Microreactors in Organic Chemistry and Catalysis E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
For the second edition of 'Microreactors in Organic Chemistry and Catalysis' all chapters have been revised and updated to reflect the latest developments in this rapidly developing field. This new edition has 60% more content, and it remains a comprehensive publication covering most aspects of the topic. The use of microreactors in homogeneous, heterogeneous as well as biphasic reactions is covered in the main part of the book, together with catalytic, bioorganic and automation approaches. The initial chapters also provide a solid physical chemistry background on fluidics in microdevices. Finally, a chapter on industrial applications and developments covers recent progress in process chemistry. An excellent reference for beginners and experts alike.
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Veröffentlichungsjahr: 2013
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Contents
Cover
Related Titles
Title Page
Copyright
Preface to the First Edition
Preface to the Second Edition
List of Contributors
Chapter 1: Properties and Use of Microreactors
1.1 Introduction
1.2 Physical Characteristics of Microreactors
1.3 Fluid Flow and Delivery Regimes
1.4 Multifunctional Integration
1.5 Uses of Microreactors
References
Chapter 2: Fabrication of Microreactors Made from Metals and Ceramic
2.1 Manufacturing Techniques for Metals
2.2 Etching
2.3 Machining
2.4 Generative Method: Selective Laser Melting
2.5 Metal Forming Techniques
2.6 Assembling and Bonding of Metal Microstructures
2.7 Ceramic Devices
2.8 Joining and Sealing
References
Chapter 3: Microreactors Made of Glass and Silicon
3.1 How Microreactors Are Constructed
3.2 The Structuring of Glass and Silicon
3.3 Isotropic Wet Chemical Etching of Silicon
3.4 Other Processes
3.5 Thin Films
3.6 Bonding Methods
3.7 Other Materials
References
Chapter 4: Automation in Microreactor Systems
4.1 Introduction
4.2 Automation System
4.3 Automated Optimization with HPLC Sampling
4.4 Automated Multi-Trajectory Optimization
4.5 Kinetic Model Discrimination and Parameter Fitting
4.6 Conclusions and Outlook
Acknowledgment
References
Chapter 5: Homogeneous Reactions
5.1 Acid-Promoted Reactions
5.2 Base-Promoted Reactions
5.3 Radical Reactions
5.4 Condensation Reactions
5.5 Metal-Catalyzed Reactions
5.6 High Temperature Reactions
5.7 Oxidation Reactions
5.8 Reaction with Organometallic Reagents
References
Chapter 6: Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis
6.1 Photochemistry in Flow Reactors
6.2 Electrochemistry in Microreactors
6.3 Radiopharmaceutical Synthesis in Microreactors
6.4 Conclusion and Outlook
References
Chapter 7: Heterogeneous Reactions
7.1 Arrangement of Reactors in Flow Synthesis
7.2 Immobilization of the Reagent/Catalyst
7.3 Flow Reactions with an Immobilized Stoichiometric Reagent
7.4 Flow Synthesis with Immobilized Catalysts: Solid Acid Catalysts
7.5 Flow Reaction with an Immobilized Catalyst: Transition Metal Catalysts Dispersed on Polymer
7.6 Flow Reaction with an Immobilized Catalyst: Metal Catalysts Coordinated by a Polymer-Supported Ligand
7.7 Organocatalysis in Flow Reactions
7.8 Flow Biotransformation Reactions Catalyzed by Immobilized Enzymes
7.9 Multistep Synthesis
7.10 Conclusion
References
Chapter 8: Liquid–Liquid Biphasic Reactions
8.1 Introduction
8.2 Background
8.3 Kinetics of Biphasic Systems
8.4 Biphasic Flow in Microchannels
8.5 Surface–Liquid and Liquid–Liquid Interaction
8.6 Liquid–Liquid Microsystems in Organic Synthesis
8.7 Micromixer
8.8 Conclusions and Outlook
References
Chapter 9: Gas–Liquid Reactions
9.1 Introduction
9.2 Contacting Principles and Microreactors
9.3 Gas–Liquid Reactions
9.4 Gas–Liquid–Solid Reactions
9.5 Homogeneously Catalyzed Gas–Liquid Reactions
9.6 Other Applications
9.7 Conclusions and Outlook
Acknowledgement
References
Chapter 10: Bioorganic and Biocatalytic Reactions
10.1 General Introduction
10.2 Bioorganic Syntheses Performed in Microreactors
10.3 Biocatalysis by Enzymatic Microreactors
10.4 Multienzyme Catalysis in Microreactors
10.5 Conclusions
References
Chapter 11: Industrial Microreactor Process Development up to Production
11.1 Mission Statement from Industry on Impact and Hurdles
11.2 Screening Studies in Laboratory
11.3 Process Development at Laboratory Scale
11.4 Pilot Plants and Production
11.5 Challenges and Concerns
Acknowledgement
References
Index
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Preface to the First Edition
Microreactor technology is no longer in its infancy and its applications in many areas of science are emerging. This technology offers advantages to classical approaches by allowing miniaturization of structural features up to the micrometer regime. This book compiles the state of the art in organic synthesis and catalysis performed with microreactor technology. The term “microreactor” has been used in various contexts to describe different equipment, and some examples in this book might not justify this term at all. But most of the reactions and transformations highlighted in this book strongly benefit from the physical properties of microreactors, such as enhanced mass and heat transfer, because of a very large surface-to-volume ratio as well as regular flow profiles leading to improved yields with increased selectivities. Strict control over thermal or concentration gradients within the microreactor allows new methods to provide efficient chemical transformations with high space–time yields. The mixing of substrates and reagents can be performed under highly controlled conditions leading to improved protocols. The generation of hazardous intermediates in situ is safe as only small amounts are generated and directly react in a closed system. First reports that show the integration of appropriate analytical devices on the microreactor have appeared, which allow a rapid feedback for optimization.
Therefore, the current needs of organic chemistry can be addressed much more efficiently by providing new protocols for rapid reactions and, hence, fast access to novel compounds. Microreactor technology seems to provide an additional platform for efficient organic synthesis – but not all reactions benefit from this technology. Established chemistry in traditional flasks and vessels has other advantages, and most reactions involving solids are generally difficult to be handled in microreactors, though even the synthesis of solids has been described using microstructured devices.
In the first two chapters, the fabrication of microreactors useful for chemical synthesis is described and opportunities as well as problems arising from the manufacture process for chemical synthesis are highlighted. Chapter 1 deals with the fabrication of metal- and ceramic-based microdevices, and Brandner describes different techniques for their fabrication. In Chapter 2, Frank highlights the microreactors made from glass and silicon. These materials are more known to the organic chemists and have therefore been employed frequently in different laboratories. In Chapter 3, Barrow summarizes the use and properties of microreactors and also takes a wider view of what microreactors are and what their current and future uses can be.
The remaining chapters in this book deal with different aspects of organic synthesis and catalysis using the microreactor technology. A large number of homogeneous reactions performed in microreactors have been sorted and structured by Ryu et al. in Chapter 4.1, starting with very traditional, acid- and base-promoted reactions. They are followed by metal-catalyzed processes and photochemical transformations, which seem to be particularly well suited for microreactor applications. Heterogeneous reactions and the advantage of consecutive processes using reagents and catalysts on solid support are compiled by Ley et al. in Chapter 4.2. Flow chemistry is especially advantageous for such reactions, but certain limitations to supported reagents and catalysts still exist. Recent advances in stereoselective transformations and in multistep syntheses are explained in detail. Other biphasic reactions are dealt with in the following two chapters. In Chapter 4.3, we focus on liquid–liquid biphasic reactions and focus on the advantages that microreactors can offer for intense mixing of immiscible liquids. Organic reactions performed under liquid–liquid biphasic reaction conditions can be accelerated in microreactors, which is demonstrated using selected examples. The larger area of gas–liquid biphasic reactions is dealt with by Hessel et al. in Chapter 4.4. After introducing different contacting principles under continuous flow conditions, various examples show clearly the prospects of employing microreactors for such reactions. Aggressive and dangerous gases such as elemental fluorine can be handled and reacted safely in microreactors. The emergence of the bioorganic reactions is described by vanHest et al. in Chapter 4.5. Several of the reactions explained in this chapter are targeted toward diagnostic applications. Although on-chip analysis of biologic material is an important area, the results of initial research showing biocatalysis can also now be used efficiently in microreactors are summarized in this chapter. In Chapter 5, Hessel et al. explain that microreactor technology is already being used in the industry for the continuous production of chemicals on various scales. Although only few achievements have been published by industry, the insights of the authors into this area allowed a very good overview on current developments. Owing to the relatively easy numbering up of microreactor devices, the process development can be performed at the laboratory scale without major changes for larger production. Impressive examples of current production processes are given, and a rapid development in this area is expected over the next years. I am very grateful to all authors for their contributions and I hope that this compilation of organic chemistry and catalysis in microreactors will lead to new ideas and research efforts in this field.
Thomas Wirth
Cardiff
August 2007
Preface to the Second Edition
The continued and increased research efforts in microreactor and flow chemistry have led to an impressive increase in publications in recent years and even to a translation of the first edition of this book into Chinese. This is reflected not only in an update and expansion of all chapters of the first edition but also in the addition of several new chapters to this second edition.
In the first three chapters, Barrow, Brandner, and Frank, respectively, describe properties and fabrication methods of microreactors. In Chapter 4, Moore and Jensen give detailed insights into current methods of online and offline analyses, the potential of rapid optimization of reactions using flow technology, and the combination of analysis and optimization. For better readability, the material on organic synthesis has been split into five different chapters. Ryu et al. have extended their chapter on homogeneous reactions in microreactors, while Watts and Wiles have elaborated the topics of photochemistry, electrochemistry, and radiopharmaceutical synthesis in a new chapter as reactions in these areas are very suitable for being carried out using flow chemistry devices and many publications have recently appeared.
Takasu has written a comprehensive chapter on heterogeneous reactions in microreactors and a many different reactions can be found in this part. We have updated our chapter on liquid–liquid biphasic reactions and Hessel et al. have provided an update on the gas–liquid biphasic reactions. The chapter on bioorganic and biocatalytic reactions by Miyazaki et al. is a comprehensive overview of the developments in this area and highlights the advantages that flow chemistry can offer for research in bioorganic chemistry.
The final chapter by Hessel et al. on industrial microreactor process development up to production has seen a dramatic increase as in many areas industry is now adopting flow chemistry with all its advantages for research and for small- to medium-scale production.
I am again very grateful to all authors for providing updates or completely new contributions and I hope that this compilation of chemistry and catalysis in microreactors will stimulate new ideas and research efforts.
Thomas Wirth
Cardiff
January 2013
List of Contributors
Batool Ahmed-Omer
Cardiff University
School of Chemistry
Main Building
Park Place
Cardiff CF10 3AT
UK
David Barrow
Cardiff University
Cardiff School of Engineering
Laboratory for Applied Microsystems
Cardiff CF24 3TF
UK
Juergen J. Brandner
Karlsruhe Institute of Technology
Institute for Micro Process Engineering
Campus North
Hermann-von-Helmholtz-Platz 1
76344 Eggenstein-Leopoldshafen
Germany
Maria Portia Briones-Nagata
Measurement Solution Research Center
National Institute of Advanced
Industrial Science and Technology
807-1 Shuku, Tosu
Saga 841-0052
Japan
Ivana Dencic
Eindhoven University of Technology
Department of Chemical Engineering and Chemistry
Laboratory for Micro-Flow Chemistry and Process Technology
STW 1.37
5600 MB, Eindhoven
The Netherlands
Thomas Frank
Porzellanstr. 16
98693 Ilmenau
Germany
Takahide Fukuyama
Osaka Prefecture University
Graduate School of Science
Department of Chemistry
Sakai
Osaka 599-8531
Japan
Lily Giles
Cardiff University
Cardiff School of Engineering
Laboratory for Applied Microsystems
Cardiff CF24 3TF
UK
Volker Hessel
Eindhoven University of Technology
Department of Chemical Engineering and Chemistry
Laboratory for Micro-Flow Chemistry and Process Technology
STW 1.37
5600 MB Eindhoven
The Netherlands
Takeshi Honda
Measurement Solution Research Center
National Institute of Advanced Industrial Science and Technology
807-1 Shuku, Tosu
Saga 841-0052
Japan
Matthew J. Hutchings
Cardiff University
School of Chemistry
Main Building
Park Place
Cardiff CF10 3AT
UK
Klavs F. Jensen
Massachusetts Institute of Technology
Department of Chemical Engineering
Room 66-566
77 Massachusetts Avenue
Cambridge
MA 02139
USA
Masaya Miyazaki
Measurement Solution Research Center
National Institute of Advanced Industrial Science and Technology
807-1 Shuku, Tosu
Saga 841-0052
Japan
Jason S. Moore
Massachusetts Institute of Technology
Department of Chemical Engineering
Room 66-566
77 Massachusetts Avenue
Cambridge
MA 02139
USA
Alex Morgan
Cardiff University
Cardiff School of Engineering
Laboratory for Applied Microsystems
Cardiff CF24 3TF
UK
Md. Taifur Rahman
Osaka Prefecture University
Graduate School of Science
Department of Chemistry
Sakai
Osaka 599-8531
Japan
and
School of Chemistry and Chemical Engineering
David Keir Building
Queen's University
Belfast BT9 5AG
Northern Ireland
UK
Ilhyong Ryu
Osaka Prefecture University
Graduate School of Science
Department of Chemistry
Sakai
Osaka 599-8531
Japan
Kiyosei Takasu
Kyoto University
Graduate School of Pharmaceutical Sciences
Yoshida
Sakyo-ku
Kyoto 606-8501
Japan
Shan Taylor
Cardiff University
Cardiff School of Engineering
Laboratory for Applied Microsystems
Cardiff CF24 3TF
UK
Paul Watts
Research Chair in Microfluidic Bio/Chemical Processing
InnoVenton: NMMU Institute for Chemical Technology
Nelson Mandela Metropolitan University
Port Elizabeth 6031
South Africa
Charlotte Wiles
Chemtrix BV
Burgemeester Lemmensstraat 358
6163 JT Geleen
The Netherlands
Thomas Wirth
Cardiff University
School of Chemistry
Main Building
Park Place
Cardiff CF10 3AT
UK
Hiroshi Yamaguchi
Measurement Solution Research Center
National Institute of Advanced Industrial Science and Technology
807-1 Shuku, Tosu
Saga 841-0052
Japan
1
Properties and Use of Microreactors
David Barrow, Shan Taylor, Alex Morgan, and Lily Giles
1.1 Introduction
Microreactors are devices that incorporate at least one three-dimensional duct, with one or more lateral dimensions of <1 mm (typically a few hundred micrometers in diameter), in which chemical reactions take place, usually under liquid-flowing conditions [1]. Such ducts are frequently referred to as microchannels, usually transporting liquids, vapors, and/or gases, sometimes with suspensions of particulate matter, such as catalysts (Figure 1.1) [2]. Often, microreactors are constructed as planar devices, often employing fabrication processes similar to those used in manufacturing of microelectronic and micromechanical chips, with ducts or channels machined into a planar surface (Figure 1.2c and d) [3]. The volume output per unit time from a single microreactor element (Figure 1.2b, c, d and e) is small, but industrial rates can be realized by having many microreactors working in parallel (Figure 1.2f).
Figure 1.1 Detailed example of a simple duct-based microreactor fabricated from polytetrafluoroethylene (with perfluoralkoxy capping layer). Reagents 1 and 2 interact by diffusive mixing within the reaction coil. The reaction product becomes the continuous phase for an immiscible discontinuous phase, which initially forms elongate slugs. When subject to a capillary dimensional expansion, slugs become spheres, which are then coated with a reagent (that is miscible with the continuous phase) fed through numerous narrow, high aspect ratio ducts made with a femtosecond laser.
Figure 1.2 Examples of modern-day microreactors and other microfluidic components. (a) Source: Reprinted with permission from Takeshi et al. (2006) Org. Process Res. Dev., 10, 1126–1131. Copyright (2006) American Chemical Society.
However, microreactor research can be conducted on simple microbore tubing fabricated from stainless steel (Figure 1.2a), polytetrafluoroethylene (PTFE), or any material compatible with the chemical processing conditions employed [4]. For instance, inexpensive fluoroelastomeric tubing was employed to prepare a packed-bed microreactor for the catalysis of oxidized primary and secondary alcohols [5]. As such, microreactor technology is related to the much wider field of microfluidics, which involves an extended set of microdevices and device integration strategies for fluid and particle manipulation [6].
1.1.1 A Brief History of Microreactors
In 1883, Reynolds' study on fluid flow was published in the Philosophical Transactions of the Royal Society [7]. Reynolds used streams of colored water in glass piping to visually observe fluid flow over a range of parameters. The apparatus used is depicted in a drawing by Reynolds himself (Figure 1.3), which shows flared glass tubing within a water-filled tank. Using this setup, he discovered that varying velocities, diameters of the piping, and temperatures led to transitions between “streamline” and “sinuous” flow (respectively known as laminar and turbulent flow today). This paper was a landmark, which demonstrated practical and philosophical aspects of fluid mechanics that are still endorsed and used in many fields of science and engineering today, including microreactor technology [8].
Figure 1.3 The original apparatus used by Osborne Reynolds to study the motion of water [7]. The apparatus consisted of a tank filled with water and glass tubing within. Colored water was injected through the glass tubing, so the characteristics of fluid flow could be observed.
An early example for the use of a microreactor was demonstrated in 1977 by the inventor Bollet, working for Elf Union (now part of Total) [9]. The invention involved mixing of two liquids in a micromachined device. In 1989, a microreactor that aimed at reducing the cost of large heat release reactions was designed by Schmid and Caesar working for Messerschmitt–Bölkow–Blohm GmbH. Subsequently, an application for patent was made by the company in 1991 [10]. In 1993, Benson and Ponson published their important paper on how miniature chemical processing plants could redistribute and decentralize production to customer locations [11]. Later, in 1996, Alan Bard filed a US patent (priority 1994) where it is taught how an integrated chemical synthesizer could be constructed from a number of microliter-capacity microreactor modules, most preferably in a chip-like format, which can be used together, or interchangeably, on a motherboard (like electronic chips), and based upon thermal, electrochemical, photochemical, and pressurized principles [12]. Following this, a pioneering experiment conducted by Salimi-Moosavi and colleagues (1997) introduced one of the first examples of electrically driven solvent flow in a microreactor used for organic synthesis. An electro-osmotic-controlled flow was used to regulate mixing of reagents, p-nitrobenzenediazonium tetrafluoroborate (AZO) and N,N-di-methylaniline, to produce a red dye [13]. One of the first microreactor-based manufacturing systems was designed and commissioned by CPC in 2001 for Clariant [14].
Microreactor systems have since evolved from basic, single-step chemical reactions to more complicated multistep processes. Belder et al. (2006) claim to have made the first example of a microreactor that integrated synthesis, separation, and analysis on a single device [15]. The microfluidic chip fabricated from fused silica (as seen in Figure 1.4) was used to apply microchip electrophoresis to test the enantioselective biocatalysts that were created. The authors reported a separation of enantiomers within 90 s, highlighting the high throughput of such devices.
Figure 1.4 Fused silica microfluidic chip compared to the size of a €2 coin. The chip was the first example of synthesis, separation and analysis combined on a single device. Source: Photograph courtesy of Professor D. Belder with permission.
Early patents in microreactor engineering have been extensively reviewed by Hessel et al. (2008) [16] and then later by Kumar et al. (2011) [17]. From 1999 to 2009, the number of research articles published on microreactor technology rose from 61 to 325 per annum (Figure 1.5a) [17]. The United States of America produced the majority of research articles, followed by the People's Republic of China and Germany (Figure 1.5c) [17]. The number of patent publications produced was also highest in the United States of America; the data are given in Figure 1.5b [17]. The number of patent publications is highest in the field of inorganic chemistry, but of particular interest, organic chemistry comes second out 18 fields of chemical applications investigated [16].
Figure 1.5 (a) The number of research articles published on microreactors from the years 1999 to 2009. (b) Distribution of patent publications produced from 10 different countries. (EP: European; US: United States; DE: Germany; JP: Japan; GB: United Kingdom; FR: France; NL: Netherlands; CH: Switzerland; SE: Sweden). (c) Distribution of published research articles from various countries. Source: Images reprinted from Ref. [17], with permission from Elsevier.
Microreactor technology has been widely employed in academia and is also beginning to be used in industry where clear benefits arise and are worthy of new financial investment. Companies contributing considerably to the development of microreactors include Merck Patent GmbH, Battelle Memorial Institute, Velocys Inc., Forschungszentrum Karlsruhe, The Institute for Microtechnology Mainz, Chemical Process Systems, Little Things Factory GmbH, Syrris Ltd, Ehrfeld Mikrotechnik BTC, Micronit BV, Mikroglas chemtech GmbH, Chemtrix BV, Vapourtec Ltd, Microreactor Technologies Inc., Xytel Corporation, and more [16, 18].
To place microreactors clearly within an historical context, we can relate the emergence of such devices to their nearest neighbors, these being from the wider field of microfluidics, which includes the flow of gases. With respect to this, we can see that some of the earliest examples of microfluidic devices go back at least to 1970, when James Lovelock filed patent US3,701,632 describing a planar chip-based chromatograph fabricated from wet-etched magnesium oxide (Figure 1.6).
Figure 1.6 Image of a planar chip chromatograph, microfabricated from wet etched magnesium oxide, described in US patent 3,701,632 filed in 1970 by James Lovelock. Image is a screen capture from a movie of Dennis Desty talking about innovations in chromatography. Source: Courtesy, Prof. Peter Myers, Liverpool University UK.
1.1.2 Advantages of Microreactors
Flow chemistry is long established for manufacturing large quantities of materials [19]. However, this can sometimes be time consuming and expensive due to the amount of materials used. Also, scaling up a small process to a much larger industrial sized application can be challenging and often results in batch processing. This type of processing can lead to variances between each batch, ultimately yielding inconclusive and unreproducible results [19]. In contrast, the use of microreactors enables chemical reactions to be run continuously [20], usually in a flowing stream, and from this the topic of microprocess chemistry was born [21]. Microreactors are therefore seen as the modern-day chemists' round-bottom flask [19] and can potentially revolutionize the practice of chemical synthesis [4]. For instance, using microscale reactors, reactions can be carried out under isothermal conditions with well-defined residence times, so that undesirable side reactions and product degradation are limited. The distinctive fluid-flow and thermal and chemical kinetic behavior observed in microreactors, as well as their size and energy characteristics, lend their use to diverse applications [22, 23] including:
high-purity chemical products [24],highly exothermic reactions [25, 26],screening for potential catalysts [27, 28],precision particle manufacture [29],high-throughput material synthesis [30],emulsification and microencapsulation [31],fuel cell construction [32],point-of-use, miniature, and portable microplants [33].These new application horizons are enabled by the following advantages: (i) reduced size through microfabrication, (ii) reduced diffusion distances, (iii) enhanced rates of thermal and mass transfer and subsequent processing yields [34, 35], (iv) reduced reaction volumes, (v) controlled sealed systems avoiding contamination, (vi) use of solvents at elevated pressures and temperatures, (vii) reduced chemical consumption, (viii) facility for continuous synthesis [36], and (ix) increased atom efficiency [37]. Microreactor research and development has been particularly promoted for high-throughput synthesis in the pharmaceutical industry, where large numbers of potential pharmaceutically beneficial compounds need to be generated, initially, in small quantities, as a component of the drug discovery process [38]. In this chapter, the key functional properties of microreactors are reviewed in the context of use in diverse fields.
1.2 Physical Characteristics of Microreactors
1.2.1 Geometries
Figure 1.7 Examples of multiple microreactors used in parallel for higher throughput and yield of products [47, 48]. Source: Figures reprinted with permission, copyright (2010), American Chemical Society.
The principle of numbering-up has been used on an industrial scale for nitration reactions performed under current good manufacturing practice (cGMP) [49]. Historically, in 2001, CPC built and commissioned one of the first microreactor-based micromanufacturing plants, which incorporated many parallel microreactors. This was for the manufacture of diazo pigments for the company Clariant. The three-step manufacturing process, which involved (i) diazotation, (ii) coupling, and (iii) pigmenting (conditioning), was found to improve the product quality through improved particle size distribution and dye properties of the diazo pigments. The so-called CYTOS Pilot System used multiples of individual microreactors, so that products developed as small quantities on a laboratory scale could be produced in bulk at a manufacturing level without changing the essential chemical processing conditions. The scale of such a system is shown in Figure 1.8.
Figure 1.8 Parallel microreactor system (the so-called CYTOS Pilot System) designed and commissioned by CPC for Clariant in 2001, for the manufacturing of diazo pigments. Source: Reprinted from Ref. [50], Copyright (2007), with permission from Elsevier.
The engineering of numbering-up solutions for processes involving reactions with heat/mass transfer usually requires a distribution system from a common reactant source through many reaction microchannels to a common product outlet such that the same residence time is experienced in all the reaction microchannels. From an analytical comparison of bifurcating and consecutive source/outlet manifold structures, as resistance networks, design guidelines have been derived, which consider manufacturing variations in microchannel geometry, microchannel aspect ratio, and microchannel blockages incurred during function [51, 52]. From this, it has been shown that a distribution system of bifurcating ducts always produces flow equipartition as long as the length of the straight channel after each channel bend is sufficient for a symmetrical velocity profile to develop. Nevertheless, it is clearly important to be able to detect blockages within channels, but placing sensors in every channel is not economically feasible. However, one scheme has shown that by careful consideration of circuit design, blockages in any one of a number of parallelized microreactors can be detected with just two in-line flow sensors [53].
A long-standing issue in the development of process chemistries is that a reaction scheme developed in a small bench top flask may not scale-up with the same output parameters when transferred to an industrial production reactor. Instead, this problem is potentially circumvented by arithmetically numbering-up, in parallel operation, the multiplicity of the same microreactors to achieve the target output [1]. However, this engineering challenge is not trivial, since many parallel reactors may be required to achieve significant volume outputs. Pioneering examples of those industrial processes, which have been successfully achieved using microreactor technology, are described in Chapter 5. Those, which have shown commercial success, appear to represent mostly high-value, relatively low-volume products, products that are particularly dangerous to manufacture, entirely new class of products, and/or those that have a short shelf life.
1.2.2 Constructional Materials and Their Properties
Microfluidic devices, which may be suitable for chemical synthesis according to the processing conditions, have been fabricated from a range of materials including glass [54], elastomers [55], silicon [56], quartz, flouropolymers [57], metals [58], and ceramics [59] employing the techniques of laser ablation [60], wet chemical etching [61], abrasive micromachining [61], deep reactive ion etching [62], molding [63], embossing [64, 65], casting [66], and milling [67].
Advanced microreactors for manufacturing-level chemical production place demanding requirements on their integrated functionality and durability. For instance, thermal tolerance to processing conditions, temporal stability of surface energy, surface chemistry, and activity of incorporated catalysts and compatibility with sterilization protocol are important considerations when choosing a constructional material. Materials are also required to [68]
be chemically inert,have appropriate thermal and electrical properties,be compatible with solvents and acids used,have some degree of light transparency if on-chip analysis is required,be compatible with fabrication protocol employed,be usable for extended processing durations.These are further complicated by application- and process-specific requirements. For example, the excitation and control of reactions may require temporal and spatial modulation of applied energies such as UV, IR, and microwave radiation. All these considerations place exacting specifications on the constructional materials in order that the required geometries may be fabricated in a manner that is cost-effectively compatible with envisaged manufacturing-level scenarios. Where massively parallel microreactor systems are required for volume outputs, constructional materials must be appropriate to the economies and micromanufacturing processes of mass-fabricated parts. Equally, levels of specific functional integration must be equated with the overall system-level integration strategy and range from monolithic to hybrid solutions. Most preferably, this is more of a long-term goal, reconfigurable or addressable component functions will allow for the creation of application-specific microreactor ensembles from a “programmable” platform technology.
Table 1.1 gives a brief overview of the different materials, advantages and disadvantages, fabrication techniques, and applications in microreactor technology. Glass and silicon have been used extensively in earlier microreactors and are slowly being supplemented by inexpensive and easy-to-fabricate polymers such as polydimethylsiloxane (PDMS), at least in academic research laboratories [69]. Many copies of a PDMS microfluidic circuit can be molded from a master made from, for example, silicon [70]. However, there are limitations in its use, and for microreactors, it is generally the swelling of the PDMS in a solvent, which first limits its application [71]. Glass is still the material of choice for many synthetic applications due to its characteristics described in Table 1.1 [68, 72]. However, due to its low thermal conductivity, glass is not quite as suitable for high-temperature and high-pressure reactions. Stainless steel, silicon, and ceramics are the alternative materials that can be used for these specific reactions [68]. More details on particular important aspects are described in Chapters 2–4 and in the given references.
Table 1.1 Overview of materials and microfabrication techniques used for microreactor construction [68, 69, 72–75]
While basic microreactors and arrays may be fabricated from glass, polymers, metals, or ceramics, advanced microreactors with multifunctional and reconfigurable capability will require construction from a diverse and integrated materials set. As example, focused microwave excitation delivered at multiple resonator nodes within a fluidic microreactor array will require constructional materials and associated machining processes suitable for both reaction chemistry and the spatial distribution of microwave energy. For this, a set of glass, polymers, and metals are required each of which might be separately microstructured using one or more techniques of subtractive machining (etching, ablation), embossing, molding, and casting. Industrial-scale processes in microreactors are often conducted under medium to high pressures and with the use and production of highly reactive chemicals. This may require the use of pressure-, solvent-, and temperature-tolerant stainless steel, ceramic, or glass with associated accessories, such as gaskets and interconnects, sometimes fabricated from polytetrafluoroethylene and polyetheretherketone (PEEK). Although fluorous polymers might be an optimal choice for many applications including corrosive or other hazardous chemicals, their micromanufacturing compatibility must be taken into account. For instance, PTFE does not lend itself to the mass-fabrication technique of embossing but can be microstructured using reactive ion etching as used frequently at a wafer level with silicon. In contrast, a thermoplastic variant, perflouroalkoxy, can be molded; it is highly solvent resistant, has FDA approval for many applications, and is sterilization compatible. In contrast to the requirements imposed by industrial application, experimental, laboratory chip-based devices for research purposes have also been fabricated from the same materials but may also include silicon, silicon-pyrex, and occasionally polymers such as poly(methyl methacrylate), polycarbonate, cyclic olefin copolymer, and polydimethylsiloxane.
Many chemical reactions performed in microreactors are conducted at room temperature, but in others that require heating and/or cooling, thermal transfer to the microdevice is an important issue and imparts on the selection of constructional materials [76]. In this respect, cooling or heating units have been combined with microdevices to allow constant reaction temperatures or controlled temperature zones [77]. In the synthesis of biologically active fluorescent quantum dots, three separate microreactor chips were used, at different temperatures for (i) the control of the size and spectral properties of cadmium selenide and cadmium telluride nanoparticles at 300 °C, (ii) their zinc sulfide capping at 110–120 °C, and (iii) ligand replacement at 60 °C. These could, of course, be potentially integrated into one larger chip with zoned temperature control [78].
As well as the basic materials from which a microreactor is fabricated, there may be additional materials that are included as coating or packing. For instance, in a glass-polymer composite continuous-flow microreactor, palladium particles have been loaded by ion exchange and reduced. This was used in a Heck reactions and demonstrated to be re-usable for >20 times post wash treatment [79]. Also, coating of the capillary channel of a microreactor with elemental palladium allowed palladium-catalyzed coupling reactions to be performed very efficiently, and the metal coating also serves as recipient for microwave energy allowing a fast heating of the reaction solution [80]. Another popular coating is TiO2 that is frequently used as a photocatalyst for the degradation of organic pollutants. This has been coated onto prefabricated ZnO nanorods on the internal walls of a glass microreactor and has been shown to significantly increase the surface area for photocatalytic oxidation [81]. As a simpler one-step method of increasing the catalytic surface area, a foam-like porous ceramic containing a catalyst as nanoparticle was formed in a microreactor by direct sol-gelation, thus avoiding any separate coating or impregnation step [82]. The result demonstrated a reasonable pressure drop due to its porosity, high thermal and catalytic stability, and excellent catalytic behavior in forming hydrogen and carbon monoxide-rich syngas from butane. Additionally, zeolite materials can function as a valuable adsorbent and catalyst in microreactors and their precision growth can be pre-seeded from nano-zeolites grafted on to silanised microreactor surfaces such as metal (Figure 1.9 [83]).
Figure 1.9 Scanning electron microscope pictures of an example surface modification, in this case, a NaA zeolite film grown on seeded porous stainless steel, multichannel plate using chloropropyl trimethoxysilane (CP-TMS) linkers (a), (c), (d), and aminopropyl trimethoxysilane (AP-TMS) linkers (b) [83]. Source: Reprinted from Yang, G. et al. (2007) A novel method for the assembly of nano-zeolite crystals on porous stainless steel microchannel and then zeolite film growth. J. Phys. Chem. Solids, 68(1), 26–31, with permission from Elsevier.
A porous organic polymer monolith may be formed within a microreactor to act as a support for catalysts, such as palladium. The size, size distribution, and surface area of the pores may be controlled by a porogen, while the chemical properties are controlled by the monomer used. Such supports can be formed and even patterned by the use of ultraviolet light, most cost-effectively using ultraviolet light-emitting-diode arrays [84, 85]. Carbon nanofibers can also be deposited within microreactors by homogeneous deposition precipitation and pulsed laser deposition to provide a larger surface area support layer upon which catalysts such as ruthenium catalytic nanoparticles can be attached [86].
1.3 Fluid Flow and Delivery Regimes
1.3.1 Fluid Flow
Flow in microreactors is typically characterized by a low Reynolds number . The Reynolds number is a dimensionless number that describes the ratio of inertial forces to viscous forces and is calculated by
(1.1)
where L is the characteristic length, is the fluid velocity, is the fluid density, and is the fluid viscosity. When viscous forces dominate, as it is typical within microreactors, fluid flow is laminar. The threshold at which transition from turbulent to laminar flow occurs is dependent on the geometry of ducts through which the fluid is flowing, but typically, in a smooth channel or capillary, transition occurs between Re value 2000 and 2500 [87, 88]. As a result, without the use of special structures or active mechanisms, there is little turbulence-based mixing, and mixing occurs mainly through diffusion. Fick's Law of diffusion says that where is the particle density or concentration, is the diffusion coefficient, and Δ is the Laplace operator, then, the diffusion flux, , can be defined as
(1.2)
The diffusion can be further described by the Schmidt number (), which is the ratio of kinematic viscosity or momentum diffusivity, , to mass diffusivity as defined by
(1.3)
The Schmidt number is also a dimensionless number but is unrelated to the geometry of the microchannel or capillary. As such, it is a characteristic of the liquid and can be used to determine how diffusion will occur within a certain liquid. Additionally, the rate of mass diffusion can be compared to the advection of a liquid within a microreactor via the Peclet number ()
(1.4)
This number is a measure of the importance of advection in relation to diffusion. As the Peclet number increases so does the dominance of flow forces over that of molecular diffusion with regard to mixing. This number is, therefore, important in determining the conditions in which diffusion is the primary mixing method [89].
To demonstrate how advantageous working at a microscale can be, consider an initially very small spot of tracer in a resting solution [89]. The time () taken by this spot to spread over a distance can be estimated as
(1.5)
This means that for reactions limited by diffusion, reaction time is proportional to the square of the rate limiting distance. Therefore, a reaction in a 10 cm flask could take 1 000 000 times less if undertaken in a 100 μm diameter microreactor. Dramatically reduced reaction times have, arguably, been the most potent driving force behind research in microreactor technology.
Figure 1.10 demonstrates the spreading of the “front” between two streams. The width of this front, δ, increases through diffusion over time as the fluids travel down the channel [89]. This width can be approximated using
(1.6)
If the width of the front is set to the width of the channel then the time it takes to mix diffusively in a microchannel can be determined.
Figure 1.10 Diffusive mixing in a square cross-sectional (side 500 μm) channel. (a) Two streams of water (colored to indicate the ratio of liquid one to liquid two, 1 on the scale indicating purely liquid one) running at 1 m/s in parallel to each other with mixing through diffusion only (b) Same simulation (as a) highlighting the region of diffusive mixing or “front” between the two fluids, in this case the lighter region indicates where diffusive mixing has occurred. The width of the front, δ, is indicated. Source: Both images obtained via COMSOL Multiphysics® simulation.
Although the limited levels of mixing in microchannels can be advantageous, sometimes greater levels of mixing are required. There are ways to encourage non-diffusion-based mixing to occur within a microchannel such as introducing an obstacle to induce turbulence-based mixing. An obstacle can cause turbulent flow as it can drastically lower the laminar flow transition threshold (into the region of Re 100 [90]). Adding turns to a channel can also initiate greater levels of mixing. In an enclosed rectangular channel, as fluid travels around a curve at appropriate flow rates, vortices are set up in the upper and lower halves of the channel; these are called Dean vortices (Figure 1.11).
Figure 1.11 Cross section of a turning rectangular channel showing Dean vortices caused by the turn. These Dean vortices can be advantageous, for example, in mixing or particle sorting. IW is the inner wall of the turn and OW is the outer wall.
These Dean vortices will cause mixing but only across the width of the channel, not from top to bottom (Figure 1.12). (For further information about microreactor mixing see Section 1.3.3.)
Figure 1.12 Two parallel streams of water, A and B, (flowing at 3 m/s) are mixed via Dean vortices in a turn. Mixing before the turn is mostly by diffusion. Source: Image obtained via COMSOL Multiphysics® simulation.
While fluid flow is often continuous and laminar, other regimes exist, such as, for example, in segmented flow. Here, immiscible fluids, or phases, are configured to provide contiguous “trains” of fluid “segments” or “packets” (see also Section 4.3). The flow within these fluid segments may be configured to be such that there occurs an internal vortex that causes rapid mixing within segment contents (Figure 1.13) and counters the lack of mixing normally characteristic of microscale fluid flow [91–94]. This fluid flow regime depends on the absolute velocity of the fluids, the fluid viscosities, their interfacial tension, and the geometry of the channels [95]. Adjacent contiguous segments may enjoy a highly dynamic fluidic interface providing many opportunities for novel interfacial chemical and other reactions. This internal vortex and interpacket dynamic interface may be readily switched to laminar flow (within packets) by simple modulation of the duct cross-sectional geometry, thereby changing the three-dimensional format of the individual fluid packets. Thus, dramatic alterations in mixing and mass transfer may be programmed within a given microreactor circuit configuration. The use of such solvent droplets resulting from controlled segmented flow has been proposed as individual nanoliter-scale reactors for organic synthesis [40, 41]. Fluid flow segmentation may be generated for a wide range of immiscible fluid matrices.
Figure 1.13 Internal circulations (indicated by the dashed lines) within segmented flow segments. Segments are white; continuous phase is the gray area. (a) Circulation over the whole length of the segment. This occurs within liquid segments suspended in an air continuous phase. (b) In a liquid–liquid system, circulation occurs at the front of the segment. The volume fraction of the circulation zone is dependent on certain parameters. Higher segment velocities increase the volume fraction of the circulation. This circulation zone can also be increased by using a lower viscosity continuous phase. Low interfacial tension also increases the size. High interfacial tension and viscosity can lead to no circulation at all. (c) At high segment velocities, counter-rotating circulation can be initiated towards the rear of the segment. Circulation zones are always set up in the continuous phase between the segments, irrespective of the other parameters [96].
Fluid packets may (i) contain particulates, including solid support beads, catalysts, and separations media, (ii) be subject to sequential additional reagent delivery through tributary ducts and channel injectors, (iii) be caused to split and/or coalesce, and (iv) be provided with individual identity through the provision of addressable molecular photonic and other codes. Segmented fluid packets as shown in Figures 1.13 and 1.17 may therefore be considered as “test tubes on the move” that are, for instance, transferred seamlessly from one functional high-throughput screening operation to another. The fluid packet format, for example, segmented by inert perfluorinated fluids, can be combined with interpacket liquid–liquid or solid-phase extractions [97] and microchannel contactor functions, enabling many possibilities for compound transfer between the different solvent streams of hyphenated functional processes. Collectively, these tools pose a radically different opportunity for synthesis, assay, and characterization procedures to traditional high-throughput screening operations such as in microtiter plate technology, storage, and information handling. This new platform paradigm with its inherent opportunities requires exploration through experimentation and modeling. For example, in a gas–liquid carbonylative coupling reaction, an annular flow regime was employed to generate a high interfacial surface area, where a thin film of liquid was forced to the wall surfaces of a microreactor (5 m length, 75 μl capacity) by carbon monoxide gas flow through the center [98].
The laminar stationary flow of an incompressible viscous liquid through cylindrical tubes can be described by Poiseuille's law. This description was later extended to turbulent flow. Flowing patterns of two immiscible phases are more complex in microcapillaries. Various patterns of liquid–liquid flow are described in more detail in Section 4.3, while liquid–gas flow and related applications are discussed in Section 4.4.
1.3.2 Fluid Delivery
Figure 1.14 Image sequences showing the nature of electro-osmotic flow (a) as compared to pressure-driven flow (b) in a 200 μm id circular cross-section capillary. The transport of the photo-injected cross-stream fluorescent markers illustrates: (a) the plug-like velocity profile characteristic of electro-osmotic flows, and (b) the parabolic velocity profile characteristic of pressure-driven flows. These images were obtained using caged-fluorescence imaging. Source: Image from Figure 1, Ref. [111] with kind permission from Springer Science and Business Media.
1.3.3 Mixing Mechanisms
Microreactors are usually characterized by geometries with a low Reynolds number. In such capillary-scale ducts, laminar flow is dominant, and mixing relies essentially on diffusion unless special measures are taken, such as to cause turbulence or reduce diffusion time. Equally, laminar flow may be exploited such that laminar flow streams moving in parallel may contain reagents, which are caused to interact by careful control of the flow rate and variations in the microreactor geometry. A range of passive and active techniques to induce mixing include (i) complex geometries within microfluidic manifolds to cause repeated fluid twisting and flattening [112], (ii) acoustic streaming [113], (iii) resonant diaphragms, and (iv) acoustic cavitation microstreaming [114, 115]. Passive techniques such as split and recombine suffer from the requirement that fluids must usually be in a state of flow, whereas active methodologies enable mixing where there is no flow, such as in microwell reactors and under temporary stopped-flow conditions in microchannel reactors. A variant on this is a stopped-flow, batch-mode technique and has been employed to induce mixing on a centrifugal platform [116]. Not dissimilarly, pulsed flow in a microchannel has also been shown to be effective at causing accelerated mixing [117] and is dependent on several factors including the Strouhal number, the Peclet number, phase difference, pulse-to-volume ratio, and microchannel geometry. Microfabricated geometries within the microreactor design and which split and recombine fluids have been shown to cause multilamination and thus reduced diffusion distances [118–120]. Chaotic advection may also be caused by channels that contain integral staggered, serial, asymmetric rib-like structures [121] or are three-dimensionally twisted [122] (Figure 1.15). Active mechanisms for mixing based on energized, ultrasonically induced transport have been demonstrated [123]. An interesting form of rapid micromixing may also be achieved in liquid–liquid multiphase flow microreactors where within serial contiguous fluid packets there exists an internal vortex flow that counters the laminar flow profile normally characteristic of low Reynolds number geometries [96, 124].
Figure 1.15 Advection caused by integral structures. A schematic diagram of a microchannel with square grooves in the bottom wall. Below the channel to the right, the average flow profile in the cross section is drawn schematically. The ribbon indicates schematically a typical helical streamline in the channel. Source: Adapted with permission from Ref. [125]. Copyright 2002 American Chemical Society.
1.4 Multifunctional Integration
Some argue that miniaturized tools for both chemical synthesis and analysis need to be integrated onto a single chip in order to gain the true benefits of miniaturization [126], not least because of the problems associated with subsystem interconnectivity, dead volumes, and chip-to-world interfaces. Demonstrations toward such a goal include, for example, a hyphenated mixing reaction channel coupled to a capillary electrophoresis column [127].
As well as miniaturized reactors, microdevices with other functionalities extend the range of functional capabilities that may be achieved when a systems approach is considered [128]. Such microdevices may include mixers, separators, heat exchangers, heaters, coolers, photoreactors, analysis sub-systems, and devices for the application of pulsed electric fields [129]. Therefore, a wide range of processes including extractions (liquid–liquid, liquid–gas, solid-phase enhanced), crystallizations, distillations, purifications, conversions, phase-changes, phase separations, and identifications may be enabled. Thermal conditions may be more readily monitored throughout a microreaction system by employing a distributed reporter such as a thermochromic dye [130] that can report <1 °C temperature variations, albeit over a limited dynamic temperature range.
Interconnects to and between such microdevices for laboratory-scale experimental apparatus have historically been problematical, since a mechanically sound, pressure-resistant, and hermetic juncture with minimal dead volume is usually required. For robust, industry-ready chemical production equipment, stainless-steel fittings are usually employed in microreactor systems. For laboratory-scale apparatus with more delicate chip-based microreactors, a range of microfabricated solutions have been explored [131, 132], resulting in both miniaturized plug-and-play microconnectors [133] and macroscale interface housings. Both adhesive [134] and mechanical [135] solutions have been developed, but it has been reported that the latter have at least an order of magnitude greater strength than the former. More widely, the issues surrounding the packaging and interconnectivity of microfluidics and associated devices have been comprehensively summarized by Velten et al. [136].
1.5 Uses of Microreactors
1.5.1 Overview
Microreactors offer a radical alternative platform for chemical synthesis, normally undertaken in macroscale flasks [137–139] as shown in Figure 1.16. When reactions in microcapillary-scale reactors are compared to that in flask-scale batch reactors, they have been shown to offer yield, rate, or selectivity advantages in a diversity of reactions schemes including carbonylative cross-coupling of arylhalides to secondary amides [98], oxidations [140], nitrations [25], fluorinations [141], hydrogenation [142], and many others detailed also in Sections 4.1–4.5.
Figure 1.16 The hydrolysis of p-nitrophenyl acetate under different reactor conditions showing the clear advantage of reaction time to that observed in a round-bottomed flask.
An important advantage of microreactor technology for organic synthesis and catalysis is that continuous flow processing is enabled [143]. This is often not possible with conventional macroscale reactors and batch production. As an example, multistep chemical synthesis of carbamates in a continuous flow process has been demonstrated using three reaction steps and two separation steps in between the reaction steps. Using a serial cascade of three microreactors and two phase separators, to enable solvent switching and in situ generation and consumption of dangerous intermediates, the safe processing of high-energy chemistries and small-scale production of chemicals in a compact chip-based processing system were demonstrated [144, 145]. One of the problems with continuous-flow microreactors is that of cross-contamination from different reactions where (i) sequential reaction steps require solvent, reagent, and other condition changes and (ii) parallel reaction requires similar types of reactions being performed using different combinations of reagents [146].
1.5.1.1 Fast and Exothermic Reactions
Microreactors provide a safe means by which reactions, including multistage schemes, can be undertaken where, otherwise, products involving unstable intermediates may be formed. This is exemplified by Fortt et al. who showed that for a serial chloro-diazotation Sandmeyer reaction performed in a microreactor under hydrodynamic pumping, significant yield enhancements (15–20%) were observed and attributed to enhanced heat and mass transfer [147]. This demonstrates the advantage of microreactor-based synthesis where diazonium salts are sensitive to electromagnetic radiation and static electricity that in turn can lead to rapid decomposition. Microreactors facilitate the ability to achieve continuous flow synthesis, which is often not possible with conventional macroscale reactors and batch production.
A key feature of microreactors is the comparatively large surface area when compared to conventional reactors. Surface-to-volume ratios of 20 000 m2/m3 may be possible for microreactors whereas 1000 m2/m3 may be more typical for a conventional reactor. The surface area may be further enhanced (i) by providing microfabricated pillared or ribbed structures within the reactor space, (ii) by introducing packing materials, and (iii) by providing high specific surface areas, which can be obtained with porous silicon. In catalytic reactions, where competition exists between the rate of diffusion to the catalyst sites and the rate of the reaction, mass transport resistance is usually eliminated in a microreactor [148]. Therefore, microreactors provide excellent environments for catalytic reactions, such as for palladium catalysis as employed for Heck and Sonogashira couplings [149, 150]. It has been highlighted that such catalysts usually form solid–liquid heterogenous systems, rendering them difficult to employ in microscale channels. However, when room temperature ionic liquids are used to dissolve the catalyst, a liquid–liquid, two-phase system can be successfully employed (as shown for a Sonogashira coupling), thus enabling fast catalyst screening [151]. Catalytic reactions performed in microreactors may be functionally extended by introducing external energy sources such as light. For instance, photocatalytic anatase titania films have been applied by slip-casting onto the internal surface of planar glass microreactors and the dramatic improvement of photocatalytic function improved hugely by the addition of gaseous oxygen [152]. Planar chip-based microreactors for photocatalytic reactions offer the potential for improvements in the coupling (increased spatial homogeneity and reduced attenuation) of applied irradiation to reaction reagents and catalysts due to the short penetration path lengths that may be enabled by efficient design [153, 154]. Such microreactors are fabricated ideally from pyrex, amorphous fluoropolymers, or quartz, most preferably the latter since it facilitates both the employment of higher operational temperatures and less light attenuation than pyrex at lower ultraviolet wavelengths.
1.5.2 Precision Particle Manufacture
Multiphase flow in a tubular, chip-based, or freestanding capillary microreactor may be controlled such that the so-called segmented flow creates serial, contiguous packets of immiscible fluids (Figure 1.17).
Figure 1.17 Example of slug-flow generation and liquid phase separation on a chip fabricated from polytetrafluoroethylene (capped with light-transmissive perfluoroalkoxy). Here, chloroform (organic phase) and water form the segmented flow stream, which is subsequently separated back into the original liquid phases using a phase separator that comprises numerous very narrow but high-aspect-ratio ducts at the outlet. Water phase is colored, whereas the chloroform is colorless.
The segmented flow condition may be created by several contrasting microreactor geometry configurations, including (i) simple T-junction, (ii) constriction junction, (iii) sheath flow junction, and (iv) fluidic oscillator arrangements [155]. The precision of fluid volume elution controlled by these means depends on several factors. Particularly critical are temperature stability of microreactor and reagents used, a long-duration stable surface energy of the material from which the microreactor is fabricated, and precision control of fluid flow rate(s). Segmented flow patterns are not always readily generated, and gas–liquid flows produced, for example, from a T-junction, may result in annular flow [98]. Such fluid packets can be created at a wide range of sizes and can exhibit a very narrow size distribution and may be converted into solid and semi-solid microparticles of different morphology (e.g., spherical, discoid, fibrous, and macroporous) by various means such as UV-polymerization, freezing, or chemical cross-linking (Figure 1.18). Further, such fluid segments are dependent on microreator size, cross-sectional shape, aspect ratio, surface tension, and contact liquid viscosities and contact angles [156].
Figure 1.18 Spheres created “on-chip” and cured using UV-polymerization.
In addition to particle manufacture, it is also possible to manipulate particles, thus enabling their movement between different chemical treatment zones [157, 158] as well as sorting them by size [159–164]. Particle manipulation theories are not just useful in particle manufacture; they can also be applied to cell enrichment and purification procedures [165, 166] or sample preparation [167] among others.
1.5.3 Wider Industrial Context
1.5.3.1 Sustainability Agenda
The increasing motivation to develop desktop-scale, integrated, microreactor-based, processing systems is led by several needs, including (i) a generic requirement for point-of-demand synthesis across several industrial sectors, (ii) individualized “designer” products, (iii) point-of-use production of dangerous products, (iv) portable power plants, and (v) universally, low-carbon footprint production processes [168]. Short “shelf life” products are good application candidates for production-on-demand in microplants. The sustainability agenda, in part, drives the need for process intensification where large-scale, expensive, energy-intensive equipment may be replaced with others that are smaller, less costly, more efficient, multifunctional and can have a reduced environmental impact and provide improvements in safety and automation [33]. These were predicted by Bensen and Ponton in 1993 [169]. As example, the ecological advantages associated with the transfer of a chemical synthesis from a macroscale semi-continuous batch process to a continuous microscale setup were demonstrated for the two-step synthesis of m-anisaldehyde from m-bromoanisole [50]. This synthesis is highly exothermic and, ordinarily, can only be carried out with stringent safety precautions and a high cooling energy effort. Reaction temperatures of T = 223 and 193 K, respectively, were used for the macroscale reaction chosen whereas in the microreactor a continuous isothermal reaction was performed at T = 273 K. In the study, 11 pilot-scale microreactors were used in parallel to enable comparable outputs from both the micro- and macroscale systems. A cradle-to-grave life cycle analysis demonstrated clear ecological benefits of employing arithmetically scaled out microreactors to achieve comparable output rates to the macroscale reactor.
