Organic Chemistry in Microreactors

Flow chemistry: Imidazole-based ionic liquid syntheses in micro-scale

The quarternization of an N-atom in the 1-methyl-imidazole with different alkylating agents was investigated to form so-called Ionic Liquids. (3-Chloropropyl)-trimethoxysilane, 1-chlorobutane, diethyl sulfate and methyl trifluoromethanesulfonate were used as alkylating agents. Reaction kinetics range from very slow to instantaneous and the reaction heat from endothermal to extremely exothermal respectively. The reactions were performed under flow conditions using different types of microstructured reactors as well as pre-structurized reactants in the micro-scale. Unusual heat management with integrated heat pipes allow safer performing of highly exothermal reactions with comparably high thr…

Reactor model for fast reactions in the micro-bubble column and validation

A simple reactor model for predicting conversions in a micro-bubble column is described. It assumes fast reactions so that the gaseous component is readily consumed at the gas-liquid interface. Then, gas-liquid mass transfer becomes determining. As input parameters for the model, the hydrodynamics, specific interfacial area, and mass transport need to be described. Two fast model reactions, the catalytic oxidation of butyraldehyde and the absorption of CO2 in aqueous NaOH, show the applicability of the model but also its limits. The model was used for predicting reaction performance in dependence of operating conditions, in particular to get maximum conversion with the antagonistic paramete…

Microreactor processing for the aqueous Kolbe-Schmitt synthesis of hydroquinone and phloroglucinol

Hydroquinone and phloroglucinol were used as substrates for the aqueous Kolbe-Schmitt synthesis, using a novel processing methodology, termed high-p,T processing, recently demonstrated for the carboxylation of resorcinol. By the high-p,T approach, the temperature limitations of classical batch synthesis, e.g., set by reflux conditions (solvent boiling point), can be overcome by simple technical expenditure, e.g., the use of a few microstructured components, a capillary, and a needle valve at very low internal holdup. In this way, favorable speed-up of chemical reaction is achieved at temperatures normally outside the useful range for organic synthesis. While the hydroquinone synthesis gave …

Heat Pipe-Mediated Control of Fast and Highly Exothermal Reactions

The synthesis of 1-ethyl-3-methylimidazolium ethyl-sulfate ([EMIM]EtSO4) from 1-methyl-imidazole and diethyl sulfate suffers from highly exothermal behavior. Once the activation energy barrier is reached (EA = 89 kJ mol–1), the bimolecular reaction accelerates with a high reaction enthalpy (ΔH = −130 kJ mol–1).(1-3) The excess of heat has to be concurrently dissipated to avoid hot spots or thermal runaways. Depending on the volume flow velocity of the reactants and the applied reactor temperature, the reaction zone can be shifted inside the reactor from the inlet to the outlet and vice versa. Therefore, a sophisticated thermal control, oscillating between providing activation energy and int…

Continuous-Flow Synthesis of Ni(0) Nanoparticles Using a Cone Channel Nozzle or a Micro Coaxial-Injection Mixer

To synthesize nickel(0) nanoparticles by wet chemical reduction using hydrazine with an average size distribution below 100 nm, two different reactor concepts were developed. With a cone channel nozzle, the reactant solutions were sprayed into a batch for further processing and reduction at elevated temperatures. Another concept uses a micro-coaxial injection mixer connected to a heated tube to establish a fully continuously operating reactor. To shorten the time for reduction of the nickel, salt temperatures up to 180 °C are applied. To avoid uncontrolled residence time, the whole system was pressurized up to 80 bar. Approximately 80 L reactant solution, i.e., 1 kg nickel(0) nanoparticles,…

Development of micro chemical, biological and thermal systems in China: A review

The interest in micro technologies for application in chemical, biological and thermal systems has increased considerably in China because microreactors or microfluidics in general demonstrate some remarkably advantages such as inherent miniaturization and portability, intensification of heat and mass transfer, quick analysis results, high-throughput and low consumption of reagents. This review focuses on the recent advances in the micro technologies in China including microreactor-based systems for chemical processing and analysis, biological microfluidics for DNA analysis, cell handling and analysis, separation based detection, protein based applications and immunoassays, micro heat trans…

Fluorenylmethoxycarbonyl-N-methylamino Acids Synthesized in a Flow Tube-in-Tube Reactor with a Liquid-Liquid Semipermeable Membrane

Both steps of the N-methylation of 9-fluorenylmethoxycarbonyl (Fmoc) amino acids were carried out in a microstructured tube-in-tube reactor equipped with a semipermeable Teflon® AF 2400 membrane as the inner tubing. In the first step, gaseous formaldehyde was passed through the inner membrane to effect the acid-catalyzed conversion of the Fmoc amino acids into the corresponding N-Fmoc oxazolidinones. In the second step, liquid–liquid transfer of trifluoroacetic acid was used for the first time in such a reactor for the reductive opening of these oxazolidinones to give Fmoc N-methylamino acids in high yields.

Polymerisationen in mikrostrukturierten Reaktoren: Ein Überblick

Polymerisationen sind in jüngster Zeit als neue Anwendung für die Mikroverfahrenstechnik und Mikrofluidik erschlossen worden. Neben homogenen Polymerisationen im Bulk oder in Lösung gibt es mittlerweile auch Ansätze für heterogene Polymerisationen mittels Miniemulsionstechnik. Zudem können Polymerpartikel mit definierter Größe, Form und Morphologie hergestellt werden. Der Beitrag stellt erste Nutzungen der neuen Technik durch die polymerproduzierende Industrie im Labor- und sogar im Produktionsmaßstab unter Einsatz mikroverfahrenstechnischer Apparate vor.

Kinetic study of ionic liquid synthesis in a microchannel reactor

Abstract A microchannel reaction system, mainly consisting of a micromixer and a tubular reactor, was used to investigate the kinetics of butylation of 1-methyl-imidazole [MIM] for the synthesis of the ionic liquid 1-butyl-3-methylimidazolium bromide ([BMIM]Br). The low variance (σθ2 = 0.019) of the residence time distribution, measured by a step stimuli–response tracer method, implies that this reaction system could be regarded as a plug flow reactor. As a fast and reliable method, the titration of bromide was established to determine the yield of [BMIM]Br. The reaction kinetics was studied by varying the molar ratio of 1-bromobutane [BrBu] to [MIM] (1.04–1.49) and temperature (75–90 °C). …

Active mixing inside double emulsion segments in continuous flow

Fast mixing is essential for many microfluidic applications, especially for flow at low Reynolds numbers. A capillary tube-in-tube coaxial flow setup in combination with a glass microreactor was used to produce immiscible multiphase segments. These double emulsion segments are composed of an organic solvent as the shell (outer) phase and a completely fluorinated liquid (Fluorinert® FC-40) as the core (inner) phase. Due to the higher density of the core droplets, they are responsive to changing their position to the force of gravity (g-force). By gently shaking or jiggling the reactor, the core drop flows very fast in the direction of the g-field without leaving the shell organic phase segme…

Paramagnetic ionic liquids as “liquid fixed-bed” catalysts in flow application

Abstract The structural diversity of Ionic Liquids is well-known and widely used to generate solvents designed for special applications. Magnetic as well as catalytic properties have been described previously. To our best knowledge we report the first time about the combination of both, the magnetic and catalytic behaviour of imidazole based magnetic ionic liquids was used to establish a so-called liquid fixed-bed (LFB) in a micro-/meso-structured reactor. As proof of priciple the esterification of Ac 2 O with cyclohexanol was investigated by bubbling generated regular microdroplets of the reaction mixture through the magnetically fixed ionic liquid catalyst. With residence times of approx.…

Carbanions on Tap – Living Anionic Polymerization in a Microstructured Reactor

The paper describes the living anionic polymerization of styrenes to homo- and diblock copolymers in continuous flow, using a microstructured mixing set-up ("microreactor"). Reaction times and experimental effort are significantly reduced compared to classical batch methods that often require stringent reaction conditions and strict drying of the apparatus by "break-seal" and "high vacuum" techniques. In continuous flow, residual impurities can be removed by purging the reactor with monomer and initiator solution before polymer samples are collected at the device outlet on a scale of up to 200 g.h -1 . Facile molecular weight adjustment is achieved by variation of the flow rates of initiato…

Macromol. Chem. Phys. 10/2009

Hydrothermal Synthesis of Ionic Liquid [Bmim]OH-Modified TiO2 Nanoparticles with Enhanced Photocatalytic Activity under Visible Light

TiO(2) nanocomposites modified with the ionic liquid [Bmim]OH are synthesized by a hydrothermal procedure. X-ray diffraction, Zeta-potential measurement, TEM, thermogravimetric analysis, photoluminescence, UV/Vis, FTIR, and X-ray photoelectron spectroscopy are used to characterize the TiO(2) nanocomposites. The TiO(2) nanocomposites consist of pure anatase particles of about 10 nm. The modification of [Bmim]OH on the surface of the TiO(2) particles extends the TiO(2) absorption edge to the visible-light region. The electrochemical redox potentials indicated that the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of [Bmim]OH match well with the valen…

Ionic Liquids on Demand in Continuous Flow

We report on the development of an alternative protocol for the facile, solvent-free synthesis of various novel imidazolium-based ionic liquids (ILs) that affords highly pure products without the necessity of subsequent purification steps. The continuous approach is based on the combination of HPLC pumps with a micromixer and a capillary residence tube. Our system provides a high degree of control over the alkylation reactions due to a high surface-to-volume ratio and superior heat and mass transport. Within the scope of our studies, we focused on ionic liquids containing differently substituted phenyl rings and characterized these compounds with respect to further use for direct applicatio…

Enhanced [4+2] cycloadditions by solvophobic effects and gravity-induced mixing in core-shell droplets

A new way to perform reactions in core—shell double emulsions is reported herein. The phase boundaries of the threephase droplet flow were used to pressurize the reactants in the shell liquid, enhancing the reaction rate of a cycloaddition greatly in comparison to known methods. As key parameters, solvophobic effects and precise control over the droplet sizes were used to exploit a reaction with a negative volume of activation. The internal pressure of the reaction solution was regulated purely by the thickness of the shell liquid without adding additional reagents. Additionally, the reaction performed better when the core droplet was used to stir the shell droplet, considerably improving t…

Preferential CO oxidation over catalysts with well-defined inverse opal structure in microchannels

Catalyst supports of CeO 2 /SiO 2 and Al 2 O 3 with three-dimensionally ordered macroporous structure were fabricated in microchannels by application of PMMA opals as templates. Pt-Rh supported on CeO 2 /SiO 2 showed high efficiency for CO removal in preferential CO oxidation in the presence of excess hydrogen. Pt-Rh supported on Al 2 O 3 with an inverse opal structure showed higher reactivity than that supported on wash-coated Al 2 O 3 layers in microchannel reactor.

Palladium-Catalyzed Carbon–Carbon Cross-Coupling Reactions in Thermomorphous Double Emulsions

The method of combining the concept of fluorous biphasic catalysis (FCB) with micro multiple emulsions benefits from the advantages of homogeneous as well as from heterogeneous catalysis in continuous micro flow. In this particular case, three immiscible fluid phases in continuous micro segmented flow were used to perform palladium-catalyzed Heck crosscoupling reactions of styrene with aryl halides. A capillary tube-in-tube coaxial flow setup in combination with a glass micro reactor was used to produce monodisperse aqueous phase/organic phase/perfluorinated phase double emulsions. The resulting emulsions had a core-shell droplet structure composed of a perfluorcarbon fluid in which a palla…

Introducing an amine functionality at the block junction of amphiphilic block copolymers by anionic polymerization strategies

A series of block copolymers bearing a single amino in-chain functionality was synthesized via anionic polymerization of styrene and ethylene oxide. By means of both a conventional and a continuous setup, living polystyrene was quantitatively end functionalized with an oxirane (DBAG) prior to the polymerization of the poly(ethylene oxide) segment. The in-chain amine was conjugated with a fluorescent dye.

C-Glycosyl amino acids through hydroboration-cross-coupling of exo-glycals and their application in automated solid-phase synthesis.

O-Glycosylation is one of the most important post-translational modifications of proteins. The attachment of carbohydrates to the peptide backbone influences the conformation as well as the solubility of the conjugates and can even be essential for binding to specific ligands in cell-cell interactions or for active transport over membranes. This makes glycopeptides an interesting class of compounds for medical applications. To enhance the long-term availability of these molecules in vivo, the stabilization of the glycosidic bond between the amino acid residue and the carbohydrate is of interest. The described modular approach affords β-linked C-glycosyl amino acids by a sequence of Petasis …

Opening of New Synthetic Routes Using Segmented Microflow in Multistep Syntheses

The application of microfluidics in organic chemistry is a valuable tool to access new synthesis pathways and to break limitations set by traditional batch chemistry. In the past, the majority of research focused on solving problems associated with individual reactions. It is necessary to advance the field by incorporating flow chemistry in longer multistep syntheses to open more direct paths towards complicated compounds. Several strategies were developed to meet the demands of a four-step synthesis, which includes biphasic nitrations, gaseous substrates, and very fast reactions on multifunctional molecules. A unique micro flow setup was applied in each reaction to meet its specific requir…

Industrial Microreactor Process Development up to Production

This chapter is about industrial applications of microprocess technology. Industry is not very active in publishing not only because of confidentiality reasons but also because of the absence of direct need for a corresponding profile. Thus, one cannot expect that the ongoing developments can be shown with a similar degree of completeness, clarity and detailedness, as this is possible for reviewing scientific contributions from academy with a wealth of peer-reviewed papers. Especially, the information of major interest of what has been transferred to production and how do the companies make profit with the new technology is usually kept secret. Thus, it has to be accepted that some informat…

Multihydroxyl-Functional Polystyrenes in Continuous Flow

We describe the synthesis of end-functionalized polystyrenes by living anionic polymerization in a microstructured reactor via termination by acetal-protected functional epoxides. Initiation of styrene polymerization by alkyllithium takes place in a micromixing device with efficient heat and mass transfer properties. A newly developed continuous polymerization−termination sequence enabled quantitative functionalization of the living carbanions by nucleophilic displacement with different, specifically designed glycidyl ethers (ethoxy ethyl glycidyl ether (EEGE), 1,2-isopropylidene glyceryl glycidyl ether (IGG), and trans-2-phenyl-1,3-dioxane glycidyl ether (PDGE)). Upon acidic hydrolysis the…

Hydrothermal synthesis of well-dispersed ultrafine N-doped TiO2 nanoparticles with enhanced photocatalytic activity under visible light

Abstract Ultrafine nitrogen-doped TiO 2 nanoparticles with narrow particle size distribution, good dispersion, and high surface area were synthesized in the presence of urea and PEG-4000 via a hydrothermal procedure. TEM observation, N 2 adsorption, XRD, UV–vis spectroscopy, the Raman spectroscopy and XPS analysis were conducted to characterize the synthesized TiO 2 particles. The synthesized TiO 2 particles were a mixture of 49.5% anatase and 50.5% rutile with a size of around 5 nm. The photocatalytic activities were tested in the degradation of an aqueous solution of a reactive Brilliant Blue KN-R under both UV and visible light. The synthesized TiO 2 particles showed much higher photocat…

Microflow Technology in Polymer Synthesis

Microflow technology, i.e., the use of microfluidic devices for continuous flow synthesis, represents a highly useful and increasingly popular method in organic chemistry. Recently, also an increasing number of polymer synthesis protocols attain benefit from this technique. In particular, the control of highly exothermic, fast polymerization reactions can be improved due to the excellent heat and mass transfer within the small dimensions of the microreactors. Continuous flow setups with different micromixer geometries and flow patterns are currently used for the preparation of a variety of macromolecular architectures by ionic and (controlled) radical polymerization techniques. This Perspec…

Heat Pipe-Cooled Microstructured Reactor Concept for Highly Exothermal Ionic Liquid Syntheses

Heat pipes used for cooling of microstructured reactors are a new approach for sustainable processing also in the lab-scale within a temperature range from ambient to more than 180 °C. The main advantage of heat pipe cooling is the dynamic behavior, i.e., the cooling rate depends on the heat released. Heat pipes can also suppress thermal runaways due to their extremely short response times on momentary temperature rises. As an example, the highly exothermal synthesis of 1-ethyl-3-methylimidazolium trifluoromethanesulfonate from the respective reactants 1-ethyl-imidazole and methyltrifluoromethanesulfonate was investigated. By transferring the protocol to continuous-flow conditions in the mi…

Heat pipe controlled syntheses of ionic liquids in microstructured reactors

Abstract The combination of a heat pipe and a microstructured reactor allows to perform highly exothermal reactions under safe conditions. First experiments for the synthesis of 1,3-dimethylimidazolium-triflate from 1-methylimidazol and methyl triflate showed that at high flow rates of more than 5 ml/min through a single 300 μm × 500 μm wide and 400 mm long channel quantitative conversion could be achieved. This chemical reaction, known for extreme heat release, can be retained under thermal control even at much higher flow rates.

Nitroxyl Radical‐Mediated Oxidation of Alcohols in Continuous Microreactors

Synthesis of Hyperbranched Polyglycerol in a Continuous Flow Microreactor

Hyperbranched polymers have been synthesized in a microreactor for the first time, employing the known ring-opening multibranching polymerization of glycidol. Microreactors are well-known to be beneficial for highly exothermic reactions because of their capability to enhance mass and heat transfer due to short diffusion pathways and large interfacial areas per volume. The characteristics of the microstructured reaction system were utilized to engineer a continuous flow process for the preparation of well-defined hyperbranched polyglycerols with molecular weights up to 1,000 g/mol. Increased flow rates, as well as the use of highly polar solvents, led to the partial formation of very narrowl…

Fluorenylmethoxycarbonyl-ProtectedO-Glycosyl-N-methyl Amino Acids: Building Blocks for the Synthesis of Conformationally Tuned Glycopeptide Antigens

Peptide antibiotics often contain N-methylated amino acids. These N-methylamino components enhance the metabolic stability and strongly influence the conformational behavior of these peptide drugs. N-Methyl-O-glycosyl amino acids, in particular, threonine and serine derivatives, are unknown so far. Fmoc-protected N-methyl-O-glycosyl-threonine and -serine building blocks, including sialyl TN antigens, have been synthesized for the first time by converting the Fmoc-protected O-glycosyl amino acids or their tert-butyl esters into the corresponding oxazolidinones followed by reductive ring-opening. These new components are considered interesting for the construction of modified mucin glycopepti…

Synthesis of Fluorinated Glycosyl Amino Acid Building Blocks for MUC1 Cancer Vaccine Candidates by Microreactor-Assisted Glycosylation

Abstract MUC1-type glycopeptides have already shown their potential as possible cancer vaccine candidates. In addition, first examples of fluorinated antigen structures, especially containing the Thomsen–Friedenreich antigen, with similar antibody recognition have been reported. Using microreactor techniques for improvement of the crucial step, the complex glycosylation reactions, is an efficient way to find optimized reaction parameter as well as to circumvent well-known scale-up drawbacks. Besides, this is the first report of continuous flow glycosylations of glycosyl amino acids, in particular with fluorinated glycosyl building blocks.

Synthesis of Defined Poly(silsesquioxane)s: Fast Polycondensation of Trialkoxysilanes in a Continuous-Flow Microreactor

The polycondensation of trialkoxysilanes to PSSQs in a microreactor setup is demonstrated. While continuous-flow processes involving microreactors found various applications in chain growth polymerization, their influence on step-growth polymerization is less explored, and the polycondensation of multifunctional monomers has not been studied in detail. We found significantly increased yields and a decreased polydispersity of the obtained polymers in comparison to the batch process. By variation of the residence time molecular weights could be adjusted reproducibly ranging from M n =1900 to 11000 g · mol -1 . Thus, the microreactor setup offers for the first time the possibility to synthesiz…

CCDC 920035: Experimental Crystal Structure Determination

Related Article: Stefan Koch, Dieter Schollmeyer, Holger Löwe, Horst Kunz|2013|Chem.-Eur.J.|19|7020|doi:10.1002/chem.201300150