Microchannels scheme

Mizuno and coworkers demonstrated an intramolecular version of [2 -I- 2] photo-cydoaddition using glass or poly(dimethoxysilane) (PDMS) microreactors (channel dimensions 100-300 pm wide, 40-50 pm deep) [27]. The reaction using a microreactor gave a better regioisomeric ratio than that with a batch reactor, since the possibility of the reverse reaction was reduced by a much shorter residence time, i.e. Imin, inside the microchannel (Scheme 6.11). 

SIP-driven polymer brush library fabrication leverages the fact that the polymerization initiation species are permanently bound to the substrate. Since the initiators are tethered, controlled delivery of monomer solution to different areas of the substrate results in a grafted polymer library. In NIST work, initiators bound via chlorosilane SAMs to silicon substrates were suitable for conducting controlled atom transfer radical polymerization (ATRP) [53] and traditional UV free radical polymerization [54, 55]. Suitable monomers are delivered in solution to the surface via microfluidic channels, which enables control over both the monomer solution composition and the time in which the solution is in contact with the initiating groups. After the polymerization is complete, the microchannel is removed from the substrate (or vice versa). This fabrication scheme, termed microchannel confined SIP ([t-SIP), is shown in Fig. 10. In these illustrations, and in the examples discussed below, the microchannels above the substrate are approximately 1 cm wide, 5 cm long, and 300-500 [tm high. 

Figure 8.3 Scheme of the microchannel reactor developed by Velocys (a) and one of the proposed configurations for this microchanneled reactor in the patent ofthe same company for a process of direct H202 synthesis (b) [20],... 

In order to detect the analyte specifically, a complex has to be formed first. To this end, the revelation moiety (e.g. an enzyme-labelled antigen or antibody) is for instance incubated in the chip so as to bind to the analyte that has previously been captured within the microchannel. In another scheme, the analyte solution is first mixed with the revelation moiety, and the formed complex is then incubated in the chip in order to be captured on the bed of antibodies coating the walls of the micro-channel. After a washing step (to remove the excess affinity partner), the microchannel is filled with the substrate which shall thus react... 

More recently, Matsuoka et al. (2006) reported the ability to supercool fluid streams within octadecylsilane-treated Pyrex microchannels, demonstrating a link between channel dimensions and the freezing point of water which range from 20 to 28 °C as the channel was reduced in width from 300 to 100 pm. Interestingly, a dimension-independent freezing temperature of —15 °C was obtained when bare Pyrex microchannels were employed. Having identified this phenomenon and found it to be independent of flow rate, the authors subsequently investigated the ability to perform asymmetric syntheses within such as system and employed the reaction depicted in Scheme 16 as a model. 

Matsushita et al. (2007) subsequently demonstrated the ability to N-alkylate amines (Scheme 57) under continuous flow, again employing a quartz microreaction channel coated with a Ti02 or Pt-loaded Ti02 layer. As Table 28 illustrates, the illuminated specific surface area per unit of liquid attained within a microchannel is large even without taking into account the surface roughness of the catalyst however, it can be seen that a shallow reaction channel provides optimal photon efficiency. 

In their pioneering work, Jensen et al. demonstrated that photochemical transformation can be carried out in a microfabricated reactor [37]. The photomicroreactor had a single serpentine-shaped microchannel (having a width of 500 pm and a depth of 250 or 500 pm, and etched on a silicon chip) covered by a transparent window (Pyrex or quartz) (Scheme 4.25). A miniature UV light source and an online UV analysis probe were integrated to the device. Jensen et al. studied the radical photopinacolization of benzophenone in isopropanol. Substantial conversion of benzophenone was observed for a 0.5 M benzophenone solution in this microflow system. Such a high concentration of benzophenone would present a challenge in macroscale reactors. This microreaction device provided an opportunity for fast process optimization by online analysis of the reaction mixture. 

Mizuno et al. demonstrated an intramolecular version of [2 + 2] photocycloaddition using a microreactor made of PDMS [poly(dimethoxysilane)] (channel dimensions 300 pm wide, 50 pm deep and 45 or 202 mm long) [40], Because one of the products photochemically reverts to the starting material, while the other does not, a much shorter residence time, that is, 3.4 min (batch reaction time = 3 h), inside the microchannel reduces the possibility of the reverse reaction. The difference in residence times explains the slight difference in regioselectivity between the microflow and batch systems (Scheme 4.27). 

Photocatalytic reduction using a Ti02-coated microchannel device was reported by Ichimura et al. [44], By using a quartz microreactor (microchannel, 500 pm wide, 100 pm deep and 40 mm long) and a 365-nm UV-LED light source, benzaldehyde was reduced to benzyl alcohol (yield of 11%) and p-nitrotoluene to p-toluidine (yield of 46%) after 1 min in the presence of ethanol (Scheme 4.30). 

Kitamori and coworkers reported the use of a Ti02-modified microchannel chip reactor (TMC, Pyrex glass chip, having branched channels 770 pm wide and 3.5 pm deep) for photocatalytic redox-combined synthesis of L-pipecolinic acid from L-lysine (Scheme 4.31) [45], Although both batch and microflow systems gave comparable yield and enantiomeric excess of the product, the conversion rate was significantly higher for the microflow reactor than for the batch system. 

Kitamura and coworkers demonstrated the photocyanation of pyrene by manipulating stable organic/aqueous (oil/water) laminar flow inside the microchannel (polystyrol microchannel chip with a channel, 100 pm wide, 20 pm deep and 350 mm long) [46], This two-layer oil/water system gave only 28% of the desired cyanated pyrene in 210 s under irradiation by a 300 W high-pressure Hg lamp (Scheme 4.32). However, the yield was improved (73%) by using a water/oil/water three-layer flow system. The 2.5-fold increase in yield was attributed to the greater surface area-to-volume ratio in the three-layer system. 

The device consisted of a 75 -pm thick polyimide foil containing microstructured slits (250 pm wide and 45 mm long) sandwiched between the working and counter electrodes (Scheme 4.34). The reaction took place inside the microchannels that were in contact with both electrodes. To maintain a constant reaction temperature, a heat exchanger block was also mounted above the working electrode. This microreactor-based electrolysis afforded 98% product selectivity, which was higher than that for common industrial processes (about 85%). 

Another immobilization method was described by Maeda and coworkers [344], They developed a facile and inexpensive preparation method for the formation of an enzyme-polymeric membrane on the inner wall of the microchannel (PTFE) through cross-linking polymerization in a laminar flow. With this approach, a-chymotrypsin was immobilized successfully. The activity of the immobilized enzyme was tested using N-glutaryl-L-phenylalanine p-nitroanilide as substrate, and the reaction products were analyzed offline by HPLC. There was no significant difference in the hydrolysis efficiency compared to solution-phase batchwise reactions using the same enzyme/substrate molar ratio (Scheme 4.87). 

Scheme 4.87 Formation of enzyme—polymer membranes in a microchannel. Reprinted with permission from [344]. Copyright 2005 The Royal Society of Chemistry.

Scheme 4.91 Schematic representation of the ELISA assay in a microchannel in which the primaryantibodyis immobilizedonthe channel wall. Reprinted with permission from [395]. Copyright 2001 Elsevier.

Scheme 4.95 Schematic view of the microreactor in which two enzymes (glucose oxidase and horseradish peroxidase) immobilized on beads are located in different parts of the microchannel. (Reprinted with permission from [406], Copyright 2002 American Chemical Society.)...

Most biocatalytic conversions are performed with the enzyme immobilized in the microreactor. Miyazaki et al. [426] developed a simple noncovalent immobilization method for His-tagged enzymes on a microchannel surface. These enzymes contain a polyhistidine-tag motif that consists of at least six histidine residues, often located at the N- or C-terminus. The H is-tag has a strong affinity for nickel and can be reversibly immobilized by a nickel-nitrilotriacetic acid (Ni-NTA) complex (Scheme 4.103), a strategy commonly used in affinity chromatography. 

With the help of this method, His-tagged L-lactate dehydrogenase was immobilized. By pumping pyruvic acid as substrate with NADH as cofactor, it was demonstrated that the enzyme was still active in the microchannel. In this case, cofactor was used up. Srinivasan et al. [433] incorporated PikC hydroxylase from Streptomyces venezuelae into a PDMS-based microfluidic channel with a similar approach. The enzyme was immobilized to Ni-NTA agarose beads with an in situ attachment, following the addition of the beads to the microchannel. This enabled the rapid hydroxylation of the macrolide YC-17 to methymycin and neomethymycin (Scheme 4.104) in about equal amounts with a conversion of >90% at a flow rate of 70nl/min. 

Figure 11. (A) Scheme of the PDMS microfluidic device. Inset channel crossing with the cell trap composed of microstmctured obstacles, (B) Scanning electron micrograph of the cell trap, (C) single cell in a channel navigated by optical tweezers in the microchannel, (D-G) optical micrographs of a single cell at the injection position during SDS lysis. SDS flow is from channel 4 through the cell trap into channel 2.

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