Knoevenagel condensation reaction between benzaldehyde and ethyl acetoacetate in microreactor and membrane microreactor

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Microporous and Mesoporous Materials 115 (2008) 156–163 www.elsevier.com/locate/micromeso

Knoevenagel condensation reaction between benzaldehyde and ethyl acetoacetate in microreactor and membrane microreactor W.N. Lau a, K.L. Yeung a,*, R. Martin-Aranda b b

a Department of Chemical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China Departamento de Quı´mica Inorganica y Quı´mica Technica, Universidad Nacional de Educacio´n a Distancia, C/Senda del Rey, 9, 28040-Madrid, Spain

Received 4 October 2007; accepted 11 December 2007 Available online 26 February 2008

Abstract The Knoevenagel condensation reaction between benzaldehyde and ethyl acetoacetate was performed in microreactor using Cs-exchanged NaX catalyst and NaA membrane. The laminar flow and slow diffusion of the bulky product molecules in the microchannel resulted in the further reactions of the main Knoevenagel condensation product, 2-acetyl-3-phenylacrylic acid ethyl ester that led to byproduct formation and poorer reaction selectivity. Replacing the powder catalyst in the microchannels with a thin CsNaX film improved the selectivity (78% vs. 55%), while increasing the microchannel height-to-width aspect ratio from 2 to 5 doubled the conversion from 25% to 60%. The selective removal of water byproduct in the membrane microreactors benefited the Knoevenagel condensation reactions. Higher conversions were observed for the reactions between benzaldehyde and (1) ethyl cyanoacetate (ECA), (2) ethyl acetoacetate (EAA) and (3) diethyl malonate (DEM), but the improvement diminished with increasing difficulty of the reaction. Higher selectivity and product yield for 2-acetyl-3-phenylacrylic acid ethyl ester were obtained for the membrane microreactor with a hybrid NaA membrane-CsNaX catalyst film deposited in the microchannels. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Fine chemicals; Base catalysis; Micromembrane; FAU; LTA

1. Introduction Microreactor benefits fast and exothermic reactions and were used to great advantage for direct fluorination [1], high temperature combustions [2] and selective oxidations [3–5]. The rapid heat and mass transfers in the microreactor are responsible for the enhanced reaction performance (i.e., better conversion, selectivity, yield or safety) [6]. However, it is agreed that the greatest need and potentially the biggest impact of the microreactor would be in the fine chemical syntheses [7–9] including selective oxidations [10–15], hydrogenation [16,17], and acid and base-catalyzed condensation reactions [18–23]. Many fine chemical reactions of interest are constrained by unfavorable thermodynamics that could benefit from the membrane *

Corresponding author. E-mail address: [email protected] (K.L. Yeung).

1387-1811/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.micromeso.2007.12.036

operation. Selective product removal could improve the product purity and achieve supra-equilibrium conversions [24], whereas the selective addition of a reactant could eliminate hot spots and enhance the product selectivity [25]. Miniaturization also enhances the selectivity and permeance of miniature membranes compared to the conventional membrane units [26,27]. The Knoevenagel condensation reaction is an important C–C bond forming reaction commonly used for the production of fine chemical intermediates and products (e.g. coumarin derivatives [28,29]) as well as pharmaceuticals (e.g. nifendipine and nitrendipine derivatives for hypertension drugs [30,31]). The reaction involves the condensation of methylene compounds (i.e., Z-CH2–Z0 or Z–CHR–Z0 ) with ketones or aldehydes [32]. Ethyl cyanoacetate (ECA, Z:COOCH2CH3 and Z0 :CN) having a low pKa (i.e., 9) is readily catalyzed by moderately strong solid bases. The reaction between benzaldehyde and ethyl cyanoacetate

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was investigated in the microreactor and membrane microreactor [20–22] using a Cs-exchanged zeolite X catalystcoated on the microchannel. Water produced by the reaction was selectively removed by pervaporation across a ZSM-5 micromembrane in the membrane microreactor unit. Both types of microreactors achieved better conversion than the conventional packed-bed reactor and packed-bed membrane reactor at a comparable catalyst loading and residence time. In a recent work [23], computer modeling was employed to guide the design of the reactor, catalyst and membrane in order to achieve an optimum microreactor performance. This work investigates the Knoevenagel condensation reaction between benzaldehyde and ethyl acetoacetate (pKa = 10.7) in the microreactor and membrane microreactor. The Knoevenagel condensation product (2-acetyl-3phenylacrylic acid ethyl ester) is an important intermediate in the production of dihyrophyridines used for treatment of angina and hypertension [30,33,34]. However, the reaction also produces numerous byproducts from the various competing side reactions as reported by Corma et al. [35]. The microreactor performance is compared to the batch and packed-bed reactor for the Cs-exchanged NaX catalyst. 2. Experimental 2.1. Microreactor and membrane microreactor The detailed procedure for the fabrication of the porous, multichannel plate was described elsewhere [21]. Thirty-five straight channels of 300 lm wide, 600 lm deep and 25 mm long were cut into the 25 mm  25 mm porous SS-316L plate (0.2 lm, Mott) using electrical discharge micromachining (EDM, AGIE Wirecut 120). The fabricated plates were cleaned with detergent and rinsed with water to remove oils and dirt. The plates were etched with a dilute 0.05 M nitric acid to remove rust, before rinsing in deionized, distilled water and ethanol. The membrane microreactor design # 1 coats a thin, uniform layer of Cs-exchanged NaX catalyst powder on

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the wall of the microchannels and deposits a layer NaA zeolite membrane on the back of the multichannel plate (Fig. 1a). The catalyst was prepared by ion-exchange of NaX powder (Aldrich) with 0.5 M CsCl solution at 353 K for 6 h. The ion-exchange was repeated three times to obtain a desired Cs/Si loading of 0.32. An active catalyst was obtained after air calcination at 673 K for 4 h. Three milligrams of catalyst was deposited on the microchannels. The NaA membrane was grown on the back of the multichannel plate by pre-seeding with 150 nm NaA zeolite nanocrystals. The zeolite seeds were assembled and attached to the stainless steel surface using mercapto-3propyltrimethoxysilane (MPTS, 99%, Aldrich) linkers [36,37] and the membrane was prepared by hydrothermal synthesis from a solution containing 5 SiO2:1 Al2O3:52 Na2O:3750 H2O at 373 K for 10 h. The synthesis was repeated three times to obtain a 6 lm thick, defect-free NaA membrane. The membrane microreactor design # 2 deposits a hybrid NaA membrane-CsNaX catalyst film on the wall of the microchannels (Fig. 1b). The NaA membrane layer was first grown on the wall of the microchannels by seeding the channels with a thin layer of NaA seeds. A 6 lm thick membrane was obtained by regrowing three times from the synthesis solution containing 5 SiO2:1 Al2O3:52 Na2O:3750 H2O at 373 K for 10 h. Prior study showed that by simply using a more concentrated and alkaline gel, it is possible to grow the FAU (NaX) on the surface of NaA membrane [23]. The three microns thick faujasite X zeolite layer was deposited on top of the NaA membrane from a solution with a molar composition of 5 SiO2:1 Al2O3:56 Na2O:2500 H2O at a temperature of 373 K and synthesis time of 12 h. Cesium ion-exchange was carried out three times by the same procedure used for preparing the powder catalyst. Characterizations were made using scanning electron microscopy (SEM, JEOL JSM 6300F), X-ray diffraction (XRD, Philips 1830) and X-ray photoelectron spectroscopy (XPS, Physical Electronics PHI 5000). A summary of the different microreactors is listed in Table 1.

Fig. 1. (a) The membrane microreactor design # 1 is illustrated in the drawing on the left, and the topview SEM pictures of (1) the 3 lm thick CsNaX catalyst powder deposited on the microchannel wall and (2) the 6 lm thick NaA grown on the back of the stainless steel plate are shown on the right. (b) The membrane reactor design # 2 is shown in the drawing on the left and the topview SEM pictures of the microchannel (top-right) and the (1) 3 lm thick CsNaX film grown on top of the (2) 6.5 lm thick NaA membrane in the microchannel shown on bottom-left.

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Table 1 Reactor and reaction conditions and performances Dimension (microchannel)

Reactor volume

Catalyst

NaA membrane

Membrane separationa

Reactionb

Membrane reactionc

Microreactor Design # 1

Width = 300 lm, Depth = 600 lm, Aspect ratio = 2

0.16 cm3

6 lm

Water flux = 0.4 kg m2 h1 W/B ratio = 150,000

Conv = 17.5 Sel = 55

Conv = 21 Sel = 60

Microreactor Design # 2a

Width = 300 lm, Depth = 600 lm, Aspect ratio = 2 Width = 300 lm, Depth = 600 lm, Aspect ratio = 2

0.16 cm3

6.5 lm

Water flux = 0.5 kg m2 h1 W/B ratio = 50,000 Water flux = 0.3 kg m2 h1 W/B ratio = 45,000

Conv = 17 Sel = 55

Microreactor Design # 2c

Width = 250 lm, Depth = 1300 lm, Aspect ratio = 5

0.11 cm3

PBR

Tube I.D. = 5 mm Length = 12 cm

2.16 cm3

CsNaX powder 3 mg 0.017 g/cm3 ( 3 lm thick) CsNaX powder 3 mg 0.018 g/cm3 CsNaX film  3 lm thick 3 mg 0.016 g/cm3 CsNaX film  3 lm thick 3 mg 0.019 g/cm3 CsNaX pellet 39 mg 5-2 mm beads 280-2 mm glass beads 0.018 g/cm3

Microreactor Design # 2b

0.16 cm3

Batch 26 mg 0.015 g/cm3 a b c

6 lm

6.3 lm

Conv = 18.5 Sel = 74

Conv = 23 Sel = 95

Conv = 28.5 Sel = 75

N.A.

N.A.

Conv = 1.5 Sel = 98

N.A.

2.2 cm3

CsNaX powder

N.A. Sel = 93

N.A.

Membrane pervaporation was conducted for a 5 wt.% H2O/benzaldehyde solution at 1 ml/h flow rate, 363 K and 17 kPa vacuum in permeate. Reaction performance for equimolar reactants, 423 K and residence/reaction time of 30 min. Membrane reaction performance for equimolar reactants, 423 K, residence/reaction time of 30 min and permeate vacuum of 17 kPa.

Conv = 13.0

N.A.

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Reactor type

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Scheme 1.

2.2. Knoevenagel condensation reaction The microreactor was assembled according to the procedure described in a previous publication [21]. The Knoevenagel condensation reaction between benzaldehyde (99%, RDH) and ethyl acetoacetate (99%, Aldrich) shown in Scheme 1 was carried out using equimolar amounts of reactants. The reaction mixture was fed to the microreactor by a syringe pump (Kd Scientific). Two sets of experiments were conducted each day. The reaction was first carried out in the microreactor mode with the permeate vacuum closed, and then the experiment was operated in the membrane microreactor mode with the permeate vacuum turned on (cf. Table 1). Samples from the reactor outlet and membrane permeate were collected and analyzed by gas chromatography/mass spectrometer (GC-MS, HP 5890 with 5971 mass selective detector (MSD) and Perkin Elmer Clarus 5000 mass spectrometer) equipped with a HP-5 chromatography column. The reaction was conducted at a temperature of 423 K for different residence time. The reaction was also performed in batch and packedbed reactors (cf. Table 1). The batch reaction was carried out in a 10 ml round bottom two-neck flask with 9.5 mmol of benzaldehyde and 9.5 mmol of ethyl acetoacetate. Nitrogen was bubbled through the solution to remove dissolved oxygen to prevent the formation of benzoic acid. The solution was heated to the reaction temperature in a silicone oil bath under a well mixed condition, before adding the 26 mg catalyst powder (ca. 1 wt.% of reaction mixture). Ten microliters samples were withdrawn at fixed time intervals, quenched and analyzed. The packed-bed reactor is a stainless steel tube with an inner diameter of 5 mm and a length of 120 mm. The 2 mm Cs-exchanged NaX catalyst beads were packed into the reactor tube. The amount of catalyst was adjusted to obtain a comparable catalyst loading per unit reactor volume as the microreactors. Glass beads (2 mm) were added to fill the reactor volume. The reactor was heated to the reaction temperature by a heating tape (Brisk Heat) wrapped around the reactor. The reaction conversion and products were analyzed for different residence time. 3. Results and discussion 3.1. Multichannel microreactors Several strategies for incorporating zeolites and molecular sieves in miniature systems were described in prior works [38–40]. The hallmark of these techniques is the pre-

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cise and localized addition of zeolite materials, as well as the direct engineering of the zeolite structure and chemistry [38,41]. The heterogeneous nature of the porous stainless steel substrate [42] necessitates surface modification by seeding to avoid undesired influence from the support. This is particularly true for the preparation of the membrane material where the growth kinetic could affect the membrane microstructure and ultimately its separation properties [43–46]. The microchannels cut by the EDM process were evenly spaced and have uniform size and shape, giving each channel an open volume of 4.75 ll and a total reactor volume of 158 ll. Unlike regular machining method that often deformed the metal grains resulting in a dense surface layer, the EDM cut channels remained porous. Fig. 1a illustrates the membrane microreactor design # 1. The SEM picture in Fig. 1a-(1) shows that the Cs-exchanged NaX catalyst powder was uniformly coated on the wall of the microchannels. The loosely packed coating was roughly 3 lm thick and consists of roughly spherical catalyst particles with poorly formed facets. The X-ray diffraction pattern and BET surface area (i.e., 400 m2/g) were typical of Cs-exchanged NaX. XPS analysis of the zeolite catalyst detected a decrease in the sodium content and the appearance of cesium after the ion-exchange. Over sixty percent of the original sodium in the NaX was exchanged for cesium (i.e., Cs/(Cs + Na) = 0.60). The 6 lm thick NaA membrane (Fig. 1a–(2)) was deposited on the back of the porous multichannel plate and served as a pervaporation membrane (25  25 mm2). The membrane gave a water/benzaldehyde separation factor of 150,000 and a flux of 0.4 kg m2 h1 for a 1 ml/h feed of 5 wt.% water in benzaldehyde at 363 K and permeate vacuum of 17 kPa. Fig. 1b displays the schematic drawing of the membrane microreactor design # 2. The SEM photo of the microchannel (Fig. 1b top-left) shows the zeolite was uniformly deposited over the entire width and length of the channel. Fig. 1b– (2) is a SEM picture of the 6 lm thick NaA membrane deposited on the channel wall. The membrane consists of intergrown NaA zeolites with (1 1 1) orientation similar to Fig. 1a–(2), but of a slightly larger size. This membrane gave a water/benzaldehyde separation factor of 50,000 and a flux of 0.5 kgm2 h1 for a 1 ml/h feed of 5 wt.% water in benzaldehyde at 363 K and permeate vacuum of 17 kPa. The faujasite layer was then deposited on top of the NaA membrane as shown in Fig. 1b–(1). XPS indicated that Cs was successfully ion-exchanged with a Cs/(Cs + Na) of 0.63. The FTIR spectra of the prepared NaX and Csexchanged NaX films display structure sensitive bands at 745 cm1, 929 cm1 and 1078 cm1 along with a shoulder at around 1057 cm1. The cesium ion-exchange neither changed the intensities nor shifted the locations of these infrared bands. The FTIR indicated that both faujasite films adsorbed water and carbon dioxide at ambient conditions. The NaX–NaA hybrid catalyst-membrane layer gave a water/benzaldehyde separation factor of 45,000 and a flux of 0.3 kgm2 h1 under identical test conditions.

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3.2. Comparisons of reactor performance Fig. 2a plots the benzaldehyde conversion as a function of reaction time for the batch reactor, and with respect to the residence time for the microreactor (design # 1) and packed-bed reactor. The reaction in the microreactor was carried out over catalyst powder coated on the microchannel wall. A comparable catalyst loading of 17 mg/cm3 was used in all three reactors and the reactions were carried out at 423 K for equimolar amounts of benzaldehyde and ethyl acetoacetate. The figure shows the reaction is slow for the packed-bed reactor (PBR) because of the transport resistance of the catalyst beads. A total of 285 beads (i.e., 5-CsNaX beads + 280 inert glass beads) were packed in the tubular reactor (Table 1). As only 3–4 beads fit across the reactor diameter channeling could be a severe problem and could explain the poor performance of the PBR. The batch reaction data was included to give a fair comparison. The conversion was higher in the microreactor (design # 1) and batch reactor where powder catalysts were used. The extent of reaction is comparable for the microreactor and the batch reactor at short residence (i.e., reaction) times (s = t<20 min). The benzaldehyde conversion is higher for the microreactor for longer residence time reaching a 25% conversion at s = 50 min as compared to 18% for the batch reactor at t = 60 min. This gave a respectable increase in conversion of about 40%. However, Fig. 2b shows the selectivity for the Knoevenagel condensation product in the microreactor decreases with residence time from a hundred to fifty-five percent. The poor selectivity could be due to retention of reaction mixture within the porous stainless steel leading to further reaction and byproduct formation. Indeed, reaction carried out on nonporous stainless steel reactor gave better selectivity (i.e., 70%) and slightly higher conversion (i.e., 22%) at a residence time of 30 min as shown in the figures. The main byproduct of the reaction between benzaldehyde and ethylacetoacetate at a short residence time in the microreactor (design 1) was benzalacetone from the decarboxylation of the Knoevenagel condensation product

(Fig. 3a). The Michael addition reaction between the Knoevenagel condensation product and ethyl acetoacetate (Fig. 3b) dominated at the longer residence time (s > 30 min), followed by the products of the aldolic condensation reactions shown in Fig. 3c. The laminar flow and slow diffusion of the bulky product molecules mean that the Knoevenagel condensation product is confined within a thin fluid volume adjacent to the catalyst-coated, microchannel wall giving it an ample opportunity to further react and form the byproducts (1–3) shown in Fig. 3. This resulted in the lower selectivity for the microreactor at long residence time. This was not a problem for the batch reactor where there is a rapid mixing between the catalyst and the reaction solution. 3.3. Microreactors with powder and thin film catalyst layers One method of improving the reaction selectivity in the microreactor is to restrict the product’s access to the catalyst. This was achieved by replacing the catalyst powder (Fig. 1a–(1)) with a thin catalyst film shown in Fig. 1b– (1). This decreased the external catalyst surface in contact with the solution from 600 cm2 to 7 cm2, and thus prevented further reaction of the product molecules, whereas the internal catalyst sites remained accessible to the smaller reactant molecules. The results of reaction study carried out on microreactor design # 2a (CsNaX powder), # 2b (CsNaX film) and # 2c (CsNaX film, high aspect ratio) are reported in Fig. 4. Fig. 4a shows the benzaldehyde conversions for the microreactor design # 2a coated with CsNaX catalyst powder and microreactor design # 2b with grown CsNaX film are comparable over the range of residence time investigated in this study, but a higher selectivity (i.e., 78% vs. 55%) is obtained as shown in Fig. 4b. The main byproduct from microreactor design # 2b was benzalacetone (product (1) in Fig. 3a) with a trace amount of benzoic acid formed by the reaction between benzaldehyde and dissolved oxygen. The figure shows that it is possible to increase the reaction conversion without causing a lost in selectivity by using different microchannel geometry (Table

Fig. 2. Plots of the benzaldehyde conversion (a) and reaction selectivity to the Knoevenagel condensation product as a function of reaction time for the batch reactor, and as a function of residence time for the packed-bed reactor and microreactor design # 1 (Equimolar benzaldehyde and EAA, 17 mg/cm3 Cs-exchanged NaX, T = 423 K). Please note the lines were drawn to guide the eyes and the star was the reaction data obtained from a nonporous microreactor.

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Fig. 3. Main byproducts detected from the reaction between benzaldehyde and ethylacetoacetate over Cs-exchanged NaX powder catalyst in the microreactor include benzalacetone (1) from the decarboxylation of the Knoevenagel condensation product (a); product (2) from Michael addition of Knoevenagel condensation product with ethyl acetoacetate (b); and products (3) from the aldolic condensation of ethyl acetoacetate followed by further condensation with benzaldehyde (c).

Fig. 4. Plots of the benzaldehyde conversion (a) and reaction selectivity to the Knoevenagel condensation product as a function of reaction time for the microreactor design # 2a (CsNaX powder), # 2b (CsNaX film) and # 2c (CsNaX film, high aspect ratio) (Note: Equimolar benzaldehyde and EAA, T = 423 K). Please note the lines were drawn to guide the eyes.

1 design # 2c). Fig. 4a shows a 60% benzaldehyde conversion can be obtained in microchannels with height-to-width aspect ratio of 5 at residence time of 55 min compared to 25% (s = 50 min) in the microreactor with a microchannel height-to-width aspect ratio of 2 (design # 2b). It was surprising that a high conversion was obtained for microreactor design # 2c as the surface area-to-volume ratio of this reactor is comparable to the microreactor design 2b. Fur-

ther study is being conducted to better understand this phenomenon. 3.4. Microreactors and membrane microreactors Fig. 5 plots the benzaldehyde conversion as a function of pKa value for the Knoevenagel condensation reactions between benzaldehyde and ethyl cyanoacetate (ECA,

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W.N. Lau et al. / Microporous and Mesoporous Materials 115 (2008) 156–163

Fig. 5. Plots of benzaldehyde conversion as a function of pKa value of the ester reactants. The reactions were carried out in the membrane microreactor (a) design # 1 and (b) design # 2b at a residence time of 40 min and reaction temperature of 423 K. Please note the lines were drawn to guide the eyes.

pKa = 9.0), ethyl acetoacetate (EAA, pKa = 10.7) and diethyl malonate (DEM, pKa = 13.3). These reactions are well documented as the same series of Knoevenagel condensation reactions were used to measure the basicity of solid base catalysts [35]. The ECA, EAA and DEM molecules have comparable sizes and could access the catalytic sites within the pores of the zeolite catalyst. As expected, the reaction conversion decreases as the pKa value of reactant increases as shown in the figures. The reactions of benzaldehyde with ECA and DEM produced only the Knoevenagel condensation products. Except for trace amounts of benzoic acid, no other byproducts were detected from these reactions and the reaction selectivities were better than ninety eight percent. The data in Fig. 5a shows the selective removal of water resulted in an increase in the reaction conversion, as water adsorption competes with the reactants for the zeolite catalyst. The selectivity of the reaction between benzaldehyde and EAA remained unchanged, but the main byproduct changed from benzalacetone to the aldolic condensation products shown in Fig. 3c–(3). It appears that the selective removal of water byproduct also favored the Claisen condensation of the EAA molecules (Fig. 3c). It is evident from Fig. 5b that placing the catalyst layer adjacent to the NaA membrane resulted in an improvement in the reaction conversion. The NaA being a good dessicant can remove water from the catalyst layer by adsorption resulting in the enhanced conversions observed in the microreactor (Fig. 5b). The adsorbed water can be continuously removed by applying a vacuum transforming the adsorption process into a membrane separation. Ninety percent selectivity was attained for the reaction between benzaldehyde and EAA in this microreactor configuration. 4. Concluding remarks This work showed that microreactor is suitable for complex reactions that typified many fine chemical syntheses, but it is necessary that the reactor must be properly designed in order to achieve optimum performance. The laminar flow and slow diffusion of the product molecules

in the microchannel resulted in poor selectivity as the Knoevenagel condensation product was consumed by further reactions to form byproducts. The undesired reaction was suppressed by using catalyst film instead of powder, because the smaller external catalyst surfaces in contact with the solution and prevented further product reaction. An increase in microchannel height-to-width aspect ratio contacted a larger volume of the reaction solution with the catalyst, resulting in a proportional increase in the reaction conversion. Selective water removal by membrane pervaporation increased the reaction conversion and suppressed side reactions leading to overall increase in product yield and purity. Acknowledgments The authors gratefully acknowledge the financial support from the Hong Kong Research Grant Council (604406) and the Materials Characterization and Preparation Facility (MCPF) for the use of their equipment. References [1] R.D. Chambers, D. Holling, R.C.H. Spink, G. Sandford, Lab-on-aChip 2 (2001) 132. [2] G. Vesser, Chem. Eng. Sci. 56 (2001) 1265. [3] A. Gavriilidis, P. Angeli, E. Cao, K.K. Yeong, Y.S.S. Wan, Chem. Eng. Res. Des. 80 (2002) 3–30. [4] M. Fichtner, J. Mayer, D. Wolf, K. Schubert, Ind. Eng. Chem. Res. 40 (2001) 3475. [5] V. Hessel, W. Ehrfeld, K. Golbig, C. Hogmann, St. Jungwirth, H. Lo¨we, T. Richter, M. Storz, A. Wolf, in: W. Ehrfeld (Ed.), Microreaction technology: industrial prospects, Proceedings of the 3rd International Conference on Microreaction Technology, IMRET 3, Springer-Verlag, Berlin, 2000, pp. 249–301. [6] K.F. Jensen, Chem. Eng. Sci. 56 (2001) 293. [7] A. de Mello, R. Wootton, Lab-on-a-Chip 2 (2002) 7N. [8] S.J. Haswell, P. Watts, Green Chem. 5 (2003) 240. [9] K. Ja¨hnisch, V. Hessel, H. Lo¨we, M. Baerns, Angew. Chem. Int. Ed. 43 (2004) 406. [10] Y.S.S. Wan, J.L.H. Chau, A. Gavriilidis, K.L. Yeung, Chem. Commun. 8 (2002) 878. [11] Y.S.S. Wan, A. Gavriilidis, K.L. Yeung, Chem. Eng. Res. Des. 81 (2003) 753.

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