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

• laboratory equipment, but also to manufacture functional chemical and thermally compatible reactors with embedded functionality. Conclusion AM has been shown to be a highly versatile manufacturing process for the production of multifunctional bespoke flow reactors. This allows conceptual parts to be realised

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

• homogeneous NHCs [13][14]. On the other hand, heterogeneous catalysis in microstructured flow reactors represents a robust synthetic platform, with benefits over the corresponding batch processes such as catalyst stability, lower degradation of supports, and ease of scale-up with minimal changes to the

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• batch made continuous processing an attractive alternative for scale-up due to its capacity for excellent temperature control. Efficient heat transfer due to the high surface, low volume geometry of tubular flow reactors makes it possible to achieve extremely rapid temperature transitions. It was

• coiled tube reactor at 120 °C. The high surface area–volume ratio of tubular flow reactors is ideal for such rapid temperature transitions. It was noted that a relatively short residence time of only 20 min could be used, with a longer time of 50 min offering only a modest improvement on the reaction

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

• microreactor technology offers to organic syntheses such as this one by performing both reaction steps in continuous flow reactors. Continuous flow synthesis of Sudan II azo dye in LTF-MS microreactors Having determined the reaction parameters that affect the azo coupling reaction in the synthesis of Sudan II

• azo dye, an attempt to perform both reaction steps involved in this synthesis in continuous flow reactors was thus made. This was achieved in LTF-MS reactors with the aid of statistical modeling where the continuous flow synthesis of Sudan II azo dye was optimized and used a model reaction. Based on

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

• due to the inherent properties of micro/flow reactors: high mass-transfer rates [8], spatial separation of reagent addition and mixing, high reagent dispersion, high energy efficiency, improved irradiation [9][10][11], ease of upscaling, low hazard potential and multidimensional parameter control [7

• alkylbenzenes [48] and [2 + 2]-cycloadditions with ethylene [49]. Results and Discussion Microreactor parts and setup When studying the numerous literature reports of applications of flow reactors to organic synthesis it became obvious that there are no simple and quick technical solutions to such endeavours

• processes (e.g., N-alkyl maleimides, ε = ~700 M−1 cm−1) [62] lead to more efficient light penetration in batch reactions and therefore only show a limited benefit of using flow reactors for such purposes. On the other hand, a 1 mM solution of methylene blue exhibits total absorption (>99.9%) at 0.35 mm

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

• ”; 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

• efficient mixing along with high heat and mass transfer that are achieved through the use of small dimensioned channels such as those found in flow reactors, allow for the use of a wider range of reaction conditions which are otherwise difficult or impossible to achieve. The interfacial mixing area is also

• smaller when larger volume flasks are used as in scale up procedures making the mass transfer even less efficient. In contrast, high interfacial areas can be achieved in flow reactors especially microchannel reactors (a = 3400–18000 m2 m−3) [30], which increases the mass transfer and thus helps solubilise

Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors

• A. John Blacker and
• Katherine E. Jolley

Beilstein J. Org. Chem. 2015, 11, 2408–2417, doi:10.3762/bjoc.11.262

• -BuOCl in situ for chloramine formation, applying the methodology to a broad range of substrates in high yields [20]. Published literature on chloramine formation is limited to batch procedures, however, the use of continuous processes could offer significant advantages. Use of continuous flow reactors

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

• selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process. Keywords

• a sample loop). In addition both of these pumping solutions require homogeneous solutions where particulates or precipitates (slurries) are extremely detrimental. These shortcomings obviously impact the performance of flow reactors when attempting reaction scale-up, especially when precise and

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

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

• be elaborated in section 3. In this review, we analyze recent studies on continuous flow nitration using miniaturized flow reactors. We provide a guideline that helps to quickly decide under which conditions it is worthwhile to conduct continuous flow nitration from a practical point of view. Key

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

• flow reactions All reactions were performed in 300 or 100 cm stainless steel tubular plug flow reactors (PFRs) of 1 mm internal diameter. A larger diameter (3.9 mm) PFR was also used as a comparison in one example (Figure 2). Initial studies used flow rates commensurate with the concentration used in

• the autoclave reactor. Residence time in the continuous flow reactors The volume of the unpacked 1 mm diameter reactors in the styrene and methyl acrylate reactions were 2.36 and 0.79 mL respectively. The reactors containing catalyst with packing were found to have a porosity of 0.80, so neglecting

• using the instrument software. ICP–AE analysis gave the concentration of palladium metal on the silica gel support as 0.02 g or 0.189 mmol Pd/g. This was later diluted with Chromopac for use in the flow reactors at a ratio of 1:3 catalyst/packing. Stirred autoclave reactions The autoclave reaction set

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

• 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

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

• Ashley R. Longstreet,
• Suzanne M. Opalka,
• Brian S. Campbell,
• B. Frank Gupton and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292

• reactions are performed by passing reagents through devices containing small-dimensional channels as opposed to using batch reactors [15][16][17]. Flow reactors are particularly advantageous in multistep syntheses where telescoping steps avoids isolation of dangerous and/or unstable intermediates and

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

• Erli Sugiono and
• Magnus Rueping

Beilstein J. Org. Chem. 2013, 9, 2457–2462, doi:10.3762/bjoc.9.284

• dihydropyridine as hydrogen source providing the desired products in good yields and with excellent enantioselectivities. Keywords: asymmetric transfer hydrogenation; binolphosphate; continuous-flow reactors; flow chemistry; microreactors; organocatalysis; photochemistry; Introduction Tetrahydroquinolines [1][2

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• ][7][8]. While the synthesis of diazomethane has been extensively explored in batch [9] and in continuous-flow reactors [10][11], EDA is synthesized via different routes in batch [12][13], but relatively little is known about continuous-flow approaches [14]. Considering the importance of EDA in a wide

The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow

• Kimberley A. Roper,
• Malcolm B. Berry and
• Steven V. Ley

Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207

• or facilitates direct isolation of pure compounds from flow reactors, removing the need for labour-intensive manual operations [8][9][10][11][12][13]. Reagents are typically supported on low-crosslinked gel-type or macroporous beads; however, these are characterised by poor mass transfer properties

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• from the corresponding vinyl azide. Keywords: azirines; cycloaddition; flow chemistry; flow reactors; inductive heating; nitrile ylides; photochemistry; vinyl azides; Introduction Recently, photochemistry has seen a renaissance despite the fact that under batch conditions specialized reaction vessels

• refer to [6][7][8][9][10][11][12][13][14][15]. Recently, the Seeberger group has published a flow protocol on the photochemical degradation of aryl azides and the subsequent formation of 3H-azepinones [16]. With the emergence of continuous processes involving miniaturized flow reactors in organic

• -chemistry laboratories, photochemistry has found a wider interest in the chemical community [17][18]. Particularly large-scale photochemical syntheses can simply be achieved by numbering-up miniaturized flow reactors in a parallel set-up. Uniform irradiation can be guaranteed when the penetration depth of

Chemistry in flow systems III

• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1696–1697, doi:10.3762/bjoc.9.193

• chemical synthesis in the laboratory from a classical batch approach to continuous processes by using micro- and miniaturized flow reactors. In the past two decades this technology has seen a dramatic increase of visibility. Considering an analyses of the accompanied developments in flow synthesis one has

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• still seen and there normally remains the requirement for time consuming purifications such as column chromatography in order to isolate pure products. Immobilised reagents have shown great promise as enabling technologies when incorporated in flow reactors to aid in the processing, work-up and

Simple and rapid hydrogenation of p-nitrophenol with aqueous formic acid in catalytic flow reactors

• Rahat Javaid,
• Shin-ichiro Kawasaki,
• Akira Suzuki and
• Toshishige M. Suzuki

Beilstein J. Org. Chem. 2013, 9, 1156–1163, doi:10.3762/bjoc.9.129

• XPS analysis confirmed complete oxidation of the Pd surface to PdO, as presented in our previous study [13]. Hydrogenation of p-nitrophenol in the catalytic flow reactors The experimental setup of our flow reaction system is simple, as depicted in Figure 2, where a reactor tube loop was immersed in a

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

• utilized for purification purposes after the reaction [22] and in continuous-flow reactors during the reaction [23]. Dendritic catalysts have also been applied while enclosed in commercially available dialysis bags [24][25][26]. The latter examples, however, were conducted in organic, environmentally

3D-printed devices for continuous-flow organic chemistry

• Vincenza Dragone,
• Victor Sans,
• Mali H. Rosnes,
• Philip J. Kitson and
• Leroy Cronin

Beilstein J. Org. Chem. 2013, 9, 951–959, doi:10.3762/bjoc.9.109

• simplicity of designing and building flow reactors employing 3D-printing techniques allows for an easy and convenient integration of devices in a flow setup. Therefore it represents a very attractive way to design and build new continuous-flow rigs for organic synthesis. Results and Discussion Experimental

• setup The 3D-printed flow reactors used to carry out the organic syntheses were designed by using a 3D CAD software package (Autodesk123D®), which is freely distributed and produces files that can be converted to the correct format read by the 3DTouchTM printer. This 3D printer heats a thermopolymer

• reliability of the 3D-printed devices as flow reactors, we decided to connect one reactor to the other and perform a two steps flow reaction in an automated way. To this end, we employed two R2 reactionware devices connected in series (Figure 7), to monitor the formation of the final product using the in-line

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

• -utilised technique in general organic synthesis. Recent developments in flow photochemistry have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in organic photochemistry, allowing a comparison of the various reactor types to

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

• alternative for improving the productivity of catalytic species results from the implementation of heterogenized catalysts in continuous-flow reactors. Flow chemistry has experienced a very important development in the last ten years as an emerging technology for organic synthesis [51][52][53][54][55][56][57

Multistep flow synthesis of vinyl azides and their use in the copper-catalyzed Huisgen-type cycloaddition under inductive-heating conditions

• Lukas Kupracz,
• Jan Hartwig,
• Jens Wegner,
• Sascha Ceylan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1441–1448, doi:10.3762/bjoc.7.168

• , entry 8). Finally, both flow reactors were telescoped, which allowed us to prepare vinyl azides 4a–e and 4g–i in one flow process starting from alkenes 2a–e and 2g–i (Scheme 3). Advantageously, isolation and purification of intermediate iodo azides 3 was avoided. As a consequence we achieved improved

• flow conditions. Regeneration of functionalized polymers 5 and 8. Preparation of triazoles 12a–l by using inductively heated copper turnings as a packed-bed material inside flow reactors. Azido iodination of alkenes 2a–f under flow conditions with polymer-bound bisazido iodate(I) complex 5

Continuous preparation of carbon-nanotube-supported platinum catalysts in a flow reactor directly heated by electric current

• Alicja Schlange,
• Antonio Rodolfo dos Santos,
• Ulrich Kunz and
• Thomas Turek

Beilstein J. Org. Chem. 2011, 7, 1412–1420, doi:10.3762/bjoc.7.165

• preparation in a flow reactor which could be used at a large scale. Keywords: carbon nanotubes; continuous catalyst synthesis; direct electrical heating; flow reactors; fuel cell platinum catalyst; Introduction Batch processes represent the state of the art in catalyst preparation. One reason for employing