Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up StrategyClick to copy article linkArticle link copied!
- Alexander SteinerAlexander SteinerCenter for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaMore by Alexander Steiner
- Philippe M. C. RothPhilippe M. C. RothCorning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, FranceMore by Philippe M. C. Roth
- Franz J. StraussFranz J. StraussMicroinnova Engineering GmbH, Europapark 1, 8412 Allerheiligen bei Wildon, AustriaMore by Franz J. Strauss
- Guillaume GauronGuillaume GauronCorning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, FranceMore by Guillaume Gauron
- Günter TekautzGünter TekautzMicroinnova Engineering GmbH, Europapark 1, 8412 Allerheiligen bei Wildon, AustriaMore by Günter Tekautz
- Marc WinterMarc WinterCorning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, FranceMore by Marc Winter
- Jason D. Williams*Jason D. Williams*E-mail: [email protected]Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaMore by Jason D. Williams
- C. Oliver Kappe*C. Oliver Kappe*E-mail: [email protected]Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaMore by C. Oliver Kappe
Abstract
Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attributed to additional challenges compared to thermal processes, mostly in the homogeneous irradiation of the flow reactor. Here, we detail the process of bringing a previously developed photochemical benzylic bromination, utilizing in situ bromine generation, from lab to pilot scale. The process setup is discussed in detail, alongside a comprehensive risk assessment and discussion of problems encountered in the investigation of key reaction parameters. Ultimately, an assay yield of 88% was obtained in 22 s irradiated residence time, resulting in a productivity of 4.1 kg h–1 (space-time yield = 82 kg L–1 h–1) representing a 14-fold scale-up versus the lab-scale process.
SPECIAL ISSUE
This article is part of the
Introduction
Figure 1
Figure 1. (a) Flow schematic for the intensified photochemical benzylic bromination of 2,6-dichlorotoluene 1, including bromine generation in the first FM and quench of excess bromine using sodium thiosulfate in the second FM. (b) General scale-up strategy for Corning Advanced-Flow Reactors, versus the scale-up demonstrated in this study. Scale-up workflow is based on maintaining a consistent residence time, to achieve consistent results (i.e., linear scaling of flow rates with reactor volume). The scale-up comparison demonstrated here represents a direct transfer from a G1 LF FM to a single G3 FM, whereas the standard strategy would suggest 5 × G3 FMs. Fluidic module images copyright 2015 and 2017 Corning Incorporated.
Results and Discussion
Scalability Concept and Experimental Plan
Calorimetry
Entry | Reaction | Occurrence | Experimental ΔHR [kJ mol–1] | Calculated ΔHR [kJ mol–1] (21) |
---|---|---|---|---|
1 | NaBrO3 + 6HBr → 3Br2 + 3H2O | 1st FM reaction | –65.1b | –63.5b |
2 | ArCH3 + Br2→ HBr + ArCH2Br | 1st FM reaction | – | –63b |
3 | ![]() | 2nd FM quench | –115b | –174.9b |
4 | ![]() | Pump failure | –20.0c | +31.8c |
5 | BrO3– + S2O32– → ? | Pump failure | <−0.5d | – |
6 | BrO3– + ArCH3 → ? | Pump failure | <−0.5e | – |
All measurements were performed isothermally at 25 °C. For entries 1 and 3 dilute aqueous solutions (0.1 M NaBrO3, 0.5 M HBr, 0.09 M Br2, 0.5 M Na2S2O3) were used. For entries 4–6 concentrated solutions (2.64 M Na2S2O3, 2.2 M NaBrO3, 48% HBr) and neat DCT were used. Theoretical exotherms were calculated as the difference of formation enthalpies ΔHf0(products) – ΔHf0(reactants) (entries 1, 3–4), or as a difference of bond energies (entry 2). The required values were taken from ref (21).
Calculated per mole of Br2 generated or consumed.
Calculated per mole of S2O32– consumed.
Calculated per mole of BrO3– consumed.
Calculated per mole of DCT consumed.
Reactor Setup
Figure 2
Figure 2. Piping and instrumentation diagram (PID) showing the process streams in black, heat exchange channels for the reaction and quench FMs in red, and the LED heat exchange channel in blue. PI = pressure sensor; FI = flow meter; TI = temperature sensor.
Figure 3
Figure 3. Snapshot from the live video stream captured by the webcam, showing the quench FM (streams combine and enter in top right corner, flow direction depicted by arrows, see Figure 1b for a full view of the FM). Quenching of the excess Br2 (highlighted by white ellipse) can be observed by a color change as the reaction mixture moves through the channel.
Safety Assessment
Reaction Parameter Optimization
Entry | Temp [°C]a | Residence time [s]b | Equiv of Br2b | Conversion [%] |
---|---|---|---|---|
1c | 60 | 18.1 | 1.10 | 10 |
2c | 60 | 20.1 | 1.10 | 31 |
3 | 60 | 22.1 | 1.11 | 76 |
4d | 60 | 22.0 | 1.09 | 77 |
5 | 60 | 23.9 | 1.11 | 81 |
6d | 65 | 18.0 | 1.11 | 68 |
7d | 65 | 19.6 | 1.04 | 60 |
8d | 65 | 22.0 | 1.11 | 79 |
9 | 65 | 22.0 | 1.10 | 88 |
10d | 65 | 24.0 | 1.13 | 68 |
11 | 60 | 22.0 | 1.18 | 77 |
12 | 65 | 21.9 | 1.19 | 63 |
13d | 65 | 22.0 | 1.19 | 84 |
Thermostat set temperature.
Calculated from flow rates observed at the respective mass flow meters.
Average of two separate runs.
4 bar back pressure applied; optimum conditions are highlighted in bold.
Figure 4
Figure 4. Overview of selected results from Table 2 (entries 1–10), highlighting the rough trends (dotted lines) of conversion vs residence time. Note: these trends are added only as a visual aid, and are not intended to be extrapolated or to represent a model of the reaction performance. Conversion of 1 was determined by 1H benchtop NMR.
Figure 5
Figure 5. (a) Illustrated positions of the temperature sensors in the reactor heat exchange channel. (b) Temperature increase in the heat exchange channel after passing through the reaction or quench FM, plotted against the performance of the reaction (conversion of 1).
Lab reactora | G3 reactor | |
---|---|---|
Reactor volumeb [mL] | 2.8 | 50 |
Optimal conditions | 18 s, 60 °C, 1.1 equiv of Br2 | 22 s, 65 °C, 1.1 equiv of Br2 |
Yield [%] | 97c | 88c |
Productivity [kg h–1] | 0.3 | 4.1 |
Space-time yield [kg L–1 h–1] | 108 | 82 |
Values based on the previously published scale-out experiment. (14)
Volume of the photochemical reaction FM only (G3 quench FM omitted).
Assay yield, determined by ratio of starting material to product by 1H NMR.
Further Studies
Conclusion
Experimental Section
Reactor Setup
Pumps
Inline Filters
Pressure Relief Valves
Startup Procedure
General Procedure for Optimization Runs
Shutdown Procedure
Sample Workup
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.0c00239.
Further details of reaction setup, risk assessment, experimental results and NMR data (PDF)
Video of quench FM during experimental runs (MP4)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
The authors gratefully acknowledge Patheon Austria GmbH & Co KG (Linz, Austria) for the generous loan of the Lauda Proline RP4090 CW used in this study, and would like to thank Prof. W. Goessler (University of Graz) for performing ICP analysis.
API | active pharmaceutical ingredient |
BPR | back pressure regulator |
DCM | dichloromethane |
DCT | 2,6-dichlorotoluene |
FM | fluidic module |
LED | light emitting diode |
NBS | N-bromosuccinimide |
PFA | perfluoroalkoxy alkane |
PMI | process mass intensity |
References
This article references 22 other publications.
- 1
For selected reviews of recent photochemical synthetic methods, see:
(a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322– 5363, DOI: 10.1021/cr300503rGoogle Scholar1ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFKgtLc%253D&md5=e09e6cf6a4c64fd3e8f21d55e151266eVisible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic SynthesisPrier, Christopher K.; Rankic, Danica A.; MacMillan, David W. C.Chemical Reviews (Washington, DC, United States) (2013), 113 (7), 5322-5363CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review will highlight the early work on the use of transition metal complexes as photoredox catalysts to promote reactions of org. compds. (prior to 2008), as well as cover the surge of work that has appeared since 2008. We have for the most part grouped reactions according to whether the org. substrate undergoes redn., oxidn., or a redox neutral reaction and throughout have sought to highlight the variety of reactive intermediates that may be accessed via this general reaction manifold.(b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075– 10166, DOI: 10.1021/acs.chemrev.6b00057Google Scholar1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsVSnsrw%253D&md5=82228f21987c3d000c62cf672cdcea82Organic Photoredox CatalysisRomero, Nathan A.; Nicewicz, David A.Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10075-10166CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Use of org. photoredox catalysts in a myriad of synthetic transformations with a range of applications was reviewed. This overview was arranged by catalyst class where the photophysics and electrochem. characteristics of each was discussed to underscore the differences and advantages to each type of single electron redox agent. Net reductive and oxidative as well as redox neutral transformations that could be accomplished using purely org. photoredox-active catalysts was highlighted. An overview of the basic photophysics and electron transfer theory was presented in order to provide a comprehensive guide for employing this class of catalysts in photoredox manifolds. - 2Sender, M.; Ziegenbalg, D. Light Sources for Photochemical Processes- Estimation of Technological Potentials. Chem. Ing. Tech. 2017, 89, 1159– 1173, DOI: 10.1002/cite.201600191Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCis7rJ&md5=50b4b98ad0ce47f553fe7c33df703ed3Light Sources for Photochemical Processes - Estimation of Technological PotentialsSender, Maximilian; Ziegenbalg, DirkChemie Ingenieur Technik (2017), 89 (9), 1159-1173CODEN: CITEAH; ISSN:0009-286X. (Wiley-VCH Verlag GmbH & Co. KGaA)This work theor. evaluates light sources currently com. available for the suitability to drive photoreactions. Comparative evaluation of different light sources reveals significant advantages of light-emitting diodes (LEDs) in the near UV and visible region, underlining the general superiority of narrow-band monochromatic light sources for photochem. processes. A generic anal. based on the av. volumetric rate of photon absorption shows the limits resulting from phys. fundamentals and the importance of the photon fluence rate for process intensification.
- 3
For selected examples discussing the influence of light attenuation on a the scale-up of a photochemical process, see:
(a) Harper, K. C.; Moschetta, E. G.; Bordawekar, S. V.; Wittenberger, S. J. A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light. ACS Cent. Sci. 2019, 5, 109– 115, DOI: 10.1021/acscentsci.8b00728Google Scholar3ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjsVOjtA%253D%253D&md5=b06ab0089d55b6491ef676396640c0f7A laser driven flow chemistry platform for scaling photochemical reactions with visible lightHarper, Kaid C.; Moschetta, Eric G.; Bordawekar, Shailendra V.; Wittenberger, Steven J.ACS Central Science (2019), 5 (1), 109-115CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Visible-light-promoted org. reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solns. exist to employ these reactions for multikilogram prodn. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochem. reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer-Lambert law as a guideline to optimize catalyst concn. and reactor depth for max. throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochem. reactions.(b) Horn, C. R.; Gremetz, S. A Method to Determine the Correct Photocatalyst Concentration for Photooxidation Reactions Conducted in Continuous Flow Reactors. Beilstein J. Org. Chem. 2020, 16, 871– 879, DOI: 10.3762/bjoc.16.78Google Scholar3bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVygtrzK&md5=315af5b3255a606385b0625990456284A method to determine the correct photocatalyst concentration for photooxidation reactions conducted in continuous flow reactorsHorn, Clemens R.; Gremetz, SylvainBeilstein Journal of Organic Chemistry (2020), 16 (), 871-879CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)When conducting a photooxidn. reaction, the key question is what is the best amt. of photocatalyst to be used in the reaction. This work demonstrates a fast and simple method to calc. a reliable concn. of the photocatalyst that will ensure an efficient reaction. The detn. is based on shifting the calcn. away from the concn. of the compd. to be oxidized to utilizing the limitations on the total light dose that can be delivered to the catalyst. These limitations are defined by the photoflow setup, specifically the channel height and the emission peak of the light source. This method was tested and shown to work well for three catalysts with different absorption properties through using LEDs with emission maxima close to the absorption max. of each catalyst.(c) Grimm, I.; Hauer, S. T.; Schulte, T.; Wycich, G.; Collins, K. D.; Lovis, K.; Candish, L. Upscaling Photoredox Cross-Coupling Reactions in Batch Using Immersion-Well Reactors. Org. Process Res. Dev. 2020, 24, 1185, DOI: 10.1021/acs.oprd.0c00070Google Scholar3chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVKntL7E&md5=3a112b1689753274c080d7af3715ee36Upscaling Photoredox Cross-Coupling Reactions in Batch Using Immersion-Well ReactorsGrimm, Isabelle; Hauer, Simone T.; Schulte, Tim; Wycich, Gina; Collins, Karl D.; Lovis, Kai; Candish, LisaOrganic Process Research & Development (2020), 24 (6), 1185-1193CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Herein we describe a straightforward approach for the scale-up of photoredox cross-coupling reactions from milligram to multigram scale using immersion-well batch reactors with minimal reoptimization of the reaction conditions. This approach can be applied to both homogeneous and, more significantly, heterogeneous reaction mixts. Furthermore, we have used an immersion-well side-loop reactor to perform a reaction on a 400 mmol scale (86 g of aryl bromide). - 4
For selected reviews of flow photochemistry, see:
(a) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. 2017, 117, 11796– 11893, DOI: 10.1021/acs.chemrev.7b00183Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Siu7c%253D&md5=d95f9e3c3cc5ed69d5ba5347eedd9ae9The Hitchhiker's Guide to Flow ChemistryPlutschack, Matthew B.; Pieber, Bartholomaeus; Gilmore, Kerry; Seeberger, Peter H.Chemical Reviews (Washington, DC, United States) (2017), 117 (18), 11796-11893CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)Flow chem. involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters, enhancing reactivity or in some cases enabling new reactions. This relatively young technol. has received a remarkable amt. of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, "Should we do this in flow" has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chem. and critically discusses recent flow chem. accounts.(b) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Flow Photochemistry: Old Light through New Windows. Beilstein J. Org. Chem. 2012, 8, 2025– 2052, DOI: 10.3762/bjoc.8.229Google Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVaqtbrJ&md5=c8d8baf08ac5c589d00fca25b228b561Flow photochemistry: Old light through new windowsKnowles, Jonathan P.; Elliott, Luke D.; Booker-Milburn, Kevin I.Beilstein Journal of Organic Chemistry (2012), 8 (), 2025-2052, No. 229CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A review. Synthetic photochem. carried out in classic batch reactors has, for over half a century, proved to be a powerful but under-utilized technique in general org. synthesis. Recent developments in flow photochem. have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in org. photochem., allowing a comparison of the various reactor types to be made.(c) Sambiagio, C.; Noël, T. Flow Photochemistry: Shine Some Light on Those Tubes!. Trends Chem. 2020, 2, 92– 106, DOI: 10.1016/j.trechm.2019.09.003Google Scholar4chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslejsLzF&md5=f435415805b2fc895c5e6ed2387d489bReview on flow photochemistry, shine some light on those tubesSambiagio, Carlo; Noel, TimothyTrends in Chemistry (2020), 2 (2), 92-106CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)A review. Continuous-flow chem. 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/methodol., in scale-up and prodn., and for rapid screening and optimization. Photochem. 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 chem. and its importance in modern chem. and technol. worldwide. This review highlights the most important features of continuous-flow technol. applied to photochem. processes and provides a general perspective on this rapidly evolving research field.(d) Politano, F.; Oksdath-Mansilla, G. Light on the Horizon: Current Research and Future Perspectives in Flow Photochemistry. Org. Process Res. Dev. 2018, 22, 1045– 1062, DOI: 10.1021/acs.oprd.8b00213Google Scholar4dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVegt7nN&md5=6e79f34c1b4ec557d581579243a9d36eLight on the Horizon: Current Research and Future Perspectives in Flow PhotochemistryPolitano, Fabrizio; Oksdath-Mansilla, GabrielaOrganic Process Research & Development (2018), 22 (9), 1045-1062CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Synthetic org. photochem. is a powerful tool for creating both natural products and mols. with high structural complexity in a simple way and under mild conditions. However, because of the challenges in scaling-up, it has been difficult to apply a photochem. reaction in an industrial process. Flow chem. provides an opportunity for better control over the conditions of the reaction and, addnl., improved reaction selectivity and enhanced reproducibility. Taking into account that significant interest has focused on the use of flow photochem. as a method for the synthesis of heterocycles and its applications in target-oriented synthesis over the past few years, the aim of this review is to highlight recent efforts to apply flow photochem. methodol. to diverse reactions as a greener and more scalable process for the pharmaceutical and fine chem. industries. Addnl., the review highlights future perspectives in the development of scale-up strategies, combining photochem. reactions in the continuous-flow multistep synthesis of org. mols., which is of interest for scientists and engineers alike.(e) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.; Berry, M. B.; Booker-Milburn, K. I. Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity. Chem. - Eur. J. 2014, 20, 15226– 15232, DOI: 10.1002/chem.201404347Google Scholar4ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVert7%252FO&md5=1233b84e9f56b37313f86867400c21f8Batch versus Flow Photochemistry: A Revealing Comparison of Yield and ProductivityElliott, Luke D.; Knowles, Jonathan P.; Koovits, Paul J.; Maskill, Katie G.; Ralph, Michael J.; Lejeune, Guillaume; Edwards, Lee J.; Robinson, Richard I.; Clemens, Ian R.; Cox, Brian; Pascoe, David D.; Koch, Guido; Eberle, Martin; Berry, Malcolm B.; Booker-Milburn, Kevin I.Chemistry - A European Journal (2014), 20 (46), 15226-15232CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The use of flow photochem. and its apparent superiority over batch has been reported by a no. of groups in recent years. To rigorously det. whether flow does indeed have an advantage over batch, a broad range of synthetic photochem. transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an av. productivity 20 % lower than that of batch, whereas three-layer reactors were 20 % more productive. Finally, the utility of flow chem. was demonstrated in the scale(coating process)-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.(f) Noël, T. A Personal Perspective on the Future of Flow Photochemistry. J. Flow Chem. 2017, 7, 87– 93, DOI: 10.1556/1846.2017.00022Google Scholar4fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygurs%253D&md5=c3832817edce6797a9e8be9e48227592A personal perspective on the future of flow photochemistryNoel, TimothyJournal of Flow Chemistry (2017), 7 (3-4), 87-93CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Photochem. and photoredox catalysis have witnessed a remarkable comeback in the last decade. Flow chem. has been of pivotal importance to alleviate some of the classical obstacles assocd. with photochem. Herein, we analyze some of the most exciting features provided by photo flow chem. as well as future challenges for the field.(g) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341, DOI: 10.1021/acs.chemrev.5b00707Google Scholar4ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVOjs7g%253D&md5=327c368f6e090142204920993c4faadaApplications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water TreatmentCambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, TimothyChemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.(h) Williams, J. D.; Kappe, C. O. Recent Advances towards Sustainable Flow Photochemistry. Curr. Opin. Green Sustain. Chem. 2020, DOI: 10.1016/j.cogsc.2020.05.001 .Google ScholarThere is no corresponding record for this reference. - 5
For an overview of flow photochemistry applications in industry, see:
(a) Noël, T.; Escriba-Gelonch, M.; Huvaere, K. Industrial Photochemistry: From Laboratory Scale to Industrial Scale. In Photochemical Processes In Continuous-flow Reactors: From Engineering Principles To Chemical Applications; Noël, T., Ed.; World Scientific: Singapore, 2017; pp 245– 267.Google ScholarThere is no corresponding record for this reference.(b) Pfoertner, K. H. Photochemistry in Industrial Synthesis. J. Photochem. 1984, 25, 91– 97, DOI: 10.1016/0047-2670(84)85018-2Google Scholar5bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXks1entb4%253D&md5=1cd23406514b762ab9bdc589466b3300Photochemistry in industrial synthesisPfoertner, K. H.Journal of Photochemistry (1984), 25 (1), 91-7CODEN: JPCMAE; ISSN:0047-2670.A review with 14 refs. - 6
For selected examples of “numbering up” and “scaling out” of flow photochemical processes, see:
(a) Su, Y.; Kuijpers, K.; Hessel, V.; Noël, T. A Convenient Numbering-up Strategy for the Scale-up of Gas-Liquid Photoredox Catalysis in Flow. React. Chem. Eng. 2016, 1, 73– 81, DOI: 10.1039/C5RE00021AGoogle Scholar6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSlt7%252FK&md5=58dd07aa48cbbb3b05500d00667f48bcA convenient numbering-up strategy for the scale-up of gas-liquid photoredox catalysis in flowSu, Yuanhai; Kuijpers, Koen; Hessel, Volker; Noel, TimothyReaction Chemistry & Engineering (2016), 1 (1), 73-81CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Visible-light photocatalysis is a mild activation method for small mols. and enables a wide variety of transformations relevant for org. synthetic chem. However, one of the limitations of photocatalysis and photochem. in general is the limited scalability due to the absorption of light (Lambert-Beer law). Here, we report the development of a convenient numbering-up strategy for the scale-up of gas-liq. photocatalytic reactions in which the gas is consumed. Only com. available constituents were used and the system can be rapidly assembled by any practitioner of flow chem. The modular design allows us to systematically scale the photochem. within 2n parallel reactors (herein, n = 0, 1, 2, 3). The flow distribution in the absence of reactions was excellent, showing a std. deviation less than 5%. Next, we used the numbered-up photomicroreactor assembly to enable the scale-up of the photocatalytic aerobic oxidn. of thiols to disulfides. The flow distribution was again very good with a std. deviation lower than 10%. The yield of the target disulfide in the numbered-up assemblies was comparable to the results obtained in a single device demonstrating the feasibility of our approach.(b) Kuijpers, K. P. L.; Van Dijk, M. A. H.; Rumeur, Q. G.; Hessel, V.; Su, Y.; Noël, T. A Sensitivity Analysis of a Numbered-up Photomicroreactor System. React. Chem. Eng. 2017, 2, 109– 115, DOI: 10.1039/C7RE00024CGoogle Scholar6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktFykuro%253D&md5=d59ce49f3849743021a740849c251ec7A sensitivity analysis of a numbered-up photomicroreactor systemKuijpers, Koen P. L.; van Dijk, Mark A. H.; Rumeur, Quentin G.; Hessel, Volker; Su, Yuanhai; Noel, TimothyReaction Chemistry & Engineering (2017), 2 (2), 109-115CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Limitations with regard to the scalability of photochem. reactions can be efficiently overcome by using numbered-up microreactor technol. Here, the robustness of such a numbered-up capillary photomicroreactor system is tested when subjected to potential disturbances, such as channel blockage and light source failure. Channel blockage leads to relatively large changes in both flow distribution and yield. However, we found that the performance can be accurately predicted thus making it possible to adjust the reaction parameters to obtain certain output targets. Light source failure did not lead to large variations in the mass flow distribution, highlighting the importance of the flow distributor section. Since the reaction is photocatalyzed, the impact on the reaction yield was significant in the reactor where the light failure occurred.(c) Zhao, F.; Cambié, D.; Janse, J.; Wieland, E. W.; Kuijpers, K. P. L.; Hessel, V.; Debije, M. G.; Noël, T. Scale-up of a Luminescent Solar Concentrator-Based Photomicroreactor via Numbering-Up. ACS Sustainable Chem. Eng. 2018, 6, 422– 429, DOI: 10.1021/acssuschemeng.7b02687Google Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOltLfK&md5=fbc07bc301bd7ed91a83e8aef21d5602Scale-up of a Luminescent Solar Concentrator-Based Photomicroreactor via Numbering-upZhao, Fang; Cambie, Dario; Janse, Jeroen; Wieland, Eric W.; Kuijpers, Koen P. L.; Hessel, Volker; Debije, Michael G.; Noel, TimothyACS Sustainable Chemistry & Engineering (2018), 6 (1), 422-429CODEN: ASCECG; ISSN:2168-0485. (American Chemical Society)The use of solar energy to power chem. reactions is a long-standing dream of the chem. community. Recently, visible-light-mediated photoredox catalysis has been recognized as the ideal catalytic transformation to convert solar energy into chem. bonds. However, scaling photochem. transformations has been extremely challenging due to Bouguer-Lambert-Beer law. Recently, we have pioneered the development of luminescent solar concentrator photomicroreactors (LSC-PMs), which display an excellent energy efficiency. These devices harvest solar energy, convert the broad solar energy spectrum to a narrow-wavelength region, and subsequently waveguide the re-emitted photons to the reaction channels. Herein, we report on the scalability of such LSC-PMs via a numbering-up strategy. Paramount in our work was the use of molds that were fabricated via 3D printing. This allowed us to rapidly produce many different prototypes and to optimize exptl. key design aspects in a time-efficient fashion. Reactors up to 32 parallel channels have been fabricated that display an excellent flow distribution using a bifurcated flow distributor (std. deviations below 10%). This excellent flow distribution was crucial to scale up a model reaction efficiently, displaying yields comparable to those obtained in a single-channel device. We also found that interchannel spacing is an important and unique design parameter for numbered-up LSC-PMs, which influences greatly the photon flux experienced within the reaction channels.(d) Williams, J. D.; Nakano, M.; Gérardy, R.; Rincon, J. A.; de Frutos, O.; Mateos, C.; Monbaliu, J.-C. M.; Kappe, C. O. Finding the Perfect Match: A Combined Computational and Experimental Study Towards Efficient and Scalable Photosensitized [2 + 2] Cycloadditions in Flow. Org. Process Res. Dev. 2019, 23, 78– 87, DOI: 10.1021/acs.oprd.8b00375Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1WitrvP&md5=7ed6fe1176ab82787d41b006fe529cc3Finding the perfect match a combined computational and experimental study toward efficient and scalable photosensitized [2 + 2] cycloadditions in flowWilliams, Jason D.; Nakano, Momoe; Gerardy, Romaric; Rincon, Juan A.; de Frutos, Oscar; Mateos, Carlos; Monbaliu, Jean-Christophe M.; Kappe, C. OliverOrganic Process Research & Development (2019), 23 (1), 78-87CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)With ever-evolving light-emitting diode (LED) technol., classical photochem. transformations are becoming accessible with more efficient and industrially viable light sources. In combination with a triplet sensitizer, we report the detailed exploration of [2 + 2] cycloaddns., in flow, of various maleic anhydride derivs. with gaseous ethylene. By the use of a flow reactor capable of gas handling and LED wavelength/power screening, an in-depth optimization of these reactions was carried out. In particular, we highlight the importance of matching the substrate and sensitizer triplet energies alongside the light source emission wavelength and power. Initial triplet-sensitized reactions of maleic anhydride were hampered by benzophenone's poor absorbance at 375 nm. However, d. functional theory (DFT) calcns. predicted that derivs. such as citraconic anhydride have low enough triplet energies to undergo triplet transfer from thioxanthone, whose absorbance matches the LED emission at 375 nm. This observation held true exptl., allowing optimization and further exemplification in a larger-scale reactor, whereby >100 g of material was processed in 10 h. These straightforward DFT calcns. were also applied to a no. of other substrates and showed a good correlation with exptl. data, implying that their use can be a powerful strategy in targeted reaction optimization for future substrates.(e) Malet-Sanz, L.; Susanne, F. Continuous Flow Synthesis. A Pharma Perspective. J. Med. Chem. 2012, 55, 4062– 4098, DOI: 10.1021/jm2006029Google Scholar6ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVSqtLc%253D&md5=23f3d763f8072c7404f54076f9d2d78aContinuous Flow Synthesis. A Pharma PerspectiveMalet-Sanz, Laia; Susanne, FlavienJournal of Medicinal Chemistry (2012), 55 (9), 4062-4098CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Continuous flow chem. as a technique and the latest developments in the field are being reviewed from a Pharma point of view. - 7
Smart dimensioning entails the scale-up of reactor dimensions, performed rationally, in order to maintain the desired heat and mass transfer characteristics. For further information on this concept, see:
(a) Kockmann, N. Microfluidic Networks. Handbook of Micro Reactors; Wiley-VCH: Weinheim, 2009; pp 41– 58.Google ScholarThere is no corresponding record for this reference.(b) Anderson, N. G. Using Continuous Processes to Increase Production. Org. Process Res. Dev. 2012, 16, 852– 869, DOI: 10.1021/op200347kGoogle Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1eht7s%253D&md5=50d53e5fe332220fb15154b7d4965274Using Continuous Processes to Increase ProductionAnderson, Neal G.Organic Process Research & Development (2012), 16 (5), 852-869CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. Continuous operations have become popular in both academia and the pharmaceutical industry. Continuous operations may be developed to make high-quality material safely, or because continuous operations are the only effective and economical way to make larger quantities of material. This review surveys the area of continuous processes used to make larger quantities of material and discusses the feasibility of developing economical continuous operations.(c) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Deciding Whether to Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis. Angew. Chem., Int. Ed. 2011, 50, 7502– 7519, DOI: 10.1002/anie.201004637Google Scholar7chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotVCns74%253D&md5=59de6e352a85f817def2f60aa4bcb46cDeciding whether to go with the flow: evaluating the merits of flow reactors for synthesisHartman, Ryan L.; McMullen, Jonathan P.; Jensen, Klavs F.Angewandte Chemie, International Edition (2011), 50 (33), 7502-7519, S7502/1-S7502/3CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The fine chems. and pharmaceutical industries are transforming how their products are manufd., where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chem. on all scales-from the lab. to full prodn. This article discusses the relative merits of batch and micro flow reactors for performing synthetic chem. in the lab.(d) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry. ChemSusChem 2013, 6, 746– 789, DOI: 10.1002/cssc.201200766Google Scholar7dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtFSmt78%253D&md5=54ec4b97766860a302d25e0c421d3a5dNovel Process Windows for Enabling, Accelerating, and Uplifting Flow ChemistryHessel, Volker; Kralisch, Dana; Kockmann, Norbert; Noel, Timothy; Wang, QiChemSusChem (2013), 6 (5), 746-789CODEN: CHEMIZ; ISSN:1864-5631. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Novel Process Windows make use of process conditions that are far from conventional practices. This involves the use of high temps., high pressures, high concns. (solvent-free), new chem. transformations, explosive conditions, and process simplification and integration to boost synthetic chem. on both the lab. and prodn. scale. Such harsh reaction conditions can be safely reached in microstructured reactors due to their excellent transport intensification properties. This Review discusses the different routes towards Novel Process Windows and provides several examples for each route grouped into different classes of chem. and process-design intensification. - 8(a) Rehm, T. H. Reactor Technology Concepts for Flow Photochemistry. ChemPhotoChem. 2020, 4, 235– 254, DOI: 10.1002/cptc.201900247Google Scholar8ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlyis7bE&md5=6d7c5cf13232f531905b6ce31dcc8a4bReactor Technology Concepts for Flow PhotochemistryRehm, Thomas H.ChemPhotoChem (2020), 4 (4), 235-254CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Synthetic org. photochem. has been intensively carried out in the 20th century and paved the way to the prepn. of complex org. mols., which were not yet accessible via thermal chem. Several photochem. synthesis routes have found their way into industrial applications for the prodn. of everyday commodities, but photochem. was still underutilized until recently as a synthesis method in org. chem. With the advent of novel photocatalytic and photophys. concepts for the use of high power visible light, the research field of synthetic org. photochem. has evolved to become a vivid and highly recognized technique in the last years. Fortunately, continuous flow technol. has also become an increasingly accepted tool and has proved to be an excellent key player for the advancement of photochem. in academic and industrial research settings. This Review provides an overview on the recent developments of continuous flow photoreactors and their application to photochem. syntheses under mild and defined process conditions.(b) Corcoran, E. B.; Mcmullen, J. P.; Wismer, M. K.; Naber, J. R. Photon Equivalents as a Parameter for Scaling Photoredox Reactions in Flow: Translation of Photocatalytic C–N Cross-Coupling from Lab Scale to Multikilogram Scale. Angew. Chem., Int. Ed. 2020, DOI: 10.1002/anie.201915412 .Google ScholarThere is no corresponding record for this reference.(c) Lee, D. S.; Sharabi, M.; Jefferson-Loveday, R.; Pickering, S. J.; Poliakoff, M.; George, M. W. Scalable Continuous Vortex Reactor for Gram to Kilo Scale for UV and Visible Photochemistry. Org. Process Res. Dev. 2020, 24, 201– 206, DOI: 10.1021/acs.oprd.9b00475Google Scholar8chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1WhtrY%253D&md5=5ccf393839351543f959a46d9a8c89dcScalable continuous vortex reactor for gram to kilo scale for UV and visible photochemistryLee, Darren S.; Sharabi, Medhat; Jefferson-Loveday, Richard; Pickering, Stephen J.; Poliakoff, Martyn; George, Michael W.Organic Process Research & Development (2020), 24 (2), 201-206CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)We report the development of a scalable continuous Taylor vortex reactor for both UV and visible photochem. This builds on our recent report (Org. Process Res. Dev.2017,21, 1042) detailing a new approach to continuous visible photochem. Here, we expand this by showing that our approach can also be applied to UV photochem. and that either UV or visible photochem. can be scaled-up using our design. We have achieved scale-up in productivity of over 300× with a visible light photo-oxidn. that requires oxygen gas and 10× with a UV-induced [2 + 2] cycloaddn. obtaining scales of up to 7.45 kg day-1 for the latter. Furthermore, we demonstrate that oxygen is efficiently taken up in the reactions of singlet O2, and for the examples examd., that near-stoichiometric quantities of oxygen can be used with little loss of reactor productivity. Furthermore, our design should be scalable to a substantially larger size and have the potential for scaling-out with reactors in parallel.(d) Elliott, L. D.; Berry, M.; Harji, B.; Klauber, D.; Leonard, J.; Booker-Milburn, K. I. A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram Scale. Org. Process Res. Dev. 2016, 20, 1806– 1811, DOI: 10.1021/acs.oprd.6b00277Google Scholar8dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWnt7zK&md5=2db2bb0d0f1c5f8c3707b503d5657fd0A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram ScaleElliott, Luke D.; Berry, Malcolm; Harji, Bashir; Klauber, David; Leonard, John; Booker-Milburn, Kevin I.Organic Process Research & Development (2016), 20 (10), 1806-1811CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The development of a highly compact and powerful reactor for synthetic org. photochem. is described enabling a 10-fold redn. in reaction times, with up to 30% more power efficiency than previous fluorinated ethylene propylene tube reactors. Two reactions gave over 1 kg of product in 24 h. Two other reactions had productivities of 4 and 8 kg in 24 h. The reactor consists of a succession of quartz tubes connected together in series and arranged axially around a variable power mercury lamp. This compact and relatively simple device can be safely operated in a std. fumehood.(e) Roibu, A.; Morthala, R. B.; Leblebici, M. E.; Koziej, D.; Van Gerven, T.; Kuhn, S. Design and Characterization of Visible-Light LED Sources for Microstructured Photoreactors. React. Chem. Eng. 2018, 3, 849– 865, DOI: 10.1039/C8RE00165KGoogle Scholar8ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVOjtLfJ&md5=c76c7bce4af14f36348c3c5fbe32fc72Design and characterization of visible-light LED sources for microstructured photoreactorsRoibu, Anca; Morthala, Rishi Bharadwaj; Leblebici, M. Enis; Koziej, Dorota; Van Gerven, Tom; Kuhn, SimonReaction Chemistry & Engineering (2018), 3 (6), 849-865CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)The design of stable, compact, and uniform LED light sources for continuous microstructured photoreactors is reported. The elec. and thermal properties of green LEDs are translated into an efficient control and cooling strategy. To study the irradiance uniformity and efficiency to irradiate the microfluidic channel, narrow viewing angle LEDs were configured in four arrays. The irradiance uniformity experienced by the microchannel is detd. with an irradiance model, which is improved by using near-field goniophotometer measurements for small distances between the light source and reactor. Maximum light uniformity is achieved below the LED-reactor distance of 1.5 cm. Exceeding this distance and employing arrays with a larger no. of LEDs did not improve the uniformity on the microchannel. Furthermore, the energy efficiency of the photoreactor is quantified by combining near-field goniophotometer measurements, irradiance modeling and actinometry. It was shown that below 2 cm the photon losses were reduced when the LED positions matched the microchannel geometry, however a low utilization of the consumed elec. energy is obsd. irresp. of the LED array design. The characterization methodol. presented in this study enables the identification and quantification of the limiting factors.(f) Ziegenbalg, D.; Wriedt, B.; Kreisel, G.; Kralisch, D. Investigation of Photon Fluxes within Microstructured Photoreactors Revealing Great Optimization Potentials. Chem. Eng. Technol. 2016, 39, 123– 134, DOI: 10.1002/ceat.201500498Google Scholar8fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvF2itbbO&md5=751b46ddc44ed26b302512cb764a9553Investigation of Photon Fluxes within Microstructured Photoreactors Revealing Great Optimization PotentialsZiegenbalg, Dirk; Wriedt, Benjamin; Kreisel, Guenter; Kralisch, DanaChemical Engineering & Technology (2016), 39 (1), 123-134CODEN: CETEER; ISSN:1521-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)A simple model for detg. potential bottlenecks of a photoreactor setup focusing on the photon fluxes is presented. The application of the concept can reveal optimization potentials and gives insights into the sensitivity of the reactor setup to different optimization possibilities. The introduced model benefits from the concept of using only data already available from optimization studies of the process conditions. Applying the introduced concept to the characterization of a previously developed modular org. light-emitting diode reactor setup revealed great optimization potentials, esp. with respect to the external photonic efficiency. Interestingly, the attempt to enhance the external photonic efficiency by increasing the projection area of the reactor did not provide any improvement. This is attributed to a significant effect of reflection and scattering within the setup.
- 9Saikia, I.; Borah, A. J.; Phukan, P. Use of Bromine and Bromo-Organic Compounds in Organic Synthesis. Chem. Rev. 2016, 116, 6837– 7042, DOI: 10.1021/acs.chemrev.5b00400Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xot1ertb8%253D&md5=c7dbec3b61269455bdd6ed00df766eabUse of Bromine and Bromo-Organic Compounds in Organic SynthesisSaikia, Indranirekha; Borah, Arun Jyoti; Phukan, ProdeepChemical Reviews (Washington, DC, United States) (2016), 116 (12), 6837-7042CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Bromination is one of the most important transformations in org. synthesis and can be carried out using bromine and many other bromo compds. Use of mol. bromine in org. synthesis is well-known. However, due to the hazardous nature of bromine, enormous growth has been witnessed in the past several decades for the development of solid bromine carriers. This review outlines the use of bromine and different bromo-org. compds. in org. synthesis. The applications of bromine, a total of 107 bromo-org. compds., 11 other brominating agents, and a few natural bromine sources were incorporated. The scope of these reagents for various org. transformations such as bromination, cohalogenation, oxidn., cyclization, ring-opening reactions, substitution, rearrangement, hydrolysis, catalysis, etc. has been described briefly to highlight important aspects of the bromo-org. compds. in org. synthesis.
- 10(a) Sabuzi, F.; Pomarico, G.; Floris, B.; Valentini, F.; Galloni, P.; Conte, V. Sustainable Bromination of Organic Compounds: A Critical Review. Coord. Chem. Rev. 2019, 385, 100– 136, DOI: 10.1016/j.ccr.2019.01.013Google Scholar10ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivFSkur0%253D&md5=84170aa27dff2f521bf590b48c5a038fSustainable bromination of organic compounds: A critical reviewSabuzi, Federica; Pomarico, Giuseppe; Floris, Barbara; Valentini, Francesca; Galloni, Pierluca; Conte, ValeriaCoordination Chemistry Reviews (2019), 385 (), 100-136CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)A review. This review was devoted to collect and discuss papers dealing with "green" procedures for introducing bromine atom(s) into org. mols., a reaction of primary synthetic and industrial importance. Both direct bromination and oxidative bromination are accounted for. The sustainability was critically discussed.(b) Niemeier, J. K.; Kjell, D. P. Hydrazine and Aqueous Hydrazine Solutions: Evaluating Safety in Chemical Processes. Org. Process Res. Dev. 2013, 17, 1580– 1590, DOI: 10.1021/op400120gGoogle Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVSitrbM&md5=f58290c92e9d861d26d509067e043150Hydrazine and Aqueous Hydrazine Solutions: Evaluating Safety in Chemical ProcessesNiemeier, Jeffry K.; Kjell, Douglas P.Organic Process Research & Development (2013), 17 (12), 1580-1590CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review concerning the hazards of hydrazine and its aq. solns. to understand the important role diln. plays in increasing inherent safety of aq. hydrazine solns. is given. The intent is to provide enough information to allow readers to decide if hydrazine may be acceptable for a given application, and if so, what concn. range may provide an acceptable safety and environmental risk. Examples are provided to illustrate the strong effect catalysts have on decompn. reactions. Topics discussed include: hazard overview; flammability (at atm. pressure in air, effect of pressure, potential deflagration in absence of air, effect of inerting agents, effect of catalysts); explosion risk; thermal stability and effect of materials of construction; analyzing runaway reaction potential as function of hydrazine concn. and materials of construction; evaluating pressure generation in closed vessels; emergency relief system calcns.; reactivity; toxicity and personal protection; release mitigation and air dispersion modeling; regulatory considerations; conclusions; and supplementary information (estd. heat of decompn., hydrazine properties, hydrazine hydrate properties, aq. hydrazine properties).
- 11
For selected examples of photochemical benzylic bromination using NBS, see:
(a) Bonfield, H. E.; Williams, J. D.; Ooi, W.-X.; Leach, S. G.; Kerr, W. J.; Edwards, L. J. A Detailed Study of Irradiation Requirements Towards an Efficient Photochemical Wohl-Ziegler Procedure in Flow. ChemPhotoChem. 2018, 2, 938– 944, DOI: 10.1002/cptc.201800082Google Scholar11ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFGlur%252FO&md5=a310176e0e522907fd636af51223939fA Detailed Study of Irradiation Requirements Towards an Efficient Photochemical Wohl-Ziegler Procedure in FlowBonfield, Holly E.; Williams, Jason D.; Ooi, Wei Xiang; Leach, Stuart G.; Kerr, William J.; Edwards, Lee J.ChemPhotoChem (2018), 2 (10), 938-944CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)A platform has been developed to enable standardization of light sources, allowing consistent scale-up from high-throughput screening in batch to flow, using the same pseudo-monochromatic light source. The impact of wavelength and light intensity on a photochem. reaction was evaluated within this platform using the Wohl-Ziegler benzylic bromination of 4-methyl-3-(trifluoromethyl)benzonitrile with N-bromosuccinimide as a model system. It was found that only 40% of the max. light intensity was required while still maintaining reaction rate, allowing more reliable temp. control and lower energy consumption. The optimized reaction conditions were subsequently applied to a range of synthetically relevant (hetero)arom. compds. under continuous conditions, exploring the scope of the process within a mild and scalable procedure.(b) Deshpande, S.; Gadilohar, B.; Shinde, Y.; Pinjari, D.; Pandit, A.; Shankarling, G. Energy Efficient, Clean and Solvent Free Photochemical Benzylic Bromination Using NBS in Concentrated Solar Radiation (CSR). Sol. Energy 2015, 113, 332– 339, DOI: 10.1016/j.solener.2015.01.008Google Scholar11bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslakt74%253D&md5=28a47f440192a308e55f7d6cd0085982Energy efficient, clean and solvent-free photochemical benzylic bromination using NBS in concentrated solar radiation (CSR)Deshpande, Saurabh; Gadilohar, Balu; Shinde, Yogesh; Pinjari, Dipak; Pandit, Aniruddha; Shankarling, GanapatiSolar Energy (2015), 113 (), 332-339CODEN: SRENA4; ISSN:0038-092X. (Elsevier Ltd.)An environmentally benign, clean, solvent-free approach for benzylic bromination has been developed using concd. solar radiation (CSR). The protocol was found to be superior to the conventional photochem. and thermal methods in terms of reaction time and total energy requirement. This method was adapted with concd. solar radiation in solvent-free conditions without the use of radical initiators and has proved to provide substituted benzyl bromides RCH2Br (R = 2-MeC6H4, 2-FC6H4, 3-O2NC6H4, etc.) in good yields.(c) Cantillo, D.; De Frutos, O.; Rincon, J. A.; Mateos, C.; Kappe, C. O. A Scalable Procedure for Light-Induced Benzylic Brominations in Continuous Flow. J. Org. Chem. 2014, 79, 223– 229, DOI: 10.1021/jo402409kGoogle Scholar11chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVajtbrM&md5=50d22314ca29dcd80dbf85d8eb0a9742A Scalable Procedure for Light-Induced Benzylic Brominations in Continuous FlowCantillo, David; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. OliverJournal of Organic Chemistry (2014), 79 (1), 223-229CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A continuous-flow protocol for the bromination of benzylic compds. with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates contg. different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h-1), which is not easily possible in batch photochem. reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h-1 for the desired bromide was achieved.(d) Ni, S.; El Remaily, M. A. E. A. A. A.; Franzén, J. Carbocation Catalyzed Bromination of Alkyl Arenes, a Chemoselective Sp3 vs. Sp2 C-H Functionalization. Adv. Synth. Catal. 2018, 360, 4197– 4204, DOI: 10.1002/adsc.201800788Google Scholar11dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslaiurjN&md5=ccd479aaefc53bd51bb3155192c2e393Carbocation Catalyzed Bromination of Alkyl Arenes, a Chemoselective sp3 vs. sp2 C-H functionalization.Ni, Shengjun; El Remaily, Mahmoud Abd El Aleem Ali Ali; Franzen, JohanAdvanced Synthesis & Catalysis (2018), 360 (21), 4197-4204CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)The versatility of the trityl cation (TrBF4) as a highly efficient Lewis acid organocatalyst is demonstrated in a light induced benzylic brominaion of alkyl-arenes under mild conditions. The reaction was conducted at ambient temp. under common hood light (55 W fluorescent light) with catalyst loadings down to 2.0 mol% using N-bromosuccinimide (NBS) as the brominating agent. The protocol is applicable to an extensive no. of substrates to give benzyl bromides in good to excellent yields. In contrast to most previously reported strategies, this protocol does not require any radical initiator or extensive heating. For electron-rich alkyl-arenes, the trityl ion catalyzed bromination could be easily switched between benzylic sp3 C-H functionalization and arene sp2 C-H functionalization by simply alternating the solvent. This chemoselective switch allows for high substrate control and easy prepn. of benzyl bromides and bromoarenes, resp. The chemoselective switch was also applied in a one-pot reaction of 1-methylnaphthalene for direct introduction of both sp3 C-Br and sp2 C-Br functionality. - 12Eissen, M.; Lenoir, D. Electrophilic Bromination of Alkenes: Environmental, Health and Safety Aspects of New Alternative Methods. Chem. - Eur. J. 2008, 14, 9830– 9841, DOI: 10.1002/chem.200800462Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVCrtbfP&md5=509aa9467dd782a8d14416dc3bcc7784Electrophilic bromination of alkenes: environmental, health and safety aspects of new alternative methodsEissen, Marco; Lenoir, DieterChemistry - A European Journal (2008), 14 (32), 9830-9841CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. More than twenty alternative methods for bromination of alkenes have been evaluated taking into consideration their resource demands, waste prodn. as well as environmental, health and safety aspects. The cost of bromine and the substances designated to circumvent the application of mol. bromine have also been taken into account. As bromine is only one of several problematic substances being used, its avoidance - by applying bromine supported on solid material or by performing the in situ generation of bromine - does not significantly reduce the technol. requirements. On the contrary, the resource demands and amt. of waste produced by most new methods are significantly higher compared to the std. methods, esp. if the recycling of a carrying agent is not efficient. The method using hydrobromic acid and hydrogen peroxide can be regarded as a competitive alternative to the std. method. The application of certain carrying agents could be interesting, because solvents such as carbon tetrachloride or chloroform used during synthesis could be replaced with less problematic ones during work-up. However, problems assocd. with these alternatives are not resolved as yet.
- 13(a) Van Kerrebroeck, R.; Naert, P.; Heugebaert, T. S. A.; D’hooghe, M.; Stevens, C. V. Electrophilic Bromination in Flow: A Safe and Sustainable Alternative to the Use of Molecular Bromine in Batch. Molecules 2019, 24, 2116, DOI: 10.3390/molecules24112116Google Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSlsr3O&md5=48b84f2486419c48070eca39a178be26Electrophilic bromination in flow: a safe and sustainable alternative to the use of molecular bromine in batchVan Kerrebroeck, Reinout; Naert, Pieter; Heugebaert, Thomas S. A.; D'Hooghe, Matthias; Stevens, Christian V.Molecules (2019), 24 (11), 2116CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Bromination reactions are crucial in today's chem. industry since the versatility of the formed organobromides e.g., I makes them suitable building blocks for numerous syntheses. However, the use of the toxic and highly reactive mol. bromine (Br2) makes these brominations very challenging and hazardous. A safe and straightforward protocol for bromination in continuous flow has been described. The hazardous Br2 or KOBr is generated in situ by reacting an oxidant (NaOCl) with HBr or KBr, resp., which is directly coupled to the bromination reaction and a quench of residual bromine. This protocol was demonstrated by polybrominating both alkenes (E,E,Z)-1,5,9-cyclododecatriene and arom. substrates II in a wide variety of solvents, with yields ranging from 78% to 99%.(b) Cantillo, D.; Kappe, C. O. Halogenation of Organic Compounds Using Continuous Flow and Microreactor Technology. React. Chem. Eng. 2017, 2, 7– 19, DOI: 10.1039/C6RE00186FGoogle Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVKgtb7E&md5=57cfebe54eb4ada53b66af0e247e70b2Halogenation of organic compounds using continuous flow and microreactor technologyCantillo, David; Kappe, C. OliverReaction Chemistry & Engineering (2017), 2 (1), 7-19CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)A review. The halogenation of org. substrates is one the most important transformations in org. synthesis. The most straightforward, inexpensive and atom economic halogenations involve the use of elemental halogens (X2) or hydrogen halides (HX). However, X2 and HX reagents are highly reactive, toxic and corrosive materials. Halogenations using these reagents are usually very fast and exothermic reactions, in which selectivity issues occur. Using continuous flow chem. halogenations involving X2 and HX can be performed in a safe and controllable manner. Reagents can be accurately dosed even for gas/liq. reactions, and exotherms are easily controlled. Hazardous chems. can be readily quenched in line avoiding any undesired exposures and significantly enhancing the process safety.
- 14Steiner, A.; Williams, J. D.; De Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O. Continuous Photochemical Benzylic Bromination Using In Situ Generated Br2: Process Intensification towards Optimal PMI and Throughput. Green Chem. 2020, 22, 448– 454, DOI: 10.1039/C9GC03662HGoogle Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlGhurvP&md5=e5c553cd71cc781f93e033b74e373a8aContinuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughputSteiner, Alexander; Williams, Jason D.; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. OliverGreen Chemistry (2020), 22 (2), 448-454CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The detailed development of photochem. benzylic brominations using a NaBrO3/HBr bromine generator in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photochem. reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of org. solvent, allowed a redn. in PMI from 13.25 to just 4.33. The photochem. transformation achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s. The org. solvent-free prepn. of two pharmaceutically relevant building blocks was demonstrated with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromination (15 g scale in 20 min, PMI = 3.64).
- 15Nair, S. M. K.; Jacob, P. D. The Effect of Doping on the Thermal Decomposition of Sodium Bromate. Thermochim. Acta 1991, 181, 269– 276, DOI: 10.1016/0040-6031(91)80429-MGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXkvVChsLs%253D&md5=0456f3990e3aca13ccd714857e854253The effect of doping on the thermal decomposition of sodium bromateNair, S. M. K.; Jacob, P. DaisammaThermochimica Acta (1991), 181 (), 269-76CODEN: THACAS; ISSN:0040-6031.The thermal decompn. of NaBrO3 doped with KBrO3 and NaBr, each in the mole fraction range 10-4-10-1, was studied by TG. The activation energy, frequency factor, and entropy of activation were computed using the A.W. Coats-J.P. Redfern (1964), E.S. Freeman- B. Carroll (1958) and H.H. Horowitz-G. Metzger (1963) methods. Doping enhances the decompn. and decreases the energy of activation, the effect increasing with increase in concn. of the dopant. The mechanism of decompn. follows the M. Avrami (1939) equation, 1-(1-α)1/3 = kt, and the rate-controlling process is a phase-boundary reaction assuming spherical symmetry.
- 16Procopiou, P. A.; Barrett, V. J.; Bevan, N. J.; Biggadike, K.; Box, P. C.; Butchers, P. R.; Coe, D. M.; Conroy, R.; Emmons, A.; Ford, A. J. Synthesis and Structure-Activity Relationships of Long-Acting B2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach. J. Med. Chem. 2010, 53, 4522– 4530, DOI: 10.1021/jm100326dGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvFKqt7o%253D&md5=3b59a1fdaba51d1688c14a3da96b4b4dSynthesis and Structure-Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug ApproachProcopiou, Panayiotis A.; Barrett, Victoria J.; Bevan, Nicola J.; Biggadike, Keith; Box, Philip C.; Butchers, Peter R.; Coe, Diane M.; Conroy, Richard; Emmons, Amanda; Ford, Alison J.; Holmes, Duncan S.; Horsley, Helen; Kerr, Fern; Li-Kwai-Cheung, Anne-Marie; Looker, Brian E.; Mann, Inderjit S.; McLay, Iain M.; Morrison, Valerie S.; Mutch, Peter J.; Smith, Claire E.; Tomlin, PaulaJournal of Medicinal Chemistry (2010), 53 (11), 4522-4530CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepd. by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compds. were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compds. were assessed on isolated superfused guinea pig trachea. I had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Cryst. salts of I (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for I to the β2-receptor is presented.
- 17Veraldi, S. Isoconazole Nitrate: A Unique Broad-Spectrum Antimicrobial Azole Effective in the Treatment of Dermatomycoses, Both as Monotherapy and in Combination with Corticosteroids. Mycoses 2013, 56, 3– 15, DOI: 10.1111/myc.12054Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVKktL4%253D&md5=f8dd368ab3001d862cba87020209975dIsoconazole nitrate: a unique broad-spectrum antimicrobial azole effective in the treatment of dermatomycoses, both as monotherapy and in combination with corticosteroidsVeraldi, StefanoMycoses (2013), 56 (Suppl. 1), 3-15CODEN: MYCSEU; ISSN:1439-0507. (Wiley-Blackwell)A review. Fungal skin infections, or dermatomycoses, are assocd. with a broad range of pathogens. Involvement of gram-pos. bacteria is often suspected in dermatomycoses. Inflammation plays an important role in dermatomycoses, displaying a close assocn. between frequent inflammation and reduced skin-related quality of life. Isoconazole nitrate (ISN) is a broad-spectrum antimicrobial agent with a highly effective antimycotic and gram-pos. antibacterial activity, a rapid rate of absorption and low systemic exposure potential. ISN is effective against pathogens involved in dermatomycoses, with min. inhibitory concns. well below the concn. of ISN in skin and hair follicles. The combination of the corticosteroid diflucortolone valerate with ISN (Travocort) increases the local bioavailability of ISN. Compared with ISN monotherapy, Travocort has a faster onset of antimycotic action, faster relief of itch and other inflammatory symptoms, improved overall therapeutic benefits and earlier mycol. cure rate. Travocort is effective in the treatment of inflammatory mycotic infections, and also in the eradication of accompanied grampos. bacterial infections. The rapid improvement obsd. with Travocort treatment, combined with favorable safety and tolerability, results in higher patient satisfaction, and therefore, can be an effective tool to increase treatment adherence in patients with dermatomycoses accompanied by inflammatory signs and symptoms.
- 18
For selected examples of these devices used at various scales, see:
(a) Bianchi, P.; Petit, G.; Monbaliu, J.-C. M. Scalable and Robust Photochemical Flow Process towards Small Spherical Gold Nanoparticles. React. Chem. Eng. 2020, DOI: 10.1039/D0RE00092B .Google ScholarThere is no corresponding record for this reference.(b) Steiner, A.; Williams, J. D.; Rincon, J. A.; De Frutos, O.; Mateos, C.; Kappe, C. O. Implementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid and Selective Reductive Photoredox Transformations in Continuous Flow. Eur. J. Org. Chem. 2019, 2019, 5807– 5811, DOI: 10.1002/ejoc.201900952Google Scholar18bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVelsbzE&md5=2431cf35ccf2f78821f1ba3a5f01ebcaImplementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid and Selective Reductive Photoredox Transformations in Continuous FlowSteiner, Alexander; Williams, Jason D.; Rincon, Juan A.; de Frutos, Oscar; Mateos, Carlos; Kappe, C. OliverEuropean Journal of Organic Chemistry (2019), 2019 (33), 5807-5811CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)By combining a highly reducing org. photocatalyst with a thiol hydrogen atom transfer (HAT) catalyst, a rapid and highly selective reaction of aryl halides in continuous flow was performed to afford arom. compds. The fast redn. of aryl iodides, bromides and chlorides were demonstrated with residence times in some cases below one minute. Selectivity between mono- and di-dehalogenation could also be achieved in some cases. Aryl ketones, aldehydes and imines were shown to undergo facile pinacol couplings and the coupling of an aryl chloride with a styrene was also successful.(c) Emmanuel, N.; Mendoza, C.; Winter, M.; Horn, C. R.; Vizza, A.; Dreesen, L.; Heinrichs, B.; Monbaliu, J.-C. M. Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow Conditions. Org. Process Res. Dev. 2017, 21, 1435– 1438, DOI: 10.1021/acs.oprd.7b00212Google Scholar18chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCmtbvK&md5=7a3a919538351c71f5a8fc794d2ca715Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow ConditionsEmmanuel, Noemie; Mendoza, Carlos; Winter, Marc; Horn, Clemens R.; Vizza, Alessandra; Dreesen, Laurent; Heinrichs, Benoit; Monbaliu, Jean-Christophe M.Organic Process Research & Development (2017), 21 (9), 1435-1438CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Highly efficient and chemoselective singlet oxygen oxidn. of unprotected methionine was performed in water using a continuous mesofluidic reactor. Sustainable process engineering and conditions were combined to maximize process efficiency and atom economy, with virtually no waste generation and safe operating conditions. Three water-sol. metal-free photosensitizers [Rose Bengal, Methylene Blue, and tetrakis(4-carboxyphenyl)porphyrin] were assessed. The best results were obtained with Rose Bengal (0.1 mol %) at room temp. under white light irradn. and a slight excess of oxygen. Process and reaction parameters were monitored in real-time with in-line NMR. Other classical org. substrates (α-terpinene and citronellol) were oxidized under similar conditions with excellent performances.(d) Gérardy, R.; Winter, M.; Horn, C. R.; Vizza, A.; Van Hecke, K.; Monbaliu, J.-C. M. Continuous-Flow Preparation of γ-Butyrolactone Scaffolds from Renewable Fumaric and Itaconic Acids under Photosensitized Conditions. Org. Process Res. Dev. 2017, 21, 2012– 2017, DOI: 10.1021/acs.oprd.7b00314Google Scholar18dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVCksrfM&md5=10713935291edc1e22c6cad8bbe37342Continuous-Flow Preparation of γ-Butyrolactone Scaffolds from Renewable Fumaric and Itaconic Acids under Photosensitized ConditionsGerardy, Romaric; Winter, Marc; Horn, Clemens R.; Vizza, Alessandra; Van Hecke, Kristof; Monbaliu, Jean-Christophe M.Organic Process Research & Development (2017), 21 (12), 2012-2017CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The method and results described herein concern the photosensitized addn. of various alcs. to renewable platform fumaric and itaconic acids under scalable continuous-flow conditions in glass micro- and mesofluidic reactors. Alcs. were used both as reagents and as solvents, thus contributing to a reduced environmental footprint. Process parameters such as the temp., light intensity, and the nature as well as amt. of the photosensitizer were assessed under microfluidic conditions and, next, transposed to a lab-scale mesofluidic reactor connected with an in-line NMR spectrometer for real-time reaction monitoring. Substituted γ-butyrolactones, including spiro derivs. with unique structural features, were obtained with quant. conversion of the starting materials and in 47-76% isolated yields. The model photoaddn. of isopropanol to fumaric acid was next successfully transposed in a pilot-scale continuous-flow photoreactor to further demonstrate scalability.(e) Abdiaj, I.; Horn, C. R.; Alcazar, J. Scalability of Visible Light Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, Use of Solid Reagents and in-Line NMR Monitoring. J. Org. Chem. 2019, 84, 4748– 4753, DOI: 10.1021/acs.joc.8b02358Google Scholar18ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFGqurvK&md5=c4dd5c1f5e97c49b97159ae1c3943036Scalability of Visible-Light-Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, Use of Solid Reagents, and In-Line NMR MonitoringAbdiaj, Irini; Horn, Clemens R.; Alcazar, JesusJournal of Organic Chemistry (2019), 84 (8), 4748-4753CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Photochem. Negishi coupling reactions of benzylic bromides and an aryl bromide and iodide in the presence of NiCl2(glyme) and 4,4'-di-tert-butyl-2,2'-bipyridine using solid activated zinc as reductant were performed on multigram scale using a flow reactor; the benzylzinc bromide intermediates were generated using a column contg. the solid activated zinc and their formation was monitored in line using a benchtop NMR spectrometer. Adjusting reaction times and concns. was crit. in maximizing product yield, while the changing the reactor type allowed a significant increase in scale.(f) Kassin, V. E. H.; Gérardy, R.; Toupy, T.; Collin, Di.; Salvadeo, E.; Toussaint, F.; Van Hecke, K.; Monbaliu, J.-C. M. Expedient Preparation of Active Pharmaceutical Ingredient Ketamine under Sustainable Continuous Flow Conditions. Green Chem. 2019, 21, 2952– 2966, DOI: 10.1039/C9GC00336CGoogle Scholar18fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFGlu7g%253D&md5=d92242452517863a3a15ba8a25791c79Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditionsKassin, Victor-Emmanuel H.; Gerardy, Romaric; Toupy, Thomas; Collin, Diego; Salvadeo, Elena; Toussaint, Francois; Van Hecke, Kristof; Monbaliu, Jean-Christophe M.Green Chemistry (2019), 21 (11), 2952-2966CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A robust three-step continuous flow procedure is presented for the efficient and sustainable prepn. of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from com. available chems., utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with mol. oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the prodn. of ketamine. The scalability of the crit. hydroxylation step was assessed in a com. pilot continuous flow reactor. The process can also be adapted for the prepn. of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the exptl. selectivity and the various exptl. observations reported herein.(g) Gérardy, R.; Estager, J.; Luis, P.; Debecker, D. P.; Monbaliu, J.-C. M. Versatile and Scalable Synthesis of Cyclic Organic Carbonates under Organocatalytic Continuous Flow Conditions. Catal. Sci. Technol. 2019, 9, 6841– 6851, DOI: 10.1039/C9CY01659GGoogle Scholar18ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFCmt7%252FL&md5=5795604ef898290c1f9af3fd8ff73a7fVersatile and scalable synthesis of cyclic organic carbonates under organocatalytic continuous flow conditionsGerardy, Romaric; Estager, Julien; Luis, Patricia; Debecker, Damien P.; Monbaliu, Jean-Christophe M.Catalysis Science & Technology (2019), 9 (24), 6841-6851CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)The benchmark route for the prepn. of cyclic org. carbonates starts from toxic, volatile and unstable epoxides. In this work, cyclic org. carbonates are prepd. according to alternative sustainable and intensified continuous flow conditions from the corresponding 1,2-diols. The process utilizes di-Me carbonate (DMC) as a low toxicity carbonation reagent and relies on the organocatalytic activity of widely available and cheap org. ammonium and phosphonium salts. Glycerol is selected as a model substrate for preliminary optimization with a library of homogeneous ammonium and phosphonium salts. The nature of the anion dramatically influences the catalytic activity, while the nature of the cation does not impact the reaction. Upon optimization, glycerol carbonate is obtained in 95% conversion and 79% selectivity within 3 min residence time at 180 °C (11 bar) with 3.5 mol% of tetrabutylammonium bromide as the organocatalyst. A straightforward liq.-liq. extn. procedure enables both the purifn. of glycerol carbonate and the recycling of the homogeneous catalyst. The conditions are amenable to refined and crude bio-based glycerol, although conversions are lower in the latter case. Control expts. suggest that water present in the crude samples induces significant hydrolysis of glycerol carbonate. The reaction conditions are then successfully applied on a wide variety of substrates, affording the corresponding cyclic carbonates in overall good to excellent yields (20 examples, 45-95%). The substrate scope notably encompasses bio-based starting materials such as glycerol ethers and erythritol-derived diols. In-line NMR is featured as a qual. anal. tool for real-time reaction monitoring. The scalability of this carbonation procedure on glycerol is assessed in a com. pilot-scale silicon carbide continuous flow reactor of 60 mL internal vol. Glycerol carbonate is obtained in 76% yield, corresponding to a productivity of 13.6 kg per day. - 19
For details on mixing characteristics and heat transfer in these devices, see:
Wu, K. J.; Nappo, V.; Kuhn, S. Hydrodynamic Study of Single- and Two-Phase Flow in an Advanced-Flow Reactor. Ind. Eng. Chem. Res. 2015, 54, 7554– 7564, DOI: 10.1021/acs.iecr.5b01444Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOjs7zN&md5=86db6c1cf2ee4a2a236432174815ddf9Hydrodynamic Study of Single- and Two-Phase Flow in an Advanced-Flow ReactorWu, Ke-Jun; Nappo, Valentina; Kuhn, SimonIndustrial & Engineering Chemistry Research (2015), 54 (30), 7554-7564CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)The hydrodynamics of the G1 fluidic module of the Corning Advanced-Flow reactor (AFR) was characterized using particle image velocimetry. Two series of expts., single-phase flow with liq. flow rates of 10-40 mL/min and two-phase flow with an identical overall flow rate range and gas vol. transport fractions ranging from 0.125-0.50, were performed. From the instantaneous velocity vector maps, the mean and the root-mean-square velocities were computed, which allowed a systematic investigation of the single- and two-phase flow hydrodynamics and transport processes in the AFR. In single-phase flow, the velocity field is sym. in the heart-shaped cells, and their particular design results in a stagnation zone that limits momentum exchange in each cell. The addn. of the gas phase greatly increases the momentum exchange in the heart-shaped cells, which leads to a more uniform distribution of velocity fluctuations and increased transport processes within the AFR. - 20(a) Woitalka, A.; Kuhn, S.; Jensen, K. F. Scalability of Mass Transfer in Liquid-Liquid Flow. Chem. Eng. Sci. 2014, 116, 1– 8, DOI: 10.1016/j.ces.2014.04.036Google Scholar20ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFykurzF&md5=c1bae64e5826ed688eace4ee2c0a086eScalability of mass transfer in liquid-liquid flowWoitalka, A.; Kuhn, S.; Jensen, K. F.Chemical Engineering Science (2014), 116 (), 1-8CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)We address liq.-liq. mass transfer between immiscible liqs. using the system 1-butanol and water, with succinic acid as the mass transfer component. Using this system we evaluate the influence of two-phase flow transitions from Taylor flow to stratified flow and further to dispersed flow at elevated flow rates. In addn., we address the scale-up behavior of mass transfer coeffs. and the extn. efficiency by using reactors on the micro- and the milli-scale. Flow imaging enables us to identify the different flow regimes and to connect them to the trends obsd. in mass transfer, and the obtained results highlight the dependence of mass transfer on flow patterns. Furthermore, the results show that on the milli-scale fluid-structure interactions are driving the phase dispersion and interfacial mass transfer, and such a reactor design ensures straightforward scalability from the micro- to the milli-scale.(b) Lavric, E. D.; Woehl, P. Advanced-Flow Glass Reactors for Seamless Scale-Up. Chim. Oggi/Chemistry Today 2009, 27, 45– 48Google Scholar20bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptFGis7s%253D&md5=c310c5b4f08c9a5877246696115aa7aeAdvanced-Flow glass reactors for seamless scale-upLavric, Elena Daniela; Woehl, PierreChimica Oggi (2009), 27 (3), 45-48CODEN: CHOGDS; ISSN:0392-839X. (Tekno Scienze)A review. Flow reactors with millimetric internal dimensions, to which Corning Advanced-Flow glass reactors belong, are a proven technol. which enables the switch from batch mode to continuous processing of chem. reactions. This results in more economical, efficient and safer processes. These reactors can be used from development to prodn. An efficient scale-up, complementary to numbering-up, is obtained by increasing channel height or/and the footprint and internally dividing the flow. The effects of both approaches on a specific design are presented. The soln. proposed - higher footprint and internal split - shows comparable pressure drop, emulsion quality and residence time distribution with better heat transfer at equiv. residence times. These good performances achieved in scaled-up Advanced-Flow reactors enable the increase of overall prodn. without altering the productivity achieved at lower scale.
- 21(a) Weast, R. C.; Astle, M. J.; Beyer, W. H. Handbook of Chemistry and Physics; CRC Press: Boca Raton, FL, 1984.Google ScholarThere is no corresponding record for this reference.(b) Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of Organic Molecules. Acc. Chem. Res. 2003, 36, 255– 263, DOI: 10.1021/ar020230dGoogle Scholar21bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmt1OqsA%253D%253D&md5=e313bd3c3a7809b70baa32c83e70d135Bond Dissociation Energies of Organic MoleculesBlanksby, Stephen J.; Ellison, G. BarneyAccounts of Chemical Research (2003), 36 (4), 255-263CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. In this Account the authors have compiled a list of reliable bond energies that are based on a set of critically evaluated expts. A brief description of the three most important exptl. techniques for measuring bond energies is provided. The authors demonstrate how these exptl. data can be applied to yield the heats of formation of org. radicals and the bond enthalpies of more than 100 representative org. mols.(c) Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.Google ScholarThere is no corresponding record for this reference.
- 22For details on the G3 reactor used in this study, see: https://www.corning.com/worldwide/en/innovation/corning-emerging-innovations/advanced-flow-reactors.html.Google ScholarThere is no corresponding record for this reference.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 59 publications.
- Maksim Nikitin, Sándor B. Ötvös, Indrajit Ghosh, Maximilian Philipp, Ruth Gschwind, C. Oliver Kappe, Burkhard König. Brønsted Acid-Facilitated Thioetherification Cross-Coupling Reactions with Nickel and Visible Light. ACS Catalysis 2025, 15
(3)
, 1467-1476. https://doi.org/10.1021/acscatal.4c06734
- Arnab Chaudhuri, Wouter F.C. de Groot, Jasper H.A. Schuurmans, Stefan D.A. Zondag, Alessia Bianchi, Koen P.L. Kuijpers, Rémy Broersma, Amin Delparish, Matthieu Dorbec, John van der Schaaf, Timothy Noël. Scaling Up Gas–Liquid Photo-Oxidations in Flow Using Rotor-Stator Spinning Disc Reactors and a High-Intensity Light Source. Organic Process Research & Development 2025, Article ASAP.
- Davin Cronly, Megan Smyth, Thomas S. Moody, Scott Wharry, Julia Bruno-Colmenarez, Brendan Twamley, Marcus Baumann. Structurally Diverse Nitrogen-Rich Scaffolds via Continuous Photo-Click Reactions. Organic Letters 2024, 26
(49)
, 10559-10563. https://doi.org/10.1021/acs.orglett.4c03953
- Chenguang Liu, Lei Song, Qiong Liu, Weihao Chen, Jinhui Xu, Mu Wang, Yanbin Zhang, Ting Wei Tan, Zhexuan Lei, Lei Cheng, Saif A. Khan, Jie Wu. High-Speed Circulation Flow Platform Facilitating Practical Large-Scale Heterogeneous Photocatalysis. Organic Process Research & Development 2024, 28
(5)
, 1964-1970. https://doi.org/10.1021/acs.oprd.3c00515
- Tatjana Jerkovic, Harriet Cruickshank, Yiding Chen, Alexandre F. Trindade, Aaron M. Dumas, John Edwards, Anthony Alorati, Hon Eong Ho. Development and Kilogram-Scale Implementation of a Flavin-Catalyzed Photoredox Fluorodecarboxylation. Organic Process Research & Development 2024, 28
(1)
, 266-272. https://doi.org/10.1021/acs.oprd.3c00342
- John R. Swierk. The Cost of Quantum Yield. Organic Process Research & Development 2023, 27
(7)
, 1411-1419. https://doi.org/10.1021/acs.oprd.3c00167
- Alexander Steiner, Ryan C. Nelson, Doris Dallinger, C. Oliver Kappe. Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol–Ene/Cyclization Sequence in Continuous Flow. Organic Process Research & Development 2022, 26
(8)
, 2532-2539. https://doi.org/10.1021/acs.oprd.2c00214
- David N. Primer, Kelvin Yong, Antonio Ramirez, Matthew Kreilein, Antonio C. Ferretti, Antonio M. Ruda, Nadia Fleary-Roberts, Jonathan D. Moseley, Siân M. Forsyth, Graham R. Evans, John F. Traverse. Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2H)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control. Organic Process Research & Development 2022, 26
(5)
, 1458-1469. https://doi.org/10.1021/acs.oprd.2c00057
- Robbie Radjagobalou, Miguel Imbratta, Julie Bergraser, Marion Gaudeau, Gildas Lyvinec, Dominique Delbrayelle, Olivier Jentzer, Jérémy Roudin, Benjamin Laroche, Stéphanie Ognier, Michael Tatoulian, Janine Cossy, Pierre-Georges Echeverria. Selective Photochemical Continuous Flow Benzylic Monochlorination. Organic Process Research & Development 2022, 26
(5)
, 1496-1505. https://doi.org/10.1021/acs.oprd.2c00065
- Jie Zong, Jun Yue. Continuous Solid Particle Flow in Microreactors for Efficient Chemical Conversion. Industrial & Engineering Chemistry Research 2022, 61
(19)
, 6269-6291. https://doi.org/10.1021/acs.iecr.2c00473
- Cecilia Bottecchia, François Lévesque, Jonathan P. McMullen, Yining Ji, Mikhail Reibarkh, Feng Peng, Lushi Tan, Glenn Spencer, Jarod Nappi, Dan Lehnherr, Karthik Narsimhan, Michael K. Wismer, Like Chen, Yipeng Lin, Stephen M. Dalby. Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination. Organic Process Research & Development 2022, 26
(3)
, 516-524. https://doi.org/10.1021/acs.oprd.1c00240
- Kyle Quasdorf, James I. Murray, Hanh Nguyen, Maria V. Silva Elipe, Ari Ericson, Eric Kircher, Lianxiu Guan, Seb Caille. Development of a Continuous Photochemical Bromination/Alkylation Sequence En Route to AMG 423. Organic Process Research & Development 2022, 26
(2)
, 458-466. https://doi.org/10.1021/acs.oprd.1c00469
- Emily Schroeder, Phillip Christopher. Chemical Production Using Light: Are Sustainable Photons Cheap Enough?. ACS Energy Letters 2022, 7
(2)
, 880-884. https://doi.org/10.1021/acsenergylett.2c00142
- Laura Buglioni, Fabian Raymenants, Aidan Slattery, Stefan D. A. Zondag, Timothy Noël. Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry. Chemical Reviews 2022, 122
(2)
, 2752-2906. https://doi.org/10.1021/acs.chemrev.1c00332
- Lisa Candish, Karl D. Collins, Gemma C. Cook, James J. Douglas, Adrián Gómez-Suárez, Anais Jolit, Sebastian Keess. Photocatalysis in the Life Science Industry. Chemical Reviews 2022, 122
(2)
, 2907-2980. https://doi.org/10.1021/acs.chemrev.1c00416
- Daniel Francis, A. John Blacker, Nikil Kapur, Stephen P. Marsden. Readily Reconfigurable Continuous-Stirred Tank Photochemical Reactor Platform. Organic Process Research & Development 2022, 26
(1)
, 215-221. https://doi.org/10.1021/acs.oprd.1c00428
- Levente L. Simon, Michael Dieckmann, Alan Robinson, Thomas Vent-Schmidt, Dominique Marantelli, Ralf Kohlbrenner, Alexandre Saint-Dizier, Denis Gribkov, Jean-Philippe Krieger. Monte Carlo Analysis-Based CapEx Uncertainty Estimation of New Technologies: The Case of Photochemical Lamps. Organic Process Research & Development 2021, 25
(10)
, 2221-2229. https://doi.org/10.1021/acs.oprd.1c00245
- Mark A. Graham, Gary Noonan, Janette H. Cherryman, James J. Douglas, Miguel Gonzalez, Lucinda V. Jackson, Kevin Leslie, Zhi-qing Liu, David McKinney, Rachel H. Munday, Chris D. Parsons, David T. E. Whittaker, En-xuan Zhang, Jun-wang Zhang. Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction. Organic Process Research & Development 2021, 25
(1)
, 57-67. https://doi.org/10.1021/acs.oprd.0c00483
- François Lévesque, Michael J. Di Maso, Karthik Narsimhan, Michael K. Wismer, John R. Naber. Design of a Kilogram Scale, Plug Flow Photoreactor Enabled by High Power LEDs. Organic Process Research & Development 2020, 24
(12)
, 2935-2940. https://doi.org/10.1021/acs.oprd.0c00373
- Sergio Carrillo De Hert, Rafael Lopez-Rodriguez, Michael J. Di Maso, Jonathan P. McMullen, Steven Ferguson. Development and simulation of annular flow photoreactors: integration of light-diffusing fibers as optical diffusers with laser diodes. Reaction Chemistry & Engineering 2024, 10
(1)
, 251-266. https://doi.org/10.1039/D4RE00400K
- You Ma, Guozhi Qian, Mohsin Pasha, Yuhan Wang, Jiayi Li, Yuzhe Liu, Saier Liu, Xiao Xue, Min Qiu, Zihao Zhong, Minjing Shang, Jie Zheng, Zhigang Lin, Yuanhai Su. Oxime ether photobromination in a photomicroreactor: Process parameters and kinetic modeling. AIChE Journal 2024, 29 https://doi.org/10.1002/aic.18693
- Esai Daniel Lopez, Patricia Zhang Musacchio, Andrew R. Teixeira. Wireless μLED packed beds for scalable continuous multiphasic photochemistry. Reaction Chemistry & Engineering 2024, 9
(11)
, 2963-2974. https://doi.org/10.1039/D4RE00241E
- Kendelyn I. Bone, Thomas R. Puleo, Michael D. Delost, Yuka Shimizu, Jeffrey S. Bandar. Direct Benzylic C−H Etherification Enabled by Base‐Promoted Halogen Transfer. Angewandte Chemie 2024, 136
(39)
https://doi.org/10.1002/ange.202408750
- Yongjiu Li, Xin Liu, Qiong Liu, Yuchen Wang, Chenguang Liu, Fener Chen. Green Synthesis of Alzheimer′s Disease Probes Aftobetin and Analogues Enabled by Flow Technology and Heterogeneous Photocatalysis. ChemSusChem 2024, 19 https://doi.org/10.1002/cssc.202401214
- Kendelyn I. Bone, Thomas R. Puleo, Michael D. Delost, Yuka Shimizu, Jeffrey S. Bandar. Direct Benzylic C−H Etherification Enabled by Base‐Promoted Halogen Transfer. Angewandte Chemie International Edition 2024, 145 https://doi.org/10.1002/anie.202408750
- Yi-Hsuan Tsai, Martin Cattoen, Guillaume Masson, Gabrielle Christen, Lisa Traber, Morgan Donnard, Frédéric R. Leroux, Guillaume Bentzinger, Sylvain Guizzetti, Jean-Christophe M. Monbaliu. On a seamlessly replicable circular photoreactor for lab-scale continuous flow applications. Reaction Chemistry & Engineering 2024, 9
(7)
, 1646-1655. https://doi.org/10.1039/D4RE00109E
- Lara J. Nolan, Samuel J. King, Scott Wharry, Thomas S. Moody, Megan Smyth. A pharma perspective on sustainability advantages through adoption of continuous flow. Current Opinion in Green and Sustainable Chemistry 2024, 46 , 100886. https://doi.org/10.1016/j.cogsc.2024.100886
- Aodong Zhang, Jian Xu, Lingling Xia, Ming Hu, Yunpeng Song, Miao Wu, Ya Cheng. Efficient synthesis of vitamin D<sub>3</sub> in a 3D ultraviolet photochemical microreactor fabricated using an ultrafast laser. Light: Advanced Manufacturing 2024, 5
(1)
, 1. https://doi.org/10.37188/lam.2024.010
- Josefredo R. Pliego, Karla L. Lopes. Photochemical radical benzylic bromination with Br2: Computational modeling of the mechanism and microkinetic. Computational and Theoretical Chemistry 2023, 1227 , 114261. https://doi.org/10.1016/j.comptc.2023.114261
- Christos Xiouras, Koen Kuijpers, Dayne Fanfair, Matthieu Dorbec, Bjorn Gielen. Enabling technologies for process intensification in pharmaceutical research and manufacturing. Current Opinion in Chemical Engineering 2023, 41 , 100920. https://doi.org/10.1016/j.coche.2023.100920
- Stefan D.A. Zondag, Daniele Mazzarella, Timothy Noël. Scale-Up of Photochemical Reactions: Transitioning from Lab Scale to Industrial Production. Annual Review of Chemical and Biomolecular Engineering 2023, 14
(1)
, 283-300. https://doi.org/10.1146/annurev-chembioeng-101121-074313
- Márk Molnár, C. Oliver Kappe, Sándor B. Ötvös. Merger of Visible Light‐Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α‐Alkylation of Aldehydes. Advanced Synthesis & Catalysis 2023, 365
(10)
, 1660-1670. https://doi.org/10.1002/adsc.202300289
- Luca Capaldo, Zhenghui Wen, Timothy Noël. A field guide to flow chemistry for synthetic organic chemists. Chemical Science 2023, 14
(16)
, 4230-4247. https://doi.org/10.1039/D3SC00992K
- Haicheng Lv, Jundi Wang, Zhongming Shu, Gang Qian, Xuezhi Duan, Zhirong Yang, Xinggui Zhou, Jing Zhang. Residence time distribution and heat/mass transfer performance of a millimeter scale butterfly-shaped reactor. Chinese Chemical Letters 2023, 34
(4)
, 107710. https://doi.org/10.1016/j.cclet.2022.07.053
- Magdalena Dolna, Jakub Narodowiec, Olga Staszewska-Krajewska, Piotr Szcześniak, Bartłomiej Furman. Remotely controlled flow photo-Fries-type rearrangement of
N
-vinylazetidinones: an efficient route to structurally diverse 2,3-dihydro-4-pyridones. Reaction Chemistry & Engineering 2023, 8
(4)
, 784-789. https://doi.org/10.1039/D2RE00438K
- Giulia Brufani, Federica Valentini, Gabriele Rossini, Luigi Carpisassi, Daniela Lanari, Luigi Vaccaro. Continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles
via
consecutive β-azidation of α,β-unsaturated carbonyl compounds and CuAAC reactions. Green Chemistry 2023, 25
(6)
, 2438-2445. https://doi.org/10.1039/D2GC04672E
- Mengxue Zhang, Philippe Roth. Flow photochemistry — from microreactors to large-scale processing. Current Opinion in Chemical Engineering 2023, 39 , 100897. https://doi.org/10.1016/j.coche.2023.100897
- Hajeeth Thankappan, Conor Burke, Brian Glennon. Indium chloride catalysed benzyl bromination using continuous flow technology. Organic & Biomolecular Chemistry 2023, 21
(3)
, 508-513. https://doi.org/10.1039/D2OB01840C
- Kouakou Eric Konan, Abollé Abollé, François‐Xavier Felpin. Ultra‐Fast Continuous‐Flow Photo‐Thiol‐Ene Functionalization of Conformation‐Controlled Cinchona Alkaloids. European Journal of Organic Chemistry 2023, 26
(1)
https://doi.org/10.1002/ejoc.202201055
- Reinout Van Kerrebroeck, Tomas Horsten, Christian V. Stevens. Bromide Oxidation: A Safe Strategy for Electrophilic Brominations. European Journal of Organic Chemistry 2022, 2022
(35)
https://doi.org/10.1002/ejoc.202200310
- Laurent Vanoye, Boris Guicheret, Camila Rivera-Cárcamo, Ruben Castro Contreras, Claude de Bellefon, Valérie Meille, Philippe Serp, Régis Philippe, Alain Favre-Réguillon. Process intensification of the catalytic hydrogenation of squalene using a Pd/CNT catalyst combining nanoparticles and single atoms in a continuous flow reactor. Chemical Engineering Journal 2022, 441 , 135951. https://doi.org/10.1016/j.cej.2022.135951
- Dirk Ziegenbalg, Fabian Guba. Dynamically triggering photoreactions for high performance and efficiency. Current Opinion in Chemical Engineering 2022, 36 , 100789. https://doi.org/10.1016/j.coche.2021.100789
- Kouakou Eric Konan, Abollé Abollé, Elvina Barré, Ehu Camille Aka, Vincent Coeffard, François-Xavier Felpin. Developing flow photo-thiol–ene functionalizations of cinchona alkaloids with an autonomous self-optimizing flow reactor. Reaction Chemistry & Engineering 2022, 7
(6)
, 1346-1357. https://doi.org/10.1039/D1RE00509J
- Jiayou Zhang, Yiming Mo. A scalable light-diffusing photochemical reactor for continuous processing of photoredox reactions. Chemical Engineering Journal 2022, 435 , 134889. https://doi.org/10.1016/j.cej.2022.134889
- Victor-Emmanuel H. Kassin, Diana V. Silva-Brenes, Thomas Bernard, Julien Legros, Jean-Christophe M. Monbaliu. A continuous flow generator of organic hypochlorites for the neutralization of chemical warfare agent simulants. Green Chemistry 2022, 24
(8)
, 3167-3179. https://doi.org/10.1039/D2GC00458E
- Zhirong Yang, Yue Yang, Xuefeng Zhang, Wei Du, Jing Zhang, Gang Qian, Xuezhi Duan, Xinggui Zhou. High‐yield production of
p
‐diethynylbenzene through consecutive bromination/dehydrobromination in a microreactor system. AIChE Journal 2022, 68
(2)
https://doi.org/10.1002/aic.17498
- Wei-Hsin Hsu, Susanne Reischauer, Peter H Seeberger, Bartholomäus Pieber, Dario Cambié. Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor. Beilstein Journal of Organic Chemistry 2022, 18 , 1123-1130. https://doi.org/10.3762/bjoc.18.115
- Alexander Steiner, Oscar de Frutos, Juan A. Rincón, Carlos Mateos, Jason D. Williams, C. Oliver Kappe. N
-Chloroamines as substrates for metal-free photochemical atom-transfer radical addition reactions in continuous flow. Reaction Chemistry & Engineering 2021, 6
(12)
, 2434-2441. https://doi.org/10.1039/D1RE00429H
- Yuhang Chen, Yaheng Zhang, Hongwei Zou, Minglei Li, Gang Wang, Min Peng, Jie Zhang, Zhiyong Tang. Tuning the gas-liquid-solid segmented flow for enhanced heterogeneous photosynthesis of Azo- compounds. Chemical Engineering Journal 2021, 423 , 130226. https://doi.org/10.1016/j.cej.2021.130226
- Kian Donnelly, Marcus Baumann. Scalability of photochemical reactions in continuous flow mode. Journal of Flow Chemistry 2021, 11
(3)
, 223-241. https://doi.org/10.1007/s41981-021-00168-z
- Mara Di Filippo, Cristina Trujillo, Goar Sánchez-Sanz, Andrei S. Batsanov, Marcus Baumann. Discovery of a photochemical cascade process by flow-based interception of isomerising alkenes. Chemical Science 2021, 12
(29)
, 9895-9901. https://doi.org/10.1039/D1SC02879K
- Carlos A. Grande. Compact reactor architectures designed with fractals. Reaction Chemistry & Engineering 2021, 6
(8)
, 1448-1453. https://doi.org/10.1039/D1RE00107H
- Martin Rößler, Marcel A. Liauw. The PhotoFlexys: A Multi‐Purpose Reactor Platform to Simplify Process Intensification and Mechanistic Studies in Photochemistry. Chemistry–Methods 2021, 1
(6)
, 261-270. https://doi.org/10.1002/cmtd.202100011
- Jiadi Zhou, Zhi Chen, Yunfei He, Zhihao Lin, Chaodong Wang, Zhonghui Li, Jianjun Li. Efficient scale up of photochemical bromination of conjugated allylic compounds in continuous-flow. Journal of Flow Chemistry 2021, 11
(2)
, 127-134. https://doi.org/10.1007/s41981-020-00116-3
- Zhengya Dong, Zhenghui Wen, Fang Zhao, Simon Kuhn, Timothy Noël. Scale-up of micro- and milli-reactors: An overview of strategies, design principles and applications. Chemical Engineering Science: X 2021, 10 , 100097. https://doi.org/10.1016/j.cesx.2021.100097
- Christopher P. Breen, Anirudh M.K. Nambiar, Timothy F. Jamison, Klavs F. Jensen. Ready, Set, Flow! Automated Continuous Synthesis and Optimization. Trends in Chemistry 2021, 3
(5)
, 373-386. https://doi.org/10.1016/j.trechm.2021.02.005
- Suyong Han, Mahdi Ramezani, Patrick TomHon, Kameel Abdel-Latif, Robert W. Epps, Thomas Theis, Milad Abolhasani. Intensified continuous extraction of switchable hydrophilicity solvents triggered by carbon dioxide. Green Chemistry 2021, 23
(8)
, 2900-2906. https://doi.org/10.1039/D1GC00811K
- Victor-Emmanuel H. Kassin, Romain Morodo, Thomas Toupy, Isaline Jacquemin, Kristof Van Hecke, Raphaël Robiette, Jean-Christophe M. Monbaliu. A modular, low footprint and scalable flow platform for the expedient α-aminohydroxylation of enolizable ketones. Green Chemistry 2021, 23
(6)
, 2336-2351. https://doi.org/10.1039/D0GC04395H
- Alejandro Mata, Duc N. Tran, Ulrich Weigl, Jason D. Williams, C. Oliver Kappe. Continuous flow synthesis of arylhydrazines
via
nickel/photoredox coupling of
tert
-butyl carbazate with aryl halides. Chemical Communications 2020, 56
(93)
, 14621-14624. https://doi.org/10.1039/D0CC06787C
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.
Recommended Articles
Abstract
Figure 1
Figure 1. (a) Flow schematic for the intensified photochemical benzylic bromination of 2,6-dichlorotoluene 1, including bromine generation in the first FM and quench of excess bromine using sodium thiosulfate in the second FM. (b) General scale-up strategy for Corning Advanced-Flow Reactors, versus the scale-up demonstrated in this study. Scale-up workflow is based on maintaining a consistent residence time, to achieve consistent results (i.e., linear scaling of flow rates with reactor volume). The scale-up comparison demonstrated here represents a direct transfer from a G1 LF FM to a single G3 FM, whereas the standard strategy would suggest 5 × G3 FMs. Fluidic module images copyright 2015 and 2017 Corning Incorporated.
Figure 2
Figure 2. Piping and instrumentation diagram (PID) showing the process streams in black, heat exchange channels for the reaction and quench FMs in red, and the LED heat exchange channel in blue. PI = pressure sensor; FI = flow meter; TI = temperature sensor.
Figure 3
Figure 3. Snapshot from the live video stream captured by the webcam, showing the quench FM (streams combine and enter in top right corner, flow direction depicted by arrows, see Figure 1b for a full view of the FM). Quenching of the excess Br2 (highlighted by white ellipse) can be observed by a color change as the reaction mixture moves through the channel.
Figure 4
Figure 4. Overview of selected results from Table 2 (entries 1–10), highlighting the rough trends (dotted lines) of conversion vs residence time. Note: these trends are added only as a visual aid, and are not intended to be extrapolated or to represent a model of the reaction performance. Conversion of 1 was determined by 1H benchtop NMR.
Figure 5
Figure 5. (a) Illustrated positions of the temperature sensors in the reactor heat exchange channel. (b) Temperature increase in the heat exchange channel after passing through the reaction or quench FM, plotted against the performance of the reaction (conversion of 1).
References
This article references 22 other publications.
- 1
For selected reviews of recent photochemical synthetic methods, see:
(a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322– 5363, DOI: 10.1021/cr300503r1ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFKgtLc%253D&md5=e09e6cf6a4c64fd3e8f21d55e151266eVisible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic SynthesisPrier, Christopher K.; Rankic, Danica A.; MacMillan, David W. C.Chemical Reviews (Washington, DC, United States) (2013), 113 (7), 5322-5363CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review will highlight the early work on the use of transition metal complexes as photoredox catalysts to promote reactions of org. compds. (prior to 2008), as well as cover the surge of work that has appeared since 2008. We have for the most part grouped reactions according to whether the org. substrate undergoes redn., oxidn., or a redox neutral reaction and throughout have sought to highlight the variety of reactive intermediates that may be accessed via this general reaction manifold.(b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075– 10166, DOI: 10.1021/acs.chemrev.6b000571bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsVSnsrw%253D&md5=82228f21987c3d000c62cf672cdcea82Organic Photoredox CatalysisRomero, Nathan A.; Nicewicz, David A.Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10075-10166CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Use of org. photoredox catalysts in a myriad of synthetic transformations with a range of applications was reviewed. This overview was arranged by catalyst class where the photophysics and electrochem. characteristics of each was discussed to underscore the differences and advantages to each type of single electron redox agent. Net reductive and oxidative as well as redox neutral transformations that could be accomplished using purely org. photoredox-active catalysts was highlighted. An overview of the basic photophysics and electron transfer theory was presented in order to provide a comprehensive guide for employing this class of catalysts in photoredox manifolds. - 2Sender, M.; Ziegenbalg, D. Light Sources for Photochemical Processes- Estimation of Technological Potentials. Chem. Ing. Tech. 2017, 89, 1159– 1173, DOI: 10.1002/cite.2016001912https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCis7rJ&md5=50b4b98ad0ce47f553fe7c33df703ed3Light Sources for Photochemical Processes - Estimation of Technological PotentialsSender, Maximilian; Ziegenbalg, DirkChemie Ingenieur Technik (2017), 89 (9), 1159-1173CODEN: CITEAH; ISSN:0009-286X. (Wiley-VCH Verlag GmbH & Co. KGaA)This work theor. evaluates light sources currently com. available for the suitability to drive photoreactions. Comparative evaluation of different light sources reveals significant advantages of light-emitting diodes (LEDs) in the near UV and visible region, underlining the general superiority of narrow-band monochromatic light sources for photochem. processes. A generic anal. based on the av. volumetric rate of photon absorption shows the limits resulting from phys. fundamentals and the importance of the photon fluence rate for process intensification.
- 3
For selected examples discussing the influence of light attenuation on a the scale-up of a photochemical process, see:
(a) Harper, K. C.; Moschetta, E. G.; Bordawekar, S. V.; Wittenberger, S. J. A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light. ACS Cent. Sci. 2019, 5, 109– 115, DOI: 10.1021/acscentsci.8b007283ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjsVOjtA%253D%253D&md5=b06ab0089d55b6491ef676396640c0f7A laser driven flow chemistry platform for scaling photochemical reactions with visible lightHarper, Kaid C.; Moschetta, Eric G.; Bordawekar, Shailendra V.; Wittenberger, Steven J.ACS Central Science (2019), 5 (1), 109-115CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Visible-light-promoted org. reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solns. exist to employ these reactions for multikilogram prodn. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochem. reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer-Lambert law as a guideline to optimize catalyst concn. and reactor depth for max. throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochem. reactions.(b) Horn, C. R.; Gremetz, S. A Method to Determine the Correct Photocatalyst Concentration for Photooxidation Reactions Conducted in Continuous Flow Reactors. Beilstein J. Org. Chem. 2020, 16, 871– 879, DOI: 10.3762/bjoc.16.783bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVygtrzK&md5=315af5b3255a606385b0625990456284A method to determine the correct photocatalyst concentration for photooxidation reactions conducted in continuous flow reactorsHorn, Clemens R.; Gremetz, SylvainBeilstein Journal of Organic Chemistry (2020), 16 (), 871-879CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)When conducting a photooxidn. reaction, the key question is what is the best amt. of photocatalyst to be used in the reaction. This work demonstrates a fast and simple method to calc. a reliable concn. of the photocatalyst that will ensure an efficient reaction. The detn. is based on shifting the calcn. away from the concn. of the compd. to be oxidized to utilizing the limitations on the total light dose that can be delivered to the catalyst. These limitations are defined by the photoflow setup, specifically the channel height and the emission peak of the light source. This method was tested and shown to work well for three catalysts with different absorption properties through using LEDs with emission maxima close to the absorption max. of each catalyst.(c) Grimm, I.; Hauer, S. T.; Schulte, T.; Wycich, G.; Collins, K. D.; Lovis, K.; Candish, L. Upscaling Photoredox Cross-Coupling Reactions in Batch Using Immersion-Well Reactors. Org. Process Res. Dev. 2020, 24, 1185, DOI: 10.1021/acs.oprd.0c000703chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVKntL7E&md5=3a112b1689753274c080d7af3715ee36Upscaling Photoredox Cross-Coupling Reactions in Batch Using Immersion-Well ReactorsGrimm, Isabelle; Hauer, Simone T.; Schulte, Tim; Wycich, Gina; Collins, Karl D.; Lovis, Kai; Candish, LisaOrganic Process Research & Development (2020), 24 (6), 1185-1193CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Herein we describe a straightforward approach for the scale-up of photoredox cross-coupling reactions from milligram to multigram scale using immersion-well batch reactors with minimal reoptimization of the reaction conditions. This approach can be applied to both homogeneous and, more significantly, heterogeneous reaction mixts. Furthermore, we have used an immersion-well side-loop reactor to perform a reaction on a 400 mmol scale (86 g of aryl bromide). - 4
For selected reviews of flow photochemistry, see:
(a) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. 2017, 117, 11796– 11893, DOI: 10.1021/acs.chemrev.7b001834ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Siu7c%253D&md5=d95f9e3c3cc5ed69d5ba5347eedd9ae9The Hitchhiker's Guide to Flow ChemistryPlutschack, Matthew B.; Pieber, Bartholomaeus; Gilmore, Kerry; Seeberger, Peter H.Chemical Reviews (Washington, DC, United States) (2017), 117 (18), 11796-11893CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)Flow chem. involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters, enhancing reactivity or in some cases enabling new reactions. This relatively young technol. has received a remarkable amt. of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, "Should we do this in flow" has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chem. and critically discusses recent flow chem. accounts.(b) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Flow Photochemistry: Old Light through New Windows. Beilstein J. Org. Chem. 2012, 8, 2025– 2052, DOI: 10.3762/bjoc.8.2294bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVaqtbrJ&md5=c8d8baf08ac5c589d00fca25b228b561Flow photochemistry: Old light through new windowsKnowles, Jonathan P.; Elliott, Luke D.; Booker-Milburn, Kevin I.Beilstein Journal of Organic Chemistry (2012), 8 (), 2025-2052, No. 229CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A review. Synthetic photochem. carried out in classic batch reactors has, for over half a century, proved to be a powerful but under-utilized technique in general org. synthesis. Recent developments in flow photochem. have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in org. photochem., allowing a comparison of the various reactor types to be made.(c) Sambiagio, C.; Noël, T. Flow Photochemistry: Shine Some Light on Those Tubes!. Trends Chem. 2020, 2, 92– 106, DOI: 10.1016/j.trechm.2019.09.0034chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslejsLzF&md5=f435415805b2fc895c5e6ed2387d489bReview on flow photochemistry, shine some light on those tubesSambiagio, Carlo; Noel, TimothyTrends in Chemistry (2020), 2 (2), 92-106CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)A review. Continuous-flow chem. 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/methodol., in scale-up and prodn., and for rapid screening and optimization. Photochem. 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 chem. and its importance in modern chem. and technol. worldwide. This review highlights the most important features of continuous-flow technol. applied to photochem. processes and provides a general perspective on this rapidly evolving research field.(d) Politano, F.; Oksdath-Mansilla, G. Light on the Horizon: Current Research and Future Perspectives in Flow Photochemistry. Org. Process Res. Dev. 2018, 22, 1045– 1062, DOI: 10.1021/acs.oprd.8b002134dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVegt7nN&md5=6e79f34c1b4ec557d581579243a9d36eLight on the Horizon: Current Research and Future Perspectives in Flow PhotochemistryPolitano, Fabrizio; Oksdath-Mansilla, GabrielaOrganic Process Research & Development (2018), 22 (9), 1045-1062CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Synthetic org. photochem. is a powerful tool for creating both natural products and mols. with high structural complexity in a simple way and under mild conditions. However, because of the challenges in scaling-up, it has been difficult to apply a photochem. reaction in an industrial process. Flow chem. provides an opportunity for better control over the conditions of the reaction and, addnl., improved reaction selectivity and enhanced reproducibility. Taking into account that significant interest has focused on the use of flow photochem. as a method for the synthesis of heterocycles and its applications in target-oriented synthesis over the past few years, the aim of this review is to highlight recent efforts to apply flow photochem. methodol. to diverse reactions as a greener and more scalable process for the pharmaceutical and fine chem. industries. Addnl., the review highlights future perspectives in the development of scale-up strategies, combining photochem. reactions in the continuous-flow multistep synthesis of org. mols., which is of interest for scientists and engineers alike.(e) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.; Berry, M. B.; Booker-Milburn, K. I. Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity. Chem. - Eur. J. 2014, 20, 15226– 15232, DOI: 10.1002/chem.2014043474ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVert7%252FO&md5=1233b84e9f56b37313f86867400c21f8Batch versus Flow Photochemistry: A Revealing Comparison of Yield and ProductivityElliott, Luke D.; Knowles, Jonathan P.; Koovits, Paul J.; Maskill, Katie G.; Ralph, Michael J.; Lejeune, Guillaume; Edwards, Lee J.; Robinson, Richard I.; Clemens, Ian R.; Cox, Brian; Pascoe, David D.; Koch, Guido; Eberle, Martin; Berry, Malcolm B.; Booker-Milburn, Kevin I.Chemistry - A European Journal (2014), 20 (46), 15226-15232CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The use of flow photochem. and its apparent superiority over batch has been reported by a no. of groups in recent years. To rigorously det. whether flow does indeed have an advantage over batch, a broad range of synthetic photochem. transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an av. productivity 20 % lower than that of batch, whereas three-layer reactors were 20 % more productive. Finally, the utility of flow chem. was demonstrated in the scale(coating process)-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.(f) Noël, T. A Personal Perspective on the Future of Flow Photochemistry. J. Flow Chem. 2017, 7, 87– 93, DOI: 10.1556/1846.2017.000224fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygurs%253D&md5=c3832817edce6797a9e8be9e48227592A personal perspective on the future of flow photochemistryNoel, TimothyJournal of Flow Chemistry (2017), 7 (3-4), 87-93CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Photochem. and photoredox catalysis have witnessed a remarkable comeback in the last decade. Flow chem. has been of pivotal importance to alleviate some of the classical obstacles assocd. with photochem. Herein, we analyze some of the most exciting features provided by photo flow chem. as well as future challenges for the field.(g) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341, DOI: 10.1021/acs.chemrev.5b007074ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVOjs7g%253D&md5=327c368f6e090142204920993c4faadaApplications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water TreatmentCambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, TimothyChemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.(h) Williams, J. D.; Kappe, C. O. Recent Advances towards Sustainable Flow Photochemistry. Curr. Opin. Green Sustain. Chem. 2020, DOI: 10.1016/j.cogsc.2020.05.001 .There is no corresponding record for this reference. - 5
For an overview of flow photochemistry applications in industry, see:
(a) Noël, T.; Escriba-Gelonch, M.; Huvaere, K. Industrial Photochemistry: From Laboratory Scale to Industrial Scale. In Photochemical Processes In Continuous-flow Reactors: From Engineering Principles To Chemical Applications; Noël, T., Ed.; World Scientific: Singapore, 2017; pp 245– 267.There is no corresponding record for this reference.(b) Pfoertner, K. H. Photochemistry in Industrial Synthesis. J. Photochem. 1984, 25, 91– 97, DOI: 10.1016/0047-2670(84)85018-25bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXks1entb4%253D&md5=1cd23406514b762ab9bdc589466b3300Photochemistry in industrial synthesisPfoertner, K. H.Journal of Photochemistry (1984), 25 (1), 91-7CODEN: JPCMAE; ISSN:0047-2670.A review with 14 refs. - 6
For selected examples of “numbering up” and “scaling out” of flow photochemical processes, see:
(a) Su, Y.; Kuijpers, K.; Hessel, V.; Noël, T. A Convenient Numbering-up Strategy for the Scale-up of Gas-Liquid Photoredox Catalysis in Flow. React. Chem. Eng. 2016, 1, 73– 81, DOI: 10.1039/C5RE00021A6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSlt7%252FK&md5=58dd07aa48cbbb3b05500d00667f48bcA convenient numbering-up strategy for the scale-up of gas-liquid photoredox catalysis in flowSu, Yuanhai; Kuijpers, Koen; Hessel, Volker; Noel, TimothyReaction Chemistry & Engineering (2016), 1 (1), 73-81CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Visible-light photocatalysis is a mild activation method for small mols. and enables a wide variety of transformations relevant for org. synthetic chem. However, one of the limitations of photocatalysis and photochem. in general is the limited scalability due to the absorption of light (Lambert-Beer law). Here, we report the development of a convenient numbering-up strategy for the scale-up of gas-liq. photocatalytic reactions in which the gas is consumed. Only com. available constituents were used and the system can be rapidly assembled by any practitioner of flow chem. The modular design allows us to systematically scale the photochem. within 2n parallel reactors (herein, n = 0, 1, 2, 3). The flow distribution in the absence of reactions was excellent, showing a std. deviation less than 5%. Next, we used the numbered-up photomicroreactor assembly to enable the scale-up of the photocatalytic aerobic oxidn. of thiols to disulfides. The flow distribution was again very good with a std. deviation lower than 10%. The yield of the target disulfide in the numbered-up assemblies was comparable to the results obtained in a single device demonstrating the feasibility of our approach.(b) Kuijpers, K. P. L.; Van Dijk, M. A. H.; Rumeur, Q. G.; Hessel, V.; Su, Y.; Noël, T. A Sensitivity Analysis of a Numbered-up Photomicroreactor System. React. Chem. Eng. 2017, 2, 109– 115, DOI: 10.1039/C7RE00024C6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktFykuro%253D&md5=d59ce49f3849743021a740849c251ec7A sensitivity analysis of a numbered-up photomicroreactor systemKuijpers, Koen P. L.; van Dijk, Mark A. H.; Rumeur, Quentin G.; Hessel, Volker; Su, Yuanhai; Noel, TimothyReaction Chemistry & Engineering (2017), 2 (2), 109-115CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Limitations with regard to the scalability of photochem. reactions can be efficiently overcome by using numbered-up microreactor technol. Here, the robustness of such a numbered-up capillary photomicroreactor system is tested when subjected to potential disturbances, such as channel blockage and light source failure. Channel blockage leads to relatively large changes in both flow distribution and yield. However, we found that the performance can be accurately predicted thus making it possible to adjust the reaction parameters to obtain certain output targets. Light source failure did not lead to large variations in the mass flow distribution, highlighting the importance of the flow distributor section. Since the reaction is photocatalyzed, the impact on the reaction yield was significant in the reactor where the light failure occurred.(c) Zhao, F.; Cambié, D.; Janse, J.; Wieland, E. W.; Kuijpers, K. P. L.; Hessel, V.; Debije, M. G.; Noël, T. Scale-up of a Luminescent Solar Concentrator-Based Photomicroreactor via Numbering-Up. ACS Sustainable Chem. Eng. 2018, 6, 422– 429, DOI: 10.1021/acssuschemeng.7b026876chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOltLfK&md5=fbc07bc301bd7ed91a83e8aef21d5602Scale-up of a Luminescent Solar Concentrator-Based Photomicroreactor via Numbering-upZhao, Fang; Cambie, Dario; Janse, Jeroen; Wieland, Eric W.; Kuijpers, Koen P. L.; Hessel, Volker; Debije, Michael G.; Noel, TimothyACS Sustainable Chemistry & Engineering (2018), 6 (1), 422-429CODEN: ASCECG; ISSN:2168-0485. (American Chemical Society)The use of solar energy to power chem. reactions is a long-standing dream of the chem. community. Recently, visible-light-mediated photoredox catalysis has been recognized as the ideal catalytic transformation to convert solar energy into chem. bonds. However, scaling photochem. transformations has been extremely challenging due to Bouguer-Lambert-Beer law. Recently, we have pioneered the development of luminescent solar concentrator photomicroreactors (LSC-PMs), which display an excellent energy efficiency. These devices harvest solar energy, convert the broad solar energy spectrum to a narrow-wavelength region, and subsequently waveguide the re-emitted photons to the reaction channels. Herein, we report on the scalability of such LSC-PMs via a numbering-up strategy. Paramount in our work was the use of molds that were fabricated via 3D printing. This allowed us to rapidly produce many different prototypes and to optimize exptl. key design aspects in a time-efficient fashion. Reactors up to 32 parallel channels have been fabricated that display an excellent flow distribution using a bifurcated flow distributor (std. deviations below 10%). This excellent flow distribution was crucial to scale up a model reaction efficiently, displaying yields comparable to those obtained in a single-channel device. We also found that interchannel spacing is an important and unique design parameter for numbered-up LSC-PMs, which influences greatly the photon flux experienced within the reaction channels.(d) Williams, J. D.; Nakano, M.; Gérardy, R.; Rincon, J. A.; de Frutos, O.; Mateos, C.; Monbaliu, J.-C. M.; Kappe, C. O. Finding the Perfect Match: A Combined Computational and Experimental Study Towards Efficient and Scalable Photosensitized [2 + 2] Cycloadditions in Flow. Org. Process Res. Dev. 2019, 23, 78– 87, DOI: 10.1021/acs.oprd.8b003756dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1WitrvP&md5=7ed6fe1176ab82787d41b006fe529cc3Finding the perfect match a combined computational and experimental study toward efficient and scalable photosensitized [2 + 2] cycloadditions in flowWilliams, Jason D.; Nakano, Momoe; Gerardy, Romaric; Rincon, Juan A.; de Frutos, Oscar; Mateos, Carlos; Monbaliu, Jean-Christophe M.; Kappe, C. OliverOrganic Process Research & Development (2019), 23 (1), 78-87CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)With ever-evolving light-emitting diode (LED) technol., classical photochem. transformations are becoming accessible with more efficient and industrially viable light sources. In combination with a triplet sensitizer, we report the detailed exploration of [2 + 2] cycloaddns., in flow, of various maleic anhydride derivs. with gaseous ethylene. By the use of a flow reactor capable of gas handling and LED wavelength/power screening, an in-depth optimization of these reactions was carried out. In particular, we highlight the importance of matching the substrate and sensitizer triplet energies alongside the light source emission wavelength and power. Initial triplet-sensitized reactions of maleic anhydride were hampered by benzophenone's poor absorbance at 375 nm. However, d. functional theory (DFT) calcns. predicted that derivs. such as citraconic anhydride have low enough triplet energies to undergo triplet transfer from thioxanthone, whose absorbance matches the LED emission at 375 nm. This observation held true exptl., allowing optimization and further exemplification in a larger-scale reactor, whereby >100 g of material was processed in 10 h. These straightforward DFT calcns. were also applied to a no. of other substrates and showed a good correlation with exptl. data, implying that their use can be a powerful strategy in targeted reaction optimization for future substrates.(e) Malet-Sanz, L.; Susanne, F. Continuous Flow Synthesis. A Pharma Perspective. J. Med. Chem. 2012, 55, 4062– 4098, DOI: 10.1021/jm20060296ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVSqtLc%253D&md5=23f3d763f8072c7404f54076f9d2d78aContinuous Flow Synthesis. A Pharma PerspectiveMalet-Sanz, Laia; Susanne, FlavienJournal of Medicinal Chemistry (2012), 55 (9), 4062-4098CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Continuous flow chem. as a technique and the latest developments in the field are being reviewed from a Pharma point of view. - 7
Smart dimensioning entails the scale-up of reactor dimensions, performed rationally, in order to maintain the desired heat and mass transfer characteristics. For further information on this concept, see:
(a) Kockmann, N. Microfluidic Networks. Handbook of Micro Reactors; Wiley-VCH: Weinheim, 2009; pp 41– 58.There is no corresponding record for this reference.(b) Anderson, N. G. Using Continuous Processes to Increase Production. Org. Process Res. Dev. 2012, 16, 852– 869, DOI: 10.1021/op200347k7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1eht7s%253D&md5=50d53e5fe332220fb15154b7d4965274Using Continuous Processes to Increase ProductionAnderson, Neal G.Organic Process Research & Development (2012), 16 (5), 852-869CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. Continuous operations have become popular in both academia and the pharmaceutical industry. Continuous operations may be developed to make high-quality material safely, or because continuous operations are the only effective and economical way to make larger quantities of material. This review surveys the area of continuous processes used to make larger quantities of material and discusses the feasibility of developing economical continuous operations.(c) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Deciding Whether to Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis. Angew. Chem., Int. Ed. 2011, 50, 7502– 7519, DOI: 10.1002/anie.2010046377chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotVCns74%253D&md5=59de6e352a85f817def2f60aa4bcb46cDeciding whether to go with the flow: evaluating the merits of flow reactors for synthesisHartman, Ryan L.; McMullen, Jonathan P.; Jensen, Klavs F.Angewandte Chemie, International Edition (2011), 50 (33), 7502-7519, S7502/1-S7502/3CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The fine chems. and pharmaceutical industries are transforming how their products are manufd., where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chem. on all scales-from the lab. to full prodn. This article discusses the relative merits of batch and micro flow reactors for performing synthetic chem. in the lab.(d) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry. ChemSusChem 2013, 6, 746– 789, DOI: 10.1002/cssc.2012007667dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtFSmt78%253D&md5=54ec4b97766860a302d25e0c421d3a5dNovel Process Windows for Enabling, Accelerating, and Uplifting Flow ChemistryHessel, Volker; Kralisch, Dana; Kockmann, Norbert; Noel, Timothy; Wang, QiChemSusChem (2013), 6 (5), 746-789CODEN: CHEMIZ; ISSN:1864-5631. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Novel Process Windows make use of process conditions that are far from conventional practices. This involves the use of high temps., high pressures, high concns. (solvent-free), new chem. transformations, explosive conditions, and process simplification and integration to boost synthetic chem. on both the lab. and prodn. scale. Such harsh reaction conditions can be safely reached in microstructured reactors due to their excellent transport intensification properties. This Review discusses the different routes towards Novel Process Windows and provides several examples for each route grouped into different classes of chem. and process-design intensification. - 8(a) Rehm, T. H. Reactor Technology Concepts for Flow Photochemistry. ChemPhotoChem. 2020, 4, 235– 254, DOI: 10.1002/cptc.2019002478ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlyis7bE&md5=6d7c5cf13232f531905b6ce31dcc8a4bReactor Technology Concepts for Flow PhotochemistryRehm, Thomas H.ChemPhotoChem (2020), 4 (4), 235-254CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Synthetic org. photochem. has been intensively carried out in the 20th century and paved the way to the prepn. of complex org. mols., which were not yet accessible via thermal chem. Several photochem. synthesis routes have found their way into industrial applications for the prodn. of everyday commodities, but photochem. was still underutilized until recently as a synthesis method in org. chem. With the advent of novel photocatalytic and photophys. concepts for the use of high power visible light, the research field of synthetic org. photochem. has evolved to become a vivid and highly recognized technique in the last years. Fortunately, continuous flow technol. has also become an increasingly accepted tool and has proved to be an excellent key player for the advancement of photochem. in academic and industrial research settings. This Review provides an overview on the recent developments of continuous flow photoreactors and their application to photochem. syntheses under mild and defined process conditions.(b) Corcoran, E. B.; Mcmullen, J. P.; Wismer, M. K.; Naber, J. R. Photon Equivalents as a Parameter for Scaling Photoredox Reactions in Flow: Translation of Photocatalytic C–N Cross-Coupling from Lab Scale to Multikilogram Scale. Angew. Chem., Int. Ed. 2020, DOI: 10.1002/anie.201915412 .There is no corresponding record for this reference.(c) Lee, D. S.; Sharabi, M.; Jefferson-Loveday, R.; Pickering, S. J.; Poliakoff, M.; George, M. W. Scalable Continuous Vortex Reactor for Gram to Kilo Scale for UV and Visible Photochemistry. Org. Process Res. Dev. 2020, 24, 201– 206, DOI: 10.1021/acs.oprd.9b004758chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1WhtrY%253D&md5=5ccf393839351543f959a46d9a8c89dcScalable continuous vortex reactor for gram to kilo scale for UV and visible photochemistryLee, Darren S.; Sharabi, Medhat; Jefferson-Loveday, Richard; Pickering, Stephen J.; Poliakoff, Martyn; George, Michael W.Organic Process Research & Development (2020), 24 (2), 201-206CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)We report the development of a scalable continuous Taylor vortex reactor for both UV and visible photochem. This builds on our recent report (Org. Process Res. Dev.2017,21, 1042) detailing a new approach to continuous visible photochem. Here, we expand this by showing that our approach can also be applied to UV photochem. and that either UV or visible photochem. can be scaled-up using our design. We have achieved scale-up in productivity of over 300× with a visible light photo-oxidn. that requires oxygen gas and 10× with a UV-induced [2 + 2] cycloaddn. obtaining scales of up to 7.45 kg day-1 for the latter. Furthermore, we demonstrate that oxygen is efficiently taken up in the reactions of singlet O2, and for the examples examd., that near-stoichiometric quantities of oxygen can be used with little loss of reactor productivity. Furthermore, our design should be scalable to a substantially larger size and have the potential for scaling-out with reactors in parallel.(d) Elliott, L. D.; Berry, M.; Harji, B.; Klauber, D.; Leonard, J.; Booker-Milburn, K. I. A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram Scale. Org. Process Res. Dev. 2016, 20, 1806– 1811, DOI: 10.1021/acs.oprd.6b002778dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWnt7zK&md5=2db2bb0d0f1c5f8c3707b503d5657fd0A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram ScaleElliott, Luke D.; Berry, Malcolm; Harji, Bashir; Klauber, David; Leonard, John; Booker-Milburn, Kevin I.Organic Process Research & Development (2016), 20 (10), 1806-1811CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The development of a highly compact and powerful reactor for synthetic org. photochem. is described enabling a 10-fold redn. in reaction times, with up to 30% more power efficiency than previous fluorinated ethylene propylene tube reactors. Two reactions gave over 1 kg of product in 24 h. Two other reactions had productivities of 4 and 8 kg in 24 h. The reactor consists of a succession of quartz tubes connected together in series and arranged axially around a variable power mercury lamp. This compact and relatively simple device can be safely operated in a std. fumehood.(e) Roibu, A.; Morthala, R. B.; Leblebici, M. E.; Koziej, D.; Van Gerven, T.; Kuhn, S. Design and Characterization of Visible-Light LED Sources for Microstructured Photoreactors. React. Chem. Eng. 2018, 3, 849– 865, DOI: 10.1039/C8RE00165K8ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVOjtLfJ&md5=c76c7bce4af14f36348c3c5fbe32fc72Design and characterization of visible-light LED sources for microstructured photoreactorsRoibu, Anca; Morthala, Rishi Bharadwaj; Leblebici, M. Enis; Koziej, Dorota; Van Gerven, Tom; Kuhn, SimonReaction Chemistry & Engineering (2018), 3 (6), 849-865CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)The design of stable, compact, and uniform LED light sources for continuous microstructured photoreactors is reported. The elec. and thermal properties of green LEDs are translated into an efficient control and cooling strategy. To study the irradiance uniformity and efficiency to irradiate the microfluidic channel, narrow viewing angle LEDs were configured in four arrays. The irradiance uniformity experienced by the microchannel is detd. with an irradiance model, which is improved by using near-field goniophotometer measurements for small distances between the light source and reactor. Maximum light uniformity is achieved below the LED-reactor distance of 1.5 cm. Exceeding this distance and employing arrays with a larger no. of LEDs did not improve the uniformity on the microchannel. Furthermore, the energy efficiency of the photoreactor is quantified by combining near-field goniophotometer measurements, irradiance modeling and actinometry. It was shown that below 2 cm the photon losses were reduced when the LED positions matched the microchannel geometry, however a low utilization of the consumed elec. energy is obsd. irresp. of the LED array design. The characterization methodol. presented in this study enables the identification and quantification of the limiting factors.(f) Ziegenbalg, D.; Wriedt, B.; Kreisel, G.; Kralisch, D. Investigation of Photon Fluxes within Microstructured Photoreactors Revealing Great Optimization Potentials. Chem. Eng. Technol. 2016, 39, 123– 134, DOI: 10.1002/ceat.2015004988fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvF2itbbO&md5=751b46ddc44ed26b302512cb764a9553Investigation of Photon Fluxes within Microstructured Photoreactors Revealing Great Optimization PotentialsZiegenbalg, Dirk; Wriedt, Benjamin; Kreisel, Guenter; Kralisch, DanaChemical Engineering & Technology (2016), 39 (1), 123-134CODEN: CETEER; ISSN:1521-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)A simple model for detg. potential bottlenecks of a photoreactor setup focusing on the photon fluxes is presented. The application of the concept can reveal optimization potentials and gives insights into the sensitivity of the reactor setup to different optimization possibilities. The introduced model benefits from the concept of using only data already available from optimization studies of the process conditions. Applying the introduced concept to the characterization of a previously developed modular org. light-emitting diode reactor setup revealed great optimization potentials, esp. with respect to the external photonic efficiency. Interestingly, the attempt to enhance the external photonic efficiency by increasing the projection area of the reactor did not provide any improvement. This is attributed to a significant effect of reflection and scattering within the setup.
- 9Saikia, I.; Borah, A. J.; Phukan, P. Use of Bromine and Bromo-Organic Compounds in Organic Synthesis. Chem. Rev. 2016, 116, 6837– 7042, DOI: 10.1021/acs.chemrev.5b004009https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xot1ertb8%253D&md5=c7dbec3b61269455bdd6ed00df766eabUse of Bromine and Bromo-Organic Compounds in Organic SynthesisSaikia, Indranirekha; Borah, Arun Jyoti; Phukan, ProdeepChemical Reviews (Washington, DC, United States) (2016), 116 (12), 6837-7042CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Bromination is one of the most important transformations in org. synthesis and can be carried out using bromine and many other bromo compds. Use of mol. bromine in org. synthesis is well-known. However, due to the hazardous nature of bromine, enormous growth has been witnessed in the past several decades for the development of solid bromine carriers. This review outlines the use of bromine and different bromo-org. compds. in org. synthesis. The applications of bromine, a total of 107 bromo-org. compds., 11 other brominating agents, and a few natural bromine sources were incorporated. The scope of these reagents for various org. transformations such as bromination, cohalogenation, oxidn., cyclization, ring-opening reactions, substitution, rearrangement, hydrolysis, catalysis, etc. has been described briefly to highlight important aspects of the bromo-org. compds. in org. synthesis.
- 10(a) Sabuzi, F.; Pomarico, G.; Floris, B.; Valentini, F.; Galloni, P.; Conte, V. Sustainable Bromination of Organic Compounds: A Critical Review. Coord. Chem. Rev. 2019, 385, 100– 136, DOI: 10.1016/j.ccr.2019.01.01310ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivFSkur0%253D&md5=84170aa27dff2f521bf590b48c5a038fSustainable bromination of organic compounds: A critical reviewSabuzi, Federica; Pomarico, Giuseppe; Floris, Barbara; Valentini, Francesca; Galloni, Pierluca; Conte, ValeriaCoordination Chemistry Reviews (2019), 385 (), 100-136CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)A review. This review was devoted to collect and discuss papers dealing with "green" procedures for introducing bromine atom(s) into org. mols., a reaction of primary synthetic and industrial importance. Both direct bromination and oxidative bromination are accounted for. The sustainability was critically discussed.(b) Niemeier, J. K.; Kjell, D. P. Hydrazine and Aqueous Hydrazine Solutions: Evaluating Safety in Chemical Processes. Org. Process Res. Dev. 2013, 17, 1580– 1590, DOI: 10.1021/op400120g10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVSitrbM&md5=f58290c92e9d861d26d509067e043150Hydrazine and Aqueous Hydrazine Solutions: Evaluating Safety in Chemical ProcessesNiemeier, Jeffry K.; Kjell, Douglas P.Organic Process Research & Development (2013), 17 (12), 1580-1590CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review concerning the hazards of hydrazine and its aq. solns. to understand the important role diln. plays in increasing inherent safety of aq. hydrazine solns. is given. The intent is to provide enough information to allow readers to decide if hydrazine may be acceptable for a given application, and if so, what concn. range may provide an acceptable safety and environmental risk. Examples are provided to illustrate the strong effect catalysts have on decompn. reactions. Topics discussed include: hazard overview; flammability (at atm. pressure in air, effect of pressure, potential deflagration in absence of air, effect of inerting agents, effect of catalysts); explosion risk; thermal stability and effect of materials of construction; analyzing runaway reaction potential as function of hydrazine concn. and materials of construction; evaluating pressure generation in closed vessels; emergency relief system calcns.; reactivity; toxicity and personal protection; release mitigation and air dispersion modeling; regulatory considerations; conclusions; and supplementary information (estd. heat of decompn., hydrazine properties, hydrazine hydrate properties, aq. hydrazine properties).
- 11
For selected examples of photochemical benzylic bromination using NBS, see:
(a) Bonfield, H. E.; Williams, J. D.; Ooi, W.-X.; Leach, S. G.; Kerr, W. J.; Edwards, L. J. A Detailed Study of Irradiation Requirements Towards an Efficient Photochemical Wohl-Ziegler Procedure in Flow. ChemPhotoChem. 2018, 2, 938– 944, DOI: 10.1002/cptc.20180008211ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFGlur%252FO&md5=a310176e0e522907fd636af51223939fA Detailed Study of Irradiation Requirements Towards an Efficient Photochemical Wohl-Ziegler Procedure in FlowBonfield, Holly E.; Williams, Jason D.; Ooi, Wei Xiang; Leach, Stuart G.; Kerr, William J.; Edwards, Lee J.ChemPhotoChem (2018), 2 (10), 938-944CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)A platform has been developed to enable standardization of light sources, allowing consistent scale-up from high-throughput screening in batch to flow, using the same pseudo-monochromatic light source. The impact of wavelength and light intensity on a photochem. reaction was evaluated within this platform using the Wohl-Ziegler benzylic bromination of 4-methyl-3-(trifluoromethyl)benzonitrile with N-bromosuccinimide as a model system. It was found that only 40% of the max. light intensity was required while still maintaining reaction rate, allowing more reliable temp. control and lower energy consumption. The optimized reaction conditions were subsequently applied to a range of synthetically relevant (hetero)arom. compds. under continuous conditions, exploring the scope of the process within a mild and scalable procedure.(b) Deshpande, S.; Gadilohar, B.; Shinde, Y.; Pinjari, D.; Pandit, A.; Shankarling, G. Energy Efficient, Clean and Solvent Free Photochemical Benzylic Bromination Using NBS in Concentrated Solar Radiation (CSR). Sol. Energy 2015, 113, 332– 339, DOI: 10.1016/j.solener.2015.01.00811bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslakt74%253D&md5=28a47f440192a308e55f7d6cd0085982Energy efficient, clean and solvent-free photochemical benzylic bromination using NBS in concentrated solar radiation (CSR)Deshpande, Saurabh; Gadilohar, Balu; Shinde, Yogesh; Pinjari, Dipak; Pandit, Aniruddha; Shankarling, GanapatiSolar Energy (2015), 113 (), 332-339CODEN: SRENA4; ISSN:0038-092X. (Elsevier Ltd.)An environmentally benign, clean, solvent-free approach for benzylic bromination has been developed using concd. solar radiation (CSR). The protocol was found to be superior to the conventional photochem. and thermal methods in terms of reaction time and total energy requirement. This method was adapted with concd. solar radiation in solvent-free conditions without the use of radical initiators and has proved to provide substituted benzyl bromides RCH2Br (R = 2-MeC6H4, 2-FC6H4, 3-O2NC6H4, etc.) in good yields.(c) Cantillo, D.; De Frutos, O.; Rincon, J. A.; Mateos, C.; Kappe, C. O. A Scalable Procedure for Light-Induced Benzylic Brominations in Continuous Flow. J. Org. Chem. 2014, 79, 223– 229, DOI: 10.1021/jo402409k11chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVajtbrM&md5=50d22314ca29dcd80dbf85d8eb0a9742A Scalable Procedure for Light-Induced Benzylic Brominations in Continuous FlowCantillo, David; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. OliverJournal of Organic Chemistry (2014), 79 (1), 223-229CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A continuous-flow protocol for the bromination of benzylic compds. with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates contg. different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h-1), which is not easily possible in batch photochem. reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h-1 for the desired bromide was achieved.(d) Ni, S.; El Remaily, M. A. E. A. A. A.; Franzén, J. Carbocation Catalyzed Bromination of Alkyl Arenes, a Chemoselective Sp3 vs. Sp2 C-H Functionalization. Adv. Synth. Catal. 2018, 360, 4197– 4204, DOI: 10.1002/adsc.20180078811dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslaiurjN&md5=ccd479aaefc53bd51bb3155192c2e393Carbocation Catalyzed Bromination of Alkyl Arenes, a Chemoselective sp3 vs. sp2 C-H functionalization.Ni, Shengjun; El Remaily, Mahmoud Abd El Aleem Ali Ali; Franzen, JohanAdvanced Synthesis & Catalysis (2018), 360 (21), 4197-4204CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)The versatility of the trityl cation (TrBF4) as a highly efficient Lewis acid organocatalyst is demonstrated in a light induced benzylic brominaion of alkyl-arenes under mild conditions. The reaction was conducted at ambient temp. under common hood light (55 W fluorescent light) with catalyst loadings down to 2.0 mol% using N-bromosuccinimide (NBS) as the brominating agent. The protocol is applicable to an extensive no. of substrates to give benzyl bromides in good to excellent yields. In contrast to most previously reported strategies, this protocol does not require any radical initiator or extensive heating. For electron-rich alkyl-arenes, the trityl ion catalyzed bromination could be easily switched between benzylic sp3 C-H functionalization and arene sp2 C-H functionalization by simply alternating the solvent. This chemoselective switch allows for high substrate control and easy prepn. of benzyl bromides and bromoarenes, resp. The chemoselective switch was also applied in a one-pot reaction of 1-methylnaphthalene for direct introduction of both sp3 C-Br and sp2 C-Br functionality. - 12Eissen, M.; Lenoir, D. Electrophilic Bromination of Alkenes: Environmental, Health and Safety Aspects of New Alternative Methods. Chem. - Eur. J. 2008, 14, 9830– 9841, DOI: 10.1002/chem.20080046212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVCrtbfP&md5=509aa9467dd782a8d14416dc3bcc7784Electrophilic bromination of alkenes: environmental, health and safety aspects of new alternative methodsEissen, Marco; Lenoir, DieterChemistry - A European Journal (2008), 14 (32), 9830-9841CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. More than twenty alternative methods for bromination of alkenes have been evaluated taking into consideration their resource demands, waste prodn. as well as environmental, health and safety aspects. The cost of bromine and the substances designated to circumvent the application of mol. bromine have also been taken into account. As bromine is only one of several problematic substances being used, its avoidance - by applying bromine supported on solid material or by performing the in situ generation of bromine - does not significantly reduce the technol. requirements. On the contrary, the resource demands and amt. of waste produced by most new methods are significantly higher compared to the std. methods, esp. if the recycling of a carrying agent is not efficient. The method using hydrobromic acid and hydrogen peroxide can be regarded as a competitive alternative to the std. method. The application of certain carrying agents could be interesting, because solvents such as carbon tetrachloride or chloroform used during synthesis could be replaced with less problematic ones during work-up. However, problems assocd. with these alternatives are not resolved as yet.
- 13(a) Van Kerrebroeck, R.; Naert, P.; Heugebaert, T. S. A.; D’hooghe, M.; Stevens, C. V. Electrophilic Bromination in Flow: A Safe and Sustainable Alternative to the Use of Molecular Bromine in Batch. Molecules 2019, 24, 2116, DOI: 10.3390/molecules2411211613ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSlsr3O&md5=48b84f2486419c48070eca39a178be26Electrophilic bromination in flow: a safe and sustainable alternative to the use of molecular bromine in batchVan Kerrebroeck, Reinout; Naert, Pieter; Heugebaert, Thomas S. A.; D'Hooghe, Matthias; Stevens, Christian V.Molecules (2019), 24 (11), 2116CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Bromination reactions are crucial in today's chem. industry since the versatility of the formed organobromides e.g., I makes them suitable building blocks for numerous syntheses. However, the use of the toxic and highly reactive mol. bromine (Br2) makes these brominations very challenging and hazardous. A safe and straightforward protocol for bromination in continuous flow has been described. The hazardous Br2 or KOBr is generated in situ by reacting an oxidant (NaOCl) with HBr or KBr, resp., which is directly coupled to the bromination reaction and a quench of residual bromine. This protocol was demonstrated by polybrominating both alkenes (E,E,Z)-1,5,9-cyclododecatriene and arom. substrates II in a wide variety of solvents, with yields ranging from 78% to 99%.(b) Cantillo, D.; Kappe, C. O. Halogenation of Organic Compounds Using Continuous Flow and Microreactor Technology. React. Chem. Eng. 2017, 2, 7– 19, DOI: 10.1039/C6RE00186F13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVKgtb7E&md5=57cfebe54eb4ada53b66af0e247e70b2Halogenation of organic compounds using continuous flow and microreactor technologyCantillo, David; Kappe, C. OliverReaction Chemistry & Engineering (2017), 2 (1), 7-19CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)A review. The halogenation of org. substrates is one the most important transformations in org. synthesis. The most straightforward, inexpensive and atom economic halogenations involve the use of elemental halogens (X2) or hydrogen halides (HX). However, X2 and HX reagents are highly reactive, toxic and corrosive materials. Halogenations using these reagents are usually very fast and exothermic reactions, in which selectivity issues occur. Using continuous flow chem. halogenations involving X2 and HX can be performed in a safe and controllable manner. Reagents can be accurately dosed even for gas/liq. reactions, and exotherms are easily controlled. Hazardous chems. can be readily quenched in line avoiding any undesired exposures and significantly enhancing the process safety.
- 14Steiner, A.; Williams, J. D.; De Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O. Continuous Photochemical Benzylic Bromination Using In Situ Generated Br2: Process Intensification towards Optimal PMI and Throughput. Green Chem. 2020, 22, 448– 454, DOI: 10.1039/C9GC03662H14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlGhurvP&md5=e5c553cd71cc781f93e033b74e373a8aContinuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughputSteiner, Alexander; Williams, Jason D.; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. OliverGreen Chemistry (2020), 22 (2), 448-454CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The detailed development of photochem. benzylic brominations using a NaBrO3/HBr bromine generator in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photochem. reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of org. solvent, allowed a redn. in PMI from 13.25 to just 4.33. The photochem. transformation achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s. The org. solvent-free prepn. of two pharmaceutically relevant building blocks was demonstrated with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromination (15 g scale in 20 min, PMI = 3.64).
- 15Nair, S. M. K.; Jacob, P. D. The Effect of Doping on the Thermal Decomposition of Sodium Bromate. Thermochim. Acta 1991, 181, 269– 276, DOI: 10.1016/0040-6031(91)80429-M15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXkvVChsLs%253D&md5=0456f3990e3aca13ccd714857e854253The effect of doping on the thermal decomposition of sodium bromateNair, S. M. K.; Jacob, P. DaisammaThermochimica Acta (1991), 181 (), 269-76CODEN: THACAS; ISSN:0040-6031.The thermal decompn. of NaBrO3 doped with KBrO3 and NaBr, each in the mole fraction range 10-4-10-1, was studied by TG. The activation energy, frequency factor, and entropy of activation were computed using the A.W. Coats-J.P. Redfern (1964), E.S. Freeman- B. Carroll (1958) and H.H. Horowitz-G. Metzger (1963) methods. Doping enhances the decompn. and decreases the energy of activation, the effect increasing with increase in concn. of the dopant. The mechanism of decompn. follows the M. Avrami (1939) equation, 1-(1-α)1/3 = kt, and the rate-controlling process is a phase-boundary reaction assuming spherical symmetry.
- 16Procopiou, P. A.; Barrett, V. J.; Bevan, N. J.; Biggadike, K.; Box, P. C.; Butchers, P. R.; Coe, D. M.; Conroy, R.; Emmons, A.; Ford, A. J. Synthesis and Structure-Activity Relationships of Long-Acting B2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach. J. Med. Chem. 2010, 53, 4522– 4530, DOI: 10.1021/jm100326d16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvFKqt7o%253D&md5=3b59a1fdaba51d1688c14a3da96b4b4dSynthesis and Structure-Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug ApproachProcopiou, Panayiotis A.; Barrett, Victoria J.; Bevan, Nicola J.; Biggadike, Keith; Box, Philip C.; Butchers, Peter R.; Coe, Diane M.; Conroy, Richard; Emmons, Amanda; Ford, Alison J.; Holmes, Duncan S.; Horsley, Helen; Kerr, Fern; Li-Kwai-Cheung, Anne-Marie; Looker, Brian E.; Mann, Inderjit S.; McLay, Iain M.; Morrison, Valerie S.; Mutch, Peter J.; Smith, Claire E.; Tomlin, PaulaJournal of Medicinal Chemistry (2010), 53 (11), 4522-4530CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepd. by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compds. were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compds. were assessed on isolated superfused guinea pig trachea. I had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Cryst. salts of I (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for I to the β2-receptor is presented.
- 17Veraldi, S. Isoconazole Nitrate: A Unique Broad-Spectrum Antimicrobial Azole Effective in the Treatment of Dermatomycoses, Both as Monotherapy and in Combination with Corticosteroids. Mycoses 2013, 56, 3– 15, DOI: 10.1111/myc.1205417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVKktL4%253D&md5=f8dd368ab3001d862cba87020209975dIsoconazole nitrate: a unique broad-spectrum antimicrobial azole effective in the treatment of dermatomycoses, both as monotherapy and in combination with corticosteroidsVeraldi, StefanoMycoses (2013), 56 (Suppl. 1), 3-15CODEN: MYCSEU; ISSN:1439-0507. (Wiley-Blackwell)A review. Fungal skin infections, or dermatomycoses, are assocd. with a broad range of pathogens. Involvement of gram-pos. bacteria is often suspected in dermatomycoses. Inflammation plays an important role in dermatomycoses, displaying a close assocn. between frequent inflammation and reduced skin-related quality of life. Isoconazole nitrate (ISN) is a broad-spectrum antimicrobial agent with a highly effective antimycotic and gram-pos. antibacterial activity, a rapid rate of absorption and low systemic exposure potential. ISN is effective against pathogens involved in dermatomycoses, with min. inhibitory concns. well below the concn. of ISN in skin and hair follicles. The combination of the corticosteroid diflucortolone valerate with ISN (Travocort) increases the local bioavailability of ISN. Compared with ISN monotherapy, Travocort has a faster onset of antimycotic action, faster relief of itch and other inflammatory symptoms, improved overall therapeutic benefits and earlier mycol. cure rate. Travocort is effective in the treatment of inflammatory mycotic infections, and also in the eradication of accompanied grampos. bacterial infections. The rapid improvement obsd. with Travocort treatment, combined with favorable safety and tolerability, results in higher patient satisfaction, and therefore, can be an effective tool to increase treatment adherence in patients with dermatomycoses accompanied by inflammatory signs and symptoms.
- 18
For selected examples of these devices used at various scales, see:
(a) Bianchi, P.; Petit, G.; Monbaliu, J.-C. M. Scalable and Robust Photochemical Flow Process towards Small Spherical Gold Nanoparticles. React. Chem. Eng. 2020, DOI: 10.1039/D0RE00092B .There is no corresponding record for this reference.(b) Steiner, A.; Williams, J. D.; Rincon, J. A.; De Frutos, O.; Mateos, C.; Kappe, C. O. Implementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid and Selective Reductive Photoredox Transformations in Continuous Flow. Eur. J. Org. Chem. 2019, 2019, 5807– 5811, DOI: 10.1002/ejoc.20190095218bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVelsbzE&md5=2431cf35ccf2f78821f1ba3a5f01ebcaImplementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid and Selective Reductive Photoredox Transformations in Continuous FlowSteiner, Alexander; Williams, Jason D.; Rincon, Juan A.; de Frutos, Oscar; Mateos, Carlos; Kappe, C. OliverEuropean Journal of Organic Chemistry (2019), 2019 (33), 5807-5811CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)By combining a highly reducing org. photocatalyst with a thiol hydrogen atom transfer (HAT) catalyst, a rapid and highly selective reaction of aryl halides in continuous flow was performed to afford arom. compds. The fast redn. of aryl iodides, bromides and chlorides were demonstrated with residence times in some cases below one minute. Selectivity between mono- and di-dehalogenation could also be achieved in some cases. Aryl ketones, aldehydes and imines were shown to undergo facile pinacol couplings and the coupling of an aryl chloride with a styrene was also successful.(c) Emmanuel, N.; Mendoza, C.; Winter, M.; Horn, C. R.; Vizza, A.; Dreesen, L.; Heinrichs, B.; Monbaliu, J.-C. M. Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow Conditions. Org. Process Res. Dev. 2017, 21, 1435– 1438, DOI: 10.1021/acs.oprd.7b0021218chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCmtbvK&md5=7a3a919538351c71f5a8fc794d2ca715Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow ConditionsEmmanuel, Noemie; Mendoza, Carlos; Winter, Marc; Horn, Clemens R.; Vizza, Alessandra; Dreesen, Laurent; Heinrichs, Benoit; Monbaliu, Jean-Christophe M.Organic Process Research & Development (2017), 21 (9), 1435-1438CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Highly efficient and chemoselective singlet oxygen oxidn. of unprotected methionine was performed in water using a continuous mesofluidic reactor. Sustainable process engineering and conditions were combined to maximize process efficiency and atom economy, with virtually no waste generation and safe operating conditions. Three water-sol. metal-free photosensitizers [Rose Bengal, Methylene Blue, and tetrakis(4-carboxyphenyl)porphyrin] were assessed. The best results were obtained with Rose Bengal (0.1 mol %) at room temp. under white light irradn. and a slight excess of oxygen. Process and reaction parameters were monitored in real-time with in-line NMR. Other classical org. substrates (α-terpinene and citronellol) were oxidized under similar conditions with excellent performances.(d) Gérardy, R.; Winter, M.; Horn, C. R.; Vizza, A.; Van Hecke, K.; Monbaliu, J.-C. M. Continuous-Flow Preparation of γ-Butyrolactone Scaffolds from Renewable Fumaric and Itaconic Acids under Photosensitized Conditions. Org. Process Res. Dev. 2017, 21, 2012– 2017, DOI: 10.1021/acs.oprd.7b0031418dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVCksrfM&md5=10713935291edc1e22c6cad8bbe37342Continuous-Flow Preparation of γ-Butyrolactone Scaffolds from Renewable Fumaric and Itaconic Acids under Photosensitized ConditionsGerardy, Romaric; Winter, Marc; Horn, Clemens R.; Vizza, Alessandra; Van Hecke, Kristof; Monbaliu, Jean-Christophe M.Organic Process Research & Development (2017), 21 (12), 2012-2017CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The method and results described herein concern the photosensitized addn. of various alcs. to renewable platform fumaric and itaconic acids under scalable continuous-flow conditions in glass micro- and mesofluidic reactors. Alcs. were used both as reagents and as solvents, thus contributing to a reduced environmental footprint. Process parameters such as the temp., light intensity, and the nature as well as amt. of the photosensitizer were assessed under microfluidic conditions and, next, transposed to a lab-scale mesofluidic reactor connected with an in-line NMR spectrometer for real-time reaction monitoring. Substituted γ-butyrolactones, including spiro derivs. with unique structural features, were obtained with quant. conversion of the starting materials and in 47-76% isolated yields. The model photoaddn. of isopropanol to fumaric acid was next successfully transposed in a pilot-scale continuous-flow photoreactor to further demonstrate scalability.(e) Abdiaj, I.; Horn, C. R.; Alcazar, J. Scalability of Visible Light Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, Use of Solid Reagents and in-Line NMR Monitoring. J. Org. Chem. 2019, 84, 4748– 4753, DOI: 10.1021/acs.joc.8b0235818ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFGqurvK&md5=c4dd5c1f5e97c49b97159ae1c3943036Scalability of Visible-Light-Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, Use of Solid Reagents, and In-Line NMR MonitoringAbdiaj, Irini; Horn, Clemens R.; Alcazar, JesusJournal of Organic Chemistry (2019), 84 (8), 4748-4753CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Photochem. Negishi coupling reactions of benzylic bromides and an aryl bromide and iodide in the presence of NiCl2(glyme) and 4,4'-di-tert-butyl-2,2'-bipyridine using solid activated zinc as reductant were performed on multigram scale using a flow reactor; the benzylzinc bromide intermediates were generated using a column contg. the solid activated zinc and their formation was monitored in line using a benchtop NMR spectrometer. Adjusting reaction times and concns. was crit. in maximizing product yield, while the changing the reactor type allowed a significant increase in scale.(f) Kassin, V. E. H.; Gérardy, R.; Toupy, T.; Collin, Di.; Salvadeo, E.; Toussaint, F.; Van Hecke, K.; Monbaliu, J.-C. M. Expedient Preparation of Active Pharmaceutical Ingredient Ketamine under Sustainable Continuous Flow Conditions. Green Chem. 2019, 21, 2952– 2966, DOI: 10.1039/C9GC00336C18fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFGlu7g%253D&md5=d92242452517863a3a15ba8a25791c79Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditionsKassin, Victor-Emmanuel H.; Gerardy, Romaric; Toupy, Thomas; Collin, Diego; Salvadeo, Elena; Toussaint, Francois; Van Hecke, Kristof; Monbaliu, Jean-Christophe M.Green Chemistry (2019), 21 (11), 2952-2966CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A robust three-step continuous flow procedure is presented for the efficient and sustainable prepn. of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from com. available chems., utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with mol. oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the prodn. of ketamine. The scalability of the crit. hydroxylation step was assessed in a com. pilot continuous flow reactor. The process can also be adapted for the prepn. of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the exptl. selectivity and the various exptl. observations reported herein.(g) Gérardy, R.; Estager, J.; Luis, P.; Debecker, D. P.; Monbaliu, J.-C. M. Versatile and Scalable Synthesis of Cyclic Organic Carbonates under Organocatalytic Continuous Flow Conditions. Catal. Sci. Technol. 2019, 9, 6841– 6851, DOI: 10.1039/C9CY01659G18ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFCmt7%252FL&md5=5795604ef898290c1f9af3fd8ff73a7fVersatile and scalable synthesis of cyclic organic carbonates under organocatalytic continuous flow conditionsGerardy, Romaric; Estager, Julien; Luis, Patricia; Debecker, Damien P.; Monbaliu, Jean-Christophe M.Catalysis Science & Technology (2019), 9 (24), 6841-6851CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)The benchmark route for the prepn. of cyclic org. carbonates starts from toxic, volatile and unstable epoxides. In this work, cyclic org. carbonates are prepd. according to alternative sustainable and intensified continuous flow conditions from the corresponding 1,2-diols. The process utilizes di-Me carbonate (DMC) as a low toxicity carbonation reagent and relies on the organocatalytic activity of widely available and cheap org. ammonium and phosphonium salts. Glycerol is selected as a model substrate for preliminary optimization with a library of homogeneous ammonium and phosphonium salts. The nature of the anion dramatically influences the catalytic activity, while the nature of the cation does not impact the reaction. Upon optimization, glycerol carbonate is obtained in 95% conversion and 79% selectivity within 3 min residence time at 180 °C (11 bar) with 3.5 mol% of tetrabutylammonium bromide as the organocatalyst. A straightforward liq.-liq. extn. procedure enables both the purifn. of glycerol carbonate and the recycling of the homogeneous catalyst. The conditions are amenable to refined and crude bio-based glycerol, although conversions are lower in the latter case. Control expts. suggest that water present in the crude samples induces significant hydrolysis of glycerol carbonate. The reaction conditions are then successfully applied on a wide variety of substrates, affording the corresponding cyclic carbonates in overall good to excellent yields (20 examples, 45-95%). The substrate scope notably encompasses bio-based starting materials such as glycerol ethers and erythritol-derived diols. In-line NMR is featured as a qual. anal. tool for real-time reaction monitoring. The scalability of this carbonation procedure on glycerol is assessed in a com. pilot-scale silicon carbide continuous flow reactor of 60 mL internal vol. Glycerol carbonate is obtained in 76% yield, corresponding to a productivity of 13.6 kg per day. - 19
For details on mixing characteristics and heat transfer in these devices, see:
Wu, K. J.; Nappo, V.; Kuhn, S. Hydrodynamic Study of Single- and Two-Phase Flow in an Advanced-Flow Reactor. Ind. Eng. Chem. Res. 2015, 54, 7554– 7564, DOI: 10.1021/acs.iecr.5b0144419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOjs7zN&md5=86db6c1cf2ee4a2a236432174815ddf9Hydrodynamic Study of Single- and Two-Phase Flow in an Advanced-Flow ReactorWu, Ke-Jun; Nappo, Valentina; Kuhn, SimonIndustrial & Engineering Chemistry Research (2015), 54 (30), 7554-7564CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)The hydrodynamics of the G1 fluidic module of the Corning Advanced-Flow reactor (AFR) was characterized using particle image velocimetry. Two series of expts., single-phase flow with liq. flow rates of 10-40 mL/min and two-phase flow with an identical overall flow rate range and gas vol. transport fractions ranging from 0.125-0.50, were performed. From the instantaneous velocity vector maps, the mean and the root-mean-square velocities were computed, which allowed a systematic investigation of the single- and two-phase flow hydrodynamics and transport processes in the AFR. In single-phase flow, the velocity field is sym. in the heart-shaped cells, and their particular design results in a stagnation zone that limits momentum exchange in each cell. The addn. of the gas phase greatly increases the momentum exchange in the heart-shaped cells, which leads to a more uniform distribution of velocity fluctuations and increased transport processes within the AFR. - 20(a) Woitalka, A.; Kuhn, S.; Jensen, K. F. Scalability of Mass Transfer in Liquid-Liquid Flow. Chem. Eng. Sci. 2014, 116, 1– 8, DOI: 10.1016/j.ces.2014.04.03620ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFykurzF&md5=c1bae64e5826ed688eace4ee2c0a086eScalability of mass transfer in liquid-liquid flowWoitalka, A.; Kuhn, S.; Jensen, K. F.Chemical Engineering Science (2014), 116 (), 1-8CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)We address liq.-liq. mass transfer between immiscible liqs. using the system 1-butanol and water, with succinic acid as the mass transfer component. Using this system we evaluate the influence of two-phase flow transitions from Taylor flow to stratified flow and further to dispersed flow at elevated flow rates. In addn., we address the scale-up behavior of mass transfer coeffs. and the extn. efficiency by using reactors on the micro- and the milli-scale. Flow imaging enables us to identify the different flow regimes and to connect them to the trends obsd. in mass transfer, and the obtained results highlight the dependence of mass transfer on flow patterns. Furthermore, the results show that on the milli-scale fluid-structure interactions are driving the phase dispersion and interfacial mass transfer, and such a reactor design ensures straightforward scalability from the micro- to the milli-scale.(b) Lavric, E. D.; Woehl, P. Advanced-Flow Glass Reactors for Seamless Scale-Up. Chim. Oggi/Chemistry Today 2009, 27, 45– 4820bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptFGis7s%253D&md5=c310c5b4f08c9a5877246696115aa7aeAdvanced-Flow glass reactors for seamless scale-upLavric, Elena Daniela; Woehl, PierreChimica Oggi (2009), 27 (3), 45-48CODEN: CHOGDS; ISSN:0392-839X. (Tekno Scienze)A review. Flow reactors with millimetric internal dimensions, to which Corning Advanced-Flow glass reactors belong, are a proven technol. which enables the switch from batch mode to continuous processing of chem. reactions. This results in more economical, efficient and safer processes. These reactors can be used from development to prodn. An efficient scale-up, complementary to numbering-up, is obtained by increasing channel height or/and the footprint and internally dividing the flow. The effects of both approaches on a specific design are presented. The soln. proposed - higher footprint and internal split - shows comparable pressure drop, emulsion quality and residence time distribution with better heat transfer at equiv. residence times. These good performances achieved in scaled-up Advanced-Flow reactors enable the increase of overall prodn. without altering the productivity achieved at lower scale.
- 21(a) Weast, R. C.; Astle, M. J.; Beyer, W. H. Handbook of Chemistry and Physics; CRC Press: Boca Raton, FL, 1984.There is no corresponding record for this reference.(b) Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of Organic Molecules. Acc. Chem. Res. 2003, 36, 255– 263, DOI: 10.1021/ar020230d21bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmt1OqsA%253D%253D&md5=e313bd3c3a7809b70baa32c83e70d135Bond Dissociation Energies of Organic MoleculesBlanksby, Stephen J.; Ellison, G. BarneyAccounts of Chemical Research (2003), 36 (4), 255-263CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. In this Account the authors have compiled a list of reliable bond energies that are based on a set of critically evaluated expts. A brief description of the three most important exptl. techniques for measuring bond energies is provided. The authors demonstrate how these exptl. data can be applied to yield the heats of formation of org. radicals and the bond enthalpies of more than 100 representative org. mols.(c) Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.There is no corresponding record for this reference.
- 22For details on the G3 reactor used in this study, see: https://www.corning.com/worldwide/en/innovation/corning-emerging-innovations/advanced-flow-reactors.html.There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.0c00239.
Further details of reaction setup, risk assessment, experimental results and NMR data (PDF)
Video of quench FM during experimental runs (MP4)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.