Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry

Abstract

Photoinduced chemical transformations have received in recent years a tremendous amount of attention, providing a plethora of opportunities to synthetic organic chemists. However, performing a photochemical transformation can be quite a challenge because of various issues related to the delivery of photons. These challenges have barred the widespread adoption of photochemical steps in the chemical industry. However, in the past decade, several technological innovations have led to more reproducible, selective, and scalable photoinduced reactions. Herein, we provide a comprehensive overview of these exciting technological advances, including flow chemistry, high-throughput experimentation, reactor design and scale-up, and the combination of photo- and electro-chemistry.

Figure 1

Thermochemical (A) versus photochemical activation (B).

Figure 2

Average reaction rate versus the photon flux. (A) Linear regime where β is 1.0 can be observed at lower light intensities. The reaction is photon limited in the entire reactor. The linear part can be extended by increasing the photocatalyst loading. (B) For intermediate light intensities, β is around 0.5 and kinetic limitations are apparent in some parts of the reactor. (C) For high photon fluxes, β becomes 0, and thus, the reaction rate is independent of the light intensity. Kinetic limitations are observed in the entire reactor.

Figure 3

Maximizing the photon capture efficiency by minimizing the lost radiation through optimization of the light source-reactor distance and through use of refractors. (A) Light source is not matched with the reactor dimensions and some regions are not irradiated. This means that the photochemical reactor is effectively smaller than anticipated from its total volume. (B) Optimal positioning of the reactor and the light source. (C) When the light source is positioned too far away from the reactor, the amount of lost irradiation increases following the inverse square law for light.

Figure 4

Attenuation of light as a function of distance in a photocatalytic reaction using Ru(bpy)₃Cl₂ (c = 0.5, 1, and 2 mM, ε = 13 000 cm^–1·M^–1) utilizing the Bouguer–Lambert–Beer correlation (eq 5).

Figure 5

(A) Microreactor with LEDs aligned along the length of the entire microchannel (Courtesy of Kuhn et al.). (B) DIY-assembled photomicroreactor comprising a 3D-printed vessel in which a capillary microreactor is positioned and aligned with a blue LED strip. Reprinted with permission from ref (98). Copyright 2016 American Chemical Society. (C) High-power 365 nm LED light source integrating 48 individual LEDs in a single package, achieving 27.5 W of optical power. To the back of LED module, a heatsink is attached. (D) Schematic representation of the green LED-pumped luminescent concentrators: high power LEDs pump blue photons into the green luminescent concentrator, which after absorption is re-emitted as green light. Via total internal reflection, the light is waveguided to the edge, where it leaves the material as a highly intense light beam. Bottom: Heat sinks are positioned on the other side of the luminescent concentrator to remove generated heat (Courtesy of Signify). (E) Picture of an assembled green LED-pumped luminescent concentrator module (Courtesy of Signify).

Figure 6

Scale-up strategies for tubular flow reactors: numbering up, sizing up by increasing channel length, and sizing up by increasing the channel diameter. A tubular reactor volume can be calculated using the given equation.

Scheme 1. [2 + 2] Photocycloaddition of Maleimide and 1-Hexyne

Figure 7

Collection of several different photochemical reactors. (A) Schematic representation of a FEP-wrapped immersion well flow reactor. (B) Immersion well batch reactor. (C) Three coiled FEP flow reactors in series. (B and C) Reprinted with permission from ref (132). Copyright 2018 Royal Society of Chemistry. (D) Schematic representation of the large-scale submerged PFA reactor. Cased cylindrical (E) and plate (F) capillary reactor, with one of the two external LED panels for the plate reactor (G). (E–G) Reprinted with permission from ref (74). Copyright 2020 John Wiley and Sons.

Scheme 2. Dual-Catalytic C–N Cross-Coupling Reaction

Figure 8

Batch and flow yield for the C–N cross-coupling reaction as a function of estimated (A) and calculated (B) amount of absorbed photon equivalents. Reprinted with permission from ref (74). Copyright 2020 John Wiley and Sons.

Scheme 3. [2 + 2] Photocycloaddition of Maleic Anhydride and Ethylene Gas

Scheme 4. Formation of Cookson’s Dione from a Diels–Alder Adduct

Figure 9

Collection of several different reactor designs. The prototype parallel tube flow reactor without casing (A) and schematic representation of the Firefly reactor (B). (A and B) Reprinted with permission from ref (139). Copyright 2016 American Chemical Society. The FEP4 (C) and PQT6 (D) reactors in the homemade Rayonet-type chambers. (C) Reprinted with permission from ref (140). Copyright 2018 American Chemical Society. (D) Reprinted from ref (141). Published by MDPI. The schematic representation of the excimer lamp setup (E) and close-up of the coldfinger quartz jacket design (F). (E and F) Reprinted with permission from ref (90). Published by Royal Society of Chemistry. Archimedean glass spiral, view from the side (G) and front (H). (G and H) Reprinted with permission from ref (142). Copyright 2018 John Wiley and Sons.

Scheme 5. Photochemical Transformation of Pyridinium Salts to Bicyclic Aziridines

Scheme 6. Photodecarboxylative Cyclization of a Phthalimide, Followed by an Acid-Catalyzed Dehydration

Figure 10

Light-harvesting photoreactor designs. (A) Printing, molding, and bonding of the PDMS layers. (B) 32-Channel LSC-PM with bifurcated flow distributor and flow collection chamber. (A and B) Reprinted with permission from ref (156). Copyright 2017 American Chemical Society. (C) Several different 3D-printed light/reaction channel designs for the FFPM: serpentine/serpentine (C.1), helix/straight (C.2), cylinder/helix (C.3), and the scaled sandwich structure (C.4). (C.1–C.3) Reprinted with permission from ref (163). Copyright 2019 John Wiley and Sons. (C.4) Reprinted with permission from ref (164). Copyright 2020 American Chemical Society.

Scheme 7. Photocycloaddition of 9,10-Diphenylanthracene to an Endoperoxide

Figure 11

(A) The cloud-inspired nebulizer-based NebPhotOX photoreactor. Reprinted with permission from ref (165). Copyright 2017 John Wiley and Sons. (B) Schematic representation of the cloud-inspired glass bead packed bed reactor. Reprinted from ref (166). Published by Royal Society of Chemistry.

Scheme 8. Photooxidation of β-Citronellol to Two Hydroperoxide Products A and B

Figure 12

(A) Microstructured falling film reactor with the magnetically attached LED arrays to the inspection window. Reprinted with permission from ref (172). Published by Royal Society of Chemistry (Copyright Fraunhofer IMM). (B) 3D-printed flowmeter reactor, CAD-design, and reactor lid: pre- and postabsorption of TPP. Reprinted with permission from ref (175). Copyright 2020 American Chemical Society.

Scheme 9. Photooxidation of α-Terpinene to Ascaridole (A) and the Common Byproduct p-Cymene (B)

Figure 13

(A) Schematic representation of the pRS-SDR and (B) top-view image of the operational pRS-SDR with photosensitizer MB. Reprinted from ref (180). Published by Elsevier. (C) Flow scheme and schematic representation of the vortex reactor. Reprinted with permission from ref (183). Copyright 2017 American Chemical Society. (D) Schematic representation of the large-scale vortex reactor. Reprinted with permission from ref (184). Copyright 2020 American Chemical Society.

Figure 14

Thin film rotational reactors. (A) Schematic representation of the PhotoVap setup. (B) Film formation for the PhotoVap: (B.1) liquid pool at 50 rpm, (B.2) liquid pool and thin film at 150 rpm, and (B.3) band formation at 200 rpm. (A and B) Reprinted with permission from ref (185). Copyright 2016 American Chemical Society. (C) Schematic representation and photograph of the rotating film reactor setup (ruler indicates cm). Reprinted with permission from ref (187). Copyright 2016 Royal Society of Chemistry..

Figure 15

Commonly used schematic representations of a CSTR (A) and a PFR (B).

Figure 16

(A) Schematic representation of the high-intensity laser CSTR. Reprinted with permission from ref (197). Copyright 2019 American Chemical Society. (B) Schematic representation and (C) assembled version of the CSTR cascade reactor. Reprinted with permission of ref (198). Copyright 2019 American Chemical Society. (D) Schematic setup of the ultrasonic milli-reactor. Reprinted from ref (199). Published by Elsevier.

Figure 17

(A) Integrated photoreactor by Merck. Reprinted with permission from ref (204). Copyright 2017 American Chemical Society. (B) Open-access photoreactor. Reprinted with permission from ref (205). Copyright 2021 John Wiley and Sons. (C) EvoluChem PhotoRedOx Box by HepatoChem. (D) Photoreactor M2 by Penn PHD. (E) Photochemistry LED Illuminator (PHIL) by Pacer. (F) The PhotoCube (Courtesy of ThalesNano).

Figure 18

(A) UV-150 module by Vapourtec. (B) PhotoSyn by Uniqsis. (C) Photochemistry Module for FlowStart Evo by FutureChemistry. (D) KeyChem-Lumino by YMC. (E) Two of the Corning AFR reactors: G1 Photo Reactor (top) and G3 Photo Reactor (bottom) designs, with the heart-shaped fluidic modules. (F) HANU 2X 5 (lab-scale), HANU 2X 15 (process development) and HANU HX 150 flow reactor (pilot/production-scale) (Courtesy of Creaflow).

Figure 19

Approach for the automated accelerated discovery of new photoredox reactions and subsequent discovery of an α-amino C–H arylation reaction.

Figure 20

High-throughput screening by Merck in conjunction with MALDI-TOF MS for the screening of nanomole scale reprinted with permission from ref (257). Copyright 2018 American Association for the Advancement of Science.

Figure 21

Heat map for the high-throughput screening of the photoredox catalyzed hydroxymethylation of heteroaromatic bases.

Figure 22

Heat map for the high-throughput screening of the optimal conditions for the concurrent tandem synthesis of primary amines.

Figure 23

Heat map for the 96-well plate high-throughput screening toward the photoredox catalysis enabled late-stage methylation of lepidine.

Figure 24

Heat map for the 96-well plate high-throughput screening toward the photoredox-mediated dehydrogenation of indoline.

Figure 25

240 nanomole scale reaction for the photoredox/nickel catalyzed peptide C(sp²)-oxygen cross-coupling.

Figure 26

High-throughput screening of the direct C–H fluorination of leucine methyl ester on the route to Odanacatib.

Figure 27

High-throughput screening of aryl amination of drug scaffolds using ligand free nickel(II) salts and a selection of photoredox catalysts.

Figure 28

(A) FLOSIM device. (B) Selected HTE results from decarboxylative arylation. (C) Selected HTE results from the cross-electrophile coupling. (D) Selected HTE results from C–O coupling adapted with permission from ref (265). Copyright 2021 American Chemical Society.

Scheme 10. Selected Results from High-Throughput Screening of the Photocatalyst Mediated Decarboxylative Intramolecular Arene Alkylation Using N-(Acyloxy)phthalimides

Figure 29

High-throughput experimentation work-flow for the discovery and optimization of heteroleptic copper(I)-based complexes for photocatalysis with single electron transfer (SET), energy transfer (ET), and proton-coupled electron transfer (PCET)-based transformations.

Figure 30

High-throughput workflow for the photoredox mediated reductive arylation of arylidene malonates.

Figure 31

Parallel synthesis for the direct decarboxylative arylation of DNA by dual photoredox/nickel catalysis.

Figure 32

High-throughput screening using a liquid handling robot for the photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines.

Figure 33

High-throughput screening for the late-stage amination of dextromethorphan.

Figure 34

Mechanism-based screening approach for the discovery of new quencher classes and subsequent discovery of new reactivity of benzotriazole and phenol derivatives.

Figure 35

Synthesis of 2-substituted indoles from benzotriazoles and alkynes by photoinitiated denitrogenation and robustness and functional group tolerance screening.

Figure 36

Photocatalyzed decarboxylative trifluoromethylthiolation with robustness and functional group tolerance screening.

Scheme 11. Exploration of o-Thiolated, Borylated, and Alkylated N-Arylbenzamide Aniline Derivatives by Visible Light-Mediated Functionalization

Scheme 12. Results for the Mechanism Based Photocatalyst Screening of a Disulfide–ene Reaction

Figure 37

Combined mechanism-based and reaction-based using mass spectrometry toward the discovery of diacylhadrazides from phenylsyndones and carboxylic acids.

Figure 38

Additive based robustness screening for a photocatalyzed hydrodefluorination of trifluoromethylarenes.

Figure 39

High-throughput microscale electrochemical reactor to accelerate the discovery of photoelectrochemical reactions. Reprinted from ref (280). Copyright 2021 The Authors (CC BY NC ND 4.0 License).

Figure 40

High-throughput screening of hydrogen evolution from the reduction of water by dual eosin Y and cobaloxime catalysis adapted with permission from ref (281). Copyright 2021 American Chemical Society. (a) LED strips and camera, (b) 108 reaction vial assay, (c) 2 × 100 W blue LED chips and (d) HTE experiment results unprocessed.

Figure 41

Parallelized screening platform for the colorimetric detection of hydrogen evolution from water splitting by bimetallic cocatalysts: (A) experimental platform, (B) experiment preirradiation, (C) experiment postexperimentation, and (D) data visualization. Adapted with permission from ref (282). Copyright 2021 American Chemical Society.

Figure 42

High-throughput experimentation platform for the measurement of hydrogen evolution for an investigation of the influence of pH when using BaTiO₃/TiO₂ core/shell photocatalysts: (A) experimental platform, (B) experiment preirradiation, (C) experiment postexperimentation, and (D) data visualization. Adapted from ref (283). Published by Elsevier.

Figure 43

High-throughput experimentation platform for the colorimetric indicated quantification of the photooxidation of benzyl alcohols and benzylamines to benzaldehyde by RFTA.

Figure 44

High-throughput robotic platform for the screening of organic copolymers for the photocatalytic hydrogen generation from water adapted with permission from ref (285). Copyright 2019 American Chemical Society.

Figure 45

High-throughput work-flow for the development of structurally diverse family of covalent triazine-based framework materials for photocatalytic water splitting for the evolution of hydrogen. Adapted with permission from ref (286). Copyright 2019 American Chemical Society.

Figure 46

Photochemistry LED Illuminator (PHIL) with modules for high-throughput experimentation and batch and flow chemistry for the screening and scale-up of a diverse range of photochemical reactions. Reprinted with permission from ref (209). Copyright 2019 John Wiley and Sons.

Figure 47

Photochemical cascade CSTR platform (Freactor) for the auto-optimization of multiphasic and mass transfer limited photochemical reactions.

Figure 48

Fluorescence quenching studies and Stern–Volmer analysis using a fully automated platform showcased by the photocatalytic decarboxylation of α,β-unsaturated carboxylic acids and the decarboxylative alkylation of N-containing heteroarenes.

Figure 49

Platform for the auto-optimization of photocatalytic decarboxylative coupling.

Figure 50

Self-optimizing reactor using online SEC for the auto-optimization of the photoiniferter polymerization of methacrylates.

Figure 51

HTE system for the rapid screening of pico-mole scale reactions using ESI-MS showcased by the trifluoromethylation of amine containing drug scaffolds and alkene aminoarylations.

Figure 52

AllinOne synthesis platform for the photocatalyzed incorporation of ¹⁸F-difluoromethyl onto acyclovir.

Figure 53

Auto-optimization platform using react-IR for the optimization of the photocatalyzed Paternò–Büchi reaction of benzophenone and furan. Reprinted with permission from ref (295). Copyright 2018 Elsevier.

Figure 54

Radial synthesizer platform developed by Gilmore et al. for the automation of photoredox enabled C–N cross-coupling adapted with permission from ref (296). Copyright 2020 Springer Nature.

Figure 55

Modular, reconfigurable system for automated optimization of chemical reactions for the optimization of the trapping of iminium ion with 1,2,3,4-tetrahydroquinoline under photocatalysis. Reprinted with permission from ref (297). Copyright 2018 American Association for the Advancement of Science.

Figure 56

HTE combined with a multiheart cutting interface to decouple reaction time from analysis time showcased for the optimization of the [2 + 2] cycloaddition between 1-methyl-2-quinolinone and coumarin.

Figure 57

Parallelization of experiments through an encapsulation work-flow for the screening of metallophotoredox mediated C–N cross-couplings. Adapted with permission from ref (301). Copyright 2020 American Chemical Society.

Figure 58

Chemical inkjet printing technology for the parallelization of experimentation for the discovery of M₃S/g-C₃N₄ multicomponent photocatalysts. Reprinted with permission from ref (301). Copyright 2015 John Wiley & Sons.

Scheme 13. Intramolecular [2 + 2] Photocycloaddition of (A) Enones and (B) Enaminones

Scheme 14. Intramolecular [2 + 2] Photocycloaddition, Formation of Bicyclo[3.2.1]octadienes

Scheme 15. Photochemical Synthesis of 2,4-Methanopyrrolidines through Intramolecular [2 + 2] Photocycloaddition

Reprinted with permission from ref (332). Copyright 2018 American Chemical Society.

Scheme 16. Intramolecular [2 + 2] Photocycloaddition of a α,β-Unsaturated Ester to Form a Tricyclic Key Intermediate in the Total Synthesis of Solanoeclepin A

Scheme 17. Synthesis of Dimethyl 1,4-Cubanedicarboxylate via Intramolecular [2 + 2] Photocycloaddition as Key Step (A) in Glass Flow Cell and (B) in FEP Capillary Reactor

Reprinted with permission from ref (335). Copyright 2021 Georg Thieme Verlag KG.

Scheme 18. Formal [3 + 2] Cycloaddition Toward 1-Aminonorbornanes

Scheme 19. Biphasic [2 + 2] Photocycloaddition of Ethylene and Maleic Anhydride Analogues

Scheme 20. Stereoselective Synthesis of ε-Diaminotruxillic Acid Derivatives by [2 + 2] Photodimerization

Scheme 21. [2 + 2] Photocycloaddition in Packed Bed Reactor with Carbon Nitride Immobilized on Glass Beads

Reprinted from ref (348). Published by Springer Nature.

Scheme 22. Functionalization of Photochemically Generated Bicyclic Aziridines

Scheme 23. Synthesis of Substituted Cyclopropanes by [2 + 1] Photocycloaddition of Diiodomethylpinacol Borate and Styrene Derivatives

Scheme 24. Cyclopropanes and Cyclopropenes from Diazoacetates by Photolysis and [2 + 1] Photocycloaddition to Alkenes and Alkynes

Scheme 25. Synthesis of Rocaglates through [3 + 2] Photocycloaddition between Hydroxyflavones and Cinnamates

Scheme 26. Photoinitiated Dehydro-Diels–Alder Reaction Towards Macrocyclic Naphthalenophanes

Scheme 27. Bridged Lactones by Formal Cycloaddition of Cycloalkanols and Electron-Deficient Alkenes

Scheme 28. Diastereoselective [4 + 2] Photocycloaddition Towards Benzoxanthene and Naphthochromenone

Scheme 29. Paterno–Büchi [2 + 2] Photocycloaddition in the Total Synthesis of (+)-Goniofufurone

Scheme 30. Photochemical Synthesis of 1,3,4-Oxadiazoles from 5-Substituted Tetrazoles and Carboxylic Acids in Continuous Flow

Scheme 31. Seven-Membered Ring Benzosultams through Photocycloaddition

Scheme 32. Photocascade with [3 + 2] Cycloaddition to Form 1,3-Diazabicyclo[3.1.0]hexanes: (A) Fused β-carbolines and (B) Bicyclic Aziridines

Scheme 33. E–Z Isomerization to Yield trans-Cyclooctenes and In-Line Complexation with Ag⁺

Figure 59

Photoreactor setup for the isomerization toward trans-cyclooctenes with in-line complexation on a Ag⁺ packed bed: (A) with a round-bottom flask and (B) with FEP capillary coils and multiple packed beds to enable continuous operation.

Scheme 34. Synthesis of Quinolines through E–Z Isomerization of 2-Aminophenyl-enones and Subsequent Cyclocondensation

Scheme 35. Solar Sensitized E–Z Isomerization of 3-Benzylidene-2-ones with Inline Extraction

Scheme 36. Rapid Catalyst Screening for the E–Z Isomerization of Ethyl Cinnamate Derivatives with an Ion Mobility Spectrometer

Scheme 37. Photochemical Smiles Rearrangement of Aryl-oxybenzoic Acids to Aryl Salicates

Scheme 38. Photo-Fries Rearrangement of Aryl Benzoates to Hydroxybenzophenone

Scheme 39. Photorearrangement of 2-Pyrone Analogues to Bicyclic Cyclobutene Lactones

Scheme 40. Photoisomerization of 1,2-Azaborines to Form B,N-Substituted Cyclobutanes

Scheme 41. Two-Step Beckmann Rearrangement of Ketoximes to Secondary Amides in a Photochemical and Thermal Flow Reactor

Scheme 42. Lattes–Aubé Reaction of Chiral Oxaziridines to Chiral Lactams and Further Derivatization

Scheme 43. Isoxazole to Oxazole Rearrangement in Continuous Flow

Scheme 44. Ring-Expansion of Quinoline Scaffolds to Benzo[1,3]oxazepanes

Scheme 45. Photorearrangement of N-Ylides to Their Ring-Expanded Azepines

Scheme 46. Nonclassical Photorearrangement of Dienones and Santonin with Different Reaction Outcomes for Different Solvents

Reprinted with permission from ref (415). Copyright 2017 John Wiley and Sons.

Scheme 47. Telescoped Thermal Cycloaddition and Photoisomerization of Fullerene and Diazoalkane to PCBM

Scheme 48. Synthesis of Tricyclic Phenanthridinones from Simple Starting Materials

Scheme 49. Cossy Photocyclization of Alkynyl Halides

Scheme 50. Two-Step Photochemical Flow Process to Substituted Carbazoles

Reprinted with permission from ref (434). Copyright 2018 John Wiley and Sons.

Scheme 51. Norrish–Yang Photocyclization Towards (A) Hydroxyazetidines, (B) Hydroxycyclobutanones, and (C) as a Key Step in the Total Synthesis of Zaragozic Acid C

Scheme 52. Application of SnAP and SLAP Reagents in the Synthesis of Saturated Heterocycles

Scheme 53. Photocyclization of Aryl Enamines to Spiroindolines Enables the Short Total Synthesis of (±)-Horsfiline

Scheme 54. Biomass Valorization Strategy to γ-Butyrolactones

Scheme 55. Diastereoselective ipso-Cyclization Towards the 6,6-Spirocyclic Core Structure of Zephycarinatine

Scheme 56. Short Total Synthesis of Dearomatized Acylphloroglucinols with Photocyclization as a Key Step

Scheme 57. Photocyclization of Chiral Bisbenzylidene Succinates in the Total Synthesis of Cyclolignan Analogues

Scheme 58. Mallory Photocyclization to Phenacenes

Scheme 59. Photooxidation of Methionine Mediated by RB in Flow

Scheme 60. (A) Neutralization of a Mustard Gas Simulant through Singlet Oxygen Oxidation in Flow and (B) Reactor Design with Glass Fluid Modules and in-Line Analysis

Reprinted with modifications from ref (476). Copyright 2020 Royal Society of Chemistry.

Scheme 61. Photooxidation of α-Terpinene into Ascaridole as Benchmark Reaction

Figure 60

Schematic representation of a FFMR and its main components. Reprinted with permission from ref (479). Copyright 2005 American Chemical Society.

Figure 61

Picture of the slurry Taylor flow established between the solution of VBRB@MG in ethanol and O₂ in the Archimedean spiral reactor. Reprinted with permission from ref (485). Copyright 2020 American Chemical Society.

Figure 62

Structure of polystyrene-immobilized vinylimidazolium and BODIPY structure.

Scheme 62. Preparation of the Heterogenous Chlorinated BODIPY Photosensitizer Linked to a Merrifield-Type Resin

Scheme 63. Bead-BTZ or pHIPE-BTZ Catalyst Preparation through Copolymerization of St-BTZ with Styrene and Divinylbenzene

Scheme 64. RB-SILLP Catalyzed Furoic Acid Photooxidation in Flow

Scheme 65. (A) TPP-Photocatalyzed Photooxidation of Naphthol Derivatives in Flow and (B) TcPP-Photocatalyzed DHN Oxidation through Formation of Singlet Oxygen in the FFMR

Scheme 66. Alkene Photooxidation in Flow in Solvent-Free Conditions

Scheme 67. (A) Photooxidation of Cyclopentadiene in Flow Using liqCO2 and scCO2 as Solvents in Flow and (B) Photooxidation of Fulvene in the Same Reactor Setup

Scheme 68. Multistep Synthesis of (1R,4S)-4-Hydroxycyclopent-2-en-1-yl Acetate Starting from the Photooxidation of Cyclopentadiene in Continuous Flow

Scheme 69. Enantioselective Photooxidation of β-Dicarbonylic Compounds in Flow with TPP and a Cinchona Alkaloid As Phase-Transfer Catalyst

Scheme 70. Methylene Blue Photocatalyzed Oxidation of Ethyl 3-(2-Furyl)propanoate in a Microflow Reactor in a Gas–Liquid Membrane Reactor

Scheme 71. (R)-Limonene Photooxidation in Flow Using a Tube-in-Tube Reactor in the Presence of TPP

Scheme 72. Photocatalytic Endoperoxidation of Dienes Followed by Kornblum–DeLaMare (KDM) Rearrangement in Flow

Scheme 73. Photocatalytic ¹O₂-ene Reaction of 1-Aryl-1-cyclohexenes in Flow

Scheme 74. Artemisinin Synthesis in Flow Starting from Artemisia annua Crude Extract

Scheme 75. Photooxidation of Aminothienopyridinones with Singlet Oxygen in Continuous Flow

Scheme 76. Synthesis of Thiuram Disulfides via Visible-Light Photocatalytic Aerobic Oxidation

Scheme 77. Tandem Photodeprotection and Decarboxylation in Flow, Followed by Azide–Alkyne Click Chemistry

Scheme 78. thio-Diels–Alder Reactions of Photochemically Generated Thioaldehydes in Continuous Flow

Scheme 79. Photocatalytic N-Desulfonylation of N-Heterocycles

Scheme 80. Photocleavage of the β-O-4 Bond in Lignin Models under Blue LED or Solar Irradiation

Scheme 81. Photocleavage of a Polysaccharide from a Solid Support under Blue LED Irradiation in Continuous Flow

Reprinted with permission from ref (540). Copyright 2020 American Chemical Society.

Scheme 82. Mild and Selective Photodeprotection of Benzyl Ethers from Saccharides in Batch and Flow

Scheme 83. Phthalimide Photocleavage Initiates a Radical Cascade to Benzylidene Acetal in the Total Synthesis of (+)-Polyoxamic Acid

Scheme 84. Tosyl Hydrazone Deprotection and β-Lactam Ring Formation in the Synthesis of Methylphenidate Hydrochloride

Reprinted with permission from ref (544). Copyright 2017 Royal Society of Chemistry.

Scheme 85. Terpenoidal-enone-Driven Sensitized Fluorination in Flow

Scheme 86. (A) Schematic Representation of the Use of Segmented Flow Regime to Avoid Clogging and (B) Photocatalytic Decarboxylative Fluorination in a Segmented Flow Regime

Scheme 87. Photocatalytic Deoxyfluorination of Allylic Alcohols with SF₆ in Flow

Scheme 88. Trifluoromethylation of N-Methyl Pyrrole and Mechanistic Elucidation

Scheme 89. (A) BTP Derivative Photocatalytic C–H Functionalization of Heteroarenes with Bromomalonate and (B) C–H Fluoroalkylation

Scheme 90. (A) Photocatalytic Trifluoromethylation and (B) Hydrotrifluoromethylation of Styrene Derivatives in Batch and in Flow

Scheme 91. Photoinduced Iodoperfluoroalkylation of Alkenes and Alkynes in Continuous Flow Resulting in an ATRA Reaction

Scheme 92. Photocatalytic Fluoroalkylation/1,2-Heteroarene Migration of Allylic Alcohols in Flow

Scheme 93. Photocatalytic Perfluoroalkylation of Cysteine Residues in Flow

Scheme 94. Photocatalytic Trifluoromethylation of (Hetero)Arenes in Continuous Flow

Scheme 95. Kilogram-Scale Photocatalytic Trifluoromethylation Mediated by Trifluoroacetic Anhydride and 4-Phenyl-pyridine N-Oxide in Flow

Scheme 96. Recyclable Ru(II) Complex as a Visible-Light Photoredox Catalyst for Trifluoromethylation of Coumarin in Flow

Scheme 97. (A) Photocatalytic Trifluoromethylation/Cyclization of 1,7-Enynes and (B) Photocatalytic Tri- and Difluoromethylation/Cyclizations in Continuous Flow

Scheme 98. Hydrotrifluoromethylation of Unsaturated β-Keto Esters Mediated by the Umemoto Reagent

Scheme 99. Photocatalytic Hydroperfluoroalkylation of Alkenes and Alkynes in Continuous Flow Mediated by Fluorinated Sulfilimino Iminium and Hantzsch Ester

Scheme 100. Photocatalytic ¹⁸F-Difluoromethyl Labeling of N-Heteroaromatics in Flow

Scheme 101. Continuous-Flow Photomediated Chlorination of Benzylic Positions through in Situ Generation of Cl₂

Scheme 102. Photochemical Chlorination of Alkanes through In Situ Formation of Chlorine in Flow

Scheme 103. TBADT-Photocatalyzed Late-Stage Functionalization in a Modular, Continuous-Flow Platform

Reprinted with permission from ref (592). Copyright 2021 American Chemical Society.

Scheme 104. Photocatalytic Si–Cl Bond Formation in Flow Starting from Silanes and Dichloromethane

Scheme 105. Photochemical Benzylic Bromination in Flow with N-Bromosuccinimide

Scheme 106. Bromination of a Benzyl Ring Using N-Bromosuccinimide in a Corning G1 Photoreactor

Scheme 107. Photochemical Benzylic Bromination of Electron-Rich p-Methoxytoluene in Flow with BrCCl₃ and Its Use as a Protecting Group

Scheme 108. Br₂ Generator over Three Generations and the Use of Molecular Bromine for Benzylic Bromination

Scheme 109. Photochemical Bromination of Conjugated Allylic Compounds with NBS

Scheme 110. Photochemical Bromination of Pyrrole Ring with Variable Number of Bromine Atoms

Scheme 111. Solid Handling in Oscillatory Flow Reactor in a Bi₂O₃ Photocatalyzed ATRA Reaction for Bromine Incorporation

Scheme 112. 4DPAIPN-Photocatalyzed Hydrodefluorination of Trifluoromethylarenes

4HTP = 4-hydroxythiophenol.

Scheme 113. Photocatalytic Metal-Free Dehalogenation of Aryl Halides in Continuous Flow

Reprinted with permission from ref (604). Copyright 2019 European Chemical Societies Publishing.

Scheme 114. Photodecarboxylative Difluoromethylation of Cinnamic Acids and Aryl Propiolic Acids

Scheme 115. Decarboxylative Functionalization of Aliphatic Carboxylic Acids with an Organic Photocatalyst: (A) Cyanation and (B) Trifluoromethylselenolation

Scheme 116. Selective Decarboxylative Deuteration and Scale-up in a Glass Recirculation Reactor

Reprinted from ref (616). Published by Royal Society of Chemistry.

Scheme 117. Formal Total Synthesis of l-Ossamine via Photodecarboxylative Functionalization

Scheme 118. Decarboxylative Annulation of l-Proline to Fused Imidazoles

Scheme 119. Photochemical Generation of Benzyne in Continuous-Flow and Quenching to Form 1,2,3-Benzotriazoles, Naphthalenes, and 2H-Indazoles

Scheme 120. Decarboxylative Alkyl/Acyl Radical Addition on p-Quinone Methides

Scheme 121. (A) Decarboxylative Hydroformylation of Styrene Derivatives Towards Terminal Aldehydes in Continuous Flow and (B) Application of the Decarboxylative Method to Formylation and Cross-Coupling of Vinyl Bromides

Scheme 122. Photodecarboxylation Reactions with Phthalimides

Scheme 123. Photocatalytic CO₂ Activation for Amino Acid Synthesis under Continuous-Flow Conditions

Reprinted with permission from ref (629). Copyright 2016 Nature Publishing Group.

Scheme 124. Photocatalytic β-Selective Hydrocarboxylation of Styrenes with CO₂ in Continuous Flow

Scheme 125. Hydrocarboxylation of Electron-Deficient Alkenes in a Tube-in-Tube Reactor As a Versatile Synthetic Strategy Towards β-Lactones

Scheme 126. Direct Carboxylation by Photoinduced Enol Formation of 2-Methylbenzophenone in Continuous Flow

Scheme 127. Alkene Difunctionalization with CO₂ and Silanes or C(sp³)–H Alkanes by Dual Photoredox and HAT Catalysis

Scheme 128. Photomediated C(sp²)–C(sp³) Kumada Cross-Coupling of Aryl Halides by Iron Catalysis in Continuous Flow

Scheme 129. Light-Accelerated Negishi Coupling of Organozinc Bromide with Aryl Halide and Scale-up

Scheme 130. Photocatalytic α-Arylation of N,N-Dialkylhydrazones in Continuous Flow

Scheme 131. Metal- and Catalyst-Free Arylation via Photogenerated Phenyl Cations under Flow Conditions

Scheme 132. (A) Photocatalytic Radical Coupling of Boronic Acids in Flow in 30 mmol Scale and (B) Photocatalytic Coupling of Benzylboronic Esters and Aldehydes in Flow

Scheme 133. Photocatalytic Coupling of Styrenes and Aldehydes with p-Terphenyl in Flow

Scheme 134. Visible-Light-Induced Generation of Singlet Nucleophilic Carbenes and Its Use for the Synthesis of Fluorinated Tertiary Alcohols

Scheme 135. Scale-up of (A) the Heterobiaryl Coupling and (B) the Borylatation of an Aryl Bromide Using iPr₃SiSH as Precatalyst in Flow

Scheme 136. Activation of boronic esters for C(sp²)–C(sp³) Cross-Coupling via Dual Photoredox/Nickel Catalysis in Flow

Scheme 137. Universal Flow Protocol for Dual Catalytic C(sp²)–C(sp³) Cross-Coupling of Aryl Bromides with Primary and Secondary Alkyls

Scheme 138. C(sp²)–C(sp³) Cross-Coupling of Bromo Azaindoles and Cycloalkyl Boronic Acids to Prepare a Library of Monosubstituted 7-Azaindoles

Scheme 139. Reductive Coupling between Benzyl Chlorides and Aryl Bromides by Dual Photoredox/Nickel Catalysis

Scheme 140. Dual Catalytic C(sp²)–C(sp³) Cross-Coupling of N-Boc-Protected Proline with Aryl Halides

Scheme 141. Metal-Free Borylation of Electron-Rich Aryl Halides under Continuous Flow

Scheme 142. Eosin Y-Photocatalytic HAT Activation of C–H Bonds

Scheme 143. Chlorine Radical-Photocatalyzed C–H Activation of Alkanes in Flow

Scheme 144. TBADT-Photocatalyzed C–H Activation of Gaseous Feedstocks in Continuous Flow

Scheme 145. (A) Continuous-Flow Multistep Alkylation of Indoles Starting from the Photocatalytic Acylation of Electron-Poor Olefins and (B) TBADT-Photocatalyzed Synthesis of Aminopropylsulfone in Flow

Scheme 146. Chemo- and Regioselective Functionalization of Internal Alkynes Photocatalyzed by Ir(III)/Ni(II) in Flow

Regioselectivity and E/Z ratio are >20:1 for the three compounds.

Scheme 147. Combination of Photo- and Transition Metal Catalysis to Acylate Indoles in Continuous Flow

Scheme 148. Photocatalytic Allylic Alkylation with Acridinium Ion Performed in a SFMT Reactor with [Acr-Mes]ClO₄

Scheme 149. (A) Photocatalytic Alkylation of Unactivated C–H Bonds Mediated by Chlorine Radical in a SFMT Reactor and (B) Photocatalytic Alkylation and Amination of Unactivated C–H Bonds Mediated by Bromine Radical in a SFMT Reactor

Scheme 150. Continuous-Flow Photocatalytic C–H Arylation of 2H-Indazole

Scheme 151. (A) FFMR Design and (B) Arylation of Heteroarenes with TiO₂ as an Immobilized Photocatalyst in FFMR

Panel A: Reprinted from ref (172). Published by Royal Society of Chemistry. Copyright Fraunhofer IMM.

Scheme 152. Mn(I)-Photocatalytic Arylation of (Hetero)Arenes with Diazonium Salts

Scheme 153. Benzofuran Synthesis through Ir(III)-Photocatalyzed Carbonylation

Scheme 154. Porphyrin-Photocatalyzed Arylation of Enol Acetate in Flow with Porphyrin Photocatalyst

Scheme 155. (A) Continuous-Flow Photocatalytic Generation of Acetonyl Radical from a Diazionium Salt and (B) Photocatalytic Reaction between Acetonyl Radical and Silyl Enol Ethers in Flow

Scheme 156. (A) Azosulfone-Mediated Arylation in a Sunflow Reactor and (B) Selective Arylation of Xanthene with Aryl Azo Sulfones in a Sunflow Reactor

Scheme 157. Continuous-Flow Reactions with Oxadiazolines As Precursors of Unstable Diazo Compounds: (A) Application to Reactions with Boronic Acids, (B) Synthesis of Ketones from Aldehydes and Oxadiazolines, (C) Three-Component Synthesis of Homoallylic Alcohols and Amines, and (D) Photochemical Homologation of Nonstabilized Diazo Compounds in Flow

Scheme 158. Photocatalytic Anti-Markovnikov Alkoxylation of Styrene Derivatives in Flow

Scheme 159. Photocatalytic N-Demethylation of Oxycodone in Flow with Oxygen and RB

Scheme 160. (A) RFTA-Photocatalytic Flow C(sp³)–H Benzylic Oxidation, (B) Photocatalytic Oxidation of the Remote C–H Bonds of Aliphatic Amines, and (C) TBADT-Photocatalytic Oxidation of C(sp³)–H Bonds in Flow Using Oxygen

Scheme 161. Photoinduced Synthesis of Phthalides in Flow Mediated by the Oxidation of Aryl Ketones

Scheme 162. Photocatalytic Trifluoromethoxylation of (Hetero)Arenes Systems in Flow

Scheme 163. (A) N-Chloroamines as Intermediates to Form New C–N Bonds in Flow and (B) Photocatalytic Amination Process Scaled up in Flow

Scheme 164. C–N Bond Formation Mediated by HAT Catalysis and RPC in Flow

Scheme 165. (Hetero)Aryl Amination in Continuous Flow by Dual Photoredox/Nickel Catalysis

Scheme 166. Nickel/Photoredox Catalyzed Synthesis of Arylhydrazine Derivatives in Flow

Scheme 167. Photocatalytic Arylation of Cysteine and Cysteine-Containing Dipeptides in Flow

Scheme 168. Photoinduced S–H and C–C Bond Insertion Using [1.1.1]Propellane in Flow

Scheme 169. Thioalkyne Formation via C(sp)–S Coupling of Bromoalkyne and Terminal Thiols via Dual Photoredox/Nickel Catalysis

Scheme 170. Arylation of 1-Thiosugar through Ni(II)/Ru(II)-Photocatalyzed in Flow

Scheme 171. 4CzIPN-Photocatalytic Trifluoromethylthiolation of Benzylic Bonds in Continuous Flow

Scheme 172. (A) Organic Selenides Multistep Preparation under Visible Light Irradiation and (B) Photocatalytic Trifluoromethylselenolation of Indoles in Flow

Scheme 173. Photochemical C–H/C–X Diborylation of Haloarenes with B₂Pin₂ in Continuous-Flow

Scheme 174. Photoinduced Synthesis of Aromatic Boronic Acids and Esters from Haloarenes and Arylammonium Salts

Scheme 175. Metal-Free Borylation of Electron-Rich Aryl Halides under Continuous Flow Conditions

Scheme 176. Light-Induced Cu(I)-Photocatalyzed Borylation of Aryl Iodides in Continuous Flow

Scheme 177. Light-Induce Metal-Free Borylation of Aryl Halides under Continuous Flow Conditions

Scheme 178. Scalable Generation of Bicyclo[1.1.1]pentane Trifluoroborate Salts

Scheme 179. TiO₂-Photocatalyzed Thiol Dimerization in Flow with a Glass Packed-Bed Reactor

Scheme 180. Photocatalytic Triphasic Oxidation of Benzylic Alcohols and Amines Performed in a Packed Column Photoreactor

Scheme 181. Pt(II)-Photocatalyzed Oxidation of Sulfides to Sulfoxides in Continuous Flow

Scheme 182. Acetic Acid Accelerated Photocatalytic N-Demethylation of N,N-Dimethylphenyl Amines

Scheme 183. Photocatalytic Oxidation of Benzylic Trifluoroborates in Flow

Scheme 184. Flow Preparation of Pyocyanin in a Continuous Mode through a Photooxidation

Scheme 185. Continuous-Flow Synthesis of Isoxazoles through a Modular Flow Strategy

Scheme 186. Reactor-Dependent Photocatalytic Azoxybenzene Synthesis

Scheme 187. Photochemical Reduction of Diaryl Ketones in Flow with Water

Scheme 188. Photocatalytic Reduction of Diphenylimines in Flow with Triethylamine

Scheme 189. (A) Photocatalytic Hydrosylilation of Alkenes through an HAT Process in STFM and in Continuous Flow and (B) Scale-up of the Photocatalytic Deuteration of Triethylsilane in Continuous Flow with HAT Catalyst

Figure 63

Examples of photoelectrochemical setups: (A) Homemade photoelectrochemical batch setup based on an H-type divided cell with an “F” glass filter as membrane. Schematic representation (B) and picture (C) of a photoelectrochemical flow cell using TiO₂ deposited on FTO as photoanode. Panel A: Reprinted from ref (780). Reprinted with permission from AAAS. Panels B and C: Reprinted with permission from ref (781). Copyright 2017, with permission from Elsevier.

Figure 64

Schematic representation of generally applicable photoelectrochemical flow reactor (PEC = photoelectrochemical cell).

Scheme 190. Photoelectrogeneration of Highly Oxidizing (A) or Reducing (B) Species

PC = photocatalyst; Sub = substrate.

Scheme 191. Oxidation of Diphenylethylene Using Phenothiazine (PTZ) as a Photoelectrochemical Catalyst

Scheme 192. Photoelectrochemical Oxidation of Benzyl Alcohol with TPPD

Scheme 193. Use of TAC⁺ as a Photoelectrocatalyst: (A) SET and (B) HAT Photoelectrocatalysis with TAC⁺, (C) Proposed Mechanism for the Photoelectrolyzed Transformations with the Orbital Configuration of the Oxidized and Photoexcited TAC^2+• Species, and (D) Photoelectrocatalytic Diamination of Vicinal C–H Bonds

Scheme 194. (A) Photoelectrochemical Reductions with DCA Allow the Activation of Aryl Halides and (B) Molecular Orbitals of DCA and of Its Reduced and Excited Derivatives

Scheme 195. Electron-Primed Photoredox Catalysis with NpMI: (A) Photoelectrocatalyzed Arbuzov Reaction and Coupling with N-Methyl Pyrrole and (B) Comparison among Photoelectrochemical, Electrochemical, and Photochemical Aryl Cross-Coupling versus Reduction

Scheme 196. (A) Example of a Photocatalytic Cycle Where Electricity Is Used to Restore the Photocatalyst in the Last Step, (B) Photoelectrochemical Alkylation of Heteroarenes Using Organotrifluoroborates, (C) Photoelectrochemical Trifluoromethylation of Arenes with the Langlois Reagent, and (D) Trifluoromethylation of Mesitylene in Flow, with Spatial and Temporal Separation of the Electro- and Photocatalytic Steps

Scheme 197. Photoelectrocatalytic S_NAr Starting from Unactivated Aryl Fluorides and DDQ as Photocatalyst

Scheme 198. Flavin-Photocatalytic Oxidation of Alcohols Using Electrochemistry to Close the Photocatalytic Cycle

Scheme 199. (A) Photoelectrochemical Azidation of Secondary Benzylic and Tertiary C–H Bonds and (B) Proposed Mechanism

Scheme 200. (A) Photoelectrocatalytic Cross-Dehydrogenative Coupling between Alkanes and Benzothiazoles with TBADT and (B) the Proposed Mechanism

Scheme 201. One-Pot Electrocatalytic Oxidation–Photocatalytic Reductive Cleavage of Lignin Model Compounds

Scheme 202. Photoelectrocatalytic Acylation of Electron-Poor Alkenes with Vitamin B_12a Starting from Anhydrides

Scheme 203. Photoelectrochemical C(sp³)–H Amination Mediated by Iodide Trifluoroethoxide As Base for the Synthesis of (A) Pyrrolidines, (B) Oxazolines, and (C) Amino Alcohols

Scheme 204. (A) Photoelectrocatalytic Minisci-Type Alkylation Using CeCl₃, (B) Decarboxylative Cross-Coupling of Heteroarenes with Oxamic Acids Using 4CzIPN as a Photocatalyst, and Proposed Mechanisms (C) and (D) of the Two Transformations

Scheme 205. (A) Photoelectrochemical Dehydrogenative Cross-Coupling Using Chloride as HAT Agent and (B) Proposed Mechanism

Scheme 206. Possible Half Reactions of Electrochemical CO₂ Redcutions and Water Oxidation (E⁰ vs RHE)

Figure 65

Schematic representation of a PEC cell: in yellow the (photo)anode, in green the (photo)cathode, and in gray the reference electrode. Blue line in the middle: proton-transfer membrane.

Figure 66

p-Type (A) and n-type (B) semiconductors in PEC cells (CB = conduction band, VB = valence band, h⁺ = hole).

Figure 67

(A) Photoelectrochemical reactor in flow and its main parts: (1) catholyte inlet and location of the reference electrode, (2) optical window (transparent slab), (3, 5, and 7) microchannel arrays, (4 and 8) electrodes, (6) ion exchange membrane, (9) outlet of anolyte, (10) outlet of catholyte, and (11) inlet of anolyte. (B) CO₂ reduction products (flow rate = 5 mL·h^–1). Panel B: Reprinted with permission from ref (893). Copyright The Electrochemical Society. Reproduced by permission of IOP Publishing, Ltd. All rights reserved.

Figure 68

Photoelectrochemical oxidation of formic acid in flow using DEMS to detect the evolution of oxygen and CO₂ (SCE = standard calomel electrode).

Figure 69

(A) Microfluidic reactor for CO₂ reduction into formate and methanol. (B) Product concentration in a batch setup after different times. (C) Product concentration at different flow rates after 1 h PEC reduction. Reprinted with permission from ref (776). Copyright 2019 Royal Society of Chemistry.

Figure 70

Photoelectrochemical flow reactor for syngas production based on the use of silicon photovoltaics as photoanode. Reprinted with permission from ref (901). Copyright 2017 Royal Society of Chemistry.

Scheme 207. HMF Oxidation to FDCA in a PEC Cell with a n-Type BiVO₄ Photoanode

Figure 71

Linear sweep voltammetry curves of the NHS-mediated oxidation of benzylic alcohol (A), cyclohexene (B), and tetraline (C) in a PEC cell equipped with BiVO₄ photoanode (scan rate = 10 mV·s^–1). Reprinted from ref (906). Published by Nature Publishing Group.

Scheme 208. (A) Structure of the Modified Photoanode Material nanoITO/TiO₂ and (B) Anodic and Cathodic Reactions in a DSPEC

Scheme 209. Use of Biocatalysts in a PEC Cell to Enantioselectively Combine Oxyfunctionalization and Hydrogenation Reactions

Scheme 210. C–P Cross-Coupling in a PEC Cell

Scheme 211. (A) Bromide as a Mediator in the Methoxylation of Furan, (B) Use of WO₃ Photoanode in the Oxidation of Cyclohexane, and (C) Hematite Photoanode Used for C–H Amination