Search Results (613)

Polysiloxanes are unique polymers used in medicine and materials science and are ideal for various modifications. Classic functionalization methods involve a covalent approach, but finer tuning of the properties of the final polymers can also be achieved through sub-sequent noncovalent modifications. This study introduces a fundamentally new approach to polysiloxane functionalization by incorporating cooperative noncovalent interaction centers: selenium-based chalcogen bonding donors and polyfluoroaromatic π-hole acceptors into a single polymer platform. We developed an efficient nucleophilic substitution strategy using poly((3-chloropropyl)methylsiloxane) as a platform for introducing Se-containing groups with polyfluoroaromatic substituents. Three synthetic approaches were evaluated; only direct modification of Cl-PMS-2 proved successful, avoiding catalyst poisoning and crosslinking issues. The optimized methodology utilizes mild conditions and achieved high substitution degrees (74–98%) with isolated yields of 60–79%. Comprehensive characterization using ¹H, ¹³C, ¹⁹F, ⁷⁷Se, and ²⁹Si NMR, TGA, and contact angle measurements revealed significantly enhanced properties. Modified polysiloxanes demonstrated improved thermal stability (up to 37 °C higher decomposition temperatures, 50–60 °C shifts in DTG maxima) and increased hydrophobicity (water contact angles from 69° to 102°). These systems potentially enable chalcogen bonding and arene–perfluoroarene interactions, providing foundations for materials with applications in biomedicine, electronics, and protective coatings. This dual-functionality approach opens pathways toward adaptive materials whose properties can be tuned through supramolecular modification while maintaining the inherent advantages of polysiloxane platforms—flexibility, biocompatibility, and chemical inertness. Full article

A straightforward synthetic method is advanced to produce hard-to-reach polycyclic compounds belonging to the [1,2,5]oxadiazolo[3,4-b]quinoxaline ring system. This approach draws on a combination of the nucleophilic aromatic substitution of hydrogen (S_N^H) and Scholl cross-coupling reactions, followed by reduction of the 1,2,5-oxadiazole fragment under mild reaction conditions. All compounds were obtained for the first time with moderate to excellent yields. Electrochemical and photophysical measurements show that the synthesized compounds may serve as narrow-band n-type organic semiconductors, with energy levels ranging from 2.00 to 2.28 eV, comparable to those of the best commercially available electronic semiconductors. Full article

η⁶-Coordination catalysis has emerged as an effective strategy for activating electron-rich (hetero)arenes toward nucleophilic substitution. Recent experimental studies on Ru(II)-catalyzed amination of aminopyridines revealed a striking ortho–para reactivity difference, with ortho-substituted substrates undergoing efficient amination while para analogs are unreactive under identical conditions. Herein, we present a density functional theory investigation to elucidate the origin of this divergence. Computed free-energy profiles show that both substitution patterns follow a similar stepwise mechanism involving Ru-bound Meisenheimer intermediates and a proton-transfer relay, with C–N bond cleavage/rearomatization as the rate-determining step. However, the para pathway suffers from a substantially higher overall barrier, originating from the intrinsically less stable Meisenheimer intermediates. Energy decomposition analysis indicates that the decisive factor is weaker orbital interaction between the CpRu(II) fragment and the para-substituted Meisenheimer intermediate, whereas electrostatics and dispersion play negligible roles. These findings highlight the key role of metal–substrate orbital interactions in stabilizing dearomatized intermediates, offering mechanistic insights for rational design of η⁶-coordination catalysis with enhanced reactivity and selectivity. Full article

We describe the first solid-phase synthesis of thiazolo [4,5-d] [1,2,3] triazin-4(3H)-one derivatives using Merrifield resin. The modular sequence involves Thorpe–Ziegler cyclization, sulfone oxidation, and disulfonate nucleophilic substitution, with each step monitored by real-time ATR-FTIR spectroscopy. Conducted under mild conditions with broad functional group tolerance, the protocol delivered a library of 40 compounds in average stepwise yields of 68–97%, requiring only simple resin washing for purification. This study demonstrates a solid-phase route to thiazolotriazinones and illustrates its applicability in heterocyclic library construction and SAR studies. Full article

A new synthetic strategy for pyrazolo[1,5-d][1,2,4]triazin-7(6H)-ones 4 through intramolecular cyclization of alkyl 2-(4-nitro-1H-pyrazol-3-yl)methylene)hydrazine-1-carboxylates 3 is described, allowing us to selectively modify the N-substituent in 3-position. The reduction in nitro compounds 4 with tin(II) chloride leads to amines 5, and their acetylation leads to acetamides 6. Via alkylation of 4 with bromoacetic acid alkyl esters and 2-chloro-5-(chloromethyl)pyridine, and the subsequent reduction in alkylated nitro compounds 7, the corresponding amines 8 and amides 9 were accessible in very good yields. The molecular structure of ethyl 2-(2-morpholino-3-nitro-7-oxopyrazolo[1,5-d][1,2,4]triazin-6(7H)-yl)acetate (7b) was confirmed by single-crystal X-Ray diffraction analysis. Antibacterial and cytotoxic properties were evaluated for 61 synthesized compounds. Full article

Acyl chloride alcoholysis is a fundamental and typically high-yielding method for ester synthesis. However, competitive side reactions can occur when the acyl chloride possesses multiple electrophilic sites and the alcohol is a strong nucleophile. We report an example of this phenomenon: the reaction of pentafluorobenzoyl chloride with 1,1,1,3,3,3-hexafluoropropan-2-ol yields not only the expected ester but also a significant quantity of the 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate. The formation of the latter results from an effective nucleophilic aromatic substitution (S_NAr) at the para-fluorine position of the pentafluorophenyl ring by the hexafluoroisopropoxide anion. Full article

Current therapies for Primary Amoebic Meningoencephalitis (PAM) present several limitations; consequently, there is an urgent need to develop new therapeutic agents. In this regard, we undertook bioassay-guided isolation of Mentha rotundifolia leaves which allowed the identification of ursolic acid (1) as the main bioactive metabolite against two ATCC strains of Naegleria fowleri (ATCC^® 30808^TM and ATCC^® 30215^TM). Moreover, ten ursolic acid derivatives (2–11) were synthesized through esterification and nucleophilic substitution to obtain halo or amino ester derivatives. Among these derivatives, compound 7 exhibited the highest activity against the N. fowleri ATCC^® 30808^TM strain with an IC₅₀ value of 28.66 µM, whereas compound 10 showed the top activity against the N. fowleri ATCC^® 30215^TM strain with an IC₅₀ of 7.61 µM, surpassing the efficacy of the reference drug, miltefosine. Both compounds, 7 and 10, showed a good selectivity index and hence low toxicity in vitro. Structure–activity relationship studies revealed that the type of acylating agent played a crucial role in the activity. Furthermore, both compounds induced autophagy and apoptosis-like processes in both treated N. fowleri strains. These results highlight the potential of ursolic acid-related triterpenoids as drug scaffolds and identify M. rotundifolia as a promising natural source of amoebicidal agents against PAM. Full article

When the outer sheath of submarine cables is damaged, the degradation of cross-linked polyethylene (XLPE) insulation by anions in seawater becomes a critical factor affecting cable service life. This study investigates 500 kV three-core XLPE insulation and systematically reveals the differential and synergistic degradation mechanisms of major seawater anions (Cl⁻, SO₄²⁻, HCO₃⁻). Accelerated aging tests at 90 °C were conducted using solution systems simulating both single-ion and composite environments, combined with electrical performance evaluation, Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Results show that seawater causes significantly greater deterioration of resistivity, breakdown strength, and molecular structure than any single-ion solution. Mechanistic analysis demonstrates that Cl⁻ induces nucleophilic substitution, SO₄²⁻ promotes oxidative chain scission, and HCO₃⁻ facilitates hydrolysis via pH regulation, while their coexistence produces nonlinear synergistic effects through oxidative reactions, electrochemical coupling, and ion transport. This work provides the first systematic comparison of individual and combined anion effects on XLPE, offering new mechanistic insights and quantitative evidence for understanding multi-ion degradation, with implications for insulation material design, protective strategies, and service life prediction of submarine cables. Full article

A highly efficient method was successfully applied for the first time to the functionalization of well-defined chlorinated silsesquioxanes with a range of thiols. Thiolation was rapid (2 to 4 h), quantitative, with complete conversion of the reactants and full chemoselectivity, and proceeded under mild conditions (room temperature). This “click chemistry” approach facilitated the preparation of nine novel compounds, with good to excellent isolated yields (64–92%). The structures and purities of these compounds were comprehensively confirmed using multiple analytical techniques, including ¹H, ¹³C, and ²⁹Si NMR spectroscopy, elemental analysis, and mass spectrometry. Thermogravimetric analysis (TGA) further demonstrated that the synthesized compounds exhibited excellent thermal stability. These characteristics suggest their potential for applications in various domains of science, technology, and medicine. Full article

The stereoselective synthesis of trisubstituted alkenes has become a key topic in modern organic chemistry. At the same time, trisubstituted alkenes also serve as valuable starting materials for a wide range of transformations. However, it remains unclear to what extent these alkenes are utilized in comparison to their mono- and disubstituted counterparts. This review aims to provide a comprehensive overview of fundamental transformations involving all-carbon-substituted trisubstituted alkenes. The first section focuses on additions of carbon, oxygen, and nitrogen nucleophiles, as well as halogenation and carboxylation reactions. The second part discusses oxidative cleavage processes, while the final section addresses the cyclization and cycloisomerization reactions of trisubstituted alkenes. Full article

This paper presents the expected and unexpected, but typically substituent-dependent, ferrocene-catalyzed DDQ-mediated oxidative transformations of a series of 5,8-bis(methylthio)-1-aryl-1,2-dihydropyridazino[4,5-d]pyridazines and 8-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(methylthio)-1-aryl-1,2-dihydropyridazino[4,5-d]pyridazines. Under noncatalytic conditions the reactions were sluggish, mainly producing a substantial amount of undefined tarry materials; nevertheless, the ferrocene-catalyzed reactions of the 5,8-bis(methylthio)-substituted precursors gave the aromatic products the expected aromatic products in low yields. Their formation was accompanied by ring transformations proceeding via aryne-generating fragmentation/Diels–Alder (DA)/N₂-releasing retro Diels–Alder (rDA) sequence to construct arene-fused phthalazines. On the other hand, neither the noncatalytic nor the catalytic reactions of the 8-pyrazolyl-5-methylthio-substituted dihydroaromatics yielded the expected aromatic products. Instead, depending on their substitution pattern, the catalytic reactions of these pyrazolyl-substituted precursors also led to the formation of dearylated arene-fused phthalazines competing with an unprecedented multistep fragmentation sequence terminated by the hydrolysis of cationic intermediates to give 4-(methylthio)pyridazino[4,5-d]pyridazin-1(2H)-one and the corresponding 3,5-dimethyl-1-aryl-1H-pyrazole. When 0.6 equivalents of DDQ were applied in freshly absolutized THF, a representative pyrazolyl-substituted model underwent an oxidative coupling to give a dimer formed by the interaction of the cationic intermediate, and a part of the N-nucleophilic precursor remained intact. A systematic computational study was conducted on these intriguing reactions to support their complex mechanisms proposed on the basis of the structures of the isolated products. Full article

The tumor microenvironment plays an important role in tumor incidence, metastasis, and chemotherapy resistance. Novel therapeutic strategies targeting the tumor microenvironment have become a research focus in the field of biomedicine. In this study, we developed a smart small-molecule probe, TZ2, featuring pH/GSH dual-responsive characteristics. TZ2 exhibits a unique pH-dependent reaction mechanism: GSH is preferentially covalently modified with maleimide groups in acidic microenvironments (pH < 7), while specifically activating nucleophilic substitutions under alkaline conditions (pH > 7). It is worth noting that TZ2 effectively eliminates intracellular glutathione (GSH) in a time and concentration-dependent manner, demonstrating significant GSH depletion ability in various tumor cell lines. Pharmacodynamic studies have shown that TZ2 not only inhibits the cell cycle by regulating the expression of cell cycle-related proteins, but also effectively suppresses the cloning ability of cancer cells. Furthermore, TZ2 significantly increases the sensitivity of drug-resistant cancer cells to cisplatin. By integrating microenvironment modulation, real-time monitoring, and synergistic therapy, TZ2 provides a novel molecular tool and theoretical basis for tumor theranostics integration. Full article

Heterocycles—cyclic compounds containing at least one non-carbon heteroatom (e.g., N, O, S)—are fundamental in medicinal chemistry due to their influence on a drug’s physicochemical and biological properties. They improve solubility, bioavailability, and facilitate molecular recognition through their electronic and hydrogen-bonding features. These properties make them indispensable in drug design. This study focuses on the synthesis of a key heterocyclic intermediate: benzyl-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]carbamate. This molecule incorporates a thiazole ring, known for its rigidity and electronic properties, that enhances target interactions. The 2-position bears a Cbz-protected amine, enabling orthogonal deprotection, while the 4-position features a hydroxyethyl side chain, providing a handle for further chemical modifications via nucleophilic substitution. Herein, we report the successful synthesis of this intermediate along with its full ¹H and ¹³C NMR spectra, melting point, and crystal structure, confirming its identity and purity. Full article

A synthesis of substituted 1,4-benzodiazepines has been developed via palladium-catalyzed cyclization of N-tosyl-disubstituted 2-aminobenzylamines with propargylic carbonates. The reaction proceeds through the formation of π-allylpalladium intermediates, which undergo intramolecular nucleophilic attack by the amide nitrogen to afford seven-membered benzodiazepine cores. In reactions involving unsymmetrical diaryl-substituted carbonates, regioselectivity was observed to favor nucleophilic attack at the alkyne terminus substituted with the more electron-rich aryl group, suggesting that electronic effects play a key role in determining product distribution. The versatility of this reaction was further demonstrated by constructing a benzodiazepine framework found in bioactive molecules, indicating its potential utility in medicinal chemistry. Mechanistic insights supported by stereochemical outcomes and X-ray crystallographic analysis of key intermediates reinforce the proposed reaction pathway. This palladium-catalyzed protocol thus offers an efficient and practical approach to access structurally diverse benzodiazepine derivatives. Full article