Batch Synthesis Research Articles

Selective Late‐Stage Oxygenation of Sulfides with Ground‐State Oxygen by Uranyl Photocatalysis

AbstractOxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late‐stage oxygenation of sulfur‐containing complex molecules with ground‐state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand‐to‐metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late‐stage oxygenation in an atom‐ and step‐efficient manner.

Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis.

Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+ ) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.

Preparation of Cross-Linked Enzyme Aggregates (CLEAs) of an Inulosucrase Mutant for the Enzymatic Synthesis of Inulin-Type Fructooligosaccharides

Fructooligosaccharides are well-known carbohydrate molecules that exhibit good probiotic activity and are widely used as sweeteners. Inulin-type fructooligosaccharides (IFOs) can be synthesized from sucrose using inulosucrase. In this study, cross-linked enzyme aggregates (CLEAs) of Lactobacillus reuteri 121 inulosucrase (R483A-LrInu) were prepared and used as a biocatalyst for IFOs production. Under optimum conditions, R483A-LrInu CLEAs retained 42% of original inulosucrase activity. Biochemical characterization demonstrated that the optimum pH of inulosucrase changed from 5 to 4 after immobilization, while the optimum temperature was unchanged. Furthermore, the pH stability and thermostability of the R483A-LrInu CLEAs was significantly improved. IFOs product characterization indicated that the product specificity of the enzyme was impacted by CLEA generation, producing a narrower range of IFOs than the soluble enzyme. In addition, the R483A-LrInu CLEAs showed operational stability in the batch synthesis of IFOs.

Gelatin‐Based Capsules through Interfacial Polymerization: Batch and Continuous Flow Synthesis

AbstractCross‐linked gelatin capsules were prepared through interfacial polymerization in the inverse miniemulsion, using toluene diisocyanate (TDI) as a cross‐linker. Synthesis was performed in a batch process and in a continuous flow using a static micromixer. The obtained capsules were in the size range between 0.5 and 2 µm. The influence of TDI amount, pH of gelatin solution, and flow rates on the properties of capsules was studied by dynamic light scattering, transmission electron microscopy, and Fourier transform infrared spectroscopy. The thermoresponsive release of the hydrophilic dye sulforhodamine 101 was investigated by fluorescent spectroscopy. Furthermore, gelatin capsules loaded with magnetite nanoparticles were synthesized in a continuous way, showing the potential to produce capsules for drug release triggered by magnetic hyperthermia in large quantities.

Continuous Flow Synthesis of Highly Substituted Tetrahydrofurans

The highly diastereoselective synthesis of multiply substituted tetrahydrofurans was achieved in a sequential process under continuous flow conditions. Greatly reduced reaction times, improved selectivities and enhanced yields are the benefits of this approach in comparison to the initial batch synthesis. Moreover, gram amounts of product were produced in the flow reactor likewise due to facile upscaling. In addition, employing a novel bis(silyl)dienediolate tetrasubstituted tetrahydrofurans were made accessible as well.

An experimental study on synthesis of glycolic acid via carbonylation of formaldehyde using PTFE membrane contactor

The batch and continuous synthesis of glycolic acid via carbonylation of formaldehyde using high-temperature and high-pressure poly(tetrafluoroethylene) (PTFE) membrane contactor was demonstrated in this paper. The experiments in conventional stirred tank reactor were also conducted for comparison. The results showed that the yield of glycolic acid was significantly improved in membrane contactor system compared to the stirred tank reactor. At reaction temperature of 120 °C and reaction pressure of 5.0 MPa, the yield of glycolic acid was higher than 90% when the reaction time was 1 h, while it was only about 45% in the conventional stirred tank reactor. The enhancement of yield was due to the improvement of mass transfer or dispersion of CO in membrane contactor system, which could provide larger gas-liquid contact area and shorter mass transfer distance. The stability of PTFE hollow fibre membranes was also investigated by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), liquid entry pressure (LEP), bubble point (BP) and contact angle (CA) measurements. The characterizations indicated that PTFE membranes exhibited good chemical and thermal stability in this reaction system. This study provided new idea and reference for the carbonylation of formaldehyde and similar gas-liquid reactions.

Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples.

Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB1 and CB2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC50 (a measure of potency) and Emax (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB2 receptor than at the CB1 receptor and (S)-enantiomers had an enhanced potency to both receptors over the (R)-enantiomers. The relative potency of the enantiomers to the CB2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (R)-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials (n = 16), found 5F-MDMB-PINACA (<1.0–91.5 mg/g herbal material) and AMB-FUBINACA (15.5–58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the (S)-enantiomer predominated in all samples (93.6–99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the “intrinsic” potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.

Fabrication of polystyrene-encapsulated magnetic iron oxide nanoparticles via batch and microfluidic-assisted production

The magnetic properties of nanoparticles make them ideal for use in various applications, especially in biomedical applications. Herein, we describe the fabrication of iron oxide nanoparticles encapsulated in polystyrene (PS) using two methods: a conventional batch and microfluidic synthesis. In particular, we present a simple synthesis method of magnetic composite nanoparticles, based on the use of a microfluidic elongational flow method in a continuous-flow apparatus where magnetite particles are embedded in a polystyrene matrix. Compared to conventional batch synthesis, microfluidics-based synthesis enables precise reaction control, enhanced mixing and rapid chemical reactions, allowing flow synthesis of particles in a controllable, sustainable, and cost-saving manner that is attractive to industry. The composite particles show a high encapsulation of magnetite nanoparticles, but with an inhomogeneous size distribution; instead, the sample obtained with microfluidic approach shows a homogenous composite particle size distribution although the magnetite content is lower compared to the miniemulsion batch methods.

Microfluidic Based Fabrication and Characterization of Highly Porous Polymeric Microspheres.

Polymeric porous particles are currently used for various applications in biotechnology, tissue engineering and pharmaceutical science, e.g., floating drug delivery systems and inhaled formulations. Particle shape and size depend on variable parameters; among them, polymer type and concentration, stirring speed, pH and type of solvent. In this study, porous poly(lactic-co-glycolic) acid (PLGA) and poly(d,l-lactide) (PLA) microspheres (MPs), with varying sizes and morphologies, were synthesized and optimized using both batch formulation and a flow-focusing microfluidic device. A well-established method of preparation utilizing solvent evaporation and the double emulsion technique was performed. Similar to other batch encapsulation methods, this technique is time and reagent consuming and consists of several steps. Hence, although porous structures provide tremendous opportunity in the design of new applications for tissue engineering and as improved controlled-release carriers, the synthesis of these particles with predefined properties remains challenging. We demonstrated the fabrication of porous MPs using a simple microfluidic device, compared to batch synthesis fabrication; and the effect of solvent, polymer concentration and type, post-hydrolysis treatment, on porosity degree. Moreover, a kinetic release study of fluorescent molecule was conducted for non-porous in comparison to porous particles. An overview of future prospects and the potential of these porous beads in this scientific area are discussed.

Polyphonic pitch perception in rooms using deep learning networks with data rendered in auditory virtual environments

This paper proposes methods for generation and implementation of uniform, large-scale data from auralized MIDI music files for use with deep learning networks for polyphonic pitch perception and impulse response recognition. This includes synthesis and sound source separation of large batches of multitrack MIDI files in non-real time, convolution with artificial binaural room impulse responses, and techniques for neural network training. Using ChucK, individual tracks for each MIDI file, containing the ground truth for pitch and other parameters, are processed concurrently with variable Synthesis ToolKit (STK) instruments, and the audio output is written to separate wave files in order to create multiple incoherent sound sources. Then, each track is convolved with a measured or synthetic impulse response that corresponds to the virtual position of the instrument in the room before all tracks are digitally summed. The database now contains the symbolic description in the form of MIDI commands and the auralized music performances. A polyphonic pitch model based on an array of autocorrelation functions for individual frequency bands is used to train a neural network and analyze the data [Work supported by IBM AIRC grant and NSF BCS-1539276.]

Hertzian elasticity and triggered swelling kinetics of poly(amino ester)-based gel beads with controlled hydrophilicity and functionality: A mild and convenient synthesis via dropwise freezing into cryogenic liquid

Poly(amino ester)-based homo- and co-polymeric gel beads were prepared via “dropwise freezing into cryogenic liquid” method and multi-responsive properties of the prepared spherical beads were confirmed by the pulsatile swelling kinetics and the stress-strain relationships based on Hertzian elasticity. Dual pH- and ionic strength-responsive homopolymeric PDMAEMA as well as copolymeric poly(hydroxyethyl methacrylate-co-dimethylaminoethyl methacrylate) P(HEMA-co-DMAEMA) gel beads crosslinked with diethyleneglycol dimethacrylate (DEGDMA) were prepared by aqueous phase crosslinking copolymerization at subzero temperature within the millimeter-sized frozen droplets in the paraffin oil as continuous phase. With this method, spherical ionic gel beads of sizes 2–5 mm could be synthesized without using a stabilizer. The successful synthesis of PDMAEMA and P(HEMA-co-DMAEMA) gel beads was confirmed by ATR-FTIR and SEM. Modulus of elasticity of cross-linked poly(amino ester)-based gel beads in swollen state was measured as a function of the bead diameter. The relationship between the compressive elastic force and corresponding deformation was obtained to compare the experimental results with theoretical-analytical formulations using the constitutive relations from Hertzian elasticity. The effective crosslink density of gel beads produced in the same synthesis batch increased as a function of increasing bead diameter, which was attributed to the formation conditions of the beads via frozen droplets of the pre-gel solution. The synthesis pathway used for the production of gel beads from methacrylate-based monomer with a polar tertiary amino group offered one-way control over material geometry to design soft and smart materials with controlled size and porosity.

Quaternary ferrites by batch and continuous flow hydrothermal synthesis: a comparison

Crystalline spinel quaternary ferrites MxZn1−xFe2O4 (M = Co, Ni) were synthesised through two synthetic routes: conventional batch and continuous flow hydrothermal synthesis.

Optimal Fractional Composition of Batch for Synthesis of Foam-Glass Materials Based on Diatomite from the Chernoyarskoe Deposit

The types and function of foam glass are examined as a function of the employed foaming agents. Mixes with different granulometric composition of the batch were developed and subjected to heat-treatment. The influence of the fractional composition of the foam-glass batch on the density and volume of the foam glass and foam-glass materials was studied.

Microfluidics for silica biomaterials synthesis: opportunities and challenges.

The rational design and controllable synthesis of silica nanomaterials bearing unique physicochemical properties is becoming increasingly important for a variety of biomedical applications from imaging to drug delivery. Microfluidics has recently emerged as a promising platform for nanomaterial synthesis, providing precise control over particle size, shape, porosity, and structure compared to conventional batch synthesis approaches. This review summarizes microfluidics approaches for the synthesis of silica materials as well as the design, fabrication and the emerging roles in the development of new classes of functional biomaterials. We highlight the unprecedented opportunities of using microreactors in biomaterial synthesis, and assess the recent progress of continuous and discrete microreactors and the associated biomedical applications of silica materials. Finally, we discuss the challenges arising from the intrinsic properties of microfluidics reactors for inspiring future research in this field.

Dynamic Optimization of a Fed-Batch Microgel Synthesis

Abstract Functional microgels are novel materials, which can potentially be used for diverse applications such as drug delivery. Among other material properties, the radial cross-linker profile is of special importance to ensure desired product functionality. However, in the system under investigation, only a high cross-linker fraction in the center and a low cross-linker fraction in the shell is obtained in batch synthesis due to the fast reaction kinetics of the cross-linker. Other radial cross-linker fraction profiles can be synthesized in fed-batch, yet the determination of the required feeding profiles is not intuitively obvious. Based on recently developed quantitative nonlinear process models, a fed-batch synthesis can be dynamically optimized under constraints set by product quality and process limitations. Here, we apply dynamic optimization to microgel synthesis to obtain large microgels under constraints posed by the radial cross-linker profile and conversion. We present three different case studies to show in silico that a wide range of different cross-linker fraction profiles is feasible. The results show that the specified constraints are met and that various cross-linker profiles can be achieved while maintaining the microgel size.

Modified bluing treatment to produce nickel-cobalt-iron spinel oxide with promoted oxygen-evolving performance.

A rapid modified bluing treatment approach was proposed for the facile synthesis of a ternary NiCoFe spinel oxide catalyst. Benefitted from the synergy of multi-elements, the enriched high-valence species and good structural stability, highly efficient and durable oxygen-evolving performance was achieved, offering an economic route for the batch preparation of advanced electrocatalysts.

Water as a structure-driving agent between the UiO-66 and MIL-140A metal-organic frameworks.

We report a careful investigation of a selective phase formation in the zirconium-terephthalic acid system during solvothermal synthesis, which could result in the UiO-66 (Zr6O6(OH)4(BDC)6) or MIL-140A (ZrO(BDC)) metal-organic frameworks (MOFs). The introduction of water varies the phase from MIL-140A to UiO-66 by producing at the nucleation stage tetragonal ZrO2 nanoparticles, where the local arrangement of Zr and O atoms is similar to that in the UiO-66 SBU.

Continuous- versus Segmented-Flow Microfluidic Synthesis in Materials Science

Materials science is a fast-evolving area that aims to uncover functional materials with ever more sophisticated properties and functions. For this to happen, new methodologies for materials synthesis, optimization, and preparation are desired. In this context, microfluidic technologies have emerged as a key enabling tool for a low-cost and fast prototyping of materials. Their ability to screen multiple reaction conditions rapidly with a small amount of reagent, together with their unique physico-chemical characteristics, have made microfluidic devices a cornerstone technology in this research field. Among the different microfluidic approaches to materials synthesis, the main contenders can be classified in two categories: continuous-flow and segmented-flow microfluidic devices. These two families of devices present very distinct characteristics, but they are often pooled together in general discussions about the field with seemingly little awareness of the major divide between them. In this perspective, we outline the parallel evolution of those two sub-fields by highlighting the key differences between both approaches, via a discussion of their main achievements. We show how continuous-flow microfluidic approaches, mimicking nature, provide very finely-tuned chemical gradients that yield highly-controlled reaction–diffusion (RD) areas, while segmented-flow microfluidic systems provide, on the contrary, very fast homogenization methods, and therefore well-defined super-saturation regimes inside arrays of micro-droplets that can be manipulated and controlled at the milliseconds scale. Those two classes of microfluidic reactors thus provide unique and complementary advantages over classical batch synthesis, with a drive towards the rational synthesis of out-of-equilibrium states for the former, and the preparation of high-quality and complex nanoparticles with narrow size distributions for the latter.

Continuous enzymatic synthesis of lactulose in packed-bed reactor with immobilized Aspergillus oryzae β-galactosidase

Lactulose synthesis from fructose and lactose in continuous packed-bed reactor operation with glyoxyl-agarose immobilized Aspergillus oryzae β-galactosidase is reported for the first time. Alternative strategies to conventional batch synthesis have been scarcely explored for lactulose synthesis. The effect of flow rate, substrates ratio and biocatalyst-inert packing material mass ratio (MB/MIM) were studied on reactor performance. Increase in any of these variables produced an increase in lactulose yield (YLu) being higher than obtained in batch synthesis at comparable conditions. Maximum YLu of 0.6 g·g−1 was obtained at 50 °C, pH 4.5, 50% w/w total sugars, 15 mL·min−1, fructose/lactose molar ratio of 12 and MB/MIM of 1/8 g·g−1; at such conditions yield of transgalactosylated oligosaccharides (YTOS) was 0.16 g·g−1, selectivity (lactulose/TOS molar ratio) was 5.4 and lactose conversion (XLactose) was 28%. Reactor operation with recycle had no significant effect on yield, producing only some decrease in productivity.

Continuous synthesis of doped layered double hydroxides in a meso-scale flow reactor

Layered double hydroxides are a class of low-cost structured nanomaterials with many potential applications in environmental catalysis and sustainable technologies. Their large-scale use is hindered by the challenge of reproducible synthesis at scale. Here we report a general, readily scalable process for the reproducible synthesis of transition metal doped hydrotalcites using a two-step process: co-precipitation in a mm-scale (meso-scale) continuous flow reactor, followed by aging. We have shown that co-precipitation in flow at a residence time close to the micromixing time affords good control of particle formation. Reproducible synthesis allowed us, for the first time, to investigate the formation of the pore morphology of hydrotalcites and their thermal stability as a function of metal doping. The obtained samples exhibited surface areas (80–150 m2 g−1) higher than those typically attained in batch syntheses, with very low standard deviation between the samples, a high degree of crystallinity and small crystallite sizes, in the range of 9.5–11.9 nm, depending on composition. A systematic characterization allowed us to elucidate the mechanism of the pore morphology formation: the crystallites were found to agglomerate into disk-like platelets, whereas the pore structure of the hydrotalcites is formed by agglomeration of the platelets.