Heretsch, Philipp

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33Modern flow chemistry – prospect and advantagePhilipp HeretschEditorial Open AccessAddress:Institute of Organic Chemistry, Leibniz Universität Hannover,Schneiderberg 1B, 30167 Hannover, GermanyEmail:Philipp Heretsch - philipp.heretsch@oci.uni-hannover.deKeywords:flow chemistry; method development; reactor designBeilstein J. Org. Chem. 2023, 19, 33–35.https://doi.org/10.3762/bjoc.19.3Received: 22 December 2022Accepted: 29 December 2022Published: 06 January 2023This article is part of the thematic issue "Platform and enablingtechnologies in organic synthesis".Guest Editor: P. Heretsch© 2023 Heretsch; licensee Beilstein-Institut.License and terms: see end of document.Organic chemistry has shaped modern society by fulfilling thebasic needs for pharmaceuticals, agrochemicals, fragrances, andmany more. Implementation of new and innovative technolo-gies has played a vital role in this mission and has contributedto the opening of new research areas and to pushing the fron-tiers of existing ones. Among these new technologies, continu-ous flow chemistry has stepped on the stage in the last decades[1]. Originating from the petrochemical industry, where itenabled high productivity and scalability even for the most stan-dard processes of heating, cracking, and refining of crude oil tobulk chemicals [2], it has since entered the production of phar-maceuticals and other fine chemicals. This has again led to im-proved scalability, higher purity of products, and eventually de-creased manufacturing costs.From the undisputed role of continuous flow chemistry forprocess chemists, the advent of this technology in academicresearch laboratories, especially for method development andnatural product synthesis programs [3], has revealed someinadequacies, particularly in view of the equipment andprocedures available. These limitations have been slowly over-come with many creative but sometimes highly “academic”solutions.Thus, recent years witnessed a steady increase in the applica-tion of continuous flow technology for academic research,leading to an expansion of synthetic options and generally moresustainable operations. Among the many advantages of per-forming organic reactions in continuous flow, enhanced heat-,mass- and photon transfer, an improved safety profile, broadscalability, and higher sustainability are the most prevalentones.To provide examples and explanation for these claims, “flashchemistry”, a term coined by late Yoshida [4] for reactions atthe diffusion limit, i.e., reactions completed within millisec-onds with proper mixing, showcases the fast heat- and masstransfer of continuous flow reactors. The generation of organo-lithium species in the presence of carbonyl compounds and theirreaction has been facilitated by the extremely fast mixing ofreagents and almost instantaneous heat transfer (i.e., cooling) inspecifically designed microreactors [5].Beilstein J. Org. Chem. 2023, 19, 33–35.34Analogously, significantly increased photon transfer in flowreactors has been exploited. Where the molar attenuation coeffi-cient is high, such as in many important photoredox catalysts,most of the irradiation is already absorbed within a thin layer ofa few millimeters. Thus, in batch reactors the vast volume of thesolution is not irradiated, and the reaction can only take place inthe outermost layer [6,7]. This results in an extended reactiontime when performing such reactions in bulk and may even leadto increased side reactions. Moving such operations into tubularflow reactors with a small diameter can both accelerate thetransformations as well as lead to significantly less side prod-ucts by continuously removing the products from the irradia-tion source.As an example, Noël and co-workers performed efficient irradi-ation in flow for the C(sp3)–H functionalization of gaseoushydrocarbons [8], wherein photoexcited decatungstate was em-ployed. Decatungstate is an efficient and versatile hydrogenatom transfer (HAT) catalyst with a growing number of applica-tions. The use of decatungstate in a continuous flow setup led toshorter reaction times, increased scalability, and improvedsafety with pressurized gaseous alkanes employed in the above-mentioned transformations.Enhanced safety profiles of continuous flow reactors have beenwidely appreciated in industrial laboratories, while hazardousreactions still tend to be addressed subordinately or are evenmarginalized in academia [9]. The comparably small dimen-sions of flow reactors enable explosive, toxic, or otherwisedangerous reactions and reagents to be accumulated only to amuch lesser degree, especially when scaling up.This virtue has been exploited in process chemistry, where inthe manufacturing of HIV protease inhibitor nelfinavir mesy-late, diazomethane was an inevitable necessity. By moving thegeneration of this toxic and explosive reagent into a continuousprocess with manageable amounts present at any given pointand continuously stripping the chemical with a stream ofnitrogen, safety protocols could be met [10].Among the disadvantages when moving from batch reactions toa continuous flow regime, dispersion phenomena play a detri-mental role. These gradient effects occur when a stream ofreagent is introduced into the reactor by pushing it with puresolvent. The reagents with well-defined concentration thenleach into the solvent slug, leading to ill-defined stoichiometryand decrease in yield. While this axial dispersion is dependenton flow speed and residence time, only the central part of thereaction stream is under so-called steady-state conditions. Tozero out these effects when a process yield is to be determined,pre- and postrun fractions are discarded [6], leading to loss ofreagent and substrate as well as to increased waste. This is evenless tolerable when small quantities of precious intermediatesfrom multistep routes are to be employed, as is typically thecase in projects of the pharmaceutical industry and academia.A possible solution to this general problem was reported byJensen and co-workers, who introduced segmented gas–liquidflow by mixing the reagent stream with an inert carrier gas,forming liquid and gaseous slugs moving through the reactor,and thus insolating liquid compartments from leaching into oneanother [11]. This concept has been adapted and further refinedby Gilmore and co-workers, introducing automated multistepsynthesizers [12], as well as Heretsch et al. in a setup optimizedfor natural products synthesis and late-stage manipulations [13].To address customized reactor solutions from an engineeringperspective, the advent of computer-aided design (CAD) incombination with widely available 3D printing has become apreferred choice. Prototyping aided by these technologies hassignificantly accelerated the development of novel flow reactordesigns [14]. The challenging properties of organic solvents forstandard polymers used in commercial 3D printers remain adrawback, while industrial 3D printers remain the much moreexpensive option. Reactors or other laboratory ware printed inpolypropylene are restricted in use to only a few organic sol-vents or even to a single application, rendering this technologyrather a supportive tool than a general solution [15]. Still,having this option available significantly lowers the barrier ofinventing novel technological solutions and allows for high-throughput optimization in reactor design. Since different typesof reactions typically call for an optimized or even specificallydesigned reactor built, the modularity of flow reactor is vital forquick reconfiguration and switching between different reac-tions.This argument is particularly true when natural product synthe-sis is to be performed in continuous flow. The need for flexibleand modular reactors that address the different demands associ-ated with total synthesis poses particular challenges, amongthem performing fast reactions at low temperature, slow reac-tions at elevated temperature, reactions involving reactive gasesunder pressure, and photochemical reactions. Besides, also scal-ability is a major prerequisite in these synthetic endeavors, withreactions routinely being performed on a decagram scale in theearly stages of a route and on a milligram scale at the end of asequence. Designing modular reactors that meet these demandswill help to overcome existing reservations for continuous flowin academia [13].As guest editor of this thematic issue, I would like to expressmy gratitude to all authors for their excellent contributions.Beilstein J. Org. Chem. 2023, 19, 33–35.35I thank the referees for providing their expertise and time andthe whole team at the Beilstein Journal of Organic Chemistryfor their professional support.Philipp HeretschHannover, December 2022ORCID® iDsPhilipp Heretsch - https://orcid.org/0000-0002-9967-3541References1. Guidi, M.; Seeberger, P. H.; Gilmore, K. Chem. Soc. Rev. 2020, 49,8910–8932. doi:10.1039/c9cs00832b2. Luis, S. V.; Garcia-Verdugo, E., Eds. Chemical Reactions andProcesses under Flow Conditions; RSC Publishing: Cambridge, UK,2009. doi:10.1039/97818475597393. Newton, S.; Carter, C. F.; Pearson, C. M.; de C. Alves, L.; Lange, H.;Thansandote, P.; Ley, S. V. Angew. Chem., Int. Ed. 2014, 53,4915–4920. doi:10.1002/anie.2014020564. Yoshida, J.-i. Chem. Commun. 2005, 4509–4516.doi:10.1039/b508341a5. Kim, H.; Nagaki, A.; Yoshida, J.-i. Nat. Commun. 2011, 2, 264.doi:10.1038/ncomms12646. Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H.Chem. Rev. 2017, 117, 11796–11893.doi:10.1021/acs.chemrev.7b001837. Su, Y.; Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. – Eur. J. 2014,20, 10562–10589. doi:10.1002/chem.2014002838. Laudadio, G.; Deng, Y.; van der Wal, K.; Ravelli, D.; Nuño, M.;Fagnoni, M.; Guthrie, D.; Sun, Y.; Noël, T. Science 2020, 369, 92–96.doi:10.1126/science.abb46889. McGarry, K. A.; Hurley, K. R.; Volp, K. A.; Hill, I. M.; Merritt, B. A.;Peterson, K. L.; Rudd, P. A.; Erickson, N. C.; Seiler, L. A.; Gupta, P.;Bates, F. S.; Tolman, W. B. J. Chem. Educ. 2013, 90, 1414–1417.doi:10.1021/ed400305e10. Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6, 884–892.doi:10.1021/op020049k11. Günther, A.; Khan, S. A.; Thalmann, M.; Trachsel, F.; Jensen, K. F.Lab Chip 2004, 4, 278–286. doi:10.1039/b403982c12. Chatterjee, S.; Guidi, M.; Seeberger, P. H.; Gilmore, K. Nature 2020,579, 379–384. doi:10.1038/s41586-020-2083-513. Kleoff, M.; Schwan, J.; Christmann, M.; Heretsch, P. Org. Lett. 2021,23, 2370–2374. doi:10.1021/acs.orglett.1c0066114. Coakley, M.; Hurt, D. E. J. Lab. Autom. 2016, 21, 489–495.doi:10.1177/221106821664957815. Kitson, P. J.; Rosnes, M. H.; Sans, V.; Dragone, V.; Cronin, L. Lab Chip2012, 12, 3267–3271. doi:10.1039/c2lc40761bLicense and TermsThis is an open access article licensed under the terms ofthe Beilstein-Institut Open Access License Agreement(https://www.beilstein-journals.org/bjoc/terms), which isidentical to the Creative Commons Attribution 4.0International License(https://creativecommons.org/licenses/by/4.0). The reuse ofmaterial under this license requires that the author(s),source and license are credited. Third-party material in thisarticle could be subject to other licenses (typically indicatedin the credit line), and in this case, users are required toobtain permission from the license holder to reuse thematerial.The definitive version of this article is the electronic onewhich can be found at:https://doi.org/10.3762/bjoc.19.3

Modern flow chemistry – prospect and advantage

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Modern flow chemistry – prospect and advantage

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