Chemical synthesis with microfluidics – a review

What is chemical synthesis ?

Figure 1: Distribution of articles published in the last 20 years devoted to the use of  microfluidics in different scientific areas.

The application of microfluidics in chemistry could be generally categorized into two fields:

1. Analytical chemistry, which led to proposing the concepts of micro-total-analysis system (μTAS) and lab-on-a-chip (LOC) to the science world [2].
2. Synthesis, or in other words microreactors that are lab-on-chips devoted to synthesis chemistry [3].

A number of materials have been used to fabricate microreactors like silicon, quartz, glass, metals and polymers to name a few. But the most appropriate materials in terms of chemical resistance are glass and metal microreactors. Fig. 2 shows some examples of microstructured reactors in different materials [4]. The most important consideration for synthetic applications is chemical compatibility. For more details to know how to choose a proper material, visit our review on ”Chemical resistance of microfluidic materials”.

Figure 2: Examples of microstructured reactors in (a) silicon-Pyrex,(b) ceramics,(c) stainless steel (IMM), and (d) glass [4]

From traditional batch synthesis process toward more efficient flow chemical synthesis

Chemical synthesis has usually been performed in batch setups in conventional round bottom flasks. The output of the reaction in these traditional methods is determined by the size of the reaction vessel. If you need a higher production, you will need a larger vessel. However, this is not a good and usually applied idea as some reactions are highly exothermic and potentially explosive that are too dangerous to scale up in batch production [5]. Diazonium chemistry is one example of these types of reactions in which diazonium salts are sensitive to light, heat, and shock that can lead to explosions. Even if it would not pose a safety threat, after spending lots of time to optimize and reach the best pathway for a reaction route, the whole synthesis process has to be revised and re-optimized for larger batch sizes in case of scaling up.  Moreover, traditional batch methods can suffer from other intrinsic restrictions that can hamper dramatically their widespread use [6]. Some of the drawbacks can be noted briefly as:

1. Low selectivity
2. Poor reproducibility which is the main drawback in conventional batch synthesis processes
3. Time-consuming as it needs long reaction times
4. Poor control of mass transfer
5. Producing many by-products, unstable intermediates, unwanted and possibly toxic waste materials
6. Costly procedures
7. Requirement for high temperatures and the vigorous stirring of reaction mixtures
8. Dependence of the quality of the final product on any manual errors and environmental conditions
9. labor-intensive and complex stepwise processes
10. Need large quantities of toxic or expensive reagents

 Flow chemistry and microfluidics provide the means to overcome most of the restrictions of conventional synthesis methods.

What is flow chemistry?

“Flow chemistry” also referred to as “plug flow” or “continuous flow chemistry ‘‘is the process of performing chemical reactions in a continuously flowing stream within the narrow channels of a tube or microreactor. Microreactor chemistry has matured over the two past decades and has shown great promise in the chemical industry, pharmaceuticals, fine chemicals, and recently for use in research on chemical syntheses [7]. To learn more about the flow chemistry application in different fields please read our review on the subject.

Advantages of microfluidic synthesis over batch processes

Flow processes offer broad advantages compared to equivalent bulk reactions for chemical synthesis processes such as [8]:

1. Small reagent volumes
2. Improved heat and mass transfer
3. Minimized potential byproduct formation
4. Reduction in reaction time
5. Facilitated scale-up
6. Improved process safety
7. Potential to integrate inline analytical technologies that develop fully automated self-optimizing processes.
8. High conversion and selectivity in short residence time
9. large surface area to volume ratio
10. Intensive mixing of reagent solutions
11. Fast optimization of the synthesis parameters.
12. Increase product quality and yield.

Chemical synthesis in microfluidic reactors also reduces the optimization times and costs in industries where development costs are extraordinarily high.

Fig. 3 represents a schematic of the general concept of flow chemistry using microreactors. At the beginning reactants are pumped into a mixing device and combined along the reactor, flow continues through a temperature-controlled reactor and is heated, cooled, and quenched. It should be maintained at a precise temperature to promote the desired reaction [9].

Figure 3: a) General concept of flow chemistry using microreactors, b) Graphical representation of continuous-flow reactors [9]

Manipulating the flow and controlling what exactly is going on is an unique and important advantage of the synthetic processes in microreactors. Flow rate, flow path, residence time, and reagent transport can be easily controlled with programmable pumps by injection at precise time intervals [10]. Using syringe pumps is a common injection system to control the flow rate but it becomes far more complex to accurately control the fluidic parameters for more than two reagents. Microfluidic pressure controllers are good alternatives to syringe pumps. Elveflow® provides a unique pressure controller brand suited for flow chemistry that presents highly controllable pumps.

Examples of chemical synthesis in microfluidic systems

Various kinds of reactions have been performed in microreactors, to name a few, Carbon-Carbon and Carbon–Heteroatom bond-forming reactions, rearrangement, cycloaddition, reductions, and oxidation, Enzymatic, Photo- and Electrochemical and polymerization reactions, reactions involving organometallic and Diazo species [10]. Reported research proves the efficiency of microfluidic technology for chemical synthesis approaches in comparison with conventional macroscopic systems[11]. A summary of the reactions that have been performed in microreactors is presented in table 1.

Table 1: Examples of reactions conducted in a microreactor [11].

Microfluidics for nanoparticle synthesis

The first reports of a microfluidic system for chemical synthesis approaches were using the microreactors for nanoparticle synthesis such as quantum dots [12]. Fig. 4 represents an example [13,14]. Taking advantage of microfluidics such as flow control, faster mixing of reagents, precise pressure, heat, and mass transfer, has made microfluidic reactors excellent synthesis platforms for nanoparticles. Microfluidic chips provide a narrow particle size distribution, uniform shape, and consequently lead to homogenous quality and reproducibility of nanoparticles compared to batch-wise synthesis techniques.

Figure 4: Schematic representation of microfluidic devices for nanoparticles: a) synthesizing CdSe quantum dots, b) synthesis of water-soluble Ag2S quantum dots [13,14]. The strength of this method is most evident in the synthesis of functional nanoparticles where traditional methods suffer from lots of limitations [12,15].

To discover more about this amazing approach in nanoparticle synthesis read our other reviews about plga nanoparticle synthesis or check our LNP synthesis application pack.

As a recent example, Zhenjie Zhao et al., have proposed droplet-based microreactors, as a  practical and fast way to synthesize magnetic nanoparticles (Fe3O4) [16]. This microfluidic chip is composed of three entries “WI”(water phase inlet), “OI” (oil phase inlet), “WI” and one exit “OL” (outlet) and multifunctional units, including T-junction for droplet generation, Y-junction, and S-channels for droplet fusion and rapid mixing (Fig. 5)

Figure 5:  (a) The schematic of the microfluidic droplet device. (b) Chip inlets (c) T-junction and (d) Y-junction for droplet generation and manipulation [16]. 

If you are also interested in taking advantage of the droplet-based microdevice for your chemical synthesis approach, check here, our latest droplet pack generation to easily control all the key parameters of your experiment.

Microfluidics for chemical synthesis of pharmaceuticals

Microfluidics chemical synthesis has evolved to a wide range of applications in the pharmaceutical industry in the past two decades, as it allows the production of active pharmaceutical ingredients in less costly and more effective approaches [17]. This evolution has been driven by the inherent advantages of chemistry in microfluidics such as controlled mixing, enhanced heat and mass transfer, and safety. All these benefits coupled with an enhancement in the quality of the products and cost-effectiveness convinced several pharmaceutical companies to investigate and implement microfluidic technology as a viable alternative to the traditional batch synthesis of several complex active pharmaceutical ingredients (APIs) [18].

Various kinds of (APIs) have been prepared using microfluidics in chemical synthesis with different conversions and residence times (table 2). Residence time (RT) defines as the time it takes to exchange the volume of the reactor entirely.  RT is vital for product quality and is determined by the reactor volume divided by the volumetric flow rate. Residence time varies by either changing the volume of the reactor or the flow rate. Optimizing RT allows the use of microfluidic systems in more efficient and faster processes compared to a batch process. APIs are currently synthesized in hours or even in days and it would be a great success to be produced in a few minutes in microfluidic devices.

Table 2: Active Pharmaceutical Ingredients (API) synthesis in microfluidic devices[18].

In 2010 researchers from Takahashi’s group have reported a highly efficient, two-stage, micro-flow synthesis of vitamin D3 with no intermediate purification and in high yield Fig 6 [19].

Figure 6: Two-stage, continuous-flow synthesis of vitamin D3 using two microreactors [19].

As another example to illustrate the efficiency of microfluidics in the chemical synthesis of pharmaceuticals, in 2010, Jamison et al, reported the synthesis of Metoprolol, a selective beta-adrenoceptor blocking agent, under continuous flow conditions with high yields and residence times of about 15 seconds that has high improvements in comparison to the batch synthesis of the same product (Fig. 7)[20]. Metoprolol is used in the treatment of hypertension.

Figure 7. Microreactor layout diagram and flow chemistry setup for Metoprolol synthesis[20].

Microfluidics for electrochemical synthesis

Electrosynthesis using a flow microreactor is a new and attractive approach in synthetic organic chemistry and has been developed by several research groups in recent years [21]. In electrosynthesis, stoichiometric reagents can be replaced by electricity as a clean and available reagent equivalent. Recent reports by the research group of Timothy Noël demonstrate the power of flow electrochemistry for cleaner chemical synthesis [22]. In their report, a novel and efficient synthetic protocol is presented to generate sulfonamide products that are key pharmaceutical products. The transformation is completely driven by electricity in only 5 minutes and without any additional catalysts (see Fig. 8) [23].

Figure 8: schematic of electrosynthesis of sulfonamides in a flow microreactor by direct anodic coupling of thiols and amines [23].

In 2021, Kai Wang’s research group from Tsinghua University, [24] proposed a microfluidic reactor for the green synthesis of thiuram disulfides as versatile free radical initiators and with a higher advantage over the conventional batch methods. Thiuram disulfide is an important chemical in rubber production and pharmaceutical industries.  Using microfluidics, it has been produced successfully without over-oxidation of reactants and wastes salts in a reaction time of less than 18 sec. (Fig. 9).

Figure 9: (a) Schematics of the microfluidic reactor; (b) Continuous reaction platform for the electrosynthesis of thiuram disulfides [24].

Microfluidics for photochemical synthesis

After electrochemistry, photochemistry has attracted growing interest as a green and sustainable method in the chemical synthesis process. In these methods, photons as “traceless and green reagents” lead to new chemical bonds [25]. However, like the other classical synthesis methods in batch mode, photochemical transformation can also be a challenge which is related to the same limitations of performing reactions in batch. Recently, microfluidic reactors appeared as a solution to overcome the issues associated with batch photochemistry and provides uniform irradiation, reduces the reaction time, minimizes byproduct, and facilitates scaling-up of photochemical reactions. Regarding this subject, the research group of Timothy Noël developed a fast scaling-up strategy of luminescent solar concentrator-based photo microreactors that have the capability to produce pharmaceuticals and other fine chemicals using solar energy [26].  This reactor contains up to 32 parallel channels, which display an excellent flow distribution using a bifurcated flow distributor and allows scaling-up solar photochemistry in an efficient fashion (Fig. 10).

Figure 10:  Example of the combination of photochemistry and microfluidic in photomicroreactors: Numbering-up of luminescent solar concentrator-based photomicroreactor [26,27].

In other interesting examples, Dong-Pyo Kim et al. have fabricated a transparent dual-channel microreactor for efficient photosensitized oxygenation reactions [28]. They reported a high-throughput approach for the reaction of (-)citronellol which is an important synthetic transformation industrially. Alpha-Terpinene into Ascaridole and allylic alcohols into allyl hydroperoxide alcohols are other photosensitized oxygenations that have been performed in their microreactor. Inside this microreactor,  the surface of the microchannels is shielded by PVSZ (polyvinylsilazane) which protects the Polydimethylsiloxane (PDMS) from all effects of liquid reactants and solvents. Scaling up has also been performed successfully which resulted in higher throughput than the batch reactors. Moreover, under full exposure of reactants to light, the reaction time in high concentration has a significant reduction (in minutes rather than hours) in comparison to a batch reactor. Fig. 11 illustrates photosensitized oxygenation of allylic alcohols in a dual-channel microreactor along with a schematic of the fabrication process of a dual-channel microreactor.

Figure 11: A) Schematic illustration for fabrication of a dual-channel microreactor; (B) Cross-sectional view of dual microchannel and picture of microreactor filled with O2, photosensitizer, and reagent; (C) Photosensitized oxygenation of allylic alcohols in a microreactor [28].

We assembled an all-integrated photochemistry pilot pack for easy transition to microfluidics for chemical photosynthesis.

Conclusion

This review demonstrates the development of microfluidic techniques and their capability in performing various types of chemical synthesis. Typical examples using flow chemistry and microfluidic reactors have been highlighted to reflect their unique advantages over traditional batch-type methods. Microreactor chemistry as a novel method for chemical synthesis, generally is more efficient and produces the desired product with a higher yield and purity and in shorter periods of time with reduced waste. These microfluidic reactors can also conduct the reactions in safer conditions.  It is undeniable that flow microreactors have made a revolutionary change in chemical synthesis involving various fields of electrochemical, photochemical, pharmaceuticals, polymer, and nanoparticle synthesis.  On top of that, bibliographic research shows many examples of applications in organic reactions such as rearrangement, cycloaddition, carbon-carbon, and carbon-heteroatom bond-forming reactions.

Acknowledgment

References