Gram-scale Production Research Articles

Rapid and Environmentally-Friendly Synthesis of Thiazolidinone Analogues in Deep Eutectic Solvent Complemented with Computational Studies.

A greener, safer, and more efficient methodology for the synthesis of (Z)-5-benzylidene-2-thioxothiazolidin-4-ones (3 a-u) and (Z)-5-benzylidenethiazolidine-2,4-diones (4 a-i) has been developed. The deep eutectic solvent (DES) ZnCl2/urea used as a greener solvent as well as a catalyst in this study accelerated the condensation of rhodanine and thiazolidine-2,4-dione with different aldehydes to afford the target scaffolds in excellent yields (88-98 %). The reaction methodology adopted offered significant advantages such as mild reaction conditions, functional group tolerance, quick reaction time, column-free isolation, catalytic recyclability, and applicability to gram-scale production. Moreover, density function theory calculations were carried out to investigate the global reactivity and stability profiles of these compounds. Finally, the green metrics analysis supported the greener nature of the present methodology.

Gram-Scale Synthesis of the Fucose-Containing Fragments of Saccharomicins.

A highly efficient synthetic route has been established for the gram-scale production of fucose-aglycon (Fuc-Agl) and fucose-saccharosamine (Fuc-Sac) fragments in saccharomicins A and B. The β-glycosidic bonds within these structural components were formed through successive rhodium(II) and Brønsted-acid-catalyzed glycosylation, utilizing a stable thioglycosyl donor. Subsequent steps involving the installation of protecting groups yielded highly functionalized synthetic fragments that are suitable for further assembly of saccharomicins.

Green Approach for the Synthesis of 2-Phenyl-2H-indazoles and Quinazoline Derivatives Using Sustainable Heterogeneous Copper Oxide Nanoparticles Supported on Activated Carbon and OER Study.

This research work reports the synthesis of copper oxide (CuO) nanoparticles supported on activated carbon by a simple impregnation method using 2-propanol as a green solvent, followed by calcination. The synthesized CuO@C is used as an efficient heterogeneous nanocatalyst for the synthesis of 2H-indazoles and quinazolines utilizing commercially available 2-bromobenzaldehydes, primary amines, and sodium azide under ligand-free and base-free conditions. The present methodology demonstrates the formation of new N-N, C-N, and C═N bonds under one-pot reaction conditions using PEG-400 as a green solvent. The reaction pathways are supported by control experiments and mechanistic elucidation. Further, the synthesized catalyst was characterized by a range of microscopic and spectroscopic techniques such as powdered X-ray diffraction, fourier transform infrared spectroscopy, field emission scanning electron microscopy, energy-dispersive X-ray, UV-vis, X-ray photoelectron spectroscopy, high-resolution transmission electron microscopy, and BET-BJH analysis. Importantly, the study focused on the recyclability of the catalyst and successfully showed gram-scale production. Significantly, our active catalyst exhibited an outstanding performance in the oxygen evolution reaction, with an overpotential of 290 mV and a swallow Tafel slope of 91 mV dec-1.

Metal-Free Wet Chemistry for the Fast Gram-Scale Synthesis of γ-Graphyne and its Derivatives.

γ-Graphyne (GY), an emerging carbon allotrope, is envisioned to offer various alluring properties and broad applicability. While significant progress has been made in the synthesis of GY over recent decades, its widespread application hinges on developing efficient, scalable, and accessible synthetic methods for the production of GY and its derivatives. Here we report a facile metal-free nucleophilic crosslinking method using wet chemistry for fast gram-scale production of GY and its derivatives. This synthesis method involves the aromatic nucleophilic substitution reactions between fluoro-(hetero)arenes and alkynyl silanes in the presence of a catalytic amount of tetrabutylammonium fluoride, where the fluoride plays a crucial role in removing protective groups from alkynyl silanes and generating reactive alkynylides. Our comprehensive analysis of the as-prepared GY reveals a layered structure, characterized by the presence of the C(sp)-C(sp2) bond. The synthetic strategy shows remarkable tolerance to various functional groups and enables the preparation of diverse F-/N-rich GY derivatives, using electron-deficient fluoro-substituted (hetero)arenes as precursors. The feasibility of producing GY and derivatives from fluorinated (hetero)arenes through the metal-free, scalable, and cost-effective approach paves the way for broad applications of GY and may inspire the development of new carbon materials.

Gram-Scale Synthesis of Renal-Clearable Tantalum Nanodots with High Water Solubility for Computed Tomography Imaging In Vivo.

Tantalum (Ta) emerges as a promising element for advanced computed tomography (CT) imaging probes owing to its high X-ray attenuation coefficient and excellent biocompatibility. Nevertheless, the synthesis of renally clear Ta-based imaging probes through simple methods remains a significant challenge. Herein, we introduce a simple and gram-scale approach for the synthesis of renal-clearable Ta nanodots with high water solubility for CT imaging in vivo. The Ta nanodots, coordination polymers, are fabricated via coordination reactions involving Ta(OH)5, citric acid (CA), and hydrogen peroxide. The Ta nanodots exhibit an ultrasmall hydrodynamic diameter (2.8 nm), high water solubility (1.88 g/mL, 688 mg Ta/mL), superior X-ray absorption capacity, gram-scale production capability (>10 g in lab synthesis), renal-clearable ability, and good biocompatibility. The Ta nanodots possess superior CT imaging efficacy across diverse tube voltages, enabling highly sensitive gastrointestinal CT imaging, renal CT imaging, and CT angiography (CTA). Moreover, Ta nanodots maintain robust CT imaging capabilities even at high X-ray energies, and Ta nanodots-based spectral CT achieves metallic artifacts-minimized CTA. The proposed Ta nanodots present substantial potential as a potent CT imaging probe for diagnosing various diseases.

Tunable multi-peak emission solid-state fluorescent carbon dots: Luminescence regulation mechanism and application in single-component-based LEDs

The design of solid-state fluorescent carbon dots (CDs) with multi-peak emission has become an urgent challenge to be solved with the in-depth research of CDs in LEDs. Here, one- and two-component solid-state white light CDs are synthesized by microwave-assisted hydrothermal method using the biological pollutant cyanobacteria, respectively. The solid-state fluorescence quantum yield of the one-component CDs was as high as 41.8 %, and the solid-state fluorescence mechanism of CDs is discussed to be mainly attributed to the self-quenching-resistant feature of “core-shell” structure and the reabsorption/RET-induced long-wavelength red light emission, and attenuation of the short emission wavelength. For two-component white light CDs, blue- and red-light CDs are obtained by simple dialysis separation, realizing the fluorescence tunability. The different origins of their multi-peak emission are discussed: core, edge and surface states. The synthesis yields of CDs are up to 62 %, enabling stable gram-scale production. The white- and red-light CDs are used as phosphors to fabricate fluorescent films and cold, pure, and warm white- and red-light LEDs with good resistance to photobleaching and temperature stability and CRI of 84.4, 85.7 and 61.5.

Solvent-controlled tunable Knoevenagel-epoxidation reaction: Synthesis of diverse epoxide derivatives by aldehydes and nitrile methylenes

Here, we report a solvent-controlled tandem Knoevenagel-epoxidation reaction capable of efficiently and selectively synthesizing α-formamidoepoxide and epoxidized benzylidene derivatives of malononitrile dimers. By carefully selecting the solvent system, we demonstrate the tunability of this reaction towards different product outcomes, thereby providing a switchable synthetic platform for various epoxy derivatives. The reaction proceeds under mild conditions with short reaction times, high efficiency, and good tolerance towards diverse functional groups. Furthermore, this method is scalable to gram-scale production.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Rare-Earth-Metal-Free Solid-State Fluorescent Carbonized-Polymer Microspheres for Unclonable Anti-Counterfeit Whispering-Gallery Emissions from Red to Near-Infrared Wavelengths.

Colloidal carbon dots (CDs) have garnered much attention as metal-free photoluminescent nanomaterials, yet creation of solid-state fluorescent (SSF) materials emitting in the deep red (DR) to near-infrared (NIR) range poses a significant challenge with practical implications. To address this challenge and to engineer photonic functionalities, a micro-resonator architecture is developed using carbonized polymer microspheres (CPMs), evolved from conventional colloidal nanodots. Gram-scale production of CPMs utilizes controlled microscopic phase separation facilitated by natural peptide cross-linking during hydrothermal processing. The resulting microstructure effectively suppresses aggregation-induced quenching (AIQ), enabling strong solid-state light emission. Both experimental and theoretical analysis support a role for extended π-conjugated polycyclic aromatic hydrocarbons (PAHs) trapped within these microstructures, which exhibit a progressive red shift in light absorption/emission toward the NIR range. Moreover, the highly spherical shape of CPMs endows them with innate photonic functionalities in combination with their intrinsic CD-based attributes. Harnessing their excitation wavelength-dependent photoluminescent (PL) property, a single CPM exhibits whispering-gallery modes (WGMs) that are emission-tunable from the DR to the NIR. This type of newly developed microresonator can serve as, for example, unclonable anti-counterfeiting labels. This innovative cross-cutting approach, combining photonics and chemistry, offers robust, bottom-up, built-in photonic functionality with diverse NIR applications.

Room-Temperature Synthesis and Low Thermal Conductivity in Nanocrystalline Ag3CuS2.

Noble-metal-based chalcogenide materials recently gained massive attention in the field of thermoelectrics. In most cases, materials are synthesized using (i) high-temperature solid-state reactions or (ii) soft chemical methods where temperature requirements are lower than those of solid-state reactions (generally below 400 °C). Herein, we present a simple, surfactant-free, room-temperature, and energy-efficient synthesis of Ag3CuS2 nanocrystals. The present synthesis technique is scalable and capable of gram-scale production. A spark plasma sintering (SPS) pressed sample exhibits ultralow thermal conductivity (∼0.31 W/mK at room temperature). We found that Ag3CuS2 exhibits low sound velocity, as well as a non-Debye-like behavior based on a low-temperature heat capacity measurement. A high degree of anharmonicity of bonding, soft vibrations modes, and nanoscale grain boundary scattering in Ag3CuS2 lead to ultralow thermal conductivity, which can be important for thermoelectrics, optoelectronics, and thermal barrier coating applications.

Spatiotemporal Control of Protein Refolding through Flash-Change Reaction Conditions.

Recombinant protein production is an essential aspect of biopharmaceutical manufacturing, with Escherichia coli serving as a primary host organism. Protein refolding is vital for protein production; however, conventional refolding methods face challenges such as scale-up limitations and difficulties in controlling protein conformational changes on a millisecond scale. In this study, we demonstrate the novel application of flow microreactors (FMR) in controlling protein conformational changes on a millisecond scale, enabling efficient refolding processes and opening up new avenues in the science of FMR technology. FMR technology has been primarily employed for small-molecule synthesis, but our novel approach successfully expands its application to protein refolding, offering precise control of the buffer pH and solvent content. Using interleukin-6 as a model, the system yielded an impressive 96% pure refolded protein and allowed for gram-scale production. This FMR system allows flash changes in the reaction conditions, effectively circumventing protein aggregation during refolding. To the best of our knowledge, this is the first study to use FMR for protein refolding, which offers a more efficient and scalable method for protein production. The study results highlight the utility of the FMR as a high-throughput screening tool for streamlined scale-up and emphasize the importance of understanding and controlling intermediates in the refolding process. The FMR technique offers a promising approach for enhancing protein refolding efficiency and has demonstrated its potential in streamlining the process from laboratory-scale research to industrial-scale production, making it a game-changing technology in the field.

Organic Base-Promoted C-N- and C-O-Coupled Domino Cyclization Strategy: Syntheses of Oxazine-6-ones and 4-Pyrimidinols.

Oxazine-6-one and 4-pyrimidinol are two important frameworks in pharmaceutical production. Herein, we disclosed a simple, efficient, inexpensive organic base-promoted and additive-stimulated protocol for the syntheses of variably functionalized oxazine-6-ones and 4-pyrimidinols employing acetonitrile solvent under conventional heating conditions using an oil bath through C-N and C-O coupled domino steps. This simple practicable productive protocol utilizes easily producible cheap precursors, namely, benzimidates or benzamidines, with differently substituted dicyano-olefins, and it comprises step economy, robustness, and moisture insensitive conditions affording high yield that avoids the use of transition-metal catalysts, multistep with multicomponent strategy, and harsh reaction conditions involving hazardous chemicals. This method is scalable into gram-scale production with good yield.

A Multi-response Nonlinear Programming Model with an Inscribed Design to Optimize Bioreduction Conditions of (S)-phenyl (pyridin-2-yl)methanol by Leuconostoc pseudomesenteroides N13

AbstractAsymmetric bioreductions have the potential to synthesize chiral alcohols when catalyzed by biocatalysts. Nevertheless, the (S)-phenyl (pyridin-2-yl)methanol ((S)-2) analgesic synthesis poses significant challenges concerning unsatisfactory substrate amount and production method. Thus, this study proposes an inscribed design-focused multi-response nonlinear optimization model for the asymmetric reduction of the phenyl(pyridin-2-yl)methanone (1) with Leuconostoc pseudomesenteroides N13 biocatalyst. From the novel inscribed design-focused multi-response nonlinear optimization model, optimization conditions of the reaction, such as pH = 6, temperature = 29 °C, incubation time = 53 h, and agitation speed = 153 rpm, were found. Also, the reaction conversion was predicted to be 99%, and the product of the enantiomeric excess (ee) was 98.4% under the obtained optimization conditions. (S)-2 was obtained with 99% ee, 99% conversion, and 98% yield while performing a validation experiment using the determined optimized conditions. In addition, 1 with the amount of 11.9 g was converted entirely to (S)-2 (11.79 g, 98% isolated yield) on a high gram scale. Also, this study is noted as the first example of the gram-scale production of (S)-2 using an optimization strategy and biocatalyst. Further, the applicability of the inscribed design-focused optimization model in biocatalytic reactions has been demonstrated and provides an effective process for the analgesic synthesis of (S)-2, which is a green, cost-effective method of producing chiral aryl heteroaryl methanol.

An Improved and Scalable Synthesis of the Potent SREBP Inhibitor KK-052 via [3+2] Cycloaddition

AbstractKK-052 is a novel vitamin-D-based selective sterol regulatory element-binding protein (SREBP) suppressor that lacks vitamin D genomic activity mediated through the vitamin D receptor in both in vitro and in vivo settings. In our initial synthetic effort, KK-052 was produced as one of the structural isomers obtained via the Mitsunobu reaction involving a CD-ring allyl alcohol and 5-phenyl-1H-tetrazole. In this work, we present a refined methodology for enhancing the selective synthesis of KK-052 through a [3+2] cycloaddition between a CD-ring benzimidoyl chloride and sodium azide, a technique that proved amenable to gram-scale production. Additionally, this synthetic method permitted the production of a more potent m-methyl analogue of KK-052.

Directed Evolution of the UDP-Glycosyltransferase UGTBL1 for Highly Regioselective and Efficient Biosynthesis of Natural Phenolic Glycosides.

The O-glycosylation of polyphenols for the synthesis of glycosides has garnered substantial attention in food research applications. However, the practical utility of UDP-glycosyltransferases (UGTs) is significantly hindered by their low catalytic efficiency and suboptimal regioselectivity. The concurrent optimization of the regioselectivity and activity during the glycosylation of polyphenols presents a formidable challenge. Here, we addressed the long-standing activity-regioselectivity tradeoff in glycosyltransferase UGTBL1 through systematic enzyme engineering. The optimal combination of mutants, N61S/I62M/D63W/A208R/P218W/R282W (SMWRW1W2), yielded a 6.1-fold improvement in relative activity and a 17.3-fold increase in the ratio of gastrodin to para-hydroxybenzyl alcohol-4'-O-β-glucoside (with 89.5% regioselectivity for gastrodin) compared to those of the wild-type enzyme and ultimately allowed gram-scale production of gastrodin (1,066.2 mg/L) using whole-cell biocatalysis. In addition, variant SMWRW1W2 exhibited a preference for producing phenolic glycosides from several substrates. This study lays the foundation for the engineering of additional UGTs and the practical applications of UGTs in regioselective retrofitting.

Modulating Ni-S coordination in Ni3S2 to promote electrocatalytic oxidation of 5-hydroxymethylfurfural at ampere-level current density.

Electricity-driven oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) is a highly attractive strategy for biomass transformation. However, achieving industrial-grade current densities remains a great challenge. Herein, by modulating the water content in a solvothermal system, Ni3S2/NF with stabilized and shorter Ni-S bonds as well as a tunable coordination environment of Ni sites was fabricated. The prepared Ni3S2/NF was highly efficient for electrocatalytic oxidation of HMF to produce FDCA, and the FDCA yield and Faraday efficiency could reach 98.8% and 97.6% at the HMF complete conversion. More importantly, an industrial-grade current density of 1000 mA cm-2 could be achieved at a potential of only 1.45 V vs. RHE for HMFOR and the current density could exceed 500 mA cm-2 with other bio-based compounds as the reactants. The excellent performance of Ni3S2/NF originated from the shorter Ni-S bonds and its better electrochemical properties, which significantly promoted the dehydrogenation step of oxidizing HMF. Besides, the gram-scale FDCA production could be realized on Ni3S2/NF in a MEA reactor. This work provides a robust electrocatalyst with high potential for practical applications for the electrocatalytic oxidation of biomass-derived compounds.

Electrochemical one-pot cascade synthesis of thio(seleno)cyanato-substituted thiazolidine-2-imines without external electrolyte.

A novel synthetic method has been developed for generating thio(seleno)cyanato-substituted thiazolidine-2-imines via an electrochemical one-pot cascade reaction. This reaction employs isothiocyanates, N-2-en-1-amines, and KSCN (or KSeCN) under mild conditions, obviating the need for metals, chemical oxidants, and external electrolytes. The protocol is effective with unactivated alkenes and facilitates the synthesis of five- and six-membered thio(seleno)cyanato-substituted thiazolidine-2-imines. The versatility is demonstrated by its straightforward operation and scalability to gram-scale production, underscoring its potential for broader application.

Gram-scale green synthesis of a highly stable cationic covalent organic framework for efficient and selective removal of ReO4−/99TcO4−

Green hydrothermal synthesis achieves gram-scale production of a cationic COF sorbent with high stability for the rapid and selective removal of 99TcO4− contaminants.

Electrochemically-driven difunctionalization of the isocyanide and Mumm rearrangement cascade: expeditious synthesis of N-acyl-N-alkyl S-thiocarbamates.

We describe the novel electrochemical multicomponent reaction (e-MCR) of readily available isocyanides, thiols and carboxylic acids to form N-substituted S-thiocarbamate derivatives that are found in several biologically active compounds. The effectiveness of the μ-electro flow reactor (μ-EFR) was showcased through significant reduction in electrolyte volume during the reaction, achieving gram-scale production of 4a within a short 12 min residence time using a Pt/Pt flow cell.

Aqueous Sol-Gel Synthesis and Shaping of Covalent Organic Frameworks.

The intrinsic fragility and insoluble nature of covalent organic frameworks (COFs) have strongly impeded their processability for practical applications. Herein, an aqueous-based sol-gel synthetic strategy is reported for the synthesis and shaping of COFs with task-specific applications that satisfy the principles of green chemistry for gram-scale production of crystalline materials. Our successful approach involves three pivotal aspects: the "prodrug mimic" design of water-soluble monomers, the utilization of hydrolyzable bonds, and the manipulation of reaction kinetics. The generality of the method is demonstrated by the successful preparation of representative high-surface area two-dimensional (2D) COFs with several commonly used amines. By virtue of this strategy, a COF colloidal dispersion is achieved and can be formulated into processable fluids, structured films, and COF monoliths. Remarkably, the obtained lightweight (∼0.020 g cm-3) and robust aerogels displayed outstanding adsorption capacity (exceeding 57 times its own weight) toward a variety of organic solvents and exhibited superior thermal insulating properties compared to the widely used sponge and cotton. This work demonstrates a versatile strategy for the synthesis and shaping of processable COF materials in water that will contribute to the development of COF monoliths for advanced applications.