RESEARCH PAPER
Phase transfer catalyzed esterification:modeling
and experimental studies in a microreactor under parallel flow conditions
Ervin S
ˇinkovec •Andrej Pohar •Matjaz ˇKrajnc Received:28June 2012/Accepted:20September 2012/Published online:7October 2012
ÓSpringer-Verlag Berlin Heidelberg 2012
Abstract A liquid–liquid phase transfer catalyzed (PTC)esterification reaction of 4-t -butylphenol in aqueous phase (1M sodium hydroxide solution)and 4-methoxybenzoyl chloride in organic phase (dichloromethane)in a micro-channel under parallel laminar flow conditions was studied in this work.Tetrabutylammonium bromide was used as the PTC.Stable liquid–liquid hydrodynamic flow and a defined specific interfacial area in a microreactor offer considerable benefits over conventional batch reactors and are crucial to study interactions between kinetics and mass transfer effects.Mentioned features were used to develop a 3D mathematical model considering convection in the flow direction,di
ffusion in all spatial directions,and reactions in organic and aqueous phases.Results have shown a much higher mass transfer rate of the PTC between both phases as the one predicted by the 3D mathematical model.It may be assumed that the instability of parallel flow,along with the mass transfer of catalyst between both phases,causes rippling and erratic pulsation at the interface which then leads to interfacial convection and increased mass transfer rates.With a proposed correlation for mass transfer enhancement due to interfacial convection,all the experi-mental data were successfully predicted by the model.Keywords Phase transfer catalysis ÁMicrofluidic ÁParallel flow ÁMass transfer ÁMathematical model
1Introduction
In the fine chemical,pharmaceutical,analytical,and bio-chemical industry,microstructured devices have impres-sively demonstrated several decisive advantages,such as better heat and mass transfer due to a very large surface-to-volume ratio and superior mixing of the fluid phases
(Ehrfeld et al.2000;Ja
¨hnisch et al.2004;Wirth 2008).An important feature of microstructured reactors is the hydrodynamic flow in the microchannel.In liquid–liquid microchannel flow,different flow patterns such as annular flow,
parallel flow,droplet flow,or slug flow are found.Circulation patterns vary with the physical properties of liquids as well as with operating parameters such as the flow ratio of two immiscible liquids,mixing elements geometry,channel geometry,and capillary dimensions (Zhao et al.2006).In a glass microreactor with a rectan-gular microchannel,a high degree of control over parallel flow can be achieved and under precisely controlled con-ditions,the liquid–liquid interfacial surface-to-volume ratio may be strictly defined.Mentioned features enable the prediction and calculation of mass transport between two phases and offer considerable benefits over conventional batch reactors.In spite of its industrial importance,the details of mass transfer and the role of the interfacial area on transport enhancements for liquid–liquid two-phase microsystems are still not very well understood,especially in those where mass transfer and chemical reaction occur simultaneously,such as in two-phase phase transfer cata-lyzed reactions (PTC reactions).
PTC is one of the most important and useful techniques when anionic activation is concerned.It is estimated that PTC is used in as many as 500commercial processes with a wide range of applications (Starks et al.1994).General PTC reaction systems consist of two mass transfer steps
E.S
ˇinkovec ÁA.Pohar ÁM.Krajnc (&)Faculty of Chemistry and Chemical Technology,University
reaction massof Ljubljana,As
ˇkerc ˇeva cesta 5,1000Ljubljana,Slovenia e-mail:matjaz.krajnc@fkkt.uni-lj.si
Microfluid Nanofluid (2013)14:489–498DOI 10.1007/s10404-012-1067-7
and two reaction steps in the organic and aqueous phases. The key factor is the ability of small quantities of an agent (PTC)to transfer one reactant across the interface between two immiscible liquid–liquid phases so that the reaction can proceed.The regenerated catalyst is then transferred into another phase where it participates in another catalytic cycle(Starks1971;Dehmlow1974).
Despite many publications on the chemistry and appli-cations of PTC,only few of them involve the role of interfacial mass transfer and mathematical modeling which include reaction kinetics in both phases and mass transport between and within each phase(Wang and Wu1990;Asai et al.1993;Wu1993;Wang and Chang1994;Bhattach-arya1996;Yang1998).
Thefirst study of a PTC reaction in a microreactor was performed by Hisamoto et al.(2001)on a diazo-coupling reaction.Ueno et al.(2003)investigated PTC alkylation and Ahmed-Omer et al.(2008)investigated a number of process-intensification techniques in a two-phase slugflow reaction sys
tem.The influence of the surface-to-volume ratio on mass transfers and consequently on the overall chemical reaction rate of the Wittig reaction in a microtube reactor under liquid–liquid slugflow pattern was investi-gated in our previous work(Sinkovec and Krajnc2011). Efficient liquid–liquid PTC reactions due to more effective mass transfer between two immiscible phases,which can be attributed to the high surface-to-volume ratio and internalflow circulation in the droplets,compared to con-ventional dispersion techniques were reported by Ji et al. (2012).Aljbour et al.(2010)investigated a PTC reaction with continuous phase separation by utilizing a parallel flow pattern in a rectangular microchannel.
In this work,a PTC esterification reaction of sodium4-t-butylphenolate(MY)in the aqueous phase(1M sodium hydroxide solution)and4-methoxybenzoyl chloride(RX) in the organic phase(dichloromethane)in a microreactor with a rectangular microchannel under parallel pressure drivenflow was studied.Quaternary salt tetrabutylammo-nium bromide(QX)was used as the PT catalyst.4-t-butylphenol dissolved in1M NaOH forms with sodium hydroxide MY.QX picks up the nucleophile Y and ferries it in the form QY(tetrabutylammonium4-t-butylpheno-late)into the organic phase where the reaction with the organic substrate RX occurs,giving the desired product 4-t-butylphenyl4-methoxybenzoate(RY)and regenerated QX that continues the next PTC cycle in the aqueous phase.The reactions were performed at different ratios between organic and aqueous phasefl
ow rates,different temperatures,and at different amounts of PT catalyst. Furthermore,a3D mathematical model considering con-vection in theflow direction(z),diffusion in x,y,z direc-tions,and reactions in organic and aqueous phases was developed to analyze the experimental data and to predict reactor performance.The reaction kinetics in the organic phase and distribution coefficients of MY,QX,QY,RX, and RY were determined experimentally,whereas an empirical correlation was used to estimate molecular dif-fusion coefficients in the aqueous and organic phase.
2Experimental section
2.1Materials
4-t-butylphenol(C98%,Merck),4-methoxybenzoyl chloride (RX,C99%,Sigma-Aldrich),tetrabutylammonium bromide (QX,C99%,Sigma-Aldrich),1,3,5-trimethoxybenzene (C99%,Sigma-Aldrich),dichloromethane(C99.5%, Merck),sodium hydroxide(C99%,Merck),hydrochloric acid(C37%,Riedel-de Haen),and deionized water were used.
2.2Determination of the distribution coefficients Distribution coefficients K p were determined for QX,tet-rabutylammonium4-t-butylphenolate(QY),and sodium 4-t-butylphenolate(MY).Different concentrations of QX (4.35,
3.25,2.18and1.09mmol/L)and MY(100,75,50 and25mmol/L)in1M aqueous sodium hydroxide solu-tion were prepared,whereas QY was prepared in situ by dissolving known amounts of QX and MY in the same solvent and stirred to form different concentrations of QY (
4.34,3.25,2.17,and1.09mmol/L).The same volume of dichloromethane was added and stirred vigorously at a constant temperature(thermostated water bath)for about 1h to allow the reagents to distribute between both phases. At thefinal equilibrium state,a sample of the organic phase was taken and analyzed by1HNMR.
2.3Reaction in organic phase
To perform the organic phase reaction,QY was prepared first.Known amounts of MY and QX were dissolved in 1M aqueous sodium hydroxide solution and stirred at room temperature to form the complex QY.The same volume of dichloromethane was added,shaken vigorously for a few minutes,and then allowed to stand until the separation of the organic and aqueous phase was obtained. The concentration of QY in the organic phase was analyzed by1HNMR.
The organic chemical reaction of QY and RX was car-ried out in a poly-etheretherketone(PEEK)microtube reactor(Vici AG,Schenkon,Switzerland)with an internal diameter of1
30l m connected to high performance syringe pumps(Harvard Apparatus,Holliston,USA)with perflu-oroalkoxy(PFA)tubes(with an internal diameter of 0.75mm).Thefirst feed consisted of QY dissolved in
dichloromethane(12.5and25mmol/L)prepared as described above,and another feed consisted of different concentrations of RX(12.5,25and50mmol/L)in the same solvent.A known amount of1,3,5-trimethoxyben-zene was used as the standard for1H NMR analysis.The mixing of both solutions was done in a PEEK T-mixer (Vici AG,Schenkon,Switzerland)with an internal diam-eter of250l m.Reactants’residence time(0.25–2s)was determined by the length of the microtube reactor(from60 to120mm)and the overallflow rate which varied from 47.8to191l L/min.Experiments were performed at dif-ferent temperatures and different amounts of both reac-tants.At the exit of the microtube reactor,the reaction was quenched with1M aqueous hydrochloric acid solution. The resulting mixture was separated and the aqueous phase was extracted with dichloromethane.The combined organic layers were evaporated and analyzed by1H NMR.
2.4Two-phase PTC esterification
Two-phase PTC esterification was carried out in the glass microreactor(Micronit Microfluidics B.V.,Enschede,The Netherlands)with Y-shaped inflow and outflow channels and the main channel with
dimensions of220-l m width, 50-l m height,and332-mm length.The microchip was connected with PFA tubes(internal diameter of0.75mm) to high performance syringe pumps which insured highly controllableflow rates.The organic phase consisted of RX (25mmol/L)and1,3,5-trimethoxybenzene dissolved in dichloromethane.1,3,5-trimethoxybenzene was used as a standard for1H NMR analysis.The aqueous phase con-sisted of MY(100mmol/L)and QX(2.17and4.34mmol/ L)dissolved in1M aqueous sodium hydroxide solution.It must be mentioned that the concentrations of QX,which express characteristics of surface-active compounds,were always below the critical micelle concentration(Linden-baum and Boyd1964).The aqueous and organic phase reactants were fed at differentflow rates through two separate inlets.Two-phase PTC reaction was carried out at parallelflow conditions.The two streams were stable with a well-defined interface in between.Experiments were performed at different temperatures,different amounts of QX,and at a different aqueous-to-organic(AO)volumetric flow ratio.At the exit of the microreactor,the reaction was quenched with1M aqueous hydrochloric acid solution. The resulting mixture was separated and the aqueous phase was extracted with dichloromethane.The combined organic layers were evaporated and analyzed by1H NMR. Reactants’residence time(2.5–20s)was determined by the overallflow rate which varied from10.9to87.1l L/ min.At overallflow rates lower than10and22l L/min at AO volumetricflow ratio0.25and0.5,respectively, unstable parallelflow forming slugs were observed.2.5Analysis
The conversion of RX in samples was evaluated by1H NMR spectroscopy(Bruker Avance III500MHz NMR). Different proton chemical shift of RX aromatic ring pro-tons(at8.08ppm—1H NMR spectra of the commercial compound),RY aromatic ring protons(at8.15ppm—1H NMR spectra of the product),and standards MeO-sub-stituent’s(at3.77—1H NMR spectra of the commercial compound)may be observed.The conversion of RX was determined by the surface area ratio between reactant RX aromatic ring protons and standard MeO-substituent’s signal.Results were compared and confirmed by determi-nation of the surface area ratio between reactant RX and product RY aromatic ring protons.
The position of the interface between the organic and aqueous phase was determined by microscopicflow imaging. 3Results and discussion
3.1Distribution coefficient
The distribution of a chemical compound between two immiscible phases usually depends on the chemical struc-ture of the solute,solvent,and solute concentration(Wang and Yang1991).The model presented in this work is subject to the assumption that distribution coefficients are not affected by the changes and interactions of other compounds in the phase composition.The distribution coefficient was defined as the concentration of QX,QY,or MY in the organic phase divided by the concentration of the same solute in the aqueous phase:
K p
i
¼
c i;org
c i;aq
ð1Þ
where i represents the chemical species.
In Figs.1and2,the distribution coefficients of QX and MY are shown at different temperatures in dichlorometh-ane—1M aqueous sodium hydroxide solution two-phase system.It may be seen that the distribution coefficient of both solutes is a function of temperature,besides which the increasing of the distribution coefficient of QX with increasing concentration may be observed.The distribution coefficient of QX as a function of QX concentration in aqueous phase at20and35°C may be represented by the following two regression equations:
K p
QX
¼0:0478Âc QX;aqþ0:1343ðT¼20 CÞ
K p
QX
¼0:0644Âc QX;aqþ0:1316ðT¼35 CÞ
ð2Þ
where c QX,aq is a QX concentration in aqueous phase (mmol/L).
The concentration dependency of the partitioning coef-ficient is negligible in the case of MY and an average value of K p at 20and 35°C is equal to 0.077and 0.117,respectively.
As shown in Fig.3,the whole amount of the QY formed in the aqueous phase was transferred from the aqueous to the organic phase at all examined temperatures (from 10to 35°C).It is obvious that the addi
tion of the lipophilic part of the molecule MY will make the quaternary ammonium cation move and transfer Y into the organic phase where the organic phase reaction may proceed.
It was noticed that the reactant RX and product RY are insoluble in the aqueous phase.
3.2Prediction of diffusion coefficient
To estimate molecular diffusion coefficients D AB of MY,MX,QX,QY,RX,and RY in the aqueous and organic phase,the Wilke–Chang empirical correlation was used.It is an empirical modification of the Stokes–Einstein relation and is one of the most widely used correlations for esti-mating diffusion coefficients:
D AB ¼7:4Â10À8ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiw B MW B p T
g B "V 0:6A ð3Þwhere A and B denote solute and solvent,respectively,"V A (mL/mol)is the molar volume of the solute,MW B is the molecular weight of the solvent (g/mol),g B is solvent viscosity (cP),T is temperature in K,and w B is a constant which accounts for solvent/solvent interactions (1for nonassociated solvents,2.6for water)(Li and Carr 1997).3.3Reaction in the aqueous and organic phase
In the aqueous phase reactant,MY reacts with the PTC QX to form the active complex QY.Because no
electron-pair bonds need to be broken,the ion exchange reaction in the aqueous phase is very fast and limited only by the rate of ion diffusion.For this reason,it was impossible to deter-mine the reaction kinetics experimentally.It was also impossible to specify the reversibility of aqueous phase QY formation.Because QY is a lipophilic compound and is much more soluble in the organic than the aqueous phase,what was observed by analyzing the distribution coeffi-cients,all QY formed in the aqueous phase transfers into the organic phase,and reversibility may be neglected (Yang 1998).After the transfer of QY into the organic phase,the organic reaction with RX may occur,which may be described by the power-law kinetic
expression:
Fig.1The distribution coefficient of QX as a function of the concentration of QX in the aqueous phase at different temperatures [dichloromethane—1M aqueous sodium hydroxide solution two-phase system,T =10°C (filled triangle ),T =20°C (filled dia-mond ),T =30°C (filled square ),T =35°C (filled circle
)]
Fig.2The distribution coefficient of MY as a function of the concentration of MY in the aqueous phase at different temperatures [dichloromethane—1M aqueous sodium hydroxide solution two-phase system,T =10°C (filled triangle ),T =20°C (filled dia-mond ),T =30°C (filled square ),T =35°C (filled square
)]
Fig.3The concentration of QY in the organic phase as a function of the initial concentration of QY formed in the aqueous phase
À
d c RX ðt Þd t
¼k org c a RX ðt Þc b
QY ðt Þð4Þ
where k org is the intrinsic reaction rate constant in the
organic phase and c RX and c QY are concentrations of RX and QY in the organic phase,respectively.Exponents a and b identify the order of the reaction with respect to c RX and c QY ,respectively.The initial conditions of c RX and c QY at t =0are defined as:c RX ð0Þ¼c RX ;0c QY ð0Þ¼c QY ;0
Integration of Eq.4for a =b =1gives the following:ln c RX c QY ;0c QY c RX ;0
¼ðc RX ;0Àc QY ;0Þk org t ð5Þ
A linear relationship in Fig.4obtained by plotting ln(c RX /c QY )versus time from experimental data describes the second order reaction.
Based on experimental results at different initial con-centrations of c RX and c QY ,organic reaction parameters were defined and further confirmed with mathematical model simulations.As seen in Fig.5,experimental results are in good agreement with model simulation where the organic reaction was assumed to be of the first-order with respect to c RX and c QY (a =b =1),and the intrinsic reaction rate constant at 20°C is equal to 5.09102L/mol s.At higher reaction temperatures,almost complete conversion (from 97to 99%according to limiting reac-tant)was achieved in less than 0.5s.For this reason,it was impossible to determine the reaction kinetics at higher temperatures experimentally.
3.4A mathematical model of two-phase esterification
in a microchannel To analyze experimental data and to forecast microreactor performance,a 3D mathematical model containing convection in the flow (z )direction,diffusion in x ,y ,z directions,and reactions in the aqueous and organic phase was developed (Fig.6).It was proposed that (a)both RX and RY are insoluble in the aqueous phase,(b)the aqueous phase chemical reaction takes place only in the aqueous phase (confirmed with exper-iments),(c)the whole amount of QX in the aqueous phase irreversibly forms the complex QY with MY,(d)the flow was laminar because the highest Reynolds number calculated was below 40,which is well below the critical Reynolds number,and (e)mass transfer of QX and QY between both phases takes place at the interfacial area between parallel flows of the organic and aqueous phase.For steady-state conditions,con-sidering a developed velocity profile,isotropic diffusion,and constant physical properties,the partial differential equation for the aqueous phase is (Stojkovic et al.2011):
v x ;y ðÞ
o c i x ;y ;z ðÞo z ¼D i ;aq o 2c i x ;y ;z ðÞo x þo 2c i x ;y ;z ðÞo y þo 2c i x ;y ;z ðÞ
o z þr i
ð6Þ
with the following boundary conditions:c i ðx ;0\y \w 1;0Þ¼c i 0
o c i ð0;0\y \w 1;z Þd x ¼
o c i ðH ;0\y \w 1;z Þ
d x ¼
o c i ðx ;0;z Þd y ¼o c i ðx ;0\y \w 1;L Þ
d z ¼0wher
e r i is the reaction
term:
Fig.4Plot of ln(c RX /c QY )versus time at two different c RX /c QY ratios
at 20°C,c RX,0:c QY,0=1.2:1(filled square ),c RX,0:c QY,0=2:1(filled diamond
)
Fig.5The mathematical model simulations and experimental data of the organic product concentration versus time at different initial c RX /c QY ratios at 20°C,c RX,0:c QY,0=1:2(filled square ),c RX,0:c QY,0=4:1(filled circle ),c RX,0:c QY,0=1.2:1(filled diamond ),c RX,0:c QY,0=2:1(filled triangle )
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