Flow chemistry is a popular method in both chemical industry and research but theoretical and practical learning opportunities for future chemists at university are scarce. To address this gap, we designed and evaluated experiments for a laboratory course of a master’s program integrating current research questions with elements of inquiry-based learning. The laboratory course was developed and investigated within a participatory action research (PAR) design. This paper presents the results of students’ pre- and post-surveys on students’ perceived learning opportunities, research skills, and learning objectives. The findings indicate positive changes in students’ self-assessed research skills and the inquiry-based elements of the designed flow lab were perceived as conducive to learning. Students’ self-assessment of learning objectives achieved also improved. Following the principles of PAR, two iterative cycles of an innovative laboratory course were implemented and evaluated. This study contributes to research on curriculum innovation in higher education by providing empirical insights into the design and development of research-based laboratory courses in flow chemistry.

A continuous flow process for the N-methylation of demethylbromonarwedine employing Eschweiler-Clarke conditions is reported for the synthesis of methylbromonarwedine, an intermediate of the anti-Alzheimer’s drug (−)-galanthamine. By intensifying this reaction by performing the N-methylation at elevated temperature and pressure, the reaction time was drastically reduced from 3 h in batch to only 40 s. The robustness of this process was demonstrated by operating it for 4.5 h, resulting in a product throughput of 20 g/h. Methylbromonarwedine was obtained not only in high yield (83

Laborpraktika k & ouml;nnen f & uuml;r Studierende immer noch viel Unsicherheit hinsichtlich der Vorbereitung mit sich bringen, gerade dann, wenn das Praktikum einen Themenbereich adressiert, zu dem Studierende wenig Lerngelegenheiten hatten. Flow Chemistry ist eine bedeutende Synthesemethode in Industrie und Forschung, die aufgrund ihrer Relevanz auch in der Hochschule im Rahmen eines Laborpraktikums implementiert werden soll. Um die Studierenden bei der Vorbereitung auf dieses Laborpraktikum zu unterst & uuml;tzen, wurden Scaffolding-Ma ss nahmen auf Basis von Vorerhebungen konzipiert und mit Studierenden getestet, um ihren Nutzen in einem Partizipativen Aktionsforschungsdesign erforschen zu k & ouml;nnen und sie f & uuml;r darauffolgende Laborzyklen weiterzuentwickeln. Dabei zeigte sich, dass besonders Scaffolds, die den Aufbau und die Funktionsweise von im Labor eingesetzten neuartigen Ger & auml;ten betreffen, von Studierenden als besonders hilfreich bewertet werden und sich die Mehrheit digitale Unterst & uuml;tzungsma ss nahmen als Vorbereitung auf ein Laborpraktikum w & uuml;nscht. Laboratory courses can still cause a lot of uncertainty for students in terms of preparation, especially if the practical addresses a subject area for which students have had little learning opportunity. Flow chemistry is an important synthesis method in industry and research which, due to its relevance, should also be implemented in the university as part of a laboratory course. To support students in preparing for this course, scaffolding measures were designed on the basis of preliminary surveys and tested with students in order to explore their benefits in a participatory action research design and develop them further for subsequent laboratory cycles. This showed that scaffolds relating to the structure and mode of operation of novel devices used in the laboratory were rated as particularly helpful by students and that the majority would appreciate digital support measures as preparation for a laboratory course.

A proof-of-concept study for the synthesis of 1,2-difluorobenzene from 2-fluoroaniline via the Balz-Schiemann reaction using HF/pyridine as the fluorinating reagent is reported. Key to success for a fast reaction, a clean reaction profile-and thus high product selectivity-was a photochemically induced fluorodediazoniation of the in situ-generated diazonium salt performed in a continuous flow mode. A high-power 365 nm light-emitting diode provided a more robust and efficient irradiation system compared to a medium-pressure Hg lamp with respect to the reaction performance on scale-out runs and reaction time, allowing the generation of 1,2-difluorobenzene within a 10 min residence time and a product selectivity of >= 95% at full conversion.

An explorative study on the continuous flow generation of the N-F reagent 2,6-dichloro-1-fluoro-pyridinium tetrafluoroborate from 2-6-dichloropyridine and 10% F 2 /N 2 and its telescoped downstream electrophilic fluorination reaction with an enamine is reported. The 2-step procedure was performed in a modular lab-scale silicon carbide flow reactor, which safely allowed processing corrosive F 2 and precise temperature control. Both reaction sequences turned out to be very fast when carried out in flow at − 10 °C: the N-F generation step could be done within 7.9 s and only 6.6 s were necessary for the fluorination of the enamine. Graphical abstract

Substituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and 'chiral pool' strategies. Herein, we report multi-enzymatic and chemo-enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee > 99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N-heterocycles using either platinum(0)-catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one-pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr & GE;98:2) and isolated yields of up to 73%. Lead-likeness analysis of five representative products using an open-source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery.

The front cover picture shows the assembly of a trisubstituted piperidine derivative through the controlled formation of C−N and C−H bonds. Different stereoselective synthetic tools – namely transaminase and IRED enzymes, and platinum(0)-catalysed flow hydrogenation – are combined to obtain the target N-heterocycles from achiral, open-chain precursors with excellent enantio- and diastereocontrol. The cover design is by Verena Resch and used with her permission. Details can be found in the Research Article by Joerg Schrittwieser and co-workers (P. Petermeier, C. Kohlfuerst, A. Torvisco, R. C. Fischer, A. Mata, D. Dallinger, C. O. Kappe, J. H. Schrittwieser, W. Kroutil, Adv. Synth. Catal. 2023, 365, XXXX–XXXX; DOI: 10.1002/adsc.202300050)

Despite a strong demand for fluorinated molecules in the pharma and agrochemical industry, the production of fluorinated compounds is often outsourced to specialized laboratories. This is likely the result of safety concerns in handling hazardous fluorinating reagents, alongside the lack of expertise and equipment. Continuous flow chemistry has become an established method to perform hazardous reactions in a safe and controlled manner. To address safety issues and technical challenges, we herein provide a detailed description of the design of an advanced fluorine gas delivery system using 10% fluorine in nitrogen. Furthermore, an overview of suitable flow reactor components and the reactor design on laboratory scale is furnished. The safety precautions to mitigate risks associated with handling 10% fluorine in nitrogen are also covered and include safety equipment integrated in the fluorine facility, risk assessment, personal protective equipment, and first aid measures.

A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol–ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1–0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.

This study provides a comparative life cycle assessment (LCA) of four different polyurethane dispersion production processes from cradle-to-gate. The environmental performances of the NMP process, the acetone process, the melt process, and a conceptualized continuous flow process were evaluated and compared following the CML 2001 methodology. The LCA revealed that the conceptualized flow process exhibits the lowest environmental impact in all investigated impact categories. Depending on the impact category, the melt process or the acetone process rank second. The NMP process was observed to have the highest impact in all categories. Consequently, the flow process has the lowest carbon footprint (1.13 kg CO2-eq), according to the global warming potential (100 years), followed by the melt (1.45 kg CO2-eq), the acetone (1.95 kg CO2-eq) and the NMP process (3.11 kg CO2-eq).

A simple reordering of the reaction sequence allowed the improved synthesis of EIDD-2801, an antiviral with promising activity against the SARS-CoV-2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17% to 61%, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.

CONSPECTUS: In recent years, a steadily growing number of chemists, from both academia and industry, have dedicated their research to the development of continuous flow processes performed in milli- or microreactors. The common availability of continuous flow equipment at virtually all scales and affordable cost has additionally impacted this trend. Furthermore, regulatory agencies such as the United States Food and Drug Administration actively encourage continuous manufacturing of active pharmaceutical ingredients (APIs) with the vision of quality and productivity improvements. That is why the pharmaceutical industry is progressively implementing continuous flow technologies. As a result of the exceptional characteristics of continuous flow reactors such as small reactor volumes and remarkably fast heat and mass transfer, process conditions which need to be avoided in conventional batch syntheses can be safely employed. Thus, continuous operation is particularly advantageous for reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry). In addition to conditions that are outside of the operation range of conventional stirred tank reactors, reagents possessing a high hazard potential and therefore not amenable to batch processing can be safely utilized (forbidden chemistry). Because of the small reactor volumes, risks in case of a failure are minimized. Such hazardous reagents often are low molecular weight compounds, leading generally to the most atom-, time-, and cost-efficient route toward the desired product. Ideally, they are generated from benign, readily available and cheap precursors within the closed environment of the flow reactor on-site on-demand. By doing so, the transport, storage, and handling of those compounds, which impose a certain safety risk especially on a large scale, are circumvented. This strategy also positively impacts the global supply chain dependency, which can be a severe issue, particularly in times of stricter safety regulations or an epidemic. The concept of the in situ production of a hazardous material is generally referred to as the "generator" of the material. Importantly, in an integrated flow process, multiple modules can be assembled consecutively, allowing not only an in-line purification/separation and quenching of the reagent, but also its downstream conversion to a nonhazardous product. For the past decade, research in our group has focused on the continuous generation of hazardous reagents using a range of reactor designs and experimental techniques, particularly toward the synthesis of APIs. In this Account, we therefore introduce chemical generator concepts that have been developed in our laboratories for the production of toxic, explosive, and short-lived reagents. We have defined three different classes of generators depending on the reactivity/stability of the reagents, featuring reagents such as Br-2, HCN, peracids, diazomethane (CH2N2), or hydrazoic acid (HN3). The various reactor designs, including in-line membrane separation techniques and real-time process analytical technologies for the generation, purification, and monitoring of those hazardous reagents, and also their downstream transformations are presented. This Account should serve as food for thought to extend the scope of chemical generators for accomplishing more efficient and more economic processes.

A detailed investigation of the regioselectivity in the thermal cyclization of (pyridyl)aminomethylenemalonates both in the gas‐ and solution phase is presented. Flash vacuum pyrolysis (FVP) as a gas‐phase thermolysis technique is used to study the Gould–Jacobs reaction at temperatures between 450–650 °C, while different solution‐phase heating techniques (reflux, microwave, and continuous flow) were employed at 260–350 °C. Depending on the position of the substituent in the pyridine moiety and the applied thermolysis technique, the regioselectivity of the cyclization can be controlled either in favor of the kinetic (pyridopyrimidinone) or the thermodynamic (naphthyridinone) product. Under FVP conditions, 6‐substituted pyridopyrimidinones were obtained in high regioselectivity, which was not demonstrated before under standard Gould–Jacobs reaction conditions. DFT calculations have been additionally performed to provide further insights into the mechanistic pathways of this specific Gould–Jacobs reaction.

The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied for the telescoped three-step synthesis of a chiral α-chloroketone, a key building block for many HIV protease inhibitors, via a modified Arndt–Eistert reaction starting from N-protected l-phenylalanine. The initial mixed anhydride was generated in a coil reactor and directly introduced into the CSTR diazomethane cascade. The use of a semipermeable Teflon membrane (AF-2400) allowed the generation of anhydrous diazomethane, which diffuses through the membrane into the CSTR where it is immediately consumed by the anhydride to furnish the corresponding diazoketone. The subsequent halogenation with concentrated HCl was performed downstream in batch and allowed production of the α-chloroketone on a multigram scale, with a productivity of 1.54 g/h (5.2 mmol/h).

A safe and scalable continuous flow strategy for Wolff–Kishner reductions that employs methanol as the solvent has been developed. The use of low-cost hydrazine as the reducing agent in combination with a caustic base provides an atom-efficient, environmentally friendly method for the deoxygenation of aldehydes and ketones to alkanes. Because of the required harsh and corrosive reaction conditions (200 °C, 50 bar), reactor materials such as stainless steel, glass, or any type of polymer have compatibility problems, rendering this process problematic on a production scale. The use of corrosion-resistant silicon carbide (SiC) as the reactor material opens up the possibility of performing Wolff–Kishner reductions on scale with a considerably improved safety profile. Methanol as the solvent significantly simplifies the workup procedure compared with the generally employed high-boiling solvents such as diethylene glycol. The continuous flow protocol was applied to a number of substrates and provided the desired products in good to high yields with space-time yields of up to 152 g L–1 h–1. In addition, a pharmaceutically valuable active pharmaceutical ingredient precursor was synthesized by employing this high-temperature/pressure Wolff–Kishner protocol.

A continuous-flow process for the in situ on-demand generation of cyanogen bromide (BrCN) from bromine and potassium cyanide that makes use of membrane-separation technology is described. In order to circumvent the handling, storage, and transportation of elemental bromine, a continuous bromine generator using bromate-bromide synproportionation can optionally be attached upstream. Monitoring and quantification of BrCN generation was enabled through the implementation of in-line FTIR technology. With the Br-2 and BrCN generators connected in series, 0.2 mmol BrCN per minute was produced, which corresponds to a 0.8m solution of BrCN in dichloromethane. The modular Br-2/BrCN generator was employed for the synthesis of a diverse set of biologically relevant five-and six-membered cyclic amidines and guanidines. The set-up can either be operated in a fully integrated continuous format or, where reactive crystallization is beneficial, in semi-batch mode.

Diazomethane is useful for inserting methyl or methylene groups in organic synthesis. Unfortunately, it is explosive. A tube-in-flask reactor where the Teflon AF-2400 tube allows only the diazomethane produced to enter the flask can be used to prepare it safely.

Enhanced heat and mass transfer, precise residence time control, shorter process times, increased safety, reproducibility, better product quality and easy scalability are just a few of the advantages of flow chemistry and reason for the increasing implementation of continuous processes not only in academia but also into the fine chemical manufacturing sector. Notably, to make a process greener and more sustainable becomes eminently important when going from lab-scale to production scale. In this review, the question to which extent continuous flow processing has an impact as green technology, in particular on the synthesis of active pharmaceutical ingredients (APIs) on manufacturing scale, is discussed. Based on the principles of both green chemistry and green engineering selected continuous processes are evaluated.