The Hitchhiker's Guide to Flow Chemistry - Chemical Reviews (ACS

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The Hitchhiker’s Guide to Flow Chemistry∥ Matthew B. Plutschack,§,† Bartholomaü s Pieber,§,† Kerry Gilmore,*,† and Peter H. Seeberger*,†,‡ †

Department of Biomolecular Systems, Max-Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany

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‡

ABSTRACT: Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions. This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, “Should we do this in flow?” has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts.

CONTENTS 1. Introduction 2. Why Run a Reaction in Flow? 2.1. Multiphasic Systems 2.1.1. Gas−Liquid Reactions 2.1.2. Solid−Liquid Reactions 2.1.3. Liquid−Liquid Reactions 2.2. Mixing 2.3. Temperature 2.3.1. Exothermic Reactions 2.3.2. High-Temperature/High-Pressure 2.3.3. Small Temperature Profile 2.4. Photo- and Electrochemistry 2.4.1. Photochemistry 2.4.2. Electrochemistry 2.5. Batch Versus Flow Analysis 2.6. Automation 3. Anatomy of a Flow Reaction 3.1. Connecting Flow Zones 3.2. Fluid and Reagent Delivery 3.2.1. Liquid Delivery 3.2.2. Gas Delivery 3.2.3. Solid Delivery 3.3. Mixer 3.3.1. Single-Phase Reactions 3.3.2. Multi-Phase Reactions 3.4. Reactor Unit 3.4.1. Chip-Based Reactor Units 3.4.2. Coil-Based Reactor Units 3.4.3. Packed Bed Reactor Units 3.4.4. Electrochemical Devices 3.4.5. Miscellaneous 3.5. Quenching Unit 3.6. Pressure Regulating Unit 3.7. Collection Unit © 2017 American Chemical Society

3.8. Optional Zones 3.8.1. Analysis 3.8.2. Purification 4. Considerations for Flow Experiments 4.1. Key Parameters 4.2. Common Problems 5. Multiphasic Reactions 5.1. Gas−Liquid Reactions 5.1.1. Carbon Monoxide 5.1.2. Carbon Dioxide 5.1.3. Oxygen 5.1.4. Ozone 5.1.5. Fluorine, Chlorine, and HCl 5.1.6. Hydrogen 5.1.7. Ethylene 5.1.8. Ammonia 5.1.9. Diazomethane 5.1.10. Phosgene 5.2. Solid−Liquid Reactions 5.2.1. Heterogeneous Catalysis Involving Metals 5.2.2. Heterogeneous Organocatalysis 5.3. Gas−Liquid−Solid Reactions 5.4. Liquid−Liquid Reactions 5.5. Liquid−Liquid−Solid Reactions 6. Mixing 6.1. Outpacing Intermediate Decomposition 6.2. Outpacing Intramolecular Reactions 6.3. Nucleophilic Reactions with Multiple Electrophiles 6.4. Selective Carbonyl Syntheses

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Special Issue: Natural Product Synthesis Received: March 30, 2017 Published: June 1, 2017 11796

DOI: 10.1021/acs.chemrev.7b00183 Chem. Rev. 2017, 117, 11796−11893

Chemical Reviews 6.5. Reductions with DIBAL-H 6.6. Electrophilic Trapping for Subsequent CrossCoupling Reactions 6.7. Miscellaneous Fast Reactions 7. Temperature 7.1. Heated Reactions below 100 °C 7.2. Heated Reactions between 100 and 200 °C 7.3. Reactions above 200 °C 8. Traceless Reagents in Flow: Photo- and Electrochemistry 8.1. Photochemistry 8.1.1. Photoexcitation of Substrates 8.1.2. Singlet Oxygen-Mediated Reactions 8.1.3. Photoredox Catalysis 8.2. Electrochemistry 8.2.1. Anodic Oxidation 8.2.2. Cathodic Reduction 9. Feedback Optimization 10. Conclusions 11. Diagram Legend Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments References

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covers reports only where flow enhancements were experimentally observed or easily inferred from the flow conditions employed. One of the challenges of discussing flow chemistry, however, stems from the difference of interests between industry and academia. Industrial interests are largely founded in cost. With the rising cost of energy, energy management is a key element in chemical industry.81 For this reason, a reaction in flow which can reduce energy input might be particularly interesting from an industrial perspective, however, is likely irrelevant to an academic whose interest likely pertains to yield or convenience. Accordingly, industry’s interest in flow chemistry is outside the scope of this review unless the impact in a laboratory can be envisioned. For example, multistep syntheses74 or end-to-end production82 of active pharmaceutical ingredients is currently an attractive area in flow chemistry since these processes have a lower space-time demand. However, too much time and resources need to be allocated for the production of one compound for this to be useful for the average synthetic lab. Therefore, this literature is not included unless one of the steps illustrates a benefit in flow. Additionally, terms like scale or scaling in the context of this review refers to laboratory scale reactions transitioning from optimization scale to preparative scale. For instance, “easy to scale” in this review should not be taken as the progress from discovery to pilot and production scales.

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2. WHY RUN A REACTION IN FLOW? Continuous flow has affected many fields over the last 20 years, and the rapid increase in flow chemistry publications has led to a vast collection of examples with many authors reporting what can be done utilizing continuous flow conditions. As of late, scientists have begun to contemplate which tasks should be done with continuous flow.16,20,83 In an attempt to help chemists address this question, this section summarizes reaction conditions that can be improved and/or intensified by adopting continuous flow conditions. Our discussion of these reaction parameters pertain to optimization and preparatory quantities, and any scaling benefits refer to the transition from optimization to preparatory experiments. In addition, a decision diagram is constructed from these concepts to facilitate a batch versus flow verdict. A critical analysis of potential obstacles and overarching goals is presented to show that while many microscale reactions outperform their batch counterparts, the financial and time costs of some processes outweigh the benefits flow has to offer.

1. INTRODUCTION The aim of technology is to enhance or facilitate the ability to complete a task. In chemistry, microfluidic equipment emerged as a technology which aimed to enhance a researcher’s ability to perform chemical reactions since the small dimensions of the reactors provided unique control over key reaction parameters. At one point the flow community seemingly wanted to phase out the round-bottom flask,1 and over the past decade, the field of flow chemistry has received remarkable attention.2−79 Even so, flow chemistry is not implemented in every synthetic laboratory. Rather, scientists are left sifting through a vast collection of literature which has been poorly indexed and scattered throughout reports with generalized flow enhancement claims. Among these commonly reported benefits are better mixing, more efficient heat transfer, and easy scale-up. While these enhancements are generally true, they are occasionally reported with little relevance to the topic of the paper, leaving readers wondering if it is really worth the time to run the reaction in flow. Recently, Whitesides noted that a clear interest in new technology was an underlying problem for this flood of information.80 “It is that the devices that have been developed have been elegantly imagined, immensely stimulating in their requirements for new methods of fabrication, and remarkable in their demonstrations of microtechnology and fluid physics, but they have not solved problems that are otherwise insoluble. Although they may have helped the academic scientist to produce papers, they have not yet changed the world of those with practical problems in microscale analysis or manipulation.” The aim of this review is to take a critical look at the past five years of literature and summarize which reports exploit microfluidic devices in order to improve the state of synthetic chemistry in a research laboratory. To this end, this review

2.1. Multiphasic Systems

Many relevant chemical transformations involve multiple phases (gas−liquid, solid−liquid, liquid−liquid, or solid− liquid−gas). For productive reactivity, efficient phase mixing is necessary. In the case of liquid−liquid reactions, methods exist to combat poor interfacial mixing via phase-transfer catalysis (PTC) which shuttle reactants from one phase to the other. Several disadvantages, however, prevent this method from being applied universally. Therefore, reactor design is important for achieving efficient phase mixing. Generally, microfluidic systems increase surface area to volume ratios due to the decreased size of the reactor. In multiphasic systems, the interfacial area plays an important role in phase transfer which can be rate limiting. For this reason, microfluidic systems tend to outperform their batch counterparts. For each of these multiphasic systems, different multiphase flow regimes exist. 11797


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For gas−liquid mixtures, bubble, slug, and annular flow regimes are commonly observed in microreactors (Figure 1).

Figure 1. At a constant liquid flow rate, three flow regimes are commonly observed for gas−liquid mixtures in microfluidic devices. Common conditions in tube reactors (>0.25 mm) usually result in slug flow. Figure 3. Laminar and slug flow regimes for immiscible liquid−liquid mixtures. Common conditions in tubing reactors (>0.25 mm) usually result in slug flow.

These regimes are influenced by flow rates, viscosities, and channel properties. Typical tubing reactors (0.25−0.75 mm i.d.) highlighted in this review most likely exhibit slug flow behavior. For solid−liquid reactions, three different reactor beds are predominantly used (Figure 2). Packed beds are characterized

ν), and large channels (A) generally produce laminar flow (Re < 2040).85

QDH (1) νA Most tubing reactors, however, will exhibit slug flow (Figure 3, bottom) which is often achieved using a T-mixer (section 3.3.1). Slugs are formed when the perpendicular phase (phase 2) plugs the channel, causing a buildup of pressure behind it in phase 1. When the pressure becomes high enough, a droplet is broken off. This process occurs over and over, forming alternating slugs of each phase. 2.1.1. Gas−Liquid Reactions. Gas−liquid reactions include a wide range of very powerful chemistries. Gaseous reagents tend to be very atom economical but tend to be used in large stoichiometric excess due to poor interfacial mixing.59 Poor interfacial mixing can result in extended reaction times making processes prohibitively slow. Microfluidic systems can eliminate headspace and increase the surface area per reactor volume (Table 1). While small round-bottom flasks can provide Re =

Figure 2. Different solid−liquid reactors, characterized by solid mass transfer. Within each bed, liquids typically exhibit slug flow or turbulent flow.

Table 1. Interfacial Surface Areas for Various Reactorsa

by the entire column or channel being filled with a solid material so that particle movement is restricted. Liquid flow within this bed is generally plug flow but can be turbulent at higher flow rates. In a fluidized bed reactor, the particles are free-flowing and suspended within the channel by the turbulent flow of the liquid phase. These reactors offer benefits such as improved heat distribution, however, are not typically used in a laboratory setting as they are still not completely understood and optimal conditions are time-consuming to achieve.84 Mixed beds are a combination of a packed bed and a fluidized bed. The movement of the solid at the bottom of the reactor is restricted, while the top layers are suspended and mixed via the flowing liquid phase. In the context of this review, packed beds and mixed beds offer the most convenience, owing to the limited experience required for their set up and use. Many different flow regimes can exist for liquid−liquid mixtures; however, laminar and slug flow are most commonly described for reactions in microchips and tube reactors (Figure 3). Laminar flow occurs when parallel phases do not interrupt each other’s longitudinal flow (Figure 3, top). The Reynolds number (Re) is a dimensionless mass transfer coefficient that can be used to predict whether the flow conditions lead to laminar flow (eq 1). Low flow rates (Q), viscous liquids (high

interfacial area (m2 m−3)

type of reactor 5 mL round-bottom flask (rbf) 50 mL rbfb 250 mL rbfb tube reactors, horizontal and coiled tube reactors, vertical gas−liquid microchannel b

141 66 38 50−700 100−2000 3400−18000

a

Reproduced from Mallia et al.59 bCalculated for half-filled rounda 150 bottom flasks when the liquid is static using, v = 3 . 1/2

3v / 4 π

sufficient interfacial areas with vigorous stirring, flow conditions are advantageous, especially if the end-goal is synthetic scale preparation. Additionally, the increased surface area to volume ratio of microreactors effectively increases mass transfer by 2 orders of magnitude, enhancing rates of reactions where mass transfer is rate limiting.20 Additionally, Taylor flow is a type of gas−liquid mixing where the slug flow of gas and liquid adopts a certain geometry creating a thin film of liquid on the channel wall, separating the gas from the reactor (Figure 4).86 This internal mixing created within the liquid phase increases mass transfer 11798


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supported catalysts.15,47,91 Packed beds simulate high concentrations and can have improved lifetime due to decreased exposure to the environment.26 Additionally, the ease of screening continuous reaction parameters for a given catalyst makes continuous flow attractive. On the other hand, when a catalytic system is not purely heterogeneous, catalyst leaching is a dilemma for which flow does not offer advantages. In this case, selecting a homogeneous precatalyst may be more appropriate since reactivity and selectivity can be modulated by changing the ligand.37 2.1.3. Liquid−Liquid Reactions. Like other heterogeneous transformations, the small dimensions of microreactors can enhance phase mixing. The challenges associated with liquid−liquid mixtures in flow, however, deal with maintaining a stable fluid distribution, which subsequently leads to poor residence time distributions.92 The flow rates and flow patterns are particularly important. At lower flow rates (longer residence times), different flow patterns have equal mass transfer efficiency. At higher flow rates, however, the importance of the reactor structure is apparent and the presence of obstacles enhances the liquid−liquid surface area and mass transfer. Reactors packed with inert materials such as stainless steel beads create “tortured paths” and have been employed to create chaotic mixing which improves mass transfer.93 While these types of reactors are useful for scaling out a reaction, they tend to use large amounts of material because of the high flow rates required to achieve efficient mixing. Therefore, if complications in scaling a reaction are not anticipated then small scale batch reactions with rapid stirring may be sufficient to achieve the desired results.

Figure 4. Taylor flow within the liquid phase of a gas−liquid mixture in a microfluidic channel.

and can reduce mixing lengths by 2- to 3-fold when compared to similar passive mixing with patterned side walls or threedimensional channel geometries.87 Finally, gas solubility will play a role because gas−liquid reactions occur in solution with soluble gas. Compared to most reagents, gas solubility is low at room temperature. Henry’s law is used to quantify the solubility of gases in solvents (eq 2) where the partial pressure (p) is related to the concentration of gas in solution (c) by a temperature-dependent constant (kH).

p = kHc

(2)

In general, fluidic devices can withstand higher pressures than screw-cap and sealed vessels (Table 2), permitting better Table 2. Relative Pressure Ratios for Various Reaction Vessels reaction vessel

pressure rating (bar)a

2 mL screw-cap vial 0.2−30 mL microwave tubes 250 mL screw-cap flask polymer-based tubing stainless steel tubing

10 30 ∼4 ∼30 >100

2.2. Mixing

Often mixing is highly influential in the conversion and selectivity of reactions. Therefore, the degree to which mixing influences a reaction should be a major question when deciding whether or not to conduct an experiment in flow. Mixing describes the way two phases come together and become intertwined. Batch and flow reactors exhibit different mixing mechanisms which in combination with reaction kinetics will determine if flow conditions are beneficial. The Reynolds number (Re) is used to predict flow patterns in fluids, where ranges of Re divide mixing into three regimes: laminar, transitional, and turbulent. Low Re values correspond to laminar flow, whereas high Re values describe turbulent flow. Typically, mixing in laboratory-size batch reactors is laminar or transitional.94 A transitional regime normally results in segregation inside the vessel, with turbulent mixing near the stir bar and laminar regimes at outlying parts. The movement of molecules to and from these isolated regions generally relies on diffusion.95 Smaller vessels have smaller diffusion times; however, they are not capable of completely eliminating this segregation of mixing regimes. Tube reactors inherently have much smaller diffusion times and achieve mixing much faster than in batch. Mixing, however, is more complicated than simple diffusion and requires analysis of the Damköhler number (Da). This dimensionless unit is a ratio of the rate of the reaction to the rate of mass transfer by diffusion (eq 3).

a

Values are approximated from ratings or recommendations of commercial vendors and are not indicative of the burst pressure.

gas solubility. Additionally, scaling out optimized conditions in flow is a significant advantage, considering that sealed vessel reactions are limited to approximately 30 mL. Flow chemistry with gas−liquid mixtures offers benefits such as improved interfacial mixing and safely achieving high pressures. For these reasons, the reaction rate, scalability, and safety can be improved by adopting flow conditions. In addition, controlling the stoichiometry of gases is possible with a mass-flow controller, and quenching toxic gases can be more convenient. 2.1.2. Solid−Liquid Reactions. Heterogeneous reactions involving solids and liquids are especially attractive due to the ease of separation upon workup. Heterogeneous catalysis, in particular, is an important field as many of the present industrial processes use a heterogeneous catalyst.88,89 Recently, continuous flow has been exploited to enhance heterogeneous catalysis by essentially combining the reaction and separation into one step using a packed bed reactor. Gas−liquid−solid reactions such as hydrogenation reactions are exceptionally valuable transformations and comprise the majority of heterogeneous catalysis reactions in flow.19,90 These hydrogenations take advantage of the high interfacial area which facilitates better mass transfer. Beyond this type of chemistry is a wide variety of transformations involving diverse heterogeneous catalysts and

Da =

χdt2 4τD

(3)

For reactions where Da is less than 1, mixing (>95% homogeneity) can be achieved before the reaction occurs. 11799


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However, for reactions where Da is greater than 1, the reaction is faster than mass transport, causing concentration gradients within the system. Usually, these gradients have adverse effects on ideal reactor performance and may affect the overall selectivity of the reaction. For instance, mixing greatly influences a competitive, consecutive side reaction, where A + B → C and C + B → S (Da > 1). Since diffusion is slower than the rate of the reaction, A and B will react before achieving homogeneity. Local concentrations of B in proximity to C are created (Figure 5b, middle), which subsequently react to form higher quantities of side-product S (Figure 5b, right).

reaction. This regime can lead to side-products or dangerous safety issues such as rapid boiling of solvents, occasionally resulting in an explosion. The small dimensions of tube reactors enhance the performance of these reactions not only with better mixing but also with more efficient heat transfer. An overall heat transfer coefficient (U) is commonly applied to the calculation of heat transfer in heat exchangers. In this application, U can be used to determine the heat transfer rate (q) where A is the heat transfer surface area and ΔTLM is the logarithmic mean temperature difference (eq 4). q = UAΔTLM

(4)

By this relationship, the rate of heat transfer is directly proportional to the surface area; thus, dissipation of heat is faster with larger surface areas. As a point of reference, a 10 mm flask reactor with vigorous stirring and a 400 × 400 μm flow reactor have the same resistance to heat transfer.20 For this reason, small-scale optimizations (1% of incident light when flushed through tubing with an inner diameter of 0.02 in. (0.5 mm). This means that the reaction will not be limited by the ability of the reagent or catalyst to absorb light. In addition to better irradiation, all of the other benefits of flow chemistry apply. This is particularly the case for biphasic gas−liquid photoreactions, where both phase mixing and photon absorption can be limiting. For this reason, flow reactors can be highly beneficial to photochemical reactions. 2.4.2. Electrochemistry. Organic electrochemistry is a sustainable method to replace stoichiometric oxidants and reducing agents for organic transformations. The synthetic community is increasingly applying this method for the mild conditions and high chemoselectivity it offers.105 Essentially, electrochemical reactions are redox reactions that are mediated by the application of an external voltage via the incorporation of electrodes in the reaction vessel. Within the reaction media, molecules are reduced at the cathode and oxidized at the anode. Solid electrodes are most often used, but alternatively packed or fluidized beds can be used.111 In electrochemical analysis, proper placement of the electrodes is not a problem since the instrumentation employs small electrodes. In bulk electrolysis methods, however, the placement is critical. Inconsistent ohmic drops (or IR drops) produce a nonuniform potential across the working electrode which can cause undesired side reactions or ineffective use of the total electrode area.112 Another challenge bulk electrolysis faces are high cell resistances. This is particularly a problem when nonaqueous solvents are used since they have lower dielectric constants than water and therefore lower conductivities. As most organic transformations are performed in an organic solvent, supporting electrolytes are used to improve the conductivity of the solution. Since large scale reactions can require one or more equivalents by weight, this can be costly and is counterproductive to sustainability.113,114 While some recyclable electrolytes are available, eliminating the need for them would be ideal. Even with supporting electrolytes, however, batch scale up can lead to an undesirable evolution of heat caused by larger distances between electrodes. For these reasons, scaling electrochemistry, even on a laboratory scale, is not trivial. Flow chemistry offers solutions to these problems.40 First, the associated resistance can be described by eq 8, where I is the current, Rdrop is the electrolyte ohmic resistance, i is the current density, d is the distance between electrodes, and κ is the specific ionic conductivity. The distance between electrodes and conductivity of electrolytes are directly proportional, therefore if the distance between electrodes is reduced 10fold, the conductivity of the electrolytes can similarly be reduced. For this reason, the small dimensions of flow reactors permit the removal of supporting electrolytes. As such,

Photo- and electrochemistry have reemerged as sustainable means for synthesis.104,105 Both of these methods provide “traceless” reagents in the form of photons or electrons and electron holes and benefit from the small dimension of flow reactors as well. Flow conditions offer more efficient and uniform irradiation of reactions mixtures for photochemistry, and for electrochemistry, the small dimensions eliminate the need for supporting electrolytes. While both of these processes can be scaled to preparative amounts in batch, scaling can be more convenient and reproducible in flow.106,107 Finally, these branches in combination with other flow chemistry benefits prove particularly advantageous (gas−liquid reactions and flash chemistry). 2.4.1. Photochemistry. Photochemical reactions occur when light provides energy to trigger a reaction. This includes chemistry where the excited state of a molecule decomposes, rearranges, or combines with another molecule but can also include electron transfer chemistry initiated by the excitation of a chromophore (photoredox catalysis). The latter is an attractive method for organic synthesis, owing to the fact that these reactions are mediated by visible light, of which starting materials and products generally do not absorb.104,108 Photochemistry in general relies on efficient irradiation of the reaction mixture. Starting materials, products, photosensitizers, and photocatalysts, at the point of incident light, can all act as filters reducing the light intensity available for the rest of the reaction mixture. According to the Beer−Lambert-Bouguer law (eq 7), this attenuation of light is dependent on the molar attenuation coefficient of the molecule (ε) and the concentration of the molecule (c). A = εcl

(7)

To illustrate how attenuation of light affects a reaction, the % transmittance of a common photocatalyst, tris(bipyridine)ruthenium(II) chloride [Ru(bpy)3]2+, was plotted against the path length for different concentrations (Figure 8). For a typical catalyst concentration (2.5 mM), less than 0.1% of light

Figure 8. % transmittance109 plotted against the path length for [Ru(bpy)3]Cl2 in methanol (ε = 14600 M−1 cm−1).110 The dashed vertical line represents the inner diameter of 0.02 in. tubing (0.5 mm). % T = 100% × 10(−εcl). 11802


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Figure 9. Decision diagram for flow chemistry.118

electrochemistry in flow is preferred when purification, cost,

IR drop = i

d κ

(8)

time, and sustainability are important to the end goal. 11803


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Batch electrochemistry setups can suffer from unwanted heat formation necessitating the use of a heat exchanger. Generally, heat exchangers add or remove heat by passing a fluid over a surface. Flow electrochemistry setups are advantageous to batch setups because the reaction mixture is essentially a heat exchanger fluid. The continuous flow of the reaction mixture over the surface of the electrodes permits operation at quasiisothermal conditions, offering better control over reaction temperatures. This, in combination with continuous removal of products and other impurities, can result in higher current yields and better product qualities.115 Finally, in the case of gas formation, flow conditions can outperform batch setups. Under batch conditions, the formation of gas bubbles on the surface of the electrode can lead to temporary or even permanent areas of low conductivity, resulting in the formation of heat and reduced performance. Coalescence of gas bubbles in a microreactor has an overall opposite effect to performance. As gas bubbles grow inside the microreactor, gas−liquid slug flow is created, increasing mass transfer by Taylor flow (section 2.1.1.).116 Continuous addition of the reaction mixture forces the slugs through the reactor, removing the gas which could otherwise be detrimental to the electrolysis.

reactor temperature can easily be changed and precise control of the reaction time can be varied via flow rates. Further analysis of the reaction involves multiphasic systems. Generally, flow reactions outperform batch reactions when one of the reagents is a gas. The headspace to solvent ratio is lower and pressurizing the reactor increases the solubility of the gas in solution. Small-scale pressurized batch reactions are feasible; however, preparative scales are not possible or are dangerous. Circumstances involving solids can be broken into three categories. First, a batch setup is more convenient when precipitation drives a reaction to completion. Precipitation in flow frequently results in the mixer, channel, or pressure regulator clogging. While specialized equipment exists for preventing clogging, there is no universal solution to this problem and troubleshooting involves a higher degree of engineering experience. Similarly, the accurate delivery of suspensions remains a challenge for laboratory scales with reagents which are insoluble in the reaction medium. In this scenario, batch reactions are more convenient and reliable. For reactions with heterogeneous catalysts, on the other hand, flow conditions are preferred. Packed beds simulate high catalyst loadings, reducing reaction times and performing especially well under triphasic conditions. Likewise, two considerations should be taken into account for liquid−liquid reactions. In batch, vigorous stirring can efficiently produce emulsions and the setup is also simpler in batch. These emulsions, however, are less homogeneous in terms of droplet size. Therefore, when homogeneous, highly reproducible emulsions are required, flow conditions are necessary. Fields producing droplets and particles take advantage of flow in particular because narrower size distributions can be obtained.117 In flow, there are tortured path reactors which maintain emulsions via turbulent mixing; however, for convenience, a batch reaction is a better starting point unless scaling is the issue. Other considerations mostly pertain to the reaction’s rate and selectivity. For extremely fast reactions mixing is very important. Generally, these reactions are performed in batch by cooling the reactor to a temperature in which no reactions are occurring, followed by reagent addition. After brief stirring to reach homogeneity, the reaction mixture is warmed up to a temperature in which the reaction can occur. For small scale preparations, batch is convenient. For preparative scales, however, some reactions are lower yielding due to poorer mixing and/or heat transfer. Generally, in flow, faster mixing and better heat transfer will benefit the yield of fast, exothermic reactions greatly. Similarly, selectivity can be enhanced in flow as well. Since flow reactors generally have a narrower temperature profile than batch reactors, side reactions close in energy to the desired reaction can be reduced or eliminated. Additionally, for extremely slow reactions, intensification of reaction conditions can produce compounds in a timely fashion. While sealed vessels are a convenient small scale option, preparative scale high-temperature, high-pressure reactions are much safer in flow. Finally, reactions which are photochemically or electrochemically driven benefit from flow conditions. The Beer− Lambert−Bouguer law describes the attenuation of light as path length increases. Therefore, reaction mixtures will experience more uniform irradiation in flow because of the small dimensions of the reactor. If reactions employ gas−liquid mixtures, flow conditions offer further enhancements. Electrochemistry also benefits from the small dimensions of flow

2.5. Batch Versus Flow Analysis

Flow conditions are not the cure-all for chemistry. This section has pointed out that flow is advantageous for certain transformations; however, developing a flow process can be time-consuming. For this reason, a flow versus batch analysis must be conducted in order to strike a balance between convenience and achieving the overall goal. Since a flow versus batch decision is never black and white, to pigeonhole similar reactions as batch or flow would be foolhardy. However, several generalizations can be made in order to expedite a cost-benefit analysis. For this decision diagram (Figure 9), discovery and preparative scales are taken into consideration. First, a safety assessment is a suitable starting point. Hazardous materials, heat exchange, and pressurized reactions pose safety hazards in which flow conditions can alleviate or nullify risks. Chip reactors, in particular, allow chemists in the discovery phase to work with very small quantities of hazardous materials, reducing exposure risks for the chemist. Additionally, built in quenches avoid equipment manipulations, eliminating human error which can result in spills. Finally, the small dimensions of flow reactors promote efficient heat exchange and are conducive to high-pressure conditions, reducing dangers involved with runaway reactions and “extreme” conditions, respectively. The next question requires an evaluation of one’s overarching goals. For “safe” reactions that are already reported in batch, a chemist must decide whether or not literature conditions meet a project’s needs. If it is not broken, do not fix it. Nonetheless, some discovery scale procedures may not be conducive to preparative scales. As such, the immediate goal should also be taken into consideration. For new transformations, it is more convenient to screen reagents, solvents, and additives in batch. All of these variables can be tested simultaneously, whereas they must be done sequentially in flow. One exception might be screening conditions where starting materials are scarce. Here, small volume chip reactors enable a chemist to perform and analyze a large number of reactions using minimal quantities of a reagent. Additionally, temperature and time optimizations are generally easier in flow because the 11804


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the redesign and optimization steps, however, generally struggles to screen continuous parameters effectively. In addition, only the experiment execution step is expedited and many parameters are tested which are unlikely to work or be informative. Inline and online analytics permit feedback optimization, accelerating the entire central loop (Figure 10, green). Continuous parameters are conveniently screened in flow. The reaction time and the concentration are modulated by the solvent and reagent flow rates, and the reactor temperature is adjusted by a heating or cooling unit. These parameters can be adjusted in real-time, avoiding the need for the setup of individual batch reactions. Recent reports on “black box” and various kinetic optimizations have demonstrated the power of automated feedback optimizations;120 however, like nonautomated flow processes are unable to effectively screen discrete variables. Collecting data and determining an optimal starting point is becoming an important part of cheminformatics. In combination with continuous flow optimization, these two fields could expedite black box optimization, saving significant time and money for the chemists.

conditions. Since reactions can be carried out without supporting electrolytes, the cost may be reduced and the purification simplified. Continuous removal of products and improved mass transfer can also benefit the product quality. Additionally, scaling the reaction to multiple grams can be more convenient for flow via simply extending the operation time of the flow process. This is equally the case for photochemistry, where the attenuation of light is problematic for large dimension reaction vessels. 2.6. Automation

As technologies become more developed and commercialized, they may shift from high-cost/limited-benefit laboratory methods to tools for expediting research. While some of these processes are being developed mostly for industrial purposes, others aim to enhance discovery and synthesis for research laboratories. Currently, these methods are not practical for the average laboratory. Automated feedback optimization was chosen as an emerging reason to perform flow chemistry since recent progress in this field has shown promise for the everyday chemist. Currently, however, the equipment and process setup are too costly for the occasional user. These areas currently target very specific tasks and usually require a larger engineering effort. Even so, this area is showing promise for reducing the time of reaction optimization. The scientific method is a thought process for testing hypotheses and obtaining new knowledge. A reaction optimization follows this method (Figure 10). A researcher

3. ANATOMY OF A FLOW REACTION In the previous section, the reasons for performing a process utilizing flow chemistry methodologies were presented and discussed based on the characteristics of the respective chemical transformation. Once the decision for the development of a continuous process is made, a flow unit suiting the specific requirements of the transformation needs to be designed. Developing a novel reaction system in flow, or conducting a known chemical transformation using this enabling technology, is not, at least initially, as trivial as utilizing traditional batch techniques where the respective reagents are simply dissolved or suspended in a solvent and stirred at a defined temperature until the limiting reagent is consumed. A continuous flow process is significantly more complex from a technological point of view, which may explain why, in the previous century, this technique was predominantly used only in bulk chemical processing and engineering sciences. However, around the turn of the millennium, interest in continuous processing began to increase in the synthetic chemistry community. This rise resulted from the considerable advantages offered over traditional round-bottomed-flask chemistry and/or the access given to otherwise forbidden or impossible transformations. In the subsequent years, a plethora of relatively simple and userfriendly reactor setups have been introduced which are dedicated for synthetic applications on the laboratory scale ranging from home-built systems to fully integrated commercial equipment. For those who wish to apply this enabling technology and are not yet familiar with flow chemistry techniques, a detailed description of all parts necessary for developing a flow reactor unit will be given in this section. In order to give the reader an idea of the potential of such devices, the key features of each component will be discussed in detail with a particular focus on their applicability in synthetic organic chemistry. This review will not discuss fully integrated commercial flow reactors. For recent contributions which cover this topic, see Glasnov and Darvas et al.76,121 Flow chemistry is a modular technique which provides a toolbox for synthetic chemists. A typical continuous flow setup for synthetic applications can be broken down into eight basic zones: fluid and reagent delivery, mixing, reactor, quenching,

Figure 10. Scientific method and the role of automation.

identifies a target reaction, collects literature on how similar reactions were carried out, and creates a hypothesis about the best conditions to start the reaction optimization. Currently, a chemist designs and executes experiments then collects and analyzes data. Depending on the outcome of the original experiments, the chemist changes certain parameters in order to test their effects on the desired outcome. These parameters can be categorized as continuous or discrete. Continuous parameters include the reaction time, temperature, and concentration, while discrete parameters are variables such as solvent, catalyst, or ligand. Recently, high-throughput experimentation (HTE) has accelerated the discovery of new reactions and drugs by increasing the number of experiments, in particular, screening of discrete parameters.33,119 HTE provides researchers with a vast amount of data, accelerating 11805


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Figure 11. Zones of a standard two-feed continuous flow setup. For definitions of the individual flow elements, see the diagram legend at the end of the review.

control is, in most instances, achieved by pressure-driven flow techniques (hydrodynamic pumping), where a pressure difference between the inlet and the outlet of the reactor unit is created.8,76 In other words, the fluid delivery system always needs to be able to surpass the pressure set by the pressure regulation module (section 3.6), and different methods are available for the delivery of homogeneous and heterogeneous solutions as well as gases (vide infra). 3.2.1. Liquid Delivery. The vast majority of flow chemistry reactor units incorporate at least one liquid delivery unit. Depending on the flow rate, the system pressure, and the nature of the liquid phase, three different types of pumps are commonly utilized (Figure 12).129

pressure regulation, collection, analysis, and purification (Figure 11). First, a fluid and reagent delivery system is necessary to accurately feed the respective substances into the flow system. These feeds are combined in the next module by a dedicated mixing device before entering the reactor unit where the chemical reaction occurs. This core unit is directly connected to a quenching module, which allows for accurate control of the residence time. Elevated pressure regimes are easily achieved with a pressure regulator, usually located immediately before the final collection of the product stream. In addition, several tools for analysis,120,122−125 as well as continuous purification modules can be implemented.126 Importantly, all of these individual parts can be arranged interchangeably and repetitively, resulting in an infinite number of possible modifications. Highly complex multistep sequences can be applied to natural product synthesis or on-demand production of pharmaceuticals.32,82 3.1. Connecting Flow Zones

Standardized connections between zones make interchangeability a strength of flow chemistry. Generally, the connections between the different basic zones consist of tubings and nonwetted parts, such as nuts and ferrules used to securely attach the tubing to each respective unit. In most cases, all the components required for connecting the modules are identical to those used in standard HPLC devices and are therefore readily available. The dimensions and composition of the tubing are crucial since it is in direct contact with the reagent stream. Physical parameters like the desired system pressure and chemical compatibility must be considered. In general, for low and medium pressure applications (5 in flow compared to 14 mL min−1, the conversion increased significantly, indicative of mixing-dependent reactions.468 Switching methanol with a solution of trimethyl borate and including a batch quench with 10% citric acid (Scheme 92), the authors prepared 11 boronic acids in fair-to-quantitative yields. Aryl bromides bearing fluorine and cyano groups were prepared; both of which are difficult to access in batch. All of

Scheme 93. Flow Synthesis of Arylboronic Ester Bearing Electrophilic Functional Groups

Scheme 92. Flow Setup for the Rapid Synthesis of Boronic Acids via Aryllithiums

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ester 175 was hydrolyzed, prior to being combined at 50 °C with a mixture of aryl bromide 176, palladium(II) acetate, and tritert-butylphosphine. This process did not require any additional base, producing the biaryl compounds such as 177 in 52−97% yield. Modification of this process by incorporating a monolithic palladium catalyst allowed for activated boronic acid esters to be generated and coupled with aryl iodides in a semicontinuous flow process (Scheme 94).471 First, 179 was generated using

Scheme 95. Continuous Flow Zincation and Subsequent Batch Negishi Coupling

Scheme 94. Semicontinuous (a) Arylboronic Acid Ester Synthesis and (b) Suzuki-Miyaura Coupling in Flow

quenched via a batch Negishi cross-coupling. Arylmagnesium species were also formed by this method using magnesium chloride instead of ZnCl2·2LiCl. Various arenes and heterocyclic compounds were coupled using this method in fair-toexcellent yields. A later report by Roesner generated orthofluoro arylzinc species in flow and telescoped this process with a subsequent Negishi coupling; however, this process required sonication to avoid clogging.478 6.7. Miscellaneous Fast Reactions

Similar to the coupling reaction in the synthesis of eribulin mesylate, researchers at Merck reported a Mannich-type reaction which performed better in flow compared to batch (Scheme 96).479 In the synthesis of verubecestat, the coupling Scheme 96. Flow Setup for a Mannich-Type Reaction toward the Synthesis of Verubecestat

the previously developed conditions and collected in a flask (Scheme 94a). A solution of aryl iodide 180 was added to the mixture and pumped through a monolithic material supporting Pd(0) at 100 °C, producing 1.55 g (85%) of adapalene 181 (Scheme 94b). Various biaryl compounds that are difficult to prepare in batch were synthesized using this process. Catalyst leaching was not investigated; however, the Pd column functioned for greater than 21 h without a loss of activity. Similar to the Suzuki-Miyaura cross-coupling, the Negishi coupling is broadly applicable,472 whereby transmetalation of organozinc reagents to a palladium catalyst allows for the coupling to a wide range of unsaturated halides. Organozinc reagents can be prepared by oxidative addition to zinc metal,473 transmetalation, and iodide or boron−zinc exchange.474 Recently the Knochel group reported the zincation of functionalized arenes via a lithium/zinc transmetalation using lithium 2,2,6,6-tetramethylpiperidide (TMPLi) for the deprotonation of various aryl compounds in the presence of zinc(II) chloride at −78 °C.475 While these conditions tolerated some reactive functional groups, the authors faced problems related to decomposition, unwanted side reactions, and difficulties with scaling-up. For these reasons, Knochel and co-workers developed flow processes using this zincation method.476,477 Preliminary experiments indicated that higher temperatures were tolerated (0 °C vs −78 °C). In particular, in batch at −78 °C, the iodination of ethyl 4-bromobenzoate resulted in the desired aryl iodide in only 53% yield, whereas flow conditions yielded the product in 95% at 0 °C. Flow conditions tolerated a broader range of functional groups and was more easily scaled up. The authors also noted that the less bulky, cheaper lithium dicyclohexylamide (Cy2NLi) was tolerated in flow because of better mixing. The bulky TMPLi base was required in batch to reduce reactivity and prevent side reactions. With this modified setup (Scheme 95), solutions of an aryl compound, zinc(II) chloride, and lithium chloride were mixed with a stream of Cy2NLi at 0 °C. The newly formed arylzinc species was

of 182 and imine 184 resulted in 73% yield and required temperatures below −70 °C. The authors determined via a deuterated acetic acid quench that low conversion and yield was due to the deprotonation of 184 by 186 to form enamine 185 (87% deuterium incorporation). This side reaction could, therefore, be alleviated by better mixing. When this reaction was adapted to flow (Scheme 96), initial conversion at −10 °C was low (55%). However, increasing the flow rate significantly increased conversion (86−88%) supporting their hypothesis related to mixing. However, the process was haunted by increasing pressure as a result of gradual clogging of the mixer. To combat erratic pressure, an inline tube mixer that is less prone to clogging was incorporated and the temperature was lowered to −20 °C to prevent decomposition of 183. Under these flow conditions, 87−91% yield was obtained for prolonged periods of time without detectable pressure fluctuations. 11847


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The Brook rearrangement involves the migration of an organosilyl group from a carbon to an oxygen.480 In the presence of a strong base, the equilibrium is shifted and silyl ethers can be employed in the construction of carbon−silicon bonds.481 Michel et al. investigated the performance of the retro-Brook rearrangement under flow conditions (Scheme 97).482 The reaction using n-butyllithium generally requires

Scheme 98. (a) Generation and Reaction of Vinyllithiums in Flow. (b) Importance of Residence Time Control

Scheme 97. Retro-Brook Rearrangement in Flow for the Synthesis of 2-Trimethylsilyl Nonafluorobutylsulfonates

cryogenic conditions (< −100 °C) and produces a number of side-products which can be difficult to separate from the target compound. When a solution of bromophenol 188 was combined with a stream of n-butyllithium at room temperature, the retro-Brook reaction took place within 1 min to afford ortho-TMS phenols in 75−96% yield. The high purity led the authors to incorporate a downstream quench with trifluoromethanesulfonic anhydride (Tf2O) for the two-step flow production of 2-trimethylsilylaryl trifluoromethylsulfonates in 75−97% yield. The process was scaled out by continuous operation for 30 min yielding 2.7 g of 2-(trimethylsilyl)phenyl trifluoromethylsulfonate (91% yield). Aryl nonaflates share similar reactivity to triflates, however, are more resistant to hydrolysis. Also, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (NfF) is more stable and cheaper than Tf2O. For these reasons, the authors employed similar conditions in the synthesis of arylnonafluorobutylsulfonates (Scheme 97). Since NfF was less reactive than Tf2O, it required activation by 4pyrrolidinopyridine 189. After a retro-Brook rearrangement, 189 and NfF were added and mild heating produced arylnonafluorobutylsulfonates in very good yield. Vinylmetals are effective reagents for the construction of molecules containing carbon−carbon double bonds. The conditions developed by Seebach are a generally applicable method for the generation of terminal vinyllithiums via a Br/Liexchange with tert-butyllithium (Scheme 98a).483 These conditions, however, require < −100 °C and at least two equivalents of tert-butyllithium. Yoshida and co-workers explored the generation and utilization of vinyllithiums under microfluidic conditions.484 When various lithiating reagents were tested under batch conditions at −78 °C, sec-butyllithium performed the best (100% conversion, 59% yield). When the same lithiating reagents were tested under flow conditions, much higher temperatures were tolerated (0 °C) and secbutyllithium similarly outperformed the others reagents (96% conversion, 86% yield). The improved yield was a result of expedient quenching. Therefore, the authors tested the effect of residence time (R1) on the conversion and yield. Keeping the flow rates constant, the length of the reactor was varied (Scheme 98). At both 20 and 0 °C, the yield of 190 increased

with decreasing residence time (Scheme 98b). Above 10 s, the yield dropped off considerably, suggesting that the lifetime of these vinyllithiums is limited at this temperature. Reducing the residence time to 55 ms produced allyl alcohol 190 in 95% yield. Various vinyl bromides and electrophiles were combined using this setup generating compounds in 43−98% yield. Radicals are dynamic intermediates in natural product synthesis.485 Since radical reactions are faster than the rate of diffusion,486 they are attractive reactions to carry out in flow. In early reports,487−490 carbon-centered radicals were generated via a well-known redox process where catalytic iron(II) reduces hydrogen peroxide forming a hydroxyl radical. This radical reacts with dimethyl sulfoxide promoting decomposition which generates a methyl radical. The highly reactive methyl radical abstracts iodine from an alkyl iodide to finally form a new carbon-centered radical. The coupling of this radical with an alkene results in a new radical that is finally oxidized by iron(III) to close the catalytic cycle. Under batch conditions, hydrogen peroxide typically has to be dosed dropwise and used in a large excess. A crude kinetic model suggested that >90% conversion should be reached in a fraction of a second. The fast nature of this reaction suggests that enhanced mass transfer in flow would enhance reactivity. Monteiro et al. designed a flow setup for the production and coupling of electrophilic radicals using this method (Scheme 99).491 When an injection loop containing the electron-rich aromatic substrate and electron-deficient alkyl iodide was mixed with hydrogen peroxide in flow, high conversion (91%) was obtained in as little as 0.1 s. Substrates 191, 192, and 193, which are intermediates in the synthesis of fipronil, tolmetin, and ketorolac were prepared using this setup in comparable yields to previously reported values.492 Additionally, the trifluoromethylation of dihydroergotamine mesylate 194 was performed under fluidic conditions yielding the monotrifluoromethylated compound 195 in 83% yield on a 0.6 kg scale. The 11848


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Pyridine rings are common motifs in pharmaceuticals, agrochemicals, and materials.495 Various methods are reported for the synthesis of functionalized pyridine rings,496−499 one of which is the introduction of a functional group via a Br/Liexchange of bromopyridines. These reactions, however, are complicated by lithium migration and addition to the ring, leading to numerous side reactions. For instance, lithiation of 2,3-dibromopyridine with n-butyllithium and trapping with methyl iodide resulted in a complex mixture at −78 °C with the target 2-bromo-3-methylpyridine comprising only 48%.500 Raising the temperature to −28 °C resulted in 0% yield of the desired product. Nagaki et al. developed a flow process for this reaction where 2,3-dibromopyridine 203 was lithiated with n-butyllithium at 0 °C and promptly trapped (0.055 s) with a solution of an electrophile (E1, Scheme 101).501,502 Under

Scheme 99. Flow Setup for the Creation and Reaction of Electrophilic Carbon-Centered Radicals

Scheme 101. Flow Setup for the Consecutive Lithiation and Trapping of Dibromopyridines primary benefit of these conditions is the ability to reduce the equivalents of the substrate, alkyl iodide, and hydrogen peroxide (1:1.6:1.6) when compared to previous batch reports which utilize as much as 15−75 equiv of the aromatic compound and 2−12 equiv hydrogen peroxide. Benzyne is a highly reactive intermediate with diverse reactivity for the formation of multiple carbon−carbon and carbon-heteroatom bonds.493 However, three component coupling reactions with benzyne can be difficult or impossible in batch because of the short lifetimes of the intermediates. Yoshida developed a flow setup consisting of stainless steel tubing and T-mixers for efficiently performing this three component reaction (Scheme 100).494 Solutions of 1-bromo-2-

these conditions, the target compound was obtained in 87% yield, a substantial improvement over batch conditions. Incorporating an additional lithiation and trapping step using a second electrophile (E2) afforded seven examples of difunctionalized pyridines in 47−75% yield. Liu et al. found similar enhancements for the functionalization of other heteroaromatic compounds using a split and recombine mixer in flow.503 Lithiation of 2-bromopyridine 206 and quenching with methanol was used as a model reaction for the optimization of the flow setup. In batch, the yield of pyridine was below 50% at −40 °C and dropped by nearly half after warming to 20 °C. Using two T-mixers and a residence time of one second, approximately 80% of pyridine was produced at −40 °C. A significant drop-off in yield did not occur until 0 °C. Integrating an inline mixer into the setup increased the yield and operating temperature (Scheme 102a). Using this flow method, 17 examples such as the conversion of 204 to 205 were performed in 45−94% yield. To demonstrate the ease of scaling out a process, the authors also prepared 5.60 g (62%) of 207 in 40 min (Scheme 102b). Most fast reactions (1 min). For example, E-cinnamonitrile 213 reacted smoothly with TMPZnCl·LiCl in THF at 90 °C with a 10 min residence time producing zincate 214 (Scheme 105a), which was combined with a solution of allyl

Scheme 106. Microwave-Assisted Synthesis of 1,2,5Thiadiazepane 1,1-Dioxides Using a Multicapillary Flow Reactor

Scheme 105. (a) Continuous Flow Zincation and CopperCatalyzed Allylation and (b) Selected Examples

sulfonamide 219, DBU, and a different amine 220 for each capillary were reacted simultaneously. The output from each capillary was collected in separate sealed vials producing four different analogs. Only the optimization of a single capillary was necessary for the production of a library of 48 different 1,2,5thiadiazepane 1,1-dioxides 221 in 50−80% yield using this fourcapillary reactor setup. 7.2. Heated Reactions between 100 and 200 °C

The Strecker reaction522 is one of the earliest one-pot multicomponent reactions. It has garnered much attention since the products, α-aminonitriles, are well-known precursors to α-amino acids.523 Our laboratory synthesized primary αaminonitriles via a Strecker reaction utilizing a cooled photoreactor.157 We utilized this process for the synthesis of various fluorinated amino acids.524 Hydrolysis of the αaminonitriles in batch took hours to days even under reflux. This was due to the loss of acid to the headspace of the batch reactor. For this reason, the hydrolysis step was incorporated into a flow reactor. Crude aminonitrile 222 from the photooxidative Strecker reaction was dissolved in a 30% HCl(aq)/acetic acid mixture and introduced to a heated reactor via an injection loop (Scheme 107). An 8 bar back pressure was applied to prevent boiling, and after a 37 min residence time, full conversion was obtained with no observable amide intermediate. In combination with the flow Strecker process, good-to-very good yields were achieved for the two-step production of fluorinated amino acids 223 from their corresponding fluorinated amines.

bromide and CuCN·2LiCl to produce 215. After quench, workup and column chromatography, 215 was isolated in 75% yield. Repeating the reaction under identical conditions, but with a longer operation time (∼35 min versus ∼7 min), 1.4 g (83%) of 215 was isolated. This 5-fold increase in scale demonstrates the ease of scaling when compared to a sealed vessel reaction. In addition to reactions with 213, the metalation of 4,5-substituted butenolides was carried out with the same setup producing compounds 216−218 in 59−87% yield (Scheme 105b). These reactions were carried out near or above the boiling point of THF with the same setup, illustrating the ease with which a reaction can be transitioned from subboiling to superheated. The same group expanded upon this process with the high-temperature zincation of arenes and heteroarenes.512 Not only were they able to use (Cy2N)2Zn· 11851


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with a solution of phenoxide 229, and heated to 90 °C, 54% yield of 230 was obtained (Scheme 109). Increasing the heat to

Scheme 107. Hydrolysis of α-Aminonitriles toward the Synthesis of Fluorinated Amino Acids

Scheme 109. SNAr Substitution under Flow Conditions

Recently, the biaryl moiety of odanacatib, a bone resorption inhibitor, was synthesized in a combined batch/flow process (Scheme 108).525 First, the authors optimized the stereo-

100 and 110 °C further increased the yield to 71% and 87%, respectively. Additional increases in the temperature did not significantly improve the yield. With these conditions, nine other heteroaromatic chloro compounds were reacted with phenoxides and alkoxides in good-to-very good yields. The discovery of nifedipine, used for the treatment of hypertension, sparked interest in the synthesis and pharmacological properties of 1,4-dihydropyridines.530,531 Dihydropyridine chemistry began much earlier, however, with pioneering work from Hantzsch, for which the pyridine synthesis is named.532 Baraldi et al. published an accelerated Hantzsch pyridine synthesis in a flow reactor (Scheme 110).533 In the

Scheme 108. Batch/Flow Process for the Synthesis of the Biaryl Moiety of Odanacatib

Scheme 110. Flow Setup for the Preparation of 1,4Dihydropyridines

selective reduction of 224 using E. coli cells overexpressing the alcohol dehydrogenase ADH-A, NADH, and isopropanol. Chiral alcohol 224 was obtained in excellent yield (98%) and high enantiomeric excess (98%). In an attempt to improve the overall process efficiency, the crude reaction mixture containing chiral alcohol 225 was used directly for the subsequent palladium-catalyzed Suzuki coupling. Initial experiments in a batch microwave reactor showed that E. coli cells had a devastating effect on the yield (2%). This challenge was overcome by centrifugation of the biocatalytic reaction mixture prior to addition of the coupling reagents. With microwave conditions in hand, the reaction was translated to flow (Scheme 108). A solution of alcohol 225 with tetrakis(triphenylphosphine)palladium(0) in isopropanol, and a solution of potassium carbonate and boronic acid 226 were introduced into a heated reactor at 110 °C. A 3 bar back pressure regulator prevented boiling and with a 5 min residence time, biaryl compound 227 was isolated in 45% yield after column chromatography. Aryl halides are useful substrates for nucleophilic aromatic substitution reactions.526 Primary and secondary amines, as well as alkoxides, are generally good nucleophiles for this reaction. Aryl ether linkages such as those found in natural products like vancomycin can be formed using this method.527 Unless the compound is activated by an electron-withdrawing group, many of these reactions require elevated temperatures.528 Alam et al. utilized a heated chip reactor for the formation of C−O bonds in heteroaromatic compounds via an SNAr substitution.529 Initial experiments were carried out in THF, however, due to the formation of NaCl, clogging prevented extended reactions. A THF/water (3:2) solvent mixture was ideal and used for further studies. When chloropyrimidine 228 was combined

synthesis of darodipine 232, aldehyde 231, ethyl acetoacetate, and ammonium hydroxide in ethanol was pumped through a PFA reactor heated at 120 °C and 6.9 bar. At 6 min residence time, daropine 232 was obtained in 76% yield. Using the same setup, nine other dihydropyridines were synthesized with residence times of 6−11 min in 45−88% yield. The complexity of macrocycles provides them with valuable pharmacological properties attractive for use in therapeutics.534 Due to the ring size, however, macrocyclization is normally slow and low concentrations must be employed to prevent oligomerization. The Collins group developed microwave conditions for the macrocyclization of diynes via a GlaserHay coupling reaction employing PEG400, which facilitates high concentrations with short reaction times (hours vs days).535 They proceeded to adapt this reaction to flow, following the microwave-to-flow paradigm.536 Employing CuCl2·2H2O, a TMEDA ligand, triethylamine, and a Ni(NO 3 ) 2 ·6H 2 O cocatalyst, the authors found the optimal temperature to be the same in flow as in a microwave batch reactor (120 °C) with a residence time of 1.5 h. Their previously reported microwave batch conditions afforded a 21-membered lactone in 81% yield, while their new flow conditions yielded the same lactone in 97%. The reaction was scaled, and the macrolactone was obtained in a comparable 93% isolated yield. Given the promising scalability of this cyclization, the Collins group applied this process toward the formal synthesis of ivorenolide 11852


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particles,541 copper wire,294,296 metal oxides,542 and steel beads.543 In their synthesis of olanzapine, they employed a steel capillary reactor encased by a high-frequency generator (Scheme 113).544 Using this setup, aniline 242, was flowed

A, a macrolide with immunosuppressive activity (Scheme 111).537 A solution containing diyne 233 was injected into a Scheme 111. Flow Setup for the Catalytic Macrocyclization in a Formal Synthesis of Ivorenolide A

Scheme 113. Flow Setup for the Acid-Catalyzed Cyclization toward Olanzapine

reactor heated at 120 °C via an injection loop, and after a 1.5 h residence time, the corresponding macrolactone 234 was obtained in 52% isolated yield. β-Amino alcohols 236 are common motifs in active pharmaceuticals such as oxycodone, carvedilol, and metoprolol. One of the most common ways to construct β-amino alcohols is by the aminolysis of epoxides.538 Since many of these reactions require lengthy reaction times, this reaction has been optimized in a microwave reactor.539 Elevated temperatures promote epoxide opening without the use of Lewis acid catalysts. The groups of Jamison and Jensen compared the aminolysis of various epoxides in a heated flow reactor.102,103 They found that flow conditions could match or even improve the reactivity when compared to the equivalent batch microwave reactions. With low-boiling amines, product distributions (mono- vs dialkylation) varied with the amount of headspace in microwave batch reactions. The lack of headspace in flow led to consistent product distributions. Our group capitalized on this advantage for the synthesis of various β-blockers 237−241 (Scheme 112).540 Epoxides 235 were

through the heated reactor producing a solution temperature of 140 °C. With less than a 1 min residence time (95% yield for each substrate. Notably, compounds 278, 279, and 280 were produced on gram scales in excellent yield. This process was also applied to the reduction of various aliphatic nitro compounds as well as several azides. Heck-type chemistry has become a staple for the assembly of molecules.582 Heck reactions are well-known to perform better at higher temperatures as long as the reagents, substrates, and products can survive such intense conditions.583 Microwave conditions have improved various Heck reactions, and while some substrates have improved yield,584 substantially reduced reaction times is the largest benefit over conventional heating at reflux. The Kappe group investigated the ligandless Heck reaction using microwave batch and continuous flow setups.585 They found that batch experiments under reflux (ca. 80 °C) using a heterogeneous Pd/C catalyst required 2−3 h for full conversion. On the other hand, both batch conditions employing microwave heating and conventional heating in a sealed vessel at elevated temperature (105 °C) required less time (20 min), and at 150 °C, the reaction was complete in as little as 2 min. No significant differences were observed between the two batch processes; however, when this reaction was adapted to flow using a packed bed, the number of side products increased significantly. The authors attributed this to a higher effective molarity in the packed bed where alternate mechanisms leading to the dehalogenation of aryl halides has been proposed.586,587 For this reason, they developed a homogeneous method employing Pd(OAc)2 as a catalyst. At 170−200 °C, full conversion of aryl iodides and bromides was

batch investigations in sealed microwave vials showed that the amount of headspace in the reactor had a significant effect on the conversion of the reaction. Heating 0.6 mmol of 4cyanobenzaldehyde with 4 mol % Rh(OAc)2 and 8 mol % 1,2bis(diphenylphosphanyl)propane (dppp) at 180 °C for 15 min in a 10 mL vial resulted in full conversion. When the scale was increased to 1.4 mmol (less head space), the conversion decreased to 26%. Similarly, when the reaction was performed in a pressurized flow reactor (no head space), the conversion was only 30%. The authors incorporated a nitrogen feed into their flow system in order to drive the reaction forward by removing carbon monoxide from the reaction mixture. The reaction mixture and nitrogen were combined at 0.5 and 15 mL/min, respectively, and heated at 180 °C and 6 bar. Carbon monoxide was detected at the outlet in as little as 3−4 min, while the product was not detected until 8−9 min. This result is indicative of an annular flow regime where the rapidly flowing gas phase passes quickly through the center of the reactor, and the more viscous, slower reaction mixture travels along the surface of the reactor (Scheme 123). Increasing the temper11856


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ature to 200 °C and the gas flow rate to 25 mL min−1, 4cyanobenzaldehyde was fully converted to benzonitrile in 25 min. Ten different aldehydes were decarbonylated in fair-tovery good yields. Notably, decarbonylation of 281 yielded chromene 282 85% yield. The previously reported batch conditions employed diglyme at reflux (∼162 °C) for 16 h and only afforded 39% yield.

Scheme 125. Nucleophilic Aromatic Substitution of Heterocycles in Flow

7.3. Reactions above 200 °C

In the synthesis of amitriptyline 285, the Kirschning group prepared ketone 18 in flow via a Wurtz-type coupling and a Parham cyclization.205 Addition to the ketone using Grignard 283, followed by the elimination of water using 7 M HCl to form amitriptyline was reported in batch.599 To avoid using such highly corrosive conditions, the authors envisaged an elimination reaction of alcohol 284 under high-temperature conditions without added acid (Scheme 124). The Grignard

aromatic substitution in batch requires 8−32 h at reflux in a formamide solvent (153 °C for DMF).607,608 Acidic additives such as para-toluenesulfonic acid, acetic acid, and ammonium chloride afforded dimethylaminopyrdine in poor yield. Aqueous potassium carbonate produced the product in 45% yield in a microwave batch reactor; however, precipitation occurred preventing this process from being adapted to flow. When an aqueous ammonia solution was used, the N,N-dimethyl-3nitropyridine-2-amine was produced in 76% and 93% in microwave and flow reactors, respectively. With the use of ammonia as an additive, the optimal temperature for the generation of dimethylamine was 240 °C with a residence time of 30 min. Half of the substrates were reacted under these conditions (Scheme 126a); however, some substrates or

Scheme 124. Continuous Flow Grignard Addition and Elimination with Inductive Heating

Scheme 126. (a) Nucleophilic Aromatic Substitutions Using Dimethylamine Generated in Situ by Decomposition of N,NDimethylformamide. (b) Pre-Generation of Dimethylamine for Temperature Sensitive Substrates

addition proceeded smoothly at room temperature with just a 30 s residence time. After an ethanol quench, the reaction mixture was passed through a reactor packed with steel beads which were heated by induction (210 °C). Elimination occurred with a 36 s residence time, and a 1 M HCl quench initiated crystallization producing amitriptyline hydrochloride 285 in 71% yield. The corresponding elimination reaction in batch yielded no product after 20 h. Similar to other reports of nucleophilic aromatic substitutions in flow,600−604 Charaschanya and co-workers used hightemperature flow conditions to accelerate the nucleophilic reaction of amines with 2-chloroquinazoline 286.605 Unlike many of these reports which employ high boiling solvents, the authors utilized ethanol and high pressure to suppress boiling. Side reactions were more prevalent above 325 °C, and an increase to 400 °C led to significant decomposition. Reactions run at 225 °C with a 16 min residence time led to 97% yield for the reaction of 2-chloroquinazoline 286 and benzylamine 287 (Scheme 125). The majority of substrates were produced in fair-to-excellent yields. The hydrochloride amine salts were less reactive, and anilines also resulted in poor yields. With the use of this setup, reactions with 2-chloroquinoxaline and 2chlorobenzimidazole yielded aminated compounds 288 in 42−78%. In a related report for the synthesis of N,N-dimethylaminoarenes, Petersen et al. used high temperatures for the generation of dimethylamine via the decomposition of DMF.606 The generation of dimethylamine and subsequent nucleophilic

products were not stable at such high temperatures. Therefore, the authors developed an alternative setup consisting of a stream of aqueous ammonia/DMF heated at 240 °C for 40 min prior to mixing with a line of aryl halide (Scheme 126b). A temperature of 30−50 °C was sufficient for the second reactor, producing dimethylamino arenes 289 in 68−97% yield. Since high-temperature/pressure reactions are difficult or dangerous to scale, the authors applied the setup (Scheme 126a) to the gram-scale synthesis N4,N4,6-trimethylpyrimidine-2,4-diamine 291. The Kondrat’eva reaction is a general method for synthesizing annulated pyridines.609,610 It has widespread use, including the synthesis of vitamin B6 by Roche.611 In general, this method involves an inverse electron demand Diels−Alder cycloaddition, followed by loss of water. Typically, these reactions are carried out at reflux or in a sealed tube.612,613 Lehmann et al. described a convenient flow setup using a GC oven to heat a reactor at 230 °C for the Kondrat’eva synthesis of 11 pyridines.614 Initial investigations were conducted in a microwave reactor at 180 °C using 1,2-dichlorobenzene as a solvent. 11857


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Temperatures from 120 to 210 °C provided no product, and the addition of DBU to promote the loss of water also failed. The addition of Brønsted acids such as trifluoroacetic acid (TFA), led to the production of small amounts of the annulated pyridines; however, the conversion could not be increased due to high pressure (>13.8 bar) and subsequent instrument shutdown. In light of this, the authors adapted this reaction to flow since higher temperatures and pressures are safely reached. Increasing the temperature from 210 to 230 °C increased the yield from 17% to 58%. Extending the residence time from 60 to 120 min further increased the yield to 75% (Scheme 127).

pyrimidines (R1 = OMe, O(CH2)2CCH) were significantly less reactive, with yields of 23% and 16%, respectively. Dimethylcarbonate (DMC) is a green solvent and reagent.617 At lower temperatures, it can be used as a methoxycarbonylating reagent, while at higher temperatures it acts as a methylating reagent. Various examples are reported for methylation in flow, most of which focus on ether synthesis.618−624 In one example, Glasnov et al. described the use of catalytic base for methylating indoles, phenols, thiophenols, and carboxylic acids.625 Microwave batch optimization using indole 299 showed that at low temperatures (90 °C) conversion was low and the formation of N-methoxycarbonyl was favored. Increasing the temperature to 230 °C resulted in 99% conversion with the N-methylated compound 300 as the primary component. Increasing the reaction time from 10 to 20 min resulted in full conversion and no detectable methoxycarbonyl compound. Without added base, the conversion was lower (85%) and product selectivity favored the N-methoxycarbonyl product. Transition to a flow reactor and further intensification showed that at 285 °C and 150 bar, the conversion of indole 299 to 1-methylindole 300 was complete with only a 3 min residence time (Scheme 129). Using this setup, ten substrates were methylated in fair-to-excellent yields.

Scheme 127. Kondrat’eva Reaction in Flow

This setup was used for the synthesis of 12 different annulated pyridines and was run continuously for 6.75 h without significant fluctuations in the pressure to produce 6.9 g of pyridine 296 in 60% yield (Scheme 127). Alternatively, annulated pyridines can be reached via an inverse-electron-demand Diels−Alder reaction with pyrimidines and alkynes.615 Martin et al. revisited this reaction owing to the ease with which high-temperature and pressure can be reached in flow.616 Previous reports used high boiling solvents such as nitrobenzene which is toxic and must be removed by column chromatography. Flow conditions using a 17.2 bar back pressure regulator permitted the use of toluene as a solvent. Initially, the reaction of pyrimidine 297 at 210 °C produced only 1% of the desired pyridine 298. Increasing the temperature to 250 °C resulted in a considerable increase in yield (49%) and extending the residence time from 20 to 50 min resulted in 96% conversion. However, with extended operation times, the channel clogged with a black polymer-like substance. Hypothesizing that this was a result of HCN polymerization, the authors included 3-pentanone (1% v/v) in order to trap HCN by the formation of a cyanohydrin. These conditions were stable over many hours without pressure spikes or reactor fouling. For example, after several hours, 21 g (84%) of 5chloro-2,3-dihydro-1H-indene (R1 = Cl, A = CH2, R2, R3, R4 = H) was produced using this setup. Since substrates where A = O or NH are known to be much less reactive, the temperature was elevated to 310 °C, and the pressure increased to 51.7 bar (Scheme 128). With the use of these conditions, 20 other examples were produced in 16−95% yield. Alkoxy-substituted

Scheme 129. Methylation Using Dimethylcarbonate in Flow

The tert-butyloxycarbonyl (Boc) protecting group is by far the most widely used group for amines, constituting over 50% of all amine-related protecting group manipulations in the synthesis of drug candidates.626 Acidic conditions are widely employed for deprotection; however, electron-rich substrates and other acid labile groups are not tolerated. As such, more tolerant conditions have been developed like the thermal removal of Boc.627−629 Recently, researchers from AbbVie described a continuous flow reactor for the Boc-deprotection of amines in mere minutes.630 Initially, when Boc-protected 301 was pumped through a reactor at 200 °C with a residence time of 8 min, no product was observed. An 8 min batch microwave reaction corroborated these results. Increasing the temperature to 300 °C resulted in full conversion; however, only 52% of the desired product was formed as a result of numerous other sideproducts. Shortening the residence time to 2 min reduced the number of side-products and resulted in 80% yield of the desired compound 302 (Scheme 130a). Another 13 amines such as secondary amine 304 were produced by Bocdeprotection in over 90% yield. An additional six compounds containing a second protecting group were selectively deprotected in 54−95% yield (Scheme 130b, 305−307). Finally, the authors demonstrated the versatility of this setup by incorporating it into a multistep process (Scheme 130c). Sulfonylation of amine 309 with sulfonyl chloride 308 was carried out at ambient temperature before mixing with a solution of 2-chloro-5-nitropyridine 310. This solution was reacted at 300 °C and 100 bar, which was sufficient for Boc deprotection of 311. The subsequent nucleophilic aromatic substitution yielded 312 in 81% after flash chromatography.

Scheme 128. Annulated Pyridines by an Intramolecular Inverse-Electron−Demand Hetero Diels-Alder Reaction

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Scheme 130. (a) Continuous Flow Boc Cleavage. (b) Selected Examples Which Demonstrate Excellent Functional Group Tolerance. (c) Multistep Process Incorporating Boc Cleavage Process

Scheme 131. Continuous Flow Claisen Rearrangement and Downstream Hydrogenations in the Synthesis of (a) 2Propylphenol and (b) 2-Propyl-Cyclohexanone

flow rate. The ease with which temperature and reaction time can be varied facilitated rapid parameter screening and optimization for each individual substrate. For example, the unsaturated compound 317 was reacted at 350 °C with a 10 min residence time affording biphenyl compound 318 in 96% yield (Scheme 132a). Other substrates such as imine 319, Scheme 132. (a) Thermal Cyclization Reactions of Alkylidene Esters in Flow, and the Similar (b) ConradLimpach and (c) Gould-Jacobs Syntheses

The Claisen rearrangement offers chemists a powerful tool for the synthesis γ,δ-unsaturated ketones and C-allylphenols via a [3,3]-sigmatropic rearrangement.631 Its discovery has led to the development of numerous related [3,3]-sigmatropic rearrangements, further expanding the synthetic chemists’ toolbox.632−634 Many of these rearrangements, however, require high temperatures and frequently employ high boiling solvents like xylenes. For this reason, a number of groups have investigated its performance under continuous flow.17,601,635,636 Recently, Ouchi and co-workers reported a solvent-free Claisen rearrangement in flow.637 When O-allylphenol 313 was pumped through a reactor heated at 320 °C, only a 1 min residence time was required for full conversion to 2-allylphenol 314. To demonstrate the potential impact in a laboratory environment with regard to production time frame and solvent waste, the reactor was run continuously for 30 min, producing 240 g of 314 in 94% yield (Scheme 131). A subsequent reduction at 120 °C and 20 bar using hydrogen over a packed bed of 20% palladium on carbon produced 2-propylphenol 315 selectively in 94% yield (Scheme 131a). The combined twostep sequence was capable of producing 100 g of 315 in 50 min. A simple reduction in flow rate and an increase in the temperature and pressure resulted in a complete conversion of phenol 314 to 2-propyl-cyclohexanone 316 (Scheme 131b). Under these conditions, 21.9 g of 316 was produced in 45 min. Numerous routes have been reported for the synthesis of quinoline derivatives.638,639 Among them are the ConradLimpach640−642 and Gould-Jacobs syntheses.643,644 These reactions require extremely high temperatures and have been reported at >250 °C in mineral oil. For this reason, Lengyel and co-workers applied flow conditions.645 The authors used THF as a solvent and began optimizations varying temperature and

tolerated higher temperatures and reached completion in under a minute producing hydroxyquinoline 320 in 92% yield (Scheme 132-b). The similar Gould-Jacobs synthesis produced hydroxyquinoline 322 in excellent yield when reacted at 350 °C with a 4.5 min residence time (Scheme 132c). Not only did this process greatly reduce the production time, it also facilitated purification. In most cases, the output from the reactor was concentrated, washed with diethyl ether, and filtered. Other reports employing high-boiling solvents required column chromatography just to remove the solvent. Nitriles are important starting materials for polymers, pharmaceuticals, and agrochemicals.646 There are many routes to nitriles,647 among them a nitrile exchange using acetonitrile.648 The exchange proceeds through an equilibrium which requires high temperatures in an autoclave649 or superstoiciometric sulfuric acid.650 Cantillo et al. developed a hightemperature flow process for the conversion of carboxylic acids 323 to nitriles 324 without high-boiling solvents or added acid.651 Microwave batch reactions of benzoic acid in acetonitrile required 1 h at 250 °C. At this temperature, the pressure was around 31 bar, the upper limit of the instrument. Stainless steel reactors on the other hand safely handle temperatures greater than 350 °C and pressures greater than 200 bar. For this reason, the authors opted for flow conditions. 11859


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The temperature was gradually increased from 250 to 350 °C. The best conversion occurred at 350 °C and notably, there were no side-products observed. Increasing the residence time from 10 to 25 min resulted in 94% conversion of benzoic acid to benzonitrile (Scheme 133). This setup tolerated functional

steel reactors offer temperature and pressure regimes that cannot easily be reached in batch.

8. TRACELESS REAGENTS IN FLOW: PHOTO- AND ELECTROCHEMISTRY When continuous processing entered organic chemistry laboratories, researchers immediately realized that flow techniques complimented photo- as well as electrochemical transformations. These reactions use traceless reagents (i.e., photons or electrons) and strongly benefit from the small dimensions. In addition, the accurate control of process parameters (reaction time and temperature) enhances the potential of these powerful reactions. Therefore, flow chemical techniques strongly contributed to the recent revitalization of these long-known methodologies.

Scheme 133. Continuous Flow Preparation of Nitriles from Carboxylic Acids in Supercritical Acetonitrile

groups well. Nitriles containing halo-, nitro-, phenol, and ester groups were produced in good-to-excellent yield. Furans, thiophenes, and alkyl carboxylic acids were also obtained in good-to-very good yields. Water at very high temperature and pressure exhibits very different properties than at room temperature. The polarity is lower, and the ionic constants and diffusion coefficient are increased. This helps to improve solubility of organic compounds and can increase the rates of reactions. Additionally, workup and purification procedures can be expedited after cooling back to room temperature. Nagao et al. exploited these benefits in the synthesis of benzazoles using water as a solvent at high temperature and pressure.652 Benzazole derivatives have diverse applications as fluorescent molecules, pharmaceuticals, veterinary anthelmintics, and fungicides.653−655 Benzazole synthesis is commonly achieved by reaction of ortho-phenylenediamines by reaction with carbonyls or carbonyl equivalents.656 For initial optimization, Nagao et al. cyclized N-[2(phenylamino)phenyl]benzamide. At 400 °C and 300 bar, the corresponding benzazole 327 was produced in 59% yield. Increasing the pressure from 300 to 450 bar increased the yield to 94%, and increasing the temperature to 445 °C afforded the benzazole product quantitatively. Attempts to perform this reaction in batch were fruitless, yielding only 9−12% of the desired product after 24 h at reflux. To demonstrate the applicability of this process, the N-acylation and cyclization were performed (Scheme 134). A solution of anhydride 325

8.1. Photochemistry

Using light to accelerate a chemical reaction is undoubtedly one of the most promising possibilities to access more sustainable chemical manipulations. In contrast to conventional reagents, photons are not only traceless but also nontoxic. However, a serious problem limiting photochemical transformations on larger scales arises from the logarithmic decrease of the transmission of light as a function of path length through a liquid medium (Beer−Lambert−Bouguer law). Consequently, the reaction mixture is inefficiently irradiated, and low reaction rates are obtained. This issue is elegantly avoided by changing from conventional batch processes to continuous flow approaches.657 The large surface-to-volume ratio ensures increased irradiation efficiency for the entire solution. This not only results in significantly intensified protocols but also allows for scaling these chemistries to synthetically useful quantities. Due to these fundamental advantages, flow processing is routinely used in all areas of photochemistry and one of the most important subfields of continuous organic synthesis. A recent review covering the theoretical, technological, and historical aspects of the field of flow-photochemistry in organic synthesis was recently published.64 Therefore, this section will be restricted to representative examples and publications which appeared since 2016. Most flow reactors for photochemical applications are basically light transparent chips or coil reactors placed adjacent to a light source. A number of different home-built or commercially available setups and arrangements exist, and the technological aspects of continuous photoreactors have been discussed thoroughly.62,64,658−660 8.1.1. Photoexcitation of Substrates. Reactions which are induced by UV light involve various powerful transformations such as rearrangements, cycloadditions, cyclizations, or radical chain processes and have a plethora of applications in the synthesis of valuable molecules.661 Under photochemical conditions, an active molecule can be transformed into its excited electronic state, enabling transformations that are usually inaccessible by other synthetic methods. Chemical structures with high complexity can be generated in a single photochemical step, sometimes even without any additional reagents. Such strategies are therefore particularly interesting in the context of green and sustainable manufacturing. Among all photochemical transformations, [2 + 2] cycloadditions are one of the most studied classes of transformations in organic synthesis and are a straightforward approach to cyclobutane derivatives from olefins. One of the first reports on continuous [2 + 2] photocycloadditions between cyclo-

Scheme 134. Flow Synthesis of Benzazole Derivatives in Water

and diamine 326 in NMP were combined with preheated water and reacted at 445 °C and 450 bar. Benzazoles containing halo-, nitro-, methoxy-, and trifluoromethyl groups were produced in 90−99% yield. Additionally, benzoxazoles (X = O) and benztohiazoles (X = S) were produced in 69−99% yield. While many heated reactions can be carried out in sealed vials with conventional or microwave heating, flow conditions offer an easy option for scaling reactions. Additionally, stainless 11860


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complex reaction mixture was obtained. Conversely, a temperature of 30 °C gave a cleaner reaction profile but the conversion was below 80%. This issue was resolved by using a filter placed between the coil and light source which provided an almost monochromatic irradiation of 365 nm. These modified conditions resulted in full conversion and good selectivity (84%) without the need for active cooling. On a preparative scale, the authors isolated 1.56 g (76%) of the API 331 within 4 h, thus showing the potential of photochemical flow techniques for larger scale synthesis of valuable molecules. UV irradiation can be used to trigger chemical reactions via photoinduced electron transfer processes. When an organohalide is irradiated in the presence of a stoichiometric amount of an electron donor such as a tertiary amine, a radical dehalogenation can take place to generate a carbon radical. This strategy can be used for intramolecular cyclizations, which usually require an H-donating radical mediator such as Bu3SnH.669 Ryu and co-workers used a stainless steel chip reactor (width 1 mm, depth 200 μm) equipped with a quartz cover to initiate 5-exo-dig cyclizations in continuous flow (Scheme 137).670 Residence times of 3.8−8 min were sufficient

hexenones and vinyl acetates was published by Ryu and coworkers,662 and since then a plethora of studies utilizing a broad range of starting materials and conditions were reported.64 In an attempt to extend the scope of this transformation to more challenging starting materials, Beeler and co-workers studied the [2 + 2] photocycloaddition of methyl cinnamate 328 in flow (Scheme 135).663 Initial experiments using a coil reactor Scheme 135. Continuous [2 + 2] Photocycloaddition of Methyl Cinnamate Using a Hydrogen-Bonding Catalyst

illuminated at wavelengths above 305 nm gave modest conversions within 8 h. On the basis of earlier reports using macromolecular host−guest systems,664,665 the authors hypothesized that this process can be improved by a dual hydrogen-bonding catalyst to template the substrates and thus facilitate dimerization. Moreover, the catalyst could further contribute to reaction enhancement by lowering the HOMO/ LUMO gap of the coupling partners. A thiourea derivative 329 improved the conversion from 29 to 76% (60% isolated). The diastereoselectivity also improved significantly compared to the uncatalyzed process. As a result of mechanistic investigations, the authors suggested a triplet sensitization effect in addition to the proposed templating. The generality of their catalytic methodology was tested on several cinnamates, and similar improvements were obtained in all cases. Rearrangements are another class of important photochemical reactions. They can offer useful strategies for the synthesis of valuable molecules via reversible or irreversible isomerization. The synthesis of the anti-inflammatory drug ibuprofen is one the classic examples for API production in continuous flow and has been accomplished by the groups of Jamison666 and McQuade667 using purely thermal reactions. In 2016, Baxendale and co-workers presented an alternative approach based on a photochemical Favorskii rearrangement of an α-halopropiophenone intermediate 330 which can be synthesized via a Friedel−Crafts acylation of isobutylbenzene with chloropropionyl chloride.668 The α-chloroketone 330 and 2-methyloxirane were dissolved in an acetone/water mixture and pumped through a coil reactor which was wrapped around a medium pressure metal halide lamp (Scheme 136). A detailed study on the reaction conditions revealed that temperatures above 80 °C led to full conversion of 330 within 20 min, but a

Scheme 137. Photochemically Induced 5-exo-dig Radical Cyclizations in a Chip Reactor

for moderate-to-excellent yields using a low-pressure mercury lamp (254 nm) at a concentration of 0.1 M. For comparison, a reaction in a quartz test tube (1.3 cm i.d.) showed low conversion (13%) under these conditions. The authors used a larger flow reactor (width 2 mm, depth 1 mm) to produce ∼4 g of a representative cyclic product within 18 h (residence time 20 min). Photochemistry is a standard technique for the chlorination of hydrocarbons on an industrial scale.671 These free-radical chain reactions are initiated by homolytic fission of Cl2 under UV irradiation. Reactions involving Cl2 are usually avoided on laboratory scales due to safety hazards. To circumvent these safety limitations, the groups of Kappe246 and Ryu672 reported on the continuous, on-demand generation of Cl2, which was utilized for the photochlorination of alkanes in a downstream process. Aqueous solutions of HCl and NaOCl were mixed in a T-mixer which ultimately resulted in the formation of gaseous Cl2.672 The resulting stream was mixed with the neat hydrocarbon and pumped through a glass chip reactor irradiated with a 352 nm light source (Scheme 138). After the reactor unit, the reaction mixture was quenched with Scheme 138. Photochemical Chlorination of Hydrocarbons Using On-Demand Generated Cl2

Scheme 136. Continuous Synthesis of Ibuprofen by a PhotoFavorskii Rearrangement

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Na 2 SO 3 . For all tested substrates, the photochemical chlorination was complete within a maximum residence time of 1 min, yielding the desired products in good-to-excellent yields as determined by GC-analysis. Similarly, Kappe and co-workers demonstrated the in situ generation of bromine azide for the photochemical 1,2bromoazidation of aromatic olefins (Scheme 139).673 The

Scheme 141. Photochemical Borylation of Aryl Halides under Continuous Flow Conditions

Scheme 139. In Situ Generation of BrN3 for Photochemical 1,2-Bromoazidation of Olefins

N,N,N′,N′-tetramethyldiamino methane (TMDAM) was necessary for a successful transformation. In batch, decomposition of B2(pin)2 was observed and the researchers hypothesized that the desired reaction could outpace this side reaction under flow conditions. A flow setup using a FEP coil reactor irradiated by a mercury lamp led not only to a significantly reduced reaction time (15 min instead of 4 h) but also to a reduction of the amount of B2(pin)2 (1.5 instead of 2 equiv). With the optimized conditions in hand, the authors examined the scope and limitation of their photochemical process. In general, good-to-excellent yields were obtained using aryl iodides and bromides. Moreover, the authors showed that diboronic acid can be used to prepare aryl boronic acids, which could be subsequently transformed into the corresponding potassium aryltrifluoroborates using KHF2. Lebel and co-workers developed an iron-catalyzed photochemical amination of sulfides and sulfoxides (Scheme 142).676

liquid−liquid biphasic system consisted of an organic feed containing the respective starting material in DCM and two aqueous feeds for delivering oxone and NaBr/NaN3. Upon mixing of NaN3/NaBr with the oxidizing agent, the highly explosive intermediate (BrN3) was formed. The water sensitive compound was directly extracted with DCM or ethyl acetate in the slug flow regime and reacted with various alkenes. Since the nonphotochemical ionic addition was slow, a continuous photoreactor was installed to access the more efficient radical addition pathway. FEP tubing was wrapped around a compact fluorescent lamp (max 365 nm), and a BPR (7 bar) was installed to properly control the residence time. Under optimized conditions, the researchers synthesized nine different 1,2-bromine azide adducts within a residence time of 10 min in good-to-excellent yields without chromatography. The high purity profile allowed the authors to use the crude reaction mixture for several follow-up reactions in batch such as the formation of aziridines, azirines, and indoles. Fagnoni and co-workers used a coil-based photoreactor for the continuous arylation of π nucleophiles with aryl halides (Scheme 140).674 Upon irradiation with a medium pressure Hg

Scheme 142. Iron-Catalyzed Photochemical Amination of Sulfides and Sulfoxides in Flow

The authors suggested that Fe(acac)3 is activated by UV light (365 nm) and reacts with trichloroethoxysulfonyl azide (TcesN3) forming an Fe nitrene or nitrenoid species, which subsequently induces amination. In their continuous setup, the reaction mixture was introduced via a sample loop and irradiated at 365 nm in a coil reactor made out of PFA. No active cooling was used since the reaction worked equally well at a higher temperature (40 °C). Since stoichiometric nitrogen is formed, a backpressure regulator was used to control the residence time. Under optimized conditions, 10 mol % of the iron catalyst and 1.5 equiv of the azide were used. Good-toexcellent yields were observed with residence times of 50−90 min. Moreover, the authors showed that their methodology is stereospecific, and the enantiomeric ratio of the sulfoxide starting materials was retained. 8.1.2. Singlet Oxygen-Mediated Reactions. Flow conditions which combine both gas−liquid and photochemical reactions are clearly appealing, making the chemistry of singlet oxygen (1O2) particularly attractive. This highly energetic, short-lived oxygen species is generated by irradiation of a suitable photosensitizer in the presence of O2 and can be used for ene reactions, cycloadditions, or oxidations.677 The most common sensitizers for 1O2 generation are methylene blue (MB), rose bengal (RB), porphyrins such as tetraphenylprophyrin (TPP), and 9,10-dicyanoanthracene (DCA) which, from

Scheme 140. Continuous Arylation of Aryl Halides under Photochemical Conditions

lamp, heterolytic cleavage of an Ar-X bond yielded a triplet phenyl cation, which could be subsequently trapped with mesitylene, resulting in the desired biphenyl motif. The batch protocol suffered from long reaction times (up to 45 h), which was dramatically reduced in the flow system with residence times of 75−300 min. The scope was expanded by using other π nucleophiles such as allyltrimethylsilane, ethyl vinyl ether, pentenoic acid, and 1-hexyne. Li and co-workers reported the photochemical borylation of aryl halides under continuous flow conditions (Scheme 141).675 During an initial screening in batch using 4-iodoanisole and bis(pinacolato)diboron, the authors realized that a MeCN/ H2O/acetone solvent mixture in combination with 50 mol % 11862


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demonstrated by using simulated moving bed chromatography and continuous crystallization.172 The optimized continuous system enabled the isolation of the target compound in 62% with a purity of 99.9%. We expanded our flow protocol for the synthesis of all active pharmaceutical ingredients for ACTs following a modular approach, which also included inline purification via continuous filtration, multicolumn chromatography, and crystallization.270 Amara et al. developed a more sustainable alternative to the aforementioned approach using liquid CO2 and a dual-function heterogeneous catalyst (Scheme 145).681 The catalyst was

a practical point of view, mainly differ in their solubility and absorption spectra in the visible region of light. The vast majority of examples were performed in similar gas−liquid photochemical reactors (Scheme 143).677 In Scheme 143. General Continuous Flow Setup for the Generation and Utilization of Singlet Oxygen

Scheme 145. Continuous Synthesis of Artemisinin Using a Dual-Function Heterogeneous Catalyst. Catalyst is reprinted with permission from ref 681. Copyright 2015 Nature Publishing Group

general, a solution of the substrate and catalytic amounts of the photosensitizer are mixed with O2 whose rate of addition is controlled via a MFC. The gas−liquid mixture subsequently enters a coil or chip-based reactor unit that is irradiated by a light source. The reaction is further enhanced by installing a back pressure regulator to increase the amount of the gaseous reagent in the liquid phase while simultaneously enabling a better control of the residence time. The above-mentioned sensitizers can also be immobilized on either the channel wall of a reactor or on dedicated supports.677 The synthesis of artemisinin in continuous flow is an illustrative example,678,679 since artemisinin combination therapies (ACTs) are the recommended first-line treatment for malaria.680 Currently, artemisinin 23 is extracted from Artemisia annua, which also contains significant amounts of the biological precursors dihydroartemisinic acid 22 and artemisinic acid 21. While the total synthesis of artemisinin is too laborious, its semisynthesis from 22 can be rapidly achieved through photooxidation. Moreover, 21 can be transformed into 22 via a selective reduction.219 When DHAA reacts with 1O2, it forms an allylic hydroperoxide, which undergoes Hock cleavage in the presence of acid. Oxidation by 3O2 triggers a condensation cascade, eventually yielding the desired compound 23. Our laboratory optimized the entire reaction sequence resulting in a single, fully continuous process using a sequence of coil reactors (Scheme 144).25 In the final process, a solution

prepared by noncovalently anchoring meso-tetraphenylporphyrin to an Amberlyst-15 via protonation of the porphyrin core. The resulting material not only generates singlet oxygen but also catalyzes the Brønsted-acid mediated Hock cleavage. In the final continuous protocol, O2 was mixed with CO2 using a modified 6-way-valve and combined with a solution of 22 in toluene at a system pressure of 180 bar. The reaction mixture was fed into the packed bed reactor made out of sapphire containing the solid dual-catalyst. The reactor unit was cooled to 5 °C, and irradiation was carried out using an array of LEDs emitting light in the visible region. A residence time of 20 min was sufficient to quantitatively convert 22 in a single pass, resulting in 48% of 23 as determined by NMR. In addition, a second continuous strategy utilizing [Ru(bpy)3]Cl2 and TFA in an aqueous solvent mixture of THF/H2O produced artemisinin 23 inasmuch as 66% yield. Singlet oxygen is also useful for the oxidation of amines to the corresponding imines.682 The condensation of the unreacted amine with the primary aldimine, however, is a main drawback of the original procedure. Our group developed a continuous procedure for the formation of primary aldimines which can subsequently undergo oxidative cyanation to provide valuable α-aminonitriles (Scheme 146a).157 A flow reactor cooled to −50 °C suppressed the nucleophilic addition, thus enabling a quantitative photooxidation. In our final protocol, a solution of the substrate, TPP, TMSCN, and substoichiometric amounts of TBAF were mixed with O2 and pumped through the cooled photoreactor (420 nm LEDs). The resulting αaminonitriles were utilized for the synthesis of fluorinated αamino acids524 and hydantoins.209 Moreover, a similar flow

Scheme 144. Continuous Synthesis of Artemisinin from Dihydroartemisinin Acid Using 1O2

of DHAA 22, 9,10-anthracenedicarbonitrile (DCA), and TFA in toluene was mixed with O2 and fed into an irradiated coil reactor which was cooled to −20 °C. Then, the mixture was slowly warmed in two consecutive coil reactors to accomplish the nonphotochemical steps, resulting in 57% of the final antimalaria drug 23 after isolation. A continuous isolation of artemisinin from the crude reaction mixture was also 11863


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Scheme 146. Photooxidation of Amines using 1O2 in (a) Synthesis of α-Aminonitriles by a Low-Temperature Flow Approach and (b) Direct Utilization of Imines in a Consecutive Mannich Reaction/Epoxidation

approach was used for studying the regioselectivity of the photooxidation of unsymmetrical secondary amines.683 During the photooxidative imine generation, stoichiometric amounts of H2O2 are generated, which potentially limits the possibility of directly using the resulting imine for downstream processes. We developed a consecutive process to utilize the H2O2 byproduct. The newly generated imine was reacted with a nucleophile such as methyl cyanoacetate in a deaminative Mannich coupling forming an olefin, which reacted with H2O2 forming the corresponding epoxide in good yields. (Scheme 146b).684 8.1.3. Photoredox Catalysis. Over the past decade, radical chemistry, in particular photoredox catalysis, has emerged as a valuable tool for synthetic organic chemistry and is a highly active research area.104,685,686 In general, a photoredox catalyst (PRC) absorbs light promoting an electron to an excited state (PRC*, Figure 30). This species can undergo a single-electron

Figure 31. Photoredox catalysts used in continuous flow experiments discussed in this section.

A significant enhancement was identified for the visible lightmediated decarboxylative Michael addition of a threonine derivative 338 with methyl acrylate 339, in the formal synthesis of L-ossamine (Scheme 147).688 In the optimized batch Scheme 147. Visible Light Decarboxylative Michael Addition Using an Iridium-Based Photoredox Catalyst under Flow Conditions

procedure, a mixture of 338, methyl acrylate 339, [Ir[dF(CF3)ppy]2(dtbpy)][PF6] 332, and Cs2CO3 in DMF was irradiated for 45 h with two 6.5 W LED bulbs producing 340 in 70% yield (d.r. 65:35). A different solvent system (DMF/H2O 10:1) resulted in a homogeneous solution, albeit significantly lower isolated yields (50%). When the same reaction mixture was passed through a transparent chip reactor illuminated with a 48 W LED bulb, the isolated yield increased to 80% (d.r. 62:38) at a residence time of just 4 h. In order to avoid the use of photoredox catalysts based on rare noble metal such as Ru and Ir, researchers from Merck in collaboration with the group of Nicewicz prepared a set of acridinium-based PRCs. The most promising candidate 336 was applied to the decarboxylative conjugate addition of Cbzproline 341 to dimethyl maleate 342 under continuous flow conditions (Scheme 148).689 During the course of the reaction more than 50% of the catalyst decomposed by HPLC. This serves as an example showcasing that replacement of expensive Ir and Ru bipyridyl complexes by organic dyes is generally possible, but further catalyst modifications must be carried out to reduce catalyst degradation over time.

Figure 30. Quenching cycles in photoredox catalysis.

transfer (SET) with either an electron donor (D) or acceptor (A), in a quenching cycle. Overall oxidative, reductive, and redox neutral reaction are possible depending on the substrates and conditions. The catalytically active species are most often ruthenium or iridium polypyridyl complexes,104,685,686 but also organic catalysts687 have been applied. The photoredox catalysts used in the continuous flow examples discussed in this section are depicted in Figure 31. 11864


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Scheme 148. Visible Light Decarboxylative Michael Addition Using an Acridinium Photoredox Catalyst under Flow Conditions

Scheme 150. Dual Catalytic Cross-Coupling in Flow for the Synthesis of Cycloalkyl-Substituted 7-Azaindoles

Several groups developed methodologies in which a PRC was used to activate substrates for use by another catalyst in a dualcatalytic process. Dual-catalytic processes involve the combination of photoredox chemistries with Lewis acid-, organo-, transition metal-, Brønsted acid/base-, as well as electro- and biocatalysis.690−692 Among those, the combination of photoredox and nickel catalysis, which was pioneered by the groups of MacMillan and Molander, has resulted in a number possibilities for the construction of carbon−carbon bonds.691−693 Adapting a reaction from Tellis et al.,694 Ley and colleagues, developed a continuous protocol for the C(sp2)-C(sp3) coupling of boronic esters with aryl bromides (Scheme 149a).695 The authors obtained the coupling products within 2

dioxane solvent system avoided clogging issues. Moderate-togood isolated yields were obtained within 40 min for a broad range of cycloalkyl-substituted 7-azaindoles. Moreover, the same group expanded the scope of their reaction system for the synthesis of a small library of alkyl-substituted quinazolines.697 Dual catalysis for the decarboxylative coupling of readily available carboxylic acids with aryl halides was originally reported in 2014.698 Due to the high potential of this transformation for replacing thermal catalytic cross-coupling reactions, Abdiaj and Alcázar developed homogeneous conditions for translating the light-mediated coupling protocol to continuous flow (Scheme 151).699 Cesium carbonate was Scheme 151. Dual Photoredox Nickel Catalysis for Continuous Decarboxylative Coupling Reactions

3

Scheme 149. Continuous C(sp )-C(sp ) Couplings Using (a) Dual Photoredox Nickel Catalysis of Boronic Esters with Aryl Bromides and (b) Photoredox Catalysis for the Coupling of Electron-Deficient Cyanoarenes and Organoboron Compounds

replaced by DBU. Moreover, [Ir(dtbbpy) (ppy)2][PF6] 333 showed better results than the original photoredox catalyst 332. With this homogeneous reaction system, the authors moved to flow using a two feed approach and a coil reactor which was irradiated with a 450 nm light source. Interestingly, slightly elevated temperatures (40−60 °C) proved to be ideal for the continuous coupling procedure using residence times of 20−40 min (vs 72 h in batch). The utilization of gaseous reagents in photoredox processes has also been used with continuous processing techniques. Oxygen, for instance, is an electron acceptor, generating superoxide (O2•−) which can be used as a reactant. Noël and co-workers utilized the reactive species to oxidize thiols to disulfides in flow (Scheme 152a).700−704 Eosin Y 337 gave significantly better results compared to common Ru and Ir complexes in an initial batch screening.700 Substoichiometric quantities of tetramethylethylenediamine (TMEDA) significantly increased the reaction rate using EtOH as a sustainable reaction medium. The rate of the biphasic batch reaction was strongly influenced by the stirring speed. Therefore, the researchers argued that the oxidation could be significantly enhanced in flow by taking advantage of the increased mixing/ interfacial area and the highly efficient irradiation achieved in thin tubing. In fact, MFC-controlled O 2 addition, in combination with an illuminated PFA coil reactor decreased the reaction time from 2 to 16 h (batch) to 20 min. Under optimized conditions, excellent isolated yields were obtained. Notably, the continuous protocol was utilized for a selective synthesis of oxytocin, a cyclic peptide hormone.

a residence time of 50 min in a coil reactor using 420 nm LEDs as the light source. Compared to the original protocol, the flow process allows for a significant reduction of the reaction time (24 h in batch). Electron-rich organoboron compounds gave good-to-excellent yields, whereas electron-poor derivatives did not work as well. In addition, the authors also evaluated an alternative protocol using electron-deficient cyanoarenes 345 instead of the organohalide 344 coupling partners (Scheme 149b).695 In the case of cyanoarenes, the use of an organometallic catalyst was not necessary as the reaction is photoredox neutral, where the organoboron compound is oxidized and the cyanoarene is reduced. Researchers from Vertex Pharmaceuticals reported a very similar dual catalytic cross-coupling for the synthesis of cycloalkyl substituted 7-azaindoles, which are utilized in a variety of drug discovery programs (Scheme 150).696 Several modifications to the original protocols were made to obtain homogeneous conditions necessary for translating this coupling procedure to flow. In this case, 2,6-lutidine and a DMA/ 11865


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higher activity compared to other PRCs such as Ru2+(bpy)3 and Ir3+(ppy)3. In the final flow approach, a solution of 335 and substrate in THF was pumped through a tube-in-tube gas loading unit and subsequently irradiated in a coil reactor at a back pressure of 8 bar. Within a 3.33 h residence time, a series of carbazoles were synthesized in good-to-excellent yields. Moreover, a numbering-up strategy was presented to improve the productivity to ∼1 g d−1. The incorporation of trifluoromethyl groups into organic compounds is an extremely active research area due to the importance of this structural motif for medicinal chemistry as well as crop and material sciences.710 Among the plethora of reagents which can be used as CF3 sources, CF3I is particularly interesting due to its high atom economy and relatively low cost. Noël and co-workers developed a series of strategies for utilizing this gaseous reagent in the continuous trifluoromethylation of thiols,711,712 heterocycles,713,714 and styrenes715 via photoredox catalysis. The latter is particularly interesting since it not only allows for trifluoromethylations (Scheme 154a) but

Scheme 152. Photocatalytic Aerobic Oxidation of Thiols to Disulfides Using (a) Homogeneous and (b) Heterogeneous Photoredox Catalysts

Scheme 154. Utilization of CF3I for the Continuous (a) Trifluoromethylation and (b) Hydrotrifluoromethylation of Styrenes Using Photoredox Catalysis One of the main challenges in photoredox catalysis is the replacement of homogeneous PRCs by heterogeneous catalysts such as semiconductors.705,706 This represents a highly interesting opportunity for potential large-scale applications, as the classical homogeneous PRCs are often very expensive, usually difficult to recycle, and necessitate additional purification steps. Therefore, the Noël group tested the applicability of TiO2 nanoparticles for the disulfide formation using a packed bed reactor (Scheme 152b).707 TiO2 has a relatively high energy band gap (3.2 eV for anatase) which requires UV irradiation. However, if amines, such as TMEDA, are present in the heterogeneous reaction mixture, surface interactions enable excitation by light in the visible region.705,706 Taking advantage of this phenomenon, the authors realized a continuous protocol utilizing a packed bed reactor of TiO2 nanoparticles and glass beads. With this setup, reaction times of 3−5 min proved sufficient for the triphasic transformation, whereas the batch reactions needed up to 8 h for full conversion. Importantly, the authors showed that during a 28 h experiment, the yield did not decrease, showcasing the high potential of the semiconducting material for heterogeneous photoredox catalysis. Additionally, the continuous formation of an unsymmetrical disulfide 348 was performed by using an excess of the less reactive thiol 347 (Scheme 152b). Building on their previous results,708 the Collins group developed a sustainable photocyclization system using [Fe(phen3)][(NTf2)2] 335 in combination with O2 (Scheme 153).709 The iron phenanthroline complex showed significantly

also can be modified by replacing the base with a suitable H atom donor to access hydrotrifluoromethylated compounds 349 (Scheme 154b).715 In both protocols, CF3I is controlled by an MFC and mixed with the liquid phase before irradiation with blue light in a coil reactor at room temperature. The desired compounds were obtained in good-to-excellent yield with 30− 90 min residence times. Moreover, the authors also showed that this catalytic system is applicable to other perfluoroalkyl halides. In another approach to incorporate fluorine into organic molecules using continuous photoredox catalysis, McTeague et al. reported the use of gaseous SF6 for deoxyfluorinations of allylic alcohols (Scheme 155).716 The reaction system was

Scheme 153. Photochemical Synthesis of Carbazoles Using Oxygen as Oxidant

Scheme 155. Continuous Deoxyfluorination of Allylic Alcohols Using SF6 by Continuous Photoredox Catalysis

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found that for the photocatalytic reduction of azides with hydrazine, their recycling strategy is applicable without a significant decrease in the catalytic activity over five process cycles (Scheme 157). Rackl et al. synthesized a polyisobutylene-tagged fac-Ir(ppy)3 complex [Ir(ppy)2(PIB-ppy)] which could be continuously recycled and reused with a thermomorphic solvent system (Scheme 158).719 The photoredox-catalyzed isomerization of

optimized in batch, resulting in a combination of [Ir(ppy)2(dtbbpy)][PF6] 333, DIPEA, and DCE for acceptable conversion and selectivity. The realization of a continuous version of their protocol was achieved by mixing the gaseous reagent with the liquid producing a slug flow regime. Prior to irradiation, a small residence time unit was installed for better mixing. Further, a system pressure of 6.9 bar was utilized to increase the solubility of the gaseous fluorine source. More recently, the same group developed a photoredox process for the activation of carbon dioxide in the αcarboxylation of amines (Scheme 156).717 The potential of

Scheme 158. Continuous Recycling of PolyisobutyleneTagged fac-Ir(ppy)3 Complex [Ir(ppy)2(PIB-ppy)] Using a Thermomorphic Solvent System

Scheme 156. Carboxylation of Amines with CO2 Using Continuous Photoredox Catalysis

CO2 (E0 = −2.21 V vs SCE) is too high for common PRCs which absorb visible light. A combination of para-terphenyl (E0 = −2.63 vs SCE) and UV irradiation was chosen to overcome this. A base screening revealed that potassium trifuoroacetate (CF3CO2K) provided the highest yield in DMF. Optimization using a two-feed gas−liquid photoflow setup resulted in a system pressure of 3.4 bar and a residence time of 10 min for the synthesis of a broad range of aromatic amino acid derivatives in moderate-to-excellent yields. The vast majority of photoredox protocols suffer from the utilization of expensive transition metal based PRCs which are normally not recycled. Therefore, the development of effective recovery strategies for these powerful catalysts is important. In order to tackle this problem, Kappe and co-workers immobilized a Ru polypyridyl complex on a G2-PAMAM dendrimer which enabled a recycling strategy via nanofiltration (Scheme 157).718 A liquid−liquid separator was equipped with

(E)-3-phenylallyl acetate 350 was chosen as a model reaction for their proof-of-concept study.720 In their setup, the substrate 350 and DIPEA were dissolved in heptane-saturated MeCN and mixed with a solution of the modified catalyst in heptane. The resulting biphasic mixture (slug flow pattern) was pumped through a photoreactor (455 nm) heated to 90 °C. At this temperature, the mixture becomes monophasic, thus setting the stage for an efficient photoredox reaction. After cooling, a biphasic mixture was collected in a receiving flask. The MeCN phase contained the product, whereas the heptane phase contained the catalyst which could be recycled. Constant E/Z ratios of 3-phenylallyl acetate were measured over the entire experiment, and loss of the Ir catalyst in the heptane phase was only observed at the beginning. NMR analysis revealed that only catalyst molecules with shorter PIB chains were lost into the MeCN phase due to their higher polarity. The development of cheap, readily available and recyclable catalysts is not the only obstacle for sustainable (continuous) photochemical processes. To date, the vast majority of processes rely on the utilization of artificial light sources such as LEDs rather than natural sunlight. While flow reactors for sunlight-mediated chemical transformations have been developed, solar concentrators are usually highly engineered reactor setups limited to areas with a high amount of solar irradiation.63 A novel reactor concept combines continuous microreactor technology with the concept of luminescent solar concentrators (LSCs).721 A “classical” LSC device is made by dispersing a luminophore in a waveguide which can be made out of polymeric materials or glass (Figure 32a).722 Light can penetrate the surface of the waveguide where it is absorbed by the luminophore. The re-emitted light is guided and concentrated by total internal reflection toward the edge of the device where a photovoltaic cell is attached. The researchers adapted this principle to continuous flow synthesis, by building a chip-based reactor made out of PDMS doped with the fluorescent dye Lumogen F red 305 (Figure 32b). This dye absorbs visible light from ∼400−600 nm and re-emits light at ∼600−700 nm, which perfectly overlaps with the absorption spectrum of methylene blue (MB), a common photosensitizer. They studied the singlet oxygen cycloaddition to 9,10-

Scheme 157. Nanofiltration Recycling Strategy for a Macromolecular Ru Photoredox Catalyst

a nanofiltration membrane instead of the usual hydrophobic material in order to separate the catalyst from the reaction material. While the catalytic material showed promising reactivity in several photoredox catalysis processes, continuous recycling was problematic. The catalytic material was retained on the membrane in certain solvents, and the dendritic material decomposed in the presence of acids. Nevertheless, the authors 11867


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possibility to reduce/remove supporting electrolytes.727 Nevertheless, continuous synthetic organic electrochemistry is still in its infancy.40,151 This section discusses recent developments in continuous electrochemical organic synthesis. The literature examples are divided into anodic and cathodic reactions. 8.2.1. Anodic Oxidation. The anodic oxidation of amides to N-acyl iminium ions and its subsequent reaction with nucleophiles (Shono oxidation) is among the most studied electrochemical reactions in organic synthesis.728 This operationally straightforward reaction forms a new carbon−carbon bond generating H2 as the only byproduct. Brown and Pletcher studied the methoxylation of Nformylpyrrolidines in continuous flow utilizing several undivided electrochemical flow devices (Scheme 159). In all cases, Scheme 159. Dehydrogenative Methoxylation of NFormylpyrrolidine in Flow

Figure 32. (a) Concept of luminescent solar concentrators (LSCs). (b) A LSC chip reactor fabricated from PDMS doped with the fluorescent dye Lumogen F red 305 for harvesting sunlight. Reprinted with permission from ref 721. Copyright 2017 John Wiley and Sons.

a carbon/polymer anode (C-Anode) and a stainless steel cathode (SS-Cathode) was utilized with different reactor geometries such as a rectangular device with a “snaking” microchannel729,730 and a round cell design with a starshaped116 or spiral107,731 channel pattern. In the latter case, the authors showed that by using a 0.2 M solution of 352 at high flow rate (16 mL min−1) and cell currents (12 A), 353 was produced in high yields (84%) within a residence time of 19 s (productivity of 20.7 g h−1). Pitting of the carbon-based anode was observed at cell currents above 10 A but had no effect on the performance of the reaction system. Nevertheless, this pitting issue is detrimental to long-term experiments, and therefore alternative anode materials or less aggressive conditions should be considered. Similarly, Ley and co-workers applied the continuous Shono oxidation methodology to access the natural product Nazlinine and related congeners (Scheme 160).732 The authors did not

diphenylanthracene using sunlight during a partly cloudy summer day; the researchers showed that this reactor is significantly more efficient than a nondoped version. Nevertheless, this promising concept has to be expanded to a broader range of wavelengths to access more powerful photocatalysts, in particular PRCs which usually absorb wavelengths below 500 nm. 8.2. Electrochemistry

In electrochemical processes, chemical reactions take place at the interface of an electrode and an ionic conductor (electrolyte). The setups are either undivided cells where the anodic oxidation and the cathodic reduction occur within the same compartment or divided cells where the oxidation and reduction chamber are physically separated by a semiporous membrane (section 3.4.4). Electrochemical methods are used on an industrial scale for the production of commodity chemicals such as the chloralkali process for the production Cl2 and caustic soda, the electrochemical production of elemental Al from aluminum oxide in the Hall-Héroult process, and the electrosynthesis of adiponitrile from acrylonitrile.723 Nevertheless, examples of electrochemistry in synthetic organic chemistry are extremely rare in the scientific literature, which is relatively surprising since instead of stoichiometric oxidants/ reductants, electric current is used as a traceless reagent.105,724−726 In a recent outlook on synthetic organic electrochemistry, it was argued that electrochemistry is feared by organic chemists due to sophisticated setups and a lack of “standard” instrumentation for preparative electrolysis.105 In other words, electrochemistry is not considered a standard technique in organic synthesis but more as the last option when other possibilities have failed. The availability of commercial flow electrochemistry devices may be able to address these issues, allowing for a straightforward and convenient access to organic electrochemistry.40,151 Electrochemical reactions in flow offer the

Scheme 160. Shono Oxidation of N-Protected Cyclic Amines in Flow

observe any conversion with a stainless steel or platinum-coated anode. A carbon anode, on the other hand, gave quantitative conversions and excellent selectivity (95%) at a current density of 49 mA cm−2 in the presence of Et4NBF4. The system proved completely stable during a 14 h experiment in which 10 mmol of the N-Boc pyrrolidine was successfully processed. The authors further showed that LiBF4 lowered selectivity (85%). Under optimized conditions, a small library of α-methoxylated N-protected cyclic amines was prepared in excellent isolated yields. The researchers further presented a subsequent PictetSpengler reaction between the electro-synthesized N-Boc αmethoxypyrrolidine and tryptamine derivatives yielding nazlinine and related congeners in a batch microwave reactor. 11868


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In the Kolbe electrolysis, a carboxylic acid undergoes electrochemical decarboxylation generating a carbon-centered radical which reacts with alkenes forming a new C−C bond.725 In 1991, Uneyama reported the generation of a CF3 radical from trifluoroacetic acid for trifluoromethylation reactions.733 On the basis of their previous experience with the continuous Kolbe electrolysis,734 Wirth and colleagues chose TFA due to the high economic potential as a CF3 source. The electrochemical reactor consisted of a cathode and anode made out of Pt foil with a FEP flow channel situated between (Scheme 161).735 The reaction of acrylates with TFA, forming the

Scheme 162. Anodic Coupling of Creosol with 1,2,4Trimethoxybenzene in Flow

acid, but this reaction suffered from a large amount of homocoupling. Methanol was used to reduce homocoupling; however, also had a negative impact on the overall yield. The in situ electrogeneration of ortho-benzoquinone 360 from catechol 359 in the reaction with thiophenols by a Michael-type addition resulted in unsymmetrical aromatic disulfides (Scheme 163).739 Initial experiments of this reaction

Scheme 161. Electrochemical Trifluoromethylation Reactions of Electron-Deficient Alkenes with TFA

Scheme 163. In Situ Generation of ortho-Benzoquinone for the Continuous Generation of Unsymmetrical Aromatic Disulfides

respective trifluoromethylated dimeric species, was chosen for initial investigations. Optimization of the reaction parameters resulted in a cell current of 50 mA and a residence time of 66 s. Notably, these results are comparable to those obtained using the original batch procedure (2 A, 16 h).733 Moreover, by changing the conditions to a lower cell current (10 mA) and a significantly longer residence time (10.5 min) a trifluoromethyl acetamidation was carried out, affording 354 from methyl methacrylate in 25% yield. The mechanism most likely proceeds via a nucleophilic attack of acetonitrile to a carbocation intermediate during the electrolytic process.736 By using a high excess of TFA in combination with a high cell current (200 mA), the bis(trifluoromethylated) product 355 of acrylamide was obtained in good isolated yield (67%). Similar results were obtained in all cases for the respective difluoromethylation reaction when difluoroacetic acid was used instead of TFA. Anodic oxidation processes are potential tools for C−C coupling reactions via the Shono oxidation of amides or the decarboxylative Kolbe electrolysis. Alternatively, Waldvogel and co-workers developed a regioselective, direct cross coupling of phenols and arenes.737 The reaction proceeds via anodic oxidation of an alcoholic solvent generating an alkoxy radical which subsequently abstracts a hydrogen atom from the phenol substrate to generate a reactive electrophilic radical intermediate. This species is trapped by an electron-rich arene affording the desired biphenyl motif 358. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was used to stabilize the anodically generated radical species. In flow, a boron-doped diamond (BDD) anode and a Ni cathode were used in an undivided cell continuous flow reactor (Scheme 162).738 A broad range of supporting electrolytes and solvent systems were tested for the anodic coupling of creosol 356 with 1,2,4-trimethoxybenzene 357. The most promising results were obtained with formic

using a batch electrolysis cell gave low yields (13%), as the oxidation potentials of both substrates are similar. When catechol was oxidized followed by addition of the thiophenol, just 32% of the desired coupling product was obtained due to decomposition of ortho-benzoquinone 360. The researchers designed a flow setup where a solution of 359 and NaClO4 in MeCN was oxidized on a graphite (G) anode for the desired electrochemical transformation. Upon leaving the electrolytic cell, a solution of the respective para-substituted thiophenol was fed into the flow system via a mixing unit. By optimizing the flow rates and cell currents, decomposition and overoxidation of 360 were minimized, yielding the respective sulfides in good-to-excellent yields. The oxidative esterification of aldehydes using NHCs proceeds via the formation of a Breslow intermediate 362, oxidation, and subsequent alcoholysis to regenerate the NHC.740 The crucial oxidation step is usually carried out with a stoichiometric oxidant; however, it can also be carried out via anodic oxidation (Scheme 164a), though with reactions times of 2−36 h required for full conversion.741 Green et al. hypothesized that this process could benefit from continuous processing to achieve a significantly more productive procedure (Scheme 164b).742 The respective aldehyde, thiazolium salt 361, and alcohol were dissolved in THF/DMSO and mixed with DBU in a T-mixer. The resulting reaction mixture was fed into an undivided cell reactor (carbon anode, stainless steel cathode) set to a cell current of 850 mA. Full conversion was achieved within a residence time of less than 13 s for a range of different aldehyde and alcohol combinations, affording the respective esters in moderate-to-excellent isolated yields. 11869


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achieved using a cell current of 20 mA. At 10 mA, a significantly lower conversion (54%) was obtained, whereas higher currents resulted in a drop in selectivity. The optimized conditions were applied on a set of 15 different primary and secondary alcohols, including benzylic, allylic, and aliphatic species. Most benzylic and allylic alcohols resulted in good-to-excellent isolated yields, whereas aliphatic alcohols were somewhat less reactive. Overoxidation was observed at longer residence times inhibiting further improvements to yield. Organic electrochemistry is not just a potentially useful tool for accessing sustainable alternatives for synthetic procedures but can be used to simulate the metabolism of drugs.745 In the liver, a drug can be oxidized by cytochrome P450 (CYP450) and the outcome of this hepatic oxidation is crucial for drug development processes. Stalder and Roth utilized a continuous flow electrolytic cell to mimic this oxidation process for five different commercially available drugs in order to produce 10− 100 mg of the respective metabolites for full characterization.746 The main electrochemical oxidation products for the anodic oxidation of diclofenac 363, primidone 366, albendazole 368, and chlorpromazine 370 in an undivided cell reactor were in good agreement with known metabolites (Scheme 166). The

Scheme 164. (a) Anodic Oxidation of a Breslow Intermediate Resulting in an Activated Acyl Species and Its Application for the Oxidative (b) Esterification and (c) Amidation of Aldehydes in Continuous Flow

Scheme 166. Continuous Anodic Oxidation of Drugs to Mimic Metabolic Oxidation Processes

Importantly, the productivity was high in all cases (1.5−4.3 g h−1), showing the potential of the electrochemical flow process. Moreover, attempts to reduce the amount of the thiazolium salt 361 indicated that the reaction can also be carried out catalytically. More recently, the scope of this synthetic strategy was expanded by the synthesis of amides in a similar process (Scheme 164c).743 A simple replacement of the alcohol by an amine was not feasible, presumably due to a competing imine formation. Therefore, the respective amines were added after the formation of the Breslow intermediate 362, and a heated chip reactor was installed after the electrochemical cell to enhance the reaction of the amine with the acyl thiazolium intermediate. Under optimized conditions, the desired amides were obtained in good-to-excellent yields with an overall residence time of less than 1 min. Stoichiometric co-oxidants such as NaOCl in the TEMPOmediated oxidation of alcohols can be substituted by anodic oxidation on preparative scales (Scheme 165).744 By using 30 mol % TEMPO and a mixture of tert-butanol and a carbonatebicarbonate buffer for the oxidation of cyclohexanol, a good balance between conversion (86%) and selectivity (99%) was Scheme 165. TEMPO-Mediated Electrochemical Oxidation of Alcohols in Flow

oxidation of tolbutamide 372 was carried out in a divided cell where a carbon anode and a platinum cathode were separated by a spectra/por membrane (Scheme 167). Interestingly, while the oxidation is governed by the most redox-active site, the resulting oxidation product has not been reported as a metabolite. Nevertheless, the authors concluded that flow electrosynthesis can complement biosynthetic methods due to 11870


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Scheme 167. Oxidation of Tolbutamide in a Divided Cell Reactor

Scheme 169. Deprotection of iNoc Protected Phenols in an Electrochemical Flow Reactor

its scalability, allowing for straightforward access to isolatable quantities of metabolic products for full characterization. 8.2.2. Cathodic Reduction. For the reduction of functional groups, chemists usually consider well-established methods using metal hydrides (LAH, NaBH4, and DIBAL), transition metal catalyzed hydrogenation/hydrogenolysis reactions, or single electron-reducing agents such as sodium. Electrochemistry offers a sustainable alternative via cathodic reduction which overcomes the economic and environmental implications associated with traditional procedures. Waldvogel and co-workers surveyed different methods for the dehalogenation of the spirocyclopropane-proline derivative 374, which is a key step in the synthetic route toward NS5A inhibitors.747,748 A Birch reduction gave 65% of the desired compound, though a significant amount of ring-opening side products were obtained. Further, hydrogenolysis with Pd/C (48% yield) also suffered from several side products and a tedious product purification. Therefore, the authors developed an electrochemical process via reduction on a leaded bronze (LB, CuSn7Pb15) cathode in an electrochemical batch reactor to afford the desired compound 375 in 93% isolated yield on a multigram scale. In order to make this process industrially applicable, the authors developed a divided flow electrolysis cell (Scheme 168).747 By

the case of iNoc protected amines, as the carbamate seems to be stable under their electrochemical conditions. The group of Atobe utilized a cathodic reduction process for generating a 2-pyrrolidone anion 377,750 which can be used as a reagent for follow up chemistries (Scheme 170).751,752 Their Scheme 170. Electrogeneration of a 2-Pyrrolidine Anion for (a) Trichloromethylation of Benzaldehyde and (b) Monoalkylation of Methyl Phenylacetate

Scheme 168. Anodic Dehalogenation of 374 in a Divided Cell Reactor

approach used a laminar flow regime in order to mimic a divided cell reactor. With this special feature, a solution containing 2-pyrrolidone 376 can be fed into the reactor near the “cathodic part” where the reductive generation of the base occurs. The separation of the two streams prevents the reactive anion from being reoxidized at the anode. By adding a mixture of benzaldehyde and chloroform immediately after the electrolytic cell, the researchers synthesized 2,2,2-trichloro-1phenylethanol 378 in good yields within less than 15 s (Scheme 170a).752 In this transformation, the 2-pyrrolidone anion 377 deprotonates CHCl3, generating a trichlorocarbanion which ultimately reacts with the aldehyde. The authors showed that the reaction gives a significantly lower yield (20%) when no laminar flow was created. Moreover, no reaction occurred if benzaldehyde and chloroform are present during the initial electrochemical step. The same concept was applied to the monoalkylation of methyl phenylacetate 379 with MeI (Scheme 170b).751 The reaction was highly selective in flow at room temperature, whereas the same experiment in a divided cell batch reactor required cooling to −70 °C for high selectivity.

optimizing the flow rate, applied electricity and current density, the authors were able to obtain 375 in good isolated yield (70%) in a scalable continuous procedure. Moreover, a simple offline procedure for electrolyte and solvent recycling was presented to improve the sustainability of the dehalogenation process. An undivided cell reactor was utilized by Wirth and Arai for the continuous electrochemical deprotection of isonicotinyloxycarbonyl (iNoc) protected phenols.749 A mixture of the protected substrate and tetrabutylammonium iodide (TBAI) in DMF/water was pumped through an electrochemical flow reactor consisting of a cathode and anode made out of platinum (Scheme 169). Under optimized conditions, 43−61% of the respective unprotected phenol derivatives were obtained within 92 s. A comparison reaction carried out in batch gave slightly lower yield, but a reaction time of 6.5 h was required for full conversion. When the authors tried to apply their methodology on iNoc protected thiols, the respective disulfides were obtained instead. Unfortunately, no deprotection occurred in 11871


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Table 9. Recent Publications for the Automated Optimization of Reactions in Flow Reactors entry

reaction

1

CdSe nanoparticle synthesis761

2

Knoevenagel condensation, benzyl alcohol oxidation762 Diels−Alder763

3

6

Heck reaction764 alcohol etherification in sCO2624,765−767 Paal-Knorr reaction768

7

nucleophilic aromatic substitution769

8

phenylisocyanate with t-butanol770

9 10

Petasis-Ugi reactions771 monoalkylation of an amine759

4 5

11 12

772

13

imine formation nitrile hydrolysis to an amide, Appel reaction773 Heck-Matsuda reaction774

14

aminocarbonylation775

15

amidation

776

16

Suzuki-Miyaura cross-coupling760

17

amidation777

18

linear chain growth free radical polymerization778

19

Pd-catalyzed aziridination779

parameters

analysis

temperature, residence time, and stoichiometry temperature, residence time, and concentration temperature, residence time, and concentration residence time and stoichiometry temperature, pressure, sCO2 flow rate, and stoichiometry temperature and residence time

fluorescence

temperature, residence time, concentration, and stoichiometry temperature, residence time, and concentration temperature and residence time temperature, residence time, stoichiometry, and solvent residence time and volume fraction temperature, residence time, concentration, and stoichiometry temperature, residence time, stoichiometry, and catalyst loading temperature, residence time, stoichiometry, and pressure temperature, residence time, and stoichiometry temperature, residence time, catalyst loading, catalyst, and ligand temperature, residence time, and stoichiometry temperature, residence time, concentration

HPLC

temperature, residence time, and stoichiometry

As discussed in this section, flow chemical techniques, in combination with “traceless” reagents such as photons and electrons, are highly appealing from a sustainable standpoint, and due to the benefits of flow reactors, these protocols are generally more efficient and easier to scale compared to batch. While photochemical reactions are already routinely carried out under continuous flow conditions, electrochemistry in flow is still in its infancy, which can be attributed to the fact that electrochemistry is generally feared by organic chemists. Due to the availability of commercial flow electrochemistry devices, this uneasiness toward electrochemistry may change in the future, resulting in the discovery of new exciting chemical transformations and pathways.

notes

HPLC

yield, throughput, and selectivity were optimized

HPLC

kinetic information was used for a 500-fold scale-up.

HPLC GC and IR

50-fold scale up

IR

incorporation of an Armijo-type line-search algorithm increased efficiency

IR UPLC LC−MS

time-varying experiments reduce the amount of material used droplet screening system which permitted automated solvent screening

NMR MS and IR GC-MS

optimized for maximum yield, highest throughput, and lowest production cost

GC and IR HPLC HPLC

droplet screening system enabling discrete variable screening

MS UV/vis, viscometer, MALS UV and GC

reactions utilizing feedback optimization have been summarized (Table 9).25,120,124,125,756−758 In general, these setups are comprised of a reagent delivery system, a temperaturecontrolled reactor, an inline or online analysis device, and a computer (Figure 33). A LabVIEW program controls the delivery system, usually syringe pumps or HPLC pumps, and by varying the flow rates of the respective reagent or solvent feeds, it controls the time, stoichiometry, and concentration of the reaction. The temperature, and in some cases pressure (Table

9. FEEDBACK OPTIMIZATION High-throughput experimentation (HTE) has led to the rapid, cost-effective identification of optimal conditions for new transformations.33,119,753 This method facilitates the swift screening of discrete variables such as solvent, reagents, catalysts, and ligands. It is, however, less effective at scanning continuous variables like temperature, reaction time, and concentration. Automated continuous flow, on the other hand, can easily vary continuous parameters such as temperature, reaction time, stoichiometry, and concentration but struggles with changing discrete variables. Recently, feedback algorithms and real-time reaction optimization methods have been realized due to the establishment of online and inline flow analysis.754,755 This area has been reviewed recently, and those

Figure 33. Main components of an automated optimization system. 11872


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9, entries 5 and 14), are also controlled by LabVIEW. Upon exiting the reactor, the reaction flows through an inline analysis device or is automatically sampled for online analysis. Data from this analysis is often exported to Microsoft Excel and analyzed using MATLAB. A number of mathematical optimization methods exist for maximizing properties such as percent conversion, product yield, productivity, and selectivity. With this algorithm, new reaction parameters are identified and employed in the next experiment. Since flow setups struggle to efficiently scan discrete variables, the majority of the examples to date only optimize continuous parameters. This is in part due to the setup where the delivery of stock solutions is invariable. That is, stock solutions are usually delivered by a single syringe or static lines for each input stream. By this setup, syringes must be manually changed or reagent lines manually transferred to other stock solutions. Entries 10 and 16, on the other hand, varied discrete parameters with a droplet-based reaction design using a liquid handler.759,760 These two examples are particularly promising for the rapid self-optimization of discrete and continuous variables for a given transformation. Reizman et al. utilized the droplet-based system for the optimization of the temperature, residence time, stoichiometry, and solvent for the monoalkylation of 1,2-diaminocylochexane 382 with 4-methoxylbenzyl chloride.759 Their setup, in contrast to other reports, utilized a liquid handler for the injection of samples into the system (Scheme 171). This permitted the

Scheme 172. Setup for the Automated Optimization of Suzuki-Miyaura Cross-Couplings with Precatalyst and Ligand Screening

formation. Refractive index sensors were used to time the addition of a solution of DBU in THF to the droplet. The reaction was quenched with a 1:1 solution of acetone/water after exiting the reactor. Online HPLC analysis was performed, and the data was used to optimize turnover number and yield for various heteroaryl substrates. Additionally, investigations using this system revealed information about the ligands and the mechanism. Between 0.2 and 0.8 equiv of ligand were ideal, and the yield decreased significantly with 2.0 equiv. The optimal conditions for classes of ligands showed trialkyl/ triarylphosphine ligands worked best at high temperatures with short residence times, whereas dialkylbiarylphosphine ligands were best at lower temperatures and longer residence times. These two examples highlight how automated feedback optimization in flow is a promising alternative to highthroughput experimentation. It permits the intelligent design of subsequent reactions, saving time and materials. In addition to reaction optimization, screening discrete variables can simultaneously offer insight into reaction mechanisms which can aid in scale-up or the design of new reactions.

Scheme 171. Primary Components of the Microliter Slug Flow Self-Optimization System with Solvent Screening

10. CONCLUSIONS Continuous flow has made immense progress and has been applied to a vast number of transformations over the past decade. Recently, the research community has focused on using the available technology to carry out reactions which underperform in batch. As such, flow chemistry is finding its niche in the laboratory. Biphasic reactions, especially gas−liquid reactions, are becoming more common in flow since mass-flow controllers enable the precise control over flow rates and equivalents. Extremely fast reactions, notably lithiations, have remained a prominent part of flow chemistry as subsecond mixing facilitates reactions that cannot be conducted in batch. Interestingly, high-temperature and -pressure flow reactions are becoming a complementary technique to microwave batch reactions that are poorly scalable. Meanwhile, photochemistry has seen a reemergence in the past decade, and the small dimensions of flow reactors have ushered in many reports of photoflow reactions. While electrochemistry remains underdeveloped by comparison, it still remains a promising field since the short path lengths allow for reactions to be run with no added electrolytes. Finally, self-optimizing systems are promising for expediting organic synthesis. Online and inline analytics enable feedback optimization, and useful kinetic and mechanistic details can be gleaned from the data. The question now is whether or not these processes can find their place in the organic chemists’ everyday toolbox.

formation of droplets of 4-methoxylbenzyl chloride in different solvents. Nitrogen carried the slugs through the tubing, and a refractive index sensor was used to detect slugs and guarantee accurate injection of 382 into the droplet. The droplets were reacted at 30−120 °C for 1−10 min. A continuous stream of acetic acid in acetonitrile was used as a quench, and a third refractive index sensor was used to time the sampling for analysis by HPLC. The pressure of the system was controlled with a nitrogen-regulated Parr bomb at 6.9 bar. Increasing the temperature too high led to overalkylation. Additionally, the authors were able to correlate H-bond-donating capacity of the solvent with the predicted reaction yield. Polar aprotic solvents like DMSO, DMF, and pyridine outperformed other solvents. After 93 slug experiments, the yield was optimized to 62%, with a residence time of 7.5 min, 78 °C, and 4-methoxylbenzyl chloride (1.00 M in DMSO). A scale-up using these optimized conditions afforded 383 in 59% (0.5 g) isolated yield. Using a nearly identical setup (Scheme 172), authors by the same group carried out an optimization for a Suzuki-Miyaura coupling.760 Samples of precatalyst, ligand, aryl halide, boronic acid or boronic pinacol ester, and an internal standard were prepared in THF and stored under argon prior to droplet 11873


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continuous flow. After receiving his Ph.D. in 2015, he joined the group of Professor Peter H. Seeberger for postdoctoral studies. His current research relates to heterogeneous photoredox catalysis using semiconducting materials in batch and flow systems.

11. DIAGRAM LEGEND

Dr. Kerry Gilmore was born in Brewster, Massachusetts in 1984. He received his Ph.D. in 2012 from Florida State University, during which time he was a Fulbright Scholar. He then moved to the Max-Planck Institute of Colloids and Interfaces for postdoctoral work, and in 2014, he was promoted to Group Leader of the Continuous Chemical Systems team. His current research interests stem from the controlled conditions achievable in flow and span mechanistic studies, photochemistry, and the development of novel approaches towards modular chemical synthesis. Prof. Peter H. Seeberger studied chemistry in Erlangen (Germany) and completed his Ph.D. in biochemistry in Boulder (CO). After postdoctoral work at the Sloan-Kettering Cancer Center in New York, he was Firmenich Associate Professor with tenure MIT (1998−2003). After six years as Professor at ETH Zurich, he assumed positions as Director at the Max-Planck Institute in Potsdam and Professor at the Free University Berlin. His research interests include the glycosciences as well as flow chemistry.

ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the MaxPlanck Society and the DAAD. REFERENCES (1) Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Microreactors as Tools for Synthetic ChemistsThe Chemists’ Round-Bottomed Flask of the 21st Century? Chem. - Eur. J. 2006, 12, 8434−8442. (2) Jas, G.; Kirschning, A. Continuous Flow Techniques in Organic Synthesis. Chem. - Eur. J. 2003, 9, 5708−5723. (3) Fredrickson, C. K.; Fan, Z. H. Macro-to-Micro Interfaces for Microfluidic Devices. Lab Chip 2004, 4, 526−533. (4) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Chemistry in Microstructured Reactors. Angew. Chem., Int. Ed. 2004, 43, 406−446. (5) Hessel, V.; Löwe, H.; Schönfeld, F. MicromixersA Review on Passive and Active Mixing Principles. Chem. Eng. Sci. 2005, 60, 2479− 2501. (6) Günther, A.; Jensen, K. F. Multiphase Microfluidics: from Flow Characteristics to Chemical and Materials Synthesis. Lab Chip 2006, 6, 1487−1503. (7) Song, H.; Chen, D. L.; Ismagilov, R. F. Reactions in Droplets in Microfluidic Channels. Angew. Chem., Int. Ed. 2006, 45, 7336−7356. (8) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Greener Approaches to Organic Synthesis Using Microreactor Technology. Chem. Rev. 2007, 107, 2300−2318. (9) Glasnov, T. N.; Kappe, C. O. Microwave-Assisted Synthesis under Continuous-Flow Conditions. Macromol. Rapid Commun. 2007, 28, 395−410. (10) Kockmann, N.; Roberge, D. M. Harsh Reaction Conditions in Continuous-Flow Microreactors for Pharmaceutical Production. Chem. Eng. Technol. 2009, 32, 1682−1694. (11) Hessel, V. Novel Process Windows − Gate to Maximizing Process Intensification via Flow Chemistry. Chem. Eng. Technol. 2009, 32, 1655−1681. (12) Kashid, M. N.; Kiwi-Minsker, L. Microstructured Reactors for Multiphase Reactions: State of the Art. Ind. Eng. Chem. Res. 2009, 48, 6465−6485. (13) Hartman, R. L.; Jensen, K. F. Microchemical Systems for Continuous-Flow Synthesis. Lab Chip 2009, 9, 2495−2507. (14) Webb, D.; Jamison, T. F. Continuous Flow Multi-Step Organic Synthesis. Chem. Sci. 2010, 1, 675−680. (15) Frost, C. G.; Mutton, L. Heterogeneous Catalytic Synthesis Using Microreactor Technology. Green Chem. 2010, 12, 1687−1703.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Kerry Gilmore: 0000-0001-9897-6017 Peter H. Seeberger: 0000-0003-3394-8466 Author Contributions §

M.B.P. and B.P. contributed equally.

Notes ∥ The title of this review is a rewording of the comedy science fiction novel The Hitchhiker’s Guide to the Galaxy by Douglas Adams. Additionally, the first question in our batch versus flow diagram plays on the quote “Answer to the Ultimate Question of Life, the Universe, and Everything” from the same book. The authors declare no competing financial interest.

Biographies Matthew B. Plutschack studied chemistry at the University of Wisconsin-Madison with the guidance of Professor Howard E. Zimmerman. He received his master’s degree under the supervision of Prof. D. Tyler McQuade at Florida State University in the field of continuous flow. He is currently a Ph.D. candidate at the Freie Universität Berlin, conducting research at the Max Planck Institute of Colloids and Interfaces under the supervision of Professor Peter H. Seeberger. Bartholomäus Pieber studied chemistry at the University of Graz and the Graz University of Technology in Austria. He received his master’s degree under the supervision of Professor C. Oliver Kappe in the field of microwave-assisted organic synthesis. He proceeded with Ph.D. studies in the same group working on multiphasic reaction systems in 11874


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