Generation and Reaction of Functional Alkyllithiums by Using Microreactors and Their Application to Heterotelechelic Polymer Synthesis

Flow microreactors enabled the successful generation of various functional alkyllithiums containing electrophilic functional groups, as well as the use of these alkyllithiums in subsequent reactions. The high reactivity of these series of reactions could be achieved by the extremely accurate and selective control of residence time. Moreover, integrated flow microreactor systems could be used to successfully synthesize heterotelechelic polymers with two functionalities, one at each end, via a process involving controlled anionic polymerization initiated by functional alkyllithium compounds, followed by trapping reactions with difunctional electrophiles.     

Ionic-liquid supported oxidation reactions in a silicon-based microreactor

The combination of microfabrication and reaction engineering techniques has the potential to produce powerful microreactors. In a microreactor, aqueous buffers provide high electroosmatic mobility and no external pumping is required. While numerous reactions have been demonstrated to be highly efficient in microreactors, so far there has been no report on the epoxidation of cyclohexene in a microreactor. This is mainly due to the reduced solubility of cyclohexene in aqueous media. The greater volatility of cyclohexene leading to long reaction times is another reason. To improve the solubility of cyclohexene in the reaction buffer, a water soluble ionic-liquid 1-butyl-3-methylimidazolium tetrafluoroborate was used, also for the first time in microreactor work. In this letter, four different catalysts (i.e., manganese(II) and copper(II) complexes of Schiff and reduced Schiff bases) were synthesized and used for the oxidation reactions considered. The reactions were monitored by gas chromatography/mass spectrometry. The microreactor performance was evaluated by comparing with a conventional (batch scale) reaction. Catalytic activities and yields were found to be relatively high for the copper(II) complexes as compared with the conventional route.     

Difluoro-and Trifluoromethylation of Electron-Deficient Alkenes in an Electrochemical Microreactor

Electrochemical microreactors, which have electrodes integrated into the flow path, can afford rapid and efficient electrochemical reactions without redox reagents due to the intrinsic properties of short diffusion distances. Taking advantage of electrochemical microreactors, Kolbe electrolysis of di-and trifluoroacetic acid in the presence of various electron-deficient alkenes was performed under constant current at continuous flow at room temperature. As a result, di-and trifluoromethylated compounds were effectively produced in either equal or higher yields than identical reactions under batch conditions previously reported by Uneyamas group. The strategy of using electrochemical microreactor technology is useful for an effective fluoromethylation of alkenes based on Kolbe electrolysis in significantly shortened reaction times.     

Microreaction Technology for Synthetic Chemistry

Microreaction technology as an emerging tool for synthetic chemistry has been extensively applied in academic and industrial researches. Normally, synthetic chemists used to running reactions in the classical glassware for centuries are unfamiliar and unaccustomed to use microreaction technology for routine synthetic work. This review tries to give a general introduction of the capabilities of microreaction technology. After introducing the origin and history of microreaction technology, we review and discuss mainly several synthetic examples of high T‐P reactions, hazardous reactions, flash chemistry, polymerization, photochemistry, electrochemistry and multistep API's syntheses to demonstrate the capabilities of microreactors. A summary and perspectives on microreactor technology are also given in this paper. It is anticipated that more and more chemists will understand the capabilities and limitations of microreaction technology, and could work together with chemical engineers for the synergic development of chemistry and chemical engineering.     

A Teflon microreactor with integrated piezoelectric actuator to handle solid forming reactions

We present a general inexpensive method for realizing a Teflon stack microreactor with an integrated piezoelectric actuator for conducting chemical synthesis with solid products. The microreactors are demonstrated with palladium-catalyzed C-N cross-coupling reactions, which are prone to clogging microchannels by forming insoluble salts as by-products. Investigations of the ultrasonic waveform applied by the piezoelectric actuator reveal an optimal value of 50 kHz at a load power of 30 W. Operating the system at these conditions, the newly developed Teflon microreactor handles the insoluble solids formed and no clogging is observed. The investigated reactions reach full conversion in very short reaction times and high isolated yields are obtained (>95% yield).     

Microreactors as the new way of intensification of heterogeneous processes

Microstructure reactors (microreactors) in recent decades became one of the most actively studied subjects of the reaction equipment aimed at intensification of chemical processes and increase in their safety. It is not surprising because due to miniature dimensions of microstructures which do not exceed 2 mm microreactors contribute to minimization of the material at their production as well as raw material and energy in the process of exploitation. Moreover, due to acceleration of heat and mass transfer the productivity of equipment with microreactors in a range of cases is significantly higher than classical batch reactors applied in industry. The brief overview of the modern development and achievements of microreactor technology is given in this article by an example of heterogeneous reaction systems which are different by their nature and occur in different types of microreactors: phase-transfer catalysis, biocatalysis, and synthesis of nanoparticles. A special attention in the article is paid to the aspects of intensification of the considered processes because exactly the possibility of intensification makes microreactor technology attractive for the industry.     

Development of a multireactor microfluidic system for the determination of DNA using real-time polymerase chain reaction

A microfluidic system that allowed us to perform the real-time polymerase chain reaction (PCR) in a glass-silicon microchip containing nine 250-nL microreactors was developed and studied. The resulting high heating/cooling rates of a PCR mixture in a microreactor allowed us to optimize the amplification mode (1 min/cycle). The silicon surface of microreactors was successfully passivated. The resulting analytical system allowed us to measure the PCR kinetic curves in chip microreactors at a DNA concentration of ～5 × 10⁴ copies per microreactor. It was found that, if the PCR is performed in a microchip with real-time detection using the optimized amplification mode, the result can be obtained 13–14 min after the onset of reaction.     

Pigments with improved properties – microreaction technology as a new approach for synthesis of pigments –

Clariant, as an important pigment producer forces the investigation of new pigments with improved qualities and properties to fulfill the rising tomorrow's demands of customers. For these reasons, new production ways like microreaction technology are included. This paper focuses on results obtained in manufacturing pigments in a lab-scale microreactor as well as in a microreactor pilot plant. Investigations of the diazotation, azo-coupling and laking steps of pigments have shown not only the principle feasibility of these reactions in laboratory microreactors but also significant improvement of coloristic properties. The microreactor pilot plant, realized by the concept of numbering-up instead of conventional scaling-up process, allowed more detailed investigations of the complete azo-pigments synthesis under production conditions.     

Conformally anchoring nanocatalyst onto quartz fibers enables versatile microreactor platforms for continuous-flow catalysis

Continuous-flow microreactors offer increased reactivity and reusability via unique reaction pathways to address a wide range of practical nanocatalysis problems. However, only limited platforms exist to employ these microreactors for versatile nanocatalytic reactions. In this work, we conformally anchored nickel oxide(Ni O) nanosheets onto quartz fibers(QFs), which exhibited a high catalytic activity using the hydrogenation of 4-nitrophenol(4-NP) as a model reaction in a batch reaction study. More importantly, we demonstrated that fiber-based QF@Ni O composites(e.g., cotton, fabric, belt, felt) can be integrated as versatile platforms to develop microreactors for continuous-flow catalytic applications including hydrogenation reactions and dyecatalyzed degradation. This fiber-based three-dimensional(3 D) nanocatalyst architecture effectively drives continuous-flow catalytic reactions with unprecedented efficiency due to the easy diffusion of reactant molecules into the fibrous structure,allowing contact with catalytic active sites. Our approach to continuous-flow microreactor design uses surface hybridization as a guideline to immobilize nanocatalysts onto the QFs. These QF-based platforms, coupled with rational design, are expected to be applied to a wide range of nanocatalytic reactions.     

Indirect micromanipulation of single molecules in water-in-oil emulsion

Based on real-time observation and micromanipulation, analytical methods for single DNA molecules have been under development for some time. Precise manipulation, however, is still difficult because single molecules are too small for conventional techniques. We have developed a chemical reaction system that uses water droplets in oil as containers of materials. The water droplets can be manipulated by optical force. The manipulation of the water droplets permits the fusion of two selected droplets. This process corresponds to mixing of different samples. We designate this system as "w/o (water-in-oil emulsion) microreactor system", and each droplet can be thought of as a "microreactor". In this system, single molecules can be manipulated readily, as a molecule can be contained in a microm-sized microreactor. The microreactor utilizes extremely small quantities of samples, therefore, reactions are rapid, as diffusion times in the microreactor are very short. The manipulation technique of the microreactors based on optical force has been applied to induce fusion between microreactors loaded with DNA and YOYO, a fluorescent dye that binds to DNA. This fusion induced a rapid binding of YOYO.     

Automated Generation and Reactions of 3‐Hydroxymethylindoles in Continuous‐Flow Microreactors

An automated sequential approach for the generation and reactions of 3‐hydroxymethylindoles in continuous‐flow microreactors is described. Consecutive halogen–magnesium exchanges of four 3‐iodoindoles followed by addition to three aldehydes provided twelve 3‐hydroxymethylindoles in a multi‐microreactor setup. The synthetic flow strategy could be coupled with an in line continuous liquid–liquid extraction workup protocol for each reaction. Further elaboration of each of these indoles within the fluidic setup was achieved by acid‐catalysed nucleophilic substitutions with allyltrimethylsilane and methanol used as nucleophiles. Overall, a set of four 3‐iodoindoles was converted into thirty‐six indole derivatives by a range of transformations including iodo–magnesium exchange/electrophile trapping and acid‐catalysed nucleophilic substitution in a fully automated sequential fashion.     

Preparation of calcium alginate microgel beads in an electrodispersion reactor using an internal source of calcium carbonate nanoparticles

An electrodispersion reactor has been used to prepare calcium alginate (Ca-alginate) microgel beads in this study. In the electrodispersion reactor, pulsed electric fields are utilized to atomize aqueous mixtures of sodium alginate and CaCO3 nanoparticles (dispersed phase) from a nozzle into an immiscible, insulating second liquid (continuous phase) containing a soluble organic acid. This technique combines the features of the electrohydrodynamic force driven emulsion processes and externally triggered gelations in microreactors (the droplets) ultimately to yield soft gel beads. The average particle size of the Ca-alginate gels generated by this method changed from 412 +/- 90 to 10 +/- 3 microm as the applied peak voltage was increased. A diagram depicting structural information for the Ca-alginate was constructed as a function of the concentrations of sodium alginate and CaCO3 nanoparticles. From this diagram, a critical concentration of sodium alginate required for sol-gel transformation was observed. The characteristic highly porous structure of Ca-alginate particles made by this technique appears suitable for microencapsulation applications. Finally, time scale analysis was performed for the electrodispersion processes that include reactions in the microreactor droplets to provide guidelines for the future employment of this technique. This electrodispersion reactor can be used potentially in the formation of many reaction-based microencapsulation systems.     

Fabrication and characterization of high-temperature microreactors with thin film heater and sensor patterns in silicon nitride tubes

In this paper the fabrication and electrical characterization of a silicon microreactor for high-temperature catalytic gas phase reactions, like Rh-catalyzed catalytic partial oxidation of methane into synthesis gas, is presented. The microreactor, realized with micromachining technologies, contains silicon nitride tubes that are suspended in a flow channel. These tubes contain metal thin films that heat the gas mixture in the channel and sense its temperature. The metal patterns are defined by using the channel geometry as a shadow mask. Furthermore, a new method to obtain Pt thin films with good adhesive properties, also at elevated temperatures, without adhesion metal is implemented in the fabrication process. Based on different experiments, it is concluded that the electrical behaviour at high temperatures of Pt thin films without adhesion layer is better than that of Pt/Ta films. Furthermore, it is found that the temperature coefficient of resistance (TCR) and the resistivity of the thin films are stable for up to tens of hours when the temperature-range during operation of the microreactor is below the so-called "burn-in" temperature. Experiments showed that the presented suspended-tube microreactors with heaters and temperature sensors of Pt thin films can be operated safely and in a stable way at temperatures up to 700 degrees C for over 20 h. This type of microreactor solves the electrical breakdown problem that was previously reported by us in flat-membrane microreactors that were operated at temperatures above 600 degrees C.     

Thin Organic-Inorganic Anti-Fouling Hybrid-Films for Microreactor Components

Deposit formation and fouling in reactors for polymer production and processing especially in microreactors is a well-known phenomenon. Despite the flow and pressure loss optimized static mixers, fouling occurs on the surfaces of the mixer elements. To improve the performance of such parts even further, stainless steel substrates are coated with ultra-thin films which have low surface energy, good adhesion, and high durability. Perfluorinated organosilane (FOTS) films deposited via chemical vapor deposition (CVD) are compared with FOTS containing zirconium oxide sol-gel films regarding the prevention of deposit formation and fouling during polymerization processes in microreactors. Both film structures led to anti-adhesive properties of microreactor component surfaces during aqueous poly(vinylpyrrolidone) (PVP) synthesis. To determine the morphology and surface chemistry of the coatings, different characterization methods such as X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy as well as microscopic methods such as field-emission scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM) are applied. The surface free energy and wetting properties are analyzed by means of contact angle measurements. The application of thin film-coated mixing elements in a microreactor demonstrates a significant lowering in pressure increase caused by a reduced deposit formation.     

Digital Imaging-based Colourimetry for Enzymatic Processes in Transparent Liquid Marbles

Liquid marbles are a promising microreactor platform that recently attracts significant research interest owing to their ability to accommodate a wide range of micro reactions. However, the use of destructive and ex-situ methods to monitor reactions impairs the potential of liquid-marble-based microreactors. This paper proposes a non-destructive, in situ, and cost-effective digital-imaging-based colourimetric monitoring method for transparent liquid marbles, using the enzymatic hydrolysis of starch as an illustrative example. The colourimetric reaction between starch and iodine produces a complex that exhibits a dark blue colour. We found that the absorbance of red channel of digital images showed a linear relationship with starch concentration with high sensitivity and repeatability. This digital-imaging-based colourimetric method was used to study the hydrolysis of starch by α-amylase. The results show high accuracy and applicability of first-order kinetics for this reaction. The demonstration of digital-imaging-based colourimetry indicates the potential of liquid marble-based microreactors.     

Perspectives of heterogeneous process intensification in microreactors

Recent developments in microreactor technology basing on different types of heterogeneous reaction systems: phase transfer catalysis, biocatalysis, and synthesis of nanoparticles are reviewed. Special attention is focused on the intensification of processes in microreactors compared with traditional approaches, which makes microtechnique of great interest for industry.     

Bioproduction of Food Additives Hexanal and Hexanoic Acid in a Microreactor

Hexanal and hexanoic acid have number of applications in food and cosmetic industry because of their organoleptic characteristics. Problems like low yields, formation of unwanted by-products, and large quantities of waste in their traditional production processes are the reasons for developing new production methods. Biotransformation in a microreactor, as an alternative to classical synthesis processes, is being investigated. Because conditions in microreactors can be precisely controlled, the quality of the product and its purity can also be improved. Biocatalytic oxidation of hexanol to hexanal and hexanoic acid using suspended and immobilized permeabilized whole baker’s yeast cells and suspended and immobilized purified alcohol dehydrogenase (ADH) was investigated in this study. Three different methods for covalent immobilization of biocatalyst were analyzed, and the best method for biocatalyst attachment on microchannel wall was used in the production of hexanal and hexanoic acid.     

Rapid multistep synthesis of 1,2,4-oxadiazoles in a single continuous microreactor sequence

A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles from readily available arylnitriles and activated carbonyls in a single continuous microreactor sequence is described. The synthesis incorporates three sequential microreactors to produce 1,2,4-oxadiazoles in approximately 30 min in quantities (40-80 mg) sufficient for full characterization and rapid library supply.     

Microreactors as Tools for Synthetic Chemists—The Chemists' Round‐Bottomed Flask of the 21st Century?

Will microreactors replace the round‐bottomed flask to perform chemical reactions in the near future? Recent developments in the construction of microstructured reaction devices and their wide‐ranging applications in many different areas of chemistry suggest that they can have a significant impact on the way chemists conduct their experiments. Miniaturizing reactions offers many advantages for the synthetic organic chemist: high‐throughput scanning of reaction conditions, precise control of reaction variables, the use of small quantities of reagents, increased safety parameters, and ready scale‐up of synthetic procedures. A wide range of single‐ and multiphase reactions have now been performed in microfluidic‐based devices. Certainly, microreactors cannot be applied to all chemistries yet and microfluidic systems also have disadvantages. Limited reaction‐time range, high sensitivity to precipitating products, and new physical, chemical, and analytical challenges have to be overcome. This concept article presents an overview of microfluidic devices available for chemical synthesis and evaluates the potential of microreactor technology in organic synthesis.