Review done thanks to the support of the PhotoTrain H2020-MSCA-ITN-2016-Action”Innovative Training Networks” – Grant agreement number: 722591
Author: Alex McMillan, PhD & Guilhem Velvé-Casquillas, CEO
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Owing to its operation on the micro-scale, microfluidics presents high surface-area-to-volume ratios to allow for rapid heat and mass transfer and make them ideal for efficient and safe chemical reactions that can be precisely controlled and monitored.
The emergence of microfluidics in the recent decades has provided unprecedented precision in continuous flow technology, bringing new capabilities to a wide range of fields, from biological analysis and chemical synthesis, to optics and information technology [1]. Microfluidic devices (see figure 1) – made from polymers, glass, silicon, metal, and other materials – manipulate small volumes of fluids through geometrically controlled environments, often separated into distinct subunits, such as reactors, mixers, and detectors [2]. Microfluidics owes its distinct advantages in these fields to some fundamental characteristics. It is characterized by laminar flows (see figure 2), or those with a low Reynolds number (Re, indicating the relative importance of inertial forces to viscous forces in a fluid), which helps eliminate any back-mixing in the system that may be caused by fluid turbulence [3]. Figure 3 shows a schematic illustrating the diffusion-based mixing that the laminar flow in microfluidic devices facilitates.
While microfluidics has been longer established in biological research areas, such as cell culture research [12], polymerase chain reaction (PCR) diagnostic tools [13], and even the simulation of entire organ systems [14], its application to chemistry is far more recent and less developed [15]. Though this may be the case, there are inherent advantages of microfluidics in its applications in chemistry, primarily based on the scale-dependent processes of heat and mass transfer [16]. The small length scales result in high surface-area-to-volume ratios, which allow for greater thermal homogeneity across the reaction site and rapid heat transfers, whereas the laminar flow regime can result in diffusion-controlled reactions of compounds at the interface of two fluid streams [17]. This review intends on providing an overview of the application of microfluidics in chemistry (i.e. microreactors), including an elaboration of its advantages, its current uses in industry and academia, challenges it faces, and its future potential. There are some outstanding reviews in literature of chemical synthesis using microfluidics, such as “The past, present and potential for microfluidic reactor technology in chemical synthesis” by Elvira et al. and this review relies on many of the sources presented there.
As one may expect when working with significantly smaller volumes of materials – as one does with microfluidics when compared to bulk-batch chemical reactions (see figure 5) – substantial cost savings can be made. This could be the case when working with reagents of limited availability or excessive cost, or especially true when the chemical reactions being performed are for the purpose of gathering information rather than synthesizing a functional end-product. The precise and targeted nature of microreactors can allow acquisition of the same amount of information as, or indeed more information than, their bulk system counter parts by using far smaller reagent quantities [19][20]. The small size of microreactors also provides the very practical advantage of having a smaller footprint than conventional flow reactors, and smaller yet than macroscale reactors [21], due in part to the smaller heat-exchange equipment needed for the more efficient microfluidic heat transfers [22]. Figure 6 provides an example of a chemical synthesis reaction performed at the small scale available with microfluidics.
Furthermore, chemical reactions in microfluidic devices can be performed with more inherent safety than before and with the ability to handle high pressures and temperatures at small scales [27]. By virtue of the fact that only small volumes of reagents are used in microreactors, reactions that are particularly reactive, explosive or toxic can be mitigated with relative ease [24]. Additionally, exothermic reactions can be more safely performed due to the high surface-area-to-volume ratios and the rapid heat transfer that it entails [3], [28].
In contrast to the scaling up of microreactors (i.e. increasing their characteristic dimensions for increased production), the true strength of microfluidics comes in “scaling out” these systems (see figure 8). Instead of increasing the size of microreactors, scaling out simply denotes the increase of the number of microreactors in order to produce a parallel network[29]. The advantage comes from the fact that by using multiple reactors of the same size, the chemistry performed in each one remains the same at any level of scaling out [30]. This approach also allows for the ease of transferring the use of the same reactors between research and industrial applications, as will be elaborated on further below [31].
While it is undoubted that microfluidics technology can enable a wide range of chemical processes, its primary barrier in its more universal implementation lies primarily in just that: it is viewed as an enabling technology, perhaps more than a replacing technology. Much of the development of microfluidic techniques in chemistry stem from applications that are considerably difficult or hazardous at larger scales [36], where the use of microreactors can bypass certain limitations that exist in conventional process conditions [25]. On the other hand, for reactions that are not problematically hazardous or for those dominated by slow reaction rates (rather than being limited by the rate of heat or mass transfer), [15] the advantages granted by microfluidics become less apparent or in fact non-existent. Similarly, those reactions that take advantage of bulk forces like gravity and buoyancy (such as distillation, centrifugation and phase separation) may be better suited to large scale operations than integration with microfluidics [3].
Even when the microfluidic approach to certain processes is advantageous in terms of speed, throughput, and analytical efficiency, if there lies no obvious constraint in existing practices, then few have chosen to adopt microfluidics in lieu of the familiar ease of using conventional techniques [37]. Thus the challenge for microfluidics lies in attaining the recognition from the research and industrial communities that microfluidic techniques are applicable and superior in a greater range of areas than those in which they are currently being used.
Multiphase reactions (those between solids, liquids, gases, etc. – see figure 10) have long presented challenges for microfluidics. The high surface-area-to-volume ratios inherent to microfluidic reactions present great potential advantages for multiphase reactions, but complications with the clogging of solid reagents, in particular, has been a concern [38]. While more recent progress has been made in the synthesis of micro and nano particles through droplet-based microfluidics (see figure 11) [39] and of materials using non-Newtonian multiphase microfluidic systems [40], solutions for the operation of continuous flow reactions with relatively large solid particles remain difficult (i.e. particles in the size range of 0.01-0.1 times the channel diameter) [41]. While heterogeneous catalysis (where the catalysis is of a different phase to the reagents, often a solid) remains less complicated in conventional reactors, systems have successfully been designed to immobilize solid catalysts to microchannel walls to perform three-phase hydrogenation reactions [42].
The choice of microfluidic chip material dominates its function [43]. While this presents a variety of options to the operator, factors such as cost, complexity of fabrication, and suitability for involved reagents present distinct pros and cons for each type of material. For organic chemistry applications, chips made from polydimethylsiloxane (PDMS), commonly used due to their low cost and ease of prototyping, are not ideal for organic chemistry high-throughput industrial use, as organic solvents can swell of dissolve PDMS [44]. Chips made of glass (see figure 12), poly(methylmethacrylate) (PMMA), cyclic olefin copolymer (COC), teflon, or fluorinated ethylene propylene (FEP), coupled with the development of lower cost fabrication techniques will likely allow for a greater range of chemical applications on longer timescales [45]. Find more information about chemical resistance of different materials for microfluidics.
Due to the numerous benefits of microfluidics discussed above, many stemming from the scale-dependent processes of heat and mass transfer, microreactors have found application in a variety of academic and industrial areas, such as the synthesis of nanomaterials [50], natural products [51], and various small molecule drugs and pharmaceuticals (see figure 14) [37], [52]. While microfluidics up to this point have more commonly been used in an academic setting, their industrial use in growing. This section aims to provide an insight into the numerous applications adopted in research and industry that have expanded upon the fundamental advantages of microfluidics in chemistry outlined above.
The continuing growth in commercially available microfluidic devices [58] has helped bridge the gap between academic research and industrial applications in relevant fields. The commercial availability of microfluidic devices allows researchers to access this powerful technology without the technical skills and experience needed to fabricate the devices themselves. Furthermore, any chemical process developed with microfluidics in an academic setting can easily be scaled up, as mentioned above, for industrial use simply by virtue of the fact that the same commercially available microfluidic platforms can be used in both settings [3].
The extended capabilities of microreactors when compared to traditional laboratory techniques also helps narrow the gap between research and industry. For example, multiphase homogeneously catalysed reactions are usually studied at relatively low temperatures and pressures in order to facilitate the ease of these processes in a small setting, whereas similar techniques in industry are performed at high temperatures and pressures in order to make these processes more economical [59]. Microreactors present the capability of working at similarly high temperatures and pressures to those used in industry, but at a small scale that would otherwise be difficult to achieve in a laboratory setting [60].
The more recent development of droplet-based microfluidics has significantly influenced chemical synthesis, micro and nano fabrication, and synthetic biology [61]. This alternative method of microfluidic processes involves splitting a fluid stream into small, discrete droplets, and provides the added benefits of removing the effects of Taylor dispersion and the subsequently increased ease of droplet transport (see figure 17) [62]. Reactions performed in droplets have been shown to have significantly affected reaction kinetics, showing increased equilibrium and forward rate constants as the droplet radius decreased [63]. Droplet-based techniques, by isolating reactions from the microfluidic channel walls, can also prevent microfluidic channel fouling, a problem that can sometimes occur in continuous flow methods [64].
Organic photochemistry presents the potential for more sustainable chemical synthesis processes. By achieving selective transformations with high chemical and quantum yields [65], and in many cases requiring no chemical catalysts or activating groups [66], organic photochemistry effectively addresses the principles of green chemistry [67]. Current technologies, however, most often involve energy-demanding mercury lamps, and batch reactors, with difficulty in coupling parameters such as hydrodynamics, radiative transfer, mass transfer, and photochemical kinetics present many process limitations with these methods [65]. Continuous flow microreactor technology, on the other hand, in addition to the advantages offered for chemical processes in general, introduce further benefits to photochemistry, including more precise and efficient control of irradiation time and more effective light penetration [68], [69]. For example, in the continuous flow investigation of the [2+2]-cycloadditions of cyclopentene and 2,3-dimethylbut-2-ene to furanone using UVC light (see figure 18), it was found that the use of microreactors resulted in faster conversions and improved product qualities when compared to their batch analogues [70].
Elveflow developed a microfluidic flow photochemistry Pack for chemistry applications.
Since its inception in the early 1990s, microfluidics has rapidly evolved and continues to demonstrate its transformative potential, particularly in chemistry. By leveraging the unique properties of working at the microscale, microfluidics in chemistry—especially in the form of microreactors—enables rapid heat and mass transfer, allowing for efficient, controlled, and safer chemical reactions. While initially more popular in the biological sciences, microfluidic technology has increasingly gained traction in chemistry, offering substantial benefits such as precise reaction control and scalability. This shift is supported by innovations like Elveflow’s best microfluidics technology, which makes high-performance, off-the-shelf microfluidic tools more accessible for both research and industrial applications.
More recent advances in chemical microfluidics have focused primarily on droplet-based techniques, creating the possibility of generating highly monodisperse droplets on chips, merging and breaking them, manipulating their geometry, chemical contents, and internal flow profiles, all with in situ monitoring [61]. These techniques are becoming ever more complex, with demonstrations of double or triple emulsion microstructures being formed by forcing droplets into larger droplets (see figure 19) [72]. The obvious next step is to transform these primarily proof-of-concept demonstrations into further productive applications.
Microreactors, in particular, shine in scenarios involving hazardous reactions, which are otherwise challenging at larger scales, and have demonstrated the ability to improve efficiency across a range of chemical processes. Recent advancements in microfluidics in chemistry—such as droplet-based techniques—are paving the way for more complex applications, including manipulating droplets with precise control over their size, content, and structure. These developments highlight the next phase in chemical microfluidics: transforming proof-of-concept designs into robust, productive applications that redefine chemical synthesis and production.
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