Flow Chemistry

A continuous flow cascade of multi-step catalytic reactions is a cutting-edge concept to revolutionize stepwise catalytic synthesis yet is still challenging in practical applications. Herein, a method for practical one-pot cascade catalysis is developed by combining Pickering emulsions with continuous flow. Our method involves co-localization of different catalytically active sub-compartments within droplets of a Pickering emulsion yielding cell-like microreactors, which can be packed in a column reactor for continuous flow cascade catalysis. As exemplified by two chemo-enzymatic cascade reactions for the synthesis of chiral cyanohydrins and chiral ester, 5 − 420 fold enhancement in the catalysis efficiency and as high as 99% enantioselectivity were obtained even over a period of 80 − 240 h. The compartmentalization effect and enriching-reactant properties arising from the biomimetic microreactor are theoretically and experimentally identified as the key factors for boosting the cat...

Sustainability concerns are reshaping the way chemists work, not only at the stage of process design, but also when actually performing reactions. This change of paradigm is exemplified by the deployment of continuous flow techniques, which are slowly becoming a mainstream practice. Indeed, the possibility of performing catalytic processes (the flagship of sustainable chemistry) in flow presents distinctive advantages. Thus, several authors are focusing their efforts in trying to get the best of these two worlds, with the consequent challenge of finding common solutions for their respective issues. In the last years, this approach has been taken one step further with the use in flow processing of enantioselective organocatalysts, which allow the production of enantiopure compounds free of metal contaminants. Herein, we will cover the literature concerning the use of solid-supported organocatalysts for the continuous flow production of enantiomerically enriched compounds.

General concept of flow chemistry is based on practical work to develop modern method of chemical synthesis with help of modern technology. Batch processes were not linear, reaction cannot be performed on actual reaction parameters such as reaction temperature, reaction time and molar ratio, it has lots of disadvantages over flow chemistry, also its required larger space for synthesis of chemicals and produce lots toxic and waste product which is directly affect on the environment. Flow chemistry has advantages over batch production. Flow chemistry provides channel or tube for conduction of reactant rather than in batch. Concept of flow chemistry brings us to potential scale up and efficient marketing,improved safety, fasterreaction, decreased waste production and space requirement, well optimized heat control, reduced cost and way to settle the explosive reaction. There by day to day flow chemistry has reached the number of application. Most important is it can be used both in laboratory as well as industrial scale up. Flow reactors can be employed in small housing area. Micro reactor is micro device that efficiently mixes the reactant thus extremely fast and explosive reaction can be carried out at good heat control and mass control. The Microreactor of Flow chemistry provide series of continuous reaction occurring at correct reaction parameters, chemical analysis of reactant can be done during process flow. Due to these advantages and acceptability it is now increasingly employed in pharmaceutical industries (API and chemical synthesis) since it developed more sustainable and environmental ecofriendly techniques.

Assessing the sustainability of chemical processes in terms of environmental, economic, and social aspects, especially during the early stages of development, is crucial to designing sustainable manufacturing routes. In this study, we compared the sustainability performance of an electrochemical route for synthesizing noroxymorphone, an intermediate in the synthesis of opioid antagonists, with that of a conventional process. For that purpose, we followed the Safe and Sustainable by Design (SSbD) framework of the European Commission and applied selected sustainability indicators from the literature. Compared to the conventional procedure, the electrochemical process has the potential to offer advantages in all three dimensions of sustainability, primarily due to the lower environmental impacts of the employed reagents in the upstream supply chain and their reduced hazards during the production process. Furthermore, it was found that further steering the electrochemical process toward sustainability is possible by optimizing the solvents and reducing the use of hazardous reagents.

Tetrabutylammonium decatungstate (TBADT) has emerged as an efficient and versatile photocatalyst for hydrogen atom transfer (HAT) processes that enables the cleavage of both activated and unactivated aliphatic C-H bonds. Using a recently developed oscillatory millistructured continuous-flow photoreactor, investigations of a decatungstate-catalyzed C(sp 3 )-H alkylation protocol were carried out, and the results are presented here. The performance of the reactor was evaluated in correlation to several chemical and process parameters, including residence time, light intensity, catalyst loading, and substrate/reagent concentration. In comparison with previously reported batch and flow protocols, conditions were found that led to considerably higher productivity, achieving a throughput up to 36.7 mmol/h with a residence time of only 7.5 min.

The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the residence time up to 16 times in comparison to the batch procedure, while achieving similar or higher yields. In addition, the use of inorganic bases was demonstrated to increase the reaction yield under batch conditions.

Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field. The use of light to promote chemical reactions has been exploited since the 18th century, but only recently a resurgence has been observed in synthetic organic chemistry, in particular due to the development of visible-light photoredox catalysis . All transformations involving light (e.g., Figure ) must consider, besides classical chemical parameters (i.e., reaction conditions), the photophysical aspects of the sensitizer (see Glossary)/photocatalyst (when used), and the reactor design. The latter, although often neglected by chemists, is a critical aspect for the outcome of the studied chemical transformation. This includes, for example, the size, shape, and material of the reaction vessel, the characteristics and positioning of the light source(s), and heat-transfer properties, particularly when high-intensity lamps are used . The engineering and technological aspects of photochemical processes are often at the basis of the irreproducibility and non-scalability of such transformations. According to the Beer-Lambert law, light transmittance decreases exponentially with the distance from the light source (Figure ). For a standard batch reactor (diameter at least in the centimeter range), light intensity decreases considerably from the flask walls to the middle of the reaction mixture, resulting in slow reactions and nonhomogeneous irradiation of the reaction mixture. Performing photochemical reactions in microchannels (ID < 1 mm) allows a higher and more homogeneous photon flux, resulting in shorter reaction times and consequently less side-product formation due to over-irradiation, often observed in batch . Another advantage of microflow chemistry, correlated with the large surface:volume ratio, is improved heat and mass transfer, with the possibility to perform mass-transfer-limited multiphasic reactions efficiently . Reactive chemicals and intermediates can be handled more safely in flow than in batch, as no accumulation of dangerous components occurs within the confined reactor volume due to the continuous nature of the process. Together, these result in often faster, safer, and higher-yielding reactions, with the possibility to perform reactions under conditions impossible in batch (high P/ T; so-called novel process windows [11]), and make microflow systems a valid alternative to traditional batch chemistry for many purposes. Moreover, the ease of automation and coupling with inline analysis, separation, and purification methods allows the development of continuous multistep synthesis and automated production platforms. These advantages are nicely showcased in the growing use of flow in the pharmaceutical industry . The typical flow setup for photochemical processes comprises transparent tubing made of perfluorinated materials (e.g., PFA, ETFE) efficiently coiled around a light source , or surrounded by it, for uniform irradiation (Figure ). A more expensive alternative is the use of flat, transparent microreactors with engraved microchannels irradiated from both sides of the plate.

The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β 2 -adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of respiratory disease. A flow sequence is developed for the preparation of the lipophilic amine tail portion of abediterol. The sequence comprises of a phase-transfer-catalyzed liquid/liquid O-alkylation, a rhodium-catalyzed hydroformylation, and a ruthenium-catalyzed reductive amination. The reactions were optimized separately within continuous-flow environments to identify important parameter effects. The strongly basic O-alkylation operates with greater than 90% conversion within a 23 min residence time. The hydroformylation uses 1 mol % Rh(acac)(CO) 2 (acac = acetylacetone) as a catalyst and 6 mol % Xantphos as a ligand with 1.1 equiv of hydrogen and carbon monoxide. The optimized O-alkylation and hydroformylation telescoped flow process was successfully operated over 6 h. The protocol is shown to be high yielding for the desired linear aldehyde (75% gas chromatography yield, ∼2.5 g/h). The sequence requires a solvent switch prior to the reductive amination. The final step is a high-pressure (40 bar) and high-temperature (150 °C) Ru-catalyzed reductive amination using ammonia and hydrogen to afford the amine tail. The solution yield for the formation of the amine tail was 78%. The yield of the reductive amination with an unoptimized isolation was 50%, resulting in an overall isolated yield for the three-step sequence of 38%. This compares favorably against the batch yield of 26% using a different synthetic route.

A miniaturized flow device has been developed to combine microfluidics technology and plasma process. In this microreactor, atmospheric pressure dielectric barrier discharges are generated in a gas in contact with a liquid phase. This study was conducted with plasma generated in ammonia in contact with a flow of liquid cyclohexane. Cyclohexylamine was synthesized with a good selectivity, and the process can be implemented to improve conversion and effectiveness. Numerical simulations confirmed that NH 2 radicals are generated in the plasma and react with cyclohexyls radicals to achieve the reaction, giving a selectivity of 50% and a total molar conversion of 20% of cyclohexane. The effects of voltage and frequency on the selectivity and the experimental conversion rate were studied and discussed.

The use of deep eutectic solvent (DES)/water mixtures were explored for the selective enzymatic synthesis of α‐monobenzoate glycerol (α‐MBG) from glycerol and benzoic acid as substrates. Experiments were performed with four DES, three of them containing choline chloride (ChCl), combined with urea (URA), glycerol (GLY), and ethylene glycol (ETA) (in all cases ChCl/HBD 1:2 mol ratio), and another one formed with methylammonium chloride and glycerol (MA/GLY 1:3 mol ratio). The best conversions (99 %) were achieved with immobilized lipase B from Candida antarctica (CAL‐B) when ChCl/GLY was used as the solvent and the substrate at the same time. The use of water as a cosolvent (8 % v/v) led to a significant decrease in the viscosity of the DES, and full conversions were then reached. Reusability studies of the biocatalyst revealed a 37 % decrease in activity after the first batch, but the activity remained mostly constant for the rest of the cycles.

Article Recommendations M any industrial chemical incidents happen around the world every year, causing fatalities, property damage, and disrupted supply chains. For example, the Tianjiayi Chemical explosion in Jiangsu, China, on March 21, 2019, at a plant producing chemical intermediates caused 78 fatalities, 76 severe injuries, 640 hospitalizations, and an estimated direct economic loss of $300 million. 1 An explosion at AB Specialty Silicones in Waukegan, Illinois, on May 3, 2019, killed four workers. 2 More recently, on July 27, 2021, an explosion at the Chempark complex in Leverkusen, Germany, caused seven fatalities and left 31 injured. 3 While these were local events, process safety incidents like these can have international consequences. For example, the Tianjiayi explosion caused disruptions for many global chemical and pharmaceutical companies who were buyers of the company's products. Systematically studying process safety performance and learning from the past is an effective way to prevent such incidents. 5 But improving process safety does not mean we need to wait to learn when the next explosion, death, or injury occurs. Instead, research that contributes to preventing process safety incidents from ever occurring is regularly published in several journals, including Organic Process Research & Development (OPR&D), ACS Chemical Health & Safety (ACS CHAS), and the Journal of Loss Prevention in the Process Industries (JLPPI). These three journals have now pooled their efforts to publish a joint Virtual Special Issue, "Process Safety from Bench to Pilot to Plant." This unique collaboration between American Chemical Society and Elsevier journals highlights work that merges natural, social, management, and engineering sciences. The scope and audience of each journal can be found online. Briefly, OPR&D publishes research on industrial process chemistry to enable safe, environmentally benign, and ultimately economical manufacturing of organic compounds in larger quantities. ACS CHAS publishes work on current and emerging technical, human, and organizational factors affecting chemical risk management, safety information, regulatory updates, effective chemical hygiene practices, safety training, and hazard assessment tools. JLPPI publishes on technical, human, and organizational process safety measures to prevent and mitigate process-related injuries and damage arising from fire, explosion, and toxic release during the use, storage, manufacture, handling, and transportation of hazardous materials. Process safety starts with students, as they are the foundation Biographies ACS Chemical Health & Safety pubs.acs.org/acschas

Article Recommendations M any industrial chemical incidents happen around the world every year, causing fatalities, property damage, and disrupted supply chains. For example, the Tianjiayi Chemical explosion in Jiangsu, China, on March 21, 2019, at a plant producing chemical intermediates caused 78 fatalities, 76 severe injuries, 640 hospitalizations, and an estimated direct economic loss of $300 million. 1 An explosion at AB Specialty Silicones in Waukegan, Illinois, on May 3, 2019, killed four workers. 2 More recently, on July 27, 2021, an explosion at the Chempark complex in Leverkusen, Germany, caused seven fatalities and left 31 injured. 3 While these were local events, process safety incidents like these can have international consequences. For example, the Tianjiayi explosion caused disruptions for many global chemical and pharmaceutical companies who were buyers of the company's products. Systematically studying process safety performance and learning from the past is an effective way to prevent such incidents. 5 But improving process safety does not mean we need to wait to learn when the next explosion, death, or injury occurs. Instead, research that contributes to preventing process safety incidents from ever occurring is regularly published in several journals, including Organic Process Research & Development (OPR&D), ACS Chemical Health & Safety (ACS CHAS), and the Journal of Loss Prevention in the Process Industries (JLPPI). These three journals have now pooled their efforts to publish a joint Virtual Special Issue, "Process Safety from Bench to Pilot to Plant." This unique collaboration between American Chemical Society and Elsevier journals highlights work that merges natural, social, management, and engineering sciences. The scope and audience of each journal can be found online. Briefly, OPR&D publishes research on industrial process chemistry to enable safe, environmentally benign, and ultimately economical manufacturing of organic compounds in larger quantities. ACS CHAS publishes work on current and emerging technical, human, and organizational factors affecting chemical risk management, safety information, regulatory updates, effective chemical hygiene practices, safety training, and hazard assessment tools. JLPPI publishes on technical, human, and organizational process safety measures to prevent and mitigate process-related injuries and damage arising from fire, explosion, and toxic release during the use, storage, manufacture, handling, and transportation of hazardous materials. Process safety starts with students, as they are the foundation

BACKGROUNDDevelopment of circular economy requires significant advances in the technologies for valorisation of waste, as waste becomes new feedstock. Food waste is a particularly important feedstock, containing large variation of complex chemical functionality. Although most food waste sources are complex mixtures, waste from food processing, no longer suitable for the human food chain, may also represent relatively clean materials. One such material requiring valorisation is cocoa butter.RESULTSEpoxidation of a triglyceride from a food waste source, processing waste cocoa butter, into the corresponding triglyceride epoxide was carried out using a modified Ishii‐Venturello catalyst in batch and continuous flow reactors. The batch reactor achieved higher yields due to the significant decomposition of hydrogen peroxide in the laminar flow tubular reactor. Integral and differential models describing the reaction and the phase transfer kinetics were developed for the epoxidation of coc...

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Microreactor technology can help to reduce the time to market new drugs. It was applied to produce (Z)‐5‐benzylidenethiazolidine‐2,4‐dione, a heterocyclic intermediate in the synthesis of various drugs. Ethanol was the optimum solvent and piperidine the best catalyst in the batch process. The continuous/microreactor process exhibited a much better performance than the batch process. The productivity, which was strongly influenced by solvent and temperature, reached a maximum at 160 °C using methanol as solvent. A kinetic/thermodynamic study indicated that the reaction followed the second‐order model and allowed estimating its main thermodynamic parameters. A product recovery protocol was finally proposed. The microreactor proved an efficient alternative to the batch reactor in scaling up the production of active pharmaceutical ingredients.

Process intensification based on micro reactor technology allows safe manner and a new pathway to run organic synthesis due to its intrinsic characteristics, and can reduce time-to-market of new drugs. The main objective of this work was to study the batch and flow reaction of five n-substituted 5-benzylidenethiazolidine-2,4-dione heterocyclic intermediates present in the synthesis of glitazone class drugs, in capillary micro reactor. Batch process was conducted with ethanol as solvent at the boiling point and pyrrolidine as promoting base of the reaction. Higher yields were obtained in shorter reaction times in temperatures above solvent boiling point. Also, we evaluated that 3.8 micro reactors in parallel would be necessary to reach the same mean molar flow rate of a 60 mL batch reactor. Kinetic and thermodynamic study indicated that the reaction followed the second-order model and allowed estimating its main thermodynamic parameters. The continuous flow micro reactor proved to be...

The synthesis of racemic and enantiopure tricyclic and tetracyclic pyrrolopyrimidinones, pyrimidoisoindoles, and spiropyrimidinones, as valuable new chemical entities (NCE), based on a highly controlled continuous-flow (CF) retro-Diels-Alder protocol is presented. This approach ensures enhanced safety, and gave the target pyrimidinone derivatives 17-25 in yields higher than those obtained in batch and microwave

Singlet oxygen, a reactive oxygen species, has been a basic synthetic tool in the laboratory for many years. It can be generated either through a chemical process or most commonly via a photochemical process mediated by a sensitizing dye. The relative paucity of singlet oxygen employment in fine chemical industrial settings can be attributed to many factors, not least the requirement for excessive quantities of oxygenated organic solvents and the dangers that these represent. Microcapillary films (MCFs) are comprised of multiple parallel channels embedded in a plastic film. In this study, MCFs are employed as flow reactor systems for the singlet oxygen mediated synthesis of ascaridole. No gaseous oxygen is supplied directly to the reaction, rather mass transport occurs exclusively through the reactor walls. The rate of production of ascaridole was found to be strongly dependent on the partial pressure of oxygen present within the reaction system. This methodology significantly simplifies reactor design, allows for increased safety of operation, and provides for space-time yields over 20 times larger than the corresponding bulk synthesis.

Titanium dioxide was applied as an immobilized photocatalyst in a microstructured falling film reactor for the continuous-flow C-H arylation of heteroarenes with aryldiazonium salts as the starting material. Detailed investigations of the catalyst and a successful long-term run proved its excellent usability for this process. Very good yields up to 99% were achieved with broad substrate scope and were compared with batch synthesis. The transfer to the continuous-flow mode revealed an impressive boost in reactor performance solely resulting from the improved irradiation and contact of the catalyst, substrate and light. † Electronic supplementary information (ESI) available: Catalyst preparation and immobilisation, surface roughness, TEM, nitrogen physisorption, XRD, SEM, EDX, lab plant description and flow chart, synthesis of aryldiazonium salts, 19 F NMR analysis during long-term run, and product characterization: 1 H-, 13 C-, and 19 F-NMR spectroscopy. See

Alkalimetallhydride wären ideal zur Darstellung von Carbanionen geeignet, da als zweites Reaktionsprodukt nur H2 entstünde, sind jedoch normalerweise wenig reaktiv. Hier wird nun eine Synthese von LiH, NaH und KH durch Hydrierung von BuM (M=Li, Na, K) in Hexan beschrieben, die zu hochreaktiven Metallhydriden führt. Sie deprotonieren zudem selektiver als andere Metallierungsreagentien.

Metal-organic frameworks (MOFs) are a class of crystalline and porous adsorbents, with wide-ranging applications in gas separations, membrane materials as well as sensors. Commonly used batch synthesis techniques for MOF production are limited by low productivity, high operating costs, and slow crystallization timescales, severely impeding the large-scale manufacturing of these materials. However, batch synthesis is a useful and easy technique to screen multiple reaction parameters to find an optimal chemistry. Therefore, in this study, we have used the batch process and screened a multidimensional reaction space consisting of 45 sample variations based on the crystallinity, yield and instantaneous precipitation, which could lead to tube clogging under flow conditions. We have found one optimized reaction chemistry, that could be used in flow conditions, which in this study is a novel millifluidic droplet-based reactor for the continuous synthesis of HKUST-1 crystals. The biphasic f...

We report a semiautomated synthesis of sequence and architecturally defined, unimolecular macromolecules through a marriage of multistep flow synthesis and iterative exponential growth (Flow-IEG). The Flow-IEG system performs three reactions and an in-line purification in a total residence time of under 10 min, effectively doubling the molecular weight of an oligomeric species in an uninterrupted reaction sequence. Further iterations using the Flow-IEG system enable an exponential increase in molecular weight. Incorporating a variety of monomer structures and branching units provides control over polymer sequence and architecture. The synthesis of a uniform macromolecule with a molecular weight of 4,023 g/mol is demonstrated. The user-friendly nature, scalability, and modularity of Flow-IEG provide a general strategy for the automated synthesis of sequence-defined, unimolecular macromolecules. Flow-IEG is thus an enabling tool for theory validation, structure-property studies, and a...

In this work, we have investigated the biocatalytic continuous flow process with a packed-bed reactor for the kinetic resolution of (±)-1,3,6-tri-O-benzyl-myo-inositol ((±)-1) by alcoholysis using Novozym 435. Excellent conversions and stereselectivities were attained in short reaction time. We found that this enzymatic transformation under continuous flow in TBME with vinyl acetate (10:1 ratio with (±)-1) at 50 • C, with a 3 min-residence time secured the best results (50% conversion and ee p > 99%). The feasibility of a continuous operation of the Novozym 435-containing-packed-bed reactor over a longer period of time was demonstrated via a 9-cycle experiment wherein the lipase remained stable.

A 3-D printed cartridge was fabricated using acrylonitrile-butadiene-styrene (ABS) printer filament. The cartridge was printed with an internal helical honeycomb channel pattern-providing a high surface area suitable for flow chemistry. The internal chamber of the cartridge was treated with fuming sulfuric acid to anneal the surface and functionalize the material with sulfonic acid groups. The 3-D printed catalyst was then used in a variety acid-catalyzed organic reactions, with conversions in 52-97 % yields.

Effects of microwave and non-microwave heating methods on the synthesis of ethyl levulinate (EL) from levulinic acid (LA) has been investigated in the present study. The levulinic acid esterification experiments were performed in the presence of silicotungstic acid catalyst and ethanol in a microwave and non-microwave instant heating reactor. An experimental fit of experimental data in kinetic model suggested that LA esterification follows pseudo first order reaction mechanism. Consequently, activation barriers were calculated (44-45 kJ/mol) and a negligible difference was found for LA esterification reaction performed in both the reactors. Nevertheless, slightly higher LA conversions were measured under microwave irradiations as compared to experiments performed in a non-microwave instant heating reactor. Thus, series of experiments were performed to study the (i) non-thermal and (ii) thermal effects of microwave heating irradiations. Eventually, it was found that the enhanced LA conversion in microwave reactor could be due improved heat transfer into the reaction mixture owing to direct heating by microwaves, as compared to conventional conductive and convective heat transfer in the instant heating reactor. In addition, experiments performed under different operating conditions such as at varying stirring speed, varying sample volume, different catalysts concentration and reactant concentration indicated the absence of non-thermal microwave effects.

The evolution from early medicinal chemistry to large-scale production of the chemical synthesis of Lilly D1 positive allosteric modulator (PAM) mevidalen (LY3154207) and its hydroxybenzoate cocrystal is outlined. The issues and steps taken to resolve them are outlined across several generations of synthesis, including unexpected issues that arose during cryogenic addition of MeLi to a key imine intermediate and the use of flow chemistry to enable the largescale production. Ultimately a process that was used to deliver >100 kg of API to support ongoing clinical trials is described.

Visible‐light photoredox catalysis has recently emerged as a viable alternative for radical reactions otherwise carried out with tin and boron reagents. It has been recognized that by merging photoredox catalysis with flow chemistry, slow reaction times, lower yields, and safety concerns may be obviated. While flow reactors have been successfully applied to reactions carried out with UV light, only recent developments have demonstrated the same potential of flow reactors for the improvement of visible‐light‐mediated reactions. This review examines the initial and continuing development of visible‐light‐mediated photoredox flow chemistry by exemplifying the benefits of flow chemistry compared with conventional batch techniques.

Cinchona alkaloid and proline derivatives as enantioselective catalysts were covalently attached onto the inner walls of a microreactor using glycidyl methacrylate polymer brushes. The successful formation of the organocatalystfunctionalized brush layers on flat silicon oxide surfaces was confirmed by several techniques such as Fourier transform infrared (FT-IR), ellipsometry, and X-ray photoelectron spectroscopy (XPS). The applicability of the cinchona alkaloid (cinchonidine or quinidine)-and proline-containing polymer brushes in a microreactor was demonstrated for the Diels-Alder reaction between anthrone and N-substituted maleimides, and the aldol reaction between 4-nitrobenzaldehyde and cyclohexanone, respectively, which showed moderate conversions (up to 55% and 23%, respectively) and moderate to good enantioselectivities (up to 55% and 93%, respectively). The pristine catalytic activity of the microreactor was intact even after 1 month.

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 reviewed. Some recent selected applications have been collected, including synthetic applications, the determination of the kinetic and thermodynamic parameters and reaction optimization, even in single experiments and on the μL scale. Finally, software that allows automatic reaction monitoring and optimization is discussed.

Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the reaction conditions using the flow reactor allowed minimization of secondary photochemical reactions.

A microwave-assisted, continuous-flow organic synthesis (MACOS) protocol for the synthesis of functionalized 1,2,5-thiadiazepane 1,1-dioxide library, utilizing a one-pot elimination and inter-/intramolecular double aza-Michael addition strategy is reported. The optimized protocol in MACOS was utilized for scale-out and further extended for library production using a multicapillary flow reactor. A 50-member library of 1,2,5-thiadiazepane 1,1-dioxides was prepared on a 100- to 300-mg scale with overall yields between 50 and 80% and over 90 % purity determined by proton nuclear magnetic resonance ((1)H-NMR) spectroscopy.

Naturstoffe mit biologischer Aktivität sind als Leitstrukturen für die Pharmaforschung von höchstem Interesse, um Abkömmlinge mit höherer Selektivität und damit einem verträglicheren Nebenwirkungsprofil darzustellen oder z. B. durch QSAR den Pharmakophor zu ermitteln. In diesem Zusammenhang stellen vor allem Alkaloide aufgrund ihrer starken Wirkung auf den tierischen und menschlichen Organismus eine besonders interessante Substanzklasse dar. Der Alkaloidbegriff wurde bereits 1819 vom Hallenser Apotheker MEISSNER für alkalisch reagierende Pflanzenstoffe eingeführt. 1 Als erstes Alkaloid wurde 1817 das starke Analgetikum (-)-Morphin, das als stark suchterregend gilt, von SERTÜRNER in Reinform isoliert und charakterisiert. 2 Sowohl die strukturelle Vielfalt als auch die mannigfaltige Komplexität innerhalb der Gruppe der Alkaloide ist verblüffend (Abbildung 1). Abbildung 1. Einige ausgewählte Alkaloide, die strukturelle Diversität zeigen. Eines der vermutlich einfachsten und wohl auch bekanntesten Alkaloide stellt das aus der Tabakpflanze (Nicotiana tabacum) isolierte und agonistisch auf die nicotinischen Acetylcholinrezeptoren wirkende (-)-Nicotin dar. 3 Wesentlich höhere Komplexität besitzt das aus den Samen der gewöhnlichen Brechnuss (Strychnos nux-vomica) gewonnene stark giftige Alkaloid (-)-Strychnin, 4 das durch seine kompetitive Wirkung am Cholinrezeptor den Cl --Kanal beeinflusst 5 und somit schnell zu tödlicher neuronaler Übererregung führt. Durch seine hohe Komplexität vergingen ca. 130 Jahre von der ersten Isolierung 6 bis zu seiner Strukturaufklärung durch ROBINSON 7 und WOODWARD 8 im Jahre 1946 und 1947 mit ca. 400 vorhergegangenen Publikationen. 4 Die erste Totalsynthese von (-)-Strychnin durch WOODWARD 9 stellt einen bedeutenden Meilenstein in der stereoselektiven organischen Synthese dar. Aufgrund seiner sechs Stereozentren, von denen eines quartär ist und des schwer zugänglichen, stark gespannten CDE-Tricyclus bei relativ niedrigem Molekular-1.1 ALKALODE 2 gewicht, ist (-)-Strychnin nach wie vor schwer darstellbar 10 und stellt somit für den organischen Synthetiker, ähnlich wie auch (-)-Morphin, 11 eine Schlüsselverbindung dar. Das unter anderem im blauen Eisenhut (Aconitum napellus) vorkommende (+)-Aconitin ist noch etwas komplexer gebaut und eines der stärksten bekannten Pflanzengifte (LD Lo (Mensch) = 28 µg/kg), das durch Beeinflussung der Na + -Kanäle rasch zu einer tödlichen Lähmung führt. Das Spindelgift (-)-Vinblastin wurde in der rosafarbenen Catharanthe (Catharanthus roseus) gefunden und spielt mittlerweile in der chemotherapeutischen Behandlung von Krebspatienten eine wichtige Rolle. 12 Wie bereits an der Strukturvielfalt und Komplexität der kurz vorgestellten Alkaloide zu vermuten ist, wurde die Alkaloiddefinition öfters revidiert. So wurde der Alkaloidbegriff auf durch Mikroorganismen, Pilze oder Tiere erzeugte basische Sekundärmetaboliten ausgeweitet. Bis dato konnte leider keine generelle Alkaloiddefinition gefunden werden. Daher gibt es je nach Betrachtungsweise verschiedene weitere Einschränkungen: 13  Das Stickstoffatom muss in einem Heterocyclus gebunden sein.  Die Biosynthese muss aus einer Aminosäure hervorgehen.  Das Alkaloid muss eine gewisse Basizität aufweisen. Da das starke Halluzinogen Mescalin aus dem Peyote-Kaktus (Lophophora williamsii) keinen aza-Heterocyclus besitzt (Abbildung 2), ist es im obigen Sinne kein echtes Alkaloid. Vertreter dieser Substanzklasse werden oft als Protoalkaloide bezeichnet. Es gibt einige basische Sekundärmetaboliten, die nicht aus Aminosäuren aufgebaut werden und oft als Pseudoalkaloide bezeichnet werden. So wird z. B. (+)-Coniin, das Gift des gefleckten Schierlings (Conium maculatum), über den Polyketidweg 14 und das oben gezeigte (+)-Aconitin über den terpenoiden Methylerythritolphosphatweg biosynthetisiert. Abbildung 2. Das Protoalkaloid Mescalin neben dem Pseudoalkaloid (+)-Coniin und den beiden nicht basischen, aber oft als Alkaloide bezeichneten Verbindungen Capsaicin und (-)-Colchicin. Oftmals werden aber die Einschränkungen nicht so eng genommen, so dass auch oben erwähnte Stoffe oder der nicht basische Scharfstoff Capsaicin 15 der Chilli-Schoten (Capsicum annuum) und der Mitose-Hemmer (-)-Colchicin 16 aus der Herbstzeitlosen (Colchicum autumnale) als Alkaloide bezeichnet werden. Somit werden heute alle stickstoffhaltigen Sekundärmetabolite bis auf basische Antibiotika oder Aminozucker zu den Alkaloiden gezählt. Zur Einteilung der Alkaloide gibt es verschiedene Möglichkeiten, wie z. B. nach

Glycolipids are a class of biodegradable biosurfactants that are non-toxic and based on renewables, making them a sustainable alternative to petrochemical surfactants. Enzymatic synthesis allows a tailor-made production of these versatile compounds using sugar and fatty acid building blocks with rationalized structures for targeted applications. Therefore, glycolipids can be comprehensively designed to outcompete conventional surfactants regarding their physicochemical properties. However, enzymatic glycolipid processes are struggling with both sugars and fatty acid solubilities in reaction media. Thus, continuous flow processes represent a powerful tool in designing efficient syntheses of sugar esters. In this study, a continuous enzymatic glycolipid production catalyzed by Novozyme 435 ® is presented as an unprecedented concept. A biphasic aqueous-organic system was investigated, allowing for the simultaneous solubilization of sugars and fatty acids. Owing to phase separation, the remaining non-acylated glucose was easily separated from the product stream and was refed to the reactor forming a closed-loop system. Productivity in the continuous process was higher compared to a batch one, with space-time yields of up to 1228 ± 65 µmol/L/h. A temperature of 70 • C resulted in the highest glucose-6-O-decanoate concentration in the Packed Bed Reactor (PBR). Consequently, the design of a continuous biocatalytic production is a step towards a more competitive glycolipid synthesis in the aim for industrialization.

A continuous synthesis route of the metal-organic framework (MOF) CPO-27-Ni (also known as Ni 2 (dhtp), Ni/DOBDC or Ni-MOF-74) from aqueous solutions of the nickel acetate and sodium salt of the 2,5-dihydroxyterephtalate linker using tubular reactor techniques has been developed. When running the reaction at 90 °C, a conversion of above 90% is reached in just 20 min. The resulting MOF has a specific surface area (Brunauer-Emmett-Teller [BET]) of around 1085 m 2 /g and a powder X-ray diffraction pattern consistent with the known CPO-27-Ni structure. Scanning electron microscopy clearly shows that crystallite sizes around 40 nm are obtained when using the tubular reactor approach, while state-of-the-art batch synthesis in water typically gives micrometer-sized crystallites as product. The tubular reactor setup can be easily up-scaled by parallelization.

Tetrahydro-β-carbolines were coupled with α-keto vinyl azides through an unprecedented visible light-Ru(bpy) 3 (PF 6 ) 2 /TBHP mediated photocascade strategy that involves photosensitization, photoredox catalysis and [3 + 2] cycloaddition reaction. The scope and scale-up feasibility of the photocascade strategy was demonstrated by synthesizing 18 different fused β-carbolines in moderate to good yields using batch and continuous flow microreactor. This operationally simple synthetic protocol allows the formation of one C-C and two C-N new bonds in the overall transformation.

Makalah ini dilatarbelakangi oleh adanya masalah limbah bahan kimia yang berbahaya dan tidak ramah lingkungan. Sehingga, di sarankan untuk lebih mengoptimalkan kimia hijau dan digitalisasi, baik di laboratorium atau industri kimia, seperti penggunaan flow chemistry berbasis Internet Of Things (iot).

Tributyltin hydride-mediated radical reactions of organic halides were successfully carried out in a continuous flow system using a microreactor. The reactions proceeded within a very short period of time, coupled with quickly decomposing radical initiators such as V-65 and V-70. The continuous flow reaction system was applied to gram scale synthesis of a key intermediate for furofuran lignans. The recent evolution of microreactor technology has presented a fine opportunity for synthetic chemists to use this precisely sophisticated reaction apparatus in place of the venerable glassware batch flasks. 1,2 We previously reported that Pd-catalyzed cross-coupling reactions such as the Sonogashira reaction, 3 the Mizoroki-Heck reaction, 4 and the carbonylative Sonogashira reaction, 5 in which ionic liquids were used as the reaction media, could be successfully carried out using a microreactor in a continuous flow system. We also reported on the effective execution of a [2+2]-type photoinduced cycloaddition reaction 6 and a Barton reaction, using a glass-made microreactor in combination with a compact photoirradiation system using a black light. 7

A chiral dimethylpyridino-18-crown-6 ligand was attached to silica gel by first forming an allyloxy-substituted crown. This material was treated with triethyoxysilane and then coated and covalently attached to silica gel. This report shows the synthesis of the silica gel-bound chiral crown and its use in separating a-(1-naphthyl)ethylammonium perchlorate into its (R)and (S)-forms.

A general outlook of the changing face of chemical synthesis is provided in this article through recent applications of continuous flow processing in both industry and academia. The benefits, major challenges and limitations associated with the use of this mode of processing are also given due attention as an attempt to put into perspective the current position of continuous flow processing, either as an alternative or potential combinatory technology for batch processing.