Efficient “One-Column” grignard generation and reaction in continuous flow

One of the obstacles preventing the commercialization of colloidal nanoparticle catalysts is the difficulty in fabricating these materials at scale while maintaining a high level of control over their resulting morphologies, and ultimately, their properties. Translation of batch-scale solution nanoparticle syntheses to continuous flow reactors has been identified as one method to address the scaling issue. The superior heat and mass transport afforded by the high surface-area-to-volume ratios of micro- and millifluidic channels allows for high control over reaction conditions and oftentimes results in decreased reaction times, higher yields, and/or more monodisperse size distributions compared to an analogous batch reaction. Furthermore, continuous flow reactors are automatable and have environmental health and safety benefits, making them practical for commercialization. Herein, a discussion of continuous flow methods, reactor design, and potential challenges is presented. A thorough account of the implementation of these technologies for the fabrication of catalytically active metal nanoparticles is reviewed for hydrogenation, electrocatalysis, and oxidation reactions.

Innovative determination of the specific anammox activity for anammox sludge from continuous flow reactors: A comparison between continuous flow test and batch test

Efficient start‐up, cultivation and maintenance of aerobic granular sludge (AGS) in continuous flow reactors (CFRs) is critical for its full‐scale application in wastewater treatment plants (WWTPs). The successful implementation of AGS under continuous flow condition depends on the configuration of CFR that provides the selective pressures and hydraulic shear force (HSF) to sludge required for rapid granulation. Important progress has been witnessed with respect to CFR configurations in recent decades for in‐situ granulation of aerobic sludge. This review summarized the difficulties of granulation during continuous flow, as well as the reactor configuration, granulation mechanism and the AGS characteristics, along with the future research prospects. It is of significance to promote the innovation of continuous flow configuration in order to realize the AGS application in mainstream WWTPs in the future. © 2021 Society of Chemical Industry (SCI).

Modelling the synthesis of nanoparticles in continuous microreactors: The role of diffusion and residence time distribution on nanoparticle characteristics

Introduction: This work was carried out to understand if a heterogeneous biocatalytic hydrogenation system could be implemented in a slurry mode continuous flow reactor, as a “slot-in” alternative to a metal/carbon catalyst with minimal process or chemical engineering development.Method: Biocatalytic hydrogenation was compared to metal (Pd/C) catalysed hydrogenation for ketone to chiral alcohol conversion in both a continuous flow reactor (Coflore ACR, AM Technology) and analogous scaled down batch reactions.Results and discussion: Initial results demonstrated that batch reactions can achieve high conversions in 30 min, with relatively low biocatalyst loadings, meeting critical criteria for operation as continuous slurry mode process. Further results demonstrated full conversion of quinuclidinone to (3R)-quinuclidinol in continuous flow under mild conditions (35°C, 2 bar H2). On intensification of the process to higher substrate loading (50 mM), conversion was similar to with Pd/C, however the biocatalytic system achieved far higher turnover frequency and total turnover number (65 min−1 and 20,000, respectively) than the metal system (0.16 min−1, 37). Comparison to an analogous batch reaction highlights that the biocatalytic system has promise for further optimisation and intensification in the scalable Coflore ACR. Overall, biocatalytic hydrogenation is shown to offer a decarbonised biocatalytic route and a “slot-in” replacement to metal catalysts for hydrogenation reactions in continuous flow reactors.

The pharmaceutical industry has great need to reduce costs and improve manufacturing efficiency while consistently manufacturing quality drug product. Continuous flow reactors (CFRs) offer an option for a flexible, leaner, and cleaner process. CFRs are flow cells optimized for the continuous production of a target compound. Small-volume CFRs avoid some of the reaction control problems associated with scale-up to large-batch chemistry, while still allowing for process intensification through modular scale-out. Compared to batch reactors, CFRs are more energy efficient due to their superior mixing schemes and heat transfer properties. Reactions typically proceed much faster than in batch and require less excess solvent. Currently, CFRs are limited by the technologies available for online monitoring, which require product stream sampling and off-line analytics. This work addresses the analytical challenges inherent to CFRs by demonstrating the ability to assess the quality of product from a reactor stream rapidly, using effective online sampling and monitoring systems. Additionally, following the Quality by Design paradigm, techniques such as statistically based design of experiments, process analytical technologies, and multivariate statistical modeling methods were implemented to facilitate enhanced product and process understanding. An online sampling system that is able to interface with CFRs was developed, with custom software to monitor and control process variables using online analytics. Knowledge of these in-process parameters, combined with appropriate online process analytical technologies, provided a complete understanding of both the physical and chemical system. These improvements reduced the time and effort required to develop and optimize a chemical reaction for large-scale continuous production.

Flow chemistry uses channels or tubing to conduct a reaction in a continuous stream rather than in a flask. This method provides chemists with unique control over reaction parameters, enhancing reactivity or in some cases enabling new reactions. Flow chemistry has received a remarkable amount of attention in the past decade with many reports on what can be done in flow. While this approach to publishing papers has led to the development of elegantly conceived processes, it has neglected to properly differentiate the examples which have benefits over conventional batch methods. This poor distinction between what can be done and what should be done in flow has shrouded useful contributions to synthetic organic chemistry and created flow chemistry skeptics. For this reason, flow techniques are still not integrated into synthetic laboratories and probably will not be for years to come. In order to make flow equipment part of the every-day-toolbox, reactions need to be classified and applied on the basis of the benefits that flow offers. In this thesis, how flow enhances these classes of reactions is explained and various examples of these different methods are highlighted. Biphasic reactions and photochemistry are two classes of reactions that benefit flow fluidic conditions. The small dimensions of microreactors increase mass transfer and accelerate the rate of biphasic reactions involving gases. Pressurizing the system is also more convenient in flow and is done by simply incorporating a backpressure regulator into the setup. Photochemistry benefits greatly from fluidic conditions because of the attenuation of light. According to the Beer-Lambert-Bouguer law, common reaction mixture concentrations can result in less than 0.5 mm of light penetration. For a batch reaction, this is detrimental to the rate of the reaction since the reactor dimensions are usually on the order of centimeters. On the other hand, the inner diameter of common tubing for photoflow reactors is usually between 0.25-0.8 mm, resulting in the irradiation of a much higher percentage of the reaction mixture. Singlet oxygen generation in flow is one example which exploits both of the enhancements of biphasic reactions and photochemistry and is applied here for studying the oxidation of secondary amines. Aerobic amine oxidation is an attractive process for the α-functionalization of amines because of its sustainability. However, there were still several mechanistic uncertainties; for instance, the factors governing the regioselectivity of the oxidation of asymmetric secondary amines. In the present work, flow conditions were used to generate singlet oxygen and perform mechanistic studies on the factors influencing the regioselectivity for the oxidation of asymmetric secondary amines. A predictive model was constructed with the use of a substrate scope of 20 secondary amines. The strength of the α-CH bonds and the functional groups’ steric bulk influenced the selectivity the most. This model estimated oxidation selectivity on the basis of the relative bond dissociation energy which was determined by natural bond order analysis or NMR spectroscopy. Similar to aerobic oxidations, photoredox chemistry is another example of the recent movement toward greener, more sustainable chemistry. This field of photocatalysis has led to the emergence of a wide berth of new visible-light- mediated transformations and flow chemistry has been utilized to enhance the productivity of these photoredox processes. The increased productivity is particularly interesting for the development of a wide variety of practical, preparative methods for synthesis. Organometalic polypyridyl structures offer versatility in terms of reactivity providing access to a multitude of oxidative and reductive transformations. vi The Achmatowicz rearrangement involves the oxidative ring expansion of furfuryl alcohols into dihydropyranones. It is utilized in natural product synthesis since it is a versatile method for constructing highly functionalized pyran moieties. Here, photoredox-catalysis was used to perform the Achmatowicz reaction with [Ru(bpy)3Cl2] and sodium persulfate. Sodium persulfate is an attractive oxidant because it is cheap, shelf-stable, and produces water soluble byproducts which facilitate column-free synthesis. This was exemplified with the direct Boc-protection of the resulting Achmatowicz product without column purification of the intermediate. Also, the reaction was very robust and permitted the use of various aqueous solutions and light sources including sunlight. Investigations into other oxidation reactions with this catalyst/oxidant combination are currently underway.

A continuous flow reactor setup as a tool for rapid synthesis of micron sized NaA zeolite

Very high surface area thin nanosheets of MoS2, with also low lateral dimension, as well as high number of edges sites, were prepared via a solvent free, easily controllable and scalable process. The syntheses were performed by thermolysis of ammonium thiomolybdates (NH4)2MoS4 in a continuous flow reactor, monitored with a mass spectrometer. The precursor decomposition was promoted in the temperature range 25-400 °C, obtaining amorphous MoS2. Nanosheets were obtained thought a successive annealing, while material order can be improved by progressively increasing temperature and time. It was found that the annealing time at the end of the first step determines a reduction of the final nanosheets lateral size and number of layers. The samples were characterized by Raman Spectroscopy, Scanning (SEM) and Transmission (TEM-EDS) Electron Microscopy, thermogravimetric analysis (TG-DTG-MS), X-ray diffraction (XRD).

Variability of ozone reaction kinetics in batch and continuous flow reactors

Ultralong ZnO/Pt hierarchical structures for continuous-flow catalytic reactions

Transition-metal catalyzed asymmetric reactions under continuous flow from 2015 to early 2020

The review highlights the different advantages associated with organocatalytic transformations performed in continuous-flow systems and presents the reactions which have been successfully achieved to date. Particular focus is placed on the comparison between batch and flow applications in order to show the advantages and disadvantages and to demonstrate the great potential for applying organocatalysis as well as combined organo and photoredox catalyzed reactions in continuous flow.

An efficient Suzuki cross-coupling reaction under continuous flow conditions was developed utilizing an immobilized solid supported catalyst consisting of bimetallic nickel-palladium nanoparticles (Ni-Pd/MWCNTs). In this process, the reactants can be continuously pumped into a catalyst bed at a high flow rate of 0.6 mL/min and the temperature of 130 °C while the Suzuki products are recovered in high steady-state yields for prolonged continuous processing. The catalyst was prepared by mechanical shaking of the appropriate nickel and palladium salts using ball-mill energy without the requirement of any solvent or reducing agent. This straightforward, facile, and simple method allows for bulk production of Ni-Pd/MWCNTs nanoparticles with a small particle size ideal for application in continuous flow cross-coupling catalysis. The as-prepared catalyst mostly contains nickel (7.9%) with a very small amount of palladium (0.81%) according to ICP-OES analysis. This remarkable immobilized catalyst can be used several times for different Suzuki reactions with a minimum loss of reactivity and no detectable leaching of the metal nanoparticles. Notably, by modifying the groups on both aryl halides and phenylboronic acids, the method provides access to a diverse array of the Suzuki products in flow with high steady-state yield, making it suitable for applications in industrial and pharmaceutical scales. Moreover, several spectroscopic techniques were employed to identify the structure and composition of the as-prepared Ni-Pd/MWCNTs nanoparticles before and after the reaction in flow such as transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), BET surface area (physisorption), and FTIR spectroscopy.

The challenges of light-dependent biocatalytic transformationsof lipophilic substrates in aqueous media are manifold. For instance,photolability of the catalyst as well as insufficient light penetrationinto the reaction vessel may be further exacerbated by a heterogeneouslydispersed substrate. Light penetration may be addressed by performingthe reaction in continuous flow, which allows two modes of applyingthe catalyst: (i) heterogeneously, immobilized on a carrier, whichrequires light-permeable supports, or (ii) homogeneously, dissolvedin the reaction mixture. Taking the light-dependent photodecarboxylationof palmitic acid catalyzed by fatty-acid photodecarboxylase from Chlorella variabilis (CvFAP) asa showcase, strategies for the transfer of a photoenzyme-catalyzedreaction into continuous flow were identified. A range of differentsupports were evaluated for the immobilization of CvFAP, whereby Eupergit C250 L was the carrier of choice. As the photostabilityof the catalyst was a limiting factor, a homogeneous system was preferredinstead of employing the heterogenized enzyme. This implied that photolabileenzymes may preferably be applied in solution if repair mechanismscannot be provided. Furthermore, when comparing different wavelengthsand light intensities, extinction coefficients may be considered toensure comparable absorption at each wavelength. Employing homogeneousconditions in the CvFAP-catalyzed photodecarboxylationof palmitic acid afforded a space-time yield unsurpassed by any reportedbatch process (5.7 g·L–1·h–1, 26.9 mmol·L–1·h–1) for this reaction, demonstrating the advantage of continuous flowin attaining higher productivity of photobiocatalytic processes.