The preparation of a series of nitrostilbene ester compounds using micro reactor technology

The synthesis of stilbene esters using Wittig chemistry has been used to illustrate the generic diversity micro reactors offer in terms of chemical control and rapid method development. The micro reactor consisted of a 'T' design based on channel geometries 200 microns wide and 100 microns deep, etched into borosilicate glass and sealed with a borosilicate top plate using a thermal bonding technique. The movement of the reagent and products was achieved using electroosmotic flow (EOF), assisted by the incorporation of micro porous silica frits within the micro-channels to allow accurate solution control. To optimise the operating conditions methyl 4-formylbenzoate, premixed with sodium methoxide, was reacted with 2-nitrobenzyl-triphenylphosphonium bromide in dry degassed MeOH using flow conditions for both reagents of 0.40 microL min-1 for 20 min. A product yield of 70% (2:1 reaction stoichiometry with the aldehyde in excess) was obtained representing a 10% increase compared with the traditional batch synthesis. To demonstrate the capability of micro reactors to perform atom efficient synthesis a series of experiments based on an injection methodology (optimised to 30 s) were performed in the micro reactor at 1:1 stoichiometry resulting in a yield of 59%. Finally, the capability of micro reactors to perform a series of analogue reactions was investigated. The yields for a further three aldehydes indicated that the technology will be suitable for the development of automated device to support the generation of combinatorial libraries and rapid high throughput synthetic methods.     

Substantial rate enhancements of the esterification reaction of phthalic anhydride with methanol at high pressure and using supercritical CO2 as a co-solvent in a glass microreactor

The esterification reaction of phthalic anhydride with methanol was performed at different temperatures in a continuous flow glass microreactor at pressures up to 110 bar and using supercritical CO(2) as a co-solvent. The design is such that supercritical CO(2) can be generated inside the microreactor. Substantial rate enhancements were obtained, viz. a 53-fold increase was obtained at 110 bar and 60 degrees C. Supercritical CO(2) as a co-solvent gave rise to a 5400-fold increase (both with respect to batch experiments at 1 bar at the same temperature).     

Preliminary studies into the direct interfacing of a microreactor to a gas chromatographic instrument

The paper reports on a preliminary study into the coupling of a microreactor to a GC-FID, using a standard GC needle as the interface between the microreactor and the injection port of a conventional GC. Using the injection needle as the ground electrode, electroosmotic flow was used to control the injection of reagent/sample into the GC. Photolithographic and wet etching techniques were used to fabricate the microreactor (channels 200 microns id, 100 microns deep) in a borosilicate glass substrate. The results of the effects of voltage and injection times on the response signal are presented. The critical obstacles to overcome were the backpressure posed by the carrier gas disrupting the liquid flow in the channels and reservoirs of the microreactor and the need to thermally insulate the microreactor, to prevent evaporation of solvent and reagents from the device.     

Pyrolysis of arylglycol-β-propylphenyl ether lignin model in the presence of borosilicate glass fibers. : I. Pyrolysis reactions of β-ether compounds

Two β-aryl ether type model compounds, guaiacylglycol- and veratrylglycol-β-propylphenyl ethers, were copyrolyzed with borosilicate glass fibers. The results provided a better understanding of the effect of copyrolysis with the fibers on the yields of lignin-derived products from lignocellulosics.

The observed products indicated the following reactions occurring in the models; (1) cleavage of the C-aromatic ring bond, (2) cleavage of the β-ether bond, (3) cleavage of the C-Cβ bond, (4) ,β-dehydration, and (5) demethylation, and others. Of these reactions, reactions (1), (2) and (4) were the main pyrolysis reactions and fully explained the increase in the total yield of lignin-derived pyrolysis products from Japanese red pine (Pinus densiflora Sieb. et Zucc.) in the presence of borosilicate glass fibers. Reaction (1) was a particularly characteristic reaction in copyrolysis with the fibers. Important reactions relating to the increase in the total yield of lignin-derived pyrolysis products were reproduced on the models used.     

Alkyllithium Compounds Bearing Electrophilic Functional Groups: A Flash Chemistry Approach

Flash chemistry based on flow microreactor systems allowed alkyllithiums bearing electrophilic functional groups to be successfully generated and used for subsequent reactions. The series of reactions with high reactivity was achieved by extremely accurate control over residence time in a controlled and selective manner.     

Removal of iron (III) oxide particles from a quartz plate by liquid flow

The detachment of submicron particles of iron (III) oxide from a quartz plate in aqueous solutions was investigated by using a well-defined flow of electro-osmosis in comparison with the ordinary flow of water without electrokinetic effect. A rectangular quartz cell was used for removal experiments. Zeta potentials of the particles and the plate were determined by electrophoresis and electro-osmosis, respectively. When the iron (III) oxide particles adhering to the quartz plate were removed by the electro-osmotic flow or the ordinary (Poiseuille) flow, the removal efficiency increased with increasing hydrodynamic force. The removal efficiency by electro-osmotic flow was almost the same as that by ordinary flow under the condition of the same magnitude of applied hydrodynamic force. The values of volume flow rate for the removal efficiency of 0.5 for the electro-osmotic flow was extremely small compared with that for the ordinary flow, showing the effectiveness of particle removal by electrokinetic effect of electro-osmosis. The kinetic analysis of the particle removal process showed that it was characterized by two different rate constants, the rate constant of the rapid process and that of the slow process. The rate constant of slow process increased with increasing electro-osmotic velocity. This shows that the electro-osmotic flow acts as a mechanical force to overcome the energy barrier in the removal process. The rate constant increased with increasing surfactant concentration and this trend became more noticeable as electro-osmotic velocity increased. It is concluded from this result that the effect of surfactant on particle removal is enhanced by the mechanical force in removal processes.     

Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system

This paper presents the synthesis of combinatorial libraries performed on a single-channel glass micro reactor under hydrodynamic flow control. The experiments were carried out in a non-well based micro chip and consisted of the preparation of libraries of pyrazoles by means of a Knorr reaction of 1,3-dicarbonyl compounds with hydrazines. The aim of this work is to investigate the capabilities of an automated micro reactor based system to synthesise sequentially multiple analogue reactions. Small slugs of reactants were introduced automatically by an autosampler in a serpentine-etched glass chip. The mobility of the reagents and products was achieved using hydrodynamic driven flow. Reaction slug dilution and UV slug detection took place at the outlet. A sample of the slug was analysed by using an on-line LC-UV-MS system. The degree of conversion was quantified using the UV signal and comparing with standards of starting materials and final products. After the LC-UV-MS analysis, the automated system proceeds to inject the slugs to carry out the next reaction programmed. The results suggest that the micro reactor system is capable of repeating the process of injection, mixing and reaction in an automated manner as many times as required.     

A Flow Microreactor System Enables Organolithium Reactions without Protecting Alkoxycarbonyl Groups

A flow microreactor system consisting of micromixers and microtube reactors provides an effective tool for the generation and reactions of aryllithiums bearing an alkoxycarbonyl group at para‐, meta‐, and ortho‐positions. Alkyl p‐ and m‐lithiobenzoates were generated by the I/Li exchange reaction with PhLi. The Br/Li exchange reactions with sBuLi were unsuccessful. Subsequent reactions of the resulting aryllithiums with electrophiles gave the desired products in good yields. On the other hand, alkyl o‐lithiobenzoates were successfully generated by the Br/Li exchange reaction with sBuLi. Subsequent reactions with electrophiles gave the desired products in good yields.     

PDMS-glass hybrid microreactor array with embedded temperature control device. Application to cell-free protein synthesis

A microreactor array was developed which enables high-throughput cell-free protein synthesis. The microreactor array is composed of a temperature control chip and a reaction chamber chip. The temperature control chip is a glass-made chip on which temperature control devices, heaters and temperature sensors, are fabricated with an ITO (indium tin oxide) resistive material. The reaction chamber chip is fabricated by micromolding of PDMS (polydimethylsiloxane), and is designed to have an array of reaction chambers and flow channels for liquid introduction. The microreactor array is assembled by placing the reaction chamber chip on the temperature control chip. The small thermal mass of the reaction chamber resulted in a short thermal time constant of 170 ms for heating and 3 s for cooling. The performance of the microreactor array was examined through the experiments of cell-free protein synthesis. By measuring the fluorescence emission from the products, it was confirmed that GFP (Green Fluorescent Protein) and BFP (Blue Fluorescent Protein) were successfully synthesized using Escherichia coli extract.     

Product selectivity control induced by using liquid-liquid parallel laminar flow in a microreactor

Product selectivity control based on a liquid-liquid parallel laminar flow has been successfully demonstrated by using a microreactor. Our electrochemical microreactor system enables regioselective cross-coupling reaction of aldehyde with allylic chloride via chemoselective cathodic reduction of substrate by the combined use of suitable flow mode and corresponding cathode material. The formation of liquid-liquid parallel laminar flow in the microreactor was supported by the estimation of benzaldehyde diffusion coefficient and computational fluid dynamics simulation. The diffusion coefficient for benzaldehyde in Bu(4)NClO(4)-HMPA medium was determined to be 1.32 × 10(-7) cm(2) s(-1) by electrochemical measurements, and the flow simulation using this value revealed the formation of clear concentration gradient of benzaldehyde in the microreactor channel over a specific channel length. In addition, the necessity of the liquid-liquid parallel laminar flow was confirmed by flow mode experiments.     

Adhesion of nylon particles to a quartz plate in an aqueous solution and their removal by electro-osmosis

Particle removal by electro-osmotic flow was investigated by comparison with the removal by ordinary flow of water without electrokmetic effect. The relationship between adhesion and removal of particles in terms of force acting on the particle was also discussed. Experiments were carried out in an aqueous solution using nylon particles and a quartz plate. The adhesive force,F _T, for the particles which adhered to the quartz plate in secondary minima in the total potential energy of interaction versus separation distance curves was calculated. Particle removal experiments were carried out applying electro-osmotic and Poiseuille flows. The hydrodynamic force,F _d, which was required to remove particles from the plate was estimated using flow velocities. The effectiveness of electro-osmotic flow on particle removal was larger than that of Poiseuille flow. In the particle removal by electro-osmotic flow, the minimum of the ratioF _d/F _t for particle removal was found to be 50 and the ratio for removal efficiency of 0.5 was about 140.     

硼硅酸盐生物玻璃表面多层结构的形成机理

描述了硼硅酸盐生物活性玻璃在体外含磷溶液中的转变过程,并采用XRD、SEM和EDS对反应产物的微观结构、形貌和成分进行了分析。结果显示,产物为多层结构,由羟基磷灰石和无定型SiO₂层交替排列而成。此外,提出了一个定性模型来解释层状结构的形成机制。研究证实,反应动力学及反应产物的微观结构主要取决于生物活性玻璃的成分和含磷溶液的浓度。     

Monitoring of chemical reactions within microreactors using an inverted Raman microscopic spectrometer

An inverted Raman microscope spectrometer has been used to profile the spatial evolution of reactant and product concentrations for a chemical reaction within a microreactor operating under hydrodynamic flow control. The Raman spectrometer was equipped with a laser source at wavelength of 780 nm, confocal optics, a holographic transmission grating, and a charge-coupled device (CCD) detector. The microreactor consisted of a T-shaped channel network etched within a 0.5 mm thick glass bottom plate that was thermally bonded to a 0.5 mm thick glass top plate. The ends of the channel network were connected to reagent reservoirs that were linked to a syringe pump for driving the solutions by hydrodynamic pumping within the channels. The microchannels were 221 micro m wide and 73 micro m deep. The synthesis of ethyl acetate from ethanol and acetic acid was investigated as a model system within the microreactor as Raman scattering bands for each reactant and product species were clearly resolved. Raman spectral intensities of each band were proportional to concentration for each species and hence all concentrations could be quantitatively measured after calibration. By scanning specific Raman bands within a selected area in the microchannel network at given steps in the X-Y plane, spatially resolved concentration profiles were obtained under steady-state flow conditions. Under the flow conditions used, different positions within the concentration profile correspond to different times after contact and mixing of the reagents, thereby enabling one to observe the time dependence of the product formation. Raman microscopy provides a useful complementary technique to UV/VIS absorbance and fluorescence methods for the in situ monitoring and analysis of chemical reaction species having their lowest S(0)-S(1) absorption bands too far in the UV to be of use, due to their probable overlap with the bands from other reactant, product and solvent molecules.     

Improved efficiency and product selectivity in the photo-Claisen-type rearrangement of an aryl naphthylmethyl ether using a microreactor/flow system

Ultraviolet (UV) irradiation of 2-[(2,4,6-trimethylphenoxy)methyl]-1-(methoxycarbonyl)naphthalene promotes a photochemical reaction that gives a cyclohexa-2,4-dienone product arising from a photo-Claisen-type ortho-rearrangement and a phenol derivative arising from a meta-rearrangement, along with 1-methoxycarbonyl-2-methylnaphthalene and 1,2-bis[1-(methoxycarbonyl)naphthalen-2-yl]ethane. When this process is carried out in a microreactor/flow system, its efficiency is dramatically enhanced and selectivity of products is improved. The effects on efficiency and product selectivity caused by the microreactor/flow system are attributed to more efficient light absorption and the suppression of secondary reactions.     

Generation and reactions of oxiranyllithiums by use of a flow microreactor system

A flow microreactor system consisting of micromixers and microtubes provides an effective reactor for the generation and reactions of aryloxiranyllithiums without decomposition by virtue of short residence time and efficient temperature control. The deprotonation of styrene oxides with sBuLi can be conducted by using the flow microreactor system at -78 or -68 °C (whereas much lower temperatures (< -100 °C) are needed for the same reactions conducted under macrobatch conditions). The resulting α-aryloxiranyllithiums were allowed to react with electrophiles in the flow microreactor system at the same temperature. The sequential introduction of various electrophiles onto 2,3-diphenyloxiranes was also achieved by using an integrated flow microreactor, which serves as a powerful system for the stereoselective synthesis of tetrasubstituted epoxides.     

Multistage Microfluidic Platform for the Continuous Synthesis of III–V Core/Shell Quantum Dots

We present a fully continuous chip microreactor‐based multistage platform for the synthesis of quantum dots with heterostructures. The use of custom‐designed chip reactors enables precise control of heating profiles and flow distribution across the microfluidic channels while conducting multistep reactions. The platform can be easily reconfigured by reconnecting the differently designed chip reactors allowing for screening of various reaction parameters during the synthesis of nanocrystals. III–V core/shell quantum dots are chosen as model reaction systems, including InP/ZnS, InP/ZnSe, InP/CdS and InAs/InP, which are prepared in flow using a maximum of six chip reactors in series.     

Spurring radical reactions of organic halides with tin hydride and TTMSS using microreactors

Tributyltin hydride-mediated radical reactions of organic halides were successfully carried out in a continuous flow system using a microreactor. The reactions proceeded within a very short period of time, coupled with quickly decomposing radical initiators such as V-65 and V-70. The continuous flow reaction system was applied to gram scale synthesis of a key intermediate for furofuran lignans.     

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.     

High-throughput nanoparticle catalysis: partial oxidation of propylene

Partial oxidation of propylene was investigated at 1 atm pressure over Rh/TiO(2) catalysts as a function of reaction temperature, metal loading and particle size using high-throughput methods. Catalysts were prepared by ablating thin sheets of pure rhodium metal using an excimer laser and by collecting the nanoparticles created on the external surfaces of TiO(2) pellets that were placed inside the ablation plume. Rh nanoparticles before the experiments were characterized by transmission electron microscopy (TEM) by collecting them on carbon film. Catalyst evaluations were performed using a high-throughput array channel microreactor system coupled to quadrupole mass spectrometry (MS) and gas chromatography (GC). The reaction conditions were 23% C(3)H(6), 20% O(2) and the balance helium in the feed, 20,000 h(-1) GHSV and a temperature range of 250-325 degrees C. The reaction products included primarily acetone (AT) and to a lesser degree propionaldehyde (PaL) as the C(3) products, together with deep oxidation products COx.