Self-optimisation and model-based design of experiments for developing a C–H activation flow process

• Alexander Echtermeyer,
• Yehia Amar,
• Jacek Zakrzewski and
• Alexei Lapkin

Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

• this is the complexity of chemistry and the duration of time required for the development of good mechanistic models. A game changer in this area is the recently emerged field of automated continuous-flow experiments driven by algorithms for sequential design of experiments (DoE), which significantly

• , guided by D-optimal design. In a different approach, transient data from continuous-flow experiments were used to identify parameters of a known mechanistic scheme to discriminate between several alternative model structures and to identify model parameters, but no specific design of experiments method

• algorithm would learn the response surface as fast as it was the case for its previous application. A framework of closed-loop or self-optimisation combining smart DoE algorithms, process analytics, chemoinformatics and automated reactor systems. Schematics of the automated continuous-flow system used for

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• different naturally occurring and synthetic dienophiles. The synthesis of the Diels–Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This

• continuous-flow approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times. Keywords: continuous processing; flow chemistry; renewable feedstock; surfactant

• of compact continuous-flow reactors has begun to transform the way chemical synthesis is conducted in research laboratories and small manufacturing over the past few years [14][15][16][17][18][19][20][21]. In several applications, where reaction times are short and heat management is important

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

• solvents and reagents, making it ideally suited to continuous flow chemistry. The part was again tested using the semicarbazide preparation previously outlined (Scheme 1), and automated through the Chemstation software. For this optimisation an 1100 series binary pump module was used to pump the two

• of using 3D printing to produce microfluidic devices using AM techniques such as stereolithography (SL) [11], polymer jetting and fused deposition modelling (FDM) [12][13]. There is therefore considerable interest in the optimisation of chemical systems using this type of multifunctional continuous

• flow reactor. Notable recent work in this area has been carried out by Cronin [14], Ley [15] and Jensen [16]. This research highlights the array of benefits that manufacturing fluidic devices via AM processes can bring, including the ability to produce multimaterial parts with complex microscale

Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

• continuous flow chemistry is typically very narrow of several millimetres. Furthermore, the kneading segments can be positioned at angles of 30o, 60o and 90o relative to each other, with the latter angle providing the greatest kneading (and shear). The kneading section can be quite hostile as it involves not

• pyrophoric reagent, such as s-BuLi, is involved is quite remarkable, and it is carried out as a continuous process and not on a small scale. This suggests that solvent-free extrusion can be on par with continuous flow technology, allowing a wider range of hazardous reagents to be used continuously and on

• point to react with polystyrene in a second reaction (Scheme 2) [16]. This is an example of telescoping which is considered to be very advantageous in continuous flow technology for example. As a result of being able to carry out polymerisation and post polymerisation functionalisation by TSE, different

The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot

• Philip J. Kitson,
• Stefan Glatzel and
• Leroy Cronin

Beilstein J. Org. Chem. 2016, 12, 2776–2783, doi:10.3762/bjoc.12.276

• continuous-flow synthesis of ibuprofen. The reaction was designed specifically such that the byproducts and excess reagents of each step were compatible with the subsequent transformations, eliminating the need for isolation and purification of intermediate products. This approach suited the development of

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

• heterogeneous continuous-flow procedure for the polarity reversal of aromatic α-diketones is presented. Propaedeutic batch experiments have been initially performed to select the optimal supported base capable to initiate the two electron-transfer process from the carbamoyl anion of the N,N-dimethylformamide

• chemical and pharmaceutical industries facilitating the automation of the production processes with reduced costs and improved safety and sustainability [18][19][20][21]. Very recently, Monbaliu and co-workers described a convenient continuous-flow setup for the generation of common free NHCs under

• umpolung catalysis (Figure 1). Significantly, the current investigation on the heterogeneous continuous-flow version of the α-diketone activation process resulted in the fabrication of fixed-bed reactors with elevated stability, allowing their operation for about five days with maintenance of productivity

Towards the development of continuous, organocatalytic, and stereoselective reactions in deep eutectic solvents

• Davide Brenna,
• Elisabetta Massolo,
• Alessandra Puglisi,
• Sergio Rossi,
• Giuseppe Celentano,
• Maurizio Benaglia and
• Vito Capriati

Beilstein J. Org. Chem. 2016, 12, 2620–2626, doi:10.3762/bjoc.12.258

• stereoselective aldol reaction in DES. Aldol reaction under continuous flow conditions in DESs. ChCl-based eutectic mixtures used in the present work. DES screening for the proline-catalyzed in batch aldol reaction. Three different set-ups for the aldol reaction in continuo. In continuo aldol reactions of

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• performed for the first time under continuous-flow conditions. Aromatic as well as aliphatic nitro derivatives were converted to the corresponding primary amines in high yields and very short reaction times with no need for purification. The methodology was also extended to the synthesis of two

• transformation safer and more appealing in view of an industrial application and a possible scale-up of the process [18][19][20]. Herein we report a very convenient, metal-free reduction of both aromatic and aliphatic nitro derivatives, including chiral compounds, to amines with HSiCl3 under continuous-flow

• conditions. Typically, the transformation of nitro compounds to amines under continuous-flow conditions is performed through the metal-catalyzed hydrogenation [21][22][23] with ThalesNano H-Cube®, which exploits H2 generated in situ by water electrolysis [24]. The procedure involves relatively mild reaction

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

• key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts. Keywords: α-thio-β

• as an alternative solvent. As 1H NMR analysis indicated that the crude reaction product from batch tests (using methanol as solvent) consisted of 98% α-thioamide 2, the process was subsequently transferred to a continuous flow system (Scheme 5). A variety of temperatures (60–120 °C), bases (NaOMe

• , Table 1). After an improved stoichiometry of reagents had been established, lowering the residence time was investigated to facilitate efficient large scale synthesis by a continuous flow process. Ultimately, a residence time of 5 min at 120 °C, using a 0.25 M concentration of α-chloroacrylamide, was

Solvent-free synthesis of novel para-menthane-3,8-diol ester derivatives from citronellal using a polymer-supported scandium triflate catalyst

• Lubabalo Mafu,
• Ben Zeelie and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 2046–2054, doi:10.3762/bjoc.12.193

• , the catalyst was reusable in the process without significant change towards the substrate conversion and product selectivity. Using the methodology described herein, further studies are currently underway within our laboratory to optimise the developed method in a continuous flow process. Experimental

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

• Faith M. Akwi Paul Watts Nelson Mandela Metropolitan University, University Way, Port Elizabeth, 6031, South Africa 10.3762/bjoc.12.186 Abstract In this paper, a micro-fluidic optimized process for the continuous flow synthesis of azo compounds is presented. The continuous flow synthesis of Sudan

• documented in literature [26][27][28][29][30], the ease of reaction parameter optimization in the synthesis of azo compounds in microreactors is highlighted. In this study, the continuous flow synthesis of Sudan II azo dye (19, Scheme 6) constituting of the diazotization of 2,4-dimethylaniline (16) and its

• 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

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

• active compounds [11][12]. In 2009 the groups of Stevens and van der Eycken reported on the Chan–Lam reaction as a continuous flow protocol using copper(II) acetate (1.0 equiv), pyridine (2.0 equiv) and triethylamine (1.0 equiv) in dichloromethane [13]. Generally, when using anilines or phenols as the

• potentially an improvement on the use of stiochiometric copper(II) acetate in continuous flow, the use of TEMPO or tert-butyl peroxybenzoate as a co-oxidant introduces waste. Employing oxygen gas as an oxidant is preferred as it is cheap, renewable and environmentally benign. We therefore set out to develop a

• . Comparison of 1H NMR spectra of non-purified (top) and QP-DMA purified (bottom) continuous flow synthesis of compound 20. NOESY NMR spectrum for 30 with the characteristic NOESY signal encircled. NOESY NMR spectrum for 33 with the characteristic NOESY signal encircled. NOESY NMR spectrum for 35 with the

Dinuclear thiazolylidene copper complex as highly active catalyst for azid–alkyne cycloadditions

• Anne L. Schöffler,
• Ata Makarem,
• Frank Rominger and
• Bernd F. Straub

Beilstein J. Org. Chem. 2016, 12, 1566–1572, doi:10.3762/bjoc.12.151

• bioactive surfaces [8][14], imaging of biochemical processes [15], localization of bioactive compounds inside living cells [16], syntheses of small-molecule screening libraries [17], catenane and rotaxane syntheses [18], in reactions under continuous flow processing [19], polymer and surface science [20][21

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

• continuous flow hydroxy-carbonylation method. Flow carbonylation of 2-iodonaphtalene. Scale up synthesis of 2-chloro-4-fluorobenzoic acid (20). Optimisation for the carbonylation of ortho-substituted substrates in flow. Supporting Information Supporting Information File 427: Experimental part. Supporting

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• transformations [1][2][3][4][5]. In these processes one of the major problems is related to the recovering of the catalysts. The support of the small molecules on different materials has been proposed as a solution, including their use in continuous flow processes [6][7][8][9]. The most popular supports include

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

• that are operating in continuous flow mode [4][43][44]. Preparation of monosubstituted CD derivatives MW irradiation has been exploited in the synthesis of mono and persubstituted CDs. Several syntheses of CD derivatives have been successfully carried out under MW with higher yield, higher purity, and

• miniaturized continuous flow reactor, also called microreactor, offers many advantages over conventional scale reactors, including considerable improved energy exploitation, increased reaction speed and yield, safety, reliability, scalability, on-site/on-demand production, etc., and a much finer degree of

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

• A. John Blacker Katherine E. Jolley Institute of Process Research and Development, School of Chemistry and School of Chemical and Process Engineering, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, Leeds, UK 10.3762/bjoc.11.262 Abstract The continuous flow synthesis of a range of organic

• solutions of N,N-dialkyl-N-chloramines produced continuously will enable their use in tandem flow reactions with a range of nucleophilic substrates. Keywords: amine; biphasic; chloramine; chlorination; continuous flow chemistry; CSTR; static mixer; sodium hypochlorite; tube reactor; Introduction N

• -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

• Marcus Baumann Ian R. Baxendale Department of Chemistry, Durham University, South Road, DH1 3LE Durham, United Kingdom 10.3762/bjoc.11.134 Abstract The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our

• route was able to successfully deliver sufficient quantities of imatinib (23) and several of its analogues (~30–50 mg each) in high purity within one working day allowing subsequent testing of new derivatives. Although this approach was conducted as a fully integrated telescoped continuous flow sequence

• also been employed in the flow synthesis of a carprofen analogue [69] as well as in the regioselective bromination towards a rosuvastatin precursor [70] showcasing how continuous flow photochemistry is receiving a significant level of interest. This is not least because of the perceived green reagent

Automated solid-phase synthesis of oligosaccharides containing sialic acids

• Chian-Hui Lai,
• Heung Sik Hahm,
• Chien-Fu Liang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2015, 11, 617–621, doi:10.3762/bjoc.11.69

• equiv TfOH, NIS, DCM, −30 °C (5 min), −10 °C (25 min) for 9 and 10. Fmoc Deprotection: e) 3 × 20% NEt3 in DMF, 5 min. Photocleavage: f) UV irradiation using a continuous flow reactor, DCM, rt. Synthesis of 12 or 13: (1) 6, b, (2) e, (3) 4 or 5, a (4) f, 30% for four steps to yield 12, 40% for four steps

Photocatalytic nucleophilic addition of alcohols to styrenes in Markovnikov and anti-Markovnikov orientation

• Martin Weiser,
• Sergej Hermann,
• Alexander Penner and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2015, 11, 568–575, doi:10.3762/bjoc.11.62

• chemistry has significant advantages over batch chemistry, such as easier temperature control, larger surface-to-volume ratio and more efficient photoirradiation. Two setups were used to transfer the reaction to continuous-flow systems. The first mesoflow reactor was equipped with four 250 mW high-power

3α,5α-Cyclocholestan-6β-yl ethers as donors of the cholesterol moiety for the electrochemical synthesis of cholesterol glycoconjugates

• Aneta M. Tomkiel,
• Adam Biedrzycki,
• Jolanta Płoszyńska,
• Dorota Naróg,
• Andrzej Sobkowiak and
• Jacek W. Morzycki

Beilstein J. Org. Chem. 2015, 11, 162–168, doi:10.3762/bjoc.11.16

• eliminate chloride ions that are formed by the reduction of dichloromethane. The solutions in both compartments were stirred during electrolysis and, additionally, a continuous flow of argon was applied in the anodic compartment. A platinum mesh was used as a cathode and a platinum plate (2 × 1.5 cm) was

An integrated photocatalytic/enzymatic system for the reduction of CO₂ to methanol in bioglycerol–water

• Michele Aresta,
• Angela Dibenedetto,
• Tomasz Baran,
• Antonella Angelini,
• Przemysław Łabuz and
• Wojciech Macyk

Beilstein J. Org. Chem. 2014, 10, 2556–2565, doi:10.3762/bjoc.10.267

• enzymes FateDH, FaldDH, and ADH were encapsulated into silicate cages made from Ca alginate and tetraethoxysilanes (TEOS) and used at a controlled pH of 7. CO2 was admitted in a continuous flow reactor at such a rate to generate a 20% excess with respect to the stoichiometric amount required by the

Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

• Laura Morelli,
• Damiano Cancogni,
• Marta Tontini,
• Alberto Nilo,
• Sara Filippini,
• Paolo Costantino,
• Maria Rosaria Romano,
• Francesco Berti,
• Roberto Adamo and
• Luigi Lay

Beilstein J. Org. Chem. 2014, 10, 2367–2376, doi:10.3762/bjoc.10.247

• to 3 min, 46 mg of the α-H-phosphonate 7 were obtained in 0.5 h at higher isolated yield (76%) and purity than batch reaction. Based on the maximum volume of the syringes employed in our continuous-flow system (5 mL, see Supporting Information File 1), we can estimate that a production rate of 2.2 g

• /day would be achievable. To the best of our knowledge, this is the first example of the synthesis of glycosyl H-phosphonates using the continuous-flow MRT [30][31][32][33]. The occurrence of the H-phosphonate 7 was ascertained by a signal at 1.87 ppm in the 31P NMR, and the presence in the 1H NMR of

• fragments, based on the synthetic improvements and also the benefits of the continuous-flow microreactor technology herein described, is currently ongoing in our laboratory and it will be reported in due course. Besides the length of the carbohydrate haptens, the saccharide loading onto the protein is

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

• temporal evolution has been followed using a microreactor continuous-flow technique. Keywords: charge tag; electrospray; mass spectrometry; organocatalysis; proline; template; Introduction Electrospray ionization (ESI) mass spectrometry [1] has not only developed into a standard characterization method

• both reactions by ESIMS. These so-called continuous-flow experiments [5][20] allow the sampling of reaction times down to seconds. Solutions of the reagents are mixed in the first microreactor and diluted to concentrations suitable for ESIMS in the second microreactor. The reaction time between the

• (not reaction time) because analytes gradually accumulate in the system the longer their solutions are passed through. The extent of this effect depends on the height of the flow rate which necessarily has to be changed when observing a reaction process with the continuous-flow method. Nevertheless, we

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• elemental fluorine for the key construction of the carbon–fluorine bond by complementary direct selective direct fluorination [41][42][43][44], continuous flow [45][46][47][48][49] and building block [50] strategies, in this paper, we describe nucleophilic aromatic substitution reactions of carbanions