/min at 80 °C, respectively. Substituting the diffusivities into expression (S2) when Sh = 2 yields kca values of 1.9 and 5.2 min−1. The calculated mass transfer coefficients being an order of magnitude greater than our measured value both indicate a kinetically controlled direct arylation. Strictly speaking, the corresponding molar flux rate is an order of magnitude greater than the reaction rate. However, best practices of performing kinetic measurements when the mass transfer coefficient exceeds at least 1 of order magnitude ensure the discovery of intrinsic mechanistic knowledge. Reducing the flow reactor characteristic length from 1.0 mm to microreactor dimensions (e.g., < 0.5 mm), hence an order of magnitude increase in the interfacial liquid−liquid contact area, is expected to eliminate any mass transfer influences on the measured kinetics altogether. The batch results of Figure 5b (at 1100 rpm) further support that the kinetics are principally

additionally highlights the calculated yields for batch and flow experiments. In all cases, however, comparisons of the physical rate processes to the chemical rate processes are needed to identify the mechanisms truly governing the complex reaction system. Instantaneous Reaction with Respect to Mass Transfer. The mass transfer rates derived for instantaneous reaction at the liquid−liquid interface elucidate the role of molecular diffusion on the kinetics. Expressions (S3) and (S4) are shown in Figures 5a and b via plotting the natural logarithm of the substrate concentrations. One observes that in Figure 5a strong correlations exist for stirrer rates of 176 and 522 rpm. Plausible explanations are that the reactions were mass transfer limited rather than kinetically controlled by either the deprotonation or the carbopalladation catalytic cycles. The resulting mass transfer coefficients, kca, are 7.0 × 10−3 and 1.0 × 10−2 min−1 for stirrer rates of 176 and 522 rpm, respectively. Predicted initial substrate concentrations of 0.418 and 0.420 M are in agreement with the actual initial 4-bromobenzotrifluoride concentration of 0.424 M. These results undergird that, at stirrer rates of 176 and 522 rpm, the molecular flux of the substrate controls the reaction rather than the deprotonation or the carbopalladation mechanisms themselves. 1265



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Figure 6. Calculated and measured aryl bromide, aryl alkyne, and base concentrations as functions of their reaction times (at 50, 70, and 80 °C and 1100 rpm) for the deprotonation mechanism. Rate-determining step scenarios of (a) oxidative addition far from equilibrium (OA), (b) coordination far from equilibrium (COR), (c) reductive elimination (RE), and (d) dissociation (DISS) were calculated. Each set of oxidative addition and coordination calculations of the deprotonation mechanism match those for the carbopalladation mechanism. Calculated values for (MI) migratory insertion also are reported for the carbopalladation mechanism. Near equilibrium simulation results for oxidative addition (OA, EQ) and coordination (COR, EQ) steps are available in the Supporting Information as Figures S3a and S3b, respectively.

far from equilibrium and [PdnLX] ≈ [PdnLX−1] ≈ [Pd]T and [L] ≈ [L]T. The conditions are relevant during the early stages of the reaction (e.g., reaction times 0.99 for all scenarios.

concentrations, as shown in Figure 7 and by the s2 values of Table 2. Revisiting the kinetic expressions of (S5) and (S7) offers fundamental insight into the catalytically active species’ transition states. Our initial condition of the palladium mole balance is an approximation [PdnLX] ≈ [PdnLX−1] ≈ [Pd]T, but it offers fundamental insight into the activation energies of the steps in either mechanism. Using the aforementioned assumption, the fitted kinetic parameters of Table 2 do not accurately describe the measured kinetics when fully constructing and solving the ODEs of expressions (S5) and (S7) both near and far from equilibrium, an indication that the concentration of catalytic intermediates are a fraction of the total palladium concentration. Accordingly, the corresponding coupled ODEs were solved numerically for both mechanisms by varying the fraction of the catalytically active palladium species, ϕ, using expressions (S9), (S10), and (S11). Varying ϕ values to minimize s2 values for expressions (S5) and (S7) reveals the fraction of the total palladium in the form of any catalytically active intermediate under far equilibrium conditions for either mechanism. Thus, the apparent reaction rate constants of Table 2 are recalculated using expressions (S12) and (S13) for scenarios when one does not assume our initial condition that all of the palladium participates in the reaction.

As a consequence, the smallest reaction rate constant ki,app = 0.616 min−1 at 80 °C, as shown in Table 2. Our capillary flow calculations of the mass transfer coefficient, kca, indicate values on the order of 0.1 min−1. Therefore, one must also consider mixed mass transfer and reaction rate limitations to properly evaluate the activation barriers of the cross-coupling kinetics. Mixed Mass Transfer and Reaction Rate Limited Regime. When the molar flux rate approaches the same order of magnitude as the reaction rate there exists the potential for mixed mass transfer and kinetically limited regimes. Thus, the measured rate constants are expected to be less than their true values. The measured, true activation energy in classical heterogeneous catalysis is derived as twice that of the apparent activation energy (i.e., ET = 2EApp).13,26 The rule applies when spherical liquid droplets with diameters, di, contain film resistance, and both chemical reaction and molecular diffusion have Arrhenius temperature dependencies. Further analysis of the apparent values of Table 2 offers additional scientific insights on the kinetics in the mixed mass transfer and intrinsically limited regime. From Table 2, our true activation energies of the oxidative addition of the aryl bromide (ET = 19.6 kcal/mol) and the coordination of the alkyne (ET = 19.5 kcal/mol), for either deprotonation or carbopalladation, are in excellent agreement with recent DFT calculated values of 1268



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17.0 and 23.0 kcal/mol for iodides, respectively.22a Density Functional Theory predictions of the highest activation barrier, the rate-determining step of reductive elimination, for the cationic (ET = 14.0 kcal/mol) and the anionic (ET = 13.1 kcal/ mol) deprotonation mechanisms are less than the measured value of 19.2 kcal/mol from our aqueous phase crosscoupling. 22a Differences of 5.2 and 6.1 kcal/mol are theoretically the result of the hydrophilic nature of the ligand. Our measured activation energy of the diaryl product dissociation in the deprotonation mechanism (ET = 15.1 kcal/mol) is 3.6 kcal/mol greater than DFT calculated values,22a supporting that the hydrophobic nature of the product could inhibit it from being expelled into the mixed aqueous−organic solvent. Further analysis of the carbopalladation mechanism in the mixed mass transfer and reaction-controlled regime fosters a deeper understanding of its kinetics. The energy barrier of the intramolecular rearrangement (5) of the alkyne−PdII complex 3 via migratory insertion of the aryl group Ar to the terminal alkyne has been calculated to be 14.2 kcal/mol.22a Our measured value of 15.1 kcal/mol confirms the DFT predictions. Remarkably, the hydrophilic ligand coordination step exhibits a true activation energy of 14.8 kcal/mol, which is greater than the value of 6.4 kcal/mol calculated by DFT.22a The difference is possibly the outcome of competing hydrogen-bonding effects during the ligand’s stereochemical coordination. Recent DFT calculations of the carbopalladation mechanism reveal its energy barrier for reductive elimination (i.e., the ratedetermining step) in the purely organic cross-coupling to be 40.4 kcal/mol, implying that the deprotonation mechanism exhibits an overall lower energy catalytic cycle. The measured true activation energy of reductive elimination in our hydrophilic cross-coupling (ET = 19.7 kcal/mol) is 20.7 kcal/ mol less than the DFT calculated value.22a Consequently, either the deprotonation or the carbopalladation mechanism could dominate in the aqueous phase cross-coupling, which supports that water plays a vital role in the catalysis.

into new 15 mL vials sealed under a nitrogen atmosphere. The two solutions were then used to carry out reactions in batch and flow reactors. General Procedure for Batch Experiments. 1 mL each of the acetonitrile and aqueous solutions was transferred into three sealed 4.0 mL vials containing magnetic stir bars. The 4.0 mL vials had each been sealed with a screwcap and PTFE coated septums under a nitrogen atmosphere. The three vials were then tied together and carefully centered in an oil bath (80 ± 1 °C) on a stir plate. Aliquots of 25 μL were taken from each vial at intervals of 1 to 30 min and diluted into 1.0 mL of ethyl acetate in ambient air. Gas chromatography (Varian 3800) was used to analyze each aliquot to determine the progression of the reaction. No byproducts were detected in any experiments. The procedure was repeated at 70 ± 1 °C and 50 ± 1 °C) and stir speeds of 2 (176 rpm), 5 (522 rpm), and 10 (1100 rpm). General Procedure for Flow Experiments. Reagents were transferred to glass syringes (5.0 mL, SGE) and delivered to a 0.1 mL PFA capillary reactor (1/16″ O.D., 1.0 mm I.D.) with a Harvard Apparatus PHD2000 syringe pump. All fluidic connections were made using 1/4″-28 PTFE fittings and PFA tubing (1/16″ O.D., 1.0 mm I.D., VWR). The capillary reactor was coiled and submerged into a well mixed oil bath (80 ± 1 °C) on a stir plate. The bath temperature was monitored via a thermocouple and maintained with a Waage immersion heater controlled by a J-KEM Scientific Gemini PID controller. Upon exiting the reactor, the mixture was introduced with 1.0 M HCl to quench the reaction before it was collected in a GC vial sealed with a septum. Three experiments were performed each at three different residence times of 1, 3, and 5 min. Gas chromatography (Varian 3800) was used to analyze each aliquot to determine the progression of the reaction. No byproducts were detected in any experiments. Procedure for Evaluation of Kinetic Parameters. Raw data from synthesis experiments were fit using nonlinear regression for each rate-determining step separately. The coupled ODEs were then solved numerically by the Runge− Kutta−Fehlberg28 and the Rosenbrock methods29 using Polymath 6.1,30 with the resulting solutions fit using the nonlinear least-squares method, and the kinetic parameters for each rate-determining scenario identified.

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EXPERIMENTAL SECTION Reagent Preparation and Analytical. Bis(acetonitrile)palladium dichloride was synthesized from palladium chloride by refluxing in acetonitrile for several hours, then precipitating with cold diethyl ether, and filtering to yield a yellow-orange powder.27 3-(Di-tert-butylphosphonium)propane sulfonate (DTBPPS) was synthesized according to a previously reported procedure.5j Di-tert-butylphosphine was obtained from FMC, Lithium Division. All other materials were purchased from VWR and used without further purification. The 4.0 mL vials were 13 mm in diameter, and the magnetic stir bars were 10 mm × 3.0 mm × 4.0 mm. The stir plate used was a Corning PC-420 stirrer/hot plate. All reaction vials were assembled in a nitrogen-filled drybox (MBraun Labmaster 130). In the drybox, PdCl2(CH3CN)2 (41.5 mg, 0.160 mmol) was measured into a 15 mL vial and sealed with a septum. DTBPPS (48.0 mg, 0.160 mmol) and CsOH·H2O (1.47 g, 8.75 mmol) were measured into a separate 15 mL vial and sealed with a septum. Both vials were removed from the drybox, and the first vial was charged with 4-bromobenzotrifluoride (1.12 mL, 8.00 mmol), phenylacetylene (0.960 mL, 8.75 mmol), mesitylene (0.800 mL, 5.74 mmol), and 8 mL of nitrogen flushed acetonitrile. The second vial was charged with 8 mL of nitrogen flushed deionized water. Both vials were allowed to sit for 1 h before filtering through a nitrogen flushed PTFE syringe filter

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CONCLUSION The phase behaviors of aqueous Pd-catalyzed cross-couplings using hydrophilic ligand are key to their study in the laboratory and their scale-up to production systems. Synthetic organic chemistry and chemical reaction engineering points-of-views must be considered in parallel to discover the most efficient routes to useful synthesis products. Otherwise, molar flux and interfacial contact areas potentially control the kinetics instead of either postulated catalytic cycle, deprotonation or carbopalladation. Synthesis in isothermal batch reactors at low stirring rates supports the fact that mass transfer indeed influences the multiphase reaction, whereas isothermal multiphase flow reactors offer intrinsic kinetic insights. Multiphase capillary reactors offer the unique opportunity to elucidate the role of mass transfer in isothermal batch reactors. Our analysis of mass transfer coefficients measured in flow and their comparison to theoretical predictions motivates the need for special considerations when performing kinetic studies on multiphase reactions with classical batch techniques. The present work lays the groundwork for studies on heat transfer influences on the aqueous biphasic reaction kinetics. 1269



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Our discovery that the aqueous Pd-catalyzed Cu-free direct arylation of terminal alkyne with 4-bromobenzotrifluoride exhibits activation energies in excellent agreement with DFT calculated values reported for purely organic systems establishes the groundwork for exciting possibilities. Additional work on the modified ionic deprotonation mechanism will aid in defining the molecular interactions of water that potentially influence either the deprotonation or the carbopalladation mechanism. Computational techniques in collaboration with precise experimental control of the reaction conditions (e.g., the use of microreactors) could potentially resolve ambiguity revolving around either the deprotonation or the carbopalladation mechanisms. Our discoveries thus far support that either mechanism could control the reaction kinetics in aqueous phase cross-couplings. Time-dependent changes in both the ligand and the palladium intermediate concentrations, smaller in magnitude relative to the substrates, are expected to have a profound impact on the near-equilibrium kinetics. Moreover, the kinetics of formation of the catalytically active palladium species could ultimately control the overall reaction when the rates of the individual steps in either catalytic cycle are fast, relatively speaking (e.g., approaching flash chemistry). The palladium and the hydrophilic ligand lifecycles themselves, especially in multiphase reactions, are interesting pathways that demand the attention of laboratory techniques that offer an even deeper molecular understanding of the science. Innovations of microreactors with online analytics have the potential to reveal the true reaction mechanism, carbopalladation and/or deprotonation, and the rate-determining step(s) over the entire kinetically controlled reaction space of aqueous phase crosscouplings. The study of well-characterized multiphase microfluidics, where reaction-rate-limited conditions exist, is expected to provide a first principle understanding of the science of water and its potential use in the continuous processing of fine chemicals.

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ASSOCIATED CONTENT

Experimental details. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Authors

*First corresponding author. E-mail: [email protected]. Tel: +1 (205) 348-1696. Fax: +1 (205) 348-7558. *Second corresponding author. E-mail: [email protected]. edu. Tel: +1 (205) 348-4435. Fax: +1 (205) 348-9104. Author Contributions §

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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REFERENCES

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ACKNOWLEDGMENTS

We thank the National Science Foundation (EEC-1062705; CBET-1264630; CHE-1058984) for partial financial support of this work; FMC, Lithium Division for donation of di-tertbutylphosphine; and Johnson-Matthey for donation of palladium salts. 1270



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