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

• light [40]. The design allows the screening to be more material- and time-efficient in the optimization of both continuous variables (e.g., temperature and residence time) and discrete variables (e.g., catalyst, base). Pieber et al. [46] reported the application of a segmental flow reactor for

• , each comprising 650 µL within a slug flow reactor [48]. This innovative system features precise monitoring of the reaction slug through a dedicated array of phase sensors and an algorithm designed for detecting its passage. As a result, the workflow delivers a notable boost in productivity, surpassing

• . In addition to organic synthesis, the slug flow methodology has found application in polymer synthesis. A flow platform capable of polymerizing 397 unique copolymer compositions was developed by Reis et al. [51] using a droplet flow reactor. The methodology and high-fidelity data enabled them to

Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• and development of a visible light-assisted modular photo-flow reactor with a seamlessly integrated post-synthetic work-up procedure enabling the efficient synthesis of dihydropyranones from furfuryl alcohols. The reaction uses sun light as green energy source, and the novel photo-flow reactor

• illustrated in Figure S1, Supporting Information File 1, a flat photo-flow reactor was predesigned comprising a wide-surface polystyrene sheet (length 50 cm × width 50 cm × height 5 cm) bearing a reactor (PFA tubing) that was manually put and hooked on the polystyrene surface (Figure S1b, Supporting

• molar ratio of 1:1:0.005:70:54:408 was taken in one syringe and pumped to our fabricated photo-flow reactor (10 mL – PFR). The passing solution was then exposed to solar light (February to April sunlight in Hyderabad, India), to execute the Achmatowicz rearrangement, and a complete conversion was

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

• HNO3 is also 1, which transforms Equation 4 into Equation 7. Also, with M=cHNO30cIO0, Equation 6 can be rewritten to Equation 8. After the reaction order being determined, the rest of the experiments were conducted in the continuous flow reactor and t in Equation 8 refers to the residence time

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• the conjugate addition of propanal (22) and trans-β-nitrostyrene (11) catalysed by a simple solid-supported peptidic catalyst 24 using a continuous flow reactor. To overcome the diffusion limitations, elevated pressure was applied. Increasing the pressure from atmospheric to 60 bar resulted in a 12

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• solution and in the solid state [127]. Furthermore, even sugar-functionalized pyrazoles have been accessed by this approach [128], and it was readily implemented in a continuous flow reactor [129]. Besides traditional Sonogashira catalyst systems, highly reactive and reusable immobilized Pd-complexes, such

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• 0.1 mmol to 0.5 mmol of 1a in consideration of the dead volume of the flow reactor, the product 3a was obtained in markedly improved yield (Table 1, entry 10: 77%) [59] which was comparable to that of the batch reaction (76%). Notably, however, the present flow reaction was performed at 25 °C (batch

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• -sensitive substrates. Another challenge, shared with Nicewicz's method [90], is the preparation of arylacridine 159 in a single step from the relatively expensive 9-chloroacridine through Pd-catalyzed cross-coupling with 2-chlorophenylboronic acid. Additionally, for large-scale reactions, a flow reactor is

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

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

• flow using the HANU flow reactor, indicating scalability and improving safety. Keywords: catalyst-free; flow chemistry; oxygen; photochemistry; sustainable oxidation; Introduction Oxidation reactions are widely used in the chemical industry, but are often problematic due to challenges with

• protocol demonstrates excellent scalability, as we have successfully transferred it to the HANU flow reactor. This flow photoreactor is designed for multi-phase reactions (solid–liquid, gas–liquid) [30][31][32], and allows for seamless scale-up to production scale. Finally, by the use of specific “easy to

• appealing production method. The oxygenation of triphenylphosphine was used as a model reaction, since the batch results showed fast kinetics (15 minutes). Since triphenylphosphine is insoluble in the reaction mixture we opted to use an oscillatory flow reactor (OFR), specifically the HANU flow reactor (i.e

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

• to handle aerobic oxidation. Therefore, passive mixing should be more suitable for aerobic oxidation. The whole flow reactor with passive mixing can be immersed in incombustible medium such as water, leading to the improvement of the process safety. Passive mixing is commonly realized using slug-flow

• the reactor. As the gas–liquid reaction mixture passes through the honeycomb reactor, the porous material functions as a static mixer, maintaining high mixing efficiency throughout the aerobic oxidation process. We believe that this processing technology offers much potential for application as a flow

• reactor with a highly efficient and reliable static mixer in its full range. Such a reactor should become one of the ideal devices for aerobic oxidation under continuous-flow conditions and contribute to the further development of aerobic oxidation processes and related oxidation processes such as

C3-Alkylation of furfural derivatives by continuous flow homogeneous catalysis

• Grédy Kiala Kinkutu,
• Catherine Louis,
• Myriam Roy,
• Juliette Blanchard and
• Julie Oble

Beilstein J. Org. Chem. 2023, 19, 582–592, doi:10.3762/bjoc.19.43

• using a laboratory-built pulsed-flow system to save reagents. The optimized conditions in this pulsed-flow mode were then successfully transferred to a continuous flow reactor. In addition, the versatility of this continuous flow device allowed both steps of the reaction to be carried out, namely the

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

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

• solutions from an engineering perspective, the advent of computer-aided design (CAD) in combination with widely available 3D printing has become a preferred choice. Prototyping aided by these technologies has significantly accelerated the development of novel flow reactor designs [14]. The challenging

• typically call for an optimized or even specifically designed reactor built, the modularity of flow reactor is vital for quick reconfiguration and switching between different reactions. This argument is particularly true when natural product synthesis is to be performed in continuous flow. The need for

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• oxidation of iodoarenes to form DIS by Wirth et al. (Scheme 1B) [39]. Herein, established conditions for synthesizing DIS were transferred into flow chemistry utilizing a model flow reactor with two platinum electrodes. Other recent examples include the generation of five-membered CDIS utilizing fluorinated

• with only two equivalents of TfOH forming product 1a in 74% yield (Table 2, entry 1). We found that these reaction conditions cannot be applied in the proposed multi-step procedure since the added benzene clogs the flow reactor through precipitation of a black solid. We could overcome this issue by

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

• flexibility at low cost or exploit standardized flow reactor modules readily available from various vendors. The growing popularity of flow chemistry over the last two decades has led to many developments to streamline important chemical reactions, overcome limitations due to highly unstable intermediates

• operate under homogeneous conditions within the thin tubing that makes up the flow reactor components. The handling of slurries whether because of unintended precipitation or as a deliberate means to process insoluble materials presents the risk of clogging and pressure built-up which can severely

• regulated automated input crystallizer (KRAIC) was reported [114]. This segmented flow reactor consists of a controlled temperature gradient reactor where the reactor inlet is heated while the outlet is actively cooled. Temperature gradient curves can be generated by varying the inlet/outlet temperatures

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

• . Results and Discussion Reactor assembly and model reaction We started our investigations by preparing a packed-bed reactor using a glass column (6.6 mm i.d., 100 mm length) that can be used in a dedicated setup for heterogeneous flow photocatalysis carried out in a commercial photochemical flow reactor

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• (Table 4). Although the current yield (49%) for the batch electrolysis in pure IL is higher than in flow, the yields for 0.1 M solutions are comparable between batch (29%) and flow (32%). In this case, the rate of production of the NHC in the electrolysis step was higher in the flow reactor (1.60 mmol/h

• ) than in batch using pure IL (0.37 mmol/h). However, other factors should also be highlighted, including the 8× larger electrode area in the flow reactor, which enables a higher current to be passed while maintaining the same current density (15 mA/cm2). In the case of the NHC organocatalysis, we

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

• a method for the acetylation of isoamyl alcohol (9) catalyzed by Candida antarctica lipase B (Scheme 3) [26]. A biphasic system consisting of n-heptane and an aqueous buffer solution is used and efficiently mixed in a Corning AFRTM Low Flow reactor providing a fine dispersion of the reaction mixture

• and co-workers developed a flow protocol to overcome these limitations and prepared various macrolactones from triperoxides by pyrolysis in an inductively heated flow reactor (Scheme 13) [50][51]. Due to the commercial relevance of juniper lactone (56), they designed a flow setup for a scalable and

• ) to (+)-nootkatone (8) under catalyst and solvent-free conditions in a segmented flow. Enzyme-catalyzed acetylation of isoamyl alcohol (9) in a biphasic n-heptane/water mixture utilizing a CorningTM Low Flow reactor. Esterification of alcohols by transesterification, catalyzed by immobilized

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

• , e.g., from the metals magnesium or zinc, (thermal) activation is required. This was demonstrated for the Reformatzky reaction (Scheme 11, case B) [53][74], in which zinc powder was mixed with MagSilicaTM and positioned inside the flow reactor. For example, 2-bromopropanoic acid ethyl ester (52) and

• was cyclized under acidic conditions with Amberlyst 15TM ion exchange resin embedded inside the flow reactor. However, successful conversion to an industrial process was hindered by the fact that polymerization of the starting material myrcene (85) could not be suppressed, leading to fouling of the

• opportunities. Inductive heating, a powerful tool in industry and the Life Sciences. Electric displacement field of a ferromagnetic and superparamagnetic material. Temperature profiles of reactors heated conventionally and by RF heating (Figure 3 redrawn from [24]). A. Flow reactor filled with magnetic

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

• Medical Science, Nijigaoka, Kani-city, Gifu Prefecture, 509-0293, Japan 10.3762/bjoc.18.67 Abstract The enhanced reaction rate in the epoxidation of cyclohexene with air as an oxidant was discovered without any added catalyst utilizing a continuous flow reactor constructed with readily available

• concentration of cyclohexene in 1,2-dichloroethane was set to 0.065 M for the initial study and three equivalents of isobutyraldehyde were dissolved in the solution. While the solution was sent to the flow reactor at the flow rate of 2.6 mL/min, the air was at the flow rate of 480 mL/min with keeping the molar

• air is remarkably higher than that of the solution (480 mL/min of air vs 2.6 mL/min of solution). Although we have no clear evidence for now, the solution could form a very thin layer due to plug-type flow. In such a case, the interfacial area is greatly enlarged in the flow reactor due to the high

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

• recycling steps, and were characterized regarding the reaction kinetics (initial rate) and scalability (different lab scales) in a batch reactor. The reaction kinetics were studied in a continuous flow reactor. A high-pressure circular reactor (up to 130 MPa) was applied for the investigation of changes in

High-speed C–H chlorination of ethylene carbonate using a new photoflow setup

• Takayoshi Kasakado,
• Takahide Fukuyama,
• Tomohiro Nakagawa,
• Shinji Taguchi and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2022, 18, 152–158, doi:10.3762/bjoc.18.16

• ; ethylene carbonate; photo flow reactor; vinylene carbonate; Introduction The C–H chlorination by molecular chlorine is a highly exothermic reaction that proceeds via a radical chain mechanism as illustrated in Scheme 1 [1][2][3][4][5][6]. Frequently, photoirradiation is used for radical initiation through

• , sustaining the radical chain. Chlorine gas is a cheap feedstock since it is formed as a byproduct of the electrolysis of NaCl to produce NaOH in an industrial process [7]. We felt that C–H chlorination would be updated by using scalable flash chemistry [8]. Flow C–H chlorination using a compact flow reactor

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• process in a continuous-flow reactor. The mechanistic studies indicated that a nickel hydride intermediate generated with C(sp3)–H as the hydride source is involved in this catalytic transformation. The hydronickelation step results in the sterically less hindered vinylnickel intermediate 15-I, which

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

• mixing elements, reactor residence coils, heating/cooling segments and additional downstream components such as phase separators, quenching stages and crystallisers. A typical flow reactor will comprise two or more pumps (isocratic/peristaltic/syringe) that feed an HPLC manifold (into which samples may

• flow [86]. Due to the inherently low active volumes of reactants that are processed in the reaction zone within a continuous-flow reactor, the safety risks associated with critical event are greatly diminished. In addition, process reliance and sustainability are further improved by adding extra safety

• %) over 10 hours of continuous runtime [155]. As such a simple chromatographic column can be exploited as flow reactor to perform initial feasibility tests. As with all condensation reactions, the main problem when performed in flow is the elimination of water. Yeung et al. provided a solution using a

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• cholesterol 44 and histamine 45. Scientific literature [97] reports a three-step continuous synthesis of [6,6]-tert-butyl phenyl-C61-butyrate 47 based on tert-butyl 4-benzoylbutyrate hydrazone in a microstructured flow reactor that eliminates the need for stage-by-stage isolation of intermediate products and

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

• reaction crudes were re-introduced into the flow reactor under the same conditions, azirines 2h–j were obtained quantitatively (2h, 98%; 2i, 97%; 2j, 97%). Pursuing in our aim to develop a green approach to prepare substituted NH-aziridines from vinyl azides in a single procedure, the solution of 2a from