Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• group developed the electrocatalytic racemic C(sp³)–H alkynylation of THIQs with terminal alkynes in a continuous-flow microreactor using copper/TEMPO relay catalysis [51]. The electrocatalytic reaction in continuous flow facilitates straightforward scale-up and demonstrating a broad substrate scope. In

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• , automation in ASFRs reduces the need for constant human oversight, lowering operational costs and minimizing the risk of human errors. A schematic representation of ASFR is provided in Figure 5a. A self-optimizing microreactor system has been devised specifically for closed-loop optimization of the Heck

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• its control difficult and risky. In this paper, a homogeneous continuous flow microreactor system was developed for the nitration of O-methylisouronium sulfate under high concentrations of mixed acids, with a homemade static mixer eliminating the mass transfer resistance. In addition, the kinetic

• ]. Guo et al. constructed a continuous flow microsystem for o-xylene nitrification and proved the process safety of by the adiabatic temperature rise of the nitrification reaction and the characteristic heat transfer time of the microreactor [9]. The residence time of the microreactor was reduced by an

• order of magnitude and the volumetric mass transfer coefficient was increased by several orders of magnitude compared with that of a conventional stirred-tank reactor. Jin et al. developed a continuous flow microreactor system for the non-homogeneous nitrification of nitrobenzene using mixed acids [10

Rapid gas–liquid reaction in flow. Continuous synthesis and production of cyclohexene oxide

• Kyoko Mandai,
• Tetsuya Yamamoto,
• Hiroki Mandai and
• Aiichiro Nagaki

Beilstein J. Org. Chem. 2022, 18, 660–668, doi:10.3762/bjoc.18.67

• 1,2-dichloroethane and air could react efficiently inside a pressurized microfluidic channel at high temperature in the flow microreactor. It is important to be noted that precise control of reaction temperature and residence time in our flow system are keys to inhibit overreactions in cyclohexene

• with air in the flow microreactor A flow microreactor system consisting of a T-shaped micromixer, and one microtube reactor was used for epoxidation of cyclohexene with air. A solution of cyclohexene (0.065 M), isobutyraldehyde (0.195 M), and tridecane as an internal standard in 1,2-dichloroethane

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• available imine and terminal dihaloalkanes in a flow microreactor. Reduction of the substrate imine on the cathode proceeded efficiently due to the large specific surface area of the microreactor. This method provided target compounds in good yields compared to a conventional batch-type reaction

• . Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour. Keywords: electrochemical synthesis; electrocyclization; flow microreactor; heterocyclic amines; imine; Introduction Heterocycles are a very important class of

• microreactor has recently attracted attention as an excellent alternative tool to conventional batch-type electrochemical reactors [28][29][30][31][32]. The potential advantages of electrochemical flow microreactors over conventional batch-type reactors are a large surface-to-volume ratio, precise residence

Electrocatalytic C(sp³)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

• Bin Guo and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2021, 17, 2650–2656, doi:10.3762/bjoc.17.178

• terminal alkynes has been achieved in a continuous-flow microreactor through 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)/copper relay catalysis. The reaction is easily scalable and requires low concentration of supporting electrolyte and no external chemical oxidants or ligands, providing straightforward

• electrosynthesis was conducted in a microreactor equipped with two Pt electrodes as the anode and cathode and operated with a constant current (Table 1). Under the optimized conditions, a solution of tetrahydroisoquinoline 1a (1 equiv), alkyne 2 (1.5 equiv), Cu(OTf)2 (10 mol %), TEMPO (20 mol %), n-Bu4NPF6 (0.2

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

• was evident (Scheme 3). Within the microreactor acetone was first deprotonated by merging with a 2.5 M sodium hydroxide stream at room temperature, then, after a residence time of just 45 seconds, the resultant enolate was introduced to a stream containing the aldehyde as a 5.5 M solution also in

• as proline. However, a major drawbacks of these process are the long reaction times and high catalyst loading that often need to be used [101][102]. In 2009, Seeberger et al. described a version of an enantioselective aldol reaction in flow using a microreactor (Scheme 6) [103]. The approach allowed

• -bed microreactor was found to possess good long-term stability and could be used for the catalysis of a range of aldol reactions, one example is given in Scheme 8. Conveniently, just one starting material stock solution was all that was necessary, meaning that 4-chlorobenzaldehyde (64) could be

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• equivalents of KHMDS. Further application of this “batch protocol” for a “continuous-flow microreactor” reaction is now ongoing in our laboratory towards industrial collaboration. Experimental A test tube containing 1 (0.4 mmol) in triglyme (0.7 mL) was charged with HCF3 (9.9 mL, 1.1 equiv, measured by a

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• Michael Andresini Leonardo Degannaro Renzo Luisi Flow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, Via E. Orabona 4, Bari, 70125, Italy 10.3762/bjoc.17.20 Abstract The reported flow-batch approach enables the easy

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

• : microreactor; microreactor scale-up; monolith reactors; packed bed reactor; photoreactor scale-up; Review Introduction In the traditional chemical industry, thermochemical activation routes are mostly preferred. Light can also activate some molecules, which leads to fast and selective reaction pathways

• - and mesostructures in larger-scale photoreactors, such as packed beds and monoliths coated with catalysts can also enhance the mass transfer and operate at microreactor reaction rates. Together with photomicroreactors, these structured reactors are opening a new era in photochemistry by providing a

• applications. The lab-on-a-chip concept has enabled researchers to work on intrinsic kinetics. Intrinsic data acquisition is crucial while designing and operating large-scale reactors. Several microreactors, such as a spiral channel microreactor carved on a flat aluminum plate [23], a capillary tube [24], a

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• applied to various C–H functionalization reactions [92][93]. In 2017, Noël, Van der Eycken and co-workers hence astutely combined the dual catalysis strategy with flow microreactor technology to achieve C2-acylation of indole derivatives with aldehydes (Figure 30) [94]. Both electron-rich and electron

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

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• , Road, North Chicago, Illinois 60064, United States of America 10.3762/bjoc.16.111 Abstract The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• effort to address the safety concerns raised by the potentially explosive acyl azide 1a (Scheme 1), Hayashi and co-workers [14] demonstrated the handling of the Curtius rearrangement reaction (transformation from acyl azide 1a to isocyanate 1b) in a microreactor system (Scheme 1 and Figure 1). Acyl azide

• eventual microreactor blockage caused by a resulting precipitate from the acetone/aqueous NaN3 mixture. Fortunately, acetonitrile is also an acceptable green solvent [21][22]. Furthermore, acetonitrile has a higher boiling point than acetone which is desirable for high temperature reaction interrogation

• . Consequently, acetonitrile was the preferred solvent for mesyl shikimate 4 for further optimisation in continuous-flow systems. Mesyl shikimate 4 (0.1 M) in acetonitrile was treated with aqueous NaN3 (0.11 M, 1.1 equiv) in a thermally controlled microreactor system (Figure 2). Generally, good mesyl shikimate

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• system by charging an HPLC column with PFA-supported catalyst 3. Thus, polymer 3 was packed into a stainless-steel column (Ø = 0.21 cm (diameter), l = 15 cm (length), particle size = 45 µm). The main features of the resulting packed microreactor were determined by pycnometry methodology [20][21], as

• reported in Table 2. This method consists in filling the microreactor successively with two distinct solvents (here noted as 1, ethanol and 2, n-hexane) and then weighing the filled microreactor accurately. The difference between the masses (w) of the filled reactor divided by the differences of solvent

• densities (δ) permits to calculate the microreactor void volume (V0, dead volume). This feature is important because it provides an idea of the volume not utilized in the microreactor. The catalyst’s loading was kept as determined by microanalysis, as previously described for polymeric catalyst 3. The

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

• the mounted reactor R3. The small picture shows the fixed reactor in the rail. b) In-printed screw nuts during 3D-printing: The print was paused, the nuts inserted and the print resumed. a) Microreactor R4 with a reactor volume of 12 µL filled with a blue dye solution. b) Magnification of the reactor

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• )-enantiomer. The good results obtained in the batch recycling reactions prompted us to investigate the possibility of a recycling process under flow conditions. For this purpose a microreactor was built consisting of a PEEK column which was filled with the enzyme. The reaction mixture was circulated within

Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

• Anne Schnell,
• J. Alexander Willms,
• S. Nozinovic and
• Marianne Engeser

Beilstein J. Org. Chem. 2019, 15, 30–43, doi:10.3762/bjoc.15.3

• solution of substrate 4∙Br and L-proline was mixed with acetone in a commercial PEEK microreactor mixing tee. The reacting solution was diluted with acetonitrile using a second microreactor and subsequently fed into the ESI source of the mass spectrometer. Beside a very prominent signal of the charge

• with a flow rate fA = 75 µL/h into microreactor mA, where they were mixed. From microreactor mA the combined solutions flowed towards microreactor mB where they were diluted with DMSO, which was injected with flow rate fB = 150 µL/h. The outlet of microreactor mB was directly fed into the spectrometer

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• 150 as an electrophile and trifluoroacetic anhydride (TFAA) as an additive at 80 °C in a microreactor without using any solvent (Scheme 56). Additionally, synthesised compound 133 was used as precursor for the synthesis of (±)-oxomaritidine (151). In 2007, Lalic and Corey [138] reported the synthetic

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• -mediated aldol reactions in H2O was proposed for the present methodology. Accordingly, a hydrophobic region and a hydrophilic region may be created through the hydrogen bonds between functionalized calix[4]arene and water molecules. This leads to in situ formation of a microreactor that improves the

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

• described in the literature to alleviate the inactivation issue described above [9][10][11][12]. The continuous-flow microreactor technology has emerged as a safe and scalable way to approach oxidation reactions [13][14]. Due to its small dimensions, hazardous reactions can be easily controlled, owing to

• ABTS·+ by an excess of POD (500 U mL−1). The reactions were performed at 30 °C in oxygen-saturated 50 mM KPi buffer at pH 7.0. Flow reactor experiments PFA microreactor coils (750 μm ID) with a volume of 3 and 6 mL were constructed. The reaction mixture was introduced via a syringe pump (Fusion 200

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• reactor – Cambridge Reactor Design). The system pressure was controlled using a 75 psi inline back pressure regulator. The flow stream was quenched by mixing with a solution of hydrochloric acid (1 M) at a flow rate of 2 mL/min within a glass microreactor (1 mL, Little Things Factory). The biphasic

New bio-nanocomposites based on iron oxides and polysaccharides applied to oxidation and alkylation reactions

• Daily Rodríguez-Padrón,
• Alina M. Balu,
• Antonio A. Romero and
• Rafael Luque

Beilstein J. Org. Chem. 2017, 13, 1982–1993, doi:10.3762/bjoc.13.194

• basic probe molecules applying a pulse chromatographic titration methodology. The catalyst used (≈0.025 g) was fixed inside a tubular stainless steel microreactor (4 mm internal diameter) by Pyrex glass wool. A cyclohexane solution of titrant (0.989 M in PY and 0.686 M in DMPY, respectively) was

• injected into a gas chromatograph through a microreactor in which the catalyst was previously sited. The injected base was analyzed by gas chromatography with a flame ionization detector and using an analytical column of 0.5 m length, containing 5 wt % of polyphenylether in the Chromosorb AW-DMCS in 80/100

A recursive microfluidic platform to explore the emergence of chemical evolution

• David Doran,
• Marc Rodriguez-Garcia,
• Rebecca Turk-MacLeod,
• Geoffrey J. T. Cooper and
• Leroy Cronin

Beilstein J. Org. Chem. 2017, 13, 1702–1709, doi:10.3762/bjoc.13.164

• evolution in droplets Here, we propose a system for facilitating chemical evolution in populations of co-incubating aqueous, single emulsion microfluidic droplets. Each microdroplet can be considered an autonomous microreactor, loaded with a self-propagating chemical reaction network. However, it has been

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

• temperature profiles inside the reactor. Whenever it is not possible to insert temperature sensors along the flow reactor/microreactor due to its compact dimensions (although miniaturized sensors are available almost everywhere), the temperature should be monitored at the inlet (preferably at mixing points