The intensification of rapid reactions in multiphase systems using slug flow in capillaries

A multiphase microreactor based upon the use of slug flow through a narrow channel has been developed. The internal circulation, which is stimulated within the slugs by their passage along the channel, is responsible for a large enhancement in the interfacial mass transfer and the reaction rate. Mass transfer performance data has been obtained for a glass chip-based reactor in a 380 microm wide channel by monitoring the extraction of acetic acid from kerosene slugs as they moved along the reactor channel. Finally, the data was compared with that provided from other inter-phase contacting techniques.     

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.     

A Hantzsch synthesis of 2-aminothiazoles performed in a heated microreactor system

This paper presents the first example known to the authors of a heated organic reaction performed on a glass microreactor under electro-osmotic flow control. The experiments consisted of the preparation of a series of 2-aminothiazoles by means of a Hantzsch reaction of ring-substituted 2-bromoacetophenones and 1-substituted-2-thioureas carried out in microchannels, with the aim of investigating the generic utility of the reactor in carrying out analogue reactions. The reactions were performed on T-design microchips etched into a thin borosilicate glass plate and sealed over with a thick borosilicate top plate containing reservoirs. The mobility of the reagents and products was achieved using electro-osmotic flow (EOF), with the driving voltages being generated by a computer-controlled power supply. During the experiments the T-shaped chip was heated at 70 C using a Peltier heater, aligned with the channels and the heat generated by this device was applied to the lower plate. The degree of conversion was quantified by LC-MS using UV detection by comparison with standard calibration curves for starting materials and final products. In all cases, conversions were found to be similar or greater than those found for equivalent macro scale batch syntheses, thus illustrating the potential of this heated microreactor system to generate a series of compounds which contain biologically active molecules.     

An investigation of electroosmotic flow and pressure pumped luminol chemiluminescence detection for cobalt analysis in a miniaturised total analytical system

The luminol chemiluminescence reaction has been investigated for the determination of cobalt in a planar glass micro reactor. Reagents were mobilised within an etched glass chip with 200 microm wide channels using either electrically driven flow with voltages below 200 V cm(-1) or negative pressure pumping. Surfactants were used to assist mobilisation of the luminol for electrically driven flow and this also increased the chemiluminescence intensity in that system. A calibration over seven orders of magnitude was achieved for cobalt(II) nitrate with the negative pressure pumping system, and the limit of detection at the 95% confidence level was 3 x 10(-11) mol l(-1). The limit of detection for the electrokinetic flow was 4 x 10(-11) mol l(-1) and the linear range was between 10(-10) to 10(-6) mol l(-1). The advantages and disadvantages of both mobilisation methods are discussed for this reaction.     

Surface effects in the esterification of 9-pyrenebutyric acid within a glass micro reactor

Surface phenomena are an important contribution to the "chip effect", leading to higher yields and shorter reaction times, as demonstrated for the acid-catalysed esterification of 9-pyrenebutyric acid within a glass fabricated micro reactor.     

Polymerisation of Butyl acrylate in the two Phase Slug Flow Regime of Parallel Microcapillary Reactors

Summary: The potential and problems of conducting a free radical polymerisation in parallel capillary reactors are presented. By operating in the so-called slug flow regime of immiscible liquid-liquid flow, one can achieve perfectly uniform residence times which are inaccessible using single phase flow. The excellent performance available in microreactors can be exploited for higher throughputs through the simple expedient of numbering-up, i.e. operation of multiple similar reactors in parallel under identical hydrodynamic conditions. In practice this approach often comes to grief on the coupling between hydrodynamics and chemical reaction, for example due to the strong influence of polymerisation on viscosity. Rigorous modeling reveals that the operating conditions sought are actually unstable. Furthermore, the uniformity of flow distribution between parallel capillaries was found to be very sensitive to the manufacturing tolerances of the capillaries used in the presence of polymerisation. Two strategies for resolving such problems are discussed. In the first case, coupling between reaction and the flow distribution is suppressed by a sufficiently high pressure drop upstream of the temperature regulated reactor segments. The pressure drop necessary to achieve this decoupling was estimated by the model. An alternative technique involves an appropriately inexpensive flow control system for each individual capillary. Since commercially available microvalves and flow measurement equipment are too costly for parallelisation purposes, it is necessary to develop new components to fulfill these functions. An optical monitoring technique is presented that meets both the technical and economic criteria, and which can be readily combined with recently developed new micro valves. 1     

A microfluidic protease activity assay based on the detection of fluorescence polarization

This article describes a fluorescence polarization (FP)-based protease assay on a microfluidic device that is compatible with fast and reproducible analyses of protease activities. The optical systems were arranged for simultaneously measuring fluorescence intensities of vertical and horizontal polarization planes, and the binding of tetramethylrhodamine (TMR) labeled-biotin with streptavidin was utilized for optimizing FP detection in continuously flowing solutions within 74-μm wide, 12-μm deep microchannels of a glass chip. In developing off-chip FP-based assays for proteinase K, trypsin, papain and elastase, TMR conjugated-casein protein (TMR-α-casein) was employed as a universal substrate. After optimization of the hydrodynamic flow control to allow complete mixing of TMR-α-casein and short proteolysis time as possible, and of buffer composition to minimize protein sticking problems, the developed assay was transferred to the microfluidic chip by monitoring FP changes of TMR-α-casein in the main microchannel. The results indicate that the proposed device would serve as an integrated microfluidic platform with automated injection of reacting species, diffusion-controlled mixing, reaction and detection for protease activities without the need to separate the products.     

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.     

The generation of concentration gradients using electroosmotic flow in micro reactors allowing stereoselective chemical synthesis

The stereoselective control of chemical reactions has been achieved by applying electrical fields in a micro reactor generating controlled concentration gradients of the reagent streams. The chemistry based upon well-established Wittig synthesis was carried out in a micro reactor device fabricated in borosilicate glass using photolithographic and wet etching techniques. The selectivity of the cis (Z) to trans (E) isomeric ratio in the product synthesised was controlled by varying the applied voltages to the reagent reservoirs within the micro reactor. This subsequently altered the relative reagent concentrations within the device resulting in Z/E ratios in the range 0.57-5.21. By comparison, a traditional batch method based on the same reaction length, concentration, solvent and stoichiometry (i.e., 1.0:1.5:1.0 reagent ratios) gave a Z/E in the range 2.8-3.0. However, when the stoichiometric ratios were varied up to ten times as much, the Z/E ratios varied in accordance to the micro reactor i.e., when the aldehyde is in excess, the Z isomer predominates whereas when the aldehyde is in low concentrations, the E isomer is the more favourable form. Thus indicating that localised concentration gradients generated by careful flow control due to the diffusion limited non-turbulent mixing regime within a micro reactor, leads to the observed stereo selectivity for the cis and trans isomers.     

Nonthermal Atmospheric Pressure Plasma for Methylene Blue Dye Decolorization by Using Slug Flow Reactor System

Plasma Chemistry and Plasma Processing - Non-equilibrium pulsed discharge plasma using a gas–liquid slug flow in a glass column as a plasma reactor is developed and applied to methylene blue...     

Fully automated continuous flow synthesis of 4,5-disubstituted oxazoles

[Structure: see text] A multipurpose mesofluidic flow reactor capable of producing gram quantities of material has been developed as an automated synthesis platform for the rapid on-demand synthesis of key building blocks and small exploratory libraries. The reactor is configured to provide the maximum flexibility for screening of reaction parameters that incorporate on-chip mixing and columns of solid supported reagents to expedite the chemical syntheses.     

Electric field-induced mobilisation of multiphase solution systems based on the nitration of benzene in a micro reactor

This paper describes the electric field-induced flow characteristics of multiphase solutions in a micro reactor device using the nitration of benzene as a model process. Photolithographic and wet etching techniques were used to fabricate the micro reactor (channels, 200 microns id, 100 microns deep) in a borosilicate glass substrate. The results focus specifically on the flow parameters of reagents/reactants (i.e., voltage, solution concentration and pH ranges and current-voltage relationships) used in this study. The benzene was introduced and mobilised by electroosmotic flow (EOF), as a microemulsion using an appropriate surfactant (sodium dodecyl sulfate), whilst the nitronium ions, produced in situ from mixed H2SO4-HNO3 (the nitrating agent), underwent electrophoretic-induced (electrokinetic) mobility. A co-surfactant, butan-1-ol, was used owing to (a) its relative solubility in the aqueous surfactant solution, (b) its ability to aid the solubilization of benzene, (c) the provision of a water-rich (oil-in-water) rather than oil-rich (water-in-oil) microemulsion system and (d) its lack of significant adverse effects on the EOF. The optimum conditions used for the nitration of benzene within the micro reactor were a run of the microemulsion as main reagent stream, then three 30 s segmented injections of mixed acid, with a 5 s push of the microemulsion into the system after each injection, and then a 60 s stopped-flow reaction time before driving reaction product segments to a collection reservoir.     

Microfluidic chip accomplishing self-fluid replacement using only capillary force and its bioanalytical application

A polymer microfluidic chip accomplishing automated sample flow and replacement without external controls and an application of the chip for bioanalytical reaction were described. All the fluidic operations in the chip were achieved by only natural capillary flow in a time-planned sequence. For the control of the capillary flow, the geometry of the channels and chambers in the chip was designed based on theoretical considerations and numerical simulations. The microfluidic chip was made by using polymer replication techniques, which were suitable for fast and cheap fabrication. The test for a biochemical analysis, employing an enzyme (HRP)-catalyzed precipitation reaction, exhibited a good performance using the developed chip. The presented microfluidic method would be applicable to biochemical lab-on-a-chips with integrated fluid replacement steps, such as affinity elution and solution exchange during biosensor signaling.     

在微流控芯片上合成对甲氧基苯甲醛肟

本文用负压进样的方法, 在自制的玻璃微流控芯片中进行了对甲氧基苯甲醛和盐酸羟胺合成对甲氧基苯甲醛肟的相转移反应. 测定了不同反应时间的产率, 并与常规方法进行了比较. 讨论了相接触面积和塞流对产率的影响.     

集成核酸提取的实时荧光PCR微全分析系统

集成核酸提取的实时荧光PCR微全分析系统将核酸提取、PCR扩增与实时荧光检测进行整合,在同一块微流控芯片上实现了核酸分析过程的全自动和全封闭,具有试剂用量少、分析速度快、操作简便等优点。本研究采用微机械加工技术制作集成核酸提取微流控芯片的阳极模,使用组合模具法和注塑法制作具有3D通道的PDMS基片,与玻璃基底通过等离子体键合封装成集成核酸提取芯片。构建了由微流体速度可调节(0~10 mL/min)的驱动控制装置、温控精度可达0.1℃的TEC温控平台、CCD检测功能模块等组成的微全分析系统。以人类血液裂解液为样品,采用硅胶膜进行芯片上核酸提取。系统根据设置好的时序自动执行,以2 mL/min的流体驱动速度完成20μL裂解液上样、清洗;以1 mL/min的流体驱动速度完成DNA洗脱,抽取PCR试剂与之混合注入到反应腔。提取的基因组DNA以链上内参基因GAPDH为检测对象,并以传统手工提取为对照,在该系统平台上进行PCR扩增和熔解曲线分析实验。片上PCR扩增结果显示,扩增曲线明显,Ct值分别为25.3和26.9。扩增产物进行熔解曲线分析得到的熔解温度一致,均为89.9℃。结果表明,此系统能够自动化、全封闭的在微流控芯片上完成核酸提取、PCR扩增与实时定量分析。     

Development of a new casting method to fabricate U–Zr alloy containing minor actinides

Metal fuel slugs of U–Zr alloys for a sodium-cooled fast reactor (SFR) have conventionally been fabricated using an injection casting method. However, casting alloys containing volatile radioactive constituents, such as Am, are problematic in a conventional injection casting method. As an alternative fabrication method, low pressure gravity casting has been developed. Casting soundness, microstructural characteristics, alloying composition, density, and fuel losses were evaluated for the following as-cast fuel slugs: U–10 wt% Zr, U–10 wt% Zr–5 wt% RE, and U–10 wt% Zr–5 wt% RE–5 wt% Mn. The U and Zr contents were uniform throughout the matrix, and impurities such as oxyen, carbon, and nitrogen satisfied the specification of total impurities less than 2,000 ppm. The appearance of the fuel slugs was generally sound, and the internal integrity was shown to be satisfactory based on gamma-ray radiography. In a volatile surrogate casting test, the U–Zr–RE–Mn fuel slug showed that nearly all of the manganese was retained when casting was done under an inert atmosphere.     

High-efficiency aminocarbonylation by introducing CO to a pressurized continuous flow reactor

Halogenated aryl carboxylic acids were efficiently converted to the corresponding dicarboxylic acid monoamides by a one-step Pd-catalyzed aminocarbonylation in a micro/meso fluidic continuous flow reactor (X-Cube) operated at high pressure and high temperature with CO gas introduction. Reaction parameters (solvent, base, catalyst, pressure, temperature) were rapidly optimized in the reactions, which required less than 2 min. The method gave improved results over comparable batch techniques and is also suited to automated parallel syntheses of compound libraries.     

Integration of immobilized trypsin bead beds for protein digestion within a microfluidic chip incorporating capillary electrophoresis separations and an electrospray mass spectrometry interface

A microfluidic device is described in which an electrospray interface to a mass spectrometer is integrated with a capillary electrophoresis channel, an injector and a protein digestion bed on a monolithic substrate. A large channel, 800 microm wide, 150 microm deep and 15 mm long, was created to act as a reactor bed for trypsin immobilized on 40-60 microm diameter beads. Separation was performed in channels etched 10 microm deep, 30 microm wide and about 45 mm long, feeding into a capillary, attached to the chip with a low dead volume coupling, that was 30 mm in length, with a 50 microm i.d. and 180 microm o.d. Sample was pumped through the reactor bed at flow rates between 0.5 and 60 microL/min. The application of this device for rapid digestion, separation and identification of proteins is demonstrated for melittin, cytochrome c and bovine serum albumin (BSA). The rate and efficiency of digestion was related to the flow rate of the substrate solution through the reactor bed. A flow rate of 1 or 0.5 microL/min was found adequate for complete consumption of cytochrome c or BSA, corresponding to a digestion time of 3-6 min at room temperature. Coverage of the amino acid sequence ranged from 92% for cytochrome c to 71% for BSA, with some missed cleavages observed. Melittin was consumed within 5 s. In contrast, a similar extent of digestion of melittin in a cuvet took 10-15 min. The kinetic limitations associated with the rapid digestion of low picomole levels of substrate were minimized using an integrated digestion bed with hydrodynamic flow to provide an increased ratio of trypsin to sample. This chip design thus provides a convenient platform for automated sample processing in proteomics applications.     

纳米TiO_2光催化芳香醛的缩醛反应研究

本文以纳米TiO2为催化剂,UV-LED（=365 nm）为紫外光源,在自制的恒温石英玻璃光催化反应器中成功实现了芳香醛的非均相光催化缩醛反应.以乙醇等作为溶剂和反应物,快速高效和高选择性地合成了苯甲醛二乙基缩醛（BDA）.在光强为0.6 mw/cm2,苯甲醛初始浓度为0.05 mol/L,催化剂TiO2（P25）用量为5.0 g/L,反应时间为15 min的条件下,苯甲醛二乙缩醛的产率可达99.86%.研究表明,氧气的存在是顺利发生光催化缩醛反应的重要条件.反应液pH值、醇溶剂种类及苯环对位取代基等因素都会对光催化缩醛反应速率和产率产生影响.pH值及醇溶剂的pKa越小,缩醛反应速率越快.苯环上对位取代基会抑制缩醛反应的进行,其中供电子取代基相对吸电子取代基更有利于缩醛反应进行.结合实验,提出了光催化缩醛反应的机理.     

Microwave heating of heterogeneously catalysed Suzuki reactions in a micro reactor

The Suzuki cross-coupling reaction of aryl halides with phenylboronic acid to form biaryls has been used to illustrate the development of a microwave based technique capable of delivering heat locally to a heterogeneous Pd-supported catalyst located within a micro reactor device. A 10-15 nm gold film patch, located on the outside surface of the base of a glass micro reactor, was found to efficiently assist in the heating of the catalyst when irradiated with 5-7 W of microwave power at 2.45 GHz. Using a hydrodynamically pumped system, reactant-catalyst contact times of less than 60 s were found to give conversions for different substrates which were in the range 50-99%. Two methods of loading catalysts into the micro reactor were investigated which required either 1.5 or 6 mg of material.