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

• chemistry. Packed bed reactors are used when solid heterogeneous catalysts and reagents (e.g., inorganic bases) are handled. Specialized reactors for electro- [36][37] and photochemical [38][39][40] experiments have also been developed. Depending on the flow of the reaction mixture, flow reactions can be

• Bédard et al. [62] to mitigate some of the challenges in traditional organic synthesis by the integration of hardware, software, and analytics. Comprising an array of modular components, including units for heating, cooling, LED light exposure, and packed bed reactors, it provides a flexible platform for

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

• , Figure 1a) [17], rotor-stator spinning disk reactors (Figure 1b) [18], and the combination of oscillatory pumps with microstructured reactors (Figure 1c) [19][20]. When the (photo)catalyst is the solid material in a heterogeneous reaction, packed-bed reactors are the most appealing solution for flow

• development of several strategies to immobilize transition-metal photocatalysts [22]. In the case of flow-metallaphotoredox catalysis packed-bed reactors were not applied to date. This is likely because these reactions are mainly carried out using homogeneous catalysis. Several studies have shown that the

• point for applications in large-scale synthesis or automated reaction optimization. Based on literature precedents on catalyst leaching in packed-bed reactors [37][38], we assumed that the decreased activity could be linked to nickel leaching. Based on ICP results on the reactor outlet collected in 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

• min isoamyl acetate (10) is obtained in 59% yield according to GC analysis [26]. Related methods for the enzyme-catalyzed acetylation of isoamyl alcohol (9) have been developed utilizing biphasic systems, supercritical carbon dioxide as a solvent, or packed-bed reactors with immobilized enzymes [27

• -bed reactors were developed by the groups of de Souza and Yadav [33][34]. Very recently, Kirschning and co-workers presented a general method for the Matteson reaction in flow, allowing iterative homologation of various terpene boronate esters 17, which are subsequently oxidized to the corresponding

• esters with mainly fruity odor profiles are obtained in moderate to excellent yields. Some selected esters (14–16) and their odor profiles are shown in Scheme 4 [32]. Related methods for the esterification of natural occurring alcohols, such as geraniol, utilizing immobilized enzyme-catalysis in packed

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

• dioxide (core-shell nanostructured particles), called MagSilicaTM to be used as fixed-bed materials in many different continuous flow processes (Figure 4A) [50]. These materials are excited very rapidly in a medium frequency (25 kHz) electromagnetic field, heating reaction mixtures in packed bed reactors

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

• ). Packed-bed reactors have also been exploited to facilitate enantioselective nitroaldol processes. In 2013, Shibasaki and Kumagai made use of an entangling network of multiwalled carbon nanotubes (MWNT) to trap a Nd/Na bimetallic catalyst, which was shown to be an efficient combination for nitroaldol

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

• intrinsic kinetics, is to create micro- or mesostructures in large vessels. Translucent packed bed reactors and aerosol photoreactors are examples of such designs. Below, we will discuss several scale-up strategies applied in photochemistry. Most researchers that utilize photomicroreactors suggest that

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry. Keywords: Knochel–Hauser base; lithium chloride; magnesium; on-demand; packed-bed reactors; plug and flow reactor; synthesizer; turbo Grignard reagent

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

• synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous

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

• . It is important mentioning that different flow regimes can be attained in miniaturized channels, depending on the gas and liquid rates, as these may affect both conversion and selectivity of the process (Figure 2). Packed-bed reactors are among the most used systems since they are relatively simple

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification

• Anna Zaghi,
• Daniele Ragno,
• Graziano Di Carmine,
• Carmela De Risi,
• Olga Bortolini,
• Pier Paolo Giovannini,
• Giancarlo Fantin and
• Alessandro Massi

Beilstein J. Org. Chem. 2016, 12, 2719–2730, doi:10.3762/bjoc.12.268

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

• Franqués, 1. E-08028, Barcelona, Spain 10.3762/bjoc.7.172 Abstract The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of β

• -aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min. Keywords: α-aminoxylation; continuous flow; packed-bed reactors; polystyrene

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

• chemocatalyst from the lipase by spatial separation in a single column [29] or in consecutive packed-bed reactors [31], however, similarly allowed the process to be efficiently run with high enantiomeric excesses of up to 99%, but with a reduced yield of 60%. A reaction sequence for the continuous synthesis of

• -ribulose 1,5-bisphosphate (58) in a series of eleven packed-bed reactors containing immobilized enzymes (Scheme 17) [41]. The aim of the process is to continuously regenerate D-58, which is used as an acceptor for the biocatalytic fixation of CO2 resulting in the formation of two molecules of D-57. The

• of 4-cyanopyridine (59) to isonicotinic acid (61), serves as an illustration of this method [42]. There, a cascade of two packed-bed reactors was set up with the second reactor loaded with an immobilized amidase, which catalyzed the hydrolysis of the residual amide 60 (Scheme 18). Both reactions were

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

• reactor capacity can be increased by employing additional packed-bed reactors, operated under identical reaction conditions, compared to batch where increases in reactor volume/capacity will result in the need for longer dosing times for the oxidant 2. Conclusion In conclusion, we have demonstrated the