Microflow chemistry and its electrification for sustainable chemical manufacturing

Abstract

Sustainability is vital in solving global societal problems. Still, it requires a holistic view by considering renewable energy and carbon sources, recycling waste streams, environmentally friendly resource extraction and handling, and green manufacturing. Flow chemistry at the microscale can enable continuous sustainable manufacturing by opening up new operating windows, precise residence time control, enhanced mixing and transport, improved yield and productivity, and inherent safety. Furthermore, integrating microfluidic systems with alternative energy sources, such as microwaves and plasmas, offers tremendous promise for electrifying and intensifying modular and distributed chemical processing. This review provides an overview of microflow chemistry, electrification, their integration toward sustainable manufacturing, and their application to biomass upgrade (a select number of other processes are also touched upon). Finally, we identify critical areas for future research, such as matching technology to the scale of the application, techno-economic analysis, and life cycle assessment.

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1 Introduction

Sustainability is key to the well-being of society and is a holistic grand challenge which, in the context of the chemicals industry, includes three main domains: product, feedstock, and manufacturing (Fig. 1). While making end products, the current economy creates a large volume of waste streams, including food and agricultural waste, lignin from the paper industry, lubricants, tires, methane leaks from shale gas wells, plastic waste, etc. Circularity and upcycling can mitigate this issue.^1–3 In the former, one recycles the product at its life's end to its constituents to build back the product. In the latter, one seeks to make higher-value products than the recycled one to extend the lifetime of the entire chain.

Fig. 1 Domains of sustainability in the chemical industry and the manner by which microflows can support and enhance the circular economy.

With the depletion of fossil fuels (conventional feedstock), global warming, and increased demand stemming from a growing population and improved living standards, circularity alone cannot achieve sustainability. Renewable sources are needed. Therefore, researchers have focused on utilizing renewable feedstocks in the past twenty years (Fig. 1). Many efforts have been devoted to using biomass as carbon source, developing electrochemical devices for CO₂ conversion, hydrogen production via water splitting, and other chemicals and artificial photosynthesis for solar fuels.^4–8

Importantly, due to atom and energy inefficiencies in manufacturing, chemical reactors and separations require significant energy, producing copious amounts of CO₂. It is thus imperative to consider sustainable manufacturing in conjunction with product circularity and feedstock availability (Fig. 1). However, in our view, the sustainability of chemical manufacturing has received less attention compared to the other two domains. Driving the industry into zero-emissions requires significant technological advances. Chemical manufacturing needs to sustain the natural resources and the ecosystem while ensuring product quality. The cores of sustainable development include resource availability, improved atom and energy efficiency, and minimal environmental footprint. Green chemistry and engineering values for the design of products, processes, and manufacturing^9–12 embody 12 principles (P),⁹ summarized in Fig. 2.

Fig. 2 Green chemistry and engineering principles.

Continuous manufacturing using microfluidics can achieve several of these principles, benefitting from small reactor sizes, fast mixing, precise temperature control, effective heat management, and high energy efficiency (Fig. 1).^13–15 For example, the reduced solvent volumes in microreactors minimize waste and environmental burden (P1). The enhanced mixing and transport can improve atom efficiency by increasing product yield and selectivity and reducing byproducts (P2, P9). Temperature control and fast heat transfer broaden the operation window, enhancing energy and atom efficiency (P2, P6) and reducing the energy requirements (P6). The precise heat management and the small volumes of processed hazardous materials make the processes safer (P3, P4, P12).

Because of these advantages, microflow chemistry has emerged as a central pillar of green catalytic engineering for processing renewable sources (P7), such as biomass,¹⁶ as the most accessible and reliable renewable carbon source. Agricultural waste, such as corn stover and sugarcane, food waste, such as potato and orange peels, energy crops, etc., are promising feedstocks as they do not interfere with edible biomass and land or have negative ecological impacts.^16–19 Lignocellulose, in the microfibrils of the cell walls of plants, consists mainly of polysaccharides and lignins.^20–22 During the past twenty years, efforts have been devoted to transforming lignocellulosic biomass into fuels, chemicals, and other products and developing catalysts, (batch) processes, and mechanistic insights. These chemistries become more efficient (P2) in microreactors due to enhanced product yield and selectivity.^23–25

Biomass usually contains a significant amount of water and requires considerable energy for transportation to refineries.^26–28 As a result, onsite processing is necessary. The same applies to food waste, a vast volume, short lifetime feedstock. While plastic waste has a long lifetime (estimated to be hundreds of years) and low water content, it is spread in landfills and ecosystems. On-site processing in remote and offshore locations is essential. Microflow chemistry can provide better economic viability and higher energy efficiency (P6), supporting sustainable on-site manufacturing.

Since current chemical manufacturing depends on natural gas combustion, producing a tremendous amount of greenhouse gas emissions (GHG), achieving a zero-emissions industry requires alternative energy from solar, wind, and geothermal. Joule or direct resistive heating, inductive heating, ultrasound, microwaves, plasmas, and electrosynthesis are such electrification technologies that can use green electricity to minimize GHG emissions profoundly. Electrification can provide rapid and selective heating or alternative reaction pathways, minimize side reactions, and reduce the use of solvents (P1, P8). These technologies usually offer high energy efficiency (P6) and intensification, allowing compact devices and lower capital investments. These advantages make electrification a perfect match with microflow technology. As a result, their integration is an emerging topic for sustainable chemical production.

Despite good reviews^{13,15,22,29–36} on the design of microfluidics^15,30,33,36 and their application to organic synthesis, nanoparticles synthesis, and active pharmaceutical ingredient production,^13,32,34,35 their deployment for renewable sources has been limited, and their electrification has not been reviewed. This paper provides an overview of microfluidics, their electrification, and their application to the processing of renewable resources.

2 Design and engineering of microreactors

Microreactors expose unique flow patterns, enhanced heat and mass transfer,^37–39 fast mixing, and precise residence time and temperature control, thus greatly influencing chemical reactions. Microreactors' internal/hydraulic diameter is typically below 3 mm, and the Reynolds number (Re) is often below 250.¹³ Their walls are usually made of hydrophobic (i.e., polyether ether ketone (PEEK), perfluoro alkoxy alkane (PFA), and polytetrafluoroethylene (PTFE)) or hydrophilic (i.e., fused silica, glass, and stainless steel) materials. The material properties control the continuous phase that wets the surface and the flow patterns. This section gives a brief overview of the essential features of microreactors for chemical manufacturing.

2.1 Flow patterns

For the past two decades, micro-scale flows have been studied extensively. Single-phase microreactors consist of a liquid or gas phase. Liquid-phase microreactors entail a homogeneous catalyst mixed with a solvent and reactants flowing through them.^40–42 When a solid catalyst is employed, it is usually coated on the channel wall. The use of additional phases can enable simultaneous separation or tandem reactions. In biphasic systems, two relatively immiscible fluids (a gas–liquid or a liquid–liquid) come in contact. A common goal of microtechnology is rapid mixing. Various flow patterns can occur in micromixers upon contact of phases. Commonly used micromixers are generally passive and include simple contacting structures⁴³ (T-junction, Y-junction, cross-junction, and co-flowing junction), multilamination structures,⁴⁴ and split-recombine structures.⁴⁵ Different micromixers yield different flow patterns. Observed flow patterns include slug, droplet, parallel, annular, dispersed, slug-droplet, and irregular flow. The patterns depend on the physical properties of the solvents (density, viscosity, and surface tension), the wettability, the device diameter, the geometry of the wall, the flow rate, and the fraction of each phase.^46–48 Segmented flow (slug flow and droplet flow) and parallel/annular flow are common. In the former, alternating fluid segments occur, where the wall-wetting (continuous) phase usually forms a thin film around the non-wetting (dispersed) phase. When the flow rate is low, the slugs are shear off from the micromixer junction due to the dominant of interfacial tension, enabling the sharp break-up of the slugs.⁴⁹ When the flow rate increases, the dispersed phase flows into the downstream microchannel, and a long tail forms before the slugs are shear off since the viscous force increases, and the interfacial tension is not sufficient for quick and sharp break-up.⁴⁹ At an even higher flow rate, the tails become longer, and the slugs become smaller. Eventually, the flow turns into the latter, the liquids flow side by side. A homogeneous catalyst is in one phase, whereas the other phase serves as an extracting solvent to remove target chemicals^50–52 and enhance product yield and selectivity by preventing side reactions^23,24,53 from happening in the catalyst-containing phase. The length of the slugs, droplets, or bubbles affects mass transfer.^54–57 The length is usually predicted using semi-empirical relations (Table 1) for a simple contacting reactor. These invoke the capillary number (Ca), i.e., the ratio between the viscous force and interfacial tension, of the dispersed and continuous phases, due to the interfacial tension and viscous force dominating over the inertia in microchannels. Also, the flow rate ratio of the continuous to dispersed flow plays a vital role in deciding the slug/droplet size. The slug length decreases with increasing continuous to dispersed flow rate ratio.⁵⁸ In consideration of the governing forces, such as interfacial tension, viscous force, and inertia, there are also different dimensionless groups affecting the flow pattern formation: Reynolds number (Re) is the ratio between inertia and viscous force; Weber number (We) describes the relative importance between inertia and interfacial tension; Ohnesorge number (Oh) compares the viscous force to the product of inertia and interfacial tension; and Bonds number (Bo) characterizes the ratio between gravity to interfacial tension.⁵⁸ These dimensionless groups act as the useful descriptor for flow pattern generation.⁵⁹ A careful design of the microchannels and operating conditions is needed to obtain the desired flow pattern. For complex micromixers, computational fluid dynamics (CFD) can resolve the fluid–fluid interface and provide the flow pattern.^60–63

Table 1 The selected semi-empirical formula of the slug or droplet sizes in microchannels

Flow pattern	Formula^a
a L is the slug or droplet length; w is the microchannel width; Q represents the flow rate; subscript d denotes the dispersed phase; subscript c denotes the continuous phase; subscript g denotes the gas phase; subscript l denotes the liquid phase; dj represents the jet neck diameter; k* is the dimensionless wavenumber of the maximum growth rate of capillary perturbation; Up is the jet velocity; D demonstrates the inner diameter of the microchannel; A, B, α, and β are the fitted parameters.
Liquid–liquid slug or droplet formed in the squeezing regime using a T-junction mixer^64
Liquid–liquid droplet formed in the dripping regime using a co-flowing or T-junction mixer^65
Liquid–liquid droplet formed in the transient regime between the squeezing and dripping regime using a T-junction mixer^64
Liquid–liquid droplet formed in the jetting flow using a co-flowing mixer^66
Liquid–liquid droplet formed in the dripping flow using a flow-focusing mixer^67
Gas–liquid slug flow using a T-junction mixer^68

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Catalyst particles or solid reagents are packed into a micropacked bed or are mixed with a solvent to create a slurry.^69,70 Micropacked beds provide a high catalyst loading, a large surface area, and inherent mixing but suffer from a high-pressure drop. They are widely used in biomass derivatives' conversion,⁷¹ such as hydrogenation⁷² and oxidation,⁷³ and the majority of their applications for multiphase reactions is gas–liquid–solid system.⁷¹ Strong capillary force in the micro-scale leads to higher liquid holdups in the micropacked beds.⁷⁴ Moreover, particle size, reactor geometry, and the superficial velocity also affect the flow pattern and the transient time to achieve steady state operation.⁷⁵ These parameters also affect the interfacial surface area and the external mass transfer in a micropacked bed.^76,77 Decreasing particle size and increasing superficial velocity enhances the mass transfer.⁷⁷ Alternatively, coating a heterogeneous catalyst on the inner wall of microreactors lowers the pressure at the expense of a lower catalyst surface area. These different configurations greatly impact the flow distribution and mass transfer, and thus, the reaction performance.

2.2 Intensified mixing and transport

Many chemical reactions involve multiple co-reactants and a catalyst. Achieving homogeneity in the solution is important. The mixing is typically affected by fluid dynamics. The timescale of mixing can significantly influence the selectivity and yield.⁷⁸ Mixing in laminar flow happens by molecular diffusion. In a single-phase system, the characteristic diffusion time is proportional to the square of the characteristic length (L) and inversely proportional to the diffusivity (D), as in eqn (1),

The small dimension of microreactors results in a short diffusion path and fast mixing, enabling uniform distribution of reagents and catalysts in a solvent. The mixing time is significantly decreased compared to a conventional size reactor. In this regard, micromixers and microreactors of very short characteristic diffusion lengths are ideal.

An immiscible solvent can create secondary flows in a segmented flow, enhancing mixing within the slugs or droplets and the mass transfer due to inner circulations. The interfacial mass transfer rate increases dramatically depending on the flow patterns, the flow rates, and the geometry. It is usually described by the volumetric mass transfer coefficient (k_La), which is the product of the intrinsic mass transfer coefficient (k_L) and the interfacial surface area (a). Acetone or succinic acid between water and an organic phase is commonly used to estimate the interfacial mass transfer in liquid–liquid systems.⁵⁴ The CO₂/DEA (diethanolamine) system is used for gas–liquid systems.⁷⁹ In general, the mass transfer rate increases when total flow rate increases due to the reduced interfacial diffusion layer and enhanced internal circulations.^80–82 When the flow rate ratio increases, k_La increases with hydrophobic channel walls and decreases with hydrophilic channel walls.^83–85 This is attributed to whether the aqueous phase is dispersed or continuous, leading the enhancement or reduction of the interfacial surface area.⁸⁶ Aside from this, microchannel materials also affect the mass transfer by providing different contact angles. Surface modifications of microchannel wall can increase k_La due to enhancement of mixing and improvement of the interfacial surface area.⁸⁷k_La typically increases with decrement of microchannel diameter due to the reduction of the diffusion length. k_La in a microreactor is typically 2 to 3 orders of magnitude higher than in a conventional reactor^88,89 due to the secondary flows,⁹⁰ the small slugs and droplets, and the high specific surface area. Fig. 4a and b clearly shows the inner circulations within the slugs and droplets. The interfacial mass transfer is mainly driven by convection in the axial direction. It is only fast in the middle of the slugs and droplets and their edges. The mass transfer in the radial direction is slow and is driven by diffusion. Susanti et al.⁹¹ proposed eqn (2) to evaluate k_La in a microreactor as a function of material properties, operating conditions, and slug length.

Here τ is the averaged residence time; D represents the diffusivity; K denotes the partition coefficient; r is the radius of the microreactor; and L is the slug length. Subscripts d and c represent the dispersed and continuous phases, respectively. Fig. 4b shows an asymmetric concentration distribution between the top and bottom parts of a slug. This asymmetry is attributed to the formation mechanism of the droplet flow. The fast shear-off happens at some distance from the T-junction, forming a droplet^92,93 in a short mixing time. The mass transfer during the droplet formation may substantially contribute to the overall mass transfer. Kashid et al.⁵⁶ found that the T-junction and caterpillar structures of micromixers provide the highest k_La, almost an order of magnitude higher than a Y-junction or co-flowing structures. Tan et al.⁹⁴ also demonstrated that 90° angle of the inlet microchannel leads to better mass transfer because the stronger shear forces were exerted on the formatting droplet surface. Unlike the segmented flow, no inner circulations exist in the annular or parallel flow (Fig. 4c). Instead, the mass transfer, driven by radial diffusion, is slower. These complicated phenomena underscore that predicting k_La is important but difficult. CFD simulations can be used to predict and design biphasic microreactors. Moreover, semi-empirical correlations have been proposed to estimate the mass transfer in a biphasic system. A few examples are provided in Table 2. The Sherwood number (Sh), which represents the ratio of convective and diffusive mass transfer, commonly characterizes the mass transfer. In these correlations, the Sh number is usually a function of the slug size and the Reynolds number.

Table 2 Selected semi-empirical correlations of the mass transfer coefficients in microchannels

Flow pattern	Correlation^a
a D h is the hydraulic diameter of the microchannel; τ is the residence time; D demonstrates the inner diameter of the microchannel; L represents the length of the microchannel; subscript g denotes the gas phase; subscript l denotes the liquid phase; Q represents the flow rate; U is the superficial velocity; ε demonstrates the flow rate ratio of aqueous to the organic phase.
Gas–liquid slug flow formed using a T-junction mixer^95	k L a = 0.0002219Reg^0.3245Rel^0.7764Scl^0.5
Gas–liquid slug flow formed using a T-junction mixer^96	ShlaDh = 0.094Reg^0.0656Rel^0.654Scl^1.449Ca^0.839
Liquid–liquid slug flow formed using a Y-junction mixer^97
Liquid–liquid droplet flow formed using a T-junction mixer^98	k L a = 2.12 × 10^−6Q^−0.34U^0.53D^−1.99
Liquid–liquid droplet flow formed using a cross-flow T-junction mixer^99

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Microreactors also possess fast heat transfer, enabling precise temperature control and accurate measurement of chemical reaction kinetics. Due to dissipating the reaction energy rapidly, microreactors are suitable for highly exothermic reactions.³² The biphasic slug flow provides better heat transfer than the single-phase flow due to the internal circulations inside both dispersed and continuous slugs, which greatly enhance the heat transfer between phases.¹⁰⁰ The recirculation in the continuous slug also alters the boundary layer.¹⁰¹ Shorter slug length and higher heat Péclet number, which is the ratio between convective and diffusive transport rate, lead to faster heat transfer.¹⁰² The microchannel geometry and film thickness between the slug and the channel wall affect the heat transfer as well. Even though heat transfer between the fluid and the wall has been studied extensively, a few studies have focused on heat transfer between liquid phases. An extracting phase or inert components offer merit, such as absorbing the excess reaction heat from a reacting phase for an exothermic reaction. Considering the heat and mass transfer analogy, such interfacial heat transfer would also be affected by flow patterns. The heat conductive transport is generally much faster than the mass diffusive transport for the liquid, i.e., heat diffusivity is larger than mass diffusivity, making heat transfer in a parallel or annular flow faster than mass transfer.

2.3 Controlling residence time distribution and broadening operation windows

The fast heat and mass transfer in microreactors can shift reactions from transport control to kinetics control.³⁵ Moreover, the residence time distribution (RTD) in a microreactor is narrower,¹⁰³ enabling better control of the reaction time than a typical continuous stirred-tank reactor. This is attributed to the enhanced convective mixing and the inner circulations in slugs and droplets.¹⁰⁴ The RTD is affected by the microreactor geometry. For instance, serpentine reactor, coiled reactor, and arc flow inverter lead to narrow RTD by improving mixing or leveraging Dean vortexes.^28,104,105 Active volume in the microreactor can be >99% of nominal volume with careful design, indicating that dead volume is negligible.¹⁰⁶ The RTD of a biphasic flow can be close to the Dirichlet function.¹⁰⁷ For example, narrow RTDs occur for water–toluene and gas–liquid segmented flow.¹⁰³ Although the residence time may be affected by catalyst deactivation in long-time operations,¹⁰⁸ precise measurement of intrinsic kinetics is enabled using microreactors,³⁵ even when unstable, reactive intermediates occur. The residence time is controlled by the length of the microchannel or the flow rate. By simply decreasing the microreactor length, it is possible to directly measure the intermediates or transform them in a second reactor,²³ making reactions that are hard to perform in a typical batch reactor feasible. For example, oxidation of alcohols to aldehydes or ketones using dimethyl sulfoxide is carried out at −50 °C in a batch reactor to avoid the decomposition of the unstable, reactive intermediates.¹⁰⁹ In contrast, a microreactor can be operated at room temperature due to its short residence times,¹⁰⁹ minimizing energy consumption. Leveraging the precise and tunable residence time, a wider operating window can be safely achieved even in harsh conditions. For example, a high-temperature superheated flow microreactor is achievable for fructose dehydration, o-phenylenediamine condensation, and Kolbe–Schmitt reaction in very short residence times,^28,110,111 In addition, the precise residence time control makes chemical synthesis without auxiliary protecting substances possible. For instance, Macbecin I can be directly obtained via an alternative synthesis without protecting the amino group.¹¹² This enhances the atom efficiency of the production. Additional examples utilizing these benefits to convert renewable resources are discussed in the sections below.

3 Lignocellulosic biomass conversion in microflow

The conversion of renewable biomass into functional platform chemicals and eventually ready-to-use fuels, chemicals, and other products, can mitigate the growing CO₂ emissions (P3, P7). Most biomass transformations have been discovered and optimized in batch reactors. Batch reactors are convenient for discovery, as one does not have to worry about control of flowrates, phases, pressure build-up, catalyst deactivation, reactor plugging, etc. However, batch systems have several limitations. First, heating typical laboratory batch Parr systems is slow (it takes 20–30 min, depending on the final temperature) and temperature uniformity cannot be well controlled when scaling up due to heat transfer limitation. Consequently, batch reactors are unfit for high temperatures and short contact times operation for high productivity. We demonstrate below that broadening the operation window to short residence times with precise temperature control using continuous system is crucial for enhanced performance. Second, biphasic batch systems utilized for biomass valorization are often transport-limited; mass and heat transfers are greatly enhanced in microreactors (P6). Last but not least, the large volume of biomass and chemicals call for continuous flow operation, as commonly done in chemical manufacturing. These benefits will be discussed in this section of the review.

A continuous flow microreactor can bridge discovery with industrial practice while providing enhanced transport between phases and maximizing yields at high temperatures and ultra-short residence times. Furthermore, biomass is generated in rural areas where small, portable systems allow local-to-the-source processing while ensuring low capital costs, fast processing times, compact units, and lower-risk investments. Process intensification (PI) is essential to ensure modularity with enhanced energy efficiency and fewer emissions. Data collection time and automation in microreactors (e.g., time on stream, process variable variations) are highly suited for future digitalization. They are unmatched compared to conducting a single or a couple of measurements per day in batch systems.¹¹³ In this section, the catalytic conversion of monosaccharides to furanic derivatives using homogeneous and heterogeneous monophasic and biphasic reactors is reviewed. Productivity is a crucial advantage of continuous flow reactors and is used as a comparison metric. Due to the high cost of raw materials, the selectivity to desired products, also discussed here, is the most critical metric for economics.

3.1 Homogeneous catalytic reactors

Homogeneous monophasic or biphasic microfluidic systems precisely control reaction conditions for optimal performance, something unattainable in batch systems. One can carry out ultra-fast reactions at low residence time, with rapid heating due to reduced thermal inertia and increased mixing and mass transfer between phases. These characteristics are demonstrated with exemplary reactions.

3.1.1 5-Hydroxymethylfurfural (HMF) production. We focus on the production of HMF – a versatile platform chemical that can be converted to many chemicals, fuels, and polymers. HMF contains six carbons and is derivative of glucose, the monomer of cellulose. Direct glucose dehydration to HMF is generally 2–5 times slower, less selective, and needs higher temperatures and longer reaction time to reach decent yields compared to fructose.^114,115 For this reason, HMF production from fructose has been much more extensively studied. HMF is produced from biomass through the following sequence: (a) hydrolysis of glucan to glucose, (b) isomerization of glucose to fructose, and (c) dehydration of fructose into HMF. Lewis acids catalysts, e.g., aluminum chloride (AlCl₃) and chromium chloride (CrCl₃), isomerize glucose into fructose. Brønsted acids, e.g., hydrochloric acid (HCl) and sulfuric acid (H₂SO₄), perform hydrolysis and dehydration in an aqueous phase (Scheme 1).¹¹⁶ Tandem systems, comprising bifunctional Brønsted and Lewis acid catalysts, intensify the conversion of glucose to HMF, through fructose, in a single pot. A complication is that HMF undergoes polymerization to humins and rehydration under reaction conditions (Scheme 1). Biphasic systems have significantly mitigated HMF degradation by removing HMF into suitable organic solvents (Scheme 1; green shading). Yet, downstream aqueous/organic solvent separations and HMF purification are challenges to overcome. In this regard, both monophasic and biphasic systems are reviewed below.

Scheme 1 Reaction pathways of sugar chemistry in the aqueous phase (blue shaded area) and partition of HMF in an organic phase (green shaded area) in biphasic systems. Single-phase (blue shading) processing is feasible.

Single aqueous phase reactions. Most batch fructose dehydration reactions have been performed at <150 °C and long reaction times. Yet, there are two reasons why one should carry this chemistry at higher temperatures. First, the activation energy for HMF formation is ∼142 kJ mol⁻¹ over zeolite beta¹¹⁶ and ∼126 kJ mol⁻¹ using HCl;⁴² those for HMF side reactions are generally <100 kJ mol⁻¹,⁴² depending on catalyst. Thus, higher temperatures improve HMF selectivity. Second, the fructose mutarotation favors furanose over pyranose (Scheme 2), the active form from which dehydration occurs, enhancing the HMF rate due to having a higher concentration of the reactant's active structure.¹¹⁷ These facts underscore that high temperatures and low residence times, unattainable in batch reactors but accessible in continuous flow reactors, should be exploited. The examples discussed below demonstrate this hypothesis.

Scheme 2 Glucose isomerization and fructose mutarotation in solution.

Tarabanko et al. reported early on fructose dehydration in a microreactor using an H₃PO₄ catalyst at 240 °C.¹¹⁸ The highest HMF yield reported was 40% at a residence time of τ = 3 min.¹¹⁸ Tuercke et al. showcased continuous fructose dehydration at 185 °C, 17 bar, and 0.1 M HCl, reaching a fructose conversion of 71% and an HMF selectivity of 75% at τ = 1 min,¹¹⁹ surpassing the best batch data.⁵² The microreactor diameter of 1.2 mm provided a large surface area for heat transfer (∼1880 m² m⁻³) to reach reaction temperature at short times. Beyond rapid heating, a significant advantage for continuous systems is that production is uninterrupted. In this regard, Schon et al. compared a microreactor and a microwave (MW) heated semi-continuous batch reactor.¹²⁰ In a cartridge-based microreactor with HCl catalyst and conventional heating, HMF yields of 85.5% and 90.3% were obtained at 150 and 180 °C, respectively, at τ ∼ 3 min. On the other hand, while MWs' heating time to 200 °C is only 2 min, the productivity of the continuous reaction was 3× higher (2.07 vs. 0.72 g h⁻¹), as the semi-continuous process spends 60% of its cycle time on pause, heating, and cooling stages. In passing, the reported yields are much higher (outliers) than all other studies and the theoretical maximum discussed below; they deserve attention but are not further discussed. For single aqueous phase reaction, Desir et al. reported the highest fractional HMF yield per time, achieving 54% HMF yield at τ = 4 s with HCl (pH = 0.7) at 200 °C.²⁸

Single phase with co-solvents. Non-aqueous solvents often enhance HMF production due to the favored mutarotation of fructose to furanose. For example, in DMSO, the furanose increases from 20% to 72.3% at room temperature^121–123 to 89.4% at 150 °C.¹²¹ It is no surprise that DMSO is often used as a co-solvent or solvent.^52,124 Ly et al. described a single-phase DMSO continuous system utilizing Brønsted acidic imidazolium-based ionic liquid ([BMIMSO₃H][HSO₄]) catalyst giving a 46% HMF yield at 130 °C.¹²⁵ However, DMSO is a “yellow” solvent due to its high boiling point and poor incineration score.¹²⁶ Other organic solvents, such as acetone (greener on the solvent selection scale¹²⁶), also improve HMF yield due to the mutarotation enhancement. Bicker et al. used a 10 mM H₂SO₄ in a pipe-in-pipe continuous, high-pressure system with 90 : 10 acetone : water solvent under supercritical conditions, improving the HMF yield >2× and productivity >27× compared to the aqueous system at τ = 1 min (99% fructose conversion and 77% HMF selectivity) at 180 °C.¹²⁷ NMR experiments indicate an increased furanose : pyranose ratio of fructose in acetone (48 : 52 at 25 °C).¹²³ The furanose is similarly favored in other environmentally acceptable solvents, such as methanol and acetic acid.¹²³ However, supercritical operation imposes challenges for large-scale production. Yet, low boiling point solvents, like acetone, are good for downstream separation.
Biphasic systems. A biphasic system involves an aqueous phase to carry out the reaction and an organic solvent (e.g., 2-butanol or MIBK) for HMF extraction to prevent HMF degradation. Extraction efficiency primarily depends on the partition coefficient of the different solvents.¹²⁸ The most commonly used extraction solvents, 2-butanol and MIBK, are green and yellow,^129,130 respectively. Toluene and THF have also been used, although alternatives, such as 2-methyl tetrahydrofuran,¹³⁰ could be used (P3). Extractions are also mass transfer dependent. In batch, the two phases are vertically separated by solvent density, and stirring has limiting impact in the vertical space. On the other hand, microreactors give a high mass transfer and interfacial area and enhance extraction efficiency. HMF conversion and selectivity increase from the single-phase in batch to >70% in biphasic batch systems^23,52,53 to >90% (ref. 23, 24, 131 and 132) in continuous biphasic systems, employing various flow patterns that promote internal circulation and transport between phases (Fig. 3 and 4). Specifically, Fig. 4 showcases the HMF extraction efficiency with its concentration profile under different slug lengths and parallel flow patterns.

Fig. 3 Flow patterns in microreactors.

Fig. 4 Characteristic mass transfer processes in different microflows such as (a) slug flow, (b) droplet flow, and (c) annular flow. Reprinted from ref. 48 Copyright (2021), with permission from ACS Publications.

Tuercke et al. reported that the 53.3% HMF yield in a single-phase continuous system increases to 82% at 185 °C (17 bar, τ = 1 min) in 80 : 20 wt% water : DMSO and MIBK/2-butanol as the extraction solvent.¹¹⁹ Lueckgen et al.¹³³ showcased that increasing the MIBK to water ratio from 0 to 4 at a constant residence time increases the HMF yield from <40 to 90%, and then reaches a plateau. The partition coefficient of HMF in 0.25 M HCl at 150 °C into MIBK was a modest 2.2 ± 0.4. An optimal HMF yield >80% was achieved in <40 s at 150 °C with a MIBK/aqueous ratio of 4, and an HMF productivity increased by >1 order of magnitude. On the other hand, while most studies used co-current flow, a few theoretical studies have studied countercurrent extractions to improve HMF removal.^134,135 On this front, Roquette Freres patented a counter current process producing HMF at 80 °C using DMSO as the reaction medium to promote favorable mutarotation and MIBK as the extracting solvent. The HMF yield of 97.5% is one of the highest reported.¹³⁶ Microdispersion technologies (i.e., microporous membrane) can also be incorporated into biphasic processes to promote extraction. Typically, biphasic systems employ a slug flow pattern, whereas membrane extraction utilizes dripping flow to create droplets on the membrane; the increased surface area further improves extraction efficiency. Additionally, commercial membranes are often inexpensive and can provide low Hagen–Poiseuille resistance due to the thinness of the material. Zhou et al. demonstrate an in situ membrane dispersion microreactor with 93% HMF yield at an organic to water ratio of 2.¹³⁷ The typical organic to aqueous ratio for HMF extraction is 3–5, as the extraction efficiency plateaus at higher organic ratios, as mentioned above.^119,132 Still, an additional phase separation agent could reduce solvent usage.

For tandem catalysis, Muranaka et al. described both glucose and fructose dehydration in a microreactor using phosphate buffer saline as the reaction phase and 2-sec-butyl phenol (2BP) as the extraction phase.²³ While the highest HMF yield from glucose was 75.7 mol% at 180 °C, the long reaction time (47 min) marks a much lower HMF productivity. Guo et al. demonstrated a biphasic slug flow capillary microreactor with AlCl₃ and HCl (pH = 1.5) and MIBK as the extracting solvent (4org : 1aqu), yielding 53% HMF in τ = 16 min at 160 °C.²⁵ The HMF yield further increased to 66.2% via salting out by adding 20 wt% NaCl. The reaction rate was doubled in the microreactor due to fast heating. As expected, tandem catalysis is generally 5–10× slower than direct fructose dehydration; otherwise, the biphasic extraction and microreactor enhancement effects parallel those in fructose dehydration.

Comparison of batch and continuous flow homogeneous microreactors. The sugar conversion and HMF space-time yields in batch and continuous flow microreactors were surveyed. The results are plotted in Fig. 5a and c. There is more published data for fructose than glucose conversion. For fructose dehydration, HCl gives the highest activity for fructose dehydration among the homogeneous catalysts.^119,132,133 This is due to the stronger dissociation of HCl that increases the concentration of protons and reactivity. Simulations of single-phase fructose dehydration as a function of pH and residence time, using kinetic parameters from Swift et al.,⁴² showcase the interplay between the residence time τ and pH; the lower the pH, the higher the rate, and the shorter the residence time for highest HMF yield (Fig. 5b). Decreasing the residence time translates to increased productivity. The variation of 3–4 orders of magnitude in productivity between different catalysts, such as phosphoric acid (a weaker acid), can be explained by this acidity effect. Similarly, tandem catalysis with HCl provides higher performance due to the fast fructose dehydration, and glucose isomerization is not rate-limiting (Fig. 5c²⁵). Furthermore, as temperature increases, productivity increases in general. Experimental and simulated results at 180 and 200 °C are overlaid in Fig. 5b and d, and this τ–pH correlation explains most of the scatter in the vertical direction of Fig. 5a. Temperature and pH can be tuned in both batch and continuous systems. However, the ultrafast residence times (seconds) can only be exploited in the continuous system, as heating time is limiting for batch. This phenomenon showcases the situation where a careful design of the reactor geometry stretches the operating window, opening up the previously inaccessible regime to enhance product yields.

Fig. 5 Experimental productivity of HMF in batch and continuous flow homogeneous phase microreactors in representative literature for (a) fructose and (c) tandem glucose dehydration reactions. Productivity variation among catalysts is attributed mainly to pH differences, with longer residence times and lower productivity for weak catalysts, such as phosphoric acid, and higher pH values. Predicted HMF yields at (b) 180 C and (d) 200 C in single-phase homogeneous reactions using the model of Swift et al.,⁴² with literature values overlaid. Data and experimental conditions are summarized in Tables S1 and S2.† Referenced works correspond to literature as follows: fructose: batch single-phase reactions,^52,138–141 batch biphasic reactions,^{23,52,53,140,142} continuous single-phase reactions,^{28,118–120,127} and continuous biphasic reactions.^{23,24,53,119,132,133,137,143} Glucose: batch single-phase reaction,^{51,140,141,144–146} batch biphasic reaction,⁵¹ and continuous biphasic reactions.^23,25

Biphasic systems exhibit overall better yield and productivity than single-phase systems due to favorable furanose mutarotation and increased HMF stability. There is a clear order of magnitude increase in productivity using microreactors – particularly continuous biphasic reactors – due to the large surface contact area, enhanced mass transfer, and rapid heating. The extraction efficiency depends on the partition coefficient and flow pattern. The formal is solvent and temperature-dependent, while the latter is tuned with reactor design and optimization of experimental conditions. Desir et al. showcased different flow patterns (droplet, slug, parallel, annular, and irregular) as flow rates and organic (MIBK) to aqueous ratios varied in the HCl-catalyzed biphasic dehydration reactions.⁴⁷ Unlike most previous studies on slug flow, the irregular flow pattern gave the highest extraction efficiency of ∼97%, and thus, the highest HMF yield.¹³² As shown in Fig. 6a, temperature and residence time effects are transcribed into dimensionless Damköhler numbers and plotted against optimal extraction efficiency and HMF yields. A biphasic system can be operated under a kinetic-controlled flow regime utilizing irregular flow, giving an optimal yield is ∼60%. Higher experimental HMF yields have been reported by Desir et al. and in literature,^24,119 where additional solvent effects on the reaction itself were hypothesized. Regardless, the extraction effect should be consistent. Furthermore, the actual productivity for a batch reactor is likely >60% lower¹²⁰ as we did not include time for cleaning, refilling, heating, and cooling the reaction medium. In contrast, continuous systems operate non-stop for extended periods. Finally, co-solvents or organic solvents in biphasic systems may affect reactivity.¹³² It is important to note that the cost of hexose sugars is the highest contributor to the final HMF market selling price.¹⁴⁷ Thus, maximizing the HMF yield in continuous biphasic systems (>90% HMF yield) is crucial (Fig. 7). As mentioned in the introduction of this section, reactions at high temperatures happen at short times. Thus, the batch data in Fig. 5 and 7 does not correspond to isothermal conditions, in contrast to the impression these and subsequent graphs give. Yet, the yield vs. conversion data in the single-phase fructose chemistry falls in a universal curve, and the lack of isothermal conditions makes a slight difference for this chemistry. Still, the biphasic continuous microreactor setup marries the advantageous short residence time with the stabilizing organic solvent, leading to >90% HMF yield that led to >10% HMF yield improvement from the biphasic batch system.

Fig. 6 Predicted biphasic extraction efficiency and HMF yield in a microreactor as a function of Damköhler numbers in (a) biphasic irregular flow microreactor and (b) kinetic-controlled (KC) flow regime. KC and mass transfer-controlled (MC) regimes are delineated across the colormap. The two Damköhler numbers represent temperature and residence time effects. MC-I: mass transport is slow. MC-II: fructose dehydration rate > extraction rate. MC-III: fructose dehydration & contact time > HMF extraction rate. The solvents are MIBK and water, with HCl catalyst at pH = 0.7. Adapted with permission from Chemical Engineering Journal.¹³²

Fig. 7 Comparison of HMF yields in single and biphasic batch and continuous flow microreactors in representative literature for the fructose dehydration reaction. The single-phase reaction with 85.6% HMF yield reported by Schön et al. with pH = 0 and MW heating¹²⁰ is an outlier. Data and experimental conditions are summarized in Tables S1 and S2.† Referenced works correspond to literature as follows: fructose: batch single-phase reactions,^52,138–141 batch biphasic reactions,^{23,52,53,140,142} continuous single-phase reactions,^{28,118–120,127} and continuous biphasic reactions.^{23,24,53,119,132,133,137,143}

3.1.2 HMF conversion. Most microfluidic studies have focused on sugar chemistry and only a few on the HMF conversion to valuable products. We provide a few examples here. One downstream application of HMF is its oxidation to 2,5-diformylfuran (DFF), 5-formyl furan carboxylic acid (FFCA), and 2,5-furan dicarboxylic acid (FDCA), compounds in series (Scheme 3). These molecules find applications in phenolic resins, organic conductors, bio-based plastics, and active pharmaceutical ingredients. The reactions are generally carried out with molecular oxygen in an aqueous alkaline solution using heterogeneous platinum, gold, or palladium catalysts,¹⁴⁸ or homogeneous metal bromide complexes.¹⁴⁹ In batch, this reaction is limited by the oxygen's mass transfer and solubility, even at high stir rates.¹⁵⁰ Spray oxidizers increase the oxygen mass transfer,¹⁵¹ but require large reactor volume to treat a large amount of hot recirculating air. Slug flow drastically increases the necessary transfer surface area. Hommes et al. reported the oxidation of HMF to DFF, FFCA, and FDCA in a slug flow PTFE microreactor catalyzed by homogeneous Co/Mn/Br catalysts in acetic acid and acetaldehyde as co-oxidant.¹⁴⁹ Mass transfer limitation was not observed even at 165 °C and 5 bar. At 150 °C and τ = 2.7 min, the optimized HMF conversion was 99.2%, and the yields of DFF, FFCA, and FDCA were 22.9%, 46.7%, and 23.8%, respectively. The microreactor greatly enhanced the space-time yield to DFF and FFCA and avoided hot spots due to its excellent heat transfer. This result underscores that more chemistries should be carried out in microreactors, especially mass transfer limited ones.

Scheme 3 Downstream reaction pathways using HMF as a reactant. Compounds acronyms: furfuryl alcohol (FFA), 5-hydroxymethyl-2-furancarboxylic acid (HFCA), 2,5-diformylfuran (DFF), 5-formyl furan carboxylic acid (FFCA), 2,5-furan dicarboxylic acid (FDCA), 2,5-dimethylfuran (DMF), and 5-ethoxymethylfurfural (EMF).

3.2 Heterogeneous catalytic reactors

Heterogeneous catalysts are industrially preferred over homogeneous ones due to easier catalyst separation and regeneration and reduced environmental footprint. However, solid catalysts in microreactors can lead to channeling and a large pressure drop. These problems can be circumvented using washcoats or larger reactor diameters. There are additional challenges for heterogeneous catalytic reactors, some specific to biomass. These entail (1) significant catalyst deactivation, which occurs at a fast rate given the high functionalization and reactivity of biomass derivatives; (2) catalyst leaching, which happens due to using solvents and non-neutral media; (3) lack of suitable commercial catalysts. Instead, novel catalysts need to be synthesized, and activation and characterization procedures need to be developed; and (4) lack of knowledge of deactivation mechanisms and regeneration protocols, topics not studied systematically. For demonstration, fructose dehydration using heterogeneous catalysts is reviewed here.

3.2.1 HMF production. Overall, there are fewer studies using heterogeneous catalysts. Jeong et al. studied the catalytic dehydration of fructose to HMF in a sulfonic acid-functionalized silica capillary in DMSO.¹⁵² The conversion at 120 °C increased from 63% (yield of 57%) to 84% (yield of 80%) by increasing the residence time from 3 to 30 min. Upon increasing the reaction temperature to 150 °C, 99% fructose conversion and 99% HMF yield were achieved at τ = 6 min.¹²⁵ McNeff et al. demonstrated 13% HMF yield using TiO₂ and 1 : 1 water : n-BuOH extraction at 200 °C at τ = 3 min.¹⁵³ Despite the low HMF yield, the short contact time and high fructose concentration (23%) mark high productivity. An HMF yield of 29% was obtained at 180 °C at τ = 2 min and was further increased to 37% by adding 0.15 M HCl co-catalyst¹²⁷ using a larger organic solvent usage (1 : 10 water : MIBK) instead of the 1 : 1 water : n-BuOH. MIBK is also known to be a superior extracting solvent. Up to 35% HMF yield was obtained from cellulose in the same setup at 270 °C with τ = 2 min and MIBK extraction.

For tandem Brønsted and Lewis acid catalysis starting from glucose, the focus has been on controlling the relative abundance and strength of Brønsted and Lewis acid sites. Engineering the catalyst is essential. Guo et al. showcased that the structure, acidity, and performance of P–TiO₂ strongly depend on the synthesis.¹²⁸ An optimum ratio of Brønsted to Lewis acid sites of ∼0.5 was discovered by adjusting the phosphate loading. At 150 °C, 73% HMF yield and >95% glucose conversion were obtained in 90 min.

The HMF space-time yield in batch and continuous flow microreactors is shown in Fig. 8. Compared to homogeneous reactors, the productivities are at least one order of magnitude lower. Again, there is significant variation in productivity at similar temperatures, but the reasons remain unclear. The catalyst amount and the strength and acid site density of catalysts are obvious reasons. Normalizing the data with the catalyst site density would reveal information on the acid site strength.

Fig. 8 Experimental productivity of HMF in batch and continuous flow heterogeneous phase microreactors in representative literature for (a) fructose and (b) tandem glucose to fructose to HMF reactions. Data and experimental conditions are summarized in Tables S1 and S2.† Referenced works correspond to literature as follows: fructose: batch single-phase reaction,^{141,145,155–158} batch biphasic reactions,^{131,159–167} and continuous biphasic reactions.^131,153 Glucose: batch single-phase reaction,^{141,145,168–172} batch biphasic reactions,^{135,140,144–146} and continuous biphasic reactions.^153,154

3.2.2 HMF conversion and related reactions. The work by Jeong et al.¹⁵² exemplifies the flexibility of microreactors for specialized reaction needs. They demonstrated two-step tandem catalysis from fructose into a diverse range of furan products (Scheme 3), including furfuryl alcohol (FFA), 5-ethoxymethylfurfural (EMF), DFF, and DMF in a magnetic-based heterogeneous reactor (Fig. 9). HMF was produced in >99% yield in a sulfonic acid-functionalized silica capillary reactor (150 °C, τ = 6 min, in DMSO). The aforementioned downstream products were produced via decarbonylation or etherification in a biphasic microreactor, or oxidation or hydrodeoxygenation in a gas/liquid/solid tube-in-tube reactor. Such packed catalyst beds allow intensified production without additional product or solvent separation steps between the upstream and downstream reactions. In a second process, magnetic-based solid catalysts were immobilized by magnet rings surrounding the microreactor. Such a configuration allows controllable catalyst loading and location depending on the magnetic ring locations. Using Pd/Fe₃O₄/SiO₂ catalyst, the FFA yield was 94% at 150 °C and τ = 12 min in DMSO, under both tandem conditions from fructose and direct decarbonylation from HMF. Reduced graphene oxide (rGO) loaded with magnetic Fe₃O₄ was used for the etherification reaction to produce EMF. At 70 °C, complete HMF conversion with 99% EMF yield was obtained at τ = 6 min in ethanol. Oxidation and hydrogenolysis were performed in a tube-in-tube configuration where O₂ or H₂ diffuses from the inner tube to the outer one where the liquid and catalysts are located. Using Fe₃O₄@SiO₂@Mn with 2-salen ligand complex, the oxidation of HMF to DFF led to 93% conversion and 84% yield at 150 °C and τ = 60 min in DMSO. Ru/Cu supported on Fe₃O₄ and nitrogen-doped rGO (Ru/Cu/Fe₃O₄/N-rGO) led to 90% DMF yield with 100% conversion in 20 min. The innovative catalyst distribution and reactor design are interesting for modular manufacturing.

Fig. 9 Illustrative scheme of binary and ternary-phase reactions for converting HMF into FFA, EMF, DFF, and DMF. Adapted from NPG Asia Materials¹⁵² (CC BY 4.0).

3.3 Performance comparison of batch reactors and continuous flow microreactors

In this review section, we showed that the reactor geometry can significantly affect performance, which has been overlooked until now. Some general trends are obvious in the data. The fructose dehydration reaction with HCl catalyst is showcased here to summarize the benefits of microreactors. For a single-phase reaction, three crucial optimization parameters include temperature, residence time, and pH. Predictions using the kinetic model by Swift et al.⁴² show the interplay between variables (Fig. 5b and d). High HMF yield is obtained at high temperature and Brønsted acidity (lower pH). At relatively strong acidity, the higher HMF yield is achievable at temperatures >160 °C, where τ ≪ 1 min. The higher the temperature, the higher the yield. At sufficiently high temperatures, the yield is high over a range of pH values. The reaction time decreases profoundly by reducing the pH, i.e., by increasing the catalyst amount. These short reaction times are unachievable in batch systems due to heating constraints but are accessible at high temperatures and high catalyst concentration in flow systems. Due to the kinetics of the main and side reactions being first order in catalyst concentration, the selectivity is controlled by the temperature. In contrast, the catalyst amount affects only the processing time. This allows easy optimization of the yield and reactor volume.

For biphasic systems, similar conclusions of high temperature and low τ leading to enhanced extraction efficiency, superior HMF yield, and high productivity are only achievable in continuous microreactors. The flow patterns affect the volumetric mass transfer and extraction efficiency. The highest HMF yield (94.7%) reported to date is in a biphasic system at 180 °C with pH = 1.6.²⁴ Lowering the pH allows operation at lower temperatures,¹¹⁷ leading to an interesting tradeoff between utility cost for heating and capital cost for acid-resistant materials. While fewer studies have been conducted using heterogeneous catalysts, the evidence still points to a similar conclusion that enhanced mass transfer between the solid–liquid phases and reduced residence time led to increased HMF yields.

3.4 Outlook for microtechnology for biomass upgrading

Microreactors increase productivity at least >10× due to the increased mass and heat transfer rates, higher temperatures and shorter residence times, and minimal downtime. This field has vast opportunities for 3D printing or coating technologies to construct reactors, dowels, and catalysts deployment strategies (washcoats) and minimize pressure drop. HCl gives one of the highest HMF productivities for single-phase homogeneous fructose dehydration reported thus far. However, it is a strong acid with environmental and health concerns. It could compromise structural integrity due to corrosion at high temperatures and extended operations and increase capital costs by needing acid-resistant materials. Biphasic extraction at microscales improves yields due to enhanced heat and mass transfer and large surface areas. The compatibility of the reactor material hydrophilicity with solvents can affect flow patterns and transport. Engineering the material wettability, MW transparency, burst pressure rating, and visualization are essential for future work. Last but not least, microseparators utilizing specialized membranes can enhance separation while decreasing organic solvent usage.

A rarely explored advantage of continuous flow systems is the extraction of intrinsic reaction kinetics and networks. These are unattainable in batch reactors, especially for ultrafast reactions and high temperatures. Yet, only limited studies have focused on the kinetics of renewable substrates in microsystems.^42,123,127 Kinetics is vital in developing robust models for microreactor design and optimization using CFD.

Solid catalyst stability and reusability are vital. In most prior research, catalyst stability is assessed in batch systems, where catalysts are washed and reused after high conversion runs. Such an approach masks catalyst deactivation due to having catalyst excess, leads to catalyst loss during washing and transfer, and does not provide deactivation kinetics. Continuous operation enables estimation of the deactivation rate and, combined with catalyst characterization, can assist in developing regeneration strategies. We believe this is an area that needs significant attention for practical implementation.

4 Electrified microfluidic devices

As discussed in the previous section, microreactors demonstrate excellent potential for sustainable manufacturing by enabling the utilization of renewable, remote, and distributed feedstocks and enhancing transport rates by 2–3 orders of magnitude compared to conventional processes. However, process intensification and waste streams valorization are inadequate alone to transform manufacturing into zero emissions. Electrification is a vital pillar of this goal. It can employ renewable electricity to minimize CO₂ emissions. Notably, it can provide unique advantages. For example, microwaves (MWs) can minimize side reactions, decrease processing times, and enhance energy efficiency, whereas plasmas can operate far from equilibrium, overcome thermodynamic limitations, and activate stable molecules. These traits, combined with the continuous microflow technology, create exciting prospects for sustainable manufacturing. This section summarizes the current progress in the emerging field of integrating microreactors with microwaves and plasmas using alternative energy sources. We leave out other electrified systems, such as sonication, inductive heating, and electrochemical devices.

4.1 Electrification using microwaves (MWs)

Synthetic MW chemistry was born in 1986 with publications featuring stark rate enhancements in kitchen-grade MW ovens.^173,174 As the technology matured into commercially available mainstays,^175,176 the field has grown with more than 2000 publications every year.¹⁷⁷ Aside from rate enhancement, MWs pave the way for sustainable chemical manufacturing. Principally, MW-based process electrification enables the sourcing of energy from renewable resources, such as wind or solar (P7). Further, MW heating is driven by dipole polarization and ionic conduction, and the energy is deposited directly and volumetrically instead of relying on conventional slow conduction and convection. This direct coupling underscores rapid and selective heating that can improve energy efficiency (P6), reaction rate, and selectivity.¹⁷⁸ Selectivity improvement is associated with lower energy use in separations, and for renewable feedstocks, selectivity and conversion determine the carbon efficiency conversion and the economic viability of a process. The inherent safety from the direct energy coupling with the reaction mixture^179,180 (P12) and the compatibility of MWs with catalysts (P9) make process electrification a fertile technological ground for sustainable chemical manufacturing.

Here we focus first on the enhancements actuated by MWs, which are unachievable by conventional heating. These so-called “MW-specific” effects are often purported to improve rate, yield, and/or selectivity and are almost always related to the selective nature of MW heating. Then, we describe MW technology and efficiency at a macroscopic level and its integration with the microflow technology.

4.1.1 MW-specific effects in single-phase systems. Heating a single liquid phase often happens in an MW-transparent vial (e.g., glass) (Fig. 10). When heated conventionally, temperature gradients develop, giving a warmer wall and a colder liquid center. When heated with MWs, the vial is not heated and is colder; instead, the liquid is directly and volumetrically heated by the MWs. This inverted temperature gradient is ubiquitous in MW-heated reactors and is a “specific effect”.

Fig. 10 Microwave and conventional heating modes. Recreated from ref. 181 (CC BY 4.0).

MW-specific effects, especially those in single-phase liquid systems, have been hotly contested over the years. They are critical to understanding the reported observations and the potential of MWs for chemical manufacturing. In our opinion, the most plausible and well-documented effects (of those that impact chemical systems) pertain to bulk superheating and local overheating.

Bulk superheating. One of the earliest-recognized^173,174 and more-substantial aberrancies of MW heating is MW-induced superheating. While difficult to quantify, due to a lack of MW-appropriate thermometric methods, Baghurst and Mingos surveyed MW heating of various solvents using temperature-sensing, MW-transparent optical fibers.¹⁸² Chemat and Esveld later concluded that the MW superheating effect is driven by the inverted temperature gradients.¹⁸³ Traditional nucleate boiling occurs at the solvent–container interface, where pits and scratches serve as nucleation points. For conventional heating (CH), heat is transferred into the liquid through this interface, and, therefore, the interface is warmer than the bulk liquid. For MW heating, however, the solvent–container interface is the coldest, thereby diminishing nucleation. In the absence of such interfaces, MW boiling occurs at the gas–solvent interface at the headspace. Superheating of up to 40 °C above conventional boiling points was reported. MW superheating was applied to the esterification of benzoic acid and the cyclization of citronellal, speeding reaction rates and creating kinetic zones only accessible to MWs for a given pressure. This effect of MW-exclusive temperature zones and the ensuing kinetic enhancement is demonstrated in Fig. 11. Rate enhancements of 1–2 orders of magnitude over CH were observed, and correlations were developed to predict the MW boiling point and ensuing rate enhancements for a library of solvents and reactions.

Fig. 11 Rate constant of thermal cyclization of citronellal under conventional (solid circles) and MW heating (hollow circles). Redrawn from ref. 183 with permission from John Wiley and Sons (2022). BP = boiling point; MW = microwaves; CH = conventional heating.

Cablewski et al. demonstrated MW superheating in a continuous flow, reaching temperatures up to 100 °C above the conventional boiling point for various volatile solvents, and rate enhancements of 2–3 orders of magnitude for a wide swath of reactions.¹⁸⁰ While the authors did not rationalize this outsized superheating effect, it is perhaps not surprising that MW superheating in continuous flows might exceed batch behavior due to lack of headspace and a smooth borosilicate tubing (sometimes perfluoroalkoxy Teflon), reducing nucleation.

Aside from simply accelerating reactions, superheating improves selectivity and the use of less aggressive reagents or lower quantities of them.¹⁸⁰ For example, in the production of methyl 2-phenylethyl ether from 2-(bromoethyl)-benzene, the byproduct (styrene) selectivity was decreased. In another case, the esterification of mesitylenecarboxylic acid was performed with small fractions of sulfuric acid (∼1.5%), compared to CH,¹⁸⁴ involving 100% sulfuric acid. Polshettiwar and Varma proposed that MW superheating allows for greener solvent selection.¹⁸⁵ Higher temperatures by MWs allow water – the greenest solvent available – to behave as a “pseudo-organic” solvent and enable the solvation of organic substrates without a phase-transfer catalyst. A large swath of organic synthesis reactions proceeds at high yields in the aqueous MW environment, including Suzuki^186–188 and Heck¹⁸⁹ coupling, nucleophilic substitution,¹⁸⁷ and many others. Varma and coworkers have reviewed MW-assisted organic synthesis in aqueous media.¹⁹⁰ Nucleation-friendly solids in MW-heated liquids (shown with boiling stones and optical fibers) diminish the superheating effect,¹⁸³ likely isolating the MW superheating to systems without heterogeneous catalysts.

Local overheating. MW-heated single-phase reactions are often reported to far outperform CH at the same bulk temperature.^{178,181,191,192} Perreux and Loupy¹⁷⁸ purport that enhancements may be due to a non-thermal MW effect. Dudley and coworkers¹⁹² suppose a MW-actuated thermal effect. Contentiously,^192–195 the enhancement is often challenged in critical literature, and, in many cases, the effect is ascribed to inaccurate temperature measurements.^193,196 Kappe and coworkers showed that IR thermometry often underestimates the temperature, leading to erroneous claims of enhanced rates. Therefore, great care must be taken in measuring temperature in MW systems.^197,198 Standing atop of these efforts, the following corollary has emerged: When at the same temperature, reactions occur at the same rate under MW and conventional heat.¹⁹⁹

Abiding this corollary – and taking note of local “hot spots” purported to occur throughout the bulk of MW-heated liquids^191,200 – Keglevich and coworkers proposed that rate enhancements in homogeneous reaction mixtures could be linked to locally overheated zones in a statistical manner:^201–203

Here, Vⁱ_O and Tⁱ_O represent the volumes and temperatures of each overheated element, respectively. V_t represents the entire system volume, and V_bulk and T_bulk the bulk volume and temperature (non-overheated regions), respectively. In the simplest case, one can assume a single overheated region with a single temperature. This assumption is used in Fig. 12a for the acid-catalyzed dehydration of fructose to form HMF. Depending on the volume or temperature of the overheated zone (with bounds established by Keglevich),²⁰³ rate enhancements of >10× are seen, consistent with the homogeneous production of HMF.¹⁸¹

Fig. 12 Effect of local overheating on the rate constant of acid-catalyzed fructose dehydration to HMF (a). Calorimetric energy savings due to the same local overheating and lower bulk temperature effect (b). For these calculations, reaction parameters taken from ref. 42, T_bulk is 150 °C, and an overheated zone of only a single non-bulk temperature is considered.

While this framework resolves the impasse between observed rate enhancements, it does little to address what the size, temperature, or the number of overheated zones are. For example, Ricciardi et al. recently showed a 7–13× rate enhancement in the acid-catalyzed dehydration of xylose to furfural in aqueous media.²⁰⁴ Due to the inability to measure the overheating, they were left to fit the number, sizes, and temperatures of the overheated volumes based on the rate enhancements, making several assumptions. It was estimated that for a single overheated volume, V_OH/V_O is 5–20% and ΔT is ∼0–100 °C (despite the fact that ΔT scales with T_bulk).

Clearly, a better description of these overheated regions is required. Recently, Horikoshi and coworkers noted that the dielectric properties of polar/non-polar binary mixtures do not abide by ideal assumptions and can instead have strong excess properties at certain ratios.²⁰⁵ They also linked the excess dielectric properties and the Kirkwood g-factor – a thermodynamic quantity that estimates the magnitude of parallel polar alignment with its neighbors. Specifically, as the composition of a binary mixture is altered from one extreme to the other, it may cross the threshold of g = 1 (above which it is parallel and below antiparallel). The binary concentration at the crossing point also corresponds to the maximum/minimum excess dielectric behavior. They inferred a strong link between these properties and the microscale structural behavior (i.e., clustering) of polar and non-polar solvents. This phenomenon, in turn, aligns with the description of Keglevich and Mucsi that locally overheated regions should be well-distributed, nano-sized, and impractical to measure by conventional means.²⁰³

Dudley and coworkers have similarly theorized that overheated zones are owed to MW-absorbing solutes contained in MW-transparent solvents.^192,206,207 They analyzed the MW-heating of p-nitroanisole (pNA; polar) in mesitylene (non-polar).²⁰⁸ Small-angle neutron scattering showed agglomerates of pNA of roughly attoliter-sized (10⁻¹⁸ L) spheres, while in situ Raman spectroscopy demonstrated that agglomerates heat up to 114 °C above the bulk under MW irradiation. The same group analyzed the kinetics of a Claisen rearrangement reaction in the same pNA/mesitylene system, where the reactant, allyl naphthyl ether (non-polar), partitions between the bulk and the agglomerates.²⁰⁹ 3× rate enhancements were observed over that at the bulk temperature, constituting the first compelling evidence of MW-induced local overheating and rate enhancement.

Several questions remain regarding the MW local overheating. For example, the breadth of solvents with this microscale structural behavior is unclear. If indeed acidic aqueous solutions, such as those used in biomass processing, exhibit this clustering, why would this create local overheating given the already-polar nature of the bulk solvent? Furthermore, estimating the size of these structures is critical. While scattering methods are excellent, these methodologies are ill-suited for high-throughput solvent selection and screening. Molecular dynamics (MD) and other computations have shown such clustering in aqueous and other solutions, but to our knowledge, these methods have not yet been applied to the analysis of MW heating behavior.^210,211

The enhanced reaction rates enable more compact processes while tempering the energy requirements. Under MW heating, the acid-catalyzed dehydration of xylose takes place not at the bulk temperature, but at overheated zones.²⁰⁴ In that particular study, the bulk temperature is 140 °C while the overheated zones are estimated to be ∼200 °C and the overheated fraction is estimated to be 5–20%. On a purely calorimetric basis, one can extend the analysis of Keglevich and coworkers²⁰³ to estimate the energy Q_overall required to heat such a system:

Here T_amb, T_bulk, and Tⁱ_OH represent the system's starting (ambient) temperature, the bulk temperature, and the temperature of each overheated zone, respectively. C_p represents the heat capacity of the fluid at constant pressure. For a single overheated region at a single temperature, one can compare the energy requirements of MW (eqn (4)) and CH. Shown in Fig. 12b are the energy savings conferred by locally overheated regions via MWs over conventional heating (at which reactions predominantly proceed). Accordingly, energy savings of ∼30% may be possible. While the overheated volumes and temperatures are constrained, energy savings through temperature heterogeneity are common in MW-heated multiphase systems, as discussed next.

4.1.2 MW-specific effects in multiphase systems. Because of their heterogeneity, multiphase systems under MW irradiation experience a broad range of effects not seen in conventional systems. This is very clearly rooted in the selective nature of MW heating, whereby non-homogeneous systems absorb different quantities of energy. Here, we target systems with liquid-phase, mainly biomass conversion chemistry.
Liquid–liquid systems. In liquid–liquid biphasic systems, MWs result in selective heating of the polar aqueous phase than a non-absorbing organic phase, as illustrated in Fig. 13. Liquid–liquid biphasic systems are often employed for reactive extraction, including lignocellulosic biomass described in the previous section.

Fig. 13 Temperature profile of aqueous single-phase system (a) and water/MIBK biphasic system (b) at steady state under MW irradiation. Both systems have a total volume of 6 ml and the biphasic system has a 1 : 1 phase ratio. Adapted with permission from ref. 212 Copyright (2022) American Chemical Society.

While an organic phase extracts HMF or furfural in situ to enhance yield by removing the product from the reaction media to prevent side reactions,²¹³ recent studies have shown that MWs can further boost performance, as shown in Table 3.^214–217 For example, Breeden et al. showed that for 5-chloromethylfurfural (CMF) forming in a water/dichloroethane system, the yield increased from 75% to 85% and the selectivity from 96% to 98% over CH, while allowing the use of non-halogenated solvents like cyclohexane.¹⁸⁵ Wrigstedt et al. report 91% yield and 92% selectivity to HMF in fructose dehydration in a (0.05 M HCl + KBr)_(aq)–MeCN biphasic system in 1 min of heating at 160 °C; meanwhile, only 38% yield and 61% selectivity were achieved with CH in 10 min (optimized CH time yielded 79% at 84% selectivity).²¹⁵

Table 3 MW-mediated improvement of reactive extraction performances across the literature. Y and S indicate yield and selectivity, respectively

Study	Reaction Conditions			Performance
	Reactant & product	Catalyst & temperature	Extracting phase (Aq : Org)	Conventional	Microwave
Breeden et al.^214	Fructose, CMF	HCl, 80 °C	Dichloroethane (1 : 2)	Y: 78%	Y: 85%
				S: 96%	S: 98%
Wrigstedt et al.^215	Fructose, HMF	HCl, 160 °C	Acetonitrile (1 : 2)	Y: 79%	Y: 91%
				S: 84%	S: 92%
Yang et al.^216	Xylan, furfural	Al2(SO4)3, 130 °C	γ-Valerolactone (1 : 4)	Y: 79%	Y: 89%
				S: —	S: 98%
Ricciardi et al.^217	Xylose, furfural	H2SO4, 200 °C	Toluene (1 : 1)	Y: 65%	Y: 77%
				S: 68%	S: 79%

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Ricciardi and coworkers demonstrated using a small library of solvents that the MW-mediated boost in furfural yield correlates strongly with the MW-transparency of the organic phase (as estimated by the dielectric constant, ε′).²¹⁷ It is posited that increasing the MW-transparency leads to a colder organic phase, increased extraction, and higher yield. However, none of the works offer temperature measurements of the organic phase or demonstrated that the increased yield is due to improved extraction. While plausible that a colder organic phase enhances extraction, no explanations address the increased rates.

Recently, we have analyzed MW-induced temperature gradients in liquid–liquid systems.²¹² It is found that the dielectric properties and the temperature gradient correlate strongly but that both the real and imaginary components are important. Additionally, the specific surface area, the ratio of the two phases, the heat transfer coefficient, and the intensity of power dissipation are important. A simple analytical model predicts the temperature gradient between phases:

Here ΔT and ΔQ are the temperature and power dissipation differences between the phases, (ΔQ is often reasonably approximated as the power dissipation in the aqueous phase), U is the heat transfer coefficient, SSA is the specific surface area, C_p is the heat capacity of the aqueous phase, and φ is the aqueous-to-organic ratio. ΔT of more than 35 °C for a water/MIBK system is experimentally demonstrated. This model provides insights into the MW-enhancement on reactive extraction. More work is still necessary to delineate the MW effects on mass transfer, partition coefficient, and other physical phenomena.

Aside from rate and selectivity enhancements, there are also energy savings in MW-heated biphasic systems. With similar assumptions to those made in (4), when the aqueous phase of a 1 : 1 water/MIBK system is at 160 °C, and the organic phase is 35 °C cooler (ΔT = 35 °C), the energy savings compared to CH would be about 7.8%. With 1 : 2 and 1 : 4 water/MIBK systems, the energy savings for the same ΔT would be 12.1% and 16.6%, respectively. Because ΔT drives several phenomena, optimizing these systems for a colder organic phase will likely improve yields, selectivity, and energy consumption.

Liquid–solid systems. MWs are compatible with liquid/solid heterogeneous systems, including slurries, fixed beds, and structured catalysts. Among these, batch-phase slurries have definitively enjoyed the most attention, as this mode is used by synthetic chemists for routine heterogeneous catalytic transformations. Suspended solids can include zeolites,²¹⁸ resins,²¹⁹ clays,²²⁰ carbons,^221,222 metals,²²³ and metal oxides.²²⁴ Similarly, the liquid phase can be either polar^218,222 or non-polar.²²¹ Several recent reviews on sustainability are available.^225,226 As in other areas of MW-assisted synthesis, large rate enhancements are often reported (see Table 4). However, this literature focuses mainly on the synthetic analysis with assuredness that the methodology is efficient and eco-friendly, and little attention to the MWs. Rarer are works attempting to analyze the specific roles of MWs and how to optimize them to enhance chemical processes further. We summarize select ones below.

Table 4 Chemical reaction performance of MW-heated slurries. X, Y, and S indicate conversion, yield, and selectivity, respectively

Reaction	Catalyst & conditions	Reactants & products	Solvent	Performance		Additional differentiation
				Conventional	Microwave
Dehydrogenation^231	Pt/AC, 207 °C (120 min)	R: tetralin; P: naphthalene	Neat	X tetralin: 32%	X tetralin: 50%
Dehydrogenation^201	Pt/carbon, 207 °C (90 min)	R: tetralin; P: naphthalene	Neat	Y Naph: 3.5%	Y Naph: 17%	Carbon: AC
				Y Naph: 6%	Y Naph: 25%	Carbon: CMC
Dehydrogenation^232	Pt/AC, 220 °C (120 min)	R: tetralin; P: naphthalene	Neat	X tetralin: 32%	X tetralin: 31%	No insulation
					X tetralin: 56%	Dewar-like reactor
	Pt/AC, 220 °C (60 min)			X tetralin: N/A	X tetralin: 28%	Suspension state
					X tetralin: 68%	Liquid film state
Suzuki coupling^221	Pd/AC, 110 °C (120 min)	R: phenylboronic acid, 4-bromotoluene; P: 4-methylbiphenyl	Toluene	Y 4-mBP: 2.8%	Y 4-mBP: 11.8%	E-Field
					Y 4-mBP: 22.1%	H-Field
Suzuki coupling^230	Pd/carbon, 110 °C (150 min)	R: phenylboronic acid, 4-bromotoluene; P: 4-methylbiphenyl	Toluene	Y 4-mBP: 14%	Y 4-mBP: 23%	Carbon: AC
				Y 4-mBP: 17%	Y 4-mBP: 38%	Carbon: CMC
Suzuki coupling^227	Pd/CMC, 110 °C (80 min)	R: phenylboronic acid, 4-bromotoluene; P: 4-methylbiphenyl	Toluene	Y 4-mBP: 18.7%	Y 4-mBP: 10.2%	No MAHS
					Y 4-mBP: 34.2%	With MAHS
Suzuki coupling^228	Pd/CMC, 70 Watts (60 min)	R: phenylboronic acid, 4-bromotoluene; P: 4-methylbiphenyl	Toluene	Y 4-mBP: 21.3%	Y 4-mBP: 5.7%	E-Field
					Y 4-mBP: 34%	H-Field
				Y biphenyl: 8.8%	Y biphenyl: 3.9%	E-Field
					Y biphenyl: 5.7%	H-Field
Suzuki coupling^222	Pd/rGO, 80 °C (10 min)	R: phenylboronic acid, 4-bromobenzaldehyde; P: 4-phenylbenzaldehyde	Water + ethanol	—	Y 4-PhBAL: 100%
Ullmann coupling^223	Cu (60 min)	R: potassium phenolate, 4-chloropyridine; P: 4-phenoxypyridine	Dimethyl-acetamide	Y PhPyr: 38%	Y PhPyr: 60%	110 °C
				Y PhPyr: 83%	Y PhPyr: 85%	140 °C
Hydrogenation^224	Cu/TiO2, 125 °C (120 min)	R: furfural; P: furfuryl alcohol	cylopentyl-methyl ether	Y FOH: 26%	Y FOH: 97%
				S FOH: 94%	S FOH: 99%
Hydrolysis^218	H-Beta & HCl, 180 °C	R: microcrystalline cellulose; P: glucose, HMF, levulinic acid, formic acid	Water	X cellulose: 7%	—	360 min
				—	X cellulose: 12%	60 min

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Horikoshi and coworkers devoted considerable effort to understanding MW-heated slurries in batch systems, primarily in the Suzuki coupling^{221,227–230} and tetralin hydrogenation.^231,232 The observed MW-mediated rate enhancements in the latter over a slurry of carbon-supported platinum was attributed to selective heating of the carbon.²³¹ For the former reaction over carbon-supported palladium, the effect was sometimes enhancing^221,230 and sometimes detrimental.^227–229 Hot spots and arcing on the highly MW-absorbing carbons increase temperatures from 400 to 1400 °C,^228,229 leading to catalyst sintering and deactivation.²²¹ This sintering seemingly did not affect platinum catalysts as severely (possibly due to its higher melting point).^230–232 This undesired behavior could be controlled by placing samples in locations of high H-field intensity (rather than E-field) to produce magnetic heating and reduce hotspots. MW-heating can lead to higher yields of the desired product – 4-methylbiphenyl – and lower selectivity to byproducts, like biphenyl, than CH.^221,228

Morphologically controlled supports, such as carbon microcoils rather than activated carbon, decrease hot spots and enhance yields due to the lack of sharp edges for charge accumulation.²³⁰ In related work, Belecki, Gupton, and coworkers demonstrated strikingly fast rates for a similar reaction over palladium on graphene, reaching 100% yield in 10 min at a bulk temperature of only 80 °C.²²² They attributed this to the electron withdrawing and donating groups and reported no arcing. Finally, insulation, MW receptors, or other means can decrease the temperature gradient between the solid and liquid phases to decrease deactivation and boost yields.^227,229,232

Less MW-absorbing solids, such as zeolites, clays, and metal oxides, have also been employed in slurries. For example, Romano et al. employed copper nanoparticles supported on TiO₂ for the hydrogenation of furfural.²²⁴ At otherwise identical conditions, furfuryl alcohol yields were >3× and selectivity was modestly boosted compared to CH. Similarly, for the tandem hydrolysis and dehydration of cellulose, a zeolite slurry with HCl heated via MWs gave 10× rate enhancement over CH.²¹⁸ Solids like zeolites do not absorb MWs as aggressively as carbons and do not arc but still exhibit rate enhancements.

The phenomena in these multiphase systems (slurries) are linked directly to selective MW heating. Depending on the solid, the bulk liquid phase can be cooler than the liquid immediately surrounding the catalyst and the catalyst (if one exists). This effect is, presumably, responsible for the accelerated rates and boosted yields. However, the electric field enhancement near edges can result in Joule heating, hot spots, or even arcing. The overheating of the solid can cause catalyst sintering and deactivation. Recently, we have developed analytical expressions to predict the temperature gradients between liquid and solid in MW-heated slurries, like eqn (5), and criteria to avoid arcing.⁷⁰ Clearly, there is a need for developing principles to optimize these systems.

While a fundamental picture of the MW-heated liquid–solid systems is emerging, more work is needed to understand their best applications. For example, design principles for packed beds or structured catalysts have not been developed. It is unclear how these systems may differ from slurries, especially regarding arcing and hotspots. Structured catalysts should reduce arcing due to their monolithic structure and uniform heating.^233–235 Furthermore, unlike liquid–liquid systems, the measurement of solid temperatures is not straightforward. Finally, while elevated solid temperatures could certainly enhance rates, it has not been demonstrated that this is the sole reason for enhanced performance.

4.1.3 MW flow technology & implementation. The application of MWs to micro- and mesofluidics is an important topic, first approached by CSIRO in 1994 whereby numerous chemistries were demonstrated in continuous flow mode.¹⁸⁰ Because MWs attenuate through absorptive media, they suffer from penetration depth issues and are limited to dimensions of not more than 1–2 cm in the 2.45 GHz ISM band.^236,237 Given this, the use of microfluidics for sustainable chemical manufacturing presents a further opportunity for process electrification. Researchers in organic, enzymatic, and nanoparticle synthesis have advanced MW-heated continuous flows considerably, as discussed in recent reviews.^238–245 Here, we detail accomplishments with an emphasis on implementation and performance.
MW-heated continuous-flow reactors for single and multiple phases. Single-phase liquid systems are the most widespread, owing partly to commercially suitable MW applicators. Still, many customized designs have been demonstrated. A variety of chemistries have been demonstrated, including Claisen rearrangements,^246–249 Suzuki coupling,^{186,187,246,250} Heck reactions,²⁴⁶ nucleophilic substitution,^180,187,250 esterification,^180,250,251 transesterification,^252,253 and more. Quite often, reactions proceed very quickly. However, direct comparisons between MW-heated and CH flow reactors are difficult to make, often for reasons related to temperature measurement. For example, Organ and coworkers demonstrated a MW-heated capillary reactor built into a commercially available Biotage applicator.^186,187 This applicator uses a pyrometer to measure temperature (and, if desired, provide feedback for power modulation). However, the spot size of the pyrometer may be ill-suited for the geometry, or the capillary wall temperature may not be representative of the internal temperature. As a result, temperature measurements are not discussed, and instead, the applied power was used as a proxy.

Hoz and coworkers coiled a capillary around a sizeable MW receptor (a Weflon bar) and measured the receptor temperature via a pyrometer.²⁵⁴ Using the single-point pyrometer measurement of the receptor as representative of the entire capillary, comparison was made to a CH system. A doubling in conversion was observed for the isoxazole synthesis reaction. Another approach entails inserting a thermocouple directly into the flowpath at the exit of the MW cavity assuming an isothermal reactor.¹⁸⁰ However, MW-heated flow reactors are often non-isothermal, as demonstrated using thermal cameras^{246,255–257} or location-adjustable temperature-sensing optical fibers.^212,258,259 Of the works that consider the axial temperature distribution, an occasional rate enhancement is reported,²⁴⁶ but the number of high-quality comparisons of this sort is limited. Despite the insufficient evidence for MW-specific rate enhancements, the rapid heating rates offered by MWs (often reported as more than 5 °C s⁻¹; sometimes as high as 50 °C s⁻¹) allow for high productivity.^246,260

Relative to a single-phase, a few works exist for liquid–liquid^212,261,262 or slurry^180,219,220 flows (excluding nanoparticle synthesis). In the former, MW rate enhancement for tandem diazotization and Heck reactions was reported without an explanation.²⁶² Selective heating and liquid–liquid temperature gradients have been demonstrated without focusing on reaction enhancements.^212,261 In the slurry flow mode, Chemat and coworkers demonstrated an esterification rate enhancement of 50–150% and attributed that to selective heating of the solids (iron(II) sulfate adsorbed onto clay) calculated (but not measured) to be 9–18 °C above the bulk liquid temperature.²²⁰

MW-heated continuous flow packed beds occupy a more significant space in literature. Notably, a few have been made with carbon supports despite their problematic performance in slurries.^263–265 Bo and coworkers employed a continuous flow system to mineralize p-nitrophenol using a fixed bed of activated carbon.²⁶³ This MW reactor far outperformed an electrical oven operated at approximately the same power (500–600 W) due to the bed reaching much higher temperatures of 500 °C than 98 °C in the electric oven. Later, the same group demonstrated that a platinum catalyst deposited onto the carbon not only was compatible with MWs, but further enhanced performance.²⁶⁴ Zhao et al. demonstrated the MW-assisted oxidation of HMF into FDCA over a Ru/C catalyst in a continuous flow,²⁶⁵ giving an optimized yield of 47% vs. 88% in batch mode. The low yields were attributed to the degradation of the catalyst microstructure due to humins formation. While hot spots surely arise in MW-heated carbon beds, none of the authors have reported arcing.

MW-heated packed beds typically use metal-oxide catalysts or transition-metal catalysts deposited on metal oxide supports. For example, Ani and coworkers have recently demonstrated a CaO fixed bed for transesterification of waste cooking oil under MW irradiation. The system achieves a 73% conversion at 50 min residence time for a bulk liquid temperature of 65 °C.²⁶⁶ Accurate comparisons to conventional systems are difficult to make. With a similar catalyst and temperature, an analogous conventional system achieves 94% yield with a much longer 8 hour residence time.²⁶⁷ Haswell and coworkers reduced the reaction time for a Suzuki-coupling reaction from 15 min to 15 s using a MW-heated Pd/Al₂O₃ packed bed, but temperatures were likely inaccurate in the MW system.²⁶⁸ Benaskar and coworkers demonstrated a quasi-isothermal fixed bed of Cu dispersed on TiO₂-coated silica beads. MW heating approximately doubles the productivity of an Ullmann coupling reaction compared to CH at similar conditions.²⁵⁸

Several studies demonstrate rate enhancements in MW-heated packed beds, and while certain comparisons to conventional equivalents are more compelling than others, the rate-enhancing effects seem to parallel those observed in batch-mode slurries. Select works detailing the performance of MW-heated fixed beds are presented in Table 5. These works span a range of chemistries, including sustainable chemical domains such as the transesterification of waste cooking oil into biodiesel or the oxidation of HMF into FDCA. However, the application of MWs to continuous flows should be a generalized heating approach whereby many chemistries can be made more sustainable and intensified via rate enhancements, energy savings, and potential selectivity enhancements. Given the current state of MW-heated continuous flows, three conclusions can be drawn from the current body of literature. First, MWs are clearly compatible with catalysis (P9) and continuous flows, as various packed beds and other modes have been demonstrated. Second, improved understanding of temperature is required for MW-heated flow systems to enable meaningful comparisons to CH systems. Third, the impact of temperature gradient on performance needs to be better understood and engineered.

Table 5 Performance of MW-heated packed beds with continuous liquid flows. X and Y indicate conversion and yield, respectively. Asterisks (*) indicate batch mode

Reaction	Catalyst & conditions	Reactants & product	Solvent	Performance
				Conventional	Microwave
Mineralization^263	AC, 500 W (180 min)	R: p-nitrophenol; P: CO2, H2O	p-Nitrophenol, air	X p-NPhen: 0%	X p-NPhen: 65%
Mineralization^264	Pt/AC, 400 W (240 min)	R: p-nitrophenol; P: CO2, H2O	p-Nitrophenol, air	—	X p-NPhen: 71%
Oxidation^265	Ru/C, 220 °C (120 min)	R: HMF; P: FDCA	Aqueous H2O2	—	Y FDCA: 47%
N-Boc deprotection^269	Fe2O3/sand, 220 °C (2.5 min)	R: tert-butyl-1-indolecarboxylate; P: indole	Neat	—	Y indole: 91%
Michael addition^269	Fe2O3/sand, 220 °C (5 min)	R: diethyl amine, methyl acrylate; P: β-alanine derivative	Neat	—	Y alanine: 87%
Diels–Alder cyloaddition^269	Fe2O3/sand, 220 °C (10 min)	R: diethyl acetylenedicarboxylate, furan; P: heterocyle	Neat	—	Y heterocycle: 70%
Transesterification^266	CaO, 65 °C (50 min)	R: waste cooking oil; P: biodiesel	Methanol	—	X WCO: 72.6%
Transesterification^267	CaO/AC, 60 °C (8 h)	R: waste cooking oil; P: biodiesel	Methanol	X WCO: 94%	—
Transesterification^270	SrO/SiO2, 65 °C (8.2 min)	R: waste cooking oil; P: biodiesel	Methanol	—	X WCO: 99.2%
Suzuki coupling^271	Pd/Al2O3, ∼95 °C (∼10 min)	R: 1-bromo-4-nitrobenzene, phenylboronic acid; P: p-nitrobiphenyl	Dimethyl-formamide	—	Y biaryl: 98%
Suzuki coupling^268	Pd/Al2O3, 100 °C (15 min)	R: 4-bromobenzonitrile, phenylboronic acid; P: 4-pheynlbenzonitrile	Dimethyl-formamide	Y biaryl: 61%*	—
	Pd/Al2O3, 59 °C (0.25 min)			—	Y biaryl: 59%
	Pd/SiO2, 66 °C (0.25 min)			—	Y biaryl: 37%
Suzuki coupling^272	Pd EnCat, 50 W (3.75 min)	R: p-tolylboronic acid, 2-bromotoluene; P: 2,4′-dimethylbiphenyl	Ethanol	—	Y biaryl: 98%
Suzuki coupling^273	Pd EnCat, 110 °C (21 h)	R: p-tolylboronic acid, 2-bromotoluene; P: 2,4′-dimethylbiphenyl	Toluene, methanol	Y biaryl: 98%*	—
Ullmann coupling^223	Cu/TiO2/SiO2, unspec. (120 min)	R: potassium phenolate, 4-chloropyridine; P: 4-phenoxypyridine	Dimethyl-acetamide	—	Y PhPyr: 33%
	CuZn/TiO2/SiO2, unspec. (120 min)			—	Y PhPyr: 62%
Ullmann coupling^258	Cu (wall-coated), 140 °C (60 min)	R: potassium phenolate, 4-chloropyridine; P: 4-phenoxypyridine	Dimethyl-acetamide	Y PhPyr: 10%	—
	Cu/TiO2/SiO2, 140 °C (60 min)			—	Y PhPyr: 19%
	Cu0.5Zn0.5/TiO2/SiO2, 140 °C (80 min)			—	Y PhPyr: 26%
Hanzch reaction^274	Fe2O3, 100 °C (3 min)	R: benzaldehyde, ethyl acetoacetate, ammonium acetate; P: 1,4-dihydropyridines	Neat	Y PhPyr: 71.9%	Y PhPyr: 98.7%

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Energy efficiency in continuous-flow MW processes. Energy use and efficiency are crucial in process electrification. In recent industrial process electrification efforts, such as the “Cracker of the Future” consortium, it has been emphasized that commercial viability depends on sufficient and affordable renewable electricity.²⁷⁵ McKinsey & Company came to a similar conclusion: industrial electrification needs a maximum acceptable range of $10–25 per MW h barring the introduction of a carbon tax.²⁷⁶ The price of wind and solar is descending rapidly and may ultimately provide cheap electricity,²⁷⁷ but this does not negate that US industrial electricity prices have averaged about $69.10 per MW h over the past three years.²⁷⁸ We believe that MWs can favor process electrification by using less total energy, improved energy efficiency (P6), and processing renewable feedstocks using renewable energy (P7).

Several groups have focused on increasing energy efficiency in MW applicators, and broadly, it is the cavity design, process geometry, and process material properties that determine efficiency. Haswell and coworkers have demonstrated that in a MW-heated capillary packed bed of Pd/Al₂O₃ for Suzuki coupling, efficiency is increased by inserting thin layers of MW-absorbing metals near the bed.²⁷¹ The ratios of applied power to temperature for cases with and without the metal layer were approximately 1 and 10 W °C⁻¹, respectively. Simple vials (batch mode) of ∼1 cm in diameter give optimal heating of lossy liquids.^237,279 Altering the positioning of the vial also matters.²⁸⁰ These often-nonmonotonic trends make optimization of cavities difficult, especially for geometrically complex flow reactors.

Among MW-heated continuous flows, several demonstrate higher energy efficiency than CH systems. They utilize an energy per mole-produced metric for comparison.^281–283 Clark and coworkers demonstrate 85-times energy savings via MW over CH.²⁸³ However, this field struggles in making fair comparisons. After all, the energy efficiency of MW-heated systems is very sensitive to geometry, material, and cavity design which vary among studies,²⁸¹ and lab-scale oil baths or other CH systems do not pay attention to efficiency. Laboratory and industry process scales imply very different motivations. To this end, a more helpful methodology lies in analyzing the efficiency of conversion of MW energy into process heating. An estimation can be easily made with two values often reported in the literature: the applied MW power and the absorbed heat, which can be approximated on a calorimetric basis. For example, Akai and co-workers demonstrated that different solvents had different heating behavior.²⁵⁵ For each solvent, the applied MW power, outlet temperature, and flow rate were documented. In this way, the calorimetric heating efficiency can easily be calculated, as shown in Table 6. From this perspective, all MW-heated continuous-flow chemical processes can be compared based on a more fundamental measure than one which might otherwise not consider the power left unabsorbed or the power utilized for auxiliary functions in a commercial laboratory MW applicator.

Table 6 MW heating performance of various solvents in continuous flow mode. Data taken from ref. 255

Solvent	tan(δ)	Outlet temperature	Calorimetric efficiency
Hexane	0.020	101 °C	19%
CPME	0.039	151 °C	33%
Toluene	0.040	109 °C	19%
MeCN	0.054	209 °C	54%
EtOAc	0.059	148 °C	35%
Dimethylformamide	0.160	220 °C	63%
Dimethylacetamide	0.173	225 °C	64%
AcOH	0.174	200 °C	71%
MeOH	0.659	178 °C	51%
n-PrOH	0.757	198 °C	55%
DMSO	0.820	250 °C	81%
EtOH	0.940	185 °C	52%

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As documented in many other works and shown in Table 6, the loss tangent (the ratio of the imaginary and real parts of the complex dielectric permittivity) correlates strongly with the amount of MW heat dissipated into a fluid. Despite the strong effect of material properties on MW dissipation, geometric parameters are ubiquitously under-optimized. For select MW-heated continuous flow studies, we have plotted in Fig. 14 the calorimetric heating efficiency against process diameter, with the colored axis referring to the loss tangent. In some cases, we plot multiple data for solvents or conditions from the same work.

Fig. 14 Calorimetric heating efficiency of MW-heated continuous-flow processes. Diamond-shaped data represent works that optimize heating efficiency. Referenced works correspond to overlayed enumeration as follows: A,²⁷¹ B,²⁵⁴ C,²⁶² D,¹⁸⁶ E,²⁸⁴ F,²⁴⁷ G,²⁶⁸ H,²⁸⁵ I,⁸⁴ J,²⁸⁶ K,²⁸⁷ L,²⁸⁸ M,²⁵⁷ N,²⁸⁹ O,²⁴⁸ P,¹⁸⁰ Q,²⁵⁵ R,²⁹⁰ S,²⁹¹ T,²⁹² U,²⁹³ V,²⁵⁸ and W.²⁹⁴

While material properties clearly matter, process geometry affects performance even more. Amongst 23 studies depicted in Fig. 14, the reactor diameter has a clearer trend than the loss tangent. Our analysis complements that of Menéndez and coworkers who found two significant trends in their meta-analysis. First, the smaller the scale of the organic synthesis, the less likely it was to report the heating efficiency, and, secondly, the smaller the process, the less the energy efficiency.²⁹⁵ Clearly, geometric and material optimizations are needed in MW-heated flow reactors. Damilos et al. demonstrated that the orientation of the MW-heated microreactors has a strong effect on energy efficiency, which can lead to up to 80% difference. Recently, Chen et al. showed that geometric and process optimization can be achieved simultaneously using a machine-learning surrogate model trained on multiphysics simulations.²⁸⁷ It is demonstrated experimentally that microchannels of ID 1 mm could attain efficiencies ∼90% with NaCl solutions, even at temperatures approaching 200 °C, which provide an upper bound of most reactions in biomass processing. The concept is to enhance energy efficiency by simultaneous optimization of the cavity, reactor, media, catalyst, and processing conditions.

We conclude that energy efficiency is severely overlooked in MW-heated chemical manufacturing. In our analysis, more than half of MW-heated continuous flow processes were less than 10% efficient. Systems as small as 1 mm can approach >90% efficiency with geometry and material properties tuning.

4.1.4 Outlook for MW-heated microflows. Microwave-heated continuous flow microreactors constitute promising, fertile ground for engineering sustainable chemical manufacturing processes. MWs can increase reaction rates by raising bulk temperatures and local temperatures via selective heating. The inclusion of greener solvents, less aggressive reagents, lesser quantities of aggressive reagents, smaller reactors, and shorter processing times are associated with these same effects. The selective heating effect brings about additional opportunities for energy savings, both in terms of localized heating but also in terms of high-efficiency deposition of energy only into the desired process.

The current understanding of these phenomena, while far from complete, are the product of more than 35 years of ardent research. The selective heating of non-homogeneous systems has been demonstrated conclusively and drives rate enhancements. Fundamentals of selective MW heating and temperature gradients must be further investigated to understand reaction rate enhancements. More advanced temperature measurements will likely be required to support the analysis. Significant work is still needed to fully understand the circumstances and details of the local overheating effects of macroscopically homogeneous systems. While highly efficient MW-heated systems can be achieved, researchers interested in green chemistry principles (Fig. 2) should work more assiduously to ensure MW-heated microfluidic systems are indeed operationally efficient, with special attention being paid to configurational optimization.

The knowledge generated by these pursuits will provide a foundation for understanding energy efficiency, chemical rates, and selectivity in MW-heated chemical processes. This fundamental understanding will, in turn, allow for high-quality technoeconomic analysis. MW heating could surpass CH in efficiency and chemical reaction rates and be a pillar in electrified sustainable chemical manufacturing.

4.2 Plasma microfluidic reactors

Plasma processing is attracting attention for sustainable chemical manufacturing due to its ability to perform reactions at low temperatures and far from thermodynamic equilibrium, using electrical energy. The development of non-thermal plasma (NTP) reactors operating at atmospheric pressure has enabled the activation of very stable molecules like CH₄, N_2, and CO_2, surpassing thermodynamic conversions.^296,297 Plasma allows process intensification and versatility, suitable for decentralized chemical manufacturing with potentially low reactor and carbon footprint when renewable electricity is employed.

Plasma microreactors integrate microflow with discharges confined in submillimeter scales, enabling a highly reactive environment at mild operating conditions and low energy input (extremely non-equilibrium conditions).^298,299 Dielectric barrier discharge (DBD) plasma microreactors are the most common: the employment of at least one dielectric layer between the electrodes provides stable operation. The enhanced interfacial area between phases and mass transfer at the micro-scale is particularly beneficial for plasma processing where the reactive species forming in the gas phase are adjacent to a liquid or solid. Whilst continuous-flow plasma reactors are common for gas-phase, liquid treatment is usually limited to batch reactors. The development of continuous gas–liquid plasma microreactors could enhance productivity. The design versatility of plasma microreactors and the reliance on just a carrier gas and electrical energy make them particularly attractive for green chemical synthesis in a catalyst-free fashion.

Several configurations have been proposed with gas bubbles and adjacent gas–liquid microchannels representing the most prominent for liquid synthesis. For gas conversion, a few reactors have also included a catalyst to enhance selectivity to the target compound. Current applications of plasma microreactors, summarized in Table 7, span between gas conversion and liquid functionalization processes.

Table 7 Summary of literature for chemical synthesis using plasma microreactors

Applications	Plasma treatments	Results
Methane reforming^300	Gliding arc with and without catalyst (Ni supported on alumina–silica)	Increased methane conversion with catalyst (50% vs. 32%), comparable H2 and C2H2 selectivity (75–90%, respectively)
Methane partial oxidation^301,302	Coaxial DBD reactor with pulsed water injection and external cooling	Shift in product selectivity and methane conversion upon water injection. Promotoed condensation of formaldehyde and methanol. High concentration of H2O2 detected
Propane oxidative conversion^303–305	DBD plasma in a microchannel. Li/MgO catalyst layers on reactor wall	Significant C–C recombination with formation of C4^+ species (>20% selectivity at 22% conversion). Increased conversion and propylene selectivity with catalyst
CO2 dissociation^306	Packed-bed coaxial DBD microreactor	50–55% CO2 conversion at long residence time and low electrode gap. Low dielectric constant of the packing material results in higher conversion. Particle size effect is material-specific
Cyclohexane oxidation^307	Microfluidic chip, DBD, sine 2 kHz at 6–7 kVpp, liquid flow 6–24 μl min^−1, O2 flow 0.5–2 ml min^−1	Mostly cyclohexanol and cyclohexanone, 36% conversion at high residence time 104 s, with 82% selectivity to oxygenates at lower residence times 26 s
Cyclohexane amination^308	Microfluidic chip, dielectric barrier discharge (DBD), liquid (pure HC) flow 8 μl min^−1, NH3 flow 5 ml min^−1	20% conversion, 50% selectivity to cyclohexylamine; higher selectivity at higher NH3 fraction
trans-Stilbene epoxidation^309	Microfluidic chip, dielectric barrier discharge (DBD), liquid (solution in ACN) flow 1 ml min^−1, He/O2 flow 1 ml min^−1	Recirculation and short bubble-liquid contact times; 33% conversion and 94% epoxide selectivity
DI water oxidation^310	Helical microreactor in coaxial dielectric barrier discharge (DBD) configuration, liquid flow 0.2 ml min^−1, He flow 320 ml min^−1	Highly concentrated H2O2 >25 mM at production rate ∼0.1 μmol s^−1 and energy yield of ∼4 g kW^−1 h^−1

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4.2.1 Hydrocarbon and CO₂ transformation. The modularity of plasma makes it ideal for distributed processing in remote and offshore locations or smaller-scale production of hazardous chemicals. Plasma microreactors have successfully converted small hydrocarbons for hydrogen/olefins and oxygenate production with performance exceeding larger-scale counterparts. A Gliding Arc (GA) microreactor yields higher methane (CH₄) conversion and different product selectivity than a larger GA reactor due to the high-power density. Moreover, CH₄ conversion can be further enhanced by deploying Ni catalysts in contact with the gas stream.³⁰⁰ CH₄ partial oxidation entails a DBD plasma microreactor featuring intermittent water injections to remove oxygenates from the reactor walls to produce methanol, formic acid, and formaldehyde. Notably, the water injection produces hydrogen peroxide that can further oxidize the liquid products.³⁰¹ The enhanced heat transfer allows efficient external cooling for condensing the oxygenates.³⁰² The same reactor configuration has been employed for the methane partial oxidation via an air plasma. N₂ enhances methane conversion and reduces H₂ and liquid oxygenates.³¹¹ The conversion of propane (C₃H₈) in a customized microreactor has also been reported. A Pyrex rectangular chip contains microchannels, and a DBD plasma is produced via two copper plates attached to the outer reactor walls. C₃H₈ conversion in 1% O₂ in He resulted in propylene and cracked species, like ethane, ethylene, acetylene, methane, and longer hydrocarbons (C₄⁺). The authors ascribed this phenomenon to the recombination of hydrocarbon radicals whose density increases at higher C₃H₈ conversion resulting in more abundant heavier species. The prominence of C–C coupling is evident compared to a thermally-driven quartz tubular reactor where almost no heavier products are observed alongside the dehydrogenation species.³¹² The two systems were compared at the same conversion level of 20% which is attained at 600 °C for the thermal reactor whereas room temperature conditions are maintained in the plasma reactor. While most studies do not focus on comparing thermal (catalytic)processes with non-thermal plasma (micro)reactors, this comparison is representative of the potential of non-thermal plasma reactors to outperform their conventional counterparts at mild operating conditions, especially for the hydrocarbon chemistries reported here. Similarly, plasma-assisted conversion of methane and ethane delivers large fractions of C–C coupling products.³⁰³ The deployment of a catalyst layer on the microchannel walls changes the product selectivity due to different radical/catalyst interactions.³⁰⁴ Plasma microreactors can also be deployed for CO₂ splitting into CO and O₂. A DBD plasma microreactor enables up to 50% CO₂ conversion with decreasing discharge gap. Moreover, a low dielectric constant and a small particle size yield the highest conversion. However, these observations remain system specific.³⁰⁶

4.2.2 Gas–liquid systems. Whilst the application of microfluidics to plasma processing is straightforward for gas streams, biphasic plasma microreactors are more complex. The Tatoulian group has focused on the design and modeling of microreactor systems with liquid water and the radical chemistry through electron paramagnetic resonance (EPR).^313,314 They demonstrated the partial oxidation of cyclohexane.³⁰⁷ This challenging reaction is currently performed catalytically at high pressure and temperature, yielding a mixture of cyclohexanol and cyclohexanone (the KA oil); the product is converted to adipic acid, used for the production of polyamide (Nylon). They fabricated a microfluidic chip on glass slides connected with an adhesive and coated with indium tin oxide (ITO) electrodes, forming a DBD (Fig. 15a–c). The parallel biphasic microflow comprised a low liquid flow (6–24 μl min⁻¹) and a higher O₂ flow (0.5–2 ml min⁻¹). The plasma was sustained through sinusoidal high-voltage signals with a power dissipation of ∼500 mW. Upon plasma oxidation, the main reaction products were cyclohexanol, cyclohexanone and cyclohexyl hydroperoxide, with minimal yields of cyclohexene and other compounds (Fig. 15d). High residence time in the plasma region leads to higher conversion (36% at 104 s), whilst the selectivity towards oxygenated products is favored at lower residence time (82% at 52 s). The energy yield for all the oxygenated products was 1.48 mol kW⁻¹ h⁻¹.

Fig. 15 Microfluidic chip proposed for plasma-assisted processes. (a–c) Microfluidic chip design and picture of the discharge. (d) Distribution of the reaction products of cyclohexane in an O₂ plasma at different residence times of the liquid in the discharge. Reproduced from ref. 307 with permission from the Royal Society of Chemistry.

The same microfluidic reactor was employed for the amination of cyclohexane using an ammonia plasma to produce cyclohexylamine.³⁰⁸ Other products were cyclohexene (major fraction) and various molecular weight compounds produced from the fragmentation and oligomerization of cyclohexane. A higher cyclohexylamine selectivity was observed upon decreasing the cyclohexane to ammonia ratio, with a maximum of 50% at ∼20% conversion. Recent work introduced a plasma microchip for epoxidation reactions. The effluent of a He/O₂ discharge serves as the oxygen donor for the epoxidation of trans-stilbene (Fig. 16).³⁰⁹ The plasma generates atomic oxygen O(³P) for epoxidation, while ozone O₃ (ozonolysis) leads to benzaldehyde. Optimized experiments with continuous liquid recirculation and short bubble-liquid contact time of ∼2 s achieve selectivity of ∼94% of epoxide at ∼33% conversion.

Fig. 16 Microfluidic chip for epoxidation of trans-stilbene in a He/O₂ plasma discharge. (a and b) Design of the chip. (c) Proposed reaction scheme. Reproduced from ref. 309 with permission from Elsevier, copyright 2018.

Our group proposed a helical, modular biphasic plasma microreactor using a coaxial DBD that possesses fabrication simplicity and residence time tunability for de-centralized oxidative processing (Fig. 17).³¹⁰ We applied our set-up to the continuous production of highly concentrated hydrogen peroxide (H₂O₂) in a He plasma in contact with de-ionized water. The high gas/liquid flow ratio provided high interfacial area, combined with control of the residence time (by adjusting the gas flow rate and reactor geometry independently) and efficient heating, led to H₂O₂ concentrations >25 mM without compromising production rate (∼0.1 μmol s⁻¹) and energy yield (∼4 g kW⁻¹ h⁻¹). This set-up could offer a more sustainable alternative to the waste and energy intensive antraquinone process currently employed for large scale production of H₂O₂. This process relies on catalytic cycles of hydrogenation and oxygenation of an organic substrate, whereas the plasma microreactor runs on (preferably renewable) electricity and water for the production of one of the most relevant chemicals of modern society.

Fig. 17 Coaxial dielectric barrier discharge (DBD) microreactor assembly for continuous production of concentrated hydrogen peroxide (H₂O₂). The production rate is directly correlated to the interfacial area and residence time in the plasma region. Reproduced with permission from ref. 310 with permission from the American Chemical Society, Copyright 2022.

4.2.3 Outlook. Although plasma microreactors hold promise for sustainable chemical synthesis, the field is still in its infancy, and there are several scientific and technological challenges to overcome. A critical question is how the plasma affects the microflow and vice versa. The plasma is anticipated to strongly influence the flow pattern and interfacial properties (e.g., the mass transfer); on the other hand, the microflow and gas–liquid dynamics will also determine the plasma physics and chemistry. This interplay needs to be unraveled. Moreover, exploitation has been limited to a few processes; there is a need to screen more reactions, including biomass conversion, an application domain highlighted in this review. Given the complexity of integrating plasma in microfluidics, it is imperative to optimize reactor designs and energy efficiencies. The integration of catalysts in plasma microreactors for plasmo-catalytic applications is just emerging. Finally, techno-economic analysis (TEA) and life cycle assessment (LCA) of such processes are needed.

5 Beyond the lab scale

Microscale devices can handle small volumes but are typically unfit for large product volumes due to clogging, non-uniform flow distribution, catalyst regeneration issues, etc. The question raised then is whether microsystems and electrification can be practical for commercialization. There are not enough studies to answer this question. Yet, some takeaway points are clear. First, one has to consider the production scale. Distributed manufacturing will handle much smaller volumes than plants with the typical economy of scale. In this regard, microscale and electrification may be ideal and suitable for the job. Second, one has to consider the integration of microdevices with emphasis on flow distribution and heat integration. Numbering-up or scaling-out microchannels with the same flow patterns and residence time could reach sufficient scale. One of the earliest demonstrations is MIT's work³¹⁵ of ten silicon micro packed-bed reactors to achieve ∼100 kg per year phosgene synthesis. The small volume and high price of pharmaceuticals make these profitable. Yet, this demonstration does not answer the commercialization potential for other application domains where scales are larger and profit is less. It is clear that designing distributors to ensure uniform flow and the same pressure drop across multichannel systems is critical. For example, Conchouso et al.³¹⁶ developed a multi-layer flow distributor with 128 flow-focusing droplet generators in a parallel and circular array. Similarly, Hoang et al.³¹⁷ proposed multi-junction flow distributors to ensure droplet break-up. Al-Rawashdeh et al.³¹⁸ used a barrier-based microreactor to hydrogenate phenylacetylene to styrene and ethylbenzene with <10% difference in 8 reaction channels for the gas–liquid Taylor flow. A microsieve dispersion could scale up a typical T-junction micromixer.³¹⁹ Wang et al.³²⁰ utilized CFD simulations to reach >100-fold productivity improvement. These examples showcase the path forward for engineering modules made of microsystems. Heat integration and temperature uniformity are also essential, as cold and hot channels can create a malfunction and device failure (flow distribution contributes to this). Stacking multiple reaction channels is a commonly used strategy. For example, Mettler et al.³²¹ used a parallel-plate reactor with alternating combustion and steam reforming channels for syngas production. Similarly, stacked reaction plates with heating/cooling plates enhance heat transfer for rapid reactions delivering 237 g min⁻¹ of product with similar performance to a lab-scale system.^322,323

Third, the dimensions of a laboratory reactor are often picked arbitrarily. One could size up a system to a larger scale with the same performance while retaining the advantages at the micro-scale, such as fast mixing and excellent heat and mass transfer. Elvira et al.³²⁴ found the hydrodynamics behavior is similar in the 0.5 mm and 1 mm microchannel, but drastically changes in the 5 mm microchannel. Similarly, Krummradt et al.³²⁵ observed similar reaction yields using less than 1 mm microreactor. Recently, Desir et al.²⁸ discussed the scale-up for fructose dehydration from 500 μm to 8 mm using the Dean number (De) and the Peclet number as descriptors. Guo et al. reported minor mass transfer limitations for the tandem reaction upon scaling the reactor length and flowrates 14× while maintaining the same residence time in biphasic systems.²⁵ In addition to simply increase the reactor dimensions, altering reactor shape can improve the productivity as well. For example, deep microchannels provide enhanced throughput while maintaining a uniform flow distribution.³²⁶ Slit-like microchannels yield great extraction efficiency and comparable throughput as 300 single microchannels.³²⁷ The heart-shaped Corning Advanced-Flow reactor retain similar interfacial surface area and mass transfer rate as the typical microreactor while improving the operating flow rate by 8-fold.³²⁸

We propose combining size up and numbering up as a strategy to minimize material of construction and the number of units. Ensuring transport characteristics is the key point when enlarging the reactor dimensions. On the other hand, uniform flow and residence time distribution and similar pressure drop are considered for increasing the reactor numbers. While utilizing both strategies to scale-up the system, all of these concerns should be considered. Indeed, Zhang et al.³²⁹ studied the flow distribution and mixing characteristics for different combinations of reactor numbers and dimensions and observed different velocity profiles. Bhosekar et al.³³⁰ optimized a biomass refinery balancing the increase of the microchannel size and their number. Wang et al.³³¹ combined sizing-up and numbering-up strategy to achieve 160-fold improvement in processing capacity by increasing the reactor dimension by 16-fold and the number of channels by 10-fold. More investigations are needed to develop further understandings on effectively combining the numbering-up and size-up approach.

Fourth, TEA and LCA are vital metrics for sustainable manufacturing. The Novartis and MIT collaborative work demonstrated an integrated continuous manufacturing plant for active pharmaceutical ingredients³³² for the synthesis, separation, crystallization, and formulation of 2.7 × 10⁶ aliskiren hemifumarate tablets per year. Zhang et al.³³³ developed another platform for nicardipine hydrochloride, ciprofloxacin hydrochloride, neostigmine methylsulfate, and rufinamide.³³³ Jolliffe and Gerogiorgis³³⁴ evaluated the economic viability of ibuprofen and artemisinin. The capital expenditure (CapEx) and operating expenditure (OpEx) were lower by 57% and 52%, respectively, and the material efficiency was also better using the Environmental (E)-factors than typical batch processes.³³⁴ The high value of pharmaceutical ingredients makes the TEA favorable and the answer to the commercialization prospect hazy. Beyond pharmaceuticals, Corning achieved 10 000 metric tons annual throughput of agrochemicals using their Advanced-Flow™ Reactor Technology.³³⁵ Desir et al.²⁸ evaluated the scale and economic viability of the HMF production from fructose for the medium-scale farms. A few hundred reactors can meet demand, demonstrating the potential of microtechnology for distributed manufacturing with a target of 2.5 tons per day production rate. With the growing environmental concerns, Bhosekar et al.³³⁰ employed a multi-objective optimization approach to obtain Pareto optimal solutions for the tradeoff between profit and environmental impact of a biomass refinery. These limited number of examples are encouraging. However, TEA and LCA are crucial vectors for guiding decisions. It is also interesting to contrast the above production scales of 2.5 tons per day for biomass of a midsize farm to 100 kg per year of phosgene synthesis to realize the scale of challenges for chemical manufacturing.

6 Concluding remarks

This review advocated that sustainability demands a holistic approach. It requires applying green principles from wells-to-wheels, including feedstock extraction and handling, manufacturing of products, recycling end-of-pipe products, and using renewable carbon and energy sources. We reviewed the fundamental characteristics of flow chemistry, its applications to renewable resources, and its integration with electrification, such as microwaves and plasmas. Flow microtechnology is excellent for sustainable manufacturing due to meeting multiple green principles, including minimizing waste of solvents and materials, reducing the cost of construction, increasing energy and atom efficiency, and providing safer processes. Combining microreactors with plasma and microwaves holds tremendous promise toward sustainable manufacturing. This integration can improve energy efficiency and safety while offering unique advantages from electrification. Examples of plasma processing include overcoming thermodynamic limitations and activating very stable molecules. Examples of microwaves include rapid and volumetric heating and temperature gradients that can be harnessed to provide superior performance. More research on the design principles and scalabilities, including TEA and LCA of entire processes, is needed to advance such integrated technologies further. In this regard, one has to go beyond the flow chemistry and also consider heating, quenching, separation, and purification. Process integration with attention to micro-scale separation and purification is needed. For example, traditional distillation may not be suitable at the micro-scale, and handling solids and clogging associated with many unconventional feedstocks remains challenging. Further advancements in the fabrication, integration, and materials of electrified microflow chemistry are required.

Data availability

As this is a review and all data discussed are cited, provided in tables, and available in literature, we will refrain from providing this in yet another form.

Author contributions

Tai-Ying Chen: conceptualization, visualization, writing – original draft preparation, writing – reviewing and editing, supervision. Yung Wei Hsiao: conceptualization, visualization, formal analysis, writing – original draft preparation, writing – reviewing and editing. Montgomery Baker-Fales: conceptualization, visualization, formal analysis, writing – original draft preparation, writing – reviewing and editing. Fabio Cameli: visualization, writing – original draft preparation, writing - reviewing and editing. Panagiotis Dimitrakellis: writing – original draft preparation. Dionisios G. Vlachos: conceptualization, supervision, writing – reviewing and editing, project administration, funding acquisition.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

Funding from the RAPID manufacturing institute, supported by the Department of Energy (DOE) Advanced Manufacturing Office (AMO), award numbers DE-EE0007888-7.6 and DE-EE0007888-8.3 are gratefully acknowledged. RAPID projects at the University of Delaware are also made possible in part by funding provided by the State of Delaware. The Delaware Energy Institute gratefully acknowledges the support and partnership of the State of Delaware in furthering the essential scientific research being conducted through the RAPID projects. The authors acknowledge fruitful discussions with Dr Abhinav Malhotra and Dr Natalia Rodriguez Quiroz.

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Footnotes

† Electronic supplementary information (ESI) available. See https://doi.org/10.1039/d2sc01684b

‡ These authors contributed equally.

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