Microreactor microfluidic chip

The sequence includes several synthetic steps over polymer-supported catalysts in directly coupled commercially available Omnifit glass reaction columns [41] using a Syrris Africa microreactor system [14], Thales H-Cube flow hydrogenator [32] and a microfluidic chip. The process affords the alkaloid in 90% purity after solvent evaporation, but in a moderate 40% yield. After a closer investigation it was concluded that this is due to the poor yield of 50% in the phenolic oxidation step. On condition that this is resolved with the use of a more effective supported agent, the route would provide satisfactory yields and purities of the product. 

Enzymatic microreactors (7.5 nL) have been fabricated in the microfluidic chip to prepare the tryptic digest of equine (horse) myoglobin (14.2 pmol/p.L)... 

Microreactor technology offers the possibility to combine synthesis and analysis on one microfluidic chip. A combination of enantioselective biocatalysis and on-chip analysis has recently been reported by Beider et al. [424]. The combination of very fast separations (<1 s) of enantiomers using microchip electrophoresis with enantioselective catalysis allows high-throughput screening of enantioselective catalysts. Various epoxide-hydrolase mutants were screened for the hydrolysis of a specific epoxide to the diol product with direct on-chip analysis of the enantiomeric excess (Scheme 4.112). 

Electrophoretic microfluidic chips feature a number of microreactor characteristics and have been used for conducting chemical and biochemical reactions in channels and microfabricated chambers, mixing reagents, microextraction and microdialysis, post- and preseparation derivatizations, etc. The most recent achievements are reviewed in Ref. 63 and other similar publications. These integrated microdevices perform PCR amplification, cell sorting, enzymatic assays, protein digestion, affinity-based assays, etc. In this section we describe such integrated microsystems and the most recent advances in this field. 

Multiple PCR chambers have been fabricated on a single microfluidic chip and explored for high throughput PCRs [78-83]. An example of a multichamber micro-PCR device, the micro-DNA amplification and analysis device, (p-DAAD) consisted of 16p-DAADs in parallel with each p-DAAD consisting of four microreactors fabricated on a 4" silicon wafer (see Fig. 4). Multichamber micro-PCR devices [84] have been demonstrated for DNA amplifications of five gene sequences related to E. coli from three different DNA templates and detected by TaqMan chemistry with a limit of detection (LOD) of 0.4 copies of target DNA. 

Within the field of radical polymerization, special attention was recently drawn to the use of microreactors for controlled radical polymerization techniques, namely, ATRP, NMRP and RAFT. Shen and Zhu [126] have devised a column reactor packed with silica-gel-supported copper bromide-hexamethyltriethylenetetramine (HMTETA) for the continuous ATRP of homo- and block copolymers of MMA. Wu et al. [127] report the use of microfluidic chips made from thiolene polymer for continuous ATRP of... 

Besides the synthesis of bulk polymers, microreactor technology is also used for more specialized polymerization applications such as the formation of polymer membranes or particles [119, 141-146] Bouqey et al. [142] synthesized monodisperse and size-controlled polymer particles from emulsions polymerization under UV irradiation in a microfluidic system. By incorporating a functional comonomer, polymer microparticles bearing reactive groups on their surface were obtained, which could be linked together to form polymer beads necklaces. The ability to confine and position the boundary between immiscible liquids inside microchannels was utilized by Beebe and coworkers [145] and Kitamori and coworkers [146] for the fabrication of semipermeable polyamide membranes in a microfluidic chip via interfacial polycondensation. 

FIGURE 53.26 Microfluidic chip interfaced to an antosampler and to an ESI-TOF-MS detection system, (a) Schematic diagram of the total system. The chip comprises an enzyme microreactor/preconcentrator, a CE separation channel, and a capillary nanoESI-MS interface, (b) Tandem mass spectra of 2D-gel-isolated proteins from Neisseria meningitidis. (Reprinted from Li, J., et al., Pwteomics, 1,975-986,2001. Copyright 2001. With... 

An industrial batch reactor has neither an inflow nor an outflow of reactants or products while the reaction is being carried out. Batch reactions can be carried out in droplet microreactors, where nanoliters of fluid are individually manipulated using techniques such as electrowetting on dielectric (EWOD) and surface tension control. Semibatch reactors are used in cases where a by-product needs to be removed continuously and to cany out exothermic batch reactions where a reactant has to be added slowly. Microfluidics allows precise control of concentration and temperature, which allows batch and semibatch reactions to be carried out in a continuous manner. Figure 1 shows the general components of a simple industrial-reactor semp, compared with a laboratory-scale setup to carry out a reaction with microfluidic chips. 

In 1997, Harrison and coworkers reported on the synthesis of an azobenzene compound in microfluidic channels [37] for the purpose of combinatorial synthesis. The azo coupling of N,N-dimethylaniline and 4-nitrobenzene diazonium tetrafluor-oborate (Scheme 4.17) was carried out in a Pyrex microreactor driven by electro-osmotic flow. A few years later, Hisamoto et al. described a phase transfer diazo coupling reaction carried out in a microfluidic chip [38]. By providing a huge liquid-liquid interface between a solution of 5-methylresorcinol dissolved in ethyl acetate and an aqueous solution of 4-nitrobenzenediazonium tetrafluoroborate (Scheme 4.18), 100% conversion within a 2.3 s residence time was achieved. In contrast to macroscale experiments, the reaction could be accelerated and the formation of unwanted precipitates and bisazo side products was successfully suppressed. 

A different kind of nucleophilic aromatic substitution reaction, namely cyanation reactions, was described by Kitamura and coworkers [49]. Thqr investigated the photocyanation of pyrene by mixing an aqueous solution of NaCN and a propylene carbonate solution of pyrene and 1,4-dicyanobenzene in Y-shaped microfluidic chips made of polymers (Scheme 4.26). Since the reaction takes place at the oil-water interface, an increase in interfadal area was a major driver for employing microreactors. 

Microreactor systems have since evolved from basic, single-step chemical reactions to more complicated multistep processes. Beider et al. (2006) claim to have made the first example of a microreactor that integrated synthesis, separation, and analysis on a single device [15]. The microfluidic chip fabricated from fused silica (as seen in Figure 1.4) was used to apply microchip electrophoresis to test the enantioselective biocatalysts that were created. The authors reported a separation of enantiomers within 90 s, highlighting the high throughput of such devices. 

In the first instance, research focused on investigating if the fluorination step could be conducted within microreactors. Steel [47] used a microfluidic chip [channel dimensions, 300 pm (wide) x 50 pm (deep)], where a solution of mannose triflate (44) in anhydrous acetonitrile is reacted with a premade complex from [ F] KF, Kryptofix 2.2.2 and K2CO3 in acetonitrile. They reported a 40% conversion for the radiolabeling reaction [(44) to (45)] when a residence time of 2 min was used. 

The cost of capillaries are much cheaper than microfluidic chips, hence they have been widely used in fabrication of microreactors. 

Peterson, D.S., Rohr, T., Svec, F., Frechet, J. M.J., Enzymatic microreactor-on-a-chip Protein mapping using trypsin immobilized on porous polymer monoliths molded in channels of microfluidic devices. Anal. Chem. 2002, 74(16), 4081M088. 

Microfabrication technology used to manufacture microreactors also introduces many advantages, most notably the ability to rapidly and cheaply mass-produce devices. The low cost of microfabricated devices makes it possible for these devices to be disposable, a characteristic desirable for many medical applications. Rapid scale-up of production by operating many microreactors in parallel can also be accomplished. Microfabrication also presents the opportunity for complete systems in a single monolithic device or systems on a chip as microreactors are incorporated with chemical sensors and analysis devices, microseparation systems, microfluidic components, and/or microelectronics. 

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