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

• as an oxidant [63]. A gas−liquid segmented or a tube-in-tube strategy was adopted to achieve a higher yield within a shorter residence time. Substantial further developments have been made in applying ASFR in multiobjective optimizations, which will be discussed in detail below in the section

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• interconnected photocatalytic cycles as the hydrodehalogenation, an aryl radical 2• is formed via successive PET and C(sp2)–X bond cleavage (Figure 17B). Carbon monoxide, introduced to the reaction mixture by a tube-in-tube reactor, traps the aryl radical to generate the acyl radical 23 (Figure 17B

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

• [15][16]. A compact and closed system improves the process safety of handling molecular oxygen by eliminating unexpected ignition. The safety advantage stimulates the development of various aerobic oxidation processes under continuous-flow conditions accompanied by dedicated devices such as tube-in

• -tube reactors or fixed bed reactors [17][18][19][20]. To maximize this advantage, the gas–liquid biphasic reaction must be controlled under continuous-flow conditions. This reaction requires high mixing efficiency to assure high mass transfer of the gas to the liquid phase and a consequent high

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

• -closing metathesis [3][4]. It is well described that metathesis reactions can be significantly accelerated in flow, as the boiling point of the solvent employed can be exceeded using back pressure regulators (BPRs) and formed gases (e.g., ethylene) can be easily removed employing tube-in-tube reactors [11

• can be highly beneficial. Therefore, Skowerski and co-workers constructed a tube-in-tube reactor for the ring-closing metathesis of dienes 62 and 63 to macrocycles 65 or 66, respectively, mediated by ruthenium catalyst 64 (Scheme 15) [53]. The substrate and the catalyst are mixed in a Q-piece and

• of tube-in-tube reactors for the preparation of musk-like structures (in fact, 66 (n = 3) is an isomer of the widely used musk Habanolide, (12E)-oxacyclohexadec-12-en-2-one) [53]. Civetone (69) is the key ingredient of natural civet, which is the glandular secretion of civet cats. Civet is an

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

• continuous process could be established by oxidation with molecular oxygen introduced into the reaction stream via a tube-in-tube membrane reactor, a process which should be very attractive for industrial applications, as oxygen or air act as cheap and environmentally friendly oxidants [82]. An interesting

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

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 some cases, synthesis and chemistries can be very different such that totally different set of flow reactors (including material of construction) and operating conditions has to be employed, e.g., flow chemistry literature shows the use of a wide variety of flow reactors, e.g., tube-in-tube gas

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

• designs ranging from simple flow reactors, tube-in-tube reactors [24], agitated tube reactors [25][26] and continuous agitated cell reactors [27] have been reported. Encouraged by these contributions, we asked ourselves whether a slug-flow approach may combine mechanically less demanding conditions with

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

• to create the desired pressure and facilitate complete separation. Trimethylorthoformate and ICI promoter also need to be preheated to 90 °C and mixed with the process stream containing the aryl ketone intermediate. The reactor can be maintained at the desired temperature using a jacket or tube-in

• -tube approach. The concentration of the ester intermediate can be monitored using the suitable inline analytical technique. The reactor jacket flow rate can be varied to control the intermediate ester concentration thereby ensuring that the reactor temperature is within the set-point and does not lead

A flow reactor setup for photochemistry of biphasic gas/liquid reactions

• Josef Schachtner,
• Patrick Bayer and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2016, 12, 1798–1811, doi:10.3762/bjoc.12.170

• ], multiphasic reactions including solid-phase protocols [18], addition of gaseous reagents [19], high-pressure conditions [20], cascade conversions without intermediate work-up operations [21], as well as thin film, falling film [22], micro-channel [23], and tube-in-tube reactors [24][25] for reactions between

• rates of many common organic reactions. Additionally, the gas-permeable tubes for tube-in-tube reactors and the photo-lithographically etched [38] microchannel plates are highly sensitive and expensive parts which limit their use by the average organic lab chemist. For comparison, the home-built reactor

Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

• Carl J. Mallia,
• Paul M. Burton,
• Alexander M. R. Smith,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

• Abstract A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the

• ; oxygen; “tube-in-tube”; Introduction The functionalisation of aromatic and aliphatic amines has received considerable attention due to the number of biologically active compounds represented by these classes. For this reason different synthetic methods for C–N bond formation have been developed (Scheme

• amounts of copper catalyst to be used [15][16]. Based upon our previous experience of using the reverse “tube-in-tube” reactor with other gases, it was decided that oxygen would be delivered via this reactor set-up (Figure 1). Results and Discussion In our initial screening, four different organic

Flow carbonylation of sterically hindered ortho-substituted iodoarenes

• Carl J. Mallia,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1503–1511, doi:10.3762/bjoc.12.147

• via a reverse “tube-in-tube” flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions. Keywords: carbon monoxide; carbonylation of ortho-substituted substrates; flow chemistry; gases in flow; “tube-in-tube

• ”; Introduction Carbonylation reactions have received a great deal of attention both in batch as well as in flow (using plug/annular flow reactors [1][2][3][4][5] or “tube-in-tube” reactors [6][7][8][9][10]) and generally produce the desired products in good yields [11][12][13][14]. This is not the case though

• the gases in the liquid phase. In our work a reverse “tube-in-tube” reactor [31][32][33] was used to deliver the carbon monoxide to the reaction (Figure 3), as this was shown to be more efficient than an alternative plug flow system (Scheme 1) when evaluated on iodobenzene (2). The “tube-in-tube” gas

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• and commercialisation of a laboratory based tube-in-tube reactor by the Ley group in 2009 changed the playing field and popularised the wider use of gases and volatile components. The design of the tube-in-tube system is based on a semipermeable Teflon AF2400 tubing (1 mm o.d., 0.8 mm i.d.) being

• vacuum can enable the extraction of gaseous substances from a flow stream. This concept has since been studied in a variety of applications using for instance O3, CO, H2, CO2, O2, NH3 or syngas and has been reviewed very recently [84]. One noteworthy application of the tube-in-tube system by the Ley

• group in 2013 details the flow synthesis of the anti-inflammatory agent fanetizole (87) [85], in which ammonia gas was fed into the inner tube, whilst the outer tube contains a solution of phenethylisothiocyanate (89) in DME. The tube-in-tube system was placed onto the cooling unit of a Polar Bear Plus

Camera-enabled techniques for organic synthesis

• Steven V. Ley,
• Richard J. Ingham,
• Matthew O’Brien and
• Duncan L. Browne

Beilstein J. Org. Chem. 2013, 9, 1051–1072, doi:10.3762/bjoc.9.118

• , such as the length of tubing used and the residence time required to effect a complete reaction. For subsequent work using oxygen gas, we moved to a more elegant but still simple tube-in-tube reactor setup [79]; in this case the oxidation of a lilac solution of vanadium(II) was used to indicate the

• presence of oxygen in the solvent stream. With increased concentrations of oxygen in the reactor atmosphere, this oxidation proceeded with faster rates (Figure 18b). Having determined that the gaseous reagents were passing through the semipermeable tubing, we were able to use the tube-in-tube reactor for

• the tube-in-tube reactor. In a recent publication describing the use of ammonia gas in flow synthesis [80], a reversed, “tube-in-tube” reactor configuration was employed whereby the gas was introduced into the semipermeable tubing, while the substrate passed through a second, outer, PTFE tube. This