Flow Microreactor System Research Articles

Controlled nucleophilic aromatic substitution of hexafluorobenzene using a flow microreactor

Nucleophilic aromatic substitution (SNAr) contributes to creating a variety of useful materials. It is well-known that selective SNAr reactions of perfluorinated aromatics such as hexafluorobenzene with nucleophiles are difficult to achieve using conventional macro batch systems due to the contamination of the di-substituted products. To take advantage of flow microreactor system, we succeeded in the controlled SNAr reactions of hexafluorobenzene with organolithiums employing continuous flow reactors.

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling.

Nitration of O-methylisouronium sulfate under mixed acid conditions gives O-methyl-N-nitroisourea, a key intermediate of neonicotinoid insecticides with high application value. The reaction is a fast and highly exothermic process with a high mass transfer resistance, making its control difficult and risky. In this paper, a homogeneous continuous flow microreactor system was developed for the nitration of O-methylisouronium sulfate under high concentrations of mixed acids, with a homemade static mixer eliminating the mass transfer resistance. In addition, the kinetic modeling of this reaction was performed based on the theory of NO2 + attack, with the activation energy and pre-exponential factor determined. Finally, based on the response surface generated by the kinetic model, the reaction was optimized with a conversion of 87.4% under a sulfuric acid mass fraction of 94%, initial reactant concentration of 0.5 mol/L, reaction temperature of 40 °C, molar ratio of reactants at 4.4:1, and a residence time of 12.36 minutes.

Recent advances in fluorine chemistry using flow technology

Organofluorine compounds have proven to play an important role in pharmaceutical, agrochemical, and functional materials owing to their unique properties. However, the synthesis of these compounds is often challenging due to the difficulties in handling fluorinating agents and controlling their reactivity precisely. Recently, flow microreactor systems have attracted significant attention from chemists as a highly efficient synthetic methodology. In this review, we summarize recent advances in fluorine chemistry facilitated by continuous flow technology, highlighting its advantages and potential applications in streamlined synthesis of organofluorine compounds.

Efficient lignin depolymerization by continuous flow microreactor-assisted electrochemical advanced oxidation in water/co-solvent system

The employment of EAOP using a continuous flow microreactor for efficient lignin depolymerization under ambient conditions.

Scaling-up of carbon dots hydrothermal synthesis from sugars in a continuous flow microreactor system for biomedical application as in vitro antimicrobial drug nanocarrier

ABSTRACT Carbon dots (CDs) are a new class of nanomaterials exhibiting high biocompatibility, water solubility, functionality, and tunable fluorescence (FL) property. Due to the limitations of batch hydrothermal synthesis in terms of low CDs yield and long synthesis duration, this work aimed to increase its production capacity through a continuous flow reactor system. The influence of temperature and time was first studied in a batch reactor for glucose, xylose, sucrose and table sugar precursors. CDs synthesized from sucrose precursor exhibited the highest quantum yield (QY) (175.48%) and the average diameter less than 10 nm (~6.8 ± 1.1 nm) when synthesized at 220°C for 9 h. For a flow reactor system, the best condition for CDs production from sucrose was 1 mL min−1 flow rate at 280°C, and 0.2 MPa pressure yielding 53.03% QY and ~ 6.5 ± 0.6 nm average diameter (6.6 mg min−1 of CDs productivity). CDs were successfully used as ciprofloxacin (CP) nanocarrier for antimicrobial activity study. The cytotoxicity study showed that no effect of CDs on viability of L-929 fibroblast cells was detected until 1000 µg mL−1 CDs concentration. This finding demonstrates that CDs synthesized via a flow reactor system have a high zeta potential and suitable surface properties for nano-theranostic applications.

Heterogeneous nitration of nitrobenzene in microreactors: Process optimization and modelling

Aromatic nitration with mixed acid is an important step in the industrial synthesis of basic industrial chemicals, while the highly exothermic and heterogeneous nature of the reaction renders difficulties in achieving high safety and efficiency. In this work, a continuous flow microreactor system was developed for the nitration of nitrobenzene. Under the premise of high conversion and selectivity, the reaction time and temperature were reduced from more than 2 h and 80 ℃ in industrial operation to 10 min and 65 ℃ in microreactors, respectively. The reaction mechanism was verified that the reaction took place not only in the bulk aqueous phase but also at the phase interface. The kinetic parameters were then determined based on the assumption of pseudo-homogeneous reaction mixture. These findings may shed important insights into the high degree of controllability of nitration for a better process design and reactor optimization.

Kinetics of glyoxal oxidation by nitric acid in a capillary microreactor

Aiming at solving the problems of long operation periods, low selectivity, and low safety in the traditional batch reactor, a method of oxidation reaction of glyoxal with nitric acid through a continuous flow microreactor is proposed, with high selectivity. The method utilizes the excellent performance of mass and heat transfer in the microreactor, to improve the reaction efficiency, selectivity, and safety. The effects of the mixing performance, the molar ratio of reactants, temperature, residence time, and mass fraction of nitric acid on the oxidation of glyoxal with nitric acid are investigated, and the optimum reaction conditions are determined. The glyoxylic acid yield can reach 81.6% while the selectivity is 92.4% with the set residence time of only 7.9 min at 68 ℃ (the molar ratio of nitric acid to glyoxal is 1.4, sodium nitrite to glyoxal is 0.15, hydrochloric acid to glyoxal is 0.2, and the mass concentration of nitric acid is 35%). The apparent kinetic model of the oxidation reaction of glyoxal with nitric acid in a microchannel reactor is established. By precisely controlling the reaction temperature and residence time of the continuous flow microreactor system, the apparent reaction rate constants, pre-exponential factor, and activation energy of glyoxal oxidation to glyoxylic acid by nitric acid are obtained. This work paves the way for the promotion of the synthesis of glyoxylic acid in a microreactor by the continuous flow chemistry system.

Anionic synthesis and end-functionalization of polymyrcene in a flow microreactor system

The synthesis of functionalized polymyrcene, from bio-based myrcene and from carbon dioxide, is performed, thanks to the unique features of microflow systems.

MCM-41-Type Mesoporous Silicas Modified with Alumina in the Role of Catalysts for Methanol to Dimethyl Ether Dehydration

MCM-41-type mesoporous silicas were modified with alumina by the impregnation, co-condensation, and template ion-exchange (TIE) methods. The obtained materials were characterized with respect to their chemical composition (ICP-OES), textural parameters (low-temperature N2 sorption), structure (XRD), and surface acidity (NH3-TPD) and tested as catalysts of methanol to dimethyl ether (DME) dehydration in a flow microreactor system. The catalytic performance of the studied materials was analyzed with respect to their porous structure, as well as their density and the strength of their acid sites. It was shown that the performance of the studied catalysts depends on the contribution of the surface exposed aluminum species, as well as their aggregation. For the most active catalyst, the study of its catalytic stability under rection conditions was performed. It was shown that the catalyst can be effectively regenerated by the incineration of carbon deposits under air flow at 550 °C for 1 h.

Pentafluoroethylation of Carbonyl Compounds Using HFC-125 in a Flow Microreactor System.

The protocol of micro-flow nucleophilic pentafluoroethylation using pentafluoroethane (HC2F5, HFC-125), a nontoxic, inexpensive, and commercially available greenhouse gas, is described. The micro-flow pentafluoroethylation by HFC-125 proceeded smoothly at room temperature or at -10 °C in DMF or toluene in the presence of a potassium base, namely, t-BuOK or KHMDS. A broad range of ketones, aldehydes, and chalcones with various substituted benzene rings were successfully converted to the corresponding pentafluoroethyl carbinols instantly with good to high yields.

Improving the reaction efficiency of condensation amidation of piperazine with benzoic acid based on kinetics study in microreactors

Here we developed a continuous flow microreactor system to synthesis N-benzoylpiperazine, which is an important intermediate of novel nootropic Sunifiram. And the kinetics of the condensation amidation of piperazine and benzoic acid using HATU as coupling reagent was revealed in microreactor. A kinetic model was established, all the reactions kinetics parameters, including the reaction order of each reactant, rate constants, pre-exponential factors and activation energies were acquired. With this model the selectivity vs. reaction temperature/molar flow ratio were obtained to help understand this kind of reaction and further optimize operating conditions. Under the condition of using equivalent piperazine, 95.6% of selectivity and 91.2% of yield were obtained in microreactor with 50 s. To further expand the scope of carboxylic acid, cyclopropanecarboxylic acid was tried as acylating agent, and 92.8% of selectivity and 86.1% of yield were obtained in microreactor.

Enhanced Hydroformylation in a Continuous Flow Microreactor System

A microreactor system consisting of a honeycomb microreactor and microtubing was proposed to enhance the Rh-biphephos catalyzed hydroformylation of 1-hexene. The effects of various reaction paramet...

A Novel Approach to Functionalization of Aryl Azides through the Generation and Reaction of Organolithium Species Bearing Masked Azides in Flow Microreactors

AbstractA novel straightforward method for aryl azides having functional groups based on generation and reactions of aryllithiums bearing a triazene group from polybromoarenes using flow microreactor systems was achieved. The present approach will serve as a powerful method in organolithium chemistry and open a new possibility in the synthesis of polyfunctional organic azides.

A Novel Approach to Functionalization of Aryl Azides through the Generation and Reaction of Organolithium Species Bearing Masked Azides in Flow Microreactors.

A novel straightforward method for aryl azides having functional groups based on generation and reactions of aryllithiums bearing a triazene group from polybromoarenes using flow microreactor systems was achieved. The present approach will serve as a powerful method in organolithium chemistry and open a new possibility in the synthesis of polyfunctional organic azides.

Compact Steam-Methane Reforming for the Production of Hydrogen in Continuous Flow Microreactor Systems

The implementation of fuel cell deployment requires efficient conversion of fuels into hydrogen in a distributed energy system. Fortunately, continuous flow and microreactor technology provide unique opportunities for the portable production of hydrogen. This study focuses on determining the operation space for a thermally integrated methane reforming system, thereby providing a theoretical basis for the design and optimization of such systems. The steam-methane reforming over rhodium coupled with methane combustion over platinum in a thermally integrated microchannel reactor arranged with rectangular-shaped protuberances was studied numerically in order to improve its operability and stability. Computational fluid dynamic simulations were carried out with detailed reaction mechanisms to identify conditions for the maximum hydrogen yield and the highest output power. Various operating lines were presented, and various performance metrics were evaluated accordingly. The results indicated that the efficient production of hydrogen is made possible through improving transport performance for highly active catalysts. The flow disturbance elements designed for the reactor are of great benefit to intensification of the reforming process. There exists a trade-off between fuel utilization and output power. Autothermal operation advantages from improved transport performance in small physical dimensions were demonstrated for the system, but careful thermal management is always necessary to ensure its efficient and stable operation. The thermal conductivity of the wall separating the exothermic and endothermic reactions plays a significant role in determining the performance of the system. Highly active catalysts are required to intensify the overall reforming process and to achieve efficient thermal management. Adjustment of fluid velocities can serve as a convenient means to achieve efficient operation of the system.

Generation and Reaction of Functional Alkyllithiums by Using Microreactors and Their Application to Heterotelechelic Polymer Synthesis.

Flow microreactors enabled the successful generation of various functional alkyllithiums containing electrophilic functional groups, as well as the use of these alkyllithiums in subsequent reactions. The high reactivity of these series of reactions could be achieved by the extremely accurate and selective control of residence time. Moreover, integrated flow microreactor systems could be used to successfully synthesize heterotelechelic polymers with two functionalities, one at each end, via a process involving controlled anionic polymerization initiated by functional alkyllithium compounds, followed by trapping reactions with difunctional electrophiles.

Front Cover Picture: Toward Automated Enzymatic Glycan Synthesis in a Compartmented Flow Microreactor System (Adv. Synth. Catal. 19/2019)

The front cover picture, provided by Matthias Franzreb and Lothar Elling, and their co-workers, illustrates the automated enzymatic synthesis of the non-sulfated human natural killer cell-1 (HNK-1) glycan epitope. A cascade of compartmented magnetic enzyme beads (MEBs) in a microfluidic flow microreactor system resulted in a high-yield glycan synthesis. Expanding the repertoire of MEBs for other glycosyltransferases and enzymes for nucleotide sugar synthesis has the potential for a fully automated and programmed enzymatic glycan synthesis. Details of this work can be found in the Full Paper on pages 4506–4516 (R. Heinzler, T. Fischöder, L. Elling, M. Franzreb, Adv. Synth. Catal. 2019, 361, 4506–4516; DOI: 10.1002/adsc.201900709).

Anionic Polymerization of Acrylonitrile Using a Flow Microreactor System

A simple flow microreactor system has been applied in the anionic polymerization of acrylonitrile initiated by lithium diisopropylamide. Polyacrylonitrile (PAN) with high molecular weight and narrow molecular weight distribution (MWD) has been obtained successfully in the system for the first time. A better control over the MWD of obtained PAN has achieved (1.49–1.93) compared with that in conventional lab-scale reactors (MWD = 2.00–2.46). Side reactions could be suppressed obviously even at higher temperatures, which was demonstrated by the 1H NMR spectra. Furthermore, the polymerization time could be regulated conveniently in the flow microreactor system and the living feature of the polymerization has been verified from the relationship of monomer conversion and molecular weight of PAN products obtained at different reaction time.

Toward Automated Enzymatic Glycan Synthesis in a Compartmented Flow Microreactor System

AbstractImmobilized microfluidic enzyme reactors (IMER) are of particular interest for automation of enzyme cascade reactions. Within an IMER, substrates are converted by paralleled immobilized enzyme modules and intermediate products are transported for further conversion by subsequent enzyme modules. By optimizing substrate conversion in the spatially separated enzyme modules purification of intermediate products is not necessary, thus shortening process time and increasing space‐time yields. The IMER enables the development of efficient enzyme cascades by combining compatible enzymatic reactions in different arrangements under optimal conditions and the possibility of a cost‐benefit analysis prior to scale‐up. These features are of special interest for automation of enzymatic glycan synthesis. We here demonstrate a compartmented flow microreactor system using six magnetic enzyme beads (MEBs) for the synthesis of the non‐sulfated human natural killer cell‐1 (HNK‐1) glycan epitope. MEBs are assembled to build compartmented enzyme modules, consisting of enzyme cascades for the synthesis of uridine 5′‐ diphospho‐α‐ d‐galactose (UDP‐Gal) and uridine 5′‐diphospho‐α‐d‐glucuronic acid (UDP‐GlcA), the donor substrates for the Leloir glycosyltransferases β4‐galactosyltransferase and β3‐glucuronosyltransferase, respectively. Glycan synthesis was realized in an automated microreactor system by a cascade of individual enzyme module compartments each performing under optimal conditions. The products were analyzed inline by an MS‐system connected to the microreactor. The high synthesis yield of 96% for the non‐sulfated HNK‐1 glycan epitope indicates the excellent performance of the automated enzyme module cascade. Furthermore, combinations of other MEBs for nucleotide sugars synthesis with MEBs of glycosyltransferases have the potential for a fully automated and programmed glycan synthesis in a compartmented flow microreactor system.magnified image

Identification of kinetic models of methanol oxidation on silver in the presence of uncertain catalyst behavior

AbstractCatalytic oxidation of methanol to formaldehyde is an important industrial process due to the value of formaldehyde either as a final product or as a precursor of numerous chemicals. The study of kinetics in this system is hindered by sources of uncertainty that are inherently associated to the nature and state of the catalyst (e.g., uncertain reactivity level, deactivation phenomena), the measurement system and the structure of the kinetic model equations. In this work, a simplified kinetic model is identified from data collected from continuous flow microreactor systems where catalysts with assorted levels of reactivity are employed. Tailored model‐based data mining methods are proposed and applied for the effective estimation of the kinetic parameters and for identifying robust experimental conditions to be exploited for the kinetic characterization of catalysts with different reactivity, whose kinetic behavior is yet to be investigated.