Haswell, S.J.

Painter, S.L.

Wiles, C.

Zhang, X.

English

Southampton (e-Prints Soton)

Microreactors as toolsfor chemical researchXUNLI ZHANGCHARLOTTE WILESSARAH L. PAINTERPAUL WATTS STEPHEN J. HASWELLchimica oggi • Chemistry Today • Vol 24 nr 2 • March/April 2006 43MicroreactorsABSTRACTThe unique operational characteristics of microreactorsare described in this article, with particular reference totheir use as tools for chemical synthesis. With reference tothe future automation, an example is presented toillustrate how microreactors can be readily integrated intocurrent HPLC systems, to enable fully integrated chemicalsynthesis and product analysis to be performed.INTRODUCTIONA microreactor is generally defined as a device consistingof a number of interconnecting micro channels in whichsmall quantities of reagents are manipulated, mixed andallowed to react for a specified period of time. Themovement of fluids within such a device can be achieved ina number of ways with the most common being mechanicalmicropumping and electroosmotic flow (EOF) which mayinclude electrophoresis separations (1, 2). The typical cross-sectional dimensions of such micro channels are inthe range of 10–500 µm and are normally fabricated onthe planer surface of substrates such as glass, polymers,ceramics, and metals. Depending on the material selected,a range of fabrication methods can be used for theproduction of micro channels including photolithographyand wet-etching, powder-blasting, hot embossing, injectionmoulding and laser micromachining (2).A number of recent reviews have described thedevelopment of microreactors, based on the so-called“Lab-on-a-Chip” technology and outlined the relevanceof such techniques to the field of organic synthesis (3-12). In this article, the fundamental and practicaladvantages associated with microreactor technology arerelated to the current needs of the chemical industry, whoare constantly searching for controllable, informative,high-throughput, environmentally friendly processeswhilst retaining a high degree of chemical selectivity.Specific examples are also presented in order to illustratethe intrinsic advantages associated with micro reactiontechnology, together with an illustration of how thesedevices can be integrated into existing automatedinstrumental systems so enabling new syntheticmethodology to be coupled with an analytical finish. CHARACTERISTICS OF MICROREACTORSThe unique operating characteristics of microreactors,compared to conventional batch reactors, include a highsurface area to volume ratio, enhanced heat transfer,diffusion dominated mass transfer, spatial and temporalcontrol of reagents and products, the generation ofconcentration gradients and the opportunity to integrateprocesses and measurement systems in an automatedmanner.High surface area to volume ratioWhen scaling a conventional centimetre sized reactordown to the micron scale, the surface to volume ratiosignificantly increases to the point where the containerwalls can effectively become an active or influential partof the reaction or process occurring in the fluidic channel.Clearly this attribute of microreactors can be viewed in apositive way and leads to the opportunity of exploitingsurface dependent performance. A relatively simple, butimportant example, of this effect is where the surfacecharge of the capillary is neutralised by the solutioncontained within it to form a charged double layer, whichunder the influence of an applied electric field leads to theelectroosmotic mobilisation of the solution. In morechemical applications the surfaces could be representreagents, catalysts or even physical molecular imprintedstructures.  Enhanced heat transferThe high surface to volume ratio can also significantlyimprove thermal transfer conditions within micro channelsin two ways; firstly, the convective heat transfer whichtakes place at the solid/fluid interface, is improved via anincrease in heat transfer area per-unit-volume andsecondly, heat transfer within a small volume of fluid takesa relatively short time period to occur enabling athermally homogeneous state to be reached quickly. Theimprovement in heat transfer can certainly influenceoverall reaction rates and, in some cases, productselectivity. Perhaps one of the more profound effects of theefficient heat transfer property of microreactors is theability to carry potentially explosive or highly exothermicreactions in a safe way, due to the relatively small thermalmass and rapid dissipation of heat.Mass transfer dominated by diffusionIt is well known that the flow within microchannels isrestricted to diffusive mixing under laminar flowconditions.  Based on Fick’s law (13), the relationshipbetween the travel distance (L) of a molecule by diffusionand time (t) can be simplified asL = (2D•t)1/2 (1)where D is diffusion coefficient.  From Eq. (1) it can be seen that by scaling down thedimension in which diffusive mixing occurs, a significantreduction in the time taken to achieve complete mixing isachieved. For example, a water molecule takes 200 s todiffuse across a 1 mm wide channel, but only takes 500ms to cross a 50 µm wide channel (where the self-diffusion coefficient of water at 25 °C is 2.30x10-9 m2s-1)chimica oggi • Chemistry Today • Vol 24 nr 2 • March/April 2006 44Microreactors(14). This significant reduction in mixing time is beneficialfor controlling reaction progress, in particular forinitiating or quenching reactions in a controlled manner,enabling improvements to be made in product selectivity.  Spatial and temporal evolution of reactionsUnder such diffusive laminar flow conditions, the ability toadd reagents at specific locations or time leads to theunique ability to control and monitor the spatial andtemporal domain of dynamic chemical processes. Thisattribute has some analogies with the control exerted onbiochemical reactions by the micron-scale structures ofliving cells. Exploitation of this effect, such that a reactionwell occurs in a position where the local concentration ofa key intermediate is high, is a potentially valuableapproach towards controlling the yield and selectivity ofreactions.System integration and automationEach of the properties of a microreactor outlined abovedo not have to be exploited independently but can becombined to provide multiple functionality within onemicroreactor. In this way, multi-step processes, combininga range of physical and chemical steps, can beperformed in a controlled and reproducible way. Inaddition, the integration of in-situ, real time or end of lineanalyticalmeasurementscan be effectivelyrealised usingmicroreactortechnology,leading to rapidautomatedmethodology. Acombination ofthese two featureswill clearly createtools for the pharmaceutical and fine chemical industries,where high throughput and information rich techniquesare constantly sought for the rapid evaluation of reactionarrays.EXPLOITING THE HIGH SURFACE TO VOLUMEPROPERTIES OF MICROREACTORSAlthough the rapid growth of microreactor technologyhas led to the transfer of many common syntheticreactions from batch to “chip” (15-19), little attention hasbeen paid to the problems associated with the continuouspurification of these reactions products. To tackle this, theincorporation of solid-supported catalysts withinminiaturized flow reactors has been investigated, leadingto the synthesis of analytically pure compounds andaiding the development of efficient multi-step processes. By way of example, we describe here the use ofsupported catalysts held within a borosilicate glasscapillary (500 mm (i.d) x 3.0 cm (length) in which solventand reagents are pumped under electroosmotic conditions(Figure 1). The supported catalyst was dry packed intothe reactor and held in place by micro porous silica frits(20). The packed capillary was primed with MeCN toremove any air, ensuring the formation of an electricalcircuit; a leak-tight connection between the capillary andreagent reservoirs was achieved using PTFE thread sealtape. To mobilise reagents by EOF (from reservoir Athrough the packed-bed to reservoir B), platinumelectrodes were placed within the reservoirs and voltagesapplied using a high voltage power supply (0 to 1000 VDC); typical applied fields of 167 to 333 and 0 V cm-1were employed.In order to benchmark the technique against traditionalstirred/shaken reactors, the base-catalysed Knoevenagelcondensation of 8 α ,β -unsaturated compounds was used(Table 1) (21); this was followed by the acid-catalysedprotection of 15 aldehydes as their respective dimethylacetal (22). In all cases, high run-to-run reproducibility (< 0.9 percent RSD) was demonstrated along withexcellent product purity and isolated yields (> 94.7percent). As an extension to this investigation, theincorporation of multiple supported catalysts (a polymer-supported acid and a silica-supported base) into theaforementioned reactor was examined to demonstrate thetwo-step synthesis of 20 α ,β -unsaturated compounds;again all products were obtained in excellent yield (>99.1 percent) and analytical purity (> 99.1 percent).Furthermore, when performing the two-step reactions,Amberlyst-15 was recycled over 200 times and silica-supported piperazine over 1000 times, with no sign ofdegradation. This technique has been demonstrated to be a simple andefficient approach for the incorporation of solid-supported catalysts into miniaturised flow reactors,resulting in a system suitable for the continuous flowsynthesis of analytically pure compounds. Compared toFig. 1. Schematic illustrating the (a). reaction set-up used for the evaluation of solid-supported catalysts in miniaturised flowreactors and (b). reaction manifold used for the synthesis of 2-cyano-3-phenyl acrylic acid ethyl ester.Table 1. Summary of the results obtained for the synthesis of α -, β -unsaturated compounds in a miniaturised flow reactor.chimica oggi • Chemistry Today • Vol 24 nr 2 • March/April 2006 45MicroreactorsXUNLI ZHANG, CHARLOTTE WILES, SARAH L.PAINTER, PAUL WATTS AND STEPHEN J. HASWELL **Corresponding authorThe University of Hull Department of ChemistryHull, HU6 7RX, United Kingdomtraditional batch techniques, the application ofminiaturised flow reactors proved advantageous, as it ispossible to synthesise compounds in high yield and puritywithout the use of extended reaction times (min cf. > 24hr). Additionally, the ease with which supported catalystsare recycled provides a reaction reproducibilityunparalleled in traditional stirred or shaken reactorvessels. Consequently, whether milligrams of a compoundare required for biological evaluation (single reactor) ortonnes for the production of fine chemicals (multiplereactors), the flexibility associated with micro reactiontechnology enables these differences in scale to bridgedwith ease.INTEGRATION AND AUTOMATION OFCHEMICAL SYNTHESIS WITH ANALYTICALDETECTIONThe ability to generate a large quantity of chemicalreaction information through automation representsan important capability of microreactor systems, withthis in mind, the following example describes the useof a modified HPLC system for automated reagentselection, microreaction and chromatographicanalysis (Figure 2 and 3).  Figure 3 shows a multi valving system, locatedbetween two syringe pumps shown in the foreground,used in combination with an HPLC autosampler toallow the introduction of multiple reagents onto themicroreactor. Due to the low diffussional distancesobtained in this system, compared to the use ofreagent slugs, this approach is amenable to theindividual introduction of a large number of reagentsonto the microreactor. Hence the rapid loading ofsample introduction loops can be performed withoutcompromising either the reaction or analytical flowrates, offering time efficiency whilst ensuring thatconcentration of the sample is not reduced byexcessive diffusion into the carrier solvent. In addition,high flow rates can be maintained for thechromatographic separation which would be difficultto achieve if the exit stream of the microreactor wasdirectly coupled to the analytical column. The ability toindependently optimise the flow in all threesections of the process, is also important withrespect to reagent integrity, reaction efficiencyand chromatographic separation. Clearly, thesystem described has additional applicationsbeyond that of a quality control technique forchemical synthesis, for example it would berelatively simple to incorporate biologicalprocessing and/or couple the reactor set-up toother analytical instrumentation. In summary,the automated system described allows therapid evaluation of an array of reactionconditions such as reaction time, temperatureand reagent stoichiometry, enabling theproduction of combinatorial libraries with ease. CONCLUSIONSIt has been demonstrated that microreactors offer manyadvantages over conventional macro-scale reactors,particularly with respect to achieving controllable,information rich, high-throughput, environmentallyfriendly and automated processes capable of generatinglarge quantities of product with a high degree ofchemical selectivity. These advantages can be attributedto the dramatic reduction in scale leading to uniqueoperating conditions such as the spatial and temporalreagent control obtained under a non-turbulent,diffusive mixing regime and a high surface to volumeratio. There is no doubt that microreactor technologycan be used as a platform for a wide range ofapplications such as chemical and biological analysis,chemical synthesis, materials chemistry andbiotechnology – to name but a few.REFERENCES AND NOTES1. P. D. I. Fletcher et al., Tetrahedron, 58, pp. 4735-4757 (2002)2. T. Laurell et al., 8th International Conference on Miniaturized Systemsfor Chemistry and Life Sciences (MicroTAS 2004), pp. 26-30 (2004)Malmö, Sweden, September 3. T. Schwalbe et al., Chimia, 56, pp. 636-646 (2002)4. C. J. Cullen et al., Curr. Opin. Drug Discov. Dev., 7, pp. 798-806(2004)5. H. Pennemann et al., Org. Process Res. Dev., 8, pp. 422-439 (2004) 6. M. Brivo et al., Lab Chip, b510856j (2006)7. K. Jahnisch et al., Angew. Chem. Int. Ed., 43, pp. 406-446 (2004)8. V. Hessel, H. Lowe, Chem. Eng. Technol., 28, pp. 267-284 (2005)9. P. Watts, S. J. Haswell, Chem. Eng. Technol., 28, pp. 1-12 (2005)10. P. Watts, S. J. Haswell, Chem. Soc. Rev., 34, pp. 235-246 (2005)11. J. Yoshida et al., Chem. Eng. Technol., 28, pp. 259-266 (2005)12. P. D. I. Fletcher et al., Dekker Encyclopedia of Nanoscience andNanotechnology, 2, pp. 1547-1564 (2004)13. A. Fick, Ann. Phys. Chem., 94, pp. 59-86 (1855)14. R. Mills, J. Phys. Chem., 77, pp. 685-688 (1973)15. S. J. Haswell et al., Lab Chip, 1, pp. 164-166 (2001)16. E. Garcia-Egido et al., Lab Chip, 2, pp. 31-33 (2002)17. C. Wiles et al., Org. Process Res. Dev., 8, pp. 28-32 (2004)18. K. Jahnisch et al., Angew. Chem. Int. Ed., 43, pp. 406-446 (2004)19. C. Wiles et al., Tetrahedron, 61, pp. 10757-10773 (2005)20. P. D. Christensen et al., Anal. Commun., 35, pp. 341-344 (1998)21. C. Wiles et al., Tetrahedron, 60, pp. 8421-8427 (2004)22. C. Wiles et al., Tetrahedron, 61, pp. 5209-5217 (2005)Figure 2. Schematic illustratingthe automated reagent selection, micro reaction and HPLC analysis set-up developedFigure 3. Illustration ofthe automated reagentintroduction, reactionand analysis set-updeveloped

Microreactors as tools for chemical research

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