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

• . Photochemical reactions require uniform light penetration of the reaction mixture, and flow setups with uniform path lengths would be ideal for such reactions. A self-optimizing continuous-flow reactor was designed by Poscharny et al. [59] for [2 + 2]-cycloaddition reactions promoted by light. The optimization

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

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

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

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

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

• 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

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• and propylene oxide as a proton scavenger under flow conditions (0.05 mL/min; residence time = 20 h). The use of flow conditions drastically enhanced the kinetics of the reaction, moving from 120 h reaction time in batch to 20 h using a continuous flow reactor. The reaction allowed the synthesis of a

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

• , multiple temperature zones can also be provided if required. The reactor module also includes mixers (M1–M9) that are commonly used in flow chemistry [64][65]. The continuous flow reactor can also be equipped with in-line static mixing elements [63]. The second module includes the intermediate storage

Cobalt–metalloid alloys for electrochemical oxidation of 5-hydroxymethylfurfural as an alternative anode reaction in lieu of oxygen evolution during water splitting

• Jonas Weidner,
• Stefan Barwe,
• Kirill Sliozberg,
• Stefan Piontek,
• Justus Masa,
• Ulf-Peter Apfel and
• Wolfgang Schuhmann

Beilstein J. Org. Chem. 2018, 14, 1436–1445, doi:10.3762/bjoc.14.121

• of the various cobalt–metalloid alloys supported on Ni RDE electrodes revealed CoB to be the most efficient HMF oxidation catalyst. Using a CoB modified Ni foam as anode material, and Ni foam as the cathode in a continuous flow reactor with an anion exchange membrane separating the anodic and

• of the activities of all investigated CoX-based catalysts (X = B, Si, P, As and Te) is highlighted in Table 1. HMF oxidation in a continuous flow reactor The surprisingly high HMF oxidation activity of CoB made it especially interesting to further study the product distribution and FDCA yield in a

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

• at elevated substrate concentrations may be an indication for a slight substrate inhibition. Performing these initial rate measurements in the presence of varying product concentrations showed a pronounced product inhibition (Supporting Information File 1, Figure S2, vide infra). Continuous-flow

• reactor enzymatic oxidation Next, we performed the PeAAOx-catalysed oxidation of trans-hex-2-enol in a slug-flow reactor setup (Supporting Information File 1, Figure S1 and Figures S9–S11). In a first set of experiments we systematically varied the residence time of the reaction mixture in the flow

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

• 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

• phase. Decomposition of 2-(bromomethyl)oxazoles 6 was successfully avoided by further integrating into the continuous-flow reactor the final nucleophilic halide displacement step with NaN3. The resulting 2-(azidomethyl)oxazole derivatives 7 presented higher stability and could be isolated without

• to give the desired product. After optimization of all individual steps in batch and continuous-flow mode, the complete sequence has been integrated in a single continuous-flow reactor, in which the vinyl azide is fed as substrate and the final 2-(azidomethyl)oxazole is formed and collected from the

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

• Imane Nekkaa,
• Márta Palkó,
• István M. Mándity and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2018, 14, 318–324, doi:10.3762/bjoc.14.20

• requiring harsh conditions in batch methods. A simple, efficient and scalable production was implemented with a short processing time, which might open up new horizons for a potential CF industrial synthesis of heterocycles. Schematic outline of the continuous-flow reactor. Flow synthesis for the

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• trifluoromethylation with CF3SO2Na are highly efficient, the original Langlois’ conditions were nevertheless applied to a series of heteroarenes. Li and co-workers reported the synthesis of 3-trifluoromethylcoumarins 64 by Cu(I)-catalysed trifluoromethylation with CF3SO2Na and t-BuOOH in a continuous-flow reactor [61

• ]. After optimisation of the reaction conditions in batch, the optimal reaction conditions were established in a continuous-flow reactor at a flow rate of 100 µL min−1 at 60 °C for 40 min. The substrate scope was evaluated on 11 coumarins and showed that both electron-rich and electron-deficient functional

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

• differences among different continuous-flow reactor designs are difficult to rationalize due to the number of additional variables related to the catalyst involved, which include: - the role played by the supported metal, e.g., type, loading, MNP size, shape and location [182][183]), - the role played by the

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

• different naturally occurring and synthetic dienophiles. The synthesis of the Diels–Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This

• 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

• -type continuous-flow reactor and a batch stirred tank. The use of continuous-flow processing allows for an efficient synthesis of large quantities of the Diels–Alder adduct and we managed to scale-up the reaction of myrcene (1) with acrylic acid (2b) inside the 105 mL flow reactor to a throughput of

3D printed fluidics with embedded analytic functionality for automated reaction optimisation

• Andrew J. Capel,
• Andrew Wright,
• Matthew J. Harding,
• George W. Weaver,
• Yuqi Li,
• Russell A. Harris,
• Steve Edmondson,
• Ruth D. Goodridge and
• Steven D. R. Christie

Beilstein J. Org. Chem. 2017, 13, 111–119, doi:10.3762/bjoc.13.14

• flow reactor. Notable recent work in this area has been carried out by Cronin [14], Ley [15] and Jensen [16]. This research highlights the array of benefits that manufacturing fluidic devices via AM processes can bring, including the ability to produce multimaterial parts with complex microscale

• of using 3D printing to produce microfluidic devices using AM techniques such as stereolithography (SL) [11], polymer jetting and fused deposition modelling (FDM) [12][13]. There is therefore considerable interest in the optimisation of chemical systems using this type of multifunctional continuous

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• and acidic azo coupling conditions. Comparison of reaction conversion attained from two continuous flow reactor systems. Experimental domain. Experimental domain. Supporting Information Supporting Information File 442: Additional diagrams and NMR spectra. Acknowledgements We would like to thank the

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• miniaturized continuous flow reactor, also called microreactor, offers many advantages over conventional scale reactors, including considerable improved energy exploitation, increased reaction speed and yield, safety, reliability, scalability, on-site/on-demand production, etc., and a much finer degree of

Automated solid-phase synthesis of oligosaccharides containing sialic acids

• Chian-Hui Lai,
• Heung Sik Hahm,
• Chien-Fu Liang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2015, 11, 617–621, doi:10.3762/bjoc.11.69

• equiv TfOH, NIS, DCM, −30 °C (5 min), −10 °C (25 min) for 9 and 10. Fmoc Deprotection: e) 3 × 20% NEt3 in DMF, 5 min. Photocleavage: f) UV irradiation using a continuous flow reactor, DCM, rt. Synthesis of 12 or 13: (1) 6, b, (2) e, (3) 4 or 5, a (4) f, 30% for four steps to yield 12, 40% for four steps

An integrated photocatalytic/enzymatic system for the reduction of CO₂ to methanol in bioglycerol–water

• Michele Aresta,
• Angela Dibenedetto,
• Tomasz Baran,
• Antonella Angelini,
• Przemysław Łabuz and
• Wojciech Macyk

Beilstein J. Org. Chem. 2014, 10, 2556–2565, doi:10.3762/bjoc.10.267

• enzymes FateDH, FaldDH, and ADH were encapsulated into silicate cages made from Ca alginate and tetraethoxysilanes (TEOS) and used at a controlled pH of 7. CO2 was admitted in a continuous flow reactor at such a rate to generate a 20% excess with respect to the stoichiometric amount required by the

Continuous-flow Heck synthesis of 4-methoxybiphenyl and methyl 4-methoxycinnamate in supercritical carbon dioxide expanded solvent solutions

• Phei Li Lau,
• Ray W. K. Allen and
• Peter Styring

Beilstein J. Org. Chem. 2013, 9, 2886–2897, doi:10.3762/bjoc.9.325

• cost and product contamination [3]. Further efforts have focused on the development of heterogeneous catalysts or immobilised homogeneous catalysts, particularly for use in continuous flow reactor systems [3][4][5][6]. The yield and selectivity of Heck reactions are profoundly influenced by a number of

• -donating group relative to Pd, thereby eliminating the requirement of the phosphine ligand. The catalyst can also aid the reaction without requiring an inert atmosphere. In this paper we report the Heck reaction between 4-iodoanisole and either styrene or methyl acrylate in a continuous flow reactor. The

• although the system is far from running at equilibrium conversion. Curve fitting shows that after 24 hours approximately 60% conversion would be achieved. Therefore on comparable timescale the continuous flow reactor gives a lower conversion but with a slightly improved selectivity for the conversion to

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• disproportionation to SF4 and explosive (Et2N)2SF2 when heating at over 90 °C [41][42][43]. Therefore, special care is required in handling a large quantity of DAST concerning the danger of the explosion under heating conditions. To solve these technical issues, the use of DAST in a continuous-flow reactor employing

• using microreactor systems. Use of DAST in continuous-flow reactors. Flow microreactor synthesis of fluorinated epoxides. Highly controlled isomerization of gem-difluoroalkenes. Flow system for catalytic aromatic fluorination. Continuous-flow reactor for electrophilic aromatic fluorination. Examples of