Photochemical transformations accelerated in continuous-flow reactors: basic concepts and applications.

DOI: 10.1002/chem.201400283

Review

& Flow Chemistry

Photochemical Transformations Accelerated in Continuous-Flow Reactors: Basic Concepts and Applications Yuanhai Su,[a] Natan J. W. Straathof,[a] Volker Hessel,[a] and Timothy Nol*[a, b]

Chem. Eur. J. 2014, 20, 10562 – 10589

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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Review Abstract: Continuous-flow photochemistry is used increasingly by researchers in academia and industry to facilitate photochemical processes and their subsequent scale-up. However, without detailed knowledge concerning the engineering aspects of photochemistry, it can be quite challenging to develop a suitable photochemical microreactor for a given reaction. In this review, we provide an up-to-date overview of both technological and chemical aspects associated with photochemical processes in microreactors. Important design considerations, such as light sources, material se-

Introduction

of this energy source in the large -scale production of chemicals has been largely neglected for a variety of reasons:[6]

Photochemical transformations utilize photons to provide sufficient energy to overcome activation barriers. Light activation of organic molecules facilitates remarkable reaction pathways that are otherwise difficult to reach by thermochemical or electrochemical activation, giving rise to complex molecular structures.[1, 2] Consequently, synthetic routes can be significantly shortened making photochemistry popular in a variety of specialty applications, such as total synthesis and material science. Another reason for its popularity can be found in the fact that light can be considered as a traceless and “green” reagent. In the absence of any reaction, the starting material can often be recuperated since the molecule can return to its ground state by releasing the energy by radiative or nonradiative pathways. There can be two fundamental ways distinguished to realize the excitation of organic molecules; this includes direct and indirect excitations. Direct excitations can be realized through absorption of photons by an organic molecule. Limitations of this method arise from the photophysical aspects of organic molecules, that is, molecules should contain a chromophore that can absorb the light energy efficiently. Limited reactivity of certain compounds can be overcome by indirect excitation. Hereby, incident light is absorbed by a catalyst or sensitizer and the electrons or energy are subsequently transferred to or accepted from an acceptor molecule, which can undergo a chemical transformation.[3–5] In the past several decades, the study of photochemical processes mainly involved research towards new product formation, reaction kinetics, and mechanisms. Despite the apparent advantages of photochemical transformations, implementation [a] Dr. Y. Su, N. J. W. Straathof, Prof. Dr. V. Hessel, Prof. Dr. T. Nol Department of Chemical Engineering and Chemistry Micro Flow Chemistry and Process Technology Eindhoven University of Technology Den Dolech 2 (STW 1.48), 5600 MB Eindhoven (The Netherlands) E-mail: [email protected] Homepage: http://www.tue.nl/staff/T.Noel [b] Prof. Dr. T. Nol Department of Organic Chemistry Ghent University Krijgslaan 281 (S4), 9000 Gent (Belgium) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201400283. Chem. Eur. J. 2014, 20, 10562 – 10589

lection, and solvent constraints are discussed. In addition, a detailed description of photon and mass-transfer phenomena in microreactors is made and fundamental principles are deduced for making a judicious choice for a suitable photomicroreactor. The advantages of microreactor technology for photochemistry are described for UV and visible-light driven photochemical processes and are compared with their batch counterparts. In addition, different scale-up strategies and limitations of continuous-flow microreactors are discussed.

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1) Process complexity associated with photochemical processes leads to significant challenges for the proper reactor design and its modeling. If photons can be considered as reactants, one would be able to directly utilize the numerical models and the knowledge of thermochemical reactors for the design and development of photoreactors. However, the special characteristics of photons means that the performance of photoreactors obviously differs from those encountered in thermochemical reactors. In addition to the momentum, mass, and energy balances, one should also consider the selection of suitable light sources, the emission, transport, and absorption of photons, and the geometry and position of photoreactors in the final design of a photochemical reactor. Additional complexity is encountered when the concentration fields of radiation-absorbing species are not uniform in photoreactors.[7] 2) Compatibility aspects of the reactor with the light sources and solvents should be taken into consideration when designing an efficient photochemical process.[8] The use of transparent materials is crucial to fabricate suitable photoreactors. The reactor material should allow for efficient photon transport from the light source to the reaction medium. In addition, the geometries of photoreactors and reflectors needs to be optimized to increase the photon flux through the reactor and to reduce any light losses. Often, a cooling system has to be integrated to control the reaction temperature and avoid superheating of the light source that would lead to permanent damage of the entire photoreactor system. Further, the solvent should be compatible with the chosen light source and the reactor material.[9] While the solvent should be inert to prevent erosion of the reactor walls, it should neither be a strong light absorber, nor a quencher of the photochemical process. 3) The scale-up strategy is one of the major hurdles for the transfer of photochemical processes from laboratory to production scale.[10] Photochemical transformations are typically carried out in small batch reactors, for which the immersion-well photoreactors in conjunction with mercury-vapor discharge lamps are outstanding representatives in research laboratories. However, mixing efficiency, heat, and

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Review mass transport phenomena in large batch reactors can hardly maintain the same values as those encountered in small batch reactors. And, more importantly, the distribution of photons becomes more problematic with increasing reactor dimensions due to the attenuation effect of photon transport (Bouguer–Lambert–Beer law).[11] These limitations, which are inherently associated with photochemical transformations in batch reactors, might be overcome by utilizing microreactor technology. This branch of technology represents one of the most important areas in the process intensification concept.[12] Microreactor technology allows a high degree of control over photochemical transformations to be exerted due to its obvious advantages compared with conventional batch processing, for example, continuous-flow operation, large specific surface area, enhanced heat, and mass-transfer rates, reduced safety hazards and the ease of increasing throughput by numbering-up, etc.[13, 14] Furthermore, extremely small characteristic dimensions of microreactors ensure excellent light irradiation of the entire reaction medium and thus increased radiation homogeneity, resulting in higher reaction selectivity, shorter reaction times and lower catalyst loadings.[15] Microreactor technology shows a significant application potential for photochemical transformations and thus attracts a lot of attention from researchers both in academia and industry. In the past few years, there have been several reviews published elsewhere that detail the application of microreactor technology for photochemical syntheses.[15] So, yet another review on these aspects is not our main objective. In contrast, our aim is to provide both chemists and process engineers with useful information on when and how to use continuousflow microreactors for photochemical transformations. Hereto, we give an overview of the different design considerations that should be taken into account when designing a photochemical microreactor. This includes a discussion to make a judicious choice of a proper light source and reactor material, as well as a detailed description of the different transport phenomena, such as photon transport and mass transfer. Next, an up-to-date overview is given to demonstrate the applicability of microreactors for specific photochemical transformations. The use of mesoscale continuous-flow photoreactors will be included in this review for reasons of completeness. The results in continuous flow will be compared with the ones obtained in conventional batch reactors where possible. Furthermore, different scale-up strategies and the remaining limitations to enable photochemical transformations on a large process scale will be discussed.

Design Considerations Light sources Arc lamps and fluorescent lamps are two main types of artificial cold light sources for UV photochemical transformations (Table 1). The most-widely used UV light sources are commercially available mercury-discharge lamps, which consist of Chem. Eur. J. 2014, 20, 10562 – 10589

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Volker Hessel, born 1964, studied chemistry at Mainz University. Between 1994 and 2011, he was an employee of the Institut fr Mikrotechnik Mainz GmbH where he became Director R&D. In 2011, he was appointed as full professor for the chair of “Micro Flow Chemistry and Process Technology” at Eindhoven University of Technology, TU/e. Prof. Hessel received the AIChE award “Excellence in Process Development Research” in 2007. He received in 2010 the ERC Advanced Grant about “Novel Process Windows” and is Editorin-Chief of the journal “Green Processing and Synthesis”. Timothy Nol was born in Aalst (Belgium) in 1982. He obtained his M.Sc. degree (Industrial Chemical Engineering) in 2004. In 2009, he received his Ph.D at the University of Ghent with Professor Johan Van der Eycken (Department of Organic Chemistry). He then moved to Massachusetts Institute of Technology as a Fulbright Postdoctoral Fellow with Professor Stephen L. Buchwald, where he worked at the MIT-Novartis Center for Continuous Manufacturing. In 2012, he accepted a position as an Assistant Professor at Eindhoven University of Technology. In 2011, he received an Incentive Award for Young Researchers from the Comit de Gestion du Bulletin des Socits Chimiques Belges. In 2012, he received a prestigious Veni grant from the Dutch Government (NWO) and was nominated for the European Young Chemist Award in the same year. Since 2014, he serves as an Associate Editor of the Journal of Flow Chemistry. His research interests are focused on the combination of flow chemistry, organic synthetic chemistry and catalysis. Natan J. W. Straathof was born in the Den Haag (Netherlands), in 1984. He studied chemistry at the University of Leiden (Netherlands), where he obtained his M.Sc degree in 2011, under the supervision of Professor Hermen Overkleeft and Professor Gijs van der Marel, on the topic of bio-organic synthesis. Currently, he is pursuing a Ph.D. under the supervision of Dr. Timothy Nol and Professor Volker Hessel for his PhD degree at the Technical University of Eindhoven (Netherlands). His research interests focus on the applications of visible light photoredox catalysis in continuous microflow and the development of novel synthetic methodologies. Yuanhai Su was born in Guangxin Province (China), in 1983. He received B.E. from Tianjin University (July 2006) and a Ph.D degree from Dalian Institute of Chemical Physics (Chinese Academy of Sciences, September 2011, with the supervision of Prof. Guangwen Chen and Prof. Quan Yuan), both in chemical engineering. From May 2012 to October 2013, he was a fellow of the Alexander von Humboldt Foundation (Host Supervisor: Prof. Eugeny Kenig, Paderborn University, Germany). Currently, he is the recipient of the Marie Curie Actions fellowship (Host Supervisor: Assistant Professor Timothy Nol, Eindhoven University of Technology, The Netherlands). His research interests are in the areas of process intensification, microreactor technology and continuous-flow chemistry.

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Review Table 1. Most common light sources utilized for photochemical applications in microreactors. Light Source

Emission wavelength [l/nm]

Note

Low pressure Hg Arc Medium pressure Hg Arc High pressure Hg Arc Black light Lasers UV-LEDs

> 90 % emission at 254 nm, small fraction at 185 nm, mostly absorbed by glassware. prominent emission lines 313, 366, 405, 550 nm

10-fold intenser then low pressure Hg

continuum between 360–600 nm

expensive, short life time

360 nm discrete wavelengths 400 nm and down to 310–320 nm

Vis-LEDs

Variety of wavelengths between 400–700 nm

Sunlight

5 % UV, 43 % Vis, 52 % NIR

cheap high intensity Low-energy input, long lifetime, expensive, compatible with microreactors low-energy input, long lifetime, cheap, compatible with microreactors low and variable intensity, diffuse irradiation

vacuum glass tubes containing mercury vapor. Excitation of the vaporized Hg atoms and subsequent UV light emission are achieved through an electrical discharge. Compared to highpressure Hg lamps, the use of low and medium pressure Hg lamps is more preferred in photochemical processes due to their longer lifetime and more efficient input power. These light sources are usually located outside the microreactors.[16–18] In most cases, capillary microreactors are employed in combination with these UV lamps and are typically coiled around the lamps. The embedment of these light sources inside the microreactor is not easy due to the fact that the dimensions of the light sources are usually much larger than those of microreactors. Recently, light-emitting diodes (LEDs) have become more popular for application in continuous-flow photochemistry (Table 1). LEDs are semiconductors (PN junction) that emit light when switched on due to a recombination of the electrons with the holes. Depending on the energy band gap of the semiconductor, the wavelength can be tailored (from UV to Vis light). The emission spectrum of LEDs is very narrow (20 nm) and can be matched with the application. The latter is of importance to prevent significant byproduct formation or to match the emission with the absorption maximum of the photocatalyst or sensitizer. Another advantage of LEDs involves their small size providing a means to integrate the light source on the microreactor assembly.[17–19] Together with the low power input of these microscale light sources, their highenergy efficiency, small size and low cost make them ideal to combine with microreactors. Energy losses in LEDs are minimized and only a small amount of heat is generated. To keep the reactor at room temperature, air cooling is often sufficient to minimize reactor heating. Despite the small dimensions of LEDs, it is still difficult to integrate these into the interior of microreactors. Nanoscale light sources that can be directly integrated into the microreactors for photocatalysis have attracted the attention of researchers, although it remains to be verified whether these nanoscale light sources can provide enough energy for photochemical processes.[20]

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The use of solar energy as an infinite source of green and clean energy would be of high interest (Table 1). This energy source is often used for photochemical transformations in environmental processes, such as water treatment and air purification systems.[21] Some reports detail the development of thin-film (nanostructure film) absorbers utilizing continuousflow microreactors for solar cells, showing the importance of microreactor technology for solar energy utilization.[22] So far, there are no examples that combine microreactors and solar energy for photosynthetic transformations. This can be attributed to the low and transient intensity of solar irradiation, its diffuse nature (scattering by clouds, buildings, etc.), and the low amount of UV energy. Material and solvent constraints Microreactors can be fabricated in a wide range of materials, such as stainless steel, glass, polymers, ceramics, silicon, etc. Fabrication techniques mainly include micromachining, molding, lithography, injection molding, wet and dry etching, electrodischarge machining, laser machining, embossing, and so on. The advantages and disadvantages of these different materials and their fabrication techniques were summarized in relevant reviews.[23] For photochemical applications, it is evident that the most important criterion constitutes that at least one of the microreactor walls is transparent for the desired wavelengths. In addition, light scattering should be avoided through the reactor. This greatly limits the range of materials for microreactor fabrication. Different glass plates have been used to construct photochemical microreactors or microchannels. The glass acts as a solid filter and, depending on the choice, different wavelengths are accessible. Quartz has a wavelength cut-off below 170 nm and can, therefore, be used for both UV- and visiblelight photochemical applications. Other interesting glass microreactors are constructed out of Pyrex (> 275 nm), Corex (> 260 nm), and Vycor (> 220 nm). They can resist chemical erosion and provide a clear observation of photoreactions inside microreactors. However, deep and anisotropic etching or micromachining is almost impossible for these glass materials,

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Review and they lack compatibility with strong alkaline reaction mixtures at moderate to high reaction temperatures (erosion). A variety of polymer capillary materials, such as polymethylmethacrylate (PMMA), polydimethylsiloxane (PDMS), perfluoroalkoxyalkane (PFA), and fluorinated ethylene propylene (FEP), have the advantages of high light transmission, easy fabrication, and low cost. However, PMMA and PDMS materials are easy to swell when subjected to organic solvents. This limits their practical use for many photochemical applications. In contrast, PFA and FEP materials have high flexibility and can resist strong acidic and alkaline solvents at moderate temperatures and pressures, showing their high application potential in photochemical processes.[24] Besides their strong chemical stability, they demonstrate a higher resistance to microreactor clogging and low moisture absorbance.[25] In addition, these materials are highly transparent to both UV and visible light: PFA allows transmission of 91–96 % for visible light (400– 700 nm) and 77–91 % for UV light (250–400 nm); FEP has similar properties for visible light and a bit better for UV light. They can be used to fabricate mesoscale photochemical reactors (ID > 1 mm) and capillary microreactors (ID < 1 mm). Most often these reactors are wrapped around the lamps to maximize the photon flux. The proper selection of solvents is an important decision that should not be neglected. It is important that all reactants are soluble in the chosen solvent to ensure a reliable introduction into the microreactor. The presence of solids can complicate the continuous-flow process due to microreactor clogging and light scattering. In addition, it is crucial that solvents are transparent to the desired wavelength to minimize an additional attenuation effect. They should also avoid quenching of the photochemical process. Table 2 shows some important properties of the most common used solvents including their cut-off wavelengths and dielectric constants.[26] An important and widely used solvent for photochemical reactions is aceto-

Table 2. Most common solvents utilized for photochemical applications. Solvent

Cut-off wavelength [l/nm]

water acetonitrile n-hexane ethanol methanol cyclohexane diethyl ether 1,4-dioxane methylene chloride chloroform THF acetic acid ethyl acetate carbon tetrachloride DMF benzene toluene pyridine acetone

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185 190 195 204 205 215 215 230 230 245 245 250 255 265 277 280 285 305 330

Relative dielectric constant [er] 78.3 35.94 1.88 24.5 32.66 2.02 4.20 2.21 8.93 4.81 7.58 6.17 6.02 2.23 46.45 2.27 2.38 12.91 20.56

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nitrile. It allows a wide variety of substrates to be dissolved, does not absorb light with wavelengths above 200 nm, and is easy to separate from the products by simple evaporation. Another important solvent for organic synthetic applications constitutes acetone. Despite that this solvent absorbs wavelengths below 330 nm, it can be used as a sensitizer in photochemical processes.

Radiation Transport Phenomena In photochemical processes, reagents or catalysts will be activated by absorption of photons. Consequently, conversion and reaction rates are critically dependent on the efficiency of photon transport. Irradiation inhomogeneity and the corresponding variations in reaction conditions can reduce yield and selectivity. In this part, we will consider the different parameters that are of interest when designing an efficient photomicroreactor. The spectral specific intensity is usually used to represent the radiation distribution in reaction medium. Its physical meaning constitutes the amount of irradiative energy streaming through a unit area perpendicular to the direction of propagation (W), per unit wavelength and per unit time, which is defined as the following:[27]

Iðs; W; t; lÞ ¼

lim ð

dA;dW;dt;dl

dEl Þ dA cos qdWdtdl

ð1Þ

in which dEl is the total amount of irradiative energy passing through a surface in the time dt and within a wavelength range between l and l + dl. Based on the spectral specific intensity distribution, we can define the incident radiation (Gl), the local volumetric rate of energy absorption (LVRPA) and the radiation density flux vector (ql) as follows: Gl ðs; tÞ ¼

Z

Il;W ðs; tÞdW

ð2Þ

LVRPAl ðs; tÞ ¼ kl Gl ðs; tÞ

ð3Þ

W

ql ðs; tÞ ¼

Z

Il;W ðs; tÞWdW

ð4Þ

W

The LVRPA is an important parameter crucial for the optimal design of the photoreactor and depends on the lamp intensity, the geometry of the reactor, and photophysical properties of the reaction mixture. Due to the attenuation effect, the LVRPA is not uniform over the reactor. In microreactors, this nonuniformity can be minimized due to the small characteristic dimensions of the device. The illumination efficiencies, including the quantum yield (F) and the photonic efficiency (x), are calculated with regard to the formation of the target product (P):

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number of P molecules formed number of photons absorbed by reactive medium

ð5Þ


Review x¼

rate of the reaction photon flux

ð6Þ

in which the photon flux and the number of photons absorbed can be defined as follows: photon flux ¼

Gl l hc

Number of photons ¼

ð7Þ Gl lAt hc

ð8Þ

According to the literature, the quantum yield (F) in microreactors is much higher than those encountered in batch reactors. This can be attributed to the more homogeneous radiation distribution and the higher heat and mass-transfer rates encountered in microreactors due to the high surface-tovolume ratio.[28] The photonic efficiency (x) in microreactors (e.g. x = 0.0262) is about one order of magnitude higher than those in batch reactors (e.g. x = 0.0086–0.0042).[29] The photonic efficiency (x) in microreactors can be further improved if the compatibility between the dimensions of microreactors and light sources is ensured. In this case, most of irradiation from the light sources will be absorbed by the reaction medium and thus the reactant molecules can be transformed maximally. This can be realized through the use of microscale light sources (e.g. LEDs) or the optimization of light propagation with the help of optical fibers or mirrors as light reflectors.[30] The radiation transport is rather complex and is mainly dependent on the light source and the geometry of photoreactor. For monochromatic light, the radiation transport equation (RTE) can be described by:[27]

The first item on the left side of this equation is the variation rate of the spectral specific intensity with regard to the distance along the direction of radiation propagation. The second and third item, respectively, on the left side represent the light absorption and out-scattering of light in the reaction medium. The first and second item, respectively, on the right side represent the emission and in-scattering of light in the reaction medium. The emission in the reaction medium can be neglected when the photochemical reactions are carried out at low or medium temperatures. For single-phase (homogeneous) photochemical reactions, both in-scattering and out-scattering of light are absent and can therefore be neglected. If the radiation intensity is constant and the light propagation happens along a single direction, the radiation transport equation for homogeneous photochemical reactions can be simplified as follows:

dIl;W ðsÞ ¼ kl ðsÞIl;W ðsÞ ds Chem. Eur. J. 2014, 20, 10562 – 10589

ð10Þ www.chemeurj.org

This equation can be further transformed to describe the light absorbance (A) in a reaction medium: A ¼ log10 T ¼ log10

I0 ¼ ecl I

ð11Þ

This is the well-known Bouguer–Lambert–Beer equation, which shows that the absorption is dependent on the molar extinction coefficient (e), the concentration of the absorbing species (c), and the path length (l). The effects of characteristic dimensions of photoreactors on the light absorption can be easily illustrated for a given photocatalytic example using [Ru(bpy)3Cl2] (bpy = 2,2’-bipyridine) as a photocatalyst (Figure 1).[15a] [Ru(bpy)3Cl2], due to its high molar extinction coefficient, absorbs a significant amount of the incident light in the first few hundreds of micrometers. 50 % of the light irradiation is already absorbed within a distance of only 500 mm. This demonstrates that the small dimensions of microreactors and thus high surface-to-volume ratios of microreactors are crucial to achieve almost complete illumination homogeneity. In fact, some types of microreactors, such as interdigital micromixers with a channel characteristic size of about 25 mm, show great advantage on achieving illumination homogeneity for photochemical transformations.[31] Given the excellent photon flux through microreactors, it is evident that shorter reaction times are often required compared to large-scale vessels. In addition, similar productivities as in batch can be obtained in microreactors while utilizing much lower photocatalyst amounts. Furthermore, for simple reactor geometries with homogenous concentration profiles and simplified treatments of the light source (see Figure 2), the mean spectral specific intensity through the whole reactor can be calculated, as listed in Table 3.[32] Among the equations of mean spectral specific intensity for different kinds of reactors,

Figure 1. Absorbance of incident light as a function of distance in the reaction medium containing [Ru(bpy)3]2 + as a photocatalyst. The profile is obtained by utilizing the Bouguer–Lambert–Beer law: concentration c = 0.5 mm; molar extinction coefficient e[Ru(bpy)3]2 + = 13 000 cm1 m1; path length l; transmission T; spectral specific intensity in the reaction medium closed to reactor wall I0 ; spectral specific intensity after transmission I.

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Review

Figure 2. Simple reactor geometries with simplified treatments of light sources.

the equation for parallel plate reactors is the simplest and derived from elementary treatments of the Bouguer–Lambert– Beer equation. Table 3 shows that the characteristic dimensions of these reactors have a decisive influence on the mean spectral specific intensity. Smaller reactor dimensions result in higher mean spectral specific intensity. The advantage of microreactors in terms of photon transport on photochemical transformations can be demonstrated easily by these equations. On the basis of structure similarities, the equations for the mean spectral specific intensity in parallel plate reactors and annual reactors can be used to calculate the spectral specific intensity in falling film microreactors and capillary microreactors surrounding tube lamps, respectively. However, there is no experimental verification up to now. This is due to the relatively large photometers that cannot probe the spectral specific intensity inside microreactors. Loubiere et al. performed an intramolecular photocycloaddition in a conventional batch photoreactor and compared the results with those obtained in a continuous-flow photomicroreactor. The continuous-flow photomicroreactor consisted of FEP capillary tubing coiled around a commercially available Pyrex immersion well in which a medium pressure mercury lamp was inserted.[33] The comparison was achieved by coupling the reaction kinetics with the mass, momentum, and radiation transport equations. They identified two main criteria that were essential for designing and comparing various pho-

toreactors, that is, the power received in the system and the photonic efficiency. Keeping these two criteria constant in both photoreactors would lead to equivalent productivity. However, this comparison was made on the basis of oversimplified assumptions: 1) the batch photoreactor reaches perfect mixing behavior and 2) the photomicroreactor shows plug flow behavior. In addition, it was only valid for the case of an A!B reaction. The distribution of spectral specific intensity is more complex for multiphase reaction systems, such as gas–liquid and liquid–solid systems, in which the light-scattering phenomena should be involved in the radiation transport equation [Eq. (9)]. A full description of these phenomena is beyond the scope of this review and we direct the reader to the relevant references for more details concerning this topic.[34]

Mass transport phenomena To overcome mass transport limitations in photochemical transformations, several novel types of reactors, such as spinning-disc reactors, monolithic reactors, thin-film reactors, and microreactors have been developed.[35] Compared to spinningdisc reactors and monolithic reactors, microreactors can provide higher surface-to-volume ratios due to their smaller characteristic dimensions.[36] The mass-transport phenomena in microreactors can be represented by the characteristic mixing time and the overall volumetric mass-transfer coefficient with regard to single-phase or multiphase systems. Furthermore, one can judge whether it is justified to use microreactors to conduct a particular photochemical reaction and which type of microreactors should be selected based on the knowledge of mass-transport phenomena and reaction kinetics. For thermochemical transformations, the characteristic reaction time depends on the reaction rate constant and the reactant concentration. In contrast, the intrinsic reaction rate for photochemical transformations is strongly related to the local volumetric rate of energy absorption (LVRPA) and the quantum yield (F).[37] For example, in the case of a simplified reaction Scheme A!B, the reaction rate can be expressed as follows:[33] r ¼ l ðLVRPAÞl

ð12Þ

Table 3. Mean spectral specific intensity for different conventional reactor geometries and their microreactor equivalents.[32b] Reactor geometries

Light sources

Mean spectral specific intensity ½ Il

Available specific photochemical power [P]

Characteristic length

Microreactor equivalents

Parallel plate reactors Cylindrical reactors Cylindrical reactors

vertical light irradiation external radial irradiation parallel line light source

P m

½1 expðmlÞ

I0 l

L

P m

½1 expð2mlÞ

2I0 R

(

2f pR2

falling film microreactors with vertical light irradiation capillary microreactors with external radial irradiation capillary microreactors with parallel line light source

internal radial irradiation

P m

Annular reactors

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P m

1

1 2q1

Rq

) exp 2mRð1 g2 sin2 qÞ1=2 dq

2R arcsin

R R0

AR

q1 2I0 R1 R22 R21

f1 exp½mðR2 R1 Þg

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R2 R1

capillary microreactors surrounding tube lamps


Review The characteristic reaction time can subsequently be defined as a function of reaction rate (r) and initial reactant concentration (c0): tr ¼

c0 c0 ¼ r l ðLVRPAÞl

ð13Þ

Therefore, the characteristic reaction time is inversely proportional to both the local volumetric rate of energy absorption (LVRPA) and the quantum yield (F) in this reaction scheme. This again demonstrates the importance of achieving a homogeneous irradiation of the entire reaction medium.

Mixing time and criteria for single-phase reaction systems The characteristic times for macromixing, mesomixing, and micromixing in conventional reactors strongly depends on many influencing factors, such as kinematic viscosity, diffusivity, reactor volume, energy dissipation rate, rotational stirrer speed, etc.[38] Theoretical or semiempirical equations have been developed for the calculations of the time constants in conventional reactors. However, it is still unknown whether these equations can be directly applied to microreactors that have characteristic dimensions of less than 1 mm. For strictly laminar flow in microchannels, the mixing is only driven by molecular diffusion and the characteristic mixing time in microreactors can be calculated by the Einstein–Smoluchovski equation:

tm ¼

L2 D

ð14Þ

in which L is the diffusion path length and D is the molecular diffusivity. Figure 3 shows the characteristic length and time scales for mixing in microstructured devices and conventional devices.[39] Different categories of chemical reactions (fast and slow) are also shown. The reason why fast reactions can be carried out in microreactors is that diffusion distances are short and thus complete mixing can be achieved very fast.

Figure 3. Characteristic length and time scales for mixing in microstructured devices together with chemical reactions. Chem. Eur. J. 2014, 20, 10562 – 10589

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Kockmann et al. proposed a popular equation that can be used for various microreactors with special mixing units, such as interdigital micromixers, split- and recombine micromixers, static micromixers, caterpillar micromixers, packed-bed microchannels, and zigzag microchannels.[40] Hereby, the convection and chaotic advection are taken into account, which can further intensify the mixing efficiency: tm ¼

24:5L2 ðmRe3 Þ1=2 U

ð15Þ

The ratio of the characteristic mixing time to the characteristic reaction time is represented by the second Damkçhler number (DaII). This dimensionless number describes the relative importance of reaction and mass-transport effects: DaII ¼

tm tr

ð16Þ

To eliminate the effect of mixing on the reaction performance, DaII should be smaller than 1. If not, a concentration gradient of the compounds exists in the reaction medium that might result in the generation of an extensive amount of byproducts. Chemical transformations are reaction-rate limited when DaII < 1, mixed mass-transport–reaction rate limited when DaII 1, and mass-transport controlled when DaII > 1.[13e] This principle can be used for both thermochemical and photochemical transformations. The residence time should be larger than the characteristic reaction time, thus the components in the reaction medium must have enough time to react and reach full conversion. This can be expressed by the first Damkçhler number (DaI): DaI ¼

tp 1 tr

ð17Þ

In microreactors, the residence time can be easily varied by controlling the flow rates or the lengths of the microchannels. In general, a comparison between batch reactors and various microreactors in terms of the Damkçhler numbers should be made when choosing appropriate reactors for photochemical transformations. Oelgemoeller et al. investigated the DMBP-sensitized addition of isopropanol to furanones in a batch reactor and in three different microreactor systems, such as a micro dwell device (0.5 2 mm (D W)), a microchip (0.15 0.15 mm (D W)), and a capillary microreactor (0.56 mm ID).[16] It was observed that the continuous-flow microreactor systems provided higher or comparable chemical conversions than the batch reactor. The LED-driven microchip gave the best overall results with regards to conversion rate, reactor geometry, and energy efficiency. This was attributed to the higher illumination efficiency that can be achieved when using small light sources (UV-LEDs) and the higher mixing efficiency (shorter characteristic mixing time) arising from the confined spaces in the microchip system. In addition, the capillary microreactor system could be considered as an effective and ‘easy-to-use’ design.

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Review Mass transfer and criteria for multiphase reaction systems

conventional devices. In addition, an increase in the flow rate usually results in an even higher overall volumetric mass-transfer coefficient in microreactors. This is especially useful for achieving fast reactions with short-living species in multiphase photochemical transformations. For gas–liquid and liquid–liquid biphasic reaction systems, a dimensionless parameter, that is, Hatta number (Ha), is used to compare the reaction rate in a reactive film to the diffusion rate through this film.[38] For a reaction with mth order of A and nth order of B, in which the reactant A transfers to the bulk phase and reacts with the reactant B, Ha can be described in the following equation:

Multiphase reactions involve two-phase or three-phase systems, in which the mass-transfer of reactants from one phase to the other might be a crucial step in the chemical transformation (rate-determining step).[41] In multiphase processes, reactions can occur at the interface between different phases or in the bulk phase, depending on the mass-transfer rate of reactive compounds and the chemical reaction rate. Accordingly, different reaction regimes can be distinguished, including slow, fast, and instantaneous regimes. Especially, the mass-transfer of photosensitized reactants significantly affects the concentration distribution and the radiation distribution. An example of this phenomenon involves the direct oxygenation of organic qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi molecules with singlet oxygen and clearly demonstrates the 2 m1 ðcB;bulk Þn DA mþ1 km;n ðcA;i Þ ð18Þ importance of fast mass transfer in multiphase photochemical Ha ¼ kL reactions.[42] In these gas–liquid two-phase photoreactions, oxygen is transferred to the organic phase and then transformed to singlet oxygen by means of a sensitizer. Singlet oxygen reacts subsequently with organic molecules to form, in which km,n is the reaction rate constant, DA is the diffusivity for example, peroxide intermediates. In batch, severe disadvanof A, cA,i is the concentration of A at the interface between the tages arise, such as insufficient interfacial mass transfer of two phases, and cB,bulk is the concentration of B in the bulk oxygen, a non-uniform distribution of sensitized singlet phase, respectively. According to the value of Ha, multiphase oxygen, and inefficient irradiation of the liquid phase. The exreactions can be divided into three different categories tremely short lifetime of the singlet oxygen further aggravates (Figure 4): when Ha < 0.3, reactions are in the slow reaction these disadvantages. Moreover, the use of oxygen on a large regime and take place in the bulk phase; when Ha > 3, they scale and the accumulation of peroxide products due to ineffiare in the fast or instantaneous reaction regime, and finished cient mass transfer can easily result in severe safety issues, in the film; when 0.3 < Ha < 3, they are in the reaction regime such as explosions. with moderate reaction rates. Figure 4 shows a schematic diaThe fast interfacial mass transfer rates in microreactors can circumvent many of these issues.[43] Interfacial mass transfer rates can be best described by means of the overall volumetric mass-transfer coefficient (kLa). Table 4 gives an overview of the kLa values for a variety of multiphase reactors.[44] It can be observed that for microchannels the kLa values are at least one to two orders of magnitude higher than those obtained in conventional reactors or contactors. Such high mass-transfer rates can be rational- Figure 4. Schematic representation of the different reaction regimes according to the Hatta number in a segmented gas–liquid photochemical transformation. ized by the highly effective interfacial areas (a), arising from the small characteristic dimensions in microgram of a gas–liquid two-phase segmented flow in microchanreactors. The effective interfacial area in microreactors can nels, which is widely used in organic photochemistry. reach up to 9000 m2 m13, which is very difficult to achieve in For reactions with second-order kinetics in a fast reaction regime, the reaction rate can be expressed as follows: Table 4. Comparison of mass-transfer parameters and interfacial areas for microreactors and conventional reactors.[44] Type of reactor/contactor

kLa 102 [s1]

kL 102 [m s1]

a [m2 m3]

bubble column Couette–Taylor flow reactor impinging jet absorber packed column spray column static mixer stirred tank tube reactor microreactor

0.5–24 3–21 2.5–122 0.04–102 1.5–2.2 10–250 3–40 0.5–70 30–2100

10–40 9–20 29–66 4–60 12–19 100–450 0.3–80 10–100 40–160

50–600 200–1200 90–2050 10–1700 75–170 100–1000 100–2000 50–700 3400–9000

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r ¼ kL acB;i Ha

ð19Þ

in which cB,i is the concentration of B at the interface of bulk phase. This equation is reasonable when the maximum rate of transferring A into the film (adjacent zones of the two phase interphase) is much greater than its maximum rate of consumption. The equations described above [Eqs. (18) and (19)] are primarily used for thermochemical reactions. However, it still can be speculated that the mass transfer will play an im10570


Review portant role in photochemical transformations when Ha is larger than a certain value (e.g. Ha 1). The calculation of Ha is mainly based on the reaction rate constant and the overall volumetric mass transfer coefficient, as shown in Equation (18). It is well-known that the reaction rate constant depends on the reaction system and the temperature for thermochemical transformations. In the case of photochemical transformations, the reaction rate constant should be highly related to the reaction system and the LVRPA, similar to what we described for single-phase reactions. Furthermore, the characteristic reaction time for biphasic photoreactions is calculated based on the reaction rate and the original reactant concentration [Eqs. (13) and (19)]. Next, the Damkçhler numbers for batch reactors and microreactors are calculated and compared to evaluate the interaction between mass transfer, reaction rate and reaction time. Finally, proper reactors can be selected for biphasic photochemical transformations. In gas–solid or liquid–solid heterogeneous photocatalysis (e.g. photocatalytic degradation of pollutants in water with TiO2 particles), the reaction rate constant is also the function of the spectral specific intensity.[7c, 45] The heterogeneous photocatalytic degradations often follow Langmuir–Hinshelwood kinetics, and the reaction rate can be described as:

system, higher a-terpinene conversions (94 ~ 96 %) were achieved in shorter residence times (27 ~ 109 s). The batch reactor system required about one hour reaction time to reach similar conversions. The enhanced performance of microreactors could be ascribed to the improved irradiation of the photocatalyst, the higher mass-transfer rate of oxygen from the gas phase to the liquid phase, and the faster singlet oxygen diffusion in the liquid phase, which possibly is the rate-determining step in this transformation.

Photochemistry in Continuous-Flow Reactors In this section, photochemistry carried out in continuous-flow photoreactors will be discussed. We have grouped reactions based on the chosen light source given its impact on the chosen reactor material. Further division has been done with regard to homogeneous activation of the organic molecules, by either direct photochemical activation or homogeneous photocatalysis, and heterogeneous photocatalysis. This has important implications with regard to the design of the continuous-flow photoreactor as described in the Design Considerations section. UV photochemistry

r¼

kKcs 1 þ Kcs

ð20Þ

in which k and K are the reaction rate constant and the adsorption–desorption equilibrium constant, respectively; cs is the concentration of the reactants at the solid catalyst surface in equilibrium with the actual surface concentration. Equation (20) can be integrated into Equation (13), and then the characteristic reaction time for heterogeneous photocatalysis is calculated to obtain Damkçhler numbers for selected reactor types. It can be understood that high mass-transfer rates and large concentration differences would significantly increase the actual surface concentrations of reactants and thus their corresponding equilibrium concentrations at the solid catalyst surface. Consequently, the reaction rate will be increased and a shorter reaction time will be achieved. This will mean that for heterogeneous photocatalysis a reaction-rate-limited regime (DaII < 1) is often encountered. Carofiglio et al.[46] carried out a biphasic gas–liquid photooxidation of a-terpinene to produce ascaridole in both microreactors and batch reactors using 300 W tungsten halogen lamps. In the first microreactor system, a toluene solution of a-terpinene and [60]fullerene as a homogeneous sensitizer was merged with oxygen to establish a segmented flow regime and was subsequently introduced into a serpentine microchannel. Singlet oxygen was generated upon irradiation in the liquid phase, after which a-terpinene was converted to ascaridole. A second microreactor system was evaluated in which the [60]fullerene sensitizer was immobilized on Tentagel beads or on silicagel. In the first microreactor system, a conversion of 97 % could be obtained at 180 s. In the second microreactor Chem. Eur. J. 2014, 20, 10562 – 10589

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Due to its high energy content (200–350 nm range represents 598–342 kJ mol1), UV irradiation has been predominantly used to enable photochemical transformations.[1, 2] UV energy has been used to directly activate organic molecules or indirectly by means of homogeneous or heterogeneous photocatalysts. Direct photochemical activation UV light can be absorbed directly by organic molecules bearing a chromophoric group. As a result, they reach an excited state that allows them to undergo a chemical transformation. One of the most applied reactions in photochemical synthesis are photocycloadditions that give rise to the formation of two carbon–carbon bonds and a cyclic framework. It is, therefore, not surprising that such photocycloadditions have been very popular for the validation of many UV photomicroreactors (Figure 5). An intriguing example constitutes the UV photomicroreactor developed by Booker–Milburn that was applied for the synthesis of a variety of complex organic molecules by a photocycloaddition strategy.[47] A first device consisted of three layers of FEP tubing (2.7 mm ID) that was coiled around a Pyrex immersion well containing a 400 W medium-pressure Hg lamp. The larger diameter tubing allowed the generated back pressure at higher flow rates to be minimized, to provide a high throughput and to avoid microreactor clogging. The importance and popularity of this reactor design can be attributed to its practicality. The photoreactor is made of commercially available and inexpensive parts and can be rapidly assembled and implemented in any organic chemistry lab.[48] The reactor was next applied in the [2+2] photocycloaddition of maleimide and n-hexyne (Scheme 1A).[47a] Reagents were continuously introduced into the photoreactor for 24 h and afforded

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Figure 5. UV photomicroreactors: A) FEP continuous-flow reactor coiled around a 400 W medium-pressure Hg lamp. (reprinted with permission from ref. [47a]; Copyright 2005 American Chemical Society). B) FEP continuousflow reactor with a 36 W PL-L lamp (254 nm) (ref. [47c]; Copyright 2013 WILEY-VCH, Weinheim). C) A photomicroreactor with quartz top plate irradiated with a black light lamp (15 W, 360 nm) (reprinted with permission from ref. [49]; Copyright 2011 Akademiai Kiado). D) A photomicroreactor with quartz top plate irradiated with UV LEDs (1.7 W, 360 nm). Note that the light is better directed towards the microreactor (reprinted with permission from ref. [49]; Copyright 2011 Akademiai Kiado).

85 g of the target compound (82 % yield). The same reactor was also applied to the [5+2] cycloaddition of N-pentenyl-3,4-dichloromaleimide (Scheme 1B). In batch, this reaction can exclusively be performed on small batches (0.5–1 g) while the irradiation time has to be minimized to avoid extensive degradation of the target product. In continuous flow, this reaction could be executed in 6 min residence time affording an isolated yield of 64 % after a total operation of 11 h (38.5 g product). Notably, in batch, a similar productivity would require in total 120 independent experiments (0.5 g scale). The scalability of an intramolecular [5+2] photocycloaddition was one of the main hurdles in the total synthesis of ( )-neostenine.[47b] This key reaction could be performed on a 50 mg scale in a 100 mL immersion well batch photoreactor (40–60 % yield). However, scaling the reaction to > 100 mg batches resultChem. Eur. J. 2014, 20, 10562 – 10589

ed in poor yields (20 % yield) despite the complete consumption of the starting material. Using their continuous-flow FEP photoreactor, Booker–Milburn et al. were able to scale the reaction efficiently and synthesize 1.3 g of the target compound in a 9 hour run (63 % isolated yield; Scheme 1C). Notably, 20 % of the unreacted starting material could be recovered. The choice of an appropriate light source is given by both energy efficiency and reactivity considerations. High power light sources give a higher photon flux and can accelerate the reaction significantly [Eq. (12)]. However, the high energy can also lead to rapid degradation. To avoid extensive photodegradation in the photocycloaddition of pyrroles, a FEP capillary reactor was used and coiled around a 36 W PL-L lamp (lmax = 254 nm).[47c] The reaction could be carried out in a 9.5 min residence time yielding 0.91 g of the target aziridine after a one hour operation time (51 % yield) (Scheme 2). Affordable low-power black lights and UV LEDs have also been used in the [2+2] photocycloaddition.[49, 50] A thorough comparison between different light sources and their energy efficiency was performed by Ryu et al. From Scheme 3, it can be observed that the 300 W Hg lamp was far less efficient than the 15 W black light lamp. The use of energy efficient UV LEDs provided the best result: the photocycloaddition of cyclohexenone and vinyl acetate could be completed in 15 min resulting in an 80- and a 1780-fold increase in energy efficiency compared to the black light and Hg lamp respectively. The reason for this is probably that the light is better directed towards the

Scheme 1. Photocycloadditions in continuous-flow microreactors: A) Intermolecular [2+2] photocycloaddition of maleimide and n-hexyne in a capillary FEP microreactor. B) Intramolecular [5+2] photocycloaddition of N-pentenyl-3,4-dichloromaleimide in a capillary FEP microreactor. C) Intramolecular [5+2] photocycloaddition to prepare the key pyrrolo[1,2-a]azepine core in a capillary FEP microreactor for the total synthesis of ()-neostenine.

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Scheme 2. Photocycloaddition of pyrroles to aziridines in a capillary FEP microreactor.

Scheme 3. [2+2] photocycloaddition cyclohexenone and vinyl acetate. Comparison of different light sources in a microreactor equipped with a quartz top plate.

microchannels in the case of the UV LED irradiation (compare Figure 5C and D). These examples demonstrate again the importance of compatibility between the light source and the microreactor. Microreactors have widely been used as an enabling tool to perform gas–liquid reactions.[51] As discussed in the mass-transport phenomena section, microscale reactors provide large and well-defined interfacial areas, reduced axial dispersion and high mass-transfer rates between the gas and the liquid phase. Kakiuchi et al. have reported on the gas–liquid [2+2] photocycloaddition of a chiral cyclohexenone with ethylene gas (Scheme 4).[52] The reactor consisted of FEP microcapillary (1.0 mm ID) coiled around a quartz immersion well in which a 500 W high pressure Hg lamp was placed. The photomicroreactor was placed in a methanol cooling bath. A segmented flow regime was employed in which elongated gas bubbles (so-called Taylor bubbles) are separated from each other by liquid slugs. Meanwhile, the gas bubbles are separated from

Scheme 4. [2+2] photocycloaddition of a chiral enone with gaseous ethylene in a FEP capillary microreactor. Chem. Eur. J. 2014, 20, 10562 – 10589

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the reactor walls by a thin liquid film (< 0.1 mm). This thin film receives a very high photon flux while it is in constant contact with the gas phase. It is therefore surmised that the highest reaction rates are encountered in this thin film (see also Equation (18) and Figure 4). Full conversion was obtained in one minute with a selectivity of 52 % de. The authors found that a rigorous cooling of the microreactor was necessary to obtain these high diastereoselectivities. The importance of efficient cooling with high energy Hg lamp was also demonstrated by Jensen et al.[53] Without active cooling, temperatures in the microreactor could raise dramatically up to 250 8C.[54] The [2+2] photocycloaddition can be used as a powerful strategy to decorate polymers. Seeberger et al. have used a continuous-flow photomicroreactor to ensure a fast and reliable coupling of an alkyne-functionalized nonapod glycol-dendrimer with a poly-l-lysine polymer that was decorated with maleimide.[55] As such, glyco-dendronized poly-l-lysine polymers carrying either three or nine mannose or galactose moieties were prepared in high yield and purity. These functionalized polymers were subsequently used as a biosensor for bacteria. One of the major concerns of microprocess technology is the fouling of the microchannels, which can lead to irreversible clogging of the device.[56] The [2+2] photodimerization of maleic anhydride leads to the formation of such insoluble products. Horie et al. have developed a UV photomicroreactor that can deal with solid precipitates by means of ultrasound (Scheme 5). A FEP capillary microreactor (1.2 mm ID) was

Scheme 5. Dimerization of maleic anhydride by a [2+2] photocycloaddition in a FEP capillary microreactor by using ultrasonication and slug flow to prevent clogging.

coiled around a quartz beaker in which a 400 W high-pressure Hg lamp with a Pyrex immersion well was placed.[57] Next, the beaker was placed in a sonication batch. The presence of ultrasound breaks up the particle agglomerates into smaller particles and prevents deposition of the salts on the microreactor walls.[24] Nitrogen was added to establish a slug flow regime that allows the precipitation to be pusehed out of the microreactor. The reactor could be operated for more than 16 h without clogging. The Wolff rearrangement involves the conversion of an a-diazocarbonyl compound into a ketene by loss of dinitrogen, accompanied with a 1,2-rearrangment.[58] Konopelski has used a capillary microreactor setup to produce trans-b-lactams in flow by an intramolecular Wolff rearrangement. a-diazo-b-ketoamides were introduced in the microcapillary (FEP, 1.6 mm ID, 15 mL volume) and allowed to produce the target com-

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Review pound in 3.5 h total operation time (Scheme 6).[59] External cooling of the capillary was required to avoid thermal decomposition of the diazocompounds. Due to safety concerns associated with UV lamps in general, a CFL lamp was used instead. Despite a diminished reactivity, the product could be obtained in 48 h with a higher total yield as compared to the UV lamp.

ments could be obtained without epimerization of the stereocenter in short residence times (< 20 min). The use of laser irradiation can be beneficial since it provides a very high intensity of focused and discrete light for photoactivition. Especially for slower photochemical transformations, the combination of microreactor technology and lasers can result in a significant acceleration. Matching the wavelength of the laser with the chromophoric group or photocatalyst can provide an enhanced photoefficiency. Brase et al. have used laser irradiation for the photolysis of biphenyl azides to form carbazoles (Scheme 8 A).[63] A peek microreactor was used in which four reaction chambers with different depth were housed. Irradiation of the reaction medium was achieved with frequency-tripled Nd:YAG laser (l = 355 nm, 8 kHz pulse frequency, pulse duration 26 ns), which matches the absorption area of azides. The reaction could be completed in 12.3 s with the laser (78 % yield), while the use of a xenon lamp (400 W, l > 345 nm) required 18 h (10 mm cell). The formation of undesired diazocompounds could be avoided due to the minimized exposure time and the lower heating of the medium in a miScheme 6. Synthesis of b-lactams by an intramolecular Wolff rearrangement. croreactor. Aryl azides were also subjected to photolysis condiComparision between batch and flow, and two different light sources. tions to produce 3H-azepinones by Seeberger et al.[64] The reactor consisted of a FEP capillary wrapped around a 450 W A similar approach was used for the intramolecular photomedium-pressure Hg lamp. The formation of byproducts could Wolff-based ynamide benzannulation.[60] The time for photolybe minimized by careful control of the residence time in this sis was significantly reduced in flow (21–33 min compared to capillary microreactor. 3–50 h in batch). The popular capillary photomicroreactor assembly was used The photochemical rearrangement of 4-hydroxycyclobutefor a variety of photocyclizations, such as the synthesis of pyrinones to yield 5H-furanones was achieved in continuous flow docarbazole ligands,[65] phenanthrenes and helicenes,[66] and [61] (Scheme 7A). The reaction was difficult in batch since extetrahydroquinolines.[67] The same design was also used for the tended irradiation times resulted in substantial photodegradascalable photobromination of 5-methylpyrimidine in flow to tion of the desired product (27 % yield after 4 h). In contrast, yield 5-bromomethylpyrimidine, a precursor of Rosuvastatin.[68] excellent yields were obtained in flow (99 % yield after 90 min). The reaction in batch proved to be an unscalable process Similarly, the synthesis of peptides by a photochemical reargiving rise to long reaction times and low purity due to overrangement of nitrones in continuous flow was achieved in bromination. These hurdles could be overcome by using mia UV microreactor assembly (Scheme 7).[62] Small peptide fragcroreactors (Scheme 8B). Hereto, a FEP capillary microreactor (0.8 mm ID, 36 m length) was coiled around a quartz cooling jacket in which a 150 W medium-pressure Hg lamp was placed. The reaction could be completed in a residence time of 5 min that afforded the product on a 583 g scale per 24 h. The purity of the compound was very high (93 compared to 82 % purity in batch) and an 86 % yield was obtained after a simple recrystallization. Similar photochemical benzylic brominations could be done with a simple CFL household lamp (25 W).[69] Only a small excess of N-bromosuccinimide (NBS, 1.05 equiv) was required to get full conversion. A variety of 19 substrates could be converted within 13–50 min residence time. Photochemical thiol–ene click reactions are very useful reactions to establish a carbon–sulfur linkage for a variety of disciplines, such as material science, chemical biology, and synthetic chemistry.[70] The thiol radical can be obtained by UV irradiation of the Scheme 7. Photochemical rearrangements in continuous-flow microreactors. A) Photoreaction mixture after which the radical adds to an chemical rearrangement of 4-hydroxycyclobutenones in a capillary PFA microreactor. olefin. Hartmann, Seeberger et al. used this transforB) Amide bond formation by a photochemical rearrangement of nitrones in a capillary mation to functionalize poly- and oligoamidoamines quartz microreactor. Chem. Eur. J. 2014, 20, 10562 – 10589

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Review tomicroreactor to catalytically active species and subsequently used in an intramolecular ene– yne cycloisomerization reaction (Scheme 8C).[74b] After the reaction, [Ru(C6H6)(Cp)]PF6 could be recuperated quantitatively and reused without diminished activity. The intermolecular Pauson– Khand reaction is one of the most reliable reactions to construct a cyclopentenone framework. This is achieved by a cobalt-catalyzed carbonylative cycloaddition between an alkyne and an alkene. To increase the reactivity of the Pauson–Khand reaction, light irradiation can be used as a traceless activation method. Yoshida et al. have developed a continuous-flow protocol to make the methodology scalable.[75] A microreactor covered with a quartz glass was irradiated with a 80 W medium pressure Hg lamp. The majority of the reactions could be completed within 55 seconds. In contrast, reactions in batch required 5 min to yield the target comScheme 8. A) Photolysis of azides in a microreactor with laser irradiation. B) Photochemical benzylic bromination in a continuous-flow microreactor to yield 5-bromomethylpyrimidine, a precursor of Rosuvastatin. C) Photochemipound in 32 %. The same subcal generation of catalytically active {RuCp} + which can be subsequently used in the intermolecular ene–yne cystrate required 55 seconds in cloisomerization reaction. flow and resulted in an 88 % isolated yield (Scheme 9). The synthesis of vitamin D3 occurs by a two-step process with carbohydrates in flow.[71] A FEP capillary microreactor starting from provitamin D3. It is one of the few photochemi(750 mm ID, 10 mL) was irradiated with a pyrex-filtered cal processes that is carried out on an industrial scale.[76] To medium pressure Hg lamp to accelerate the reaction. Similarly, Du Prez et al. reported on the preparation of polymer beads avoid the formation of byproducts, a two-step continuous-flow through the combination of continuous-flow microreactor protocol was developed in which a first microreactor was used technology and photochemical thiol–ene click chemistry.[72] to enable the photochemical step with 313–578 nm irradiation The advantages of using photomicroreactors for such polymerat room temperature to yield a mixture of previtamin D3 and tachysterol.[77] Next, the reaction mixture was directed towards ization reactions are the excellent control over morphology, [73] a second photomicroreactor irradiated at 360 nm and heated size, and composition. to 100 8C to enable the formation of vitamin D3. Accordingly, Jamison et al. have used continuous-flow photochemistry to vitamin D3 could be obtained in 32 % isolated yield. prepare cationic cyclopentadienylruthenium [Ru(Cp)] + comOne of the first examples of combining photochemical reacplexes.[74] These metal complexes are useful catalysts for isotions and microreactor technology constitutes the pinacol formerizations and hetero- and carbon–carbon bond-forming remation by reaction of benzophenone with isopropanol.[25] On actions. Hereby, a sandwich complex [Ru(C6H6)(Cp)]PF6 is photolytically converted to [Ru(CH3CN)3(Cp)]PF6. The reaction in the microchip, two optical fibers were connected for online reaction monitoring. This allowed for rapid optimization of the the bath requires about 12–48 h and is not scalable due to the reaction conditions while using a minimal amount of Lambert–Beer limitation. A high purity PFA capillary microreacreactants.[78] tor (750 mm, 5 mL) was used and wrapped around a 450 W medium-pressure mercury lamp. With a residence time of 5 min, a productivity of 1.56 g h1 could be reached that outperformed the batch process with a factor of 10.[74a] In an extension of this work, [Ru(C6H6)(Cp)]PF6 was converted in a phoChem. Eur. J. 2014, 20, 10562 – 10589

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Scheme 9. Intermolecular Pauson–Khand reaction in a continuous-flow microreactor.

Scheme 10. Oxidation of citronellol with singlet oxygen in a capillary FEP microreactor with TPP as a photocatalyst.

Homogeneous photocatalysis

ture) (Scheme 10). Another reactor assembly for singlet oxygen generation constitutes the falling film microreactor and was used for the [4+2] cycloaddition of cyclopentadiene by singlet oxygen.[82] This design has 32 parallel microchannels in which liquid films of about 20 mm are formed due to gravity. As such, high interfacial areas of about 20 000 m2 m3 can be reached. The oxygen was cocurrently fed to the liquid and the reaction mixture was irradiated with a Xenon lamp. The desired compound could be obtained in 20 % yield (0.95 g). Jamison et al. have developed an interesting photochemical flow reactor that was made of a custom-made quartz capillary tubing for the photocatalytic synthesis of 2’-deoxy and 2’,3’-dideoxynucleosides.[83] The capillary was positioned around a 450 W medium pressure Hg lamp with a Pyrex sleeve (280 nm cutoff). A low photonic efficiency was overcome by placing both lamp and microreactor in a UV-reflecting cylinder (aluminium) [Eq. 6]. As such, non-utilized photons could be refracted towards the microreactor allowing a substantial increase of the yield (25 % increase). The photoinduced electrontransfer deoxygenation reaction to prepare 2’-deoxynucleosides was executed with 10 mol % of a carbazole photosensitizer at 45 8C. Reaction times could significantly be reduced in continuous flow (from 2 h to 10 min). Minimizing the exposure time of the reaction stream to the high-energy irradiation resulted in the suppression of extensive byproduct formation (i.e. 2’,3’-dideoxynucleosides) (Scheme 11A). To remove the remaining protecting groups, the reaction stream exiting the photomicroreactor was merged with an aqueous NaOH stream resulting in the formation of the fully unprotected 2’-deoxynucleosides in 10 min. Researchers from Genzyme Corporation have developed a new synthetic route towards doxercalciferol (1a-hydroxyvitamin D2).[84] A key step in this process was the photoisomerization with 9-acetylanthracene as a photocatalyst (Scheme 11B). A FEP capillary (1.59 mm ID, 15.24 m length) was wrapped around a cooled immersion well with a pyrex sleeve. A 450 W mercury vapor lamp was used and the photonic efficiency was improved by wrapping the whole setup in aluminium foil [Eq. 6]. Several parameters, such as temperature, flow rate, concentration, and amount of photocatalyst, were optimized using a design of experiments methodology (DoE). Optimal reaction conditions involved the use of diluted reaction stream (0.0076 m) and allowed the desired compound to be produced in 96 % yield, which corresponds to 9.6 mmol h1. The photocatalyst could be removed in flow by directing the reaction stream over a cartridge filled with carbon/Celite (1:2).

Homogeneous photocatalysts, such as ruthenium and iridium polypyridine complexes and organic dyes, have been very popular in organic synthetic chemistry since they allow visible light to be absorbed and thus perform under much milder conditions compared with UV photochemistry.[5] In addition, homogeneous catalysis avoids light scattering of the incident light, simplifying the photon-transport phenomena and thus the design of the photomicroreactor (see section Design Considerations). A more detailed discussion of homogeneous photocatalysis can be found in the Vis photochemistry section. However, certain homogeneous photocatalysts have their absorption maximum in the UV range and are therefore discussed in this section. Singlet oxygen has found widespread use in a variety of applications, including synthetic chemistry, biology, medicine, and materials science.[42a] It is typically prepared by a dye-sensitized photoexcitation of triplet oxygen and can be engaged in a variety of interesting synthetic reactions as a cheap and environmentally benign oxidation method.[79] However, certain limitations are associated with the formation of singlet oxygen on a large scale. First, the lifetime of singlet oxygen is highly solvent dependent and thus fast mass transfer is required to make efficient use of the generated active species [Eq. (16)].[80] Second, peroxide intermediates and products are formed that need to be safely quenched or processed. Third, the high reactivity of singlet oxygen can result into the formation of many byproducts upon prolonged irradiation times. Fourth, gas– liquid photoreactions are difficult to carry out in large scale batch reactors due to the low interfacial area. These drawbacks can be overcome by using microreactor technology. Seeberger et al. developed a transparent capillary microreactor (FEP, fluorinated ethylene propylene copolymer), which was coiled around a 450 W medium-pressure mercury lamp and cooled to 25 8C.[81] In the initial optimization studies, Rose Bengal was used as a sensitizer but, due to the high energy of the light source, extensive photobleaching was observed. Changing to tetraphenylporphyrin (TPP) resulted in a more efficient photocatalytic process. Next, several important reaction parameters (such as, pressure, stoichiometry, and concentration of TPP) were rapidly screened in flow. A variety of substrates could be oxidized in short reaction times (0.8–1.3 min). The scalability and stability of the process was demonstrated for the oxidation of citronellol reaching a productivity of 2.5 mmol min1 over 1 h (22.8 g of the desired product mixChem. Eur. J. 2014, 20, 10562 – 10589

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Review tions and to engage molecules, which lack a chromophoric group, in photochemical processes. Their photoactivity is associated with the formation of electron-hole pairs in the conduction and valence bands upon irradiation. One of the most used and well-studied semiconductor catalysts is titanium dioxide (TiO2). In the absence of any dopant, it possesses a rather wide band gap (DE > 3.2 eV) making it insensitive towards visible-light activation (< 5 % of visible light can be absorbed). The combination of microreactor technology and heterogeneous photocatalysts results in an enhanced performance of photocatalytic reactions.[36] This can attributed to shorter diffusion distances and the larger surfaceto-volume ratios that leads to a higher irradiation efficiency. In fact, the distance to photocatalytic efficiency (ds), that is, the distance at which radical intermediates are still present, is < 10 nm, making the use of confined reactors crucial for obtainScheme 11. A) Photocatalytic deoxygenation of protected thymidine in a capillary quartz microreactor with a caring high conversions.[87] UV phobazole as a photocatalyst. B) Photoisomerization of an intermediate in the synthesis of doxercalciferol with 9-acetocatalytic microreactors with tylanthracene as a photocatalyst. C) Photocatalytic deoxygenation of protected thymidine in a capillary quartz microreactor with a carbazole as a photocatalyst. TiO2 as a heterogeneous photocatalyst are typically prepared by depositing a layer of the semiThe ability of performing several reactions in parallel proconductor on one channel wall or on another carrier material vides an interesting approach to simultaneously optimize a va(Figure 6). A crucial design parameter constitutes the maximiriety of process parameters, as well as offering a tool to prezation of the photocatalytic surface, which is represented by k, pare a library of different compounds in a time-efficient the illuminated catalyst surface area per unit of liquid inside manner. Oelgemoeller et al. have reported the construction of the reactor (m2 m3). For microreactors, this value is very high (k = 11,667 m2 m3) in comparison to other photochemical rea multicapillary photomicroreactor in which 10 capillaries were [85] actors, for example, slurry photoreactor (k = 2,631 m2 m3) or coiled around two UVA fluorescent tubes (lmax = 365 nm). external type annular photoreactor (k = 27 m2 m3).[19c] The perTen different syringes were mounted on a single syringe pump and could introduce the different reaction mixtures in the phoformance can be further improved by immobilizing the catalyst tomicroreactor assembly. As such, a screening of different senon fibers that are subsequently loaded in the microreactor sitizers and concentrations was performed. Next, ten different (Figure 6a).[88] The higher photocatalytic activity compared to photosensitized additions of alcohols to furanones were done a classical TiO2 film (2–3-fold improvement) can be attributed and allowed to make a small library of different compounds to the higher specific surface area and the induction of flow (Scheme 11C).[86] perturbations due to the presence of these fibers. The film thickness is another aspect that should be considered, especially when the photocatalyst is excited from the backside of Heterogeneous photocatalysis the microreactor compared to the reactants (Figure 6c–e).[89] The use of solid semiconductors as photocatalysts in photoOn the one hand, a thicker film represents more photocatalyst chemical applications is of great importance due to their abunand thus faster reaction. On the other hand, the formed elecdance, low-cost prize, robustness, and potential to be recovtrons and holes have to move to the catalyst surface and interered/reused.[4] Such catalysts are used to facilitate uphill reacact with the substrate prior to recombination. Taking into acChem. Eur. J. 2014, 20, 10562 – 10589

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Figure 6. UV photocatalytic microreactors with TiO2 as a heterogeneous photocatalyst. A) PDMS/glass-based photomicroreactor with TiO2 immobilized on a fiberglass (reprinted with permission from ref. [88]. Copyright 2013 American Chemical Society). B) Schematic representation of a porous photocatalytic membrane microreactor (reprinted from ref. [90] with permission from Elsevier). C) Picture of a photocatalytic microreactor with a TiO2coated Pyrex lid. D) Field-emission SEM image of the TiO2-nanotubes (side view). E) TEM image of the TiO2-nanotubes (top view) (ref. [89b]—reproduced with permission of The Royal Society of Chemistry).

makes the photocatalytic process more efficient. Due to the short length scale in microreactors, the reaction was fast enough to prevent this charge recombination and no platinum was needed. Consequently, better results were obtained in more confined microreactors that reduced the diffusion distance between the bulk solution and the photocatalytic surface (98 % yield in 300 mm depth reactor, compared to 70 % yield in a 1000 mm depth reactor). The synthesis of l-pipecolinic acid starting from l-lysine was achieved in a Pyrex microreactor with a TiO2/Pt photocatalytic layer (Scheme 12B).[95] Irradiation with a high-pressure mercury lamp with a UV transmitting filter (110 mW cm2) resulted in the formation of the desired compound in 52 seconds residence time (14 % yield, 50 % ee). Similar yields could be obtained in batch; however, it required a reaction time of one hour. All the above-mentioned examples detail the use of immobilized TiO2. A single example was reported by Kappe et al. in which colloidal TiO2 nanocrystals (NC) are suspended in the reaction stream (Scheme 12C).[96] Herein, the tandem addition– cyclization reaction of N-methylmaleimide and N,N-dimethylaniline was performed in a PFA capillary microreactor that was exposed to UV LEDs (365 nm). An excellent yield of 91 % yield was obtained after recirculating the reaction mixture for 5 h in the photomicroreactor.

count these two aspects, an optimal thickness can be defined that depends on the incident wavelength. For gas–liquid reacVisible-light photochemistry tions, the TiO2-catalyst can also be immobilized on a membrane (Figure 6b).[90] Herein, the gas and liquid phase are separated The use of photoredox catalysts to absorb visible light and iniby the membrane into two different compartments, which tiate chemical reactions has received an increased interest in allows the gas–liquid contact to be maximized. Placing the catrecent years. The charm of photoredox catalysis is particularly alyst at the interface is advantageous from a reaction perspecdue its unique reactivity and the generally mild reactions contive and facilitates the gas–liquid two-phase separation after reaction. Applications of TiO2-photomicroreactors can be mostly found in the areas of fuel processing, waste water treatment, and air purification.[91] Due to the excellent control over photon and mass transfer, these devices have been used to study different photocatalysts[92] and their reaction kinetics.[93] Examples in organic synthetic chemistry are rather rare. A photocatalytic Nethylation of benzylamine was performed in a quartz microreactor on which a layer of TiO2 was deposited (Scheme 12A).[94] Irradiation of the photocatalytic layer was done by means of UV LEDs (365 nm). In batch, this reScheme 12. TiO2 photocatalytic transformations in flow: A) Photocatalytic N-ethylation of benzylamine in a quartz action requires a platinum microreactor with a TiO2 layer excited with 365 nm UV LED’s. B) Synthesis of l-pipecolinic acid in a Pyrex microdopant that slows down the reactor with a TiO2 layer excited with a high-pressure mercury lamp. C) Photocatalytic tandem addition–cyclization electron-hole recombination and reaction of N-methylmaleimide and N,N-dimethylaniline in a PFA capillary microreactor irradiated with UV LEDs. Chem. Eur. J. 2014, 20, 10562 – 10589

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Review ditions allowing for highly selective reactions. The latter stems from the low reaction temperatures and the inability of most organic molecules to absorb visible light that suppresses deleterious byproduct formation. In addition, the potential to use solar irradiation as an infinite green source of energy has attracted many researchers. However, it should be noted that many examples in continuous-flow reactors make use of conventional light sources. The use of solar energy has been hampered due to its variability in intensity and its diffusive nature arising from light scattering and reflections. One way to overcome this hurdle is to use an array of mirrors to focus the light to the reactor. However, such installations tend to become highly complex and costly and are not often used in a research laboratory. The principle of photocatalysis with ruthenium or iridium complexes is shown in Figure 7. Upon absorption of light, the photocatalyst reaches an excited state and a metal-to-ligand charge-transfer occurs. This redox-active photoexcited state can undergo single-electron transfers with organic substrates by an oxidative or reductive quenching pathway. The catalytic cycle can be subsequently closed by another single-electron transfer event. By photocatalysis, organic substrates that lack a chromophoric group can still be engaged in photochemical processes.

Figure 7. Redox quenching cycles in ruthenium and iridium photocatalysis.

talyst enabled the coupling of terminal alkenes and alkylbromides in high yields by the oxidative quenching cycle (Scheme 13C). It was found that residence times (6.5 min) were slightly longer than those that follow reductive quenching pathways. However, it should be noted that the conditions in flow were still much more efficient than the corresponding batch experiments, which typically took about 24 h.

Homogeneous photocatalysis Stephenson et al. have transferred several of their batch radical cyclization reactions to continuous flow (Scheme 13A and B).[97] The flow reactor consisted of commercial capillary PFA tubing (I.D. 750 mm), which was irradiated with a blue LED assembly (5.88 W, lmax = 447.5 nm). While the large-scale batch reaction required more than 48 h with low conversion, the intramolecular cyclization of the 1pyrrolyl alkylbromide could be completed in merely 1 min furnishing the target compound in 91 % yield. Similarly, intermolecular radical alkylation of indole derivatives could be completed in 4 min with 79 % yield. Using the same photomicroreactor assembly, the atomtransfer radical addition (ATRA) could be efficiently accelerated in flow.[97] The use of [Ir(dF(CF3)ppy)2(dtbpy)]PF6 (dF(CF3)ppy = 2-(2,4-difluorophenyl)5-(trifluoromethyl)pyridine; dtbpy = 2-(4-tert-butylphenyl)-4tert-butylpyridine) as a photocaChem. Eur. J. 2014, 20, 10562 – 10589

Scheme 13. A) Photocatalytic radical pyrrole functionalization in a PFA capillary microreactor with [Ru(bpy)3Cl2] as a photocatalyst. B) Photocatalytic radical indole functionalization in a PFA capillary microreactor with [Ru(bpy)3Cl2] as a photocatalyst. C) Photocatalytic atom-transfer radical addition (ATRA) in a PFA capillary microreactor with [Ir(dF(CF3)ppy)2(dtbpy)]PF6 as a photocatalyst. Boc = tert-butoxycarbonyl.

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Review The reduction of carbon–iodide bonds by a radical reductive dehalogenation is a powerful and mild method that is functional-group tolerant. However, certain safety issues are associated with these methods since toxic and explosive radical initiators or hydrogen atom donors, such as tributyltin hydride, azobisisobutyronitrile (AIBN), and peroxides, are typically used. Moreover, popular SET reagents for this kind of transformation, such as SmI2, are unstable in air. To avoid these problems, Stephenson et al. have utilized fac-[Ir(ppy)3] (ppy = 2-phenylpyridine) as a photoredox catalyst to convert a wide variety of unactivated alkyl, alkenyl, and aryl iodides to the corresponding radicals. These radicals readily reacted with either a Hantzsch ester or formic acid to furnish the reduced products in good to excellent yields. Next, it was demonstrated that the reaction times could be reduced significantly from 30 h to only 40 min by performing the reaction in continuous flow (Scheme 14A).[98] In addition, due to the high-photon flux through the microreactor, the catalyst loading could be reduced to 0.05 mol %, which represents an impressive TON of 1,860. In comparison, batch experiments required 1 mol % catalyst to obtain similar results. Based on these results, Stephenson et al. developed a two-step sequence to deoxygenize primary and secondary alcohols (Scheme 14B).[99] The methodology involved the initial conversion of alkyl alcohols to alkyl iodides by a so-called Garegg–Samuelsson reaction. Next, the alkyl iodides were reduced to the corresponding alkanes by a photocatalytic reduction. The second step was accelerated in

a photomicroreactor. To keep the mixture homogeneous in continuous flow and avoid clogging, the Hantzsch ester and tributylamine were replaced by N,N-diisopropylethylamine and a small amount of methanol. Notably, a 120-fold increase in productivity was observed in continuous microflow compared to analogous batch reactions. Seeberger et al. established a photocatalytic system that could reduce a carbon–chlorine bond in a-chlorophenyl acetates in a continuous-flow microreactor utilizing 1.0 mol % of [Ru(bpy)3Cl2] (Scheme 14C).[100] The microreactor consisted of a FEP tubing (750 mm, 4.7 mL volume) that was coiled around two metal rods. The reactor was irradiated with two face-toface aligned LED lamps (cold white, 17 W). The reaction could be completed within 30 min yielding 82 % of the target compound as compared to 24 h in a batch reactor. Notably, the hydrolysis of the reactive Vilsmeier–Haack intermediate formed the formate ester as a side product in 14 % yield in batch, while in the continuous-flow reaction no such side reaction could be found. The oxidative generation of iminium ions facilitated by photoredox catalysis is a powerful strategy to functionalize amines on the a-position. To prepare such a-functionalized amines in flow, Rueping et al. performed a nucleophilic addition of MeNO2 on iminium ions that were generated by a photo-oxidation of N-aryl tetrahydroisoquinolines with 5 mol % Eosin Y as a photocatalyst.[101] The reaction was carried out in a FEP capillary microreactor (800 mm ID, 9.3 mL) that was coiled around a glass tube containing green LEDs. This Henry reaction required 5 h to obtain 92 % isolated yield of the target compound. Notably, the same Henry reaction required only 30 seconds in flow when 0.5 mol % of [Ru(bpy)3Cl2] was used and BrCCl3 was added as a terminal oxidant (Scheme 15).[97] Seeberger et al. have used singlet oxygen to generate imines that can be in situ trapped with trimethylsilyl cyanide to produce a-aminonitriles (Scheme 16).[102] The reaction was carried out in a FEP capillary microreactor (750 mm ID, 7.5 mL volume) and irradiated with visible light LEDs (420 nm, 12 W). Singlet oxygen was produced by using 0.1 mol % of tetraphenylporphyrin (TPP) as a sensitizer. It was found that primary amines could undergo an oxidative coupling at 25 8C prior to the cyanide trapping. This could Scheme 14. Photocatalytic reductive dehalogenation: A and B) Photocatalytic reduction of an aryl and alkyl be overcome by performing the carbon–iodine bond in a PFA capillary microreactor with fac-[Ir(ppy)3] as a photocatalyst. C) Photocatalytic reducreaction at lower temperatures tion of an alkyl carbon–chlorine bond bond in a FEP capillary microreactor with [Ru(bpy)3Cl2] as a photocatalyst. (50 8C) and adding a substoiDIPEA = N,N-diisopropylethylamine. Chem. Eur. J. 2014, 20, 10562 – 10589

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Scheme 15. Photocatalytic Henry reaction of N-phenyl tetrahydroisoquinoline in a PFA capillary microreactor with [Ru(bpy)3Cl2] as a photocatalyst.

Scheme 16. Photocatalytic singlet-oxygen generation for the continuousflow oxidative cyanation of primary amines in a FEP capillary microreactor with tetraphenylporphyrin as a sensitizer.

organocatalyst and a reaction temperature of 5 8C (Scheme 18). In batch, similar results could be obtained; however, these required longer irradiation times (18 h). Collins et al. have developed a visible-light photocyclization protocol to synthesize chiral helicenes from stilbene-type precursors.[106] The photocatalyst was generated in situ by a complex of CuI ligated with XantPhos/DPEPhos and neocuproine. Traditionally, this transformation was achieved by utilizing UV light irradiation in the absence of a photocatalyst. This approach required a dedicated UV light source as well as quartz glassware and protective safety goggles. The visible-light approach provided a simplified reaction setup and, additionally, allowed byproduct formation to be minimized (e.g., overoxidation, regioisomers). The setup consisted of a FlowSyn Multi-X reactor system that contained a FEP capillary microreactor (1 mm ID). Two compact fluorescent light bulbs (CFL, 2 30 W) were used as a photon source. Despite the longer reaction times in flow (10 h), the reaction was still significantly faster compared to the batch protocol (120 h) (Scheme 19A). The same copper-based photocatalyst was also used for the visible-light-mediated synthesis of carbazoles by a carbon– carbon bond-forming reaction of triarylamines.[107] The reaction

chiometric amount of tetra-n-butylammonium fluoride (TBAF). Another interesting transformation, which utilizes the photocatalyzed generation of iminium ions, is the synthesis of symmetrical anhydrides from carboxylic acids.[103] Using an oxidative quenching pathway in the presence of CBr4, the Vilsmeier–Haack reagents could be generated in situ. These reagents allow the formation of a variety of anhydrides under mild conditions in continuous-flow. For example, starting from 4-tert-butylbenzoic acid, the anhydride was obtained in excellent yield (97 %) after exposing the reaction medium to light for 6.4 min (Scheme 17). Due to the high reactivity of the radical intermedi- Scheme 17. Photocatalytic synthesis of symmetrical anhydrides in a PFA capillary microates, it has been challenging to perform enantiose- reactor with [Ru(bpy)3Cl2] as a photocatalyst. lective transformations with photoredox catalysis. However, MacMillan et al. have shown that chiral centres can be formed with high enantioselectivity by combining photoredox catalysis with enamine organocatalysis.[104] Zeitler et al. have transferred this chemistry to continuous flow.[105] A metal-free variant using Eosin Y as a photoredox catalyst was developed for the organocatalytic photoredox a-alkylation of n-octanal. The photomicroreactor consisted of a 100 mL borosilicate glass microreactor (ID 600 500 mm) with LED irradiation (l = 530 nm). Optimal results (86 % yield, 87 % ee) were obtained within 45 min Scheme 18. Photoredox organocatalysis for the enantioselective a-alkylation of n-octanal in continuous flow with with 0.5 mol % Eosin Y, 20 mol % Eosin Y as a photocatalyst. Chem. Eur. J. 2014, 20, 10562 – 10589

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Scheme 19. Visible-light photocatalyt carbon–carbon bond-forming reactions: A) Visible-light-mediated photocyclization in continuous flow with an in situ generated copper-based photocatalyst. B) Visible-light mediated synthesis of carbazoles in continuous flow with an in situ generated copperbased photocatalyst.

The synthesis of reactive intermediates in microreactors and their subsequent consumption in a follow-up reaction represents one of the major advantages of microreactor technology. In essence, the amount of toxic and dangerous materials can be minimized and thus the risks of handling such materials are reduced. Nol and Wang have developed a visible light photocatalytic alternative for the Stadler-Ziegler synthesis of aryl sulfides (Scheme 21).[109] Diazonium salts were generated in situ by treating aryl amines with tert-butylnitrite and were subsequently consumed through reaction with aryl and alkyl thiols. An operationally simple microreactor design was developed using PFA capillary tubing (500 mm). This tubing was coiled around a large diameter syringe which was coated with aluminum foil to increase the photonic efficiency [Eq. (6)]. The assembly was placed in an aluminium-coated beaker in which blue LEDs were wrapped. To keep the reaction at room temperature, pressurized air cooling was used. The reaction could significantly be accelerated by performing the reaction under flow conditions (from 5 h in batch to 15 seconds in continuous-flow).

was particularly slow in batch (14 days), which prevented a time-efficient screening of the reaction conditions. Consequently, the reaction was carried out in a continuous-flow microreactor. Despite the significant acceleration, the reaction was still quite slow for microreactor technology (10–20 h). To accommodate the photoreaction, three capillary microreactors (3 10 mL volume) were placed in series and each one was coiled around a single CFL (3 23 W) Scheme 20. Photoredox conjugate addition of glycosyl radicals to acrolein in continuous (Scheme 19B). Again, the catalyst could be made in flow with [Ru(dmb)3(PF6)2] as a photocatalyst. situ, which allowed for rapid screening of different photosensitizers. Gagn et al. have developed a continuous-flow protocol for the photocatalytic conjugate addition of glycosyl radicals to acrolein.[108] A systematic study revealed a negative correlation between the diameter of the FEP tubing and the turnover frequency (TOF) of the [Ru(dmb)3(PF6)2] (dmb = 4,4'-dimethyl-2,2'-bipyridine) catalyst. In addition, increasing catalyst amounts demonstrated a lower TOF. This was rationalized by the large molar extinction coefficient (e) of Scheme 21. Photocatalytic Stadler–Ziegler synthesis of arylsulfides in continuous flow [Ru(dmb)3](PF6)2, which leads to a depletion of the in- with [Ru(bpy)3Cl2] as a photocatalyst. PTSA = p-toluenesulfonic acid. coming photons towards the centre of the tube. The photomicroreactor consisted of a single-layer layer of The same microreactor setup was used by Nol et al. for the FEP tubing (I.D. = 1.59 mm, length = 8.23 m) coiled around [Ru(bpy)3]-catalyzed trifluoromethylation reaction of five-mema Liebig condenser. Inside the Liebig condenser three 12“ strips of blue LEDs were placed. Next, a variety of protected bered heterocycles.[110] The reaction utilized gaseous CF3I as sugars were subjected under the reaction conditions and proa cheap trifluoromethylating source. Complete conversion was vided the desired compound in good yield (70–85 % yield). achieved in several minutes (8–16 min) compared to hours in The reaction could be scaled up by continuously introducing batch reactions (Scheme 22A). This acceleration was attributed starting materials in the reactor setup at 0.1 mL min1 for 24 h. to the excellent irradiation in microflow, the increased gas– liquid mass transfer of CF3I to the liquid phase and the excel14.2 mmol could be collected (85 % yield) after which the compound could be further derivatized into many biologically lent mixing due to the segmented flow regime (see Equaactive glycoconjugates (Scheme 20). tion (18) and Figure 4). In addition, these advantages allowed Chem. Eur. J. 2014, 20, 10562 – 10589

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Review

Scheme 22. Introduction of trifluoromethyl groups in continuous-flow reactors: A) Photocatalytic trifluoromethylation of indoles in continuous flow with [Ru(bpy)3Cl2] as a photocatalyst. B) Photocatalytic a-trifluoromethylation of ketones in continuous flow with Eosin Y as a photocatalyst. C) Photocatalytic trifluoroethylation of styrenes with a Co photocatalyst. TMEDA = N,N,N’,N’-tetramethylethylenediamine.

the catalyst loading to be lowered significantly (0.05 mol % Ru photocatalyst). The methodology was also used for the perfluoroalkylation of heterocycles. Due to the liquid state of the reagents, this reaction could be performed under homogeneous reaction conditions. In an extension of this work, Nol et al. have used Eosin Y as metal-free variant, which might be useful for pharmaceutical applications.[111] However, higher catalyst loadings (5 mol %) and longer reaction times (30–60 min) were required to reach full conversion. The trifluoromethylation of ketones was achieved in a two-step continuous-flow protocol by Kappe et al (Scheme 22B).[112] The ketones were first converted into the corresponding silyl enol ethers in flow. The stream exiting the first reactor was immediately mixed with CF3SO2Cl and Eosin Y and fed to a FEP-capillary photomicroreactor irradiated with 30 W CFL light source. a-Trifluoromethylated ketones could be obtained in only 20 min for the overall process. A photocatalytic trifluoroethylation of styrenes was achieved by using 2,2,2-trifluoroethyl iodide and a cobaltbased photocatalyst (Scheme 22C).[113] A glass mesoscale photoreactor chip and high-power blue LEDs were used to perform the reaction in a continuous mode. A substantial acceleration was observed in flow (30 min in flow compared to 24 h in batch). Chem. Eur. J. 2014, 20, 10562 – 10589

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The synthesis of artemisinin, one of the most potent antimalarial drugs, involves a key photochemical step that inhibits large-scale production. Seeberger et al. have developed an interesting and highyielding continuous-flow protocol that gave high overall yields (65–70 % overall yield) for artemisinin by starting from dihydroartemisinic acid (DHAA) (Scheme 23). DHAA is a product discarded in large quantities after the extraction process from the plant.[114, 115] The overall flow process required only 11.5 min and allowed 165 g artemisinin to be produced per day. Initially, a UV lamp was used to enable the photochemical singlet oxidation step of DHAA.[76] However, due to the broad emission spectrum of such light sources, a poor energy efficiency was obtained. Instead, an array of 60 high-power LEDs (12 W, l = 420 nm), which matches the absorption maximum of the photosensitizer dicyanoanthracene, was chosen to improve the photochemical step. The use of dicyanoanthracene as a photocatalyst proved to be essential since it was compatible with all reagents for the downstream reactions and was more soluble than other screened photocatalysts, thus allowing for a more efficient overall process. Optimal selectivity was observed at 20 8C. So far, most gas–liquid reactions, including photosensitized singlet-oxygen generation, described above involve the use of segmented flow (also called Taylor flow) in a single reactor channel.[116] To establish a more efficient gas–liquid interaction, Kim et al. have used membrane microreactors for the photo-

Scheme 23. Photocatalytic singlet-oxygen generation for the preparation of a key intermediate en route to artemisinin in continuous flow with dicyanoanthracene as a photocatalyst.

sensitized oxygenation of ()-citronellol and have compared the results with the ones obtained in a single microchannel in which a Taylor flow regime was established.[117] For a concentration of 0.35 m ()-citronellol, the reaction could be completed in 3 min in the membrane microreactor (97 % yield). With a Taylor flow regime, it was found that the reaction required

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Review longer reaction times to reach full conversion (15 min, 95 % yield). The difference was attributed to the increased interfacial area for membrane microreactors. For the membrane microreactor, it was found that the specific interfacial area was 50.9 cm1, while for the single-channel microreactor a value of 14.9 cm1 was calculated. deMello et al. have used microcapillary films as a scale-up version of the membrane microreactor for photosensitized singlet-oxygen generation.[118] The microcapillary film was made out of FEP and consisted of 10 parallel channels (ID 104.2 mm) in which the liquid reagents were introduced. The microcapillary film was next placed in a glass reactor that can be pressurized with oxygen. The transport of oxygen to the liquid phase happened through the semipermeable FEP membrane. Heterogeneous photocatalysis The use of organic dyes as photocatalysts is of great interest since they are cheap, abundant, and avoid the presence of metal catalyst residues in the final product. Immobilization of such organic dyes can be beneficial for several reasons.[119] First, oligomerization of the dyes is prevented, which inhibits self-quenching and improves the quantum yield. Second, the photostability of the dyes is increased due to the suppression of bimolecular degradation mechanisms. Third, the dyes can be recuperated after reaction and reused, hereby, increasing the total turnover number and avoiding contamination of the target compound. George, Poliakoff et al. have utilized supercritical carbon dioxide (scCO2) as a green solvent for the generation of singlet oxygen in continuous-flow.[120] The excellent solubility of oxygen in scCO2 and the high mass-transfer coefficients in supercritical media allow the reaction rates to increase significantly. The photoredox catalyst can be immobilized on polymer and aerogel supports.[121] Photosensitizers bound to silica aerogel supports resulted in activities comparable to the homogenous systems. However, due to the low catalyst loading in these aerosols low conversions were observed. It was found that an analogue of tetradi(2,6)chlorophenylporphyrin (TDCPP), which was covalently bound on polyvinyl chloride (PVC), provided the best immobilized photoredox catalyst. Photo-oxidation of a-terpinene could be performed over 6 h with only a marginal amount of degradation of the photoredox catalyst. Other reports demonstrated that photosensitizers can also be immobilized on the glass channel walls of the microreactor.[122] Scale-up potential for production scale Leading a photochemical route from small to gram scale is a crucial step in any organic chemistry laboratory. However, increasing the scale even further to a full production scale has been a daunting challenge and has limited the applicability of photochemistry significantly. For any chemical reaction, scaleup studies in batch reactor vessels is a time-consuming undertaking and requires a careful investigation of mass- and heattransfer characteristics on every scale, that is, lab scale, pilot scale and production scale.[123] However, the attenuation effect Chem. Eur. J. 2014, 20, 10562 – 10589

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of photon transport complicates this process even further for photochemical transformations and using larger diameter tubing/piping is not always beneficial. The promise of easy scale-up with microreactor technology by simply putting several microreactors in parallel has been overruled in recent years.[124] The fact that this technology has not been used for ton-scale photochemical syntheses demonstrates that it is indeed far from easy. In this review, we have demonstrated so far that scale-up can be achieved for photochemical reaction steps from milligram-scale to several grams in a simple microreactor. Scale-up by using microreactor technology can be essentially done in three ways: 1) longer operation times of the device, 2) numbering-up by placing reactors in parallel, and 3) increasing the throughput by applying higher flow rates through the device. The use of longer operation times of the photomicroreactor is a simple way of scaling-up in a laboratory environment. Once the optimal continuous-flow conditions have been established, the same device can be run continuously by introducing the reagents for multiple hours until the desired amount of product has been produced. Interestingly, no further reinvestigation of the reaction conditions and the device is required since the same reaction protocol can be maintained when operating at steady-state. This is especially interesting for scaling a reaction from several milligrams to maximum a few hundreds of grams and has, therefore, been popular in organic synthetic labs. The simplicity of this scale-up protocol allows the reaction to be scaled in a time-efficient fashion and often provides enough material for the different stages of a drug discovery process.[125] Numbering-up of microchannels is the method of choice to scale up the performance of photomicroreactors as required on a pilot or industrial scale.[126] One can distinguish essentially two ways of numbering-up, that is, internally and externally (Figure 8). External numbering-up is achieved by placing different photomicroreactors and their individual lamps and control units in parallel (Figure 8C,D). This ensures that the exact same processing conditions (e.g. pressure drop, photonic efficiency, heat, and mass transfer) are achieved in each reactor and, thus, provides a reliable way of scaling-up. In case of failure, this strategy allows a single device to be cleaned while the other ones are still in operation. However, one of the major issues with this strategy represents the large investment cost, since each microreactor is equipped with its own pumps, lamps, and control units. An example of this strategy can be found in the multicapillary photomicroreactor system reported by Oelgemoeller.[85] Hereby, ten different capillaries were coiled around two UVA fluorescent tubes to enable the photosensitized addition of alcohols to furanones. This simple example of external numbering-up required only one syringe pump that was equipped with a rack allowing ten different syringes to be mounted and pumped. A single industrial photochemical plant utilizing this external numbering-up strategy was achieved by researchers from Heraeus Noblelight GmbH.[127] Twelve microreactors were irradiated by individual lamps and allowed the production of 2 kg of 10-hydroxycamptothecine per day. Internal numberingup is achieved by using a single microstructured device with

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Review Conclusions and Outlook

Figure 8. Examples of internal numbering-up and external numbering-up: A) Internal numbering up in a falling film microreactor. (ref. [82]; Copyright 2005 WILEY-VCH, Weinheim). B) Internal numbering up in a FEP multichannel microcapillary film system (reprinted with permission from ref. [116]; Copyright 2013 American Chemical Society). C) Multicapillary photomicroreactor for photosensitized additions of alcohols to furanones as an example of external numbering-up (ref. [85]; Copyright 2012, Weinheim). D) External numbering-up in a photochemical production unit by Heraeus Noblelight GmbH.

microchannels in parallel (Figure 8a and b). However, from an engineering standpoint, this strategy is more complicated. Flow distributors are required to direct the reaction streams equally over the different channels. However, the realization of such an equal performance by internal numbering-up is very difficult since small differences in pressure drop in each microreactor or microchannel result in a non-uniform flow distribution. Consequently, this leads to an overall decrease of the reactor and reaction efficiency. For a photochemical process in particular, every channel should have a similar photon flux if this strategy should be successful. The use of microscale light sources may provide a feasible solution, which can be connected to the microchannel plate tightly. However, no information about the technical realization of this principle can be found. Small internal numbering-up systems have been successfully developed for photochemical transformations, for example, falling film microreactor[82] and microcapillary films.[118] Compared to the numbering-up strategy, increasing the flow rate in microreactors is an easier strategy to increase the throughput. To keep the same residence times in microreactors, their lengths should be changed according to the variation of the flow rates. It is worth noting that the hydrodynamics in the microreactors strongly depends on the flow rates. Consequently, the mixing performance and the mass transfer are highly related to the flow rates in microreactors. Encouragingly, both the mixing efficiency and the mass transfer rate increase with increasing flow rates in the microreactors. This is beneficial to the realization of this strategy. However, the increase in the flow rates or the lengths of microreactors will result in a higher pressure drop and thus larger energy dissipation. In addition, the light sources should be arranged along the flow direction to reach radiation homogeneity throughout the entire microreactor length. Chem. Eur. J. 2014, 20, 10562 – 10589

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The main drivers behind the development of continuous-flow photochemical methods in microreactors include the observation of substantial rate accelerations, the ease of scale-up from milligram to gram/kilogram quantities and the milder reaction conditions compared to conventional batch photoreactors. A remarkable amount of progress has been reported in the last decade for the application of photochemistry in continuous flow as demonstrated by the large number of examples described in this review. However, one cannot ignore that the examples have remained restricted to a laboratory scale up till now. Moving forward is not without a challenge and will require a multidisciplinary approach in which chemists and engineers will play a vital role. Consequently, there are several aspects that need thorough investigation to provide a safe scaleup from a laboratory to a full production scale: 1) Fundamentals of fluid dynamics and transport phenomena: Transport phenomena are strongly dependent on the fluid dynamics in reactors. Current available knowledge for microreactor technology is mostly focused on physical processes in the absence of any photochemical process. Even the radiation distribution in microreactors cannot be found in the literature. This can be partly attributed to the difficulty of the measurements due to the lack of adjusted equipment for microreactor technology. Further developments in microscale online detection technology is highly desired to enable the exact and detailed description of transport phenomena in photomicroreactors.[128] For example, microphotometers should be developed to detect the spectral specific intensity inside the microchannels. Once the basic understanding of these phenomena and reaction engineering is obtained, precise reactor models can be developed, which can predict the reaction performance of photomicroreactors. 2) Multiscale concepts for the engineering design of photomicroreactors: As demonstrated in this review, photochemical results obtained on a microscale are difficult to translate to an industrial production scale.[129] Internal numbering-up of microreactors provides the most promising and cost-efficient method for the industrial application of microreactor technology. This can be achieved by parallelization of the microreactors or microchannels in plates or stacks. Proper fluid distributors and industrial feed control systems should be developed to enable this strategy. Special care should be dedicated toward the compatibility of the light source with the internal numbered-up process to ensure high illumination efficiency. Furthermore, there is currently no process analysis approach, which provides an economical evaluation of the photomicroreactor strategy compared to equivalent conventional reactors. Therefore, integrated and multiscale concepts should be developed for industrial photochemical production. 3) Development of novel synthetic routes through photomicroreactors: Many synthetic chemists have been attracted by the advantages of continuous-flow technology for photo-

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Review chemistry. We foresee that in the future these research efforts will continue, if not increase, and enlarge the applicability of photochemistry in general. Further improvements are expected in the development of photocatalyst recycling strategies to improve the ecological and economic impact of the photochemical process. Several examples using hazardous intermediates in microreactors have been reported in this review and it can be expected that more research will be done in this area due to the apparent safety aspects on a microscale. Lastly, we also anticipate that photochemistry can benefit from unusual harsh process conditions (e.g. elevated temperatures and pressures, high photon flux via laser technology) and will allow for novel reaction modes that were difficult to reach in conventional batch photoreactors.[130]

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Acknowledgements [6]

T.N. would like to acknowledge financial support from the Dutch Science Foundation for a VENI Grant (No 12464) and from the European Union for a Marie Curie CIG Grant. Y.S. would like to thank the European Union for a Marie CurieIntra-European Fellowship (No 622415). V. H. greatly appreciates financial support from the Advanced European Research Council for the Grant “Novel Process Windows—Boosted Micro Process Technology” (grant number: 267443). We would like to thank L. Spijkers (TU/e) for help with the design of the cover art figure and D. J. G. P. van Osch (TU/e) for proofreading the manuscript.

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Received: January 23, 2014 Published online on July 23, 2014

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