Catalyst-free Approach Research Articles

Environmentally Friendly Synthesis of New Mono- and Bis-Pyrazole Derivatives; In Vitro Antimicrobial, Antifungal, and Antioxidant Activity; and In Silico Studies: DFT, ADMETox, and Molecular Docking

Background/Objectives: Antimicrobial resistance and oxidative stress are major global health challenges, necessitating the development of novel therapeutic agents. Pyrazole derivatives, known for their diverse pharmacological properties, hold promise in addressing these issues. This study aimed to synthesize new mono- and bis-pyrazole derivatives using an eco-friendly, catalyst-free approach and evaluate their antioxidant, antibacterial, and antifungal activities, supported by in silico ADMET profiling, molecular docking, and Density Functional Theory (DFT) analysis. Methods: The compounds were synthesized via a green condensation reaction and characterized using NMR and mass spectrometry, which was verified by DFT analysis. Biological activities were assessed through DPPH and FRAP antioxidant assays, as well as disk diffusion and MIC methods, against bacterial strains (Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli) and fungal strains (Candida albicans and Aspergillus niger). Computational ADMET profiling evaluated pharmacokinetics and toxicity, while molecular docking assessed interactions with target proteins, including catalase, topoisomerase IV, and CYP51. Results: Theoretical calculations using DFT were in agreement with the experimental results; regarding biological activities, O4 demonstrated the most significant antioxidant activity, with 80.14% DPPH radical scavenging and an IC50 value of 40.91 µg/mL. It exhibited potent antimicrobial activity, surpassing Streptomycin with a 30 mm inhibition zone against Pseudomonas aeruginosa and showing strong efficacy against Staphylococcus aureus and Candida albicans. Computational studies confirmed favorable pharmacokinetic properties, no AMES toxicity, and strong binding affinities. DFT analysis revealed O4’s stability and reactivity, further validating its potential as a therapeutic candidate. Conclusions: This study identified and characterized novel pyrazole derivatives with promising biological and pharmacological properties. O4 emerged as the most potent compound, demonstrating strong antioxidant and antimicrobial activities alongside favorable computational profiles. These findings highlight the potential of the synthetized compounds for therapeutic development and underscore the value of integrating green synthesis with computational techniques in drug discovery.

Solvent-Controlled Cascade Reaction of SeO2, Sulfonyl Hydrazides and Alkynes for Chemoselective Access to Symmetric Divinyl Sulfones Substituted Seleniums and Diseleniums.

A solvent-controlled unprecedented tandem reaction of readily accessible SeO2, a wide variety of sulfonyl hydrazides, and alkynes has been established for the chemodivergent construction of structurally complex 1,2-bis((E)-1-aryl-2-arylsulfonylvinyl)diselanes and bis((E)-1-aryl-2-(arylsulfonyl)vinyl)selanes via a catalyst-free one-pot three-component approach, respectively. The adjustable and controlled synthetic strategy shows good yields and chemoselectivities for most substrates under mild and simple conditions.

Photoredox-Catalyst-Free Carboxylation of Unactivated Alkenes in DMSO: Synthesis of Polycyclic Indole Derivatives and Aliphatic Acids.

A new method for the carboxylation of unactivated alkenes using CO2 radical anions in the absence of a photoredox catalyst has been developed. The photocatalyst-free approach enables the efficient synthesis of polycyclic indole derivatives and linear carboxylic acids under mild conditions from HCO2K with/without 1,4-diazabicyclo[2.2.2]octane (DABCO) in DMSO. This work demonstrates a significant advance in green chemistry, showcasing a catalyst-free approach for the functionalization of unactivated alkenes with cheap and readily available HCO2K.

Catalyst-Free Construction of Imidazole-Pyrrolo[1,2-a]pyrazine Hybrid, 2,6-Disubstituted Imidazo[1,2-a]pyrrolo[2,1-c]pyrazine via Regioselective Annulative Functionalizations.

Highly efficient catalyst-free annulative functionalization approaches to a novel imidazole-pyrrolo[1,2-a]pyrazine hybrid structure were devised from the reaction of β-enaminone with propargylamine where regioselective conjugate substitution of β-enaminone with propargylamine followed by cycloisomerization proceeded smoothly in a domino fashion to construct two heterocyclic moieties (pyrazine and imidazole) via successive formation of three C-N bonds, leading to the target tricyclic skeleton.

Highly selective alcohol oxidation by polyvinyl cyanuric chloride in DMSO: a metal- and catalyst-free approach

Highly selective alcohol oxidation by polyvinyl cyanuric chloride in DMSO: a metal- and catalyst-free approach

Iron-Catalyzed Laser-Induced Graphitization - Multiscale Analysis of the Structural Evolution and Underlying Mechanism.

The transition to sustainable materials and eco-efficient processes in commercial electronics is a driving force in developing green electronics. Iron-catalyzed laser-induced graphitization (IC-LIG) has been demonstrated as a promising approach for rendering biomaterials electrically conductive. To optimize the IC-LIG process and fully exploit its potential for future green electronics, it is crucial to gain deeper insights into its catalyzation mechanism and structural evolution. However, this is challenging due to the rapid nature of the laser-induced graphitization process. Therefore, multiscale preparation techniques, including ultramicrotomy of the cross-sectional transition zone from precursor to fully graphitized IC-LIG electrode, are employed to virtually freeze the IC-LIG process in time. Complementary characterization is performed to generate a 3D model that integrates nanoscale findings within a mesoscopic framework. This enabled tracing the growth and migration behavior of catalytic iron nanoparticles and their role during the catalytic laser-graphitization process. A three-layered arrangement of the IC-LIG electrode is identified including a highly graphitized top layer with an interplanar spacing of 0.343nm. The middle layer contained γ-iron nanoparticles encapsulated in graphitic shells. A comparison with catalyst-free laser graphitization approaches highlights the unique opportunities that IC-LIG offers and discuss potential applications in energy storage devices, catalysts, sensors, and beyond.

Molecular dynamics simulation study of graphene synthesis by rotating arc plasma

The rotating arc plasma method, based on its unique characteristics, provides a simple, efficient, and catalyst-free approach for graphene material synthesis. This study employs molecular dynamics simulations to theoretically investigate the detailed growth process of graphene at the atomic scale using plasma. During the growth process, different radicals serve as dissociation precursors within the plasma. Simulation results indicate that the growth process of graphene clusters involves three stages: extension of carbon clusters, cyclization of carbon chains, and coalescence of clusters into sheets. Firstly, the precursor concentration affects the size of graphene clusters; increasing the precursor concentration enlarges the cluster size but also increases the likelihood of curling. Secondly, increasing the hydrogen content in the precursor can reduce the growth rate of clusters, decrease dangling bonds at the periphery of clusters, thereby slowing down cluster closure and maintaining a well-defined sheet structure. Lastly, appropriately elevating the simulation temperature can enhance the reaction rate during the simulation process without altering the reaction pathway. These research findings establish the foundation for understanding the growth mechanism of graphene.

Bonding-Directed Crystallization of Ultra-Long One-Dimensional NbS3 van der Waals Nanowires.

The rediscovery of one-dimensional (1D) and quasi-1D (q-1D) van der Waals (vdW) crystals ushered the realization of nascent physical properties in 1D that are suitable for applications in photonics, electronics, and sensing. However, despite renewed interest in the creation and understanding of the physical properties of 1D and q-1D vdW crystals, the lack of accessible synthetic pathways for growing well-defined nanostructures that extend across several length scales remains. Using the highly anisotropic 1D vdW NbS3-I crystal as a model phase, we present a catalyst-free and bottom-up synthetic approach to access ultralong nanowires, with lengths reaching up to 7.9 mm and with uniform thicknesses ranging from 13 to 160 nm between individual nanowires. Control over the synthetic parameters enabled the modulation of intra- and interchain growth modalities to selectively yield only 1D nanowires or quasi-2D nanoribbons. Comparative synthetic and density functional theory (DFT) studies with a closely related nondimerized phase, ZrS3, show that the unusual preferential growth along 1D can be correlated to the strongly anisotropic bonding and dimeric nature of NbS3-I.

Dehydration in Water: A Reagentless and Straightforward Synthesis of Tetrahydroquinazolines under Microwave Irradiation or by Stirring at Room Temperature, and Their Subsequent Conversion into Quinazolines in a Micellar Medium

AbstractUsing a reagent- and catalyst-free approach, a series of 2-substituted 1,2,3,4-tetrahydroquinazolines is synthesized by cyclocondensation between aldehydes and 2-aminobenzylamines via dehydration in water. The reactions are complete in 2 minutes under microwave irradiation and proceed well under stirring at room temperature, affording tetrahydroquinazolines in high to excellent yields. The products are water-insoluble and are isolated by simple filtration, avoiding a conventional work-up step and offering an organic-solvent-free process. Furthermore, the tetrahydroquinazolines are efficiently oxidized in a micellar medium derived from cetyltrimethylammonium bromide (CTAB) using a cheap commercial bleaching solution (4% NaOCl in water) to give quinazolines in high yields. This sustainable protocol has a near zero E-factor.

Demethylation C–C coupling reaction facilitated by the repulsive Coulomb force between two cations

Carbon chain elongation (CCE) is normally carried out using either chemical catalysts or bioenzymes. Herein we demonstrate a catalyst-free approach to promote demethylation C–C coupling reactions for advanced CCE constructed with functional groups under ambient conditions. Accelerated by the electric field, two organic cations containing a methyl group (e.g., ketones, acids, and aldehydes) approach each other with such proximity that the energy of the repulsive Coulomb interaction between these two cations exceeds the bond energy of the methyl group. This results in the elimination of a methyl cation and the coupling of the residual carbonyl carbon groups. As confirmed by high-resolution mass spectrometry and isotope-labeling experiments, the C–C coupling reactions (yields up to 76.5%) were commonly observed in the gas phase or liquid phase, for which the mechanism was further studied using molecular dynamics simulations and stationary-point calculations, revealing deep insights and perspectives of chemistry.

Catalyst-free Approach to Dihydropyrimidones Using Glycerol/Ethyl Lactate as a Recyclable and Biodegradable Promoting Medium

Abstract: A variety of dihydropyrimidone compounds were synthesised using an effective one-pot, multicomponent, environmentally friendly reaction of aromatic aldehydes, urea/thiourea, ethyl acetoacetate, and glycerol/ethyl lactate. To the best of our knowledge, this is the first catalyst-free strategy for the synthesis of this key scaffold with medicinal chemistry applications. Other significant aspects of the current approach consist of the employment of glycerol/ethyl lactate as a biodegradable and environmentally friendly reaction medium-cum-promoter, the use of easily available substrates, moderate reaction conditions, ease of use, a wide substrate scope, a short reaction time, easy workup, and excellent yields, and atom efficiency, which make the disclosed procedure an excellent alternative to existing methods.

Exploring the Potential of High-Fatty Acid Content Oils for Biodiesel Production: A Catalyst-Free Approach

Abstract The adoption of biofuels has been recognized as one of the key approaches to strive towards achieving net zero emissions, particularly through the utilization of biodiesel derived from oils or fatty acids. To further optimize the utilization of biodiesel, it becomes crucial to explore alternative non-food resources, such as oils with a high content of fatty acids, to serve as biodiesel feedstock. This paper examines the potential use of oil with high fatty acid content, specifically palm fatty acid distillate (PFAD), as a biodiesel feedstock. Typically, the biodiesel production process from PFAD involves a two-step catalytic process that requires a strong acid catalyst, known for its corrosiveness, that needs costly equipment materials. This research explores a catalyst-free production process ensuring a non-corrosive process with reduced capital expenses and fewer chemicals, thereby lowering operational costs. The results demonstrate that biodiesel from PFAD can be obtained in concentration of 83.9% using a one-step non-catalytic process with superheated methanol vapor at a temperature of 210°C under atmospheric pressure. This highlights the significant potential of catalyst-free technology in the production of biodiesel from PFAD.

Efficient Catalyst-Free One-Pot Synthesis of Polysaccharide-Polypeptide Hydrogels in Aqueous Solution.

The preparation of polysaccharide-peptide hydrogels usually involves multiple synthetic steps, thus reducing the effectiveness and practicality of these approaches. Inspired by recent discoveries in aqueous N-carboxyanhydride (NCA) ring-opening polymerization (ROP) and ring-opening polymerization-induced nanogelation, we present an aqueous one-pot strategy to prepare polysaccharide-polypeptide hydrogels. In this study, water-soluble polysaccharide carboxymethyl chitosan is used as the macromolecular initiator to prepare polysaccharide-polypeptide copolymers through the aqueous ROP of NCA. The catalyst-free approach afforded hydrogels with properties that could be controlled by adjusting the type and amount of NCA used, with the elastic modulus ranging from 50 Pa to 18000 Pa. The hydrogen bond-cross-linked hydrogel exhibited self-healing and injectable properties. Morphology characterization revealed that micelles were formed in the early stage of reaction, suggesting that the polymerization follows an aqueous ring-opening polymerization-induced self-assembly (ROPISA) mechanism and that aggregation of micelles during the reaction caused the gelation. Moreover, the hydrogels displayed high swelling ratios (>95% water content), and hemolysis and cytotoxicity experiments demonstrated that the hydrogels had excellent biocompatibility, indicating their potential in medical applications.

High-Performance Bio-Based Non-Isocyanate Polyurethane Adhesive: A Solvent and Catalyst-Free Synthesis Approach

High-Performance Bio-Based Non-Isocyanate Polyurethane Adhesive: A Solvent and Catalyst-Free Synthesis Approach

Sustainable synthesis of imidazoles using a catalyst-free approach and ethyl lactate as a bio-based green solvent in the Debus-Japp-Radziszewski reaction

A highly substituted family of imidazoles is effectively obtained through the Debus-Japp-Radziszewski reaction. In this process, benzil, ammonium acetate, and various benzaldehydes react in a particularly notable solvent: ethyl lactate (EL). This bio-based solvent, derived from biomass fermentation, stands out not only for its sustainable origin but also for its remarkable properties. Ethyl lactate is biodegradable, health-risk-free, is easily recyclable, and is non-corrosive, categorizing it as an exemplary green solvent. The multicomponent reaction, carried out under these conditions, eliminates the need for a catalyst, resulting in products with good yields. The isolation of the products is very simple, requiring only filtration, as they are insoluble in the solvent. In this way, this methodology aligns with various principles of green chemistry, emphasizing the strategic choice of ethyl lactate. This choice has a positive impact on the synthesis of imidazoles, well-known for their pharmacological properties.

Continuous production of 5-hydroxymethylfurfural: A catalyst-free approach using non-toxic solvents for pharmaceutical applications

This work aimed to develop the continuous 5-HMF production process from cane syrup for pharmaceutical applications. A catalyst-free process and a non-toxic solvent were implemented to achieve a cost-effective production process with considerations of safety and environmental impacts. This work studied the roles and influences of various non-toxic organic solvents on production performance and cost. The most common effective solvent (methyl isobutyl ketone) was used as a benchmark. The effects of various operating conditions on the 5-HMF yield and 5-HMF productivity were investigated and optimized based on an experimental design using the most suitable solvent selected. The 5-HMF yield of 66.8 % and 5-HMF production rate of 9.35 × 10−6 kg/h were achieved under the reaction temperature of 190 °C, residence time of 80 min, syrup feed concentration of 25 g/L, and organic-to-aqueous volumetric ratio of 1:1. The satisfactory 5-HMF yield and reasonable 5-HMF production were observed when compared to other processes obtained from the literature. The feasibilities for improving this process was also discussed.

Solvent- and Catalyst-Free Synthesis of gem-Difluorinated and Polyfluoroarylated Compounds with Nucleophilic or Electrophilic Fluorine-Containing Reaction Partners, Respectively

A novel, efficient and environmentally friendly solvent-free and catalyst-free approach for the synthesis of structurally diverse gem-difluorinated and polyfluoroarylated derivatives with readily available nucleophilic and electrophilic fluorine-containing reaction partners, difluoroenoxysilane and pentafluorobenzaldehyde, is described. This neat protocol is induced by the direct hydrogen-bond interactions between fluorinated and non-fluorinated reactants without the use of heavy metal catalysts or volatile organic solvents and with no need for column chromatographic separation for most cases.

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles.

A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method enables a rapid access to heterocycles containing a trifluoromethyl group.

Intramolecular chaperone-assisted dual-anchoring activation (ICDA): a suitable preorganization for electrophilic halocyclization.

The halocyclization reaction represents one of the most common methodologies for the synthesis of heterocyclic molecules. Many efforts have been made to balance the relationship between structure, reactivity and selectivity, including the design of new electrophilic halogenation reagents and the utilization of activating strategies. However, discovering universal reagents or activating strategies for electrophilic halocyclization remains challenging due to the case-by-case practice for different substrates or different cyclization models. Here we report an intramolecular chaperone-assisted dual-anchoring activation (ICDA) model for electrophilic halocyclization, taking advantage of the non-covalent dual-anchoring orientation as the driving force. This protocol allows a practical, catalyst-free and rapid approach to access seven types of small-sized, medium-sized, and large-sized heterocyclic units and to realize polyene-like domino halocyclizations, as exemplified by nearly 90 examples, including a risk-reducing flow protocol for gram-scale synthesis. DFT studies verify the crucial role of ICDA in affording a suitable preorganization for transition state stabilization and X+ transfer acceleration. The utilization of the ICDA model allows a spatiotemporal adjustment to straightforwardly obtain fast, selective and high-yielding synthetic transformations.

Deciphering the Knoevenagel condensation: towards a catalyst-free and water-mediated process.

The Knoevenagel condensation constitutes one of the most well-studied and crucial transformations in organic chemistry, since it facilitates the synthesis of numerous valuable compounds. With the advent of green chemistry, several alternative protocols for the Knoevenagel reaction have been introduced and catalyst-free approaches to the Knoevenagel condensation have also been mentioned, however the harsh temperatures employed and the limited substrate scope restricted their application. Herein, we have performed an extensive study on the catalyst-free and water-mediated Knoevenagel reaction, with specific focus on optimising the green parameters and metrics of our methodology. Additionally, we directly compared our approach with previous catalyst-free methods, while providing a fast assembly of multiple compounds in parallel.