Cycloaddition Research Articles

Length and Sequence-Selective Polymer Synthesis Templated by a Combination of Covalent and Noncovalent Base-Pairing Interactions.

Information can be encoded and stored in sequences of monomer units organized in linear synthetic polymers. Replication of sequence information is of fundamental importance in biology; however, it represents a challenge for synthetic polymer chemistry. A combination of covalent and noncovalent base pairs has been used to achieve high-fidelity templated synthesis of synthetic polymers that encode information as a sequence of different side-chain recognition units. Dialkyne building blocks were attached to the template by using ester base pairs, and diazide building blocks were attached to the template by using H-bond base pairs. Copper-catalyzed azide-alkyne cycloaddition reactions were used to zip up the copy strand on the template, and the resulting duplex was cleaved by hydrolyzing the covalent ester base pairs. By using recognition-encoded melamine oligomers with either three phosphine oxide or three 4-nitrophenol recognition units to form the noncovalent base pairs, exceptionally high affinities of the diazides for the template were achieved, allowing the templated polymerization step to be carried out at low concentrations, which promoted on-template intramolecular reactions relative to competing intermolecular processes. Two different templates, a 7-mer and an 11-mer, were used in the three-step reaction sequence to obtain the sequence-complementary copy strands with minimal amounts of side reaction.

Utilizing MEDT analysis of [3 + 2] cycloaddition reaction: x-ray crystallography of spirooxindole linked with thiophene/furan heterocycles and triazole framework.

Hybridization of spirooxindole with different pharmacophores such as triazole and heterocycle such as thiophene and furan moiety was achieved by the [3 + 2] cycloaddition (32CA) reaction approach. Structural investigations of the compounds 4a and 4b were performed using X-ray single crystal structure determinations and Hirshfeld analysis. Both compounds crystallized in monoclinic crystal system. The space group is P21/c for 4a and P21/n for 4b. The crystal parameters are a = 10.2619(3) Å, b = 13.6776(3) Å, c = 10.9318(3), β = 116.640(4)° for the former while a = 13.0012(1) Å, b = 14.9692(1) Å, c = 14.1178(1) Å, β = 97.101(1)° for the latter. In both compounds, the aryl group and the triazole moieties are twisted from one another. The twist angle is 84.75˚for 4a while 86.64˚ for 4b. Based on Hirshfeld calculations, the Cl…H, O…H, N…H and C…H non-covalent interactions in 4a while the O…H interactions in 4b are the most important. The molecular mechanism of the key 32CA reaction between the in situ generated azomethine ylides and the corresponding chalcones has been studied within the Molecular Electron Density Theory (MEDT). The MEDT study reveals that the low activation energies and high experimental selectivity are the result of the supernucleophilic character of the ylides and the strong electrophilicity of the chalcones, which favour the process through a high polar character. This high polar character accounts for the total endo selectivity experimentally found.

Fullerene-hybridized Fused-ring Electron Acceptor with High Dielectric Constant and Isotropic Charge Transport for Organic Solar Cells.

A novel isotropic fullerene-hybridized fused-ring electron acceptor, designated C60-Y, has been synthesized via a mild [4+2] Diels-Alder cycloaddition reaction with fullerene C60 to enhance the performance of organic solar cells (OSCs). Comparative analysis shows that C60-Y significantly outperforms the control acceptor Me-Y, with a notable increase in the relative dielectric constant from 2.79 to 3.95. This improvement enhances exciton dissociation and reduces non-radiative energy losses. Additionally, the isotropic molecular packing of C60-Y, similar to fullerene, facilitates efficient interface formation with donor polymers and improves charge mobility. As a result, incorporating C60-Y as an electron acceptor increases the power conversion efficiency (PCE) of binary OSCs to 15.02%, surpassing the 13.31% achieved with Me-Y. Moreover, when integrated into a ternary blend system, an impressive PCE of 19.22% is achieved, top-performing among reported ternary OSCs utilizing fullerene derivatives as the third component. These results suggest that fullerene-hybridized acceptors like C60-Y hold great potential for advancing high-efficiency OSCs by enhancing exciton dissociation, reducing energy losses, and improving charge mobility.

Design, Synthesis, and Anti-Mycobacterial Evaluation of Triclosan-Isoniazid Hybrids.

A series of Triclosan-based hybrids and their Schiff base derivatives with isoniazid were designed through in silico modelling and synthesized using copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were then evaluated against both Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mab). However, none of the synthesized hybrids exhibited significant growth inhibition, with minimum inhibitory concentration (MIC) values consistently exceeding 100 µg/mL. To further investigate these findings, we conducted mechanistic studies including thermogravimetric analysis (TGA) and UV-Vis stability tests. TGA demonstrated thermal stability of the Schiff bases up to 270 °C, while UV-Vis analysis confirmed their chemical resilience across a wide pH spectrum, showing resistance to hydrolysis under acidic and basic conditions. The lack of observed antimicrobial activity may be attributed to the high lipophilicity of these molecules, as indicated by LogP values exceeding 5, which could limit their bioavailability. These findings suggest that although combining triclosan and isoniazid holds potential, further optimization of this hybrid strategy is necessary to improve efficacy.

Zinc Bioinspired Catalytic System for the Valorization of CO2 Into Cyclic Carbonates

AbstractCyclic organic carbonates are defined as key compounds for a sustainable chemical economy. Their synthesis from CO2 under mild conditions is a useful way to valorise this greenhouse gas as carbon source. Even if a wide range of catalysts were described to promote the carbon dioxide cycloaddition into epoxides, only few ones concern enzymatic systems. The zinc–l‐histidine active site of carbonic anhydrase inspired the present work, pointing out that the imidazole moiety of the amino acid ligand has a crucial role. An extensive study was undertaken to establish the structure–activity relationship of imidazole derivatives, zinc salts, and their respective catalytic activity in the CO2 cycloaddition reaction. The effect of aromatic, alkyl, or iodine substituents and their position in N‐heterocycles were highlighted. A synergic effect was noted when combining imidazole compounds with zinc salts. The optimization of reaction conditions emphasised the in situ ZnI2–1‐methylimidazole catalytic system, which is selective toward cyclic styrene carbonates and efficient under solvent‐free mild conditions (50 °C, atmospheric CO2 pressure). Once reusing tests confirmed the catalytic system robustness, the reaction scope was enlarged to several epoxides resulting in 84%–99% yields of their corresponding cyclic carbonates.

An Electrochemical Route to Novel N‐benzoyl‐1,2,3‐triazoles and Protein Binding Studies of Selected Triazole Derivatives

AbstractAn electrochemical, cost‐efficient and atom‐economic method for the synthesis of novel, structurally unique N‐benzoyl‐1,2,3‐triazole derivatives has been developed via cascade oxidation‐ 1,3‐dipolar cycloaddition reaction of readily available propargyl alcohol and benzoyl azide. The electro‐oxidation of propargyl alcohol and subsequent cycloaddition was performed in an undivided cell using graphite rod and stainless‐steel plate as inexpensive electrode materials. Numerous 4,5‐disubstituted N‐benzoyl‐1,2,3‐triazoles may be synthesized from milli to multi‐gram scale employing this protocol. The biological significance of few selected triazole derivatives were evaluated via protein binding studies.

Synthesis of Clickable Isotactic Poly(vinyl ether)s through Organocatalytic Stereoselective Cationic Copolymerization.

By virtue of the high reliability of click chemistry, polymers with clickable groups provide a useful platform for the rapid synthesis of polymer materials with diverse functionalities and architectures. However, the polymerization of clickable vinyl monomers with a concurrent regulation on tacticity remains underdeveloped. Herein, we report the successful development of a stereoselective cationic copolymerization of C-C triple bond-containing vinyl ethers with simple alkyl vinyl ethers by employing confined Brønsted acid as catalyst, which allows for the synthesis of alkyne-functionalized vinyl ether copolymers with high isotacticity (up to 90% m), controlled molecular weight, and variable content of C-C triple bonds. Further transformation of the pendant clickable alkyne groups via thiol-yne click reactions and copper(I)-catalyzed alkyne-azide cycloaddition reaction enables a modular access to isotactic polymers with various functional groups.

Stereochemical Shape Morphing in Diels-Alder Polymer Networks.

The intrinsic reversibility of dynamic covalent bonding, such as the furan-maleimide Diels-Alder (DA) cycloaddition reactions, enables reprocessable, self-healing polymer materials that can be reconfigured via the mechanism of solid-state plasticity. In this work, the temperature-dependent exchange rates of stereochemically distinct endo and exo DA bonds are leveraged to achieve tunable, temperature- and stress-activated shape morphing in Diels-Alder polymer (DAP) networks. Through thermal annealing, ≈35% of endo DA isomers are converted in neat DAP networks to the thermodynamically favored exo form, achieving ≈97% exo after complete annealing at 60°C. This conversion results in a ≈1.7 fold increase in elastic modulus, from 1.7 to 3.0MPa, and significantly alters the stress relaxation and shape recovery behavior. Spatially resolved annealing, is further showcased enabling the precise control of spatial distributions of endo and exo DA bonds across planar geometries. The locally distinct concentrations of endo/exo isomers, achieved by temperature-induced conversion of endo DA isomers to the thermodynamically stable exo DA isomers, gave rise to the spatial distributions of stress relaxation rates and elastic strain recovery mismatch to enable controlled stereochemical shape morphing. This approach provides a simplified, thermally driven method for shape morphing, with potential applications in soft robotics and flexible electronics.

Synthesis of 1,10-phenanthroline-2,9-bistriazoles: Evaluation as G-quadruplex binders and anti-tumor activity.

Novel 1,10-phenanthroline-2,9-bistriazoles derivatives have been synthesized by copper-catalyzed azide/alkyne cycloaddition reactions and assessed for their ability to bind and stabilize G-quadruplex (G4) structures. Ten novel compounds were evaluated using Förster resonance energy transfer (FRET) melting, circular dichroism (CD), and fluorescence spectroscopy on several G4 sequences. Biophysical characterization led to the identification of compounds 4a, 4b, and 5b as good G4 ligands of KRAS G4 sequences. The cell viability of all derivatives was also assessed, revealing weak effects. However, compound 2a exhibited cytotoxicity activity on A549 and H1299 cancer cells and low cytotoxicity towards non-malignant cells MRC-5 not connected with its G4-binding ability. Flow cytometry showed that 2a induced a cell viability decrease in S and G2/M phases for A549 and H1299; thus, more studies should be performed to explore the proteins involved in cell cycle regulation.

Selective Synthesis of Dihydro- and Dehydrogenated Spirocyclopenta[b]indoles via Acid-modulated [3+2] Cycloaddition Reaction

Selective Synthesis of Dihydro- and Dehydrogenated Spirocyclopenta[b]indoles via Acid-modulated [3+2] Cycloaddition Reaction

Pyrazoline and Analogs: Substrate-based Synthetic Strategies.

Among the many reports published on strategies applicable to synthesizing pyrazolines and its analogs, The 1,3-dipolar cycloaddition offers a remarkably wide range of utility. Many 1,3-dipolar cycloaddition reactions used for the synthesis of pyrazolines provide better selectivity, eco-friendly, and less expensive chemical processes. In the presented study, we have reviewed various recently adopted strategies for the synthesis of pyrazoline, which followed the 1,3-dipolar cycloaddition reactions mechanism and classified them based on starting materials such as nitrile imines, diazo compounds, different zwitter ions, chalcones, and isoprene units. The manuscript also focused on the synthesis of pyrazolines starting from Seyferth-Gilbert reagents (SGR) and Psilostachyin (PSH) reagents. We hope this work will help those engaged or have plans to research pyrazoline or its analogs, as synthetic protocols based on starting material are rarely available for pyrazolines. Thus, this article holds a valuable complement to the development of newer pyrazoline and its derivatives.

One-step condensation synthesis of di-tertiary ammonium salt protic ionic liquid for efficiently catalytic CO2 cycloaddition reaction under cocatalyst- and solvent-free conditions

A novel protic ionic liquid di-tertiary ammonium bromide ionic liquid (DTAB-IL) was synthesized by one-step condensation at 0 ℃ with 85 % yield. DTAB-IL also exhibited effective catalytic activity for CO2 cycloaddition without cocatalyst and solvent. The catalytic reaction conditions were optimized to 90 ℃, 4 h, 1 MPa, and the yield of propylene carbonate was obtained 96 % with high selectivity 99 %. Under the optimal conditions, DTAB-IL catalyst exhibited good recyclability and universality to various epoxides. Furthermore, temperature influence and kinetic investigation for propylene carbonate synthesis were studied. The activation energy for DTAB-IL catalyzing CO2 cycloaddition reaction was 43.93 kJ/mol, and the reaction was found to follow first-order for propylene oxide. Efficient cycloaddition reaction of CO2 and epoxide was attributed to the activation of epoxide and CO2 by di-tertiary ammonium and epoxide ring-opening by bromide anion in DTAB-IL.

CO2 Fixation via epoxide cycloaddition with a highly active and stable MOF-808/GO composite catalyst

The CO2 cycloaddition reaction effectively mitigates the greenhouse effect while producing high-value cyclic carbonates. Metal-organic frameworks (MOFs) have shown promise for CO2 cycloaddition with epoxides; however, the aggregation of MOFs due to high surface energy hinders mass transfer and catalytic performance. By pre-coordinating graphene oxide (GO) to regulate the dispersion of MOF-808, the resulting MOF-808/GO-100 composite catalyst exhibits twice the activity of pristine MOF-808, achieving 92.6% conversion of epichlorohydrin (ECH) with 98.2% selectivity to ECH carbonate without adding any co-catalysts. The incorporation of GO introduces numerous hydroxyl groups on the catalyst surface, serving as hydrogen bonding donors. The oxygen-containing groups on GO can compete with ligands for Zr coordination, generating defective Zr sites. The synergistic effect between defective Zr sites and hydrogen bonding donors collectively promotes epoxide opening. Notably, GO correspondingly enhances the dispersion of MOF-808 and induces mesopore formation through its stacking effect at the interface with MOF-808. Across various epoxide cycloaddition reactions, MOF-808/GO-100 consistently demonstrated optimal performance and maintained high stability over multiple reaction cycles.

Synergistic effects of hydroxyl and tertiary amine in the catalytic carbonatization of epoxides with CO2 at atmospheric pressure

Fixation of carbon dioxide is a key issue for the sustainable synthesis of chemical compounds. A catalyst system for the preparation of cyclic carbonates by the fixation of carbon dioxide (CO2) onto epoxides is presented. This system is designed for easy application due to the availability of the compounds on an industrial scale as well as moderate reaction conditions. Notably, it avoids the use of metal-halogen catalysts and instead employs a tertiary amine as the catalytic center, in conjunction with an alcohol acting as a hydrogen bond donor (HBD). The kinetics of the cycloaddition reaction between epoxides and CO2 were thoroughly investigated using IR spectroscopy. Remarkably, optimization of the amino-to-alcohol group ratio and the amine structure was carried out to enhance the overall performance of the catalyst system showing a synergistic effect between the tertiary amine and the hydroxyl. Most notably, this entire process is conducted without the use of solvents and operates at ambient pressure, underscoring its significant ecological advantages.

Simultaneous Cycloadditions in the Solid State via Supramolecular Assembly

AbstractChemical reactions conducted in the solid phase (specifically, crystalline) are much less numerous than solution reactions, primarily due to reduced motion, flexibility, and reactivity. The main advantage of crystalline‐state transformations is that reactant molecules can be designed to self‐assemble into specific spatial arrangements, often leading to high control over product regiochemistry and/or stereochemistry. In crystalline‐phase transformations, typically only one type of reaction occurs, and a sacrificial template molecule is frequently used to facilitate self‐assembly, similar to a catalyst or enzyme. Here, we demonstrate the first system designed to undergo two chemically unique and orthogonal cycloaddition reactions simultaneously within a single crystalline solid. Well‐controlled supramolecular self‐assembly of two molecules containing different reactive moieties affords orthogonal reactivity without use of a sacrificial template. Using only UV light, the simultaneous [2+2] and [4+4] cycloadditions are achieved regiospecifically, stereospecifically, and products are obtained in high yield, whereas a simultaneous solution‐state reaction affords a mixture of isomers in low yield. Application of dually‐reactive systems toward (supra)molecular solar thermal storage materials is also discussed. This work demonstrates fundamental chemical approaches for orthogonal reactivity in the crystalline state and highlights the complexity and reversibility that can be achieved with supramolecular design.

Machine learning-assisted screening of efficient ionic liquids for catalyzing CO2 cycloaddition reaction

The catalysis of CO2 cycloaddition reactions by ionic liquids holds significant promise in addressing environmental and chemical synthesis challenges. However, the design of effective ionic liquid catalysts is hindered by the sheer diversity of cation-anion combinations, leading to challenges in targeted catalyst development. This study addresses these issues by utilizing experimental data collected from literature on reactions involving epoxy compounds as substrates, conducted without solvents or co-catalysts, to establish a database for machine learning (ML). Simple descriptors derived from the ion pair structures of ionic liquids are employed as inputs for five ML classification algorithms to predict the yield of CO2 cycloaddition reactions. Subsequently, the highly accurate ML models are applied to forecast the catalytic performance of 1344 ionic liquids under ambient conditions. This approach identifies 13 cation structures and 8 anion structures that exhibit superior catalytic properties. Further refinement through density functional theory (DFT) calculations selects ion pair structures capable of catalyzing CO2 cycloaddition reactions at ambient temperature and pressure, demonstrating the efficacy of this method in guiding the design and development of ionic liquid catalysts for CO2 conversion reactions involving epoxy compounds.

NeuroClick: Advanced Software for Designing Blood-Brain Barrier-Permeable Drugs Using Click Reaction Simulations.

NeuroClick is a software tool designed for the in silico execution of azide-alkyne cycloaddition reactions, commonly known as click reactions. We developed this graphical user interface application to expedite the drug discovery process by generating libraries of 1,2,3-triazole compounds. NeuroClick enables users to input reagent SMILES strings, rapidly generating and screening extensive combinatorial libraries at a pace of 10,000 molecules per minute. The software applies stringent criteria to ensure the relevance and accuracy of the generated compounds, excluding molecules without azide groups or those with multiple reactive functional groups to maintain dataset integrity. NeuroClick incorporates advanced filtering options based on Lipinski's rule of five and blood-brain barrier (BBB) permeability predictors, allowing researchers to identify drug-like molecules with potential central nervous system activity. The software's high-throughput and user-friendly interface significantly enhance the efficiency of early-stage drug development by facilitating the exploration of vast chemical spaces and identifying promising lead compounds for further development. This article provides comprehensive guidance on the installation, usage, and features of NeuroClick, ensuring that users can leverage its full potential in their research endeavors. © 2024 Wiley Periodicals LLC. Basic Protocol: NeuroClick workflow for generating BBB-permeating drugs.

Pentamethine cyanine dyes with alkynyl group as perspective structure for conjugation with targeting moiety

We report a modified carbocyanine-based asymmetric fluorescent dye, suitable for the azide-alkyne cycloaddition reaction, that possesses promising photochemical properties (Φfl = 0,49). As an example of usage of the new fluorophore, it was conjugated to a ligand targeting prostate-specific membrane antigen (PSMA), one of the widely utilized prostate cancer markers.

Synthesis, Characterization, Insecticidal Activity and Antibacterial Evaluation of Some Heterocyclic Compounds Containing 1,2,3-Triazoles Moiety

A series of 1,2,3-triazole compounds having thymol or paracetamol moieties have been designed via employing ‘click’ chemistry with copper-catalyzed azide-alkyne cycloaddition reactions. Additionally, the insecticidal characterizations of many designed products were perceived with respect to second & fourth of Spodoptera littoralis instar larvae. Numerous insecticides are revealed as novelties. As a result, numerous triazole derivatives were designed chemically to assist as analogues a comprehensive class of insecticides. With LC50 value of 0.321 mg/L for second larvae instar and LC50=0.627 mg/L four instar larvae, components 10 display the highest insecticidal bioactivity. This article deliberates how to find novel compounds that could be employed as insecticidal components in the future. A few biological and biochemical properties of the compounds produced in a laboratory environment were also examined. This work also addresses the process of finding new compounds that could be used as insecticidal products in the future. Ultimately, the antibacterial effectiveness of each developed component contrary to both Gram-positive & Gram-negative bacteria was observed.

Portable Detection of Copper Ion Using Personal Glucose Meter.

A simple and sensitive method for Cu2+ detection was developed using the Cu+-catalyzed alkyne-azide cycloaddition reaction, Fe3O4 magnetic nanoparticles (MNPs) as the reaction platform, and a portable blood glucose meter (PGM) as the detection method. Gold nanoparticles (AuNPs) were labeled with glucose oxidase (GOx) and alkyne-functionalized, terminally thiolated ssDNA (C2). In the presence of Cu2+ and ascorbate, the functionalized AuNPs were captured onto MNPs modified with azide-functionalized ssDNA (C1) via the Cu+-catalyzed alkyne-azide cycloaddition reaction. The GOx on the AuNPs' surface oxidized glucose (Glu) into gluconic acid and H2O2, reducing the Glu content in the reaction solution, which was quantitatively detected by the PGM. Under optimal conditions, the PGM response of the system showed a good linear relationship with the logarithm of Cu2+ concentration in the range of 0.05 to 10.00 μmol/L, with a detection limit of 0.03 μmol/L (3σ). In actual tap water samples, the spiked recovery rate of Cu2+ was between 92.30% and 113.33%, and the relative standard deviation was between 0.14% and 0.34%, meeting the detection requirements for Cu2+ in real water samples.