Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• hydrogen-atom transfer or solvolysis are often observed. A technological solution to cope with the Beer–Lambert law was offered by flow chemistry [19][20][21] by employing microreactors with reduced optical paths to enhance irradiation efficiency [22][23][24]. Photon-limited reactions, whose efficiency is

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

• 16 microreactors capable of executing diverse conditions in parallel, including photochemistry. The temperature of the capillary reactors can be controlled independently, providing flexibility in experimentation. The reservoir-type distributor, featuring a baffle structure, not only ensures uniform

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

• reaction process of O-methylisouronium sulfate to improve the reaction efficiency and intrinsic safety. In recent years, continuous flow microreactors have been recognized due to their excellent mass and heat transfer performance, precise control over reaction parameters, and intrinsic safety [5][6][7][8

• for highly viscous reaction systems, especially at higher reactant concentrations. It is still difficult to eliminate the mass transfer effect using conventional microreactors, leading to errors in the determination of nitration kinetics. Therefore, more efficient mixers are needed to overcome the

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

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

• mass transfer of continuous flow reactors. The generation of organolithium species in the presence of carbonyl compounds and their reaction has been facilitated by the extremely fast mixing of reagents and almost instantaneous heat transfer (i.e., cooling) in specifically designed microreactors [5

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

• technology to realize reactions that are impossible in batch or to provide products in higher purity avoiding expensive purification procedures [11][12][13][14][15][16][17][18]. Given the superior heat-, mass-, and phototransfer in microreactors, flow chemistry has been outlined as a central tool for

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• microreactor has recently attracted attention as an excellent alternative tool to conventional batch-type electrochemical reactors [28][29][30][31][32]. The potential advantages of electrochemical flow microreactors over conventional batch-type reactors are a large surface-to-volume ratio, precise residence

Electrocatalytic C(sp³)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

• Bin Guo and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2021, 17, 2650–2656, doi:10.3762/bjoc.17.178

• reaction of tetrahydroisoquinolines with terminal alkynes (Scheme 1C) [10]. The chiral ligand was found to be critical for the stereoinduction as well as product formation for these electrochemical reactions that are conducted in batch. Continuous-flow electrochemical microreactors offer several advantages

• electrochemical microreactors can be a viable tool for developing efficient transition-metal electrocatalysis. C(sp3)–H alkynylation of tetrahydroisoquinolines. L* = chiral ligand. TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. BPO = benzoyl peroxide. Substrate

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

• be injected). Separate reagent streams then meet in a variety of ways, the simplest being within a T- or Y-piece. This method of sample stream merging has been demonstrated to give rise to far more efficient mixing than in the case of standard batch reactors, particularly with microreactors (lateral

• dimensions < 1 mm). In batch, inhomogeneities due to poor mixing can lead to convective dead zones, giving rise to concentration gradients and hot spots. Flow microreactors allow for rapid mixing on timescales in the order of 100 μs and much more efficient heat transfer is made possible by their high surface

• group developed an efficient homogenous NaOH-catalysed condensation of citral (79) with acetone using microreactors. The setup allowed the preparation of 80 in 93.8% yield with a throughput of 5.24 g h−1 [121]. The NaOH aqueous solution was introduced as a mixture with EtOH, which was discovered to

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

• to the large surface–volume ratio of microreactors, and may prevent the formation of undesirable byproducts that are not avoidable under the traditional batch conditions. As a consequence, efforts have been devoted to the development of synthetic processes combining GCP and enabling technologies [11

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

• emerged as alternatives to batch operation. Due to the small characteristic length of microreactors, more uniform light distribution could be obtained. The elimination of overirradiation or dark zones results in less side product formation. Mass transfer limitations can be alleviated in these

• , and spiral, as shown in Figure 2. Serpentine and square serpentine are used to increase the residence time and for mixing. Microcapillaries (Figure 2f) wrapped around a light cylinder are also commonly used in photochemistry. While designing microreactors, it is important to distinguish different

• applications. The lab-on-a-chip concept has enabled researchers to work on intrinsic kinetics. Intrinsic data acquisition is crucial while designing and operating large-scale reactors. Several microreactors, such as a spiral channel microreactor carved on a flat aluminum plate [23], a capillary tube [24], a

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• ) (Scheme 1 and Figure 1). Continuous-flow synthesis offers the generation and consumption of dangerous intermediates in situ preventing their accumulation, thus it represents a potential solution for dealing with hazardous reaction intermediates and products [15]. Additionally, microreactors can handle

• , it is evident from our study that the use of a microreactor significantly improved the selectivity and massively reduced the reaction times. The production of azide 5 in 100% conversion simplified the purification procedure. Most importantly, microreactors improved safety as the potentially explosive

• the azidating agent, an increase in both temperature and residence time resulted in the increase in mesyl shikimate conversion in microreactors (Figure 8). High temperatures easily gave full mesyl shikimate conversions. Generally, the trends found with the use of DPPA are comparable to NaN3. Figure 9

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

• et al., are also using PP as a printing material [14][20][31]. In comparison our reactors show a very fine structure, for example, as shown in Figure 3, we are able to print microreactors out of PP with a channel width of 200 µm which is to our knowledge the tightest channel achieved in FDM-PP

• -budget lab equipment for continuous flow chemistry could be manufactured for under 300 €. With this equipment, consisting of Arduino controlled syringe pumps and microreactors, the preparation of glycosyl donors and glycosylation reactions were performed in a cascade fashion to show the viability of this

Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

• Anne Schnell,
• J. Alexander Willms,
• S. Nozinovic and
• Marianne Engeser

Beilstein J. Org. Chem. 2019, 15, 30–43, doi:10.3762/bjoc.15.3

• MS2 spectra was unfortunately slightly shifted. The measured m/z values are about 35 mDa too high (Figure 10) and about 40 mDa too low (Figure 11 and Figure 12). PEEK tubes with an inner diameter of 0.127 mm and PEEK microreactors (swept volume: 2.2 µL) were used. Airtight glass syringes (250 µL and 5

A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

• Katherine E. Jolley,
• Michael R. Chapman and
• A. John Blacker

Beilstein J. Org. Chem. 2018, 14, 2220–2228, doi:10.3762/bjoc.14.196

• measures for containment. To evaluate the use of N-chloramines in the laboratory requires multiphase flow methods, and until recently these have been limited by the availability of suitable equipment. Microreactors have been used for mixing biphases and employ either static mixers or shaped chambers and

Asymmetric Michael addition reactions catalyzed by calix[4]thiourea cyclohexanediamine derivatives

• Zheng-Yi Li,
• Hong-Xiao Tong,
• Yuan Chen,
• Hong-Kui Su,
• Tangxin Xiao,
• Xiao-Qiang Sun and
• Leyong Wang

Beilstein J. Org. Chem. 2018, 14, 1901–1907, doi:10.3762/bjoc.14.164

• the calix[4]arene cavity are superior to the model catalyst in terms of catalytic reactivity. This is likely due to the formation of multiple microreactors at the water molecules’ interface, with the calix[4]arene hydrophobic cavity attracting reactants and accelerating the reaction [35][40]. The

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• synthetic applications that demonstrate the growing contribution of flow chemistry and microreactor technology in green and sustainable synthesis [4][5][6][7]. Review Flow microreactors: main features The peculiar properties of microreactors [8] derive from their small size and can be ascribed mainly to the

• following characteristics: a) fast mixing: in a flow microreactor, in striking contrast to batch conditions, mixing takes place by molecular diffusion so that a concentration gradient can be avoided; b) high surface-to-volume ratio: the microstructure of microreactors allows for a very rapid heat transfer

• concept of flash chemistry as a "field of chemical synthesis using flow microreactors where extremely fast reactions are conducted in a highly controlled manner to produce desired compounds with high selectivity" was firstly introduced by Yoshida [10]. Flash chemistry can be considered a new concept in

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• unusual for flow chemistry. Typical batch reactions are mixed by stirring; however, perfect homogeneity is not immediately obtained. Ideal mixing conditions can only be achieved with microreactors or micromixers [22]. The small diameters of these microreactors lead to almost ideal mixing conditions [23

• (residence time/flow rate and reactor temperature). The advantage of the serial use of two microreactors is that two different temperatures can be used. Three solutions were made: F1 and F2 having a concentration of 40 mM, and F3 having a concentration of 20 mM. After addition of the three reaction streams

NMR reaction monitoring in flow synthesis

• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

• 10.3762/bjoc.13.31 Abstract Recent advances in the use of flow chemistry with in-line and on-line analysis by NMR are presented. The use of macro- and microreactors, coupled with standard and custom made NMR probes involving microcoils, incorporated into high resolution and benchtop NMR instruments is

• increases the sensitivity in NMR analysis. Moreover, it is possible to use these in conjunction with microreactors and consequently to design integrated systems that can be classified in the lab-on-a-chip methodology. An interesting example was developed by Kentgens et al. [44], who designed a stripline

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

• (DMF) solvent to the α-diketone and generate the corresponding enediolate active species. After having identified the 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene (PS-BEMP) as the suitable base, packed-bed microreactors (pressure-resistant stainless-steel

• use of a readily and commercially available supported base as packing material of fixed-bed microreactors. The present study originated from our recent findings on a novel strategy for the umpolung of aromatic α-diketone donors [26] and their peculiar reactivity with aromatic aldehydes or α,β

• of microreactor void-volume Microreactor void volume (V0) was determined by pycnometry [31]. This method consists in filling the microreactor successively with two distinct solvents (solvent 1: water; solvent 2: n-hexane) and weighing the filled microreactors accurately. Simple math shows that [33

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

• II azo dye was used as a model reaction for the study. At found optimal azo coupling reaction temperature and pH an investigation of the optimum flow rates of the reactants for the diazotization and azo coupling reactions in Little Things Factory-MS microreactors was performed. A conversion of 98

• unstable intermediates [17] such as these, as well as those that give rise to explosive [18] and hazardous products [19]. The small reagent volumes used in microreactors also reduce the amount of acidic and alkaline waste associated with the synthesis of azo compounds during research and development. In

• investigative research involving the synthesis of two azo pigments (yellow and red pigments) in microreactors [24], demonstrated that scaling out in the microreactors provided better and more consistent quality of the pigments as compared to scale up in the batch vessels. Similarly, yellow pigment 12 (15) was

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

• penetration depth in a solution of acetonitrile (Figure 2) [63]. The high surface-to-volume ratio of microreactors thus increases the relative pathway of light through the solution, speeds up the rate of reactions, and minimizes competing side reactions [11][52][64][65]. Total light absorption of dye

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

• CD derivatives, CD grafted materials and polymers. Mechanochemical methods have successfully furnished greener, solvent-free syntheses and efficient complexation, while flow microreactors may well improve the repeatability and optimization of critical synthetic protocols. Keywords: ball milling

• sources been tested for their ability to activate C–C and C–X bond formation. In recent years non-conventional energy sources, such as microwaves (MW), ultrasound (US), ball mills (BM) and microreactors have made access to CD derivatives much simpler, as have heterogeneous catalysts and greener solvents

• 10% books (including non-journal conference proceedings and dissertations). However, industrial applications of such enabling techniques are a priori restricted to US and BM, owing to safety concerns on big scale MW reactors (Figure 5). Microreactors are a relatively new technologies and the small

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• experiments using two mixing tee microreactors directly coupled to the ESI needle. ESI mass spectra of acetonitrile solutions of diethyl ketomalonate and butyraldehyde (a) with unmodified L-proline or (b) with the charge-tagged catalyst 1 recorded with the continous-flow setup shown in Figure 3. ESI(+) CID MS

• continous-flow setup with two microreactors shown in Figure 3. Inverse aldol reaction with aldehyde donors according to Jørgensen [54]. We studied the reaction for R = Ph (labelled a throughout this manuscript) and for R = Et (b). Synthesis of 4-(pyridin-4-yl)phenol (5). Synthesis of the charge-tagged

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

Beilstein J. Org. Chem. 2014, 10, 405–424, doi:10.3762/bjoc.10.38

• been one of the oldest and most important unit reactions, the advent of miniaturized devices has paved the way for new opportunities to reconsider the conventional approach for exothermic and selectivity sensitive nitration reactions. Four different approaches to flow nitration with microreactors are

• acid; microreactors; tubular reactor; Review 1 Introduction Nitration of aromatics is one of the oldest and industrially most important reactions. A reaction between an organic compound and a nitrating agent leads to the introduction of a nitro group onto a carbon, nitrogen or oxygen atom of that

• extend the approach for the continuous preparation of other derivatives and (d) guidelines supporting to identify the best setup for continuous flow nitrations using microreactors. 3 Continuous flow nitration During World War II, both batch and continuous flow nitration were conducted for the production