Surface effects on homogeneous organic reactions in microreactors

SURFACE EFFECTS ON HOMOGENEOUS ORGANIC REACTIONS IN MICROREACTORS By Abhinav Jain (B.Tech (Chemical Engg.), National Institute of Technology Karnataka, India) Submitted to the Department of Chemical & Biomolecular Engineering in partial fulfillment of the requirements for the Master of Engineering in Chemical Engineering at the NATIONAL UNIVERSITY OF SINGAPORE August 2010 © National University of Singapore 2010. All rights reserved. Author…………………………………………………………………….................. Abhinav Jain Department of Chemical & Biomolecular Engineering August 19th, 2010 Certified by……………………………………………………………………………….......... Saif A. Khan Assistant Professor of Chemical & Biomolecular Engineering, Thesis Supervisor (National University of Singapore). Certified by………………………………………………………………………...................... Dr Levent Yobas Assistant Professor at Dept of Electronic & Computer Engineering, Thesis Supervisor (Hong Kong University of Science and Technology). To my grandfather Chain Sukh Das and my family for passing on immense knowledge and courage ii Acknowledgement The concept of one man army, one person solely moving a hill to bring a change or answer an unanswered question is long gone. As like most of us, I needed a team to compensate for my weaknesses and guide me in my research endeavor. This was my teamSupervisors: Dr Saif A. KHAN at the Department of Chemical and Biomolecular Engineeirng, National University of Singapore and Dr Levent YOBAS, formerly with A*STAR Institute of Microelectronics, Singapore. Thank you both for being amazing guides. Dr Khan; you have been a continuous source of inspiration and motivation for me. You ignored my blunders and look through to my intentions. Encouragement given by you to think more creatively and learn from mistakes cannot be substituted in my life. Dr Yobas; your motivation to explore fascinating world of microfabrication brought my thoughts to the real world. Mentors: Dr Md. Taifur Rahman, Singapore MIT Alliance and Dr Kang Tae Goo, A*STAR Institute of Microelectronics. Both Dr Rahman and Dr Kang played a very crucial role in shaping this thesis work. Dr Rahman; you always welcomed my queries and advised me on small yet significant hurdles I faced during the experimentation. You were always there to talk to not only as a mentor but also as a good friend. Dr Kang; you shared your experience in microfabrication and facilitated my work at the Institute. I cannot imagine fabricating microreactors without your support. Co-workers: Pravien, Suhanya, Zahra, Sophia, Annalicia, Anna, Kasun G., Vaibhav and Daniel Sutter. You guys made this happen. Daniel working with you was fun and exciting. Your observations and reasoning made while working together later helped me in cracking the bubble-problem in the UV spectrometer. Kasun your assistance in performing experiments is highly appreciated. Time spend with you in lab is a wonderful memory. Pravien and Suhanya, thanks for all your moral support and assistance in performing experiments and proof-reading the thesis. It was great arguing with you. Zahra, Sophia, Annalicia, Anna, Vaibhav, Pravien and Suhanya; you guys made my stay in laboratory fascinating. The Karaoke songs we sang together, group lunch we went out every Friday and movies we watched together were moments to savor. Facilitators: Ms Sylvia Wan, Jamie Seo, Ms Novel at National University of Singapore and Ms Trang, Ms Sarah, Dr Teo, Mr Lawrence at A*STAR Institute of Microelectronics. Thank you all for your kind support in procuring consumables and assisting in microreactor characterization and fabrication. Friends: Suresh, Naresh, Arun, Vinayak, Michael, Suvankar, Max, Anoop, Joon, Evan, Miti and Thaneer. Thank you all for your continuous support in making my stay in Singapore an amazing chapter of my life. Miti, thanks for helping me out on various fronts zillion of times. I’m lucky to have you, Piyush and Veer in Singapore. Family: My parents, uncles and aunts, brothers, cousins and in-laws, nephews and nieces, and grandparents. I cannot imagine coming so far in life without your encouragement and support. You are the light of my life. iii I also gracefully acknowledge the Department of Chemical and Biomoleular Engineering, National University of Singapore, for providing an opportunity and financial assistance to pursue my Master degree. I thank A*STAR Institute of Microelectronics for providing their facilities for my research work. Abhinav Jain August 19th, 2010, Singapore. iv Table of Contents Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iii Table of Contents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x List of Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi List of Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 1.2 1.3 2 Microreactors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1.1 General background on Microreactors. . . . . . . . . . . . . . . . . . . . 1 1.1.2 Types of Microreactors. . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 1.1.3 Transport properties in Microreactor . . . . . . . . . . . . . . . . . . . . . 7 1.1.4 Microreactors in Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Organic Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1.2.1 Heterogeneous reactions . . . . . . . . . . . . . . . . . . . . . . . . . . .10 1.2.2 Homogeneous reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Microreactors for Organic Synthesis . . . . . . . . . . . . . . . . . . . . . . . 11 1.3.1 Heterogeneous reactions in microreactors . . . . . . . . . . . . . . . . . 12 1.3.2 Homogeneous reactions in microreactors . . . . . . . . . . . . . . . . . 14 1.4 Enhancement of reaction rates: the missing link & Motivation . . . . . . . . . 15 1.5 Structure of Thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 1.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.1 2.2 Inside a Microreactor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.1.1 Effect of Temperature. . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.1.2 Effect of Pressure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.1.3 Effect of Surfaces. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.1.4 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Designing the Experiment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26 2.2.1 Selection of Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 2.2.2 Selection of Microreactor . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31 2.4 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 v 3 Silicon Microreactors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34 3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 3.1.1 3.2 3.3 4 Silicon Microreactors and Chemical Engineering. . . . . . . . . . . . . .34 Microfabrication of Silicon Microreactor. . . . . . . . . . . . . . . . . . . . . 36 3.2.1 Development of Protocol. . . . . . . . . . . . . . . . . . . . . . . . . . .39 3.2.2 Development of Photolithography mask. . . . . . . . . . . . . . . . . . . 39 3.2.3 Fabrication Steps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Interconnecting Microreactor. . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3.3.1 Solder-based interconnects. . . . . . . . . . . . . . . . . . . . . . . . . . .45 3.3.2 O ring-based interconnects . . . . . . . . . . . . . . . . . . . . . . . . . .47 3.3.3 Sealant-based interconnects. . . . . . . . . . . . . . . . . . . . . . . . . 48 3.4 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49 3.5 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Experimentation and Observations. . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.1 Experimental setup. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.2 Experimental Protocol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4.3 Sampling and detection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.4 4.3.1 UV-Vis Spectrometry. . . . . . . . . . . . . . . . . . . . . . . . . . . . .55 4.3.2 GC-FID Analysis. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 59 Experimentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 4.4.1 Silicon based microreactors. . . . . . . . . . . . . . . . . . . . . . . . .61 4.4.2 Polymer based microcapillaries. . . . . . . . . . . . . . . . . . . . . . .62 4.5 Results and Discussions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 4.5.1 Same surface-to-volume ratio. . . . . . . . . . . . . . . . . . . . . . . .64 4.5.2 Same material but different surface-to-volume ratio. . . . . . . . . . . . 66 4.6 Error Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67 4.7 Heterogeneity and Organic reactions. . . . . . . . . . . . . . . . . . . . . . . . 69 4.7.1 On Water reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 4.7.2 Surfaces and Organic reactions. . . . . . . . . . . . . . . . . . . . . . . .71 4.8 Microreactors and Organic Reactions revisited. . . . . . . . . . . . . . . . . . . 72 4.9 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 4.10 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 5 Summary and Outlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 5.1 Principal Thesis Contributions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 vi Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . .81 Appendix B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .88 vii Summary This thesis focuses on microreactors used for single-phase organic reactions and their effect on the chemical transformation. Microreactors are defined as micro-structured flow vessels in which at least one of the geometric dimensions is in micrometer size range. In recent years the area has seen extensive development, especially for studying and performing organic syntheses by both academia and industry. Microreactor technology promises superior control, safety, selectivity and yields in chemical transformations. High surface-to-volume ratio achieved in microreactors enables excellent heat and mass transfer rates by facilitating better transport of reacting species and properties. Although they are relatively expensive to fabricate and have limited capabilities to handle solid reactants, higher yield obtained and minimal waste generation makes the overall chemical synthesis economically viable. One of the striking features of using such reactors for both homogeneous and heterogeneous organic synthesis is dramatic improvement in reaction rates and yields compared to conventional macro sized reaction vessels such as bench-top flask. It is argued that this increase is a direct outcome of enhanced transport properties (heat and mass) realized in microreactors. This enhancement accelerates reaction rates, yield and selectivity by shifting diffusion controlled reaction system to kinetically-controlled reaction regime. The argument is valid for heterogeneous chemical reactions where overall reaction rate is limited by transfer of chemical species across phases, or where the reaction rate is a strong function of temperature. However in principle, factors such as inter-phase heat and mass transfer should not affect course of well-mixed quasi-isothermal homogeneous reactions. Thus, the observed increase in reaction rate for homogeneous chemical reaction in microreactors has sparked a debate regarding their reaction mechanism in the research community. In this work we attempt to analyze this deviation in theoretical and observed experimental reaction parameters by hypothesizing the increase in reaction rate as a direct consequence of appreciable participation of reactor walls (surfaces) in a microreactor. In other words, we hypothesize that homogeneous reactant experiences significant participation of reactor walls due to high surface-to-volume ratios. This leads to higher chemical transformation; in effect ‘heterogenizing’ a homogeneous reaction. The hypothesis is investigated by performing single-phase organic reaction experiments in micro-capillary reactors of different materials and internal cross-sectional areas. We compared the conversion of reactants in microreactors of different materials with same surface-to-volume ratio and vice-versa. viii The outcome of our study indicates higher conversions in the microreactors as compared to an equivalent synthesis in a macro-scale system with noticeable difference with different material of construction. However a firm conclusion could not be derive due to errors associated with the measurements. Furthermore, we attribute the observed increase in yield is due to participation of reactor surfaces, as in light of similar phenomena observed in ‘onwater’ and ‘on-surface’ reaction studies. ix List of Tables Table 2.1 – Microcapillaries and their surface-to-volume ratios. Table 3.1 – Etching of Silicon wafers. Table 3.2 – Surface-to-volume ratios for the designed microreactors. Table 4.1 – Flow rates for both Silicon microreactors and Polymer Microcapillary. Table 4.2 – Developed method used for GC-FID analysis. Table 4.3 – Retention time of reactants and products. Table 4.4 – Chemical structure and repeated units in the polymeric material. x List of Figures Figure 1.1 – Microchannels generated by wet etching of a stainless steel foil. Figure 1.2 – Typical Selective Layer Melting fabrication process layout. Figure 1.3 – FlowStart, a commercial microreactor platform for chemists. Figure 3.1 – Different types of silanol groups with hydrogen bonding. Figure 3.2 – Isotropic and Anisotropic etching of a masked surface. Figure 3.3 – Reactive Ion etching process. Figure 3.4 – Design microreactor with extended surface. Figure 3.5 – Extended surface and rectangular channel (all units in mm). Figure 3.6 – Microfabrication steps and microreactor cross sections. Figure 3.7 – Microfabrication steps and microreactor cross sections. Figure 3.8 – Soldering metal ferrules with a silicon microreactor on a hot plate. Figure 3.9 – Delamination of deposited metal layer on microreactor along the dicing lines. Figure 3.10 – O-ring based microreactor packaging. Figure 3.11 – Microreactor packed in a epoxy based sealant. Figure 4.1 – Block diagram of the experimental setup. Figure 4.2 – a) Silicon microreactor with optical fiber based online UV-vis analysis. b) Inset showing the optical fibers running inside the microreactor. Figure 4.3 – Cross-sectional view of microreactor depicting misalignment problem. Figure 4.4 – Fabricated microcross UV flow cell. Figure 4.5 – Signal intensity affected by bubbles in the flow system recorded over time at wavelengths of 450 nm(black), 400 nm(magenta) and 240 nm(blue); flow rate = 20 ml/min. Figure 4.6 – A gas chromatogram of a chemical mixture obtained using a Flame ionization detector; intensity is plotted against time. Figure 4.7 – Delamination of epoxy from a silicon microreactor. Figure 4.8 – Images of the patterned surface of a silicon wafer during microfabrication. Figure 4.9 – GC-FID chromatogram for a sample. xi Figure 4.10 – Plot of conversion in microreactors with surface-to-volume ratio of 7874 m2/m3. Figure 4.11 – Plot of conversion in microreactors with surface-to-volume ratio of 15748 m2/m3. Figure 4.12 – Plot of conversion in microreactors with surface-to-volume ratio of 22857 m2/m3. Figure 4.13 – Plot of conversion in Radel R microreactors and batch system. Figure 4.14 – Plot of conversion in PEEK microreactors and batch system. Figure 4.15 – Plot of conversion in FEP microreactors and batch system. Figure 4.16 – On water reactions in comparison to the neat and aqueous homogeneous reactions. Figure 4.17 – Mechanism for reaction of carboxylic amino acid on SiO2 surface. Figure 4.18 – Mechanism for reaction of benzoquinone with methyl indole on a surface bearing hydrogen bonds. xii List of Schemes Scheme 1.1 – Reaction between ethane and chlorine. Scheme 1.2 – Reaction between a vitamin intermediate in hexane with conc. sulfuric acid. Scheme 1.3 – Suzuki reaction between phenylboronic acid and 4-bromobenzonitrile in oxolane-water mixture. Scheme 1.4 – Suzuki reaction between 3-bromobenzaldehyde and 4-fluoro-phenyl boronic acid. Scheme 2.1 – Coupling reaction between 1,4 benzoquinone and 2-methyl indole. Scheme 2.2 – Coupling reaction between 1,4-benzoquinone and a propanethiol. Scheme 2.3 – Coupling reaction between 2,5-Dichloro-1,4-benzoquinone and 2methyl indole. Scheme 3.1 – Condensation reaction between a silane and an isolated silanol group. Scheme 4.1 – Tautomerism in benzoquinone. xiii 1. Introduction This introductory thesis chapter outlines microreactors and organic reactions in general. The discussion starts with types, fabrication approach and properties of microreactors, followed by introduction to organic reactions and application of microreactors in organic synthesis. The discussion provides a firm foundation to the investigation carried out in this work, and sets stage for the hypothesis outlined in the later sections of this chapter. 1.1 Microreactors Microreactors are miniature reaction vessels for carrying out chemical reactions in which at least one of the lateral dimensions is less than a millimeter and are also known as microstructured reactors or microchannel reactors. In the simplest form, it is a microchanneled flow confinement designed to carry out chemical transformations.1 A microreactor in practice may comprise of a single or multiple chemical unit-operations to carry out execute a desired reaction-engineering task. Depending on the application, a microreactor can also be integrated with microsensors, microactuators and microflowswitches to generate a “micro total analysis system”.2 1.1.1 General background of Microreactors Microreactor technology has tremendously grown in past decade affecting nearly all domains of science and technology. It is a relatively young technology with interesting developments happening each day. Such developments have resulted in commercial market ready products for diagnostics and syntheses purposes. Their unique ability to provide enhanced heat and mass transfer rates further make them a suitable candidate to carry out chemical and biological reactions with high yields and selectivity. The development of microreactor technology dates back to the 1980s when a unique patent on building a microstructured system for chemical processes was published in East 1 Germany.3 In the year 1989, the Forschungszentrum Karlsruhe, Germany presented the first micro-heat exchanger and identified its potential for chemical systems.4 Similar works were carried out in early 90s at Pacific Northwest National Laboratory, USA to harness potential applications for energy sector. By the late 90s, researchers around the globe started recognizing potential of the technology and the area showed an exponential growth since then.5 1.1.2 Types of Microreactors Microreactors are generally classified on the basis of material of construction. The type of material used for construction influences physical properties of microreactors such as hydrophilicity, zeta-potential, solvent compatibility, operating temperature and pressure range, durability and fabrication cost.6,7,8 Based on the material of construction, microreactors can be further classified as- 1.1.2.1 Metal based Microreactors These reactors are chosen for applications involving high temperature and pressure. The choice of metal for construction range from noble metals such as silver, platinum, rhodium to their alloys with copper, titanium, stainless steel, nickel, etc.9,10 The microfabrication methodology to process and manufacture microreactors in metals has been widely adopted from semi-conductor device processing technology. One of the following techniques or their combinations is employed to carry-out complete microreactor fabrication. Etching – Etching is a process by which a material is weathered away and patterned by selectively exposing it to an etching agent. Photolithography is the most common technique used for patterning the surface of the material. In general the removal is a chemical process in which the etching agent removes the exposed metal. There are two types of etching techniques, dry etching and wet etching. Dry etching uses reactive gases or plasma to ‘eataway’ exposed surfaces. Wet etching uses corrosive chemical solution in place of gases or 2 plasma and is relatively cheaper than dry etching techniques. Figure 1.1 shows microchannels generated by wet etching in a stainless steel foil.9 Figure 1.1 – Microchannels generated by wet etching of a stainless steel foil Micromachining – Noble metals chemically resistant and are difficult to pattern using etching agents. Precision micromachining is the most preferred choice to pattern such metals. Micromachining can be performed by spark erosion, laser machining or mechanical precision machining using diamond-tip tools. However there is a limitation to the dimensions which can be processed using micromachining and depends upon the material, technique and machine. Also, the surface smoothness of the processed patterned depends on the type of technique employed.9 Selective Laser Melting (SLM) – Although this is one of the most expensive microfabrication techniques, the process allows generation of full three dimensional microstructures. In this technique, a thin layer of metal powder is distributed on the base structure. Using a high power focused laser beam, the surface is patterned according to a 3D CAD model. The high temperature generated by the focused beam melts and patterns the metal on the layer. The process is repeated to give a full 3D structure. Figure 1.2 outlines a selective laser melting process.12,13 3 Figure 1.2 – Typical Selective Layer Melting fabrication process layout13 Bonding methods- Fabricated micropatterns are assembled and bonded together to generate a microreactor. The surface may be electropolished before assembling to have nanometer scale surface smoothness. High precision is required in aligning as misalignment may lead to poor or unusable microreactors. For metal based microreactor, diffusive bonding at high temperature is the most preferred choice for bonding. This process involves bonding the patterned laminas together under high vacuum, temperature and mechanical pressure. 1.1.2.2 Glass and Silicon based Microreactors Glass and silicon based microreactors are extensively used in engineering systems. Ease of fabrication, solvent compatibility, fabrication process flexibility and capability to operate at higher temperature and pressure makes them suitable candidate for research and development. Furthermore, extensive knowledge and expertise from semiconductor fabrication industry is available for microfabrication of glass and silicon. Microreactors in these materials are manufactured in following ways: Etching- Etching is widely used microfabrication technique for glass and silicon. Dry etching technique uses reactive gases or their plasma to preferentially ‘eat-away’ glass or silicon. The pattern to be etched is masked using a photoresist or by generating a chemically inert layer so that only the patterned surface is exposed to the reactive environment. Based 4 on type of etchant used, two types of etching can be achieved, i.e., isotropic etching or anisotropic etching. In isotropic etching, the etching direction is not influenced by the crystal lattice plane of the material and the rate of etching is uniform in all directions. In anisotropic etching, the rate of etching is non-uniform and varies with the crystal lattice plan of the material. Depending upon the type and process parameters for dry etching (using reactive ions or plasma), isotropic or anisotropic etching can be achieved for both glass and silicon. Details of plasma assisted dry etching (a.k.a. Deep reactive Ion Etching) is discussed in chapter three. Glass and silicon can be isotropically or anisotropically wet-etched. Glass can be isotropically wet etched using aqueous hydrogen fluoride (generally 10%). Silicon has an interesting etching characteristic. It gives an isotropic etch when etchant used is aqueous solution of Hydrogen Fluoride, Nitric Acid and Acetic Acid. However, the etching of Silicon is anisotropic when potassium hydroxide is used as etchant. KOH preferentially attacks plane of silicon crystal, giving rise to a V-groove when plane of silicon is exposed to the etchant.9 Anisotropic etching is useful for generation of special structures such as filters in the microchannel. Micropowder blasting – It is a micro-abrasion process in which an abrasive is impinged using compressed air. It is analogous to sandblasting which is used for polishing and cutting. In this technique, a masked surface is exposed to a stream of abrasive material striking the patterned surface with a very high momentum. The high energy microabrasive powder bombards and removes the exposed surface, leaving behind a patterned surface. Bonding methods- Special bonding methods are used for bonding silicon and glass micropatterns. Anodic bonding is one of the most popular techniques and is typically used for bonding glass and silicon surfaces together. In this process, both the surfaces are kept in close contact at a temperature of about 400~500°C and direct current between 700-1000V is applied. The high temperature makes the glass conduct sodium ions and the applied voltage 5 drifts these ions across the contact into the silicon surface. The silicon atoms thus form a strong chemical SiO bridge between the glass and silicon surfaces. Fusion bonding is another bonding technique used for bonding two silicon or glass surfaces together. In this process, surfaces are made hydrophilic by chemical treatment with aqueous solution of ammonium hydroxide and hydrogen peroxide. The surfaces (laminas) adhere to each other due to van der Waals interaction. For silicon-silicon bonding, the combined microreactor is heat treated in an oxidizing kiln at around 1050°C for an hour. In case of glass-glass bonding, the combined laminas are kept between 400~500°C for several hours.11 1.1.2.1 Polymer based Microreactors Polymers are extensively used for manufacturing microreactors these days. The most important advantages of polymeric microreactors compared to all other types are – ease of fabrication, handling and patterning, lower overall manufacturing, ease of fluidic interconnections. Microreactors in polymers are fabricated using one of the following proceduresHot embossing – In this technique, a micropattern is embossed on surface of a polymeric material such as PMMA (poly methyl meta acrylate), polycarbonate and polystyrene using hot-press die. The technique enables high throughput and is relatively inexpensive compared to other techniques. However, it may suffer from irregular and defective patterning. Extrusion – This technique generates thin microcapillary tubings like microreactors. In this technique, long microcapillaries are extruded from a plastic-melt through a micro-nozzle. The generated capillaries are widely used in commercial and industrial applications including High Performance Liquid Chromatography (HPLC). Soft lithography and patterning- Soft lithography and patterning is one of the most popular microfabrication techniques among researchers. In this technique, a micropattern is lithographed in photo-curing epoxy. SU-8® is one of the most widely used negative photo 6 curing epoxy. The generated microstructure acts as a negative mold and is used for rapid generation of microreactors in elastomers such as PDMS (poly dimethyl meta siloxane) and Poly-Urethane.14 1.1.3 Transport properties in Microreactors In comparison to conventional reactors, the dimensions of microreactors provide very high surface-to-volume ratios. In other words, same amount of chemical flowing through a microreactor will see more ‘wall’ of the microreactor than when flowing through a conventional reactor. Mathematically, A ∝ L2 V ∝ L3 ∴ when A 1 ∝ V L L > 1 V (1.1) (1.2) (1.3) (1.4) where, A is internal surface area and V is volume of a microreactor. Thus for a microreactor, surface-to-volume ratio (or specific surface area) is between 10,000 m2/m3 to 50,000 m2/m3 whereas it is 100 m2/m3 for a conventional macroscopic systems.15 The enhanced specific surface area also results in high heat-transfer coefficient of up to order of 10 kWm-2K-1, resulting in very rapid heating and cooling rates.16 It also enables us to physically carry out a chemical reaction in a microreactor at quasi-isothermal conditions with a well-defined residence time. Furthermore, rapid heat-transfer rate eliminates generation of hot-spots in a microreactors which reducing by-products formation, enhances yield of a reaction, and enables execution of highly temperature-sensitive and exothermic reactions. Mass transfer in microreactors is another important transport property which makes them an attractive choice over conventional systems. In comparison to conventional systems, mixing time in a microreactor (micromixer) is typically of the order of milliseconds. Smaller axial dimensions and enhanced contact area results in a very small diffusion time. Reactions can 7 also be quenched in milliseconds, giving ability to isolate intermediate products and precisely control yield in a multi-step reaction system. Thus, microreactors have shown turn out as the preferred choice when it comes to fast reactions. Interestingly, microreactors have proven to be useful for multi-phase flows. Conventional systems provide very limited contact area, making interphase transfer slower. In a microreactor the specific interface area can reach up to 50000 m2/m3 for liquid-liquid systems and up to 20000 m2/m3 for gas-liquid systems. Single-phase fluid flow in a microreactor is characterized by a low Reynolds number. The flow is laminar with Reynolds number of less than 1000 and most of the mixing occurs by diffusion and secondary flows and transport of materials is essentially through diffusion. If spatial features or active mixers are not used in microreactors, there will be negligible turbulence-based mixing. According to Fick’s law of diffusion the diffusive flux J is, J = − D∇c (1.5) where, c is the concentration of a diffusing entity, D is the coefficient of diffusion and V is the gradient operator. Time taken for a molecule to diffusion through a distance x will be, t= x2 D (1.6) Now for diffusion controlled reactions, decreasing the diffusion distance for a molecule will decrease the time factor by power of 2. Therefore, a reaction in 10-2 cm diameter microreactor will happen 10000 times faster than in a 1 cm diameter vial. This dramatic reduction in reaction time has been one of the most important features of research in microreactor technology. The mixing in a microreactor can be enhanced by incorporating a micro-mixer or by incorporating segmented slugs of inert gases or liquids.17,18 8 1.1.4 Microreactors in Action In recent years, microreactors have become a subject of interest for chemical process companies such as BASF, Lonza, Novartis, BP chemicals and Degussa. These companies have extensively developed chemical processes involving several aspects of the technology. It has been estimated that about 50% of reactions in fine chemicals and pharmaceuticals industry can benefit from continuous processes based on microreactor technology.19 Recently, a team at Lonza received the prestigious Sandmeyer Prize-2010 for their key achievements in design and manufacturing of microstructured devices, including laboratory studies describing pharmaceutical reactions in microreactors and the successful transfer of processes to commercial production.20 This prize is generally given to chemists for their contribution in advancement of chemistry, and awarding such prize to a process team clearly indicates significant potential of the technology for advancement of chemistry. Furthermore, substantial impact has been made by microreactor technology in synthesizing and screening of potential drug candidates which otherwise is a capital and labor-intensive task.21 1.2 Organic Reactions Organic reactions are chemical reactions involving (or producing) organic compounds. Reactions such as addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions comprises of such organic reactions.22 For example, following reaction between ethane and chlorine shown in scheme 1.1 is an example of an addition reaction. H2C CH2 + H H Cl Cl Cl Cl Scheme 1.1 9 These reactions are responsible for production of man-made chemicals such as drugs, plastics, food additives and fabrics. In fact organic molecule and dyes are now been used for development of dye-sensitized solar cells, which may in future replace silicon-based solar cells. Based on type of phases involved in an organic reaction, the reactions can be classified as homogeneous or heterogeneous organic reaction. 1.2.1 Heterogeneous Organic Reactions Heterogeneous organic reactions comprise a class of organic reactions in which reactants are present in two or more physical phase–solid and gas, solid and liquid, or two immiscible liquids. In these types of reactions one or more reactant may undergo chemical change at an interface.23 A reaction involving solid catalyst and gaseous reactants is an example of heterogeneous organic reaction. These reactions can either be a diffusion controlled reaction or a kinetically controlled reaction. In diffusion controlled reactions, the overall rate of reaction are limited by diffusion of reacting species between phases.24 Thus, rates of reaction can be increased by enhancing diffusion (or availability) of reacting species. However, in kinetically controlled reactions the rates of reaction are not affected by mass transfer of the species and can only be altered by changing reaction parameters.25 These two factors determine whether a reaction rate will be accelerated by enhancing transport of chemical species (i.e. by mixing etc.) or by changing the reaction parameters of a reaction (i.e. by changing temperature, activation energy etc.). This information is useful for analysis and usability of microreactors for chemical reactions. 1.2.2 Homogeneous Organic Reactions ‘Homogeneous’ organic reactions are organic reactions in which all reactants exist in same phase (for example, reaction between two chemical species in a miscible liquid). Similar to heterogeneous reaction systems, homogeneous reactions are also either a diffusion controlled reaction or a kinetics controlled reaction. However, for diffusion controlled reactions the intra-phase diffusion governs the overall rate of reaction. In kinetics controlled 10 homogeneous reactions, rates of reaction can only be altered by changing reaction parameters. 1.3 Microreactors for Organic Synthesis As discussed briefly in earlier sections, microreactors have promising applications in organic syntheses. Some of the key features which make this technology a hot technology for organic syntheses are – • Significantly low reagent handling. Compared to conventional diagnostics and synthesis systems, geometric dimensions of microreactors enable lesser reagent handling and waste generation, which in turn lowers the operation costs. This unique feature of microreactors is very beneficial for expensive and labor-intensive drug discovery processes. • Faster analysis, response time, and safer operation. Smaller diffusion distances and higher surface-to-volume ratio enables rapid cooling or heating of reacting species. This enables superior detection and process control, making notoriously unsafe (and runaway) reactions to be carried out even in a laboratory. • Compactness. Large scale integration allows accommodation of several processes in a small footprint. • High-throughput and scale-out capability. High-throughput for analysis and syntheses can be easily achieved by massive parallelization of microreactors. Thus eliminating engineering difficulties encountered with scaling up of a conventional process. • Lower fabrication costs. Microreactor based systems are generally cheaper when compared to conventional systems. 11 • Safer to operate. Compared to conventional reactor system, compact design and high heat and mass transfer rate of microreactors make them safer to operate. Microreactors have promising benefits however their applications are limited by some of the following key factor– • High research and process development cost. • Surface interactions and flows. Physical and chemical effects such as capillary forces, surface roughness, and chemical interactions with material of construction are dominant at microscale. Thus, these effects make operation of such reactors difficult. • Low signal-to-noise ratio. Due to geometric limitations of integrating a sensor in an integrated-microreactor will generally have lower signal-to-noise ratio. Several named organic reactions and processes have been realized in microreactors so far.26,27,28,29,30,31,32,33,34,35 Furthermore, the technology has found its application in industrial and laboratory systems for applications such as drug-screening and organic syntheses.36,37,38,39 Some key developments in the area of microreactors for organic synthesis are briefly discussed in following sections. 1.3.1 Heterogeneous reactions in microreactors Heterogeneous reactions are an integral part of an organic synthesis process. For example, several organic reactions require a solid catalyst phase on which reacting species diffuse in, react, and diffuse back in bulk medium. Diffusion of reacting molecules in an immiscible liquid system across phase boundaries in presence of phase-transfer catalyst is another such example. These heterogeneous reactions are mainly diffusion-controlled reactions. Increasing surface-to-volume ratio for such reactions increases overall contact area for the phases to interact.16 Thus, reaction rates for heterogeneous reactions are generally higher in microreactors than conventional macro-scale system. 12 In order to carry out heterogeneous reactions in microreactors, factors such as flowbehavior and clogging-issues are taken into account, which eventually calls for specially engineered systems. Following are some of the engineered system for heterogeneous reactions in microreactors. On-Bead and Monolith Systems – ‘On-bead’ synthesis became popular by Merrifield’s work on polystyrene matrix for peptide synthesis which eventually led to solid phase organic synthesis and polymer-assisted solution synthesis.40 In this process, beads are functionalized by a suitable reagent or catalyst which promotes the reaction among the reactants. However, earlier polymer support suffered from problems such as partial solubility, mechanical weakness, and broad range of particle sizes. Most of these problems were solved using an inorganic matrix to support the organic resin.41 The remaining shortcomings of ‘on-bead’ systems (such as packing problem) were eliminated in monoliths. Monoliths are continuous phase of porous material that can be used without generating high backpressure observed with fine particles.42 Non-catalytic reactions – Several non-catalytic heterogeneous organic reactions have also been successfully optimized using microreactors. For example, a rapid liquid-liquid biphasic exothermic reaction to form a vitamin intermediate was benefited by using microreactors.5 The reactant phase (hexane) was immiscible with concentrated sulfuric acid phase in which the intermediate product will eventually shift. The formed product is temperature sensitive and would quickly generate by-products, giving a lower yield of only 70% in a semi-batch industrial process. The same reaction when carried out in microreactor system with a micro-mixer and a heat exchanger gave 80~85% yield. The reaction scheme is outlined in scheme 1.2. 13 Reactant in hexane conc. H2SO4 by_product 1 Intermediate in H2SO4 Product in H2SO4 by_product 2 by_product 3 Scheme 1.2 Catalytic reactions – Several heterogeneous catalytic reactions have been investigated in microreactors. Greenway and co-workers have reported Suzuki reaction between phenylboronic acid and 4-bromobenzonitrile in oxolane-water mixture with 1.8% palladium/silicon dioxide as the catalyst, which was immobilized on the microreactor surface. A 10% higher yield was obtained in this microreactor system than compared to conventional batch reactor. The reaction scheme has been outlined in following scheme 1.3.43 OH + B 1.8% Pd/SiO2 Br CN CN THF/H2O OH 25 min Scheme 1.3 1.3.5 Homogeneous reaction in microreactors Homogeneous reactions are the organic reactions in which all the reacting species are present in a single fluidic phase. As the intra-phase diffusive timescale for reacting species is very small (order of few seconds), a reaction occurs with fast mixing and high concentration homogeneity. This influence both catalytic and non-catalytic reactions in microreactors and has been discussed below. Catalytic reactions – Catalytic reactions in homogeneous microreactor system have been shown to drastically enhance yield of a desired product. For example, Suzuki reaction between 3-bromobenzaldehyde and 4-fluoro-phenyl boronic acid in presence of dissolved 14 Pd catalyst has given 90% yield in a microreactor than just 50% yield in conventional system.44 The schematics has been outlined in scheme 1.4. CHO OH F B + OH Br CHO [Pd(PPh3)4] NaOH, DMF F Scheme 1.4 Non-catalytic reactions – Non-catalytic homogeneous reactions have also been shown to accelerate in microreactors. For example, Ahmed and coworkers have shown to enhance hydrolysis of p-nitrophenyl acetate in a microreactor.45 In the above discussion we saw how organic synthesis has benefitted from utilization of microreactors. However, in many cases (especially homogeneous reactions) it is difficult to explain the improvement of yield by using microreactors. The following section analyzes these observations in details and sets up the stage for the thesis. 1.4 Enhancement of reaction rates: the missing link & motivation As discussed in previous sections, microreactors can influence reaction rates and yield of an organic reaction. It is arguably valid to say that one of the key reasons for increase in yield for heterogeneous reactions is the improvement of heat and mass transfer rates. High surface-to-volume ratio and smaller diffusive time scale ensure that both heat and mass transfer occur rapidly with little side-products. Difficulty arises when we try to examine yields for homogeneous chemical reactions and compare it with an equivalent well-mixed conventional reactor, and leaves us with questions –“Why yield of a well-mixed homogeneous chemical reaction much higher in a microreactor than in a conventional reaction, even though the diffusive time scales can be comparable in both cases? Do the surfaces of a microreactor have something to do with this increase?”. 15 These observations have baffled several researchers and have sparked a debate in the scientific community on the possible cause of such spectacular increase.46 Furthermore, the concept of obtaining higher reaction rate and yield in a microreactor has brought many commercial platforms in the market to obtain higher yield for synthetic chemists in recent years. One such commercial platform is shown in Figure 1.3.47 Figure 1.3 FlowStart, a commercial microreactor platform for chemists These platforms are gaining popularity among the chemists as now they can obtain higher yield and selectivity for a tedious and time-consuming organic syntheses reaction. However, full potential of the technology cannot be harnessed without a proper and deep understanding of factors influencing an organic reaction in microreactor. Systematic studies conducted by Ueno et al. and Ahmed et al. provide a firsthand insight on such enhancements.34, 45 The investigations were primarily limited to analyze enhancement of mass-transfer rates as the major cause for reaction rate enhancement. However, enhancement of yield and reaction rates for homogeneous reactions cannot be explained by improved mass-transfer rates. Studies indicate that even for well-mixed conventional and microreactor system, the yield (and also reaction rate) is high in microreactor system. 45 This motivated us to consider surfaces as the potential contributor to the observed enhancement. Our belief was partially based on the fact that surfaces (especially silicon 16 dioxide) have shown to increase reaction rates and yield for some organic reactions, and partially on the fact that in previous studies most of the physical and chemical factors remained same for both conventional and microreactor system other than surface-to-volume ratio.49 Thus, we focused our investigation on surfaces (or walls) of microreactors. This was done by choosing two classes of microreactors, i.e. both silicon and polymeric microreactors with varying surface-to-volume ratio. Silicon microreactors have a native silicon dioxide layer on their surface. These reactors were designed such that they have variable surface-to-volume ratio for same volume, and were fabricated at A*STAR’s Institute of Microelectronics, Singapore. Polymeric micro-capillaries were obtained from commercial sources and were considered for the study owing to their availability and flexibility in terms of material of construction, and presence of chemical groups on their surfaces.50 1.5 Structure of Thesis The thesis consists of five chapters. The first chapter gives a brief overview about the microreactors and microreactor technology, organic reactions and their importance to industries and society, benefits of carrying out organic synthesis reaction in a microreactor and motivation of the current study. Chapter 2 outlines the methodology developed in this thesis to analyze effects of surfaces on yield of a chemical reaction for microreactors. Selection of a model chemistry and design of experiments are covered in this chapter. Design and fabrication of silicon microreactors is covered in chapter 3. This chapter describes the fabrication steps and protocols followed in development of silicon microreactors. Chapter 4 presents the experiments carried out to back the hypothesis. The necessary experimental procedures are described in details and the section closes by discussing 17 interim conclusions derived from the experiments. Later sections of the chapter talks about surface effects observed on organic reactions in other research findings. And finally experimental results of the study are analyzed in light of enhancement effects observed in the outlined research findings. Finally, chapter 5 summarizes the thesis work and the observations made. This chapter also outlines the contributions and suggestions which could further lead to deeper understanding of the enhancement effects in a microreactor. 18 1.6 References 1. Watts, P. & Wiles, C. Recent advances in synthetic micro reaction technology. Chemical communications 2007, 443-467(2007). 2. Reyes, D.R. et al. Micro Total Analysis Systems. 1. Introduction, Theory, and Technology. Analytical Chemistry 74, 2623-2636(2002). 3. Löhder, W. & Bergann, L. Akademie der Wissenschaften der DDR. (1986). 4. Schubert, K. et al. Herstellung und Test von kompakten Mikrowärmeobertregern. Chemie Ingenieur Technik 61, 172-173(1989). 5. Jähnisch, K. et al. Chemistry in microstructured reactors. Angewandte Chemie (International ed. in English) 43, 406-446(2004). 6. Arulanandam, S. & Li, D. Determining [zeta] Potential and Surface Conductance by Monitoring the Current in Electro-osmotic Flow. Journal of Colloid and Interface Science 225, 421-428(2000). 7. Lee, J.N., Park, C. & Whitesides, G.M. Solvent compatibility of poly(dimethylsiloxane)-based microfluidic devices. Analytical chemistry 75, 65446554(2003). 8. Murphy, E. et al. Solder-based chip-to-tube and chip-to-chip packaging for microfluidic devices. Lab on a Chip 7, 1309–1314(2007). 9. Madou, M. Fundamentals of microfabrication. (CRC Press LLC. London, UK:1997). 10. Brandner, J. et al. Microreactors: Epoch-Making Technology for Synthesis. MCPT, 2001 75-87(2003). 11. Wirth, T. Microreactors in Organic Synthesis and Catalysis. (John Wiley & Sons, Inc., New York: 2008). 12. Mills, P.L., Quiram, D.J. & Ryley, J.F. Microreactor technology and process miniaturization for catalytic reactions--A perspective on recent developments and emerging technologies. Chemical Engineering Science 62, 6992-7010(2007). 13. http://commons.wikimedia.org/wiki/File:Selective_laser_melting_system_schematic .jpg 14. Fujii, T. PDMS-based microfluidic devices for biomedical applications. Microelectronic Engineering 61-62, 907-914(2002). 15. Lerou, J.J. et al. Microsystem technology for chemical and biological microreactors. Dechema monographs 132, 51(1996). 16. K. Schubert, W. Bier, J. Brandner, M. Fichtner, C. Franz, G.L. Process Miniaturization - IMRET 2: 2nd International Conference on Microreaction Technology (New Orleans, USA, 1998) 88(1998). 19 17. Günther, A. et al. Transport and reaction in microscale segmented gas--liquid flow. Lab on a Chip 4, 278-286(2004). 18. Hessel, V., Löwe, H. & Schönfeld, F. Micromixers--a review on passive and active mixing principles. Chemical Engineering Science 60, 2479-2501(2005). 19. Roberge, D.M. et al. Microreactor technology: A revolution for the fine chemical and pharmaceutical industries? Chemical Engineering & Technology 28, 318323(2005). 20. http://www.lonza.com/group/en/company/news/newsreleases/lonza_team_receives. html 21. Dittrich, P.S. & Manz, A. Lab-on-a-chip: microfluidics in drug discovery. Nat Rev Drug Discov, 5, 210-218(2006). 22. Kurti, L. & Czako, B. Strategic applications of named reactions in organic synthesis. (Elsevier/Academic Press: Boston, 2005). 23. http://www.britannica.com/EBchecked/topic/264278/heterogeneous-reaction%20 24. Atkins, P. Physical Chemistry. 825-828(WH Freeman & Co: 1998). 25. Fox, M.A. & Whitesell, J.K. Organic chemistry. (Jones and Bartlett Publishers: Sudbury, US: 2004). 26. Watts, P. & Haswell, S.J. The Application of Microreactors for Small Scale Organic Synthesis. Chemical Engineering & Technology 28, 290-301(2005). 27. Greenway, G.M. et al. The use of a novel microreactor for high throughput continuous flow organic synthesis. Sensors and Actuators B-Chemical 63, 153-158 (2000). 28. Schwalbe, T., Kadzimirsz, D. & Jas, G. Synthesis of a Library of Ciprofloxacin Analogues By Means of Sequential Organic Synthesis in Microreactors. QSAR & Combinatorial Science 24, 758-768(2005). 29. Organic, M.C. Catalysis in Capillaries by Pd Thin Films Using Microwave-Assisted Continuous-Flow Organic Synthesis (MACOS)**. Reactions 2761 -2766(2006) 30. Hessel, V. et al. Aqueous Kolbe-Schmitt synthesis using resorcinol in a microreactor laboratory rig under high-p-T conditions. Organic Process Research & Development 9, 479-489 (2005). 31. Shi, G.Y. et al. Capillary-based, serial-loading, parallel microreactor for catalyst screening. Analytical Chemistry 78, 1972-1979(2006). 32. Srinivas, S. et al. A scalable silicon microreactor for preferential CO oxidation: performance comparison with a tubular packed-bed microreactor. Applied Catalysis A: General 274, 285-293(2004). 20 33. Sugimoto, A. et al. The Barton reaction using a microreactor and black light. Continuous-flow synthesis of a key steroid intermediate for an endothelin receptor antagonist. Tetrahedron Letters 47, 6197-6200(2006). 34. Ueno, M. et al. Phase-transfer alkylation reactions using microreactors. Chemical communications 936-937(2003). 35. Murphy, E.R. et al. Accelerating reactions with microreactors at elevated temperatures and pressures: profiling aminocarbonylation reactions. Angewandte Chemie (International ed. in English) 46, 1734-1737(2007). 36. Acke, D.R. & Stevens, C.V. A HCN-based reaction under microreactor conditions: industrially feasible and continuous synthesis of 3,4-diamino-1H-isochromen-1ones. Green Chemistry 9, 386(2007). 37. Watts, P. & Wiles, C. Synthesis of Analytically Pure Compounds in Flow Reactors. Chemical Engineering & Technology 30, 329-333(2007). 38. Chambers, R.D. et al. Elemental fluorine. Part 16. Versatile thin-film gas-liquid multi-channel microreactors for effective scale-out. Lab on a chip 5, 191-198(2005). 39. Becht, S. et al. Micro Process Technology as a Means of Process Intensification. Chemical Engineering & Technology 30, 295-299(2007). 40. Merrifield, R.B. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. Journal of the American Chemical Society 85, 2149-2154(1963). 41. Atherton, E. et al. A physically supported gel polymer for low pressure, continuous flow solid phase reactions. Application to solid phase peptide synthesis. Journal of the Chemical Society, Chemical Communications 1981, 1151-1152(1981). 42. Baumann, M. et al. Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions. Organic & biomolecular chemistry 6, 15871593(2008). 43. Greenway, G.M. et al. The use of a novel microreactor for high throughput continuous flow organic synthesis. Sensors and Actuators B: Chemical 63, 153158(2000). 44. Hessel, V., Hardt, S. & Löwe, H. Chemical micro process engineering: fundamentals, modelling and reactions. (John Wiley & Sons, UK: 2004). 45. Ahmed, B., Barrow, D. & Wirth, T. Enhancement of Reaction Rates by Segmented Fluid Flow in Capillary Scale Reactors. Advanced Synthesis & Catalysis 348, 10431048(2006). 46. Valera, F.E. et al. The Flow's the Thing..Or Is It? Assessing the Merits of Homogeneous Reactions in Flask and Flow. Angewandte Chemie (International ed. in English) 14, 2478–2485(2010). 47. Future Chemistry: http://www.futurechemistry.com/ (Last accessed on 1st August, 2010). 21 48. Ahmed, B., Barrow, D. & Wirth, T. Enhancement of reaction rates by segmented fluid flow in capillary scale reactors. Advanced Synthesis & Catalysis 348, 1043– 1048(2006). 49. Basiuk, V.A. Organic reactions on the surface of silicon dioxide: synthetic applications. Russian Chemical Reviews 64, 1003-1019(1995). 50. Hornung, C.H. et al. A microcapillary flow disc reactor for organic synthesis. Org. Process Res. Dev 11, 399-405(2007). {Bibliography} 22 2. Methodology This chapter describes the strategy developed for analyzing enhancement of reaction rates and yield for homogeneous reactions in microreactors. We approached the problem by first listing out possible physical and chemical factors which may affect the reaction rates and yield. We then analyze these factors and highlight the key factors which are most likely to be causing the observed enhancement. Based on these selected set of factors, we develop an experimental strategy to analyze the observed effect. 2.1 Inside a Microreactor The key characteristics of microreactors which make them unique from conventional reaction systems are rapid mixing times, large surface-to-volume ratio, and enhanced heat and mass transfer rates. Thus, some of these factors may be effecting an organic reaction such that the yield and selectivity are predominantly influenced in a microreactor. Now if we look at the rate of chemical reaction for a closed constant-volume system, it is proportional to change in concentration of chemical species participating in the reaction per unit time. For a reaction with reactants A and B producing products C and D with stoichiometric coefficients a, b, c and d respectively, aA + bB → cC + dD (2.1) the rate of chemical reaction will be mathematically defined as: rate = − 1 d [ B ] 1 d [C ] 1 d [ D] 1 d [ A] =− = = a dt b dt c dt d dt (2.2) where [X] denotes the concentration of the chemical species X.1 Alternatively, the rate of reaction can also be given by law of mass action and is defined as, rate = k[ A]α [ B] β (2.3) 23 where k is the rate constant and α, β are the order of the reaction with respect to the reacting species A and B. The order of a reaction is an experimentally determined quantity and in some cases could be equal to the stoichiometric ratio of the respective chemical species. Furthermore, rate constant is defined by Arrhenius equation as:  − Ea     RT   k = Ae (2.4) where A is frequency factor, T is temperature, Ea is activation energy, and R is universal gas constant . Activation energy here plays a very decisive role in influencing the kinetics of a reaction as it is an exponential facto and can be easily influenced by presence of catalyst or physical state of system. Looking at the system from a macroscopic level, these parameters can be analyzed from kinetic and thermodynamic perspective by studying the effect of temperature, pressure, and physical state (or surfaces) to provide a simpler and clearer picture. The following subsections analyses these factors to evaluate their effect in enhancing the reaction rates and yield. 2.1.1 Effect of Temperature Temperature can significantly influence rate and yield of a chemical reaction as it appears as an exponential term in the Arrhenius equation (2.4). Due to high heat-transfer rate in a microreactor (~10 kWm-2K-1), reactions can be potentially be carried out at quasi-isothermal conditions in a microreactor than compared to a conventional flask system.2 However most of the reactions showing enhancement effects have moderate heat of reactions which conclude that even the conventional flask systems were operating near the desired temperature conditions. Therefore, any effect of heat transfer rates which can cause such noticeable change in yield and reaction rates can be ruled out. 24 2.1.2 Effect of Pressure Pressure is another factor which may affect reaction rates and yield of a chemical reaction by increasing activity of a reaction system. Pressures were just above the atmospheric pressure (~1 atm) in most of the microreactor systems in which enhancement effects were observed. These slight pressure-differences are inadequate to give any notable change in reaction rates and yield of such reactions. Furthermore, pressure will have very little effect on rate constant for condensed-phase reactions (i.e., solid or liquid).3, 4 Thus, it is safe to rule out the effect of pressure for enhancement of organic reaction rates in microreactors. 2.1.3 Effect of Surfaces Surfaces on the other hand can potentially affect course of a chemical reaction. Surface-tovolume ratio in a microreactor is typically about 10,000 m2/m3 than compared to 100 m2/m3 achievable in a conventional reactor of.5, 6 In other words, chemical species see more of microreactor surface than surface of a conventional reactor such as flask for a given volume of reactants. There are several ways in which surfaces in microreactor can influence reaction rates, such as (i) surfaces can act as a catalyst or a co-catalyst and help to promoting reaction rates, (ii) surface energy of the surfaces can influence the enthalpy and entropy of reaction system, thereby influencing the rate constant of a reaction.7, 8 Furthermore, surfaces can enhance reaction rates by creating ‘heterogeneity’ in homogeneous reaction system (‘on-water’ reactions).9, 10, 11 Thus, surfaces seems to be the most promising candidate responsible for enhancing reaction rates and yield. 2.1.4 Conclusion Our preliminary investigation reveals that that surface effects should be the predominant factor influencing and enhancing a reaction in a microreactor. Therefore, in this thesis we restrict ourselves to the study of surfaces on homogeneous organic reaction for rate enhancement, and accordingly design experiments to verify this hypothesis. 25 2.2 Designing the experiment In previous section we found surfaces to be the most able factor which can influence reaction rates and yield. The effect was examined by carrying out a systematic experimental study using a model homogeneous reaction and microreactors with different materials and surface-to-volume ratio respectively. 2.2.1 Selection of the Chemistry The model reaction system for this study was chosen and optimized according to the following guidelines: a) The model chemical reaction should have moderate rate of reaction in batch system (t1/2~30 min). Fast reactions may have inadequate interaction with microreactors’ surface and slow reaction will require longer sampling and analysis time. b) Solvent for the model reaction should be relatively mild and non-corrosive in nature. This is to ensure that surface properties do not alter by corrosive nature of the solvent. c) Reaction rate and yield can be easily quantified using an analysis technique which require little amount of sample (in ml). For the model chemical system, a coupling reaction system was envisioned as a promising system. A coupling reaction is a reaction in which two organic molecules join together, forming a new carbon-carbon bond.12 To start with the study, coupling reaction between 1,4 benzoquinone and 2-methyl indole was considered (scheme 2.1).13 CH3 CH3 O O NH HN THF + HCl , r.t. O O 2.1 a 2.1 c 2.1 b Scheme 2.1 26 1 g each of 1,4 benzoquinone ( 98%, Sigma Aldrich, USA) and 2-methylindole (98%; Aldrich, USA) were taken in a test-tube, and were dissolved in 5ml of tetrahydrofuran (99.9%; Sigma Aldrich, USA). The content was transferred to a 25ml round-bottom flask with an air-condenser. To the reaction system, 1 ml of conc. hydrochloric acid (31% Merck, Germany) was added and the setup was maintained at 60°C for 2 hours in a silicon-oil bath. The product of the reaction (2.1 c) was an intense purple colored compound and could be easily quantified in a UV-Vis spectrometer. The reaction was also carried out at room temperature (about 25°C), however the reaction was very slow and color change indicating formation of product was observed only after leaving the reaction system overnight. This limited the scope of the reaction as a desirable model chemical system. Other reaction candidates were analyzed which can react even at the room temperature. However due to its ability to form colored product, the benzoquinone ring system was preferred as one of the reactant. An online sub-structure search for benzoquinone analogs were carried out on ACS’s Scifinder®.14 Reaction between 1,4-benzoquinone and a thiol was identified as another prospective model reaction (scheme 2.2).15 OH O H2O SH + r.t. H3C S 2.2 a O OH 2.2 b 2.2 c CH3 Scheme 2.2 2 g of 1,4-benzoquinone (98%, Sigma-Aldrich, USA) was taken in a test-tube and was dissolved in 10 ml of Acetone (99.5% Sigma-Aldrich, USA). The content was transferred to a 20 ml sampling vial and to it 500 ml of 1-propanethiol (99% Sigma-Aldrich, USA) was added. 1 ml of water was then added to the sampling vial and it was left for 15 mins to react. The solution started turning red from faint yellow, and after half hour dark red 27 solution was obtained. However, 1-propanethiol (2.2 a) has strong obnoxious odor which makes it very difficult to handle. Thus, this reaction scheme was discarded. Again, the reaction in scheme 2.1 was reanalyzed. This time however different analogs of 1,4-benzoquinone were considered for accelerating the reaction rates. In principle an electron withdrawing groups in 1,4-benzoquinone can accelerate the nucleophilic attack by making it more electron deficient. 2,5-Dichloro-1,4-benzoquinone is one such analog with two strong electron-withdrawing groups (chloride ion). Hence it was used to carry out the reaction (scheme 2.3).16 O O Cl CH3 Cl + Cl N H 4a 2.3 a Cl O 2.3 4bb O N 4c.1 2.3 c CH3 Scheme 2.3 1.5g of 2,5-Dichloro-1,4-benzoquinone (98%; Aldrich, USA) and 1g of 2-methylindole (98%; Aldrich, USA) were taken in a test-tube, and were dissolved in 5ml of tetrahydrofuran ( 99.9%; Sigma Aldrich, USA). The content was transferred to a 20ml sampling vial and was left at room temperature for reaction to happen. The solution turned purplish-red within half hour from faint red color, indicating formation of the product. The final product obtained was analyzed using Aluminum backed Thin-layer chromatography plate (‘Al Sil G/UV’, Whatman, UK). The sample resolved well with ethyl acetate-methanol mixture (Both HPLC grade, VWR LLC, USA). A batch of product mixture was synthesized and the chemical entities were separated using a column chromatography. A mixture of both single-addition (2.3 c), and double-addition products (2.3 d and 2.3 e) were obtained which were later confirmed using NMR analysis. 28 H3C N H3C O HO Cl Cl Cl Cl O N N CH3 2.3 d OH N CH3 2.3 e Therefore, direct coupling reaction between 2,5-Dichloro-1,4-benzoquinone and 2methylindole was chosen as the model chemical reaction system. 2.2.1.1 Solvent Optimization The reported reaction between 2,5-Dichloro-1,4-benzoquinone and 2-methylindole was carried out in tetrahydrofuran (THF). THF is a good aprotic solvent and is widely used in laboratories and industries for synthesis. However it is corrosive toward plastics and has detrimental effects on their polymer matrix.17 Thus, a substitute for THF was investigated to carryout reaction outlined in scheme 2.3. The reactions between 2,5-Dichloro-1,4-benzoquinone (4b) and 2-methyl indole (4b) were carried out simultaneously in following solvents (all HPLC grade): tetrahydrofuran, acetonitrile, 2-propanol, dimethyl sulphoxide(DMSO), dimethyl formamide (DMF), acetone, DI water and ethyl acetate. Both the reactants (40 mg of 4a and 36 mg of 4b) were dissolved in 3ml of each solvent. 1ml of each solution was added in respective sampling vials. To the samples, 1 ml of hydrochloric acid (31% Merck, Germany) was added and the samples were left at room temperature for 1 hr. The samples were then analyzed using thin-layer chromatography (TLC). Each sample was spotted on a pre-cut TLC plate (Whatman, UK; ‘Al Sil G/UV’) and the chromatogram was developed using HPLC grade methanol and ethyl acetate (10:1) as mobile phase for one hour. The TLC plate was dried in air for 15 mins and was analyzed under Florescent light source (ENF-240C/FBE, 29 Spectronics, USA). The comparison was done by analyzing the area of the spot on the TLC corresponding to the chemical species (retention time). The study revealed that reaction in acetonitrile is comparable to tetrahydrofuran. Acetonitrile is non-corrosive to most polymers and do not give any unwanted side products which were observed in case of dimethyl sulphoxide. Thus, acetonitrile was chosen as the solvent for carrying out the model chemical reaction. 2.2.1 Selection of Microreactors Two factors were considered while selecting microreactors for the study--material of the microreactors and internal surface-to-volume ratio of the microreactor. For the same, both custom-made silicon microreactors and polymeric microcapillaries were considered. Silicon microreactors were designed and fabricated at A*STAR’s Institute of Microrelectronics, Singapore. The detail of fabrication procedure are discussed in the next chapter. Microcapillaries are a popular choice among researchers and engineers. They are relatively inexpensive, readily available and cheaper to replace than a chip-based microreactors.18 Microcapillaries made of Radel R (Polysulfone), polyether ether ketone (PEEK) and fluorinated ethylene propylene (FEP) with different inner diameters and 1/16” outer diameter were purchased from Upchurch® Scientific, USA. Inner diameters were chosen such that for the same material, we have different surface-to-volume ratios. The surface-tovolume ratio can be easily calculated using following equation: Surface 2πrl = = 4/d Volume πr 2 l (2.2) where d is the internal diameter, r is the radius and l is a arbitrary length of a microcapillary. The chemical structure of the materials used and their surface-to-volume ratios of microcapillaries used are tabulated in the following table- 30 Table 2.1 Microcapillaries and their surface-to-volume ratios Material Chemical Structure Internal Effective Diameter surface-tovolume ratio (approx.) O S O Radel R O O n 508 mm 7874 m2/m3 254 mm 15748 m2/m3 508 mm 7874 m2/m3 254 mm 15748 m2/m3 175 mm 22857 m2/m3 508 mm 7874 m2/m3 229 mm 17467 m2/m3 175 mm 22857 m2/m3 O PEEK n O O F F F FEP F F F F n CF3 2.3 Summary In this chapter we design a methodology to experimentally analyze the effect of surfaces in a microreactor. Model chemistry was chosen and optimized according to the experimental requirements and convenience. We described the selection process for selecting right set of microreactors. In the next chapter, we also discussed the design and fabrication of silicon microreactors used in this study. 31 2.3 References 1. McNaught, A.D. & Wilkinson, A. Compendium of Chemical Terminology. (Blackwell Scientific Publications, UK: 1997). 2. K. Schubert, W. Bier, J. Brandner, M. Fichtner, C. Franz, G.L. Process Miniaturization - IMRET 2: 2nd International Conference on Microreaction Technology (New Orleans, USA, 1998). 3. Isaacs, N.S. Physical organic chemistry. (Prentice Hall, USA: 1995). 4. Ahmed, B., Barrow, D. & Wirth, T. Enhancement of reaction rates by segmented fluid flow in capillary scale reactors. Advanced Synthesis & Catalysis 348, 1043– 1048(2006). 5. Lerou, J.J. et al. Microsystem technology for chemical and biological microreactors. Dechema monographs 132, 51(1996). 6. Jahnisch, K. et al. Chemistry in microstructured reactors. Angewandte Chemie International Edition 43, 406–446(2004). 7. Basiuk, V.a. Organic reactions on the surface of silicon dioxide: synthetic applications. Russian Chemical Reviews 64, 1003-1019(1995). 8. Piloyan, G. & Bortnikov, N. Influence of the surface energy on the kinetics of chemical reactions of mineral nanoparticles. Doklady Earth Sciences 432, 690692(2010). 9. Jung, Y. & Marcus, R.A. On the Theory of Organic Catalysis "on Water." J. Am. Chem. Soc. 129, 5492-5502(2007). 10. Narayan, S. et al. "On water": unique reactivity of organic compounds in aqueous suspension. Angewandte Chemie (International ed. in English) 44, 32753279(2005). 11. Blackmond, D.G. et al. Water in organocatalytic processes: debunking the myths. Angewandte Chemie (International ed. in English) 46, 3798-3800(2007). 12. March, J. Advanced organic chemistry: reactions, mechanisms, and structure. (Wiley: New York, 1985). 13. Niu, F. et al. Promotion of organic reactions by interfacial hydrogen bonds on hydroxyl group rich nano-solids. Chemical Communications 2008, 2803– 2805(2008). 14. http://www.cas.org/products/sfacad/index.html (Last accessed on 1st August 2010). 15. Yadav, J. et al. Organic synthesis in water: Green protocol for the conjugate addition of thiols to p-quinones. Journal of Molecular Catalysis A: Chemical 274, 116-119(2007). 32 16. Zhang, H. et al. “On Water”-Promoted Direct Coupling of Indoles with 1,4Benzoquinones without Catalyst. European Journal of Organic Chemistry 2006, 869-873(2006). 17. Müller, H. Tetrahydrofuran. Ullmann's Encyclopedia of Industrial Chemistry (Wiley-VCH Verlag GmbH & Co., Germany: 2002) 18. Hornung, C.H. et al. A microcapillary flow disc reactor for organic synthesis. Org. Process Res. Dev 11, 399-405(2007). {Bibliography} 33 3. Silicon Microreactors 3.1 Introduction Silicon has remarkable physical and chemical properties which make it a very useful material for micro-machining and fabrication. It is the principal constituent of semiconductor devices, and is used primarily in mono-crystalline form. In fact, several methodologies used for fabrication of microreactors and micro-total analysis systems (mTAS) are based on physical and chemical processes designed and developed for fabrication of electronic chips.1 Thus, micro-machining of silicon utilizes immense technical know-how acquired by semiconductor industry. 3.1.1 Silicon Microreactors and Chemical Engineering Silicon has a high melting point of 1414°C and excellent thermal conductivity of 149 Wm−1K−1 at 300K. This conductivity is threefolds higher compared with stainless steel (45 Wm−1K−1).2 In a microreactor, higher thermal conductivity is advantageous in rapid cooling and heating, thermal quenching of chemical reactions and elimination of hot spots. It has a low coefficient of thermal expansion (2.6 µm·m−1·K−1 at 25 °C) which exerts relatively less internal thermal stresses at elevated temperature than other popular materials of construction such as polymers and metals.3 Young’s modulus for silicon is 185 GPa which makes it as stiff as wrought iron (190 GPa) and suitable for construction of high pressure reaction vessels.4 Furthermore, silicon is chemically stable towards most chemicals due to formation of a thin and rigid layer of silicon dioxide. This layer protects the reactive silicon underneath and comprises of silanol groups which makes the surface hydrophilic. The type of silanol group residing on a silicon surface depends on temperature and its history of chemical treatment.5 Figure 3.1 outlines three types of such groups. 34 H H O O Si Si Si O O O O Isolated Silanol groups O O H H O O O Si O O O O Germinal Silanol groups Vicinal Silanol groups c b a H Figure 3.1 Different types of silanol groups with hydrogen bonding These silanol bonds further increase the scope of silicon microreactors. They can be chemically modified to impart hydrophobicity to the silicon-surfaces, or to immobilize application-specific chemicals such as enzymes or catalysts. Generally, silanes are used for such surface modifications.6 A condensation reaction between a silane and isolated silanol group is given in Scheme 3.1. R H O Si O + H3Si H2Si R Si O O O 3.1 a 3.1 b + H2O O O 3.1 c Scheme 3.1 Silicon’s unique surface and mechanical ability makes it an excellent material of construction for microreactors designed to carry out chemical engineering processes. These microreactors have been used for applications such as catalyst screening, fuel cell analysis and construction, controlled growth of nanomaterials (quantum dots), PCR amplification, and safer on-demand analysis and synthesis of explosive precursors.7,8,9,10 35 3.2 Microfabrication of Silicon Microreactor Silicon microreactors are fabricated by performing several micro-machining steps on a monocrystalline silicon wafer. Micro-machining is carried out by etching processes as these processes offer very high geometrical resolution. The surface is masked using masking layers of suitable materials which do not react with the etchant. Two types of etching technology are available for micro-machining: anisotropic etching and isotropic etching. Anisotropic etching is micro-machining of a surface by physical and/or chemical weathering such that the etching rate is not uniform in all directions (or planes). On the other hand in an isotropic etching the etching rate is independent of the direction (or plane) of the surface and is uniform in all directions.1 Figure 3.2 outlines the difference both of these etching techniques Figure 3.2 Isotropic and Anisotropic etching of a masked surface. The etching technology features and masking layers used for micro-machining silicon are outlined in Table 3.1. Table 3.1 Etching of Silicon wafers Etching Technology Anisotropic etching Etching Process Reactive Ion Etching (eg. DRIE) Wet chemical Feature Masking layer Combination of physical and chemical dry etching technique KOH preferentially etches SiO2, Si3N4, Photoresist SiO2, Si3N4 36 etching plane of mono- crystalline silicon Wet chemical etching Isotropic etching Plasma Etching Achieved by HF : HNO3 : CH3COOH ; High etching SiO2, Si3N4, rates Combination of physical and chemical dry etching technique SiO2, Si3N4, Photoresist Reactive ion etching is a dry etching process in which plasma of reactive ions is used for etching a patterned surface. In this etching process, the etching gas is filled at low pressure (~100 mTorr) in a cylindrical etching chamber. The substrate (surface) is electrically isolated from the rest of the chamber and is connected to a radio-frequency (RF) power source. Low pressure and RF power source result in formation of very dense plasma in the chamber which accelerates in the electric field toward the substrate. The high energy reactive ions bombard the surface and anisotropically dislodge the atoms from the substrate.1 A typical reaction ion etching setup is shown in Figure 3.3. For this study, microreactors were fabricated using Deep Reaction Ion Etching (DRIE) process.11 This process is highly anisotropic and results in steep trenches with aspect ratios of 20:1 or more. The patterned wafer is etched by bombarding plasma of reactive gases which weathers the exposed silicon surface. DRIE can be achieved by employing cryogenic process or Bosch process.12 37 Figure 3.3 Reactive Ion etching process In cryogenic process, the patterned wafer is maintained at -110°C to slow down the isotropic etching rate caused by the reactive ions in the plasma. As the ions strike perpendicular to the wafer surface, only the upward facing surface is etched. In Bosch process (also known as time-multiplexed etching), vertical structures are etched by alternatively repeating between two modes: 1. First mode is standard isotropic plasma etch using sulfur hexafluoride (SF6) where ions impinge the surface vertically. 2. In the second mode, a chemically inert passive layer is deposited (generally using C4F8). The passive layer protects the entire surface from chemical attack. However, the vertical bombarding of ions on the surface etches the passive layer on the horizontal surface more than that on the sides of a feature. These modes are repeated several times with each mode lasting for several seconds. The overall effect of the etching results in high aspect ratio patterned surface. 38 3.2.1 Development of Protocol In order to analyze the effect of surfaces in enhancing organic reactions in microreactors, silicon microreactors were designed such that for the same internal volume they had different surface-to-volume ratios. This was achieved by incorporating extended surfaces inside the microchannel and is discussed along with the development of photolithography mask. Microfabrication protocol was developed at A*STAR Institute of Microelectronics (IME), Singapore for 8” double-side polished silicon wafers. Solder-based chip-to-world approach as described by Murphy et al. was adopted for packaging (fluidic interconnects).13 The detailed micro-machining protocol used at IME with wafer state is given in appendix A. 3.2.2 Development of Photolithography mask Both the front and back surfaces of the wafers were patterned. The front pattern gave us the required fluidic channels, and the back pattern was meant for generating etch-through holes for fluidic interconnects. These patterns were designed using Autodesk’s AUTOCAD® designing software.14 The patterns were sent to Infinite Graphics Pte Ltd, Singapore for printing emulsion based transparencies. Third dimension (depth) is process dependent and is decided by etching rate. The front surface was etched to give 170 mm deep trenches, and the pattern generally consisted of a long rectangular microchannel of 200 mm width. Depending on the desired surface-to-volume ratios, extended surface elements were replaced with the equivalent length rectangular microchannel element. A pattern with rectangular channel and extended surface is shown in Figure 3.4. 39 Figure 3.4 Design microreactor with extended surface The extended surfaces were designed such that each curved element had almost 1.04 times the volume of an equivalent length rectangular microchannel. However, the internal surface area of the whole element was 1.81 times that of an equivalent rectangular microchannel. Figure 3.5 outlines the features of the curved element and the rectangular element. The excess volume was corrected by reducing the equivalent length of the rectangular microchannel. Figure 3.5 Extended surface and rectangular channel (all units in mm) Five microreactors were designed with increasing number of extended surface elements such that their surface-to-volume ratios increase while their volumes remain the same (Table 3.2). These microreactors’ pattern was set to fit on an eight inch silicon wafer and 40 sent for emulsion transparency printing. The image of the actual pattern is shown in appendix A. Table 3.2 Surface-to-volume ratios for the designed microreactors Reactor No. 1 2 3 4 5 Surface-to-volume ratio m2/m3 (approx.) 12720 12275 11829 11384 9604 3.2.3 Fabrication Steps For fabrication Double-side-polished silicon wafers ( with 725 +/-20 mm thickness) were obtained from SVM Microelectronics Inc., USA. Facilities at A*STAR Institute of Microelectronics, Singapore were used for micro-fabrication. The steps followed to carry out fabrication of a single wafer are as follows: 1. A silicon dioxide layer of 1.5 mm was deposited on the silicon wafer using Novellus® CVD equipment. 2. The front surface of the wafer was spin-coated with a positive photoresist of thickness 10 mm and was baked for 10 min. 3. The wafer from Step 2 was photo-lithographed on EVG® Aligner using the designed emulsion transparency mask. 4. The photo-lithographed wafer was rinsed with lithography developer. Subsequently, the wafer was washed in iso-propyl alcohol and DI water, and spundried. 5. The wafer was descummed (plasma cleaned) using Plasmatherm® plasma cleaner and the exposed silicon dioxide layer was etched with a target depth of 1.5 mm on Lametcher® etcher. 41 6. The wafer was inspected under scanning electron microscope and the first silicon etch was performed with a target depth of 170 um on STS® MEMS etcher. 7. The wafer was checked for the target depth, and then was taken for photoresist stripping. 8. After stripping-off the photoresist, the wafer was cleaned in hot Piranah (3:1 mixture of conc. sulfuric acid and hydrogen peroxide) at 95°C for 20 mins to remove any trace amount of photoresist. 9. The backside of the wafer was then spin coated using positive photoresist. 10. The wafer was aligned with the front side using the ‘hair-lines’ pattern and photolithographed on EVG® Aligner using the designed backside emulsion transparency mask. 11. The photo-lithographed wafer was developed, rinsed, washed and dried as done in Step 4. 12. The front side of the wafer was attached to a dummy silicon wafer using pressure sensitive Nitto-Denko® double-sided heat tape. 13. Vacuum and mechanical pressure was applied to this compound-wafer to completely bond the wafer on EVG® Anodic Bonder. 14. The compound-wafer was descummed in Plasmatherm® cleaner, and etch-through was performed with a target depth of about 650 mm on STS MEMS® etcher. 15. Once etching was complete, the dummy wafer was detached from the main wafer by heating the compound-wafer on a hot plate maintained at 180°C. 16. A batch of five wafers was processed in the first round. 17. The photoresist was chemically stripped-off using acetone at the stripping bay and the wafer was subsequently washed and dried. 18. Silicon dioxide layer on the wafer was removed by using buffered oxide etch (BOE: NH4F + HF). The process was monitored visually by looking at the color of the 42 layer and once complete, the wafer was plunged in DI water. This reaction is fast and typically take 15~20 sec. 19. The wafer was further cleaned in hot Piranah for 20 mins, rinsed in DI and spindried. 20. Pyrex-glass wafer was cleaned in Piranah for 20 mins and were bonded to front side of the wafers via anodic bonding on EVG® anodic bonder. 21. Back of the wafer (silicon side) was sputter-coated with titanium (500Å), copper (2 mm) and gold (1000Å) respectively. 22. The wafer was than diced along the dicing lines to release individual microreactors. The whole microfabrication process and the cross-sectional views of an etched wafer are shown in Figure 3.6. 43 Figure 3.6 Microfabrication steps and microreactor cross sections 44 3.3 Interconnecting Microreactor The fluidic interconnects enable leak-proof entry and exit of reactants and products respectively. These interconnects are very critical in the operation of a microreactor as, they provide material exchange with the macroscopic world, and along with the microreactor governs the maximum operating pressure. Fluidic contacts may also facilitate effective heat transfer from microreactor as well.15 Figure 3.7 shows a metal packaging incorporated with a heat exchanger for a microreactor. Figure 3.7 Microfabrication steps and microreactor cross sections Interconnects used for a microreactor depends on chemical nature of reactants and products, the physical nature of the microreactor surface, and operating pressure and temperature the syste We used and tried following interconnection techniques for the For the fabricated silicon microreactors, following interconnection techniques were used in this research work. 3.3.1 Solder-based interconnect Similar to joining electronics component, solder-based interconnect is suitable when the operating pressure is quite high as it has been reported to withstand pressures up to 200 bar.13 However, its operation limit is governed by melting point of solder-metal used. 45 Another requirement of this interconnect is metallization of microreactor surface around fluidic opening so that solder can form an alloy and hold both the fluidic tubing and microreactor together. In this work, we use this technique to interconnect metalized surface of the silicon microreactors with steel microtubing. Microreactor was placed on a hot plate maintained at 180°C such that metalized back faces away from the hotplate. A thin layer of lead-free solder (Multicore, Malaysia; EN 29453) was soldered using a generic soldering iron. Thin layer of solder was also bonded around brass metal ferrules (1/16” OD, Swazlok®) using phosphoric acid as flux. The ferrules were quickly placed up on metalized and pre-soldered fluidic opening on the hot-plate using tweezers. The temperature of the hotplate was reduced to 150°C and the microreactor was removed from the hot plate. Pre-cut stainless steel microtubes were inserted in the ferrules and soldered to the metal ferrules using phosphoric acid as a flux. Figure 3.8 shows a microreactor with metal ferrules soldered using a hot plate. Figure 3.8 Soldering metal ferrules with a silicon microreactor on a hot plate. One of the major problems with such interconnect is collapse of other soldered joints while soldering itself. Silicon is an excellent conductor of heat. While soldering locally at one point, rapid heat transfer rises temperature of the whole chip. This weakens a soldered joint between other ferrules and microreactor by melting solder-metal between them. The 46 detached metal ferrule cannot be re-soldered as already metals from the metalized-layer were dissolved in the previously soldered solder-metal. In order to overcome the problem with the metal layer, a thicker metal layer was deposited during the sputtering process itself (fabrication step 21). However, proper adhesion of the metal layer with silicon surface could not be achieved. The metal layer delaminated around dicing lines and could be easily peeled off indication very poor adhesion (Figure 3.9). 3 mm Figure 3.9 Delamination of deposited metal layer on microreactor along the dicing lines As the solder based interconnection methodology failed for the designed silicon microreactor, other interconnection techniques were explored to establish fluidic contact and reuse the microreactors. The metalized layer was dissolved in aqua regia (1:3 mixture of nitric acid and hydrochloric acid) to expose a clean back surface. 3.3.2 O-ring casing based interconnect In this type of interconnect, a microreactor is sandwiched between a metal or polymer housing (chuck) with o-rings sealing the fluidic openings of the microreactor and the housing. The o-rings hermetically seal the microreactor with fluidic interconnect on the housing. This type of interconnect have following pros and consPros:  It is more convenient to replace a clogged and damaged microreactors mounted with this type of interconnect than other kind of interconnects.  It can operate a microreactor at higher temperature. 47 Cons:  The chuck is expensive and tedious to machine.  This type of interconnect impart additional mechanical stress on microreactor. Casing for our microreactors was designed using Cocreate® CAD software, and was fabricated using computer-aided machining (CAM) at the Department of Chemical and Biomolecular Engineering workshop, National University of Singapore. PEEK was used as the material of construction and Teflon was used for making o-rings. A packaged microreactor with fluidic contacts is shown in Figure 3.10. Figure 3.10 O-ring based microreactor packaging 3.3.3 Sealant-based interconnect Sealant-based interconnect is the most common type of fluidic interconnect methodology used for prototyping. In this methodology, microtubing is sealed to fluidic openings of a microreactor with an appropriate sealant such as epoxy. It is a simple and cost effective technique, and very useful for rapid prototyping. However, this type of interconnect is only useful for handling non corrosive chemicals at low pressures. For the interconnection between the fluidic opening of the designed microreactor and microtubing, the back surface of the microreactor was descummed in Plasma cleaner (PDC32G; Harrick Plasma, USA) for 10 mins at high settings. This was performed to completely remove any dust and organic impurities which will then ensure better adhesion. Microtubing with ferrule was manually aligned with fluidic opening of the microreactor and 48 the sealent (5 mins Epoxy, ITW Devcon, USA) was applied. This was performed for all fluidic opening and the microreactor was left overnight for complete curing. Figure 3.11 shows a silicon microreactor glued with microtubing. Figure 3.11 Microreactor packed in a epoxy based sealant 3.4 Summary In this chapter we discussed the design and fabrication of silicon microreactors. The fundamentals of microfabrication for silicon were discussed with detail pertaining to fabrication of the microreactor, and fluidic-interconnect methodologies used in this work was also discussed. In the next chapter, the experimental part of the thesis will be discussed. 49 3.5 References 1. Madou, M. Fundamentals of microfabrication. (CRC Press LLC. London, UK:1997). 2. Shanks, H.R. et al. Thermal conductivity of silicon from 300 to 1400 K. Physical Review 130, 1743-1748(1963). 3. Okada, Y. & Tokumaru, Y. Precise determination of lattice parameter and thermal expansion coefficient of silicon between 300 and 1500 K. Journal of Applied Physics 56, 314(1984). 4. Wortman, J.J. & Evans, R.A. Young's modulus, shear modulus, and Poisson's ratio in silicon and germanium. Journal of Applied Physics 36, 153(1965). 5. Nawrocki, J. The silanol group and its role in liquid chromatography. Journal of Chromatography A 779, 29-71(1997). 6. Jal, P.K., Patel, S. & Mishra, B.K. Chemical modification of silica surface by immobilization of functional groups for extractive concentration of metal ions. Talanta 62, 1005-1028(2004). 7. Ajmera, S.K. et al. Microfabricated cross-flow chemical reactor for catalyst testing. Sensors and Actuators B: Chemical 82, 297-306(2002). 8. Yen, B.K. et al. A Microfabricated Gas–Liquid Segmented Flow Reactor for HighTemperature Synthesis: The Case of CdSe Quantum Dots. Angewandte Chemie (International ed. in English) 34, 5447 -5451(2005). 9. Trau, D. et al. Genotyping on a complementary metal oxide semiconductor silicon polymerase chain reaction chip with integrated DNA microarray. Analytical Chemistry 74, 3168-3173(2002). 10. Srinivas, S. et al. A scalable silicon microreactor for preferential CO oxidation: performance comparison with a tubular packed-bed microreactor. Applied Catalysis A: General 274, 285-293(2004). 11. Klaassen, E.H. et al. Silicon fusion bonding and deep reactive ion etching: a new technology for microstructures. Sensors and Actuators A: Physical 52, 132139(1996). 12. Jansen, H.V. et al. Black silicon method X: a review on high speed and selective plasma etching of silicon with profile control: an in-depth comparison between Bosch and cryostat DRIE processes as a roadmap to next generation equipment. Journal of Micromechanics and Microengineering 19(3), (2009). 13. Murphy, E.R. et al. Solder-based chip-to-tube and chip-to-chip packaging for microfluidic devices. Lab on a Chip 7, 1309-1314 (2007). 14. http://usa.autodesk.com/adsk/servlet/pc/index?siteID=123112&id=13779270 (Last accessed on 1st August, 2010). 50 15. Jähnisch, K. et al. Chemistry in microstructured reactors. Angewandte Chemie (International ed. in English) 43, 406-446(2004). {Bibliography} 51 4. Experimentation and Observations In this chapter, we discuss the experiments performed to analyze effect of surfaces on with our chosen chemistry in a microreactor. The results of the experiments and inference derived are discussed in the later part of the chapter. 4.1 Experimental Setup There were three modules in our experimental setup--pumping module, microreactor module and detector module. Each of these modules were connected using PTFE microtubing (OD 1/16” and ID 254 μm; Vici Instruments, USA) and microfittings (Upchurch Scientific, USA). A block diagram of the experimental setup is shown in Figure 4.1. Pumping Module Syringe pump Microreactor Module mtubing Detector Module Si mreactor / Polymer microcapillary UV-Vis / GC-FID Figure 4.1 Block diagram of the experimental setup Pumping module comprised of a syringe pump (PHD-2000; Harvard Apparatus, USA). The reactants for the model chemistry were filled in 3 ml Luer-lock syringes (HS7687863; Terumo Medical Corp., USA) and were loaded on the syringe pump. The syringes were connected to the PTFE microtubing via female Leur adaptors (P-658; Upchurch Scientific, USA) together with flangeless nut (F-336N; Upchurch Scientific, USA). The other ends of tubing connected the pumping module to the microreactor module. Microreactor module consisted of selected microreactors with fluidic packaging (interconnect) through which reactants and product could be transported thru microreactors. For the silicon microreactors, O-ring based interconnect packaging with was used for 52 connecting the PTFE tubing. In case of sealant (epoxy) based interconnects, microtubing was glued with PEEK ferrule (F-162; Upchurch Scientific, USA) to establish proper fluid flow. For carrying out experiments using polymer microcapillaries, a micro-mixing tee with silica frit (CM1XPK; Vici Instruments, USA) was used. Silica frit in the tee imparts vigorous mixing of reactants before they enter microcapillary. Detector module is the name given to part of the setup which registers conversion achieved in performing the chemical reaction in microreactors. Two approaches were adopted for detecting the chemical conversion—continuous-online monitoring and thermal quenching followed by offline characterization—which are further discussed in section 4.3. UV-Vis spectroscopic characterization and quantification technique was used for continuous-online monitoring. Offline characterization was performed using a gas chromatograph with flame ionization detector (GC-2010; Shimadzu Corp., Japan). 4.2 Experimental Protocol All experiments were performed at room temperature of about 23°C. Dilute reactant solutions with low molarity were prepared and used. This was to ensure that neither the surface of a microreactor is oversaturated with reactant molecules, nor the intensively colored product brings anomalies in UV-Vis spectroscopic analysis. 2,5-dichloro-1,4benzoquinone was used as the limiting reagent. Two 10 ml standard flasks were cleaned with dish washer and deionized water (18 MΩ), followed by rinsing twice with acetone to remove any trace amount of organic entities. They were blow-dried by using compressed air gun. 0.040 g of 2,5-dichloro-1,4benzoquinone (98%; Aldrich, USA) was weighed on a weighing paper and was subsequently transferred to one of the 10 ml standard flask. 0.020g of Mesitylene (805890; Merck, Germany) was added to this standard flask as an internal standard. To this acetonitrile (HPLC grade dried over molecular sieve; VWR, USA) was added. The salts were dissolved and the solvent was filled up to the mark. 0.0354 g of 2-methyl indole (98%; 53 Aldrich, USA) was weighed on a weighing paper and was transferred to another 10 ml standard flask. Again, the salts were dissolved in acetonitrile and the solution was filled up to the mark. The two reactant solutions were filled in disposable syringes (3ml, HS7687863; Terumo Medical Corp., USA), and the syringes were mounted on a syringe pump (PHD-2000; Harvard Apparatus, USA). Using fluidic adapters and PTFE tubing the syringes were connected to the microreactor module. Calculation of flow rates Flow rates for each experimental runs were calculated such that residence time of the reactant mixture within the microreactors is 15 min. In case of polymeric microcapillaries, lengths were fixed at 18 cm. Thus, the required flow rates for the reactants were calculated using the following mathematical expression: f = Area * length crossectional time residence (4.1) For a circular capillary equation (4.1) will be, f = πd 2l (4.2) 4nt where f is required flow rate from the syringe pump, d is internal diameter and l is length of a microcapillary, n is number of reactor inlets and t is the residence time required (here 15 min). The calculated flow rates are given below in Table 4.1. Table 4.1 Flow rates for both Silicon microreactors and Polymer Microcapillary Microreactor type Feature Flow rate (ml/min) Silicon Microreactor Same internal volume 0.6384 ID 508 mm 1.218 ID 254 mm 0.3046 ID 229 mm 0.2467 Polymer Microcapillary 54 ID 175 mm 0.1445 Starting protocol For the experiments, following starting protocol was used for all of the studies1. The reactants were pumped at 10 times the required flow rate for first 10 min to ensure that both the reacting solutions reach the microreactor. 2. The flow rates were adjusted back to the required value and the system was left undisturbed to stabilize for 30 min. 4.3 Sampling and detection The conversion in a microreactor was calculated with respect to 2,5-dichloro-1,4benzoquinone by comparing its concentration in reactant and product samples respectively. As mentioned earlier, both UV-Vis Spectroscopic analysis and GC-FID chromatographic analysis were used. However due to system limitations and problems with executing experiments, only gas chromatography was finally used for analysis. Pure product samples were isolated using column-chromatography (as mentioned in section 2.3) and were used for standard reference. There structures were confirmed by comparing NMR data with the available literature.1 4.3.1 UV-Vis Spectroscopy Continuous analyses of the products were carried out initially using an optical guide preetched in silicon microreactors. The assembly is based on work by Jackman et al.2 A polyimide coated optical fiber (100 mm, FIBER-100-UV; Ocean Optics Inc., USA) was taken and was slipped inside PTFE tubing (254 mm, 1/16” OD; Upchurch Scientific, USA) to provide protection from mechanical wear. One end was left as it is with a bout 2 cm bare optical fiber protruding out from the PTFE tubing. To the other end a SMA optical 55 connector was glued using bare fiber adapter kit (BFA-KIT; Ocean Optics Inc., USA). In total two such optical fiber modules were fabricated. The protruding optical fiber was slipped in the optical guide of a microreactor. High pressure grease was applied to ensure that the chemicals do not leak from the surrounding orifice. The optical fiber connection with a microreactor is shown in Figure 4.2. Figure 4.2 a) Silicon microreactor with optical fiber based online UV-vis analysis. b) Inset showing the optical fibers and the microreactor. The SMA connector end of one fiber was connected to a UV light source (DH-2000; Ocean Optics, USA) and another SMA connector end was connected to an optical fiber-based UVvis spectrometer (USB 2000; Ocean Optics, USA). While performing experiments, no UV signals were detected by the spectrometer. However tapping of the microreactor was momentarily giving some low signals which indicated shortcoming in the present engineered design. A thorough analysis of the system revealed two possible factors behind such erratic operation, (i) the dimensions of guideways, and (ii) the ends of the inserted bare optical fiber. The dimensions of the guide-way for optical fiber were 200 mm by 170 mm. However, diameter of the bare optical fiber with polyimide coating was only 130 mm. This leaves a lot of room to transmitter and collector optical fibers for misalignment. Optical signals will only be collected by the collector optical fiber 56 when both transmitter and collector optical fibers are aligned exactly face-to-face. An illustration of the optical fiber in the guide-way is shown in figure 4.3. Figure 4.3 Illustration of the optical fiber in the guide-way of a microreactor. The second possible reason for low signal strength is the surface roughness of the optical fiber end thru which light travels. Rough surfaces can cause substantial electromagnetic scattering due to which the signal strength reaching the collector fiber will be very less. After repeated fabrication, the problem could not be solved. Thus, a custom made online UV flow-cell was machined in Teflon to overcome the misalignment problem and increase signal strength. Accessories for the flow cell such as quartz windows, teflon o-rings and microfitting were used from flow injection analysis kit (FIA-1000-Z ; Ocean Optics Inc., USA). The fabricated flow-cell had an optical path length of 900 mm, and arrangements to fit in 400 mm standard optical fiber cable with SMA connectors. Figure 4.4 shows an image of the fabricated UV flow cell with the accessories. Figure 4.4 Fabricated microcross UV flow cell 57 This flow-cell was attached just at the exit of a microreactor. For an experiment, acetonitrile (HPLC grade, VWR Inc., USA) was used as a blank reference. The detection system works fine except for the fact that the operation is severely affected by the presence of bubbles in the flow. Figure 4.5 shows a UV signal affected by the presence of bubbles in the flow system at a high flow rate of 20 ml/min. Figure 4.5 Signal intensity affected by bubbles in the flow system recorded over time at wavelengths of 450 nm(black), 400 nm(magenta) and 240 nm(blue); flow rate = 20 ml/min Bubbles are generated by dissolution of dissolved gases in the reactant solution. These bubbles are squeezed and acquire ellipsoidal shape while flowing in a micro-capillary. However, when these bubbles reach the optical opening of the flow-cell, they expand and become spherical. The optical opening acts as a gutter and the liquid flow through it without disturbing the bubble. Gas bubbles have lower refractive index than the liquid itself and thus acts as a diverging concave lens. This diverge the optical signals reaching the collector fiber and the intensity of the optical signal falls down. The variation destabilizes base line and spectrum of the UV spectrometer and makes detection impossible. In light of problems associated with the UV-Vis spectroscopic detection, measurement and quantification was carried out by gas chromatography. 58 4.3.2 GC-FID Analysis Gas chromatography is an analytic technique for separating and analyzing compounds that can be vaporized without decomposition. In this technique, the moving phase (or "mobile phase") is an inert carrier gas such as helium and the stationary phase is a microscopic layer of liquid or polymer on an inert solid support.3 The separated entities are analyzed using detectors such as mass spectrometers (MS) or flame-ionization detectors (FID). Flame Ionization detector works by analyzing ions generated by combustion of a sample. The positive electrode is connected to the nozzle head where the flame is produced. The negative electrode is in the form of a tubular electrode and is positioned above the flame. In FID, a small hydrogen-air flame burns at temperatures high enough to pyrolyze organic compounds in a sample, producing positively charged ions and electrons. The ions generated by pyrolysis of the sample at the positive electrode are attracted to the negative tubular electrode, inducing an electrical current. The electrical current is measured with a high-impedance ammeter and is plotted against time to give a chromatogram. The measured current is proportional to the reduced carbon atoms in the flame. Passage of inert carrier gas through the detector does not produce any signal as the gas cannot be ionized. The first peak in the chromatogram generally corresponds to the organic solvent in the sample and the remaining two peaks are the electric current signals obtained for the other two components present in the sample.4 The detector is sensitive to the mass of the organic sample rather than the concentration. However it should be noted that the relative area under the curve for the two different organic entities cannot be directly correlated to their concentration. 4.3.2.1 Method development Method development is essential for error-free identification and quantification of chemical species present in an organic sample. In method development operation parameters are optimized to give stable and reproducible results. 59 For the experiments the method was developed for analyzing 2-methyl indole, 2,5-dichloro1,4-benzoquinone and Mesitylene. Mesitylene was used as an internal standard. The reaction generates one major product and two by-products, both of which show very poor sensitivity in flame ionization detectors. Thus, conversion of 2,5-dichloro-1,4-benzoquinone was considered for analyzing effects of surfaces. Samples of the reactants and products were made in acetonitrile (HPLC grade; VWR Inc., USA) and were injected individually to obtain retention time reading using the GC-FID with fused silica capillary column (Rxi 5sil MS; Restek Inc., USA). Split ratio of 20:1 was maintained at the injector port and the carrier gas flow rate was set at 40 ml/min. Helium was used as the carrier gas and Nitrogen was used as the make-up gas. The initial column temperature was set at 80°C with a ramp of 20°C per min to reach 250°C, which was further maintained for 5 mins. By trial-and-error an optimum method was developed to obtain maximum resolution of peaks with minimum operation time. The final method developed and used is outlined in table 4.2. Table 4.2 Final method used for GC-FID analysis S.No Rate (°C/min) Temperature (°C) Hold Time (min) 1 - 120.0 0.30 2 10.00 205.0 5.00 4.3.2.2 Sampling and Analysis The samples were obtained by quenching the products at 0°C obtained from experiments described in section 4.4, and were immediately analyzed by manually injecting them in the gas chromatograph. 0.8ml of each sample was injected into the injector port of the GC system using a gas-tight syringe from about 2ml of the sample collected in GC sampling vials maintained at 0°C. 60 4.4 Experimentation 4.4.1 Silicon based microreactors Experiments were carried out for both custom-made silicon microreactors and polymer microcapillaries. However after repeated unsuccessful attempts with silicon based microreactors, the experiments involving silicon microreactors were dropped. These silicon microreactors suffered inadequate fluid-flow. Already failure of solder-based interconnect has been previously discussed in chapter 3. With the O-ring based fluidic interconnect packaging, the fluids started leaking within 15 to 20 min of operation. Initial speculation for failure was attributed to possible engineering errors incurred while micromachining of the packaging. The experiments were continued by using sealant-based fluidic interconnects packaging. However the interconnect started leaking within minutes of operation and within half hour cured epoxy layer delaminated completely (figure 4.7). Figure 4.7 Delamination of epoxy from a silicon microreactor Finally, a generic high-strength cement based epoxy was used for interconnect and water was pumped through the microreactor. It was observed that even after 30 min of pumping, no water came out from the microreactor and after about an hour of pumping, the syringe pump stalled. Stalling of the pump happens in situations when flow resistance is very high. Such a high resistance is only possible when microchannels are blocked. After analyzing previously taken microscopic images at A*STAR Institute of Microrelectronics, it was 61 discovered that most of the micropatterns have sufficient irregularities to cause blockage and render microreactors unusable. Figure 4.8 shows images of sections of the silicon wafers after DRIE with broken microchannels. Figure 4.8 Images of the patterned surface of a silicon wafer during microfabrication. The microchannels are broken or irregular in all 3 images (a,b and c). Such irregularities are known to arise at two places during microfabrication-- DRIE step and photolithography step. In DRIE step, the problem arises when debris formed during the DRIE settles in the channel and eventually leads to improper etching. In photolithography step, irregularities arise because of emulsion transparency mask. The occurrence and possibility of irregularities due to this was confirmed by analyzing other wafers photolithographed using the same mask and procedure. 4.4.2 Polymer based microcapillaries Experimental studies with polymer microcapillaries were performed using the developed experimental protocol. Gas chromatogram for the samples was used to calculate conversion of 2,5-dichloro-1,4-benzoquinone in a microreactor. A typical chromatogram obtained for a sample is shown in Figure 4.9. 62 Chromatogram Solvent Peak Internal Standard Reactant– 2 methyl indole Mesitylene Reactant– Benzoquinone Product Peak Figure 4.9 GC-FID chromatogram for a sample An important fact to note at here is that contrary to mass spectrometer detector (MS), the area under the curve for compounds analyzed by FID may not represent relative concentration in a sample. This is because the response of flame ionization detector for a chemical entity depends on the presence of unoxidized carbon atoms and mass of the entity. The retention time for the compounds is given in Table 4.3. Table 4.3 Retention time of reactants and products. Chemical Species Retention time (approx.) Acetonitrile 2.7 min Mesitylene 3.6 min 2,5-dichloro-1,4-benzoquinone 5.6 min Product peak (major product) 6.6 min 2 methyl indole 7.1 min 63 Conversion for 2,5-dichloro-1,4-benzoquinone mathematical expression- was calculated    Area    Benzoquinone      Area    mesitylene sample    × 100 1 −    Area  Benzoquinone         Area  mesitylene  reactant      using following (4.3) where AreaBenzoquinone is the area under the curve for benzoquinone and Areamesitylene is the area under the curve for mesitylene in a chromatogram. The ratio of areas for sample and reactant gives the total consumption of 2,5-dichloro-1,4-benzoquinone in a reaction as mesitylene does not participate in a reaction and is always conserved. The experimental data is tabulated in appendix B. 4.5 Results and Discussions The conversion achieved in the microcapillaries were calculated using the above formula and was compared with conversion obtained in a batch system following the same experimental protocol. 4.5.1 Same surface-to-volume ratio Following graphs were obtained for microreactors with different material of construction and having similar surface to volume ratio. Figure 4.10 is a plot of conversion achieved in microreactors with surface-to-volume ratio of 7874 m2/m3 (internal diameter of 508 mm). The conversion is higher for Radel R in comparison to the conversion achieved in batch system. However, the error bars are over lapping for the PEEK and FEP. 64 Conversion Conversion (%) 30 25 20 15 10 5 0 Radel R 508 PEEK 508 FEP 508 BATCH Microcapillaries with ID (in um) Figure 4.10 Plot of conversion in microreactors with surface-to-volume ratio of 7874 m2/m3 Although, the trend is similar for microreactors with surface-to-volume ratio of 15748 m2/m3 (internal diameter about 250 mm), the standard deviation for the conversion in way too high in comparison to batch system that it is very difficult to derive any clear conclusion. The plot is shown in Figure 4.11. Conversion (%) Conversion 16 14 12 10 8 6 4 2 0 Radel R 254 PEEK 254 FEP 229 BATCH Microcapillaries with ID (in um) Figure 4.11 Plot of conversion in microreactors with surface-to-volume ratio of 15748 m2/m3 In case of surface-to-volume ratio of 22857 m2/m3 (internal diameter about 175 mm), the overall conversion is higher for FEP and PEEK compared to batch with FEP having nonoverlapping error bars (Figure 4.12). Microreactor for Radel R was not available for the surface-to-volume ratio required in this set of experiment. 65 Conversion Conversion (%) 30 25 20 15 10 5 0 PEEK 175 FEP 175 BATCH Microcapillaries with ID (in um) Figure 4.12 Plot of conversion in microreactors with surface-to-volume ratio of 22857 m2/m3 4.5.2 Same material but different surface-to-volume ratio It was interesting to see that the conversion of 2,5-dichloro-1,4-benzoquinone reduces with increasing surface to volume ratio for Radel R (figure 4.13). Conversion Conversion (%) 30 25 20 15 10 5 0 Radel R 508 Radel R 254 BATCH Microcapillaries with ID (in um) Figure 4.13 Plot of conversion in Radel R microreactors and batch system In case of PEEK, the conversion declines initially with minimum conversion achieved in microreactors with surface-to-volume ratio of 15748 m2/m3 (internal diameter of 250 mm). Again, the data obtained data for PEEK is not conclusive as the error bars are overlapping (Figure 4.14). 66 Conversion Conversion (%) 25 20 15 10 5 0 PEEK 508 PEEK 254 PEEK 175 BATCH Microcapillaries with ID (in um) Figure 4.14 Plot of conversion in PEEK microreactors and batch system Similarly, in case of FEP microreactors the conversion is highest for surface-to-volume ratio of 17467 m2/m3 (internal diameter of 250 mm). Here the error bar does not overlap with the batch system and is shown in Figure 4.15. Conversion Conversion (%) 30 25 20 15 10 5 0 FEP 508 FEP 229 FEP 175 BATCH Microcapillaries with ID (in um) Figure 4.15 Plot of conversion in FEP microreactors and batch system 4.6 Error Analysis We believe that the principal reason for such high deviation observed in the experimental data is because of error associated with the analytical instrument. Standard deviation measured for set of eight repeated injections in GC-FID was 6.2% and was calculated by 67 manually injecting same solution of 2,5-dichloro-1,4-benzoquinone within a span of 3 hrs. Values for error calculations were obtained using equation (4.4).  Area  Benzoquinone    Area   mesitylene sample  (4.4) Now, if we look at the final conversion obtained in a microreactor using equation (4.3), it involves four measured parameters. Thus, considering that each parameter can deviate by about 6.2%, the deviation in the value of calculated conversion can be significant. Possibilities for error caused by loss of some chemical species into the environment was also analyzed by performing blank experiments without 2-methyl indole. In place of 2-methyl indole, pure acetonitrile was used and chemical entities (i.e. 2,5dichloro-1,4-benzoquinone and mesitylene) dissolved in acetonitrile were made to flow through the microcapillaries. The experiment indicated no loss of chemicals in the microcapillaries; however again, significant standard deviation was observed indicating that the error associated with the analytical instrument is the prime cause of the observed deviation. Another interesting observation derived from our experimental data was that the standard deviation was minimum for a batch system than a continuous microreactor flow experiments. We believe that there are two more factors contributing to the error. Firstly, the product is collected in a cold sampling vial manually. Although same starting and sampling protocols were followed, the process is prone to human errors. Secondly, several plasticizers are used in extrusion manufacturing of polymer based microcapillaries. These plasticizers can leach-out and influence a reaction, causing deviation in experimental results. The errors associated with the study are significantly high to give a clear insight on surface effects for homogeneous reactions in microreactors. In the next section we look at plausible 68 causes working behind the observed effect in light of established theories and experimental observations derived from scientific literature. The theories are an attempt to explain the trends, and they provide us an insight on the observed enhancement effects. 4.7 Heterogeneity and Organic reactions Some experimental observations indicate that chemical nature of surfaces as well as surface-to-volume ratio in a microreactor does affect the kinetics of a chemical reaction. However the exact science working on the reaction kinetics is unclear. In this section, we take a closer look at chemical kinetics and discuss enhancement effects observed in other experimental and theoretical studies. We analyze the experimental results in light of the known enhancement effects and present a tentative hypothesis for the observed change in kinetics for our model chemistry in microreactors. We currently believe that a surface influences an otherwise homogeneous reaction by participating in it. A homogeneous chemical reaction system ‘sees’ significant participation of material in reactor walls due to high surface-to-volume ratios, which in turn generate significant ‘heterogeneity’. Furthermore, the surface can participate in a reaction by either stabilizing transition states as observed in ‘on-water reactions’, or second by influencing enthalpy and entropy of a reaction. 4.7.1 On Water reactions ‘On water’ reaction is a group of organic reactions in which reaction in carried out in an emulsion system with water as an immiscible phase. This reaction group exhibits an unusually high reaction rate compared to the same reaction in an organic solvent alone or in a dry media reaction.5,6,7,8,9 Although, water generally acts as a dormant phase in the reaction system with no active mass transfer occurring between the organic and aqueous phases, the very presence of it influences a reaction rate. Several research groups have 69 analyzed these ‘on water’ reaction systems closely theoretically or experimentally, and have put forward several theories to explain it. Marcus and co-workers have shown that in some ‘on water’ systems, enhancement of reaction rate (upto 5 folds) can be achieved because of hydrogen bonds protruding in the organic phase.10 They argue that heterogeneity is crucial for large rate enhancements since the acceleration was found to be less dramatic if conducted in homogeneous aqueous solution. In their ‘on water’ system model, one in every 4 hydrogen bonds in the water phase protrude in the organic phase and forms stronger hydrogen bonds with the transition state than with the reactants. However, in a homogeneous reaction system within water, the effect is not prominent as the transition state ‘see’ parallel hydrogen bond which are not as effective in stabilizing the transition state as perpendicular ones protruding in oil phase. Figure 4.16 compares the highlighting difference in both cases. Figure 4.16 On-water reactions in comparison to the neat and aqueous homogeneous reactions.10 Thus, heterogeneity generated by oil-water interface can dramatically influence the kinetics of a reaction. Some researchers have proposed that the observed ‘on water’ effect of water is primarily caused by preventing deactivation of a transition state than promotion of activity.11,12 Their experimental observations showed that water suppresses the formation of proline 70 oxazolidinones in proline-mediated aldol reactions. In either case, it is safe to say that the heterogeneity generated in a chemical reaction system is capable of influencing the kinetics of the reaction. 4.7.2 Surfaces and Organic reactions Presence of seemingly inert surfaces could also influence kinetics of a chemical reaction.13 For example, oxidation of alcohols to aldehydes and ketones using potassium permanganate gives higher yield when carried out in presence of silicon dioxide.14 Although silicon dioxide here acts as an inert support, its mere presence affects the yield of reaction. Bromination of biphenyl, 4-bromobiphenyl, and 4-nitrobiphenyl showed that reaction does not occur in carbon tetrachloride as solvent if silica gel is absent. Another interesting example is cyclodehydration of carboxylic g-,d-, and e-aminoacids to the corresponding lactams on refluxing with toluene in presence of silica gel or aluminium oxide.15 In this case the surface of the oxide acts as a catalyst. The mechanism of the reaction is outlined in Figure 4.17. Figure 4.17 Mechanism for reaction of carboxylic amino acid on SiO2 surface15 71 Thus, there are cases in which surfaces have influenced chemical kinetics of organic reactions. Similarly, high surface-to-volume ratio in a microreactor may be a prime factor working towards enhancing organic reactions. 4.8 Microreactors and Organic Reactions revisited In previous section it was shown how heterogeneity generated at an inter-phase (or surface) can affect kinetics of an organic reaction. Research findings in which reaction kinetics were influenced by presence of a surface were also discussed. In this section an attempt has been made to explain trends and results of the experimental studies conducted, and provide a tentative hypothesis for influence of surfaces on homogeneous organic reactions in microreactor. Interestingly, initial model chemical system for our experimental study has previously shown ‘on water’ enhancement effects.6 Furthermore, an analogue of 2,5-dichloro-1,4benzoquinone has also shown accelerated reaction rates on ferric hydroxide nano particles surfaces for a reaction with 2-methly indole.9 The proposed mechanism for the reaction is outlined in Figure 4.18 which indicates participation of hydrogen bonds on the surface for enhancing the chemical reaction. Figure 4.18 Mechanism for reaction of benzoquinone with methyl indole on a surface bearing hydrogen bonds.9 72 A hydrogen bond is an attractive interaction of a hydrogen atom with an electronegative atom.16 If we take a closer look at polymeric structures of the material of construction for microreactors, we see that the Radel R has a sulfone bond in every repeating-unit of their polymer. Similarly, PEEK has one carbonyl group in its repeating-unit. Structures of the materials are shown in table 4.4. Table 4.4 Chemical structure and repeated units in the polymeric material Material Chemical Structure O Radel R S O O O n O PEEK n O O F F F F F n F CF3 FEP F Sulfone group has high polarity and has slightly higher donor properties than carbonyl group due to less effective sulfur-oxygen p-bonding.17 At the same time, a benzoquinone shows tautomeric isomerization (scheme 4.1). O O OH O OH OH a b c Scheme 4.1 73 It is fair to say that tautomers of benzoquinone (b, c) can participate in hydrogen bonding with sulfone group present in the backbone of Radel R.18 The hydrogen bonding between the sulfone group and the tautomers will be higher than the one between the carbonyl group and the tautomers as sulfone has slightly higher electronegativity than carbonyl group.17 Thus, conversion of 2,5-(dichloro) 1,4-benzoquinone should be highest for Radel R, followed by PEEK and FEP. As the experimental data has substantial deviations, it is hard to correlate results of the study with any of the discussed rate enhancement theories. We do see enhancement of organic reactions in microreactor however the trends could not be explained. 4.9 Summary In this chapter, we discussed development of the experimental protocol and several issues and problems encountered during experimentation. The experimental observations were reported, analyzed and discussed to arrive at an intermediate conclusion regarding effects of surfaces on a homogeneous organic reaction. The study revealed that surfaces do affect homogeneous organic reaction in a microreactor although a clear picture could not be derived due to error associated with the experimental data. Cnversion of 2,5-dichloro-1,4-benzoquinone in the model chemical reaction was highest for Radel R microcapillary with internal diameter of 508 mm (surface-to-volume ratio 7874 m2/m3). Plausible cause of the observed effect and rate enhancements effects observed was discussed in light of studies on ‘on water’ reaction and ‘reactions on surfaces’ by other researchers. ‘On water’ model proposed by Jung et al seems most convincing and applicable to our system, and was used as a base model to explain trends seen in the current research work.10 It was proposed that the tautomers of 2,5-(dichloro) 1,4-benzoquinone interacts with the surface of the microreactors (Radel R) and give higher conversion. 74 4.9 References 1. Zhang, H. et al. Synthesis of Aryl-Substituted 1,4-Benzoquinone via WaterPromoted and In(OTf)3-Catalyzed in situ Conjugate Addition-Dehydrogenation of Aromatic Compounds to 1,4-Benzoquinone in Water. Advanced Synthesis & Catalysis 348, 229-235(2006). 2. Jackman, R.J. et al. Microfluidic systems with on-line UV detection fabricated in photodefinable epoxy. Journal of Micromechanics and Microengineering 11, 263(2001). 3. Harris, D.C. Quantitative chemical analysis. (WH Freeman: 2003). 4. Mcwilliam, I.G. & Dewar, R.A. Flame Chromatography. Nature 181, 760-760(1958). 5. Narayan, S. et al. "On water": unique reactivity of organic compounds in aqueous suspension. Angewandte Chemie (International ed. in English) 44, 32753279(2005). 6. Zhang, H. et al. “On Water”-Promoted Direct Coupling of Indoles with 1,4Benzoquinones without Catalyst. European Journal of Organic Chemistry, 869873(2006). 7. Pirrung, M.C. & Sarma, K.D. Multicomponent Reactions Are Accelerated in Water. Journal of the American Chemical Society 126, 444-445(2004). 8. Meltzer, P.S. & Branch, C.G. Fast reactions ‘on water’. Nature 435, 3-4(2005). 9. Niu, F. et al. Promotion of organic reactions by interfacial hydrogen bonds on hydroxyl group rich nano-solids. Chemical Communications, 2803–2805(2008). 10. Jung, Y. & Marcus, R.A. On the theory of organic catalysis "on water." Journal of the American Chemical Society 129, 5492-502(2007). 11. Nyberg, A.I., Usano, A. & Pihko, P.M. Proline-Catalyzed Ketone-Aldehyde Aldol Reactions are Accelerated by Water. Synlett, 1891-1896(2004). 12. Blackmond, D.G. et al. Water in organocatalytic processes: debunking the myths. Angewandte Chemie (International ed. in English) 46, 3798-3800(2007). 13. Basiuk, V.A. Organic reactions on the surface of silicon dioxide: synthetic applications. Russian Chemical Reviews 64, 1003-1019(1995). 14. Regen, S.L. & Koteel, C. Activation through impregnation. Permanganate-coated solid supports. Journal of the American Chemical Society 99, 3837-3838(1977). 15. Bladé-Font, A. Facile synthesis of γ-, α-, and e-lactams by cyclodehydration of ωamino acids on alumina or silica gel. Tetrahedron Letters 21, 2443-2446(1980). Ionization Detector for Gas 75 16. Jeffrey, G.A. An introduction to hydrogen bonding. (Oxford University Press, USA: 1997). 17. Drago, R.S., Wayland, B. & Carlson, R.L. Donor Properties of Sulfoxides, Alkyl Sulfites, and Sulfones. Journal of the American Chemical Society 85, 31253128(1963). 18. Oznobikhina, L. et al. Orientation of hydrogen bond in H-complexes of sulfones and sulfonamides. Russian Journal of General Chemistry 79, 1674-1682(2009). {Bibliography} 76 5. Summary and Outlook This thesis focused on single phase organic reactions in microreactors and analyzed surface effects on homogeneous organic reactions in microreactors. The discussion started with a general overview on microreactor types, fabrication methodologies, their unique physical properties, and chemical properties. Organic reactions that have been carried out in microreactors, and reaction rates and yield enhancement cases were highlighted. The motivation to understanding the enhancement effects was discussed which laid the basis of this thesis. Enhancement effects were investigated by analyzing possible physical and chemical factors (temperature, pressure and surfaces) which could affect reaction rates and yield of an organic reaction in a microreactor. A conclusion was derived that effect of surfaces is a strong factor which can influence chemical kinetics. A thorough analysis was planned by designing systematic experimental studies with different materials and surface-to-volume ratio for microreactors respectively. A model homogeneous organic reaction was chosen to suit the engineering and analytical requirements of the study. This reaction chemistry was optimized for reaction speed and compatible solvents, and reaction between 2,5-Dichloro1,4-benzoquinone with 2-methyl indole in acetonitrile. In order to study our premise, two types of microreactors were chosen--polymer microcapillaries and custom made silicon microreactors. Polymer microcapillaries are becoming popular within scientific community as they are relatively cheaper and readily available. Thus a study which could give a better insight about their efficacy will be beneficial to the community. Microcapillaries made out of Radel R, PEEK and FEP with internal diameter of 508 mm, 254 mm, 229 mm and 175 mm were purchased, and were grouped together on the basis of similar internal surface-to-volume ratio but different material and same material but different surface-to-volume ratio. 77 Silicon microreactors were fabricated at A*STAR Institute of Microelectronics, Singapore. The silicon microreactors were designed such that they have same internal volume but different surface-to-volume ratio. In chapter 4 we discussed the setup designed for carrying out experiments. The problems associated with experiments in silicon microreactors and UV-vis analysis were discussed and analyzed. The experiments were performed such that the residence time in all the microcapillaries was 18 min. Conversion of 2,5-(dichloro) 1,4-benzoquinone in different microreactors were calculated and plotted both for similar surface-to-volume ratio and for same material with different surface-to-volume ratio. The study revealed that surfaces do affect homogeneous organic reaction in a microreactor with highest conversion obtained in Radel R microcapillary (internal dia.-508 mm), however the trend was irregular. The deviation associated with quantification by GC-FID was calculated to be 6.2%, which could be the prime reason for such a high deviation. The observed effects were explained in light of heterogeneity generated in ‘on water’ reactions and reactions occurring at surfaces of materials. The conversion trend observed for Radel R, PEEK and FEP were analyzed in light of possible van der waal interactions and hydrogen bonding occurring between transition state and microreactor surface. However, some trends observed in the experimental data are still not completely understood. 5.1 Principal Thesis Contributions A systematic study was planned and executed to analyze the enhancement in reaction rates and yield for homogeneous organic reactions in microreactors. Several physical and chemical factors were analyzed which could result in change in kinetics of the reaction. Microfabrication of silicon microreactor was reported and engineering problems and challenges encountered while performing experiments were discussed. This will be of immense use for someone fabricating and working with microreactors (especially silicon). 78 The thesis work also revealed that surfaces do affect the course of reaction and is indeed a factor which can influence chemical kinetics of a reaction. 79 Appendix A 80 Appendix A 81 Appendix A 82 Appendix A AutoCAD drawing of the patterned mask – wafer #1 - frontside 83 Appendix A AutoCAD drawing of the patterned mask – wafer #1 - backside 84 Appendix A AutoCAD drawing of the patterned mask – wafer #2 - frontside 85 Appendix A AutoCAD drawing of the patterned mask – wafer #2 - backside 86 Appendix B Experimental data obtained by GC-FID analysis of the products 87 Appendix B 88 Appendix B 89 [...]... technology in synthesizing and screening of potential drug candidates which otherwise is a capital and labor-intensive task.21 1.2 Organic Reactions Organic reactions are chemical reactions involving (or producing) organic compounds Reactions such as addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions comprises of such organic reactions. 22... heterogeneous reaction systems, homogeneous reactions are also either a diffusion controlled reaction or a kinetics controlled reaction However, for diffusion controlled reactions the intra-phase diffusion governs the overall rate of reaction In kinetics controlled 10 homogeneous reactions, rates of reaction can only be altered by changing reaction parameters 1.3 Microreactors for Organic Synthesis As... chapter outlines microreactors and organic reactions in general The discussion starts with types, fabrication approach and properties of microreactors, followed by introduction to organic reactions and application of microreactors in organic synthesis The discussion provides a firm foundation to the investigation carried out in this work, and sets stage for the hypothesis outlined in the later sections of... etc.) or by changing the reaction parameters of a reaction (i.e by changing temperature, activation energy etc.) This information is useful for analysis and usability of microreactors for chemical reactions 1.2.2 Homogeneous Organic Reactions Homogeneous organic reactions are organic reactions in which all reactants exist in same phase (for example, reaction between two chemical species in a miscible... these types of reactions one or more reactant may undergo chemical change at an interface.23 A reaction involving solid catalyst and gaseous reactants is an example of heterogeneous organic reaction These reactions can either be a diffusion controlled reaction or a kinetically controlled reaction In diffusion controlled reactions, the overall rate of reaction are limited by diffusion of reacting species... problems were solved using an inorganic matrix to support the organic resin.41 The remaining shortcomings of on- bead’ systems (such as packing problem) were eliminated in monoliths Monoliths are continuous phase of porous material that can be used without generating high backpressure observed with fine particles.42 Non-catalytic reactions – Several non-catalytic heterogeneous organic reactions have also been... Radel R microreactors and batch system Figure 4.14 – Plot of conversion in PEEK microreactors and batch system Figure 4.15 – Plot of conversion in FEP microreactors and batch system Figure 4.16 – On water reactions in comparison to the neat and aqueous homogeneous reactions Figure 4.17 – Mechanism for reaction of carboxylic amino acid on SiO2 surface Figure 4.18 – Mechanism for reaction of benzoquinone... Scheme 2.1 – Coupling reaction between 1,4 benzoquinone and 2-methyl indole Scheme 2.2 – Coupling reaction between 1,4-benzoquinone and a propanethiol Scheme 2.3 – Coupling reaction between 2,5-Dichloro-1,4-benzoquinone and 2methyl indole Scheme 3.1 – Condensation reaction between a silane and an isolated silanol group Scheme 4.1 – Tautomerism in benzoquinone xiii 1 Introduction This introductory thesis... application in industrial and laboratory systems for applications such as drug-screening and organic syntheses.36,37,38,39 Some key developments in the area of microreactors for organic synthesis are briefly discussed in following sections 1.3.1 Heterogeneous reactions in microreactors Heterogeneous reactions are an integral part of an organic synthesis process For example, several organic reactions require... replace silicon-based solar cells Based on type of phases involved in an organic reaction, the reactions can be classified as homogeneous or heterogeneous organic reaction 1.2.1 Heterogeneous Organic Reactions Heterogeneous organic reactions comprise a class of organic reactions in which reactants are present in two or more physical phase–solid and gas, solid and liquid, or two immiscible liquids In these ... (or producing) organic compounds Reactions such as addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions comprises... microreactors for chemical reactions 1.2.2 Homogeneous Organic Reactions Homogeneous organic reactions are organic reactions in which all reactants exist in same phase (for example, reaction... reaction These reactions can either be a diffusion controlled reaction or a kinetically controlled reaction In diffusion controlled reactions, the overall rate of reaction are limited by diffusion