Microreactors For Synthesis Research Articles

Opportunities and Challenges in the Synthesis of Noble Metal Nanoparticles via the Chemical Route in Microreactor Systems.

The process of noble metal nanoparticle synthesis is complex and consists of at least two steps: slow nucleation and fast autocatalytic growth. The kinetics of these two processes depends on the reductant "power" and the addition of stabilizers, as well as other factors (e.g., temperature, pH, ionic strength). Knowing these parameters, it is possible to synthesize materials with appropriate physicochemical properties, which can be simply adjusted by the type of the used metal, particle morphology and surface property. This, in turn, affects the possibility of their applications in various areas of life, including medicine, catalysis, engineering, fuel cells, etc. However, in some cases, the standard route, i.e., the chemical reduction of a metal precursor carried out in the batch reactor, is not sufficient due to problems with temperature control, properties of reagents, unstable or dangerous intermediates and products, etc. Therefore, in this review, we focused on an alternative approach to their chemical synthesis provided by microreactor systems. The use of microreactors for the synthesis of noble metal nanomaterials (e.g., Ag, Au, Pt, Pd), obtained by chemical reduction, is analyzed, taking into account investigations carried out in recent years. A particular emphasis is placed on the processes in which the use of microreactors removed the limitations associated with synthesis in a batch reactor. Moreover, the opportunities and challenges related to the synthesis of noble nanomaterials in the microreactor system are underlined. This review discusses the advantages as well as the problems of nanoparticle synthesis in microreactors.

Development of an Impinging Jet Microreactor Synthesis Process for Surfactant‐free Pt‐Nanoparticles as PEMFC Catalyst Component

Colloidal, surfactant‐free platinum nanoparticles were prepared via a self‐built continuous impinging jet microreactor synthesis process in alkaline aqueous methanol solution (Co4CatTM process). In these syntheses, methanol functions as a reducing agent as well as an additional solvent. Especially the synthesis of surfactant‐free nanoparticles remained challenging, and additionally, the transfer of this synthesis into a continuous process required several optimization steps. In this contribution we present highly controllable final particle sizes by adjusting process temperature, platinum precursor concentration and molar ratio of the hydroxide and platinum precursor used. The size objective of the surfactant‐free Pt nanoparticles was a range of 1 – 10 nm, due to the intended application in various catalytic processes, especially as PEMFC electrocatalyst. Dynamic light scattering (DLS), ζ‐potential measurements, transmission electron microscopy (TEM) and UV/Vis spectroscopy were used to monitor the particle stability over a certain period of time and study the rate of the reduction reaction in more detail.

Continuous alkylation of 1,3,5-trihydroxy-2,4,6-trinitrobenzene in microreactor: Process intensification and reaction kinetics

1,3,5-triamino-2,4,6-trinitrobenzene (TATB) is an essential insensitive energetic material. The alkylation of 1,3,5-trihydroxy-2,4,6-trinitrobenzene (Trinitrophloroglucinol, TNPG), which yields 1,3,5-triethoxy-2,4,6-trinitrobenzene (TETNB), is a pivotal step for the synthesis of TATB. The conventional synthetic process has suffered from long reaction time (∼165 min), intricate procedures, and intensive evaporation of a large number of volatile by-products, which increases the risk of spill and eruption of the reaction system, and necessitates in situ continuous gas–liquid separation. A new process for continuous alkylation in microreactors was proposed in this study. Firstly, a parametric investigation in the batch reactor was performed to explore the effects of various process parameters on the yields, resulting in the optimal experimental conditions, i.e., no reflux condensation, triethyl orthoformate (TEOF) as alkylation reagent, molar ratio of 12, reaction temperature of 120 °C and reaction time of 40 min. Subsequent continuous synthesis in microreactors was conducted, which realized the convenient process operation and no need of gas–liquid separation, leading to substantial improvement in the reaction efficiency and safety. Remarkably, within a packed microreactor, under the reaction temperature of 130 °C and residence time of 3 min, 99.24 % in the yield of TETNB was achieved. Comparing with conventional batch reactors, the required reaction time was reduced to approximately 1/50. Taking the advantages of precise control of temperature and reaction time in the microreactors, the kinetics of alkylation reaction were determined. This innovative approach of continuous synthesis can provide an efficient and alternative route for the synthesis of TATB, as well as other energetic materials and similar processes.

Internal flow in sessile droplets induced by substrate oscillation: towards enhanced mixing and mass transfer in microfluidic systems

The introduction of flows within sessile droplets is highly effective for many lab-on-a-chip chemical and biomedical applications. However, generating such flows is difficult due to the typically small droplet volumes. Here, we present a simple, non-contact strategy to generate internal flows in sessile droplets for enhancing mixing and mass transport. The flows are driven by actuating a rigid substrate into oscillation with certain amplitude distributions without relying on the resonance of the droplet itself. Substrate oscillation characteristics and corresponding flow patterns are documented herein. Mixing indices and mass transfer coefficients of sessile droplets on the substrate surface are measured using optical and electrochemical methods. They demonstrate complete mixing within the droplets in 1.35 s and increases in mass transfer rates of more than seven times static values. Proof of concept was conducted with experiments of silver nanoparticle synthesis and with heavy metal ion sensing employing the sessile droplet as a microreactor for synthesis and an electrochemical cell for sensing. The degrees of enhancement of synthesis efficiency and detection sensitivity attributed to the internal flows are experimentally documented.

Microfluidically Produced Microcapsules with Amphiphilic Polymer Conetwork Shells

AbstractMicrocapsules with an aqueous core can be conveniently prepared by water‐in‐oil‐in‐water double emulsion microfluidics. However, conventional shell materials are based on hydrophobic polymers or colloidal particles. Thus, these microcapsules feature a hydrophobic shell impermeable to water‐soluble compounds. Capsules with semipermeable hydrogel shells have been demonstrated but may exhibit poor mechanical properties. Here, amphiphilic polymer conetworks (APCNs) based on poly(2‐hydroxyethyl acrylate)‐linked by‐polydimethylsiloxane (PHEA‐l‐PDMS) are introduced as a new class of wall materials in double emulsion microcapsules. These APCNs are mechanically robust silicone hydrogels that are swellable and permeable to water and are soft and elastic when dry or swollen. Therefore, the microcapsules can be dried and rehydrated multiple times or shrunken in sodium chloride salt solutions without getting damaged. Moreover, the APCNs are permeable for hydrophilic organic compounds and impermeable for macromolecules. Thus, they can be loaded with macromolecules or nanoparticles during microfluidic formation and with organic molecules after capsule synthesis. The microcapsules serve as microreactors for catalytically active platinum nanoparticles that decompose hydrogen peroxide. Finally, the surface of the APCN microcapsules can be selectively functionalized with a cholesterol‐based linker. Concluding, APCN microcapsules could find applications for the controlled delivery of drugs, as microreactors for synthesis, or as scaffolds for synthetic cells.

Control over selectivity for demethylation in dolutegravir synthesis in microreactors: Kinetics and mechanisms

Demethylation of DTG-7 (i.e., an intermediate of an anti-HIV medication dolutegravir (DTG)) is the final step in the DTG synthesis, but its reaction network and kinetic investigations have not been reported yet. In this work, we established the reaction kinetic model of this system based on experimental data from microreactors, according with the demethylation mechanism of the complex ion formation and transformation examined by density functional theory (DFT) calculation. Due to limited solubility of the intermediate product (i.e., organolithium), various parameters were screened to reach a high DTG yield of 98.5 % at a residence time of 12 min without microreactor clogging. Detailed kinetic investigation of DTG-7 demethylation and ring-opening side reaction revealed that precise control over the temperature and residence time in the cascade microreactor system facilitated high selectivity and DTG yield with short residence times. Finally, an operating window was established for process optimization based on the kinetic model.

Microreactor-based micro/nanomaterials: fabrication, advances, and outlook.

Micro/nanomaterials are widely used in optoelectronics, environmental materials, bioimaging, agricultural industries, and drug delivery owing to their marvelous features, such as quantum tunneling, size, surface and boundary, and Coulomb blockade effects. Recently, microreactor technology has opened up broad prospects for green and sustainable chemical synthesis as a powerful tool for process intensification and microscale manipulation. This review focuses on recent progress in the microreactor synthesis of micro/nanomaterials. First, the fabrication and design principles of existing microreactors for producing micro/nanomaterials are summarized and classified. Afterwards, typical examples are shown to demonstrate the fabrication of micro/nanomaterials, including metal nanoparticles, inorganic nonmetallic nanoparticles, organic nanoparticles, Janus particles, and MOFs. Finally, the future research prospects and key issues of microreactor-based micro/nanomaterials are discussed. In short, microreactors provide new ideas and methods for the synthesis of micro/nanomaterials, which have huge potential and inestimable possibilities in large-scale production and scientific research.

High-efficiency and safe synthesis of tonalid via two Friedel-Crafts reactions in continuous-flow microreactors

Tonalid, an important fragrance ingredient with widespread application, was synthesized via two Friedel-Crafts reactions, which were catalyzed by AlCl 3 . The traditional tonalid production was conducted in batch stirring tank reactors, suffering from low production capacity and the safety hazard of temperature runaway. To solve these problems, the continuous-flow technologies were developed for the high-efficiency and intrinsically safe synthesis of tonalid in microreactors. Catalyst AlCl 3 was neatly homogenized in proper solvents by forming complex with reactant, which was a necessary step for the continuous synthesis in microreactors. Several reaction conditions, including reactant molar ratio, catalyst concentration, temperature, and microchannel hydrodynamic diameter, were investigated for the two Friedel-Crafts reactions in microreactors. At optimized conditions, the yields of the two Friedel-Crafts reactions were 44.15% and 97.55%, respectively. In comparison with the batch reactors, the reaction times of these two reactions could both be reduced by nearly two thirds in microreactors at the similar yield.

Synthesis of Lobeglitazone intermediates seeking for continuous drug production in flow capillary microreactor

Continuous flow synthesis in microreactors has been integrated into chemical-pharmaceutical industry in recent years as an alternative to the batch process due to its advantages, especially process intensification, which can reduce the time for a new drug to be placed on the market on a large scale. This work aimed to transpose the synthesis of Lobeglitazone, a drug employed in the treatment of diabetes mellitus type 2, from batch to flow process in a microreactor as well as to determine the reaction kinetics of each step. The synthesis was carried out in five-steps, being synthesized intermediates 4-chloro-6-(4-methoxyphenoxy)pyrimidine (I1), 2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethanol (I2), 4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzaldehyde (I3), 5-[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzylidene]thiazolidine-2,4-dione (I4) and Lobeglitazone. Intermediates I1 and I4 were synthesized in flow, while I4 was synthesized either in a continuous flow multistep synthesis or in a one-pot batch process. The flow syntheses of I1, I2 and I4 showed 28.0 %, 61.8 % and 32.0 % yields at 25, 160 and 120 °C, respectively, while the yield of I3 in batch process was 73.3 % at 60 °C. In one-pot batch process and continuous flow multistep synthesis, I2 was obtained with 13 and 16 % yields, respectively. These preliminary results constitute a starting point for the synthesis of this drug in flow on an industrial scale, with the aim of improving reaction performance using this new technology.

Experimental parametric analysis of biodiesel synthesis in microreactors using waste cooking oil (WCO) in ethilic route

Experimental parametric analysis of biodiesel synthesis in microreactors using waste cooking oil (WCO) in ethilic route

Automation of obtaining vinyl acetate in a microrator

Due to the lack of domestic manufacturers, the production of a microreactor with a control system for chemical processes will remain relevant. The reason for this is the demand for automated solutions and, in general, automation and research into the optimal conditions for promising chemical processes in companies and in production. Moreover, the microreactor proposed with a chemical process control system will be able to save money and time on the development of effective chemical processes for the production of a wide variety of substances. In addition, the project provides for the use of composite and polymer materials for work, which in turn will reduce the cost of manufactured products, and at the same time increase the competitive attractiveness. The aim is to develop a microreactor and a control system for chemical processes. This goal is achieved by justifying the choice of the direction of research, analysis of existing equipment for carrying out microreactor synthesis, application for their creation lightweight, composite and other technical materials, as well as through the development of technology for creating microreactor equipment using 3D printing, milling and engraving of light metals, composite and polymer materials. The article presents microreactors and the development of a microreactor for the production of vinyl acetate, a detailed description of the methodology for the development of this complex device, including a microreactor, a SCARA type robot and a control unit. Methods for the production of vinyl acetate and the possibility of automating this process with a complex device were also studied.

Microreactor synthesis of nanosized particles: The role of micromixing, aggregation, and separation processes in heterogeneous nucleation

The aim of the paper was to formulate the concept of controlled solution synthesis (a version of co-precipitation method) and to demonstrate its realization on several types of reactors, with a special focus on microreactors with free impinging jets (MRFIJ). The objects of this work are (i) co-precipitation method for synthesis of nanoparticles and (ii) various types of microreactors as a structured system consisting from dedicated elements. The procedure consisted on the decomposition of the total process into unit operations with further analysis of their spatial and temporal characteristics. It was shown that the elements for following unit operations should be presented in the microreactor: premixing; converging clusters (intense mixing in a thin layer/channel); ripening of nuclei; particle separation. Microreactors were shown as most appropriate devices for nanoparticles synthesis by co-precipitation method. Particularly, three case studies of co-precipitation synthesis in MRFIJ demonstrated possibility to produce nanoparticles having narrow particle size distribution (dmean: BiFeO3 – 20 nm, CoFe2O4 – 12 nm, GdFeO3 – 30 nm), without impurities of other phases and improved characteristics (e.g. low coercivity for GdFeO3 which makes it possible to use them as MRI-contrast agents) with high performance (4.3 m3/day). Besides, the temperature increase due to the energy dissipation in the liquid sheet in MRFIJ was analysed: it does not exceed 0.001 K and 0.2 K for characteristic jet velocities of 3.35 m/s and 40 m/s, correspondingly.

Quality management of the chemical-technological process for continuous synthesis of pharmaceutical substances of medicinal compounds in flow microreactors

Objectives. The introduction of digital tools for the development of medicines, intelligent management systems, and quality control is stipulated not only by modern requirements for the chemical and pharmaceutical industry but also by strict regulatory requirements for manufactured products. This principle ensures the release of a quality product on the first attempt. The aim of this study is to develop information support for the intelligent quality management system for the production of active pharmaceutical substances (APSs) for medicines using a fundamentally new technology: continuous synthesis in flow microreactors. To develop the necessary information support, we developed appropriate systemic, informational, and mathematical models; algorithms for the online management of the experiment; and techniques and algorithms to qualitatively assess whether the product meets official regulatory documents.Methods. System analysis techniques, information and mathematical modeling techniques with multireference regression models, and online optimization using the Hook–Jeevs algorithm (a method of expert evaluation based on the concordance factor) were used to solve the problems formulated.Results. To manage the quality of the process of continuous APS synthesis in the flow microreactor, we developed theoretic multiple system models that were designed to build the digital information environment for the process of experimental research. We developed algorithms for mathematical modeling and optimization of the control process based on multiresponse regression models and an online optimization algorithm that allows the process to be managed step by step, taking into account the limitations. Our results show that the degree of conversion is higher in reactions that contain bromodiphenylmethan.Conclusions. Based on mathematical modeling method algorithms for the quality control of the process of continuous APS synthesis on a fundamentally new microreactor system, Qmix were developed. The applicability of the proposed methods and algorithms in the production of the drug diphenhydramine from chlorobenzohydrol and bromobenzohydrol as initial substances was proven by an experimental study. The built models were statistically adequate and valid.

Flow Microreactor Synthesis of Zeolitic Imidazolate Framework (ZIF)@ZIF Core-Shell Metal-Organic Framework Particles and Their Adsorption Properties.

Metal-organic frameworks (MOFs) with core-shell structures enable to enhance intrinsic properties of constituent MOFs and impart additional functional activities. Although shell thickness is a key factor for regulating the properties of core-shell MOF particles, controlling it has been challenging. The widely used batch reactor synthesis cannot produce core-shell particles with uniform shell thickness because of poor reactant mixing. A microreactor could ensure excellent mixing, and that would allow to control shell thickness. In this study, we synthesized zeolitic imidazolate framework-8 (ZIF-8)@ZIF-67 and ZIF-67@ZIF-8 core-shell particles using a microreactor and investigated the effects of the mixing performance on the shell thickness of the obtained particles. Our results demonstrated that rapid mixing was critical for the uniformity of the synthesized particles. The concentration of core particles is another key factor that can preferentially induce heterogeneous nucleation on the surface of the core particles without inducing self-nucleation in the bulk solution, particularly when the self-nucleation rate of the shell MOF is high. The N2 adsorption isotherms of the synthesized particles revealed their unique adsorption properties, which were ascribed to the core-shell structures obtained at low shell formation rates. Our simple and versatile synthesis technique not only allowed the preparation of ZIF@ZIF particles with novel functionalities but also can be extended to synthesize core-shell MOF particles with different combinations of core particles and shells.

Synergistic effects of the alternating application of low and high frequency ultrasound for particle synthesis in microreactors

Ultrasound (US) is a promising method to address clogging and mixing issues in microreactors (MR). So far, low frequency US (LFUS), pulsed LFUS and high frequency US (HFUS) have been used independently in MR for particle synthesis to achieve narrow particle size distributions (PSD). In this work, we critically assess the advantages and disadvantages of each US application method for the case study of calcium carbonate synthesis in an ultrasonic microreactor (USMR) setup operating at both LFUS (61.7 kHz, 8 W) and HFUS (1.24 MHz, 1.6 W). Furthermore, we have developed a novel approach to switch between LFUS and HFUS in an alternating manner, allowing us to quantify the synergistic effect of performing particle synthesis under two different US conditions. The reactor was fabricated by gluing a piezoelectric plate transducer to a silicon microfluidic chip. The results show that independently applying HFUS and LFUS produces a narrower PSD compared to silent conditions. However, at lower flow rates HFUS leads to agglomerate formation, while the reaction conversion is not enhanced due to weak mixing effects. LFUS on the other hand eliminates particle agglomerates and increases the conversion due to the strong cavitation effect. However, the required larger power input leads to a steep temperature rise in the reactor and the risk of reactor damage for long-term operation. While pulsed LFUS reduces the temperature rise, this application mode leads again to the formation of particle agglomerates, especially at low LFUS percentage. The proposed application mode of switching between LFUS and HFUS is proven to combine the advantages of both LFUS and HFUS, and results in particles with a unimodal narrow PSD (one order of magnitude reduction in the average size and span compared to silent conditions) and negligible rise of the reactor temperature.

Acoustophoretic focusing effects on particle synthesis and clogging in microreactors.

The handling of solids in microreactors represents a challenging task. In this paper, we present an acoustophoretic microreactor developed to manage particles in flow and to control the material synthesis process. The reactor was designed as a layered resonator with an actuation frequency of 1.21 MHz, in which a standing acoustic wave is generated in both the depth and width direction of the microchannel. The acoustophoretic force exerted by the standing wave on the particles focuses them to the channel center. A parametric study of the effect of flow rate, particle size and ultrasound conditions on the focusing efficiency was performed. Furthermore, the reactive precipitation of calcium carbonate and barium sulfate was chosen as a model system for material synthesis. The acoustophoretic focusing effect avoids solid deposition on the channel walls and thereby minimizes reactor fouling and thus prevents clogging. Both the average particle size and the span of the particle size distribution of the synthesized particles are reduced by applying high-frequency ultrasound. The developed reactor has the potential to control a wide range of material synthesis processes.

Estimation of kinetic coefficients in micro-reactors for biodiesel synthesis: Bayesian inference with reduced mass transfer model

High yields in the production of biodiesel at very short residence times can be obtained by means of micro-reactors technology. The theoretical study of the reaction mechanisms involved in biodiesel synthesis in micro-reactors is crucial in achieving adequate design conditions towards maximizing biodiesel production. Such a physico-chemical phenomenon involves complex liquid–liquid flow and mass transfer processes, besides the transesterification reaction, and the determination of the kinetic coefficients is essential in using the mathematical models for the design of the micro-reactors. In this work, a nonlinear coupled mathematical model of first-order ordinary differential equations has been developed, using the Coupled Integral Equations Approach (CIEA) for model reduction, starting from a diffusive-convective-reactive three-dimensional mathematical model that describes the local species concentrations involved in the biodiesel synthesis. The ODEs system is numerically solved using the NDSolve routine of the Mathematica platform. The Markov Chain Monte Carlo method (MCMC) is employed in solving the inverse problem to estimate the kinetic coefficients, using synthetic experimental data with low conversion rates, which maximize the presence of intermediate species and increase the sensitivity of the problem to the desired parameters. The results presented indicate that the CIEA in combination with the MCMC statistical inference yield an efficient and robust combination for the direct - inverse analysis of such reactive mass transfer problems.

Liquid fuel synthesis in microreactors

This review paper provides an in-depth review of microreactors for the intensification of the liquid fuel production processes.

Three-dimensional reaction-convection-diffusion analysis with temperature influence for biodiesel synthesis in micro-reactors

A three-dimensional nonlinear reaction-convection-diffusion model is proposed to analyze mass transfer with temperature effects, within micro-reactors of rectangular cross-section, towards the simulation of the transesterification process in biodiesel synthesis. The coupled nonlinear partial differential equations that govern the concentration of the species involved in the synthesis, is obtained from the general three-dimensional species balance equations for an isothermal and steady state system with constant physical properties. A kinetic model is considered to describe the variation of the species due to the transesterification process, assuming second order homogeneous and reversible chemical reactions. The velocity profile is analytically derived from the Navier-Stokes equations, considering fully developed stratified laminar flow of two immiscible Newtonian fluids in a rectangular cross section micro-reactor, with a plane interface between them and without field forces, and obtained by the Classical Integral Transform Technique (CITT). The nonlinear mass transport equations are then solved by the hybrid numerical-analytical approach known as the Generalized Integral Transform Technique (GITT). In the present GITT solution, two alternative eigenvalue problems are proposed, accounting or not accounting for the space variable velocity profile influence in the eigenfunction expansion basis, in order to investigate the differences in the convergence behavior of the solutions obtained through the two different auxiliary problems. The results for the concentration profiles of the biodiesel and triglyceride species are critically compared with literature data for the limiting case of parallel plates, showing a good agreement among them. The analysis also indicates that improved convergence rates are achievable through the eigenvalue problem with variable coefficients. The effects of governing parameters such as residence time, micro-reactor dimensions, and especially temperature, are investigated. It is then inspected the relative gains in triglycerides conversion rates at higher temperatures and residence times and lower micro-reactor hydraulic diameter.

Flow microreactor synthesis of gold nanoshells and patchy particles

Silica@Au core-shell type composite particles are promising for biomedical applications due to their unique optical and chemical characteristics, although the problem lies in the synthetic processes. They are typically synthesized via batch type reactions including multiple steps, and the complexity in the synthetic process is an obstacle to practical applications. A robust and facile process is thus required. In the present study, we developed a flow synthetic process by applying a microreactor with a high mixing performance to silica@Au nanoshells and patchy particles. Following a concept of selective nucleation and subsequent growth of the gold on the core surface, we mixed a suspension of surface-modified silica particles containing gold ions with a reducing agent solution in the microreactor, and investigated the effects of the core particle size and the type of reducing agents on the composite particle synthesis. Through the investigation, we found that the ratio of the gold ion amount to the surface area of core particles is a key factor for obtaining uniform core-shell particles. In addition, the morphology of gold formed on the core surface was demonstrated to change from spherical nanoparticles to dendritic patches depending on the reducing ability of reducing agents.