Patent Publication Number: US-2007108054-A1

Title: Devices with a passageway for electroosmotic flow and method of making same

Description:
The invention relates to a method of making a device for electroosmotic flow therein, a device with a passageway for electroosmotic flow therein, and a method of generating electroosmotic flow. Additionally, the invention relates to a method of preparing a 1,3-dithiane or a 1,2-dithiolane.  
      Devices with passageways for electroosmotic flow therein are well known in the art. For example a first type of known device is described in U.S. Pat. No. 6,344,120, in a review article by Haswell S. J. in the Analyst, January 1997, Volume 122 (1R-10R), and in a review article by Fletcher et al in Tetrahedron, 58 (2002), 4735-4757. In this first type of known device, the device comprises a first member with a groove and a second member with a surface. The two members are attached to one another so that the surface closes the groove to form a passageway. A porous silica plug is located at a convenient point within the passageway. Methods of making such a device are described in the three documents referred to above. In particular, the porous silica plug, otherwise known as a frit, is prepared from a mixture of formamide and potassium silicate solutions. Before the two members are attached to one another, a drop of the solution is placed into the groove in the first member at a desired position. The solution is then heat cured, in the groove, to form a microporous silica structure.  
      The second member is then bonded to the first member so as to seal the groove with the microporous silica structure forming a plug in the passageway. The method of forming the microporous silica structure is described in detail in article by Christensen et al in Anal.Commun., 1998, Volume 35, 341-343, and also in U.S. Pat. No. 6,344,120.  
      A second type of device with a passageway for electroosmotic flow therein is described in the article by Christensen et al referred to above. In this second type of device, a microporous silica plug is formed in the passageway of capillary tube. The porous silica plug is formed in the same way as described above.  
      A problem with these known devices is that some shrinkage of the mixture of formamide and potassium silicate solution occurs during heat curing. This leads to small gaps between the porous silica plugs and the surfaces bordering the passageways in which they are located. This is disadvantageous as solutions passing along the passageways can by-pass the porous silica plugs bypassing through these gaps.  
      In the known devices described above, electroosmotic flow of liquid can be induced along the passageway, and through the pores of the porous silica plug, by applying an electric voltage across the length of the passageway. However, it has been found that in the known devices described above, electroosmotic flow will only occur in passageways which are relatively narrow—that is to say in passageways which have a maximum cross-sectional dimension of 500 μm or less. The maximum cross-sectional dimension is the longest straight line which extends across the passageway in a cross-sectional plane. This limitation in the maximum cross-sectional dimension is disadvantageous as it restricts the flow rates that can be achieved by electroosmotic flow in the passageways of these devices.  
      According to a first aspect of the invention, there is provided a method of making a device for electroosmotic flow therein, comprising, preparing a device with a passageway therein and with a porous plug in the passageway, the porous plug being formed by curing a paste comprising filler particles and a silicate solution, the device having an internal surface which borders the passageway and which is contacted by the plug all around the passageway without any gaps therebetween.  
      According to a second aspect of the invention, there is provided a device made by a method in accordance with the first aspect of the invention.  
      In accordance with a third aspect of the invention, there is provided a device with a passageway for electroosmotic flow therein, the device having an internal surface which borders the passageway, a porous plug within the passageway, the plug contacting the surface all around the passageway without any gaps therebetween.  
      According to a fourth aspect of the invention, there is provided a device according to the third aspect of the invention, made by a method in accordance with the first aspect of the invention.  
      In accordance with a fifth aspect of the invention, there is provided a method of generating electroosmotic flow comprising providing a device in accordance with any one of the second, third or fourth aspects of the invention, filling the passageway and the pores of the porous plug with a liquid, and applying an electric voltage across the length of the passageway to cause electroosmotic flow therealong.  
      In accordance with a sixth aspect of the invention, there is provided a method of preparing a 1,3-dithiane or a 1,2-dithiolane, comprising mixing an aldehyde or a ketone with a dithiol and passing the mixture through a supported acid catalyst so as to produce a 1,3-dithiane or a 1,2-dithiolane.  
      The passageways of the current invention (and also the passageways of the known devices described above) are not necessarily circular in cross-section. In general, the passageways may have any cross-sectional shape including, for example, circular, D-shapes and rectangular. The term maximum cross-sectional dimension is defined above. As used herein, the minimum cross-sectional dimension refers to the shortest straight line which extends, in a cross-section, fully across the passageway and through the mid-point of the passageway. For example, if a passageway has a circular cross-section, the minimum cross-sectional dimension will be a diameter If the passage has a rectangular cross-section, then the minimum cross-sectional dimension will be the line which passes through the centre of the passageway, between and perpendicular to the closest sides. The passageways of the current invention preferably have a regular cross-sectional shape.  
      As mentioned above, known devices with passageways for electroosmotic flow have passageways with a maximum cross-sectional dimension (as defined above) of 500 μm or less. In the known devices, electroosmotic flow is unachievable if the maximum cross-sectional dimension is greater than 500 μm. However, in the current invention, the maximum cross-sectional dimension of the passageway is preferably greater than 500 μm. More preferably, the maximum cross-sectional dimension is greater than 600 μm, or 700 μm, or 800 μm, or 900 μm, or 1000 μm, or 1200 μ, or 1400 μm, or 1600 μm, or 1800 μm, or 2000 μm (the greater the dimension, the more preferred). These maximum cross-sectional dimensions preferably apply to the whole length of the passageway. It has been found that electroosmotic flow surprisingly can take place in such passageways.  
      Alternatively, the minimum cross-sectional dimension of the passageway of the current invention, as defined above, is preferably greater than 500 μm, and more preferably greater than 600 μm, or 700 μm, or 800 μm, or 900 μm, or 1000 μm, or 1200 μm, or 1400 μm, or 1600 μm, or 1800 μm, or 2000 μm (the greater the dimension, the more preferred). These minimum cross-sectional dimensions preferably apply to the whole length of the passageway. It has been found that electroosmotic flow surprisingly can take place in such passageways.  
      In known devices having passageways for electroosmotic flow, the cross-sectional area of the passageways does not exceed 0.2 mm 2 . This is because electroosmotic flow does not occur in passageways having greater cross-sectional areas in devices of known type. However, the passageways of the current invention preferably have a cross-sectional area of greater than 0.2 mm 2 , more preferably greater than 0.3 mm 2 , even more preferably greater than 0.4 mm 2 , and most preferably greater than 0.5 mm 2 . Surprisingly, it has been found that passageways in accordance with the invention having cross-sectional areas of this magnitude can still support electroosmotic flow. These cross-sectional areas preferably apply to the whole length of the passageway. 
    
    
      The following is a more detailed description of embodiments of the invention, by way of example only, reference being made to the appended drawings in which:  
       FIG. 1  is a schematic view of a first device in accordance with the invention;  
       FIG. 2  is a schematic view of a second device in accordance with the invention;  
       FIG. 3  is a schematic view of a third device in accordance with the invention and at a stage in its manufacture prior to completion; and  
       FIG. 4  is an enlarged cross-section through a lower glass plate of the third device. 
    
    
       FIG. 1  shows a flow reactor The reactor includes a cylindrical tube  10  which may be made, for example, of glass, such as borosilicate glass, or of a polymer such as SU-8, PEEK or Teflon, The tube  10  has an internal surface  12  which borders a cylindrical passageway  14 .  
      First and second porous plugs  16 , 18  are located within the passageway  14  at opposite ends of the passageway  14 . Each plug  16 , 18  contacts the internal surface  12  of the tube  10  all around the passageway  14  so that there is no gap (other than those formed by the pores of the porous plug) between the porous plug  16 , 18  and the internal surface  12 . Each one of the plugs  16 , 18  is formed from borosilicate glass powder held together in a solid silica matrix. In this example, the glass powder is of a type commercially available under the name VitraPOR (trade mark) and has a particle size of 5 μm. However, other glass powders may be used. Suitable particle sizes may be between 1 and 20 μm, preferably between 2.5 μm and 10 μm.  
      An enclosed area  20  is located in the middle of the passageway  14  between the first and second porous plugs  16 , 18 . This enclosed area  20  may include a supported reagent or catalyst of known type, and examples of suitable supported reagents and catalysts are given below.  
      The preparation of the tube  10 , and in particular of the first and second porous plugs  16 , 18 , will now be described. As a first step, the first plug  16  is formed at one end of the passageway  14 . This is done as follows. Firstly, a potassium silicate solution is prepared which contains 21% SiO 2  and 9% K 2 O. The solvent is water. One volume of the potassium silicate solution is then mixed with two volumes of borosilicate glass powder having a particle size of 5 micrometres (or any other suitable particle size as described above). After thorough mixing, a paste is formed. A volume of the paste is introduced into the passageway  14  at one end thereof, and the tube is then heated at 100° C. for 24 hours so as to cure the paste. During the curing process, the paste hardens into the first porous plug  16 . Advantageously, the paste does not undergo shrinking and no gaps are formed between the first porous plug  16  and the internal surface  12 . The tube  10  now has a first plug  16  formed at one end of the passageway  14 .  
      If desired, a supported reagent, or a supported catalyst, is introduced into the passageway  14  with the tube  10  in a vertical position so that the supported reagent or catalyst rests on the porous plug  16 . The second plug  18  is then formed at the other end of the passageway  14 , in an identical manner to the formation of the first plug  16 , so that the supported reagent or catalyst becomes trapped in the passageway  14  between the first and second plugs  16 , 18 .  
      In the current example, the glass tube  10  has an internal diameter of 3 millimetres and a length of about 3 centimetres. However, these dimensions are not critical and any suitable dimensions may be used.  
      The flow device shown in  FIG. 1  also includes two identical supports  22   a  and  22   b.  Only one support will be described in detail and this support will be given reference numerals for its components having the suffix a. The other support (not described) will be given corresponding reference numerals with the suffix b.  
      The support  22   a  has a hollow cylindrical reservoir  24   a  which is open at a top end and closed at a bottom end. The reservoir  24   a  is held in a vertical position by a stand  26   a  attached to the bottom end of the reservoir  24   a.  The reservoir  24   a  is provided, towards its closed bottom end with a generally circular aperture  28   a  which is provided with a rubber seal  30   a.    
      The aperture  28   a  and the rubber seal  30   a  are dimensioned and designed such that the tube  10  may be inserted through the rubber seal  30   a  and through the aperture  28   a  so that the rubber seal  30   a  provides a fluid tight seal between the aperture  28   a  and the tube  10 . In this way, the passageway  14 , and most immediately the first porous plug  16 , is in direct fluid communication with the interior of the reservoir  24   a.    
      The other end of the tube  10  is inserted through the rubber seal  30   b  and the aperture  28   b  of the other support  22   b  in a similar manner In this way, the passageway  14 , and most directly the second porous plug  18  is in direct fluid communication with the reservoir  24   b.    
      Methods of using the flow reactor shown in  FIG. 1  are described below.  
      A second flow reactor is shown in  FIG. 2 . The second flow reactor includes a tube  32  which maybe formed of glass, such as borosilicate glass, or of a suitable polymer. The tube  32  defines an internal cylindical passageway  36  which is bordered by an internal surface  34 . A first porous plug  3   8  is formed at one end of the passageway  36 , a second porous plug  40  is formed approximately in the middle of the passageway  36 , and a third porous plug  42  is formed at the other end of the passageway  36 . The three porous plugs  38 , 40 , 42  are identical to the first and second plugs  16 , 18  of the flow reactor shown in  FIG. 1 , and they are formed using the same procedure. Each of the first, second and third plugs  38 , 40 , 42  contacts the internal surface  34  all around the passageway  36  so that there is no gap between the plug and the passageway  36 . A first enclosed area  44  is formed between the first and second plugs  38 , 40  and the second enclosed area  36  is formed between the second and third plugs  40 , 42 . If desired, and as discussed in more detail below, the first enclosed area  44  may contain a supported reagent or catalyst and the second enclosed area  46  may contain a different supported reagent or catalyst.  
      The second flow reactor shown in  FIG. 2  may be mounted between the supports  22   a,   22   b  described above, in place of the tube  10  shown in  FIG. 1 .  
      The tube  32  of the second flow reactor may have an internal diameter of about 3 millimetres and a length of about 6 centimetres, although these dimensions are not critical and any suitable dimensions may be used.  
      A method of using the second flow reactor will be described below.  
       FIG. 3  shows a lower glass block  48  and an upper glass block  50  which are used in the manufacture of a third flow reactor.  
      The lower glass block  48  has an upper surface  52  in which is formed a first groove  56  and a second groove  58  which extends from a mid-point of the first groove  56  so as to form a T formation.  
      The upper glass block  50  has first, second and third cylindrical holes  60 , 62  and  64  extending therethrough.  
      The upper and lower glass blocks  48 , 50  described above are similar to conventional blocks described in, for example, U.S. Pat. No. 6,344,120, the 1997 Review Article by Haswell et al referred to above, and in the 2002 Review Article by Fletcher et al referred to above. Full descriptions of how the first and second grooves  56 , 58  are formed are given in each of these three documents. The first and second grooves  56 , 58  have a generally D-shaped cross-section, as shown in  FIG. 4 . As shown in  FIG. 4 , which shows a cross-section through the second groove  58 , each groove is bordered, at its base, by a generally planar surface  66  which is generally parallel to the upper surface  52  of the lower glass block  48 . At each side of the groove  56 , 58  a respective curved surface  68 , 70  joins the generally planar surface  66  to the upper surface  52 .  
      The D cross-sectional shape of the first and second grooves  56 , 58  is similar to the shape of the grooves shown in  FIG. 2  of the  2002  Review Article by Fletcher et al. However, in contrast to the known flow reactors described in that article, the first and second grooves  5   6 , 5   8  have larger dimensions. In the current example, the depth of the first and second grooves  56 , 58  may be 500 μm or greater. Preferably, the depth will be 1000 μm or greater. The width of the first and second grooves  56 , 58  is greater than their depth.  
      Before assembling the upper and lower glass blocks  48 , 50  so as to form the third flow reactor, a porous structure is formed in a suitable position in one of the first and second grooves  56 , 58 . For example, the porous structure may be formed at the end of the second groove  58  adjacent to the first groove  56 .  
      The porous structure is formed using the same paste mixture described above for the formation of the plugs  16 , 18 ,  38 , 40 , 42 . A suitable volume of this paste is placed in the groove  58  so as to completely fill the groove and so as to be approximately flush with the upper surface  52  of the lower glass block  48 . The paste mixture is then heat cured as described above so as to form a solid porous structure.  
      The lower surface  54  of the upper glass block  50  is then placed against the upper surface  52  of the lower glass block  48  and the glass blocks  48 , 50  are heat-annealed to one another. This process is well known and described, for example, in the above-mentioned review article by Fletcher et al and in U.S. Pat. No. 6,344,120.  
      After this heat-annealing process, the lower surface  54  of the upper glass block  50  closes the first and second grooves  56 , 58  to form, respectively, first and second interconnecting passageways (not shown). The porous structure described above in the second groove  58  now forms a plug in the second passageway. As the pasty mixture does not shrink during the curing process, this plug entirely fills the second passageway. Specifically, there is no gap between the plug and any of the surfaces surrounding it. This includes the planar surface  66  and the two curved surfaces  68 , 70  of the lower glass block  48 , and also the lower surface  54  of the upper glass block  50 .  
      The dimensions of the passageways formed from the first and second grooves  56 , 58  will generally be the same as those of the first and second grooves  56 , 58 .  
      As can be seen from  FIG. 3 , the first hole  60  now lies above one end of the first passageway, the second hole  62  now lies above the other end of the first passageway, and the third hole  64  now lies above the free end of the second passageway. The third flow reactor can be used to perform chemical reactions as for similar conventional reactors known in the art—with electroosmotic liquid flow taking place in the passageways.  
      It will be appreciated that the first, second and third flow reactors described above may be altered in many different ways. For example, the pasty mixture used to form the plugs need not be as described above. Whereas the pasty mixture will preferably include glass powder, and more preferably borosilicate glass powder, other suitable filler particles maybe used. Suitable filler particles may be chosen both with regard to their inert nature and their surface charge. Specifically, filler particles will be inert with whichever electroosmotic liquid the flow reactor is intended for use with. Additionally, the filler particles will be chosen, preferably, so as to have a surface charge, preferably a negative surface charge, in the electroosmotic liquid with which the flow reactor is intended to be used. Other suitable silicate solutions such as sodium silicate may be used.  
      The passageways of the flow reactors may have any internal dimensions. However, the maximum cross-sectional dimension, as defined above, is preferably greater than 500 μm, and more preferably greater than 600 μm, 700 μm, 800 μM, 900 μm, 1000 μm, 1200 μm, 1400 μm, 1600 μm, 1800 μm or 2000 μm (the greater dimensions being most preferred).  
      Alternatively, the minimum cross-sectional dimension, as defined above, is preferably greater than 500 μm and more preferably greater than 600 μm, or 700 μm, or 800 μm, or 900 μm, or 1000 μm, or 1200 μm, or 1400 μm, or 1600 μm, or 1800 μm, or 2000 μm (the greater diemension being most preferred).  
      As a further alternative, the passageways of the current invention preferably have a cross-sectional area of greater than 0.2 mm 2 , more preferably greater than 0.3 mm 2 , even more preferably greater than 0.4 mm 2 , and most preferably greater than 0.5 mm 2 .  
      The passageways may vary in their cross-sectional dimensions and cross-sectional areas along their length. However, it is preferred that the maximum cross-sectional dimensions, or the minimum cross-sectional dimensions, or the cross-sectional areas discussed above are exceeded throughout the length of the passageways.  
      Flow reactors of the type shown in  FIG. 3 , which are formed with a first member having a groove and a second member having a surface which closes the groove so as to form a passageway, can have any number of interconnecting passageways in any desired configuration. Suitable configurations are well known in the art.  
      In the first and second flow reactors described above the enclosed spaces contain supported reagents or catalysts—the reagents or catalysts being supported on a particulate support, such as particulate silica. Preferably, all of those areas in the passageways of the current invention which are not filled by a porous plug as described above, are provided with a particulate material. This particulate material may be a supported reagent or catalyst or mixtures thereof. Alternatively, the particulate material may simply be chemically inert. The particulate material facilitates electroosmotic flow. Preferably, the particulate material will have a surface charge in the electroosmotic liquid which will be used.  
      The following are examples of how the flow reactors described above may be used to perform chemical reactions.  
     Synthesis of 1,3-Dithianes, and 1,2-Dithiolanes  
      In this reaction, a dithiol is reacted with either an aldehyde or a ketone, using a supported acid catalyst, so as to produce either a 1,3-dithiane or a 1,2-dithiolane. The reaction is performed in the first flow reactor shown in  FIG. 1 .  
      Amberlyst-15 (0.055 g, 0.23 mmol) is inserted into the enclosed area  20  of the tube  10  during manufacture of the first flow reactor described above. Accordingly, the Amberlyst-15 is trapped in the passageway  14  between the first and second plugs  16 , 18 . Amberlyst-15 is a commercially available acid catalyst. The tube  10  is then mounted in the two supports  22   a  and  22   b  as described above. One support  22   a  was filled with anhydrous acetonitrile and pressure was applied to the open end of the reservoir  24   a  so as to drive the acetonitrile through the tube  10  and into the reservoir  24   b  of the other support  22   b.  In this way, all spaces within the porous plugs  16 , 18  and between the Amberlyst-15 become filled with acetonitrile.  
      Excess acetonitrile is then removed from the reservoir  22   a  and a premixed equimolar solution of a dithiol (1.0M) and either an aldehyde or a ketone (10M) in anhydrous acetonitrile, is introduced into the reservoir  22   a.    
      Platinum electrodes are then inserted into the reservoirs  24   a,   24   b  and an electric voltage is applied between the platinum electrodes. When the pre-mixed solution contains an aldehyde, the applied voltage is 200 volts per centimetre length of the tube  10 . When the premixed solution contains a ketone, the applied voltage is 167 volts per centimetre length of the tube  10 .  
      The applied voltage causes the premixed solution to pass through the first plug/FRIT  16 , through the enclosed area  20  containing the Amberlyst-15, through the second plug  18 , and into the reservoir  22   b.  This fluid flow is driven by electroosmotic force.  
      The reaction products were collected and analysed every ten minutes and the reactions were conducted for a period of 2.5 hour. After the end of the reactions, the reaction products were collected and concentrated in vacuo prior to analysis by NMR spectroscopy.  
      The results are shown below in Table 1. As shown in Table 1, the conversion and yield for all experiments were greater than 99%. It should also be noted that the flow rates are much greater than are typically achieved in conventional electroosmosis driven flow reactors. This is clearly advantageous as larger amounts of product can be generated more quickly.  
                                   TABLE 1                               Flow                           Rate (μl   Conversion   Actual   Yield       Starting Material   Dithiol   min −1 )   (%)   Yield (g)   (%)                                                        Benzaldehyde   1,3-   65.0   99.92        1.960 g a     99.90           Propanedithiol       4-Bromobenzaldehyde   1,3-   61.4   99.99   1.0121   99.92           Propanedithiol       4-Chlorobenzaldehyde   1,3-   61.7   99.99   0.8561   99.91           Propanedithiol       4-Cyanobenzaldehyde   1,3-   65.4   99.99   0.8687   99.94           Propanedithiol       4-   1,3-   63.0   99.99   0.8796   99.97       Biphenylcarboxaldehyde   Propanedithiol       Propiophenone   1,3-   40.4   100.0   0.5467   99.94           Propanedithiol       Acetophenone   1,3-   41.5   99.99   0.5213   99.57           Propanedithiol       Cyclohexanone   1,3-   42.2   99.99   0.4742   99.62           Propanedithiol       Butyrophenone   1,3-   41.6   99.99   0.5935   99.90           Propanedithiol       4-Nitroacetophenone   1,3-   40.9   99.99   0.6255   99.95           Propanedithiol       4-Acetylbenzaldehyde   1,3-   65.2   100.0   0.9270   99.57           Propanedithiol       Benzaldehyde   1,2-   61.5   99.99   0.6709   99.90           Ethanedithiol                   a Reactor operated for 2.5 hours             
 
      Similar results using other ketones are shown in Table 2. In these cases, the dithiol is 1,3-propanedithiol. Because ketones are less reactive than aldehydes, the flow rates need to be less (approximately 40 μl/min) as compared to 60 μm/min for aldehydes.  
                               TABLE 2                           Flow                       Rate/μl       Actual       Ketone   Min-1   Conversion/%   Yield/g   Yield %                  4-Methylacetophenone   42.0   99.99 (0.001)   0.5947   99.91       2-Methylcyclohexanone   41.6   99.99 (0.001)   0.5040   99.96       Cyclopentanone   43.0   99.99 (0.001)   0.4489   99.91       4-Aminoacetophenone   40.3   99.99 (0.001)   0.5430   99.93       4-   41.9    99.99 (0.0004)   0.5680   99.90       Hydroxyacetophenone                  
 
      Having demonstrated the ability to protect both aldehydes and ketones, the ability to selectively protect an aldehyde in the presence of a ketone was investigated. By passing a pre-mixed solution of 4-acetylbenzaldehyde and 1-3, propandithiol (1.0M) in anhydrous acetonitrile through the reactor at 65 μl per minute, the aldehyde moiety was selectively protected without reaction of the ketone moiety.  
      As will be appreciated, other supported acid catalysts may be used instead of the Amberlyst-15. For example, polymer supported p-toluene sulphonic acid may be used. Another suitable catalyst is ytterbium (III) polystyrylsulfonate.  
      In an adaptation of the previous method, the tube  10  of the first flow reactor is replaced with the tube  32  of the second flow reactor shown in  FIG. 2  and described above. In this case, the supported acid catalyst is trapped in the first enclosed area  44  during preparation. Copper sulphate impregnated silica gel was inserted into the second enclosed area  46  during preparation. The second flow reactor was used for performing the production of 1,3-dithiane or a 1,2-dithiolane, as described above. However, in this case, the copper sulphate scavenged any unreacted dithiol thereby removing it from solution. This is advantageous as dithiol can poison catalysts used in subsequent reactions.  
     Synthesis of α,β-Unsaturated Compounds  
      The reaction of an aldehyde with an activated methylene in a known flow reactor is described in detail in the article by Wiles et al in Tetrahedron, Volume 60 (2004), 8421-8427. The same reaction was performed in the first flow reactor shown in  FIG. 1  above.  
      A premixed solution of aldehyde and activated methylene (1.0M, 1:1) in anhydrous acetonitrile was passed over a packed bed containing silica supported piperazine (0.100 g, 0.170 mmol N) by application of 200 V cm −1 . The silica supported piperazine was held in the enclosed area  20  between the porous plugs  16 , 18  of the first flow reactor. The reaction products were collected every 10 min and analysed by GC-MS and the reaction products combined after 1 hr. The reaction products were concentrated in vacuo and the resulting crude product analysed by NMR spectroscopy. As Table 3 illustrates, in all cases excellent product purities and yields were obtained. In addition, the reaction of benzaldehyde and ethylcyanoacetate was also performed using 3-(dimethylamino)propyl-functionalised silica gel, 3-aminopropyl-functionalised silica gel, 3-(1,3,4,6,7,8-hexahdryo-2H-pyrimido[1,2-1]-pyrimidino)propyl-functionalised silica gel and polymer supported diazabicyclo[2.2.2]octane whereby excellent conversions were obtained (&gt;99.0 %).  
                                   TABLE 3                               Flow       Actual               Activated   Rate   Conversion   Yield   Yield       Aldehyde   Methylene   (μl min −1 )   (%)   (g)   (%)                                                        Benzaldehyde   Ethylcyanoacetate   62.0   99.98   0.87   99.70       4-Bromobenzaldehyde   Ethylcyanoacetate   55.1   99.96   2.04 a     99.35       Methyl-4-formyl   Ethylcyanoacetate   56.1   100.0   0.87   99.80       Benzoate       3,5-   Ethylcyanoacetate   50.1   99.86   0.78   99.89       Dimethoxybenzaldehyde       4-   Ethylcyanoacetate   51.1   99.99   0.90   99.67       Benzyloxybenzaldehyde       Benzaldehyde   Malononitrile   62.1   99.98   0.52   99.40       4-Bromobenzaldehyde   Malononitrile   60.4   99.89   2.23 a     99.79       Methyl-4-formyl   Malononitrile   55.7   100.0   0.70   98.84       Benzoate       3,5-   Malononitrile   48.4   99.87   0.64   99.17       Dimethoxybenzaldehyde       4-   Malononitrile   48.3   100.0   0.75   99.73       Benzyloxybenzaldehyde                   a Reactor operated for 2.5 hrs             
 
     Multi-Step Syathesis of an α,β-Unsaturated Compound  
      A two-step reaction was then performed in the second flow reactor shown in  FIG. 2 . In this example, the first enclosed area  46  was used to perform an acid catalysed acetal de-protection, so as to produce an aldehyde, as described in an article by Wiles et al in Tetrahedron, Volume 61 (2005) 5209-5217. The second enclosed area  46  was then used for reaction of the aldehyde with an activated methylene as described in the article by Wiles et al in Tetrahedron, Volume 60 (2004), 8421-8427. Using this approach, 100% de-protection of the acetal to aldehyde was observed and 99% conversion of the aldehyde to the desired unsaturated product was observed. An electroosmotic flow rate much greater than those reported in the Wiles article was achieved.