Flow Photochemistry: Shine Some Light on Those Tubes!
2019; Elsevier BV; Volume: 2; Issue: 2 Linguagem: Inglês
10.1016/j.trechm.2019.09.003
ISSN2589-7209
AutoresCarlo Sambiagio, Timothy Noël,
Tópico(s)Biosensors and Analytical Detection
Resumo(Solar) Photochemistry in flow benefits from better, more uniform irradiation than in batch, resulting in shorter, more selective reactions and efficient scale-up.Photochemical multiphasic reactions fully exploit the photon- and mass-transfer enhancement properties offered by flow chemistry.Flow photochemistry is gaining popularity in the pharmaceutical industry due to the many advantages demonstrated in the chemistry itself and the large potential for automation. Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field. Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field. The use of light to promote chemical reactions has been exploited since the 18th century, but only recently a resurgence has been observed in synthetic organic chemistry, in particular due to the development of visible-light photoredox catalysis [1McAtee R.C. et al.Illuminating photoredox catalysis.Trends Chem. 2019; 1: 111-125Abstract Full Text Full Text PDF Scopus (127) Google Scholar, 2Kancherla R. et al.Visible light-induced excited-state transition-metal catalysis.Trends Chem. 2019; 1: 510-523Abstract Full Text Full Text PDF Scopus (47) Google Scholar, 3Romero N.A. Nicewicz D.A. Organic photoredox catalysis.Chem. Rev. 2016; 116: 10075-10166Crossref PubMed Scopus (2316) Google Scholar, 4Hockin B.M. et al.Photoredox catalysts based on earth-abundant metal complexes.Catal. Sci. Technol. 2019; 9: 889-915Crossref Google Scholar, 5Riente P. Noel T. Application of metal oxide semiconductors in light-driven organic transformations.Catal. Sci. Technol. 2019; 9: 5186-5232Crossref Google Scholar]. All transformations involving light (e.g., Figure 1A–D) must consider, besides classical chemical parameters (i.e., reaction conditions), the photophysical aspects of the sensitizer (see Glossary)/photocatalyst (when used), and the reactor design. The latter, although often neglected by chemists, is a critical aspect for the outcome of the studied chemical transformation. This includes, for example, the size, shape, and material of the reaction vessel, the characteristics and positioning of the light source(s), and heat-transfer properties, particularly when high-intensity lamps are used [6Noël T. Photochemical Processes in Continuous-Flow Reactors. World Scientific, 2017Crossref Google Scholar, 7Guba F. et al.Rapid prototyping for photochemical reaction engineering.Chem. Ing. Tech. 2019; 91: 17-29Google Scholar]. The engineering and technological aspects of photochemical processes are often at the basis of the irreproducibility and non-scalability of such transformations. According to the Beer–Lambert law, light transmittance decreases exponentially with the distance from the light source (Figure 1F). For a standard batch reactor (diameter at least in the centimeter range), light intensity decreases considerably from the flask walls to the middle of the reaction mixture, resulting in slow reactions and nonhomogeneous irradiation of the reaction mixture. Performing photochemical reactions in microchannels (ID < 1 mm) allows a higher and more homogeneous photon flux, resulting in shorter reaction times and consequently less side-product formation due to over-irradiation, often observed in batch [8Cambié D. et al.Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment.Chem. Rev. 2016; 116: 10276-10341Crossref PubMed Scopus (744) Google Scholar, 9Noël T. A personal perspective on the future of flow photochemistry.J. Flow Chem. 2017; 7: 87-93Crossref Scopus (52) Google Scholar]. Another advantage of microflow chemistry, correlated with the large surface:volume ratio, is improved heat and mass transfer, with the possibility to perform mass-transfer-limited multiphasic reactions efficiently [10Su Y. et al.Photochemical transformations accelerated in continuous-flow reactors: basic concepts and applications.Chem. Eur. J. 2014; 20: 10562-10589Crossref PubMed Scopus (328) Google Scholar]. Reactive chemicals and intermediates can be handled more safely in flow than in batch, as no accumulation of dangerous components occurs within the confined reactor volume due to the continuous nature of the process. Together, these result in often faster, safer, and higher-yielding reactions, with the possibility to perform reactions under conditions impossible in batch (high P/T; so-called novel process windows [11Hessel V. et al.Novel process windows for enabling, accelerating, and uplifting flow chemistry.ChemSusChem. 2013; 6: 746-789Crossref PubMed Scopus (439) Google Scholar]), and make microflow systems a valid alternative to traditional batch chemistry for many purposes. Moreover, the ease of automation and coupling with inline analysis, separation, and purification methods allows the development of continuous multistep synthesis and automated production platforms. These advantages are nicely showcased in the growing use of flow in the pharmaceutical industry [12Bogdan A.R. Dombrowski A.W. Emerging trends in flow chemistry and applications to the pharmaceutical industry.J. Med. Chem. 2019; 62: 6422-6468Crossref PubMed Scopus (65) Google Scholar, 13Bogdan A.R. Organ M.G. 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The typical flow setup for photochemical processes comprises transparent tubing made of perfluorinated materials (e.g., PFA, ETFE) efficiently coiled around a light source [17Hook B.D.A. et al.A practical flow reactor for continuous organic photochemistry.J. Org. Chem. 2005; 70: 7558-7564Crossref PubMed Scopus (290) Google Scholar], or surrounded by it, for uniform irradiation (Figure 1E). A more expensive alternative is the use of flat, transparent microreactors with engraved microchannels irradiated from both sides of the plate. In this review, we present recent advances in specific areas of flow photochemistry for which the use of flow has large advantages compared with traditional batch chemistry. Photochemistry has emerged in many cases as an alternative or complementary way to promote chemical reactions. For example, a recent review by Stephenson nicely discusses the complementarity between traditional (thermal) chemistry and photoredox processes in the fields of cross-coupling reactions and alkene functionalization [1McAtee R.C. et al.Illuminating photoredox catalysis.Trends Chem. 2019; 1: 111-125Abstract Full Text Full Text PDF Scopus (127) Google Scholar]. For instance, in the first case, more stubborn substrates in thermal reactions (e.g., alkyl halides) can be efficiently employed under photoredox conditions, or limitations in oxidative additions or transmetalation steps can be overcome. These reactions are of industrial importance and are being increasingly studied in flow, as shown in this review (e.g., Figures 3E, 4C, and 5E ). For alkene functionalization, different mechanisms become available in photoredox, allowing complementarity and broadening of the substrate scope.Figure 3Solar Photochemistry.Show full caption(A) Examples of parabolic concentrators (left) and a flat-bed reactor (right). Adapted, with permission, from [56Oelgemöller M. Solar photochemical synthesis: from the beginnings of organic photochemistry to the solar manufacturing of commodity chemicals.Chem. Rev. 2016; 116: 9664-9682Crossref PubMed Scopus (135) Google Scholar]. (B) Luminescent solar concentrator-PhotoMicroreactor (LSC-PM) and basic working principle. Adapted, with permission, from [61Cambié D. et al.A leaf-inspired luminescent solar concentrator for energy-efficient continuous-flow photochemistry.Angew. Chem. Int. Ed. 2017; 56: 1050-1054Crossref PubMed Scopus (73) Google Scholar, 63Cambie D. et al.Energy-efficient solar photochemistry with luminescent solar concentrator-based photomicroreactors.Angew. Chem. Int. Ed. 2019; 58: 14374-14378Crossref PubMed Scopus (35) Google Scholar]. (C) Down-conversion of solar light to 640-nm red light in red LSC-PM. Adapted, with permission, from [61Cambié D. et al.A leaf-inspired luminescent solar concentrator for energy-efficient continuous-flow photochemistry.Angew. Chem. Int. Ed. 2017; 56: 1050-1054Crossref PubMed Scopus (73) Google Scholar]. (D) Automated residence time adjustment according to light intensity in LSC-PM. Adapted, with permission, from [63Cambie D. et al.Energy-efficient solar photochemistry with luminescent solar concentrator-based photomicroreactors.Angew. Chem. Int. Ed. 2019; 58: 14374-14378Crossref PubMed Scopus (35) Google Scholar]. (E) Reactions in solar simulator: comparison of LSC-PM and standard microchannel reactor under identical conditions. Adapted, with permission, from [63Cambie D. et al.Energy-efficient solar photochemistry with luminescent solar concentrator-based photomicroreactors.Angew. Chem. Int. Ed. 2019; 58: 14374-14378Crossref PubMed Scopus (35) Google Scholar].View Large Image Figure ViewerDownload (PPT)Figure 4Automated Screening Platforms for Flow Photochemistry.Show full caption(A) Basic working principle and setup for screening platforms via segmented flow. (B) Beeler's reaction discovery platform via multidimensional screening. Adapted, with permission, from [78Martin V.I. et al.Multidimensional reaction screening for photochemical transformations as a tool for discovering new chemotypes.J. Org. Chem. 2014; 79: 3838-3846Crossref PubMed Scopus (28) Google Scholar]. (C) Jensen's oscillatory system for photoredox reaction study and examples of reactions investigated. Adapted, with permission, from [79Hwang Y.-J. et al.A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets.Chem. Commun. 2017; 53: 6649-6652Crossref PubMed Google Scholar, 80Coley C.W. et al.Material-efficient microfluidic platform for exploratory studies of visible-light photoredox catalysis.Angew. Chem. Int. Ed. 2017; 56: 9847-9850Crossref PubMed Scopus (25) Google Scholar, 81Hsieh H.-W. et al.Photoredox iridium–nickel dual-catalyzed decarboxylative arylation cross-coupling: from batch to continuous flow via self-optimizing segmented flow reactor.Org. Process Res. Dev. 2018; 22: 542-550Crossref Scopus (58) Google Scholar]. (D) Noël's automated procedure for photoredox quenching screening and Stern–Volmer analysis. Adapted, with permission, from [82Kuijpers K.P.L. et al.A fully automated continuous-flow platform for fluorescence quenching studies and Stern–Volmer analysis.Angew. Chem. Int. Ed. 2018; 57: 11278-11282Crossref PubMed Scopus (33) Google Scholar].View Large Image Figure ViewerDownload (PPT)Figure 5Scale-Up Strategies and Designs.Show full caption(A) Scale-up of aglain synthesis with three reactors in series. Adapted, with permission, from [87Yueh H. et al.A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues.Bioorg. Med. Chem. 2017; 25: 6197-6202Crossref PubMed Scopus (19) Google Scholar]. (B) Kilogram-scale trifluoromethylation of arenes. Adapted, with permission, from [90Beatty J.W. et al.Photochemical perfluoroalkylation with pyridine-N-oxides: mechanistic insights and performance on a kilogram scale.Chem. 2016; 1: 456-472Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. (C) External numbering-up of a segmented flow photoreaction. Adapted, with permission, from [92Su Y. et al.A convenient numbering-up strategy for the scale-up of gas–liquid photoredox catalysis in flow.React. Chem. Eng. 2016; 1: 73-81Crossref Google Scholar]. (D) Firefly reactor. Adapted, with permission, from [84Elliott L.D. et al.A small-footprint, high-capacity flow reactor for UV photochemical synthesis on the kilogram scale.Org. Process Res. Dev. 2016; 20: 1806-1811Crossref Scopus (78) Google Scholar]. (E) AbbVie's kilogram-scale continuous stirred-tank reactor (CSTR)–laser setup. Adapted, with permission, from [96Harper K.C. et al.A laser driven flow chemistry platform for scaling photochemical reactions with visible light.ACS Cent. Sci. 2019; 5: 109-115Crossref PubMed Scopus (69) Google Scholar].View Large Image Figure ViewerDownload (PPT) (A) Examples of parabolic concentrators (left) and a flat-bed reactor (right). Adapted, with permission, from [56Oelgemöller M. Solar photochemical synthesis: from the beginnings of organic photochemistry to the solar manufacturing of commodity chemicals.Chem. Rev. 2016; 116: 9664-9682Crossref PubMed Scopus (135) Google Scholar]. (B) Luminescent solar concentrator-PhotoMicroreactor (LSC-PM) and basic working principle. Adapted, with permission, from [61Cambié D. et al.A leaf-inspired luminescent solar concentrator for energy-efficient continuous-flow photochemistry.Angew. Chem. Int. Ed. 2017; 56: 1050-1054Crossref PubMed Scopus (73) Google Scholar, 63Cambie D. et al.Energy-efficient solar photochemistry with luminescent solar concentrator-based photomicroreactors.Angew. Chem. Int. Ed. 2019; 58: 14374-14378Crossref PubMed Scopus (35) Google Scholar]. (C) Down-conversion of solar light to 640-nm red light in red LSC-PM. Adapted, with permission, from [61Cambié D. et al.A leaf-inspired luminescent solar concentrator for energy-efficient continuous-flow photochemistry.Angew. Chem. Int. Ed. 2017; 56: 1050-1054Crossref PubMed Scopus (73) Google Scholar]. (D) Automated residence time adjustment according to light intensity in LSC-PM. Adapted, with permission, from [63Cambie D. et al.Energy-efficient solar photochemistry with luminescent solar concentrator-based photomicroreactors.Angew. Chem. Int. Ed. 2019; 58: 14374-14378Crossref PubMed Scopus (35) Google Scholar]. (E) Reactions in solar simulator: comparison of LSC-PM and standard microchannel reactor under identical conditions. Adapted, with permission, from [63Cambie D. et al.Energy-efficient solar photochemistry with luminescent solar concentrator-based photomicroreactors.Angew. Chem. Int. Ed. 2019; 58: 14374-14378Crossref PubMed Scopus (35) Google Scholar]. (A) Basic working principle and setup for screening platforms via segmented flow. (B) Beeler's reaction discovery platform via multidimensional screening. Adapted, with permission, from [78Martin V.I. et al.Multidimensional reaction screening for photochemical transformations as a tool for discovering new chemotypes.J. Org. Chem. 2014; 79: 3838-3846Crossref PubMed Scopus (28) Google Scholar]. (C) Jensen's oscillatory system for photoredox reaction study and examples of reactions investigated. Adapted, with permission, from [79Hwang Y.-J. et al.A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets.Chem. Commun. 2017; 53: 6649-6652Crossref PubMed Google Scholar, 80Coley C.W. et al.Material-efficient microfluidic platform for exploratory studies of visible-light photoredox catalysis.Angew. Chem. Int. Ed. 2017; 56: 9847-9850Crossref PubMed Scopus (25) Google Scholar, 81Hsieh H.-W. et al.Photoredox iridium–nickel dual-catalyzed decarboxylative arylation cross-coupling: from batch to continuous flow via self-optimizing segmented flow reactor.Org. Process Res. Dev. 2018; 22: 542-550Crossref Scopus (58) Google Scholar]. (D) Noël's automated procedure for photoredox quenching screening and Stern–Volmer analysis. Adapted, with permission, from [82Kuijpers K.P.L. et al.A fully automated continuous-flow platform for fluorescence quenching studies and Stern–Volmer analysis.Angew. Chem. Int. Ed. 2018; 57: 11278-11282Crossref PubMed Scopus (33) Google Scholar]. (A) Scale-up of aglain synthesis with three reactors in series. Adapted, with permission, from [87Yueh H. et al.A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues.Bioorg. Med. Chem. 2017; 25: 6197-6202Crossref PubMed Scopus (19) Google Scholar]. (B) Kilogram-scale trifluoromethylation of arenes. Adapted, with permission, from [90Beatty J.W. et al.Photochemical perfluoroalkylation with pyridine-N-oxides: mechanistic insights and performance on a kilogram scale.Chem. 2016; 1: 456-472Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. (C) External numbering-up of a segmented flow photoreaction. Adapted, with permission, from [92Su Y. et al.A convenient numbering-up strategy for the scale-up of gas–liquid photoredox catalysis in flow.React. Chem. Eng. 2016; 1: 73-81Crossref Google Scholar]. (D) Firefly reactor. Adapted, with permission, from [84Elliott L.D. et al.A small-footprint, high-capacity flow reactor for UV photochemical synthesis on the kilogram scale.Org. Process Res. Dev. 2016; 20: 1806-1811Crossref Scopus (78) Google Scholar]. (E) AbbVie's kilogram-scale continuous stirred-tank reactor (CSTR)–laser setup. Adapted, with permission, from [96Harper K.C. et al.A laser driven flow chemistry platform for scaling photochemical reactions with visible light.ACS Cent. Sci. 2019; 5: 109-115Crossref PubMed Scopus (69) Google Scholar]. Photochemistry is also a milder way to generate reactive intermediates otherwise obtained under thermal conditions or with specific chemicals. An example of this is the generation and reaction of singlet oxygen, a commonly encountered benchmark reaction in flow photochemistry (Figures 2A–D, 3E, and 4C) and critical in wastewater treatment. In this case, photochemistry is the traditional way to generate singlet oxygen, but other methods are available starting from alkaline metal oxides and hydrogen peroxide (dark singlet oxygen); 2 mol of peroxide generate 1 mol of singlet oxygen, reducing the atom economy of the reaction and producing water, a known quencher of singlet oxygen. Furthermore, the reaction occurs under alkaline conditions, which might interfere with the reagents, and requires often-toxic metal oxides as catalysts [18Wahlen J. et al.Solid materials as sources for synthetically useful singlet oxygen.Adv. Synth. Catal. 2004; 346: 152-164Crossref Scopus (106) Google Scholar]. In comparison, the photochemical generation of this intermediate requires only catalytic amounts of a photocatalyst and oxygen. Radical trifluoromethylation reactions are another important class of reactions investigated in flow photochemistry (Figures 2A and 5B). The trifluoromethyl radical can alternatively be generated by a variety of reagents by the action of stoichiometric oxidants or reductants. Examples are hydroperoxides (superstoichiometric amounts), often in the presence of ca. 10% of Fe or Cu catalyst for their activation. Alternatively, stoichiometric TEMPO derivatives have also been used in uncatalyzed reactions. While some of these protocols can be performed at room temperature, often the expensive and atom-uneconomic Togni or Umemoto reagents are used, and the use of ca. 10% of metal catalysts make several of these reactions considerably more wasteful than a photoredox process [19Studer A. A "renaissance" in radical trifluoromethylation.Angew. Chem. Int. Ed. 2012; 51: 8950-8958Crossref PubMed Scopus (774) Google Scholar]. Gas reagents are often cheaper, more sustainable, and more atom-economic than their liquid or solid alternatives and therefore represent the best option from a green-chemistry perspective. Gases are, however, difficult to handle in batch. Filling the headspace of a batch reactor with a gas in unpressurized systems results in serious mass-transfer limitations, while pressurized systems present serious safety concerns in case of toxic or reactive gases, and/or require the use of steel flasks (e.g., autoclaves) that prevent the use of light for photochemical reactions. Microflow chemistry represents a better alternative to these methods, as it avoids headspace and high amounts of gas in each section of the reactor. Moreover, microflow reactors can be easily pressurized in a safe manner, providing good mass transfer and large, well-defined interfacial areas without compromising safety or irradiation [20Hone C.A. et al.The use of molecular oxygen in pharmaceutical manufacturing: is flow the way to go?.ChemSusChem. 2017; 10: 32-41Crossref PubMed Scopus (71) Google Scholar, 21Cantillo D. Kappe C.O. Halogenation of organic compounds using continuous flow and microreactor technology.React. Chem. Eng. 2017; 2: 7-19Crossref Google Scholar, 22Gemoets H.P.L. et al.Liquid phase oxidation chemistry in continuous-flow microreactors.Chem. Soc. Rev. 2016; 45: 83-117Crossref PubMed Google Scholar]. Several methods for gas–liquid reactions in flow have been developed [23Mallia C.J. Baxendale I.R. The use of gases in flow synthesis.Org. Process Res. Dev. 2016; 20: 327-360Crossref Scopus (186) Google Scholar], generally suitable for photochemical conditions. It is worth noting that the transparent material of the reactor limits the usable pressure range, although relatively large pressures are easily tolerated in transparent microflow tubing. Solid–liquid reactions are, on the contrary, a constant challenge in flow chemistry, as feeding and pumping solid material in a continuous manner is not straightforward. Even initially homogeneous reactions where solid intermediates or products are formed are difficult due to clogging of the microchannels [24Hartman R.L. Managing solids in microreactors for the upstream continuous processing of fine chemicals.Org. Process Res. Dev. 2012; 16: 870-887Crossref Scopus (175) Google Scholar, 25Lapkin A.A. et al.Solids in continuous flow reactors for specialty and pharmaceutical syntheses.in: Vaccaro L. Sustainable Flow Chemistry. Wiley-VCH, 2017: 277-308Crossref Scopus (10) Google Scholar, 26Horie T. et al.Photodimerization of maleic anhydride in a microreactor without clogging.Org. Process Res. Dev. 2010; 14: 405-410Crossref Scopus (141) Google Scholar]. While some tricks exist to deal with clogging (e.g., sonication [27Fernandez Rivas D. Kuhn S. Synergy of microfluidics and ultrasound.Top. Curr. Chem. 2016; 374: 70Crossref Scopus (48) Google Scholar]), this is constant source of trouble for flow chemists. However, such processes are important in modern chemistry, particularly heterogeneous catalysis due to its sustainable aspects (e.g., catalyst recycling, ease of separation). Because of this, significant effort has been expended towards transferring these reactions into flow, and a few methods have been developed to facilitate this task. Segmented flow (Taylor flow or slug flow) is the simplest method to perform gas–liquid transformations, does not require any special flow equipment, and is therefore the most widely used approach. From a pure gas and pure liquid feed, a simple T/Y-shaped mixer is required to generate a liquid flow intercalated by gas bubbles, with a large contact surface between the two phases (Figure 2A). The internal recirculation movement of the gas and liquid segments ensures efficient mixing and diffusion of the gas inside the liquid. Many types of photochemical reactions have been performed employing this strategy, including trifluoromethylations with CF3I [28Straathof N.J.W. et al.Practical photocatalytic trifluoromethylation and hydrotrifluoromethylation of styrenes in batch and flow.Angew. Chem. Int. 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Another interesting example of gas–liquid reaction under segmented flow conditions is the synthesis of the antimalarial drug artemisinin via photogenerated singlet oxygen oxidation directly from extracts of the plant Artemisia annua, containing both the precursor of this drug [dihydroartemisinic acid (DHAA)] and the chlorophyll photocatalyst, demonstrated by Gilmore [33Triemer S. et al.Literally green chemical synthesis of artemisinin from plant extracts.Angew. Chem. Int. Ed. 2018; 57: 5525-5528Crossref PubMed Scopus (35) Google Scholar]. An alternative to segmented flow is the tube-in-tube reactor (developed by Ley [34Brzozowski M. et al.Flow chemistry: intelligent processing of gas–liquid transformations using a tube-in-tube reactor.Acc. Chem. Res. 2015; 48: 349-362Crossref PubMed Scopus (187) Google Scholar]) comprising two concentric tubes filled respectively with liquid solution and gas and separated by a gas-permeable membrane. The gas permeates the membrane and diffuses homogeneously into the liquid (Figure 2B). This reactor has been used primarily for thermal reactions, or as a method to presaturate a solution with gas prior to a photochemical reaction [35Micic N. Polyzos A. Radical carbonylation mediated by continuous-flow visible-light photocatalysis: access to 2,3-dihydrobenzofurans.Org. Lett. 2018; 20: 4663-4666Crossref PubMed Scopus (21) Google Scholar, 36de Souza J.M. et al.Continuous endoperoxidation of conjugated dienes and subsequent rearrangements leading to C–H oxidized synthons.J. Org. Chem. 2018; 83: 7574-7585Crossref PubMed Scopus (19) Google Scholar, 37Kouridaki A. Huvaere K. Singlet oxygen oxidations in homogeneous continuous flow using a gas–liquid membrane reactor.React. Chem. Eng. 2017; 2: 590-597Crossref Google Scholar]. However, as the tubes can be made of transparent materials, this method is also directly suitable for photochemical applications, as demonstrated by Park and colleagues for the photooxygenation of monoterpenes via singlet oxygen [38Park C.Y. et al.Continuous flow photooxygenation of monoterpenes.RSC Advances. 2015; 5: 4233-4237Crossref Google Scholar]. Falling-film microreactors are miniaturized reactors that can be adapted to a variety of gas–liquid transformations. In a typical setup, a liquid phase is injected into the microreactor from the top, forming a thin layer of liquid (film), while a gas is injected in counterflow from the bottom, ensuring increased contact time (Figure 2C). A transparent window allows irradiation for photochemical transformations. Applications of falling-film reactors in synthesis and catalysis are relatively rare, but a few recent studies on their use in photooxygenation reactions have been reported by Oelgemöller and Rehm [39Shvydkiv O. et al.Visible-light photooxygenation of α-terpinene in a falling film microreactor.Catal. Today. 2018; 308: 102-118Crossref Scopus (14) Google Scholar, 40Rehm T.H. et al.Photonic contacting of gas–liquid phases in a falling film microreactor for continuous-flow photochemical catalysis with visible light.React. Chem. Eng. 2016; 1: 636-648Crossref Google Scholar]. These reactors are, interestingly, also suitable for heterogeneous catalysis. An interesting example was reported by Rehm and Rueping, who studied a TiO2-catalyzed photochemical coupling between diazoarenes and heterocycles operating under blue-light irradiation [41Fabry D.C. et al.Blue light mediated C–H arylation of heteroarenes using TiO2 as an immobilized photocatalyst in a continuous-flow microreactor.Green Chem. 2017; 19: 1911-1918Crossref Google Scholar]. The reactor walls were coated with the solid catalyst, with an inert (rather than reactive
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