Microreactors in Organic Chemistry and Catalysis, Second Edition (2013)

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.

1.5.3.2 Point-of-Demand Synthesis

The progressive sophistication of tools for chemical analysis has led to the opportunity to create products that are designed for the specific genetic and phenotypic requirements of individuals, particularly for pharmaceuticals, nutriceuticals, foods, healthcare products, and cosmetics. The manufacture of designer products at the point-of-demand could be exemplified by an in-store, plant-on-a-desk manufacturing set up at the point of sale; for instance, a cosmetic tuned to the individual requirements of a client's, skin-care status, personal (e.g., age and skin color) and other factors (e.g., prevailing UV strength). Products differentiated in this way will carry a significant price premium with cosmetics arguably representing the most likely application field for an early commercial investment return. Fast-moving commodity goods are considered to represent an important, diverse, multisectorial industrial product platform that will drive the development of the point-of-demand microplant systems. Equally, the sustainability agenda has led to the potential demand for decentralized, distributed processing plant such that materials may be generated where and when they are required. This is particularly applicable where products have a short shelf-life, are exceptionally toxic, are costly (economically and environmentally) to dispose of if unused, and are dangerous to transport. However, while such market applications might appear to represent profitable opportunities for commercial exploitation, often other factors prevent their appearance in the marketplace. Such factors include corporate resistance due to existing infrastructure investment and product brands, regulatory acceptance procedures, and consumer acceptance. Frequently, it is completely new applications, for which no exiting product exists, that become the first successful, so-called killer, applications. For instance, microengineered components, including microreactors, are highly suited for the creation of lightweight, compact, integrated microscale power generators. The microscale dimensions enable low thermal and mass transport resistance rendering them highly efficient in fuel-cell applications where highly endothermic and exothermic processes must be thermally coupled. In parallel, perhaps more exotic applications, such as microscale propellant generators for use in space exploration [170, 171], can lead advances in microreactor technology due to the exacting specifications for such applications.

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