C–H bond functionalization: recent discoveries and future directions

• Indranil Chatterjee

Beilstein J. Org. Chem. 2023, 19, 1568–1569, doi:10.3762/bjoc.19.114

• techniques. Some energy-economic reactors such as ball mill, microwave, ultrasound and, most importantly, flow reactors have also evolved towards a more sustainable future. To showcase the modern approaches in this domain, this thematic issue in the Beilstein Journal of Organic Chemistry gathers recent

Selective and scalable oxygenation of heteroatoms using the elements of nature: air, water, and light

• Damiano Diprima,
• Hannes Gemoets,
• Stefano Bonciolini and
• Koen Van Aken

Beilstein J. Org. Chem. 2023, 19, 1146–1154, doi:10.3762/bjoc.19.82

• running the process in continuous flow [5][6][7][8]. Moreover, flow reactors that provide intense mixing can overcome the gas–liquid mass transfer limitations typical of batch reactions and improve productivity. Several studies have demonstrated the scalability and safety of such methods for the oxidation

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• efficiency and selectivity of the reactions (vide infra, conPET section). Electrolytes have the potential to be i) aqueous-separated and recovered in batch, or ii) decreased, even ultimately eliminated by flow reactors as an engineering control. Regarding purely the chemical reactivity and scope of

• first efforts in this direction [32][33]. Finally, both techniques are amenable to large-scale synthesis and ideally integrated with state-of-the-art reactor technology platforms, such as continuous flow reactors and high throughput screening plates. Various examples of scalability will be highlighted

Honeycomb reactor: a promising device for streamlining aerobic oxidation under continuous-flow conditions

• Masahiro Hosoya,
• Yusuke Saito and
• Yousuke Horiuchi

Beilstein J. Org. Chem. 2023, 19, 752–763, doi:10.3762/bjoc.19.55

• aerobic oxidation. Photographs of the various reactors. (a) Standard tube reactor. (b) Tube reactor with a static mixer. (c) Honeycomb reactor. Proposed catalytic cycle for aerobic oxidation using Fe(NO3)3/TEMPO. Flow setup for aerobic oxidation using various flow reactors. Flow setup for high-throughput

• conditions. Evaluation of the heat of reaction Prior to application to the flow synthesis, the heat of this aerobic oxidation was measured. Because oxidation is generally a highly exothermic reaction, the internal temperature distribution might vary depending on the heat removal efficiency of the flow

• reactors. This fluctuation makes it difficult to precisely evaluate the reaction rate. The heat of reaction, calculated with the heat flow during the reaction, was 161 kJ/mol (based on the input amount of the starting material 1a, see Supporting Information File 1). The time course of the heat of reaction

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• mass transfer of continuous flow reactors. The generation of organolithium species in the presence of carbonyl compounds and their reaction has been facilitated by the extremely fast mixing of reagents and almost instantaneous heat transfer (i.e., cooling) in specifically designed microreactors [5

• ]. Analogously, significantly increased photon transfer in flow reactors has been exploited. Where the molar attenuation coefficient is high, such as in many important photoredox catalysts, most of the irradiation is already absorbed within a thin layer of a few millimeters. Thus, in batch reactors the vast

• volume of the solution is not irradiated, and the reaction can only take place in the outermost layer [6][7]. This results in an extended reaction time when performing such reactions in bulk and may even lead to increased side reactions. Moving such operations into tubular flow reactors with a small

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• , which was assembled by a series of hold-up tanks and two MJOD flow reactors as liquid–liquid extractors. Finally, a semicontinuous step for solvent evaporation produced multigram quantities of product with good productivity and purity. Other bespoke alternatives that still need to pass further

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• [4][5]. This is underlined by several photochemical and photocatalytic transformations that have been performed on industrial scales in continuous-flow reactors [6][7][8]. A particularly appealing branch of photocatalytic organic synthesis is the combination with other modes of catalysis in dual

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• , Germany 10.3762/bjoc.18.76 Abstract Continuous flow technology is a key technology for sustainable manufacturing with numerous applications for the synthesis of fine chemicals. In recent years, the preparation of odorants utilizing the advantages of flow reactors received growing attention. In this

• conducting both generation and pyrolysis of triperoxide 55 in flow reactors, while phase separation of the biphasic mixture containing triperoxide 55 is realized in a PTFE membrane reactor [50]. Since many macrocyclic musks (or their precursors) contain internal olefins, they are frequently prepared by ring

• at low temperatures or instable intermediates, e.g., endoperoxide (55), benefit from the superior reaction control and safety profile of flow reactors. Many of the transformations in this review demonstrate the utilization of solid-supported reagents in cartridges that allow to avoid separation of

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• pressure-stable reactors, which leads to shortened residence times. Inductive heating, in addition to microwave irradiation [44][45][46] heating, can serve as an indirect and rapid heating technology that, when combined with pressure-resistant microstructured flow reactors, enables "flash" heating so that

• applications. NiO2, on the other hand, was used to achieve the dehydrogenation of amines (to nitriles) and to perform the α,β dehydrogenation of ketones 61. 3.2.3 Using chemically active fixed beds (catalysts): Copper metal in the form of wires or turnings can also be inductively heated when placed inside flow

• reactors (Scheme 12, case A). There, it performs a second role by also becoming a source for a copper catalyst, either by being released into solution or by acting as a surface-active species capable of promoting "click" reactions between alkynes and azides [76][77][78][79][80][81]. The process can be

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• Abstract The importance of a compound that helps fight against influenza is, in times of a pandemic, self-evident. In order to produce these compounds in vast quantities, many researchers consider continuous flow reactors in chemical industry as next stepping stone for large scale production. For these

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• batch mode to continuous flow mode. The use of an insoluble reagent (e.g. K2CO3) is generally problematic with continuous flow reactors, due to the high probability of blockages occurring within the reactor tubing. To overcome this, we opted to incorporate a packed bed reactor into the continuous flow

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• commercial flow reactors allow for the safe simulation of larger scale processes within the lab environment, facilitating and expediting the process optimisation experience. While some of the implications of the flow chemistry are more obvious than others, i.e., greener processes with potential cost

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• constant is another scale-up strategy. This strategy has been applied in commercial Corning Advanced-Flow™ reactors. Heart shapes provide good mixing for the liquid and gas phases and enhance the mass transfer while using the space on the microreactor chip efficiently. A photo of a Corning reactor is given

• combination of an oscillatory flow with the static mixers of the HANU reactor (Figure 5c) enabled a stable suspension of the photocatalysts without clogging of the reactor channels [58]. Corning flow reactors are designed to provide good mixing for multiphase reactions with periodic heart-shaped static mixers

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• irradiation. Herein, we review some important developments of heterogeneous photocatalytic materials and their application in flow reactors for sustainable organic synthesis. Further, the application of continuous flow heterogeneous photocatalysis in environmental remediation is briefly discussed to present

• ][7], and their applications in organic synthesis [8][9][10][11], solar fuel production [12][13][14][15][16][17], and environmental remediation [18][19][20][21][22][23]. Herein, we review the recent applications of HPCats in flow reactors for organic synthesis, as to the best of our knowledge, there

• engineers to achieve more efficient irradiance and mass transport, leading to a higher productivity (Section 1.3). Section 2 covers the fundamental aspects and recent developments of the major categories of HPCat materials. Section 3 details the types of flow reactors that HPCats can be applied in, with a

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• ) [1][2][3]. This effect limits the penetration of photons to only a short distance into the reaction vessel, provoking increases of the reaction time, photocatalyst loading, byproducts, overheating and so on. Notably, the use of continuous-flow reactors for photochemical applications allows us to

A method to determine the correct photocatalyst concentration for photooxidation reactions conducted in continuous flow reactors

• Clemens R. Horn and
• Sylvain Gremetz

Beilstein J. Org. Chem. 2020, 16, 871–879, doi:10.3762/bjoc.16.78

• centered on the combination of light with continuous flow reactors [1][2][3][4][5][6]. The reason for this increased interest is that continuous flow photochemical reactors can overcome various limitations that occur when the same reaction run in batch reactors [7]. For example, the flow reactor can

• little as possible” [8]. This phrase describes the approach used to scale up flow reactors to an industrial scale [9][10]. This is particularly true when it comes to biphasic reactions, like a gas/liquid reaction as is the case for photooxidations [11]. An interesting aspect of photooxidations is that

Low-budget 3D-printed equipment for continuous flow reactions

• Jochen M. Neumaier,
• Amiera Madani,
• Thomas Klein and
• Thomas Ziegler

Beilstein J. Org. Chem. 2019, 15, 558–566, doi:10.3762/bjoc.15.50

• this equipment we performed some multistep glycosylation reactions, where multiple 3D-printed flow reactors were used in series. Keywords: continuous flow; 3D printing; glycosylation; microreactor; multistep; Introduction The use of flow chemistry in comparison to batch chemistry shows great benefits

• most crucial one and it would be desirable to apply flow chemistry to this endeavour. Results and Discussion 3D-Printed flow reactors For our reactors, we chose a low-budget FDM 3D printer (Anet A8) which was custom-modified to improve the printing quality. The main advantage of FDM printed reactors in

• organic synthesis is the use of the inexpensive and chemically robust material PP. There are several examples for 3D printed devices, like microfluidic flow reactors with 50 µm channel width or complex mixing chambers, manufactured with SLA technology [6][12][19], but one significant disadvantage of such

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• . In some cases, synthesis and chemistries can be very different such that totally different set of flow reactors (including material of construction) and operating conditions has to be employed, e.g., flow chemistry literature shows the use of a wide variety of flow reactors, e.g., tube-in-tube gas

• minimum number of components for performing flow synthesis of different molecules. The developed platform will contain all the necessary components for synthesis (flow reactors, packed columns etc.) to the downstream processing (extractor, separator, crystallizers, dilution tank etc.). Some of these

Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor

• Morten M. C. H. van Schie,
• Tiago Pedroso de Almeida,
• Gabriele Laudadio,
• Florian Tieves,
• Elena Fernández-Fueyo,
• Timothy Noël,
• Isabel W. C. E. Arends and
• Frank Hollmann

Beilstein J. Org. Chem. 2018, 14, 697–703, doi:10.3762/bjoc.14.58

• biocatalytic processes have been reported in flow reactors [19], mostly advocating easier process intensification in combination with enzyme immobilization [20][21][22][23]. Also the higher oxygen-transfer rates in flow reactions compared to batch reactions have been emphasised by several groups. Here, reactor

• designs ranging from simple flow reactors, tube-in-tube reactors [24], agitated tube reactors [25][26] and continuous agitated cell reactors [27] have been reported. Encouraged by these contributions, we asked ourselves whether a slug-flow approach may combine mechanically less demanding conditions with

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• ) resulted in fully homogeneous conditions suitable for flow processing (Table 3, entry 3). Continuous-flow experiments Azirine formation. With the optimal conditions for the three reaction steps in hand, we translated the process to continuous-flow conditions. For that purpose, individual continuous-flow

• reactors for each step were setup, the reaction conditions re-optimized when necessary, and finally all the steps integrated in a single continuous stream. The thermolysis of vinyl azide 1 was performed in a continuous flow reactor consisting of a perfluoroalkoxy (PFA) coil (0.5 mL, 0.8 mm i.d.) immersed

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• production step. Particular attention is placed on the precursors availability as well as the substrate loading in the process. Potential new routes and recent developments are discussed, in particular on the employment of flow-reactors. The latter technology allows to develop processes with shorter reaction

• rapid reaction [44]. In this field, flow reactors offer benefits in terms of mass and heat transfer, both enhanced by the geometry of the reactor. Furthermore, the possibility to have a continuous production and to easily perform multiple modular reactions, leads to the improved scalability of these

• process. Several examples are reported in literature about substrate or product inhibition of HSDHs. Protein engineering could help to solve or lowering the effect of these issues, leading to the optimization of the biocatalyst for industrial applications. In addition, the use of flow-reactors can be

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• shows oscillations in Tr activity (with experimental conditions in inset). Adapted with permission from [94], copyright 2015 Nature Publishing Group. Functions obtained by linking multiple network modules in microfluidic flow reactors (depicted as CSTR 1 and 2). In each case, the oscillating catalyst

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• demonstrated the use of automation for integrating batch and flow reactors on a single platform [46]. Their process also involved extraction and distillation operations. III) Automation for control: The third and the most important purpose of automation is to control the process variables like temperature

• volatile or the process stream is a two-phase mixture. Recently, Movsisyan et al. have reviewed the application of flow reactors for hazardous reactions [1]. Although the flow reactors allow such reactions to be carried in a safer manner controlling such reactors at production scale could be challenging

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

• Carmen Moreno-Marrodan,
• Francesca Liguori and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• 7 was successfully achieved in the past using batch Pd catalysts (0.15–5% wt), with typical 7a yields in the range of 60–70% [147][148]. More recently, a number of catalytic flow reactors were also described for this process. Best yields (94–100%) were achieved using either 16% CeO2@TiO2 (100%) [119

• scope An explanation for efficiency differences observed in catalytic flow reactors in relation to the molecular structure and/or substituent groups of alkynes substrates is not apparent due to a number of reasons. For example, although a higher selectivity in partial hydrogenation was reported for 1

• , respectively, has been explored with a variety of catalytic flow reactors. While direct comparison in terms of substrate conversion is prevented by non-uniformity of reaction conditions, the dearth of a common trend emerges in terms of selectivity at the same level of conversion. An overall picture of

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• of compact continuous-flow reactors has begun to transform the way chemical synthesis is conducted in research laboratories and small manufacturing over the past few years [14][15][16][17][18][19][20][21]. In several applications, where reaction times are short and heat management is important

• , intensified continuous processes inside tubular or plate-type flow reactors can successfully replace batch methodologies classically carried out in stirred glass vessels. We have demonstrated the benefits of this superior heat management in previous work looking at exothermic radical polymerizations in

• continuous flow [22][23]. Over the past years, Diels–Alder reactions of isoprene using laboratory-scale flow reactors were studied by different research groups [24][25]. A continuous-flow reactor can offer a range of benefits over batch processing, with the enhanced heat and mass transfer arguable being one