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

• system comprised of a flow chemistry synthesis platform, a reagent delivery system, a packed bed reactor, process-analytical tools, and an integrated software control system that automates end-to-end process operations and monitoring. The system has been used to demonstrate the synthesis of at least ten

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

• with dried toluene to a total volume of 3.5 mL. The mixture was stirred at room temperature to completely dissolve the catalyst. The solution A is pumped into pump 1 (0.1 mL·min−1) and passed through the packed bed reactor which is set at 130 °C containing MgSO4. The residence time depends on the

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

• and scalable reaction conditions. Here, we report a continuous-flow approach to metallaphotoredox catalysis using a heterogeneous catalyst that combines the function of a photo- and a nickel catalyst in a single material. The catalyst is embedded in a packed-bed reactor to combine reaction and

• combination of solid photocatalysts (i.e., semiconductors) and homogeneous nickel complexes are feasible, but the fact that the nickel complex is in solution reduces the benefits of packed-bed reactor types [19][23][24]. Recently, several bifunctional heterogeneous catalysts that combine the photo- and the

• these heterogeneous catalysts, using a packed-bed reactor. The use of a packed-bed reactor for these solid–liquid reactions is attractive as reaction and separation can be combined in one step. This is particularly notable in our case since, after complexing poly-czbpy with nickel (Ni@poly-czbpy), the

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

• of up to 0.35 kg/h for enone 4. In the second step, the obtained 4-aryl-3-buten-2-ones 3 and 4 are selectively hydrogenated in flow using a packed-bed reactor with Raney nickel as catalyst affording raspberry ketone (5) in 91% yield and raspberry ketone methyl ether (6) in 94% yield, respectively

• smegmatis (Scheme 4) [32]. A solution of the acyl donor 12 in ethyl acetate and an aqueous buffer solution of the corresponding alcohols 11 are mixed in a T-piece and the resulting segmented flow is pumped through a packed-bed reactor containing the immobilized transferase. The reaction mixture is directly

• and warm odor; interestingly, it is also strongly antiseptic [9]. In 2005, Poliakoff and co-workers developed a synthesis of thymol by alkylation of m-cresol (39) in supercritical carbon dioxide (scCO2) using γ-Al2O3 in a packed-bed reactor (Scheme 9) [40]. In the presence of Brønsted-acidic Nafion

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

• nanostructured particles (MagSilicaTM) and packed bed reactor embedded in inductor (right); B. heating profile of different materials exposed to an electromagnetic field. Heating profiles of MagSilicaTM, MnFe2O4, BayferroxTM, and iron powder. Continuous flow synthesis of isopulegol (2) from citronellal (1). Dry

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

• approach. This entails the use of a heated packed-bed reactor filled with solid K2CO3 as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured

• 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

• setup. The initial setup consisted of a heated glass column (i.d. 7 mm, length 7 cm), packed with K2CO3, through which a solution of acyl hydrazone and iodine were passed. It was anticipated that the larger excess of K2CO3 present in the packed bed reactor (when compared to batch mode), in addition to

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

• reagent incorporation into a mixture of monomers which are co-polymerised to create a network of micro- and mesoporous channels that fill the entirety of the tube/column. In a coated wall reactor, the reagent is immobilised onto the inner surface of the reactor. Finally, packed bed reactor columns are

• ), column robustness/ease of recyclability and the facile nature of reaction condition and substrate screening. To increase the greenness and reduce the consumption of the catalyst, Yamamoto and Nakashima have recently developed a proline tetrazole 51 packed-bed reactor system, exploiting the low solubility

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

• packed bed reactor so that several microchannels were created among the beads. Glass beads were coated with a TiO2 photocatalyst. The photoreactor was illuminated with 192 LEDs that could provide 100 mW of power each. The distance between the LED board and the reactor was adjusted to give a uniform

• improvement in the space time yield was attributed to the larger ratio of the catalyst surface area to the reactor volume in the packed bed reactor as well as the flow perturbation that increased the mass transfer rate. In addition, the packed bed photomicroreactor showed a good durability. The reactor

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

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

• ]. Unfortunately, the synthetic steps for the glycoside preparation could not be combined in a multistep reaction, due to clogging of the packed bed reactor, most likely due to the formation of silver bromide during the Koenigs–Knorr reaction. No such clogging was observed when the column was packed with Fetizon’s

• bed reactor. Next, a solution of acetobromo glucose (2) in dichloromethane (0.25 M) and methanol were pumped through the reactor at such a rate that ca. 20 mol equivalents of methanol were present in the mixture. Scheme 2 shows the setup of the glycosylation reaction under flow conditions. Best

• preparing acetobromo glycoses. In order to show the suitability of our flow system for the preparation of simple glycosides, we first tested Koenigs–Knorr glycosylation conditions with silver triflate as activator. Thus, silver triflate (2 equiv) was mixed with molecular sieves (4 Å) and placed in a packed

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 performing multiple reactions in a single platform as given above: The number of valves needed to select the desired set of equipment is much higher. The reactions which take place only in a packed bed reactor and do not involve a separator, filter, crystallizer, etc. The path required for the

• interconnected. The first, reactor module includes different reactors types that are commonly used in the synthesis of APIs viz. tubular reactor (R1–R4), packed bed reactor (R5–R8) and stirred tank reactor (R9). The reactors are equipped with a jacket for maintaining the reaction temperatures. Additionally

• platform. Schematic representation of a unified platform for the flow synthesis (P1–P14 pumps, PBR packed bed reactor, HE1 heat exchanger, H1 heater, S1 and S2 separator, E1 extractor, TR1–TR4 tubular reactor, CH charcoal, CT1 crystallization tank, T1–T3 tanks, F1 filtration). Layout of a unified synthesis

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• flushed with nitrogen gas. At room temperature, the stock solutions of 5-iodopentan-2-one (10, 1.0 M) and 2-(ethylamino)ethan-1-ol (7) in THF solution (1.0 M) were streamed in at 0.5 mL min−1 via a T-piece into a 10 mL reactor coil (tR = 10 min) and passed through a packed bed reactor of potassium

• -(ethylamino)ethan-1-ol (7) in THF solution (1.0 M) were streamed in at 0.5 mL min−1 via a T-piece into a 10 mL reactor coil (tR =10 min) and passed through a packed bed reactor of potassium carbonate. The output solution was streamlined with hydroxylamine (1.0 M) at 1.0 mL min−1 via a T-piece into a 10 mL

• reactor coil (tR =10 min) and passed through a packed bed reactor of potassium carbonate at 100 °C. The reaction mixture was then concentrated in vacuo, taken up in dichloromethane (3 × 20 mL) and concentrated under reduced pressure to yield 11 as light brown liquid. The crude product was used in the next

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

• the half-life (23 h) is lower and the biocatalyst can be reused for only five cycles of conversions. In order to reduce the mechanical stress that might inactivate the immobilized enzymes, the flow-system represents a valid technology. The packed-bed reactor set up by Zheng et al. partially solved

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

• ratio using a ratio controller. This mixed stream can be passed through a packed bed reactor containing a Pd/C catalyst and maintained at 40 °C using a heating jacket. The reactor outlet concentration can be monitored inline and controlled by manipulating the jacket fluid flow rate of the reactor. The

• through a packed bed reactor containing silica-supported Ti(OiPr)4 maintained at 85 °C using a reactor jacket to obtain the olanzapine drug. While the above mentioned automated protocol can be implemented for the synthesis in Scheme 1, it is not easy to implement a few aspects that are routinely used in

• (like UV, IR or Raman spectroscopy) which may be coupled with the reactor jacket flow rate to maintain the desired conversion. The azide and amide streams can be mixed and preheated at 110 °C. The preheated stream can then flow through a copper tubing reactor or a packed bed reactor with copper packings

Selective synthesis of thioethers in the presence of a transition-metal-free solid Lewis acid

• Federica Santoro,
• Matteo Mariani,
• Federica Zaccheria,
• Rinaldo Psaro and
• Nicoletta Ravasio

Beilstein J. Org. Chem. 2016, 12, 2627–2635, doi:10.3762/bjoc.12.259

• of thiols has also been carried out under flow conditions in the presence of a heterogeneous base in a packed bed reactor but also in this case alkyl halides were used as electrophiles [28]. The reaction we are presenting here takes place in the presence of a solid catalyst starting from the alcohol

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• chemistry with solid-supported catalysts allows the advantages inherent to both technologies to be added together. Thus, the physical immobilization of the catalyst in a packed-bed reactor allows it to be submitted constantly to the reaction conditions, avoiding possible degradation of the catalyst during

• factors is an improvement in the catalyst productivity, with a corresponding reduction in the cost of any given process [42][50][73][74][75]. Herein we present the implementation of a continuous-flow packed-bed reactor with heterogenized catalyst 1 for the fast, enantioselective, direct α-aminoxylation of

• -bed reactor consisted of a vertically mounted, fritted and jacketed low-pressure Omnifit glass chromatography column (10 mm pore size and up to a maximal 70 mm of adjustable bed height) filled with 300 mg of swollen resin (ca. 17 mm bed height). Two separate piston pumps were connected to the reactor

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• . Lozano and coworkers reported on a continuous, chemoenzymatic dynamic kinetic resolution (DKR) process for the production of (R)-1-phenylethyl propionate (24) from (rac)-1-phenylethanol (22) and vinyl propionate (23) (Scheme 8) [29][30][31]. In a multiphase packed-bed reactor, commercially available

• reactions. Nevertheless, it may be assumed that in the future continuous multistep (chemo)enzymatic processes involving more than three catalysts will be realized in a single reactor as well. For instance, Liu et al. developed a packed-bed reactor containing seven enzymes co-immobilized through

• -acetylneuraminic acid (17) in a continuously operated enzyme membrane reactor. E1: Epimerase; E2: Aldolase [27]. Chemo-enzymatic epoxidation of 1-methylcyclohexene (18) in a packed-bed reactor (PBR) containing Novozym 435 (E) [28]. Continuous production of (R)-1-phenylethyl propionate (24) by dynamic kinetic

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• . Since an excess of vinyl acetate was used, all of the PEG 1500 was also acylated. A different approach was developed by Lozano et al. In their case, a thin layer of an IL phase containing the enzyme was created on the surface of silica and the resulting material was used in a packed-bed reactor, using

From discovery to production: Scale- out of continuous flow meso reactors

• Peter Styring and
• Ana I. R. Parracho

Beilstein J. Org. Chem. 2009, 5, No. 29, doi:10.3762/bjoc.5.29

• ) based on 4-bromoanisole. However, the TOF was significantly reduced from the reaction carried out at half the flow rate (1.5 h−1). It should be noted that the TOFs in flow reactors are lower than in batch as we are dealing with small flows through a packed bed reactor and hence the catalyst

The development and evaluation of a continuous flow process for the lipase- mediated oxidation of alkenes

• Charlotte Wiles,
• Marcus J. Hammond and
• Paul Watts

Beilstein J. Org. Chem. 2009, 5, No. 27, doi:10.3762/bjoc.5.27

• result of employing a packed-bed reactor and to exclude the possibility that the reaction was continuing within the collection vial, as only the hydrolysis and perhydrolysis steps were enzyme catalysed, five samples were analysed immediately and then subjected to re-analysis 5 h later. Analogous results

• containing cis-stilbene (11, 0.1 M) and 30% H2O2 (2, 0.2 M) in ethyl acetate was pumped through the packed-bed reactor (70 °C) at a flow rate of 5 μl min−1 and the reactor effluent collected over a period of 24 h. The reaction products were concentrated in vacuo and subjected to an aqueous extraction to

• consistent with that reported within the literature [39]. 1,2-Epoxycyclohexane (cyclohexene oxide) A pre-mixed solution of cyclohexene (10, 0.1 M) and 30% H2O2 (2, 0.2 M) was pumped through the packed-bed reactor at a flow rate of 5 μl min−1 and a reaction temperature of 70 °C for a period of 24 h. The