Search Results (190)

In this work, the regio- and stereochemistry as well as the molecular mechanism of the cycloaddition reaction of nitrones with (E)-3-(methylsulfonyl)-propenoic acid derivatives were analyzed based on ωb97xD/6-311G(d,p) quantum chemical calculations. In light of these data, it is possible to propose selectivity of the analyzed processes, which was not clearly determined in light of previous experimental studies. Furthermore, the mechanism of the process was diagnosed. CDFT descriptors indicate that the reaction is triggered by a nucleophilic attack of the nitrone oxygen atom on the electrophilic carbon atom of (E)-3-(methylsulfonyl)-propenoic acid derivatives. In turn, PES analysis shows that, despite the nucleophilic-electrophilic character of the reactants, the corresponding transition states are only weakly polar and highly synchronous. IRC calculations rule out zwitterionic or biradical intermediates, confirming a single-step mechanism. The in silico ADME and PASS predictions indicate that the resulting isoxazolidines possess promising biological profiles, showing potential modulation of the serotonin system through 5-HT2A and 5-HT2C antagonism and stimulation of serotonin release, with structural features compatible with P450-mediated metabolism. Considering this attractive application potential, a detailed mechanistic investigation of their formation becomes essential for understanding and ultimately controlling the reaction pathways leading to these heterocycles. Full article

In this study, an efficient and regioselective synthetic method was developed for the preparation of 3-hydroxy-3-((2-(naphthalen-2-yloxy)-2-oxoethoxy)carbonyl)pentanedioic acid, a multifunctional ether–ester compound of potential interest for pharmaceutical and material science applications. The target compound was synthesized via the nucleophilic substitution (SN2) and esterification reactions of 2-naphthyl chloroacetate with the monosodium salt of citric acid. Optimization of the reaction conditions was carried out by varying the molar ratio of the reagents, reaction temperature, and duration. The highest yield of 83% was achieved under the conditions of a 2:1 molar ratio of chloroacetate to citrate, a temperature of 70–80 °C, and a reaction time of 6 h. The enhanced product yield observed under these conditions is attributed to the dual reactivity of the citric acid monosodium salt, which contains a free hydroxyl group capable of undergoing SN2 etherification, and free carboxylic acid groups that participate in esterification with the electrophilic 2-naphthyl chloroacetate. The stoichiometric 2:1 ratio ensures that both reactive centers on the citrate anion are fully utilized, leading to efficient and selective transformation into the desired product. Mechanistically, the ether bond formation proceeds through the classical Williamson ether synthesis pathway, where the alkoxide formed from the hydroxyl group attacks the electrophilic carbon of the chloroacetate, displacing the chloride ion. Concurrently, esterification enhances molecular complexity and stability. The results underline the synthetic utility of citric acid derivatives in forming complex organic architectures via environmentally benign routes. This study not only contributes a practical approach to multifunctional molecule synthesis but also reinforces the applicability of green chemistry principles in ester–ether coupling strategies. Full article

There is an urgent need to evaluate the toxicity of xenobiotics and environmental mixtures for preventing loss in water quality for the sustainability of aquatic ecosystems. A simple prebiotic chemical pathway based on malate formation from pyruvate (pyr) and glyoxalate (glyox) is proposed as a quick and cheap screening tool for toxicity assessment. The assay is based on the pyr and glyox (aldol) condensation reactions, leading to biologically relevant precursors such as oxaloacetate and malate. Incubation of pyr and glyox at 40–70 °C in the presence of reduced iron Fe(II) led to malate formation following the first 3 h of incubation. The addition of various xenobiotics/contaminants (silver, copper, zinc, cerium IV, samarium III, dibutylphthalate, 1,3-diphenylguanidine, carbon-walled nanotube, nanoFe₂O₃ and polystyrene nanoparticles) led to inhibitions in malate synthesis at various degrees. Based on the concentration inhibiting malate concentrations by 20% (IC20), the following potencies were observed: silver < copper ~ 1.3-diphenylguanidine ~ carbon-walled nanotube < zinc ~ samarium < dibutylphthalate ~ samarium < Ce(IV) < nFeO₃ < polystyrene nanoplastics. The IC20 values were also significantly correlated with the reported trout acute lethality data, suggesting its potential as an alternative toxicity test. The pyr-glyox pathway was also tested on surface water extracts (C18), identifying the most contaminated sites from large cities and municipal wastewater effluents dispersion plume. The inhibition potencies of the selected test compounds revealed that not only pro-oxidants but also chemicals hindering enolate formation, nucleophilic attack of carbonyls and dehydration involved in aldol-condensation reactions were associated with toxicity. The pyr-glyox pathway is based on prebiotic chemical reactions during the emergence of life and represents a unique tool for identifying toxic compounds individually and in complex mixtures. Full article

Background/Objectives: DNA interstrand cross-links (ICLs) mark one of the most deleterious lesions that can preclude strand separation required for essential cellular processes. Efforts to discover ICL-inducing agents and endogenous substrates for ICL repair pathways have led to the identification of structurally diverse ICLs produced by reactive aldehydes and abasic sites, among others. While several studies point to UV rays as ICL-inducing agents, UV ray-induced ICL formation from biologically relevant DNA lesions has been rarely reported. We conjectured that solar radiation-induced reactive oxygen species may give rise to ICLs via further oxidation of DNA lesions with lower redox potential (e.g., 8-oxoadenine (oxoA)). Here, we present the discovery of ICL production via light-induced modification of the major oxidative adenine lesion oxoA. Methods/Results: In the absence of a photosensitizer, both UVC and UVB rays, but not UVA and visible rays, trigger the formation of oxoA-G ICLs, albeit in low yields. By contrast, the inclusion of the naturally occurring photosensitizer riboflavin in the cross-linking reaction makes UVA and visible rays readily generate oxoA-G ICLs, suggesting solar radiation facilitates the formation of oxoA ICLs in vivo. Conclusions: The plausible oxoA-G ICL formation mechanism concerns the further oxidation of oxoA into an iminoquinone, followed by the nucleophilic attack of the opposite guanine on the iminoquinone. OxoA-G ICLs represent rare examples of ICLs produced by photosensitization. These results will contribute to the discovery of a novel form of ICLs induced by solar radiation. Full article

The Long Interspersed Element-1 (L1) retrotransposon is an ancient genetic parasite that comprises a significant part of the human genome. ORF2p is a multifunctional enzyme with endonuclease (EN) and reverse transcriptase (RT) activities that mediate target-primed reverse transcription of RNA into DNA. Structural studies of LINE-1 ORF2p consistently show a single Mg²⁺ cation in the reverse transcriptase active site, conflicting with the common DNA polymerase mechanism which involves two divalent cations. We explored a reaction pathway of the DNA elongation based on the recent high-resolution ternary complex structure of the ORF2p. The combined quantum and molecular mechanics approach at the QM (PBE0-D3/6-31G**)/MM (CHARMM) level is employed for biased umbrella sampling molecular dynamics simulations followed by umbrella integration utilized to obtain the free energy profile. The nucleotidyl transfer reaction proceeds in a single step with a free energy barrier of 15.1 ± 0.8 kcal/mol, and 7.8 ± 1.2 kcal/mol product stabilization relative to reagents. Concerted nucleophilic attack by DNA O3′ and proton transfer to Asp703 occur without a second catalytic metal ion. Estimated rate constant ∼60 s⁻¹ aligns with RT kinetics, while analysis of the Laplacian of the electron density along the cleaving P-O bond identifies a dissociative mechanism. 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

This study proposes a co-hydrothermal method for the dechlorination of polyvinyl chloride (PVC) and the preparation of hydrothermal carbon. During the co-hydrothermal process, lignin was mixed with PVC, with ammonium carbonate serving as a supplementary additive. The effects of hydrothermal temperature, reaction time, and ammonium carbonate concentration on the dechlorination efficiency of PVC and the pH value of the system are discussed. The experimental results showed that the incorporation of lignin and ammonium nitrate manifested a remarkable synergistic effect, which substantially augmented the dechlorination process of polyvinyl chloride (PVC). Under optimal conditions (220 °C, 240 min), the dechlorination efficiency of PVC reached 99.43%. The hydrothermal carbon derived from the co-hydrothermal process exhibited a 73.9% higher calorific value (31.07 MJ/kg) compared with that obtained from pure PVC (17.87 MJ/kg). A physicochemical characterization demonstrated that lignin effectively enhanced the uniform dispersion of PVC particles during hydrothermal treatment. Concurrently, ammonium carbonate increased the solution’s alkalinity, facilitating a nucleophilic attack by OH⁻ on C-Cl bonds and accelerating dechlorination through intensified substitution reactions. Full article

The active sites of enzymes are able to activate substrates and perform chemical reactions that cannot occur in solutions. We focus on the hydrolysis reactions catalyzed by enzymes and initiated by the nucleophilic attack of the substrate’s carbonyl carbon atom. From an electronic structure standpoint, substrate activation can be characterized in terms of the Laplacian of the electron density. This is a simple and easily visible imaging technique that allows one to “visualize” the electrophilic site on the carbonyl carbon atom, which occurs only in the activated species. The efficiency of substrate activation by the enzymes can be quantified from the ratio of reactive and nonreactive states derived from the molecular dynamics trajectories executed with quantum mechanics/molecular mechanics potentials. We propose a neural network that assigns the species to reactive and nonreactive ones using the Laplacian of electron density maps. The neural network is trained on the cysteine protease enzyme-substrate complexes, and successfully validated on the zinc-containing hydrolase, thus showing a wide range of applications using the proposed approach. Full article

The search for new heterocyclic compounds with biological potential is one of the current challenges in modern chemistry. Therefore, the comprehensive study of (3 + 2) cycloaddition (32CA) reactions between a series of aryl-substituted nitrile N-oxides (NOs) and (E)-3,3,3-tribromo-1-nitroprop-1-ene (TBNP) is carried out. According to the experimental research, in all tested 32CAs, the proper (4RS,5RS)-3-aryl-4-nitro-5-tribromomethyl-2-isoxazolines are obtained as only one reaction product. In turn, the quantum–chemical MEDT study shows that the creation of heterocycles occur via the polar attack of zwitterionic moderate-nucleophilic NOs to strong electrophilic TBNP. The reactions are realized according to a two-stage, one-step asynchronous mechanism, in which the formation of the O-C(CBr₃) bond takes place once the C-C(NO₂) bond is already formed. What is more, the computational analysis confirmed the experimental results. At the end, the obtained 2-isoxazolines were docked to three proteins: gelatinase B, cyclooxygenase COX-1, and Caspase-7. We hope that the presented study will be helpful for searching for the future direction of application for this class of organic compounds. Full article

Chlorpyrifos is one of the most toxic organophosphate pesticides, prompting its ban in Europe in 2020. Consequently, developing a detection method that is both selective and sensitive is essential for protecting human health and the environment. In this study, we report for the first time a fluorescent probe based on an oxime for the direct detection of chlorpyrifos. 9-fluorenone oxime, upon deprotonation with a phosphazene base, undergoes a nucleophilic attack on chlorpyrifos, resulting in a significant alteration of its fluorescence properties. Following careful optimization, the method demonstrated excellent linearity (R² = 0.98) over a concentration range of 350 to 6980 μg/L, with a limit of detection of 15.5 μg/L. Furthermore, the probe was successfully applied to chlorpyrifos detection in water samples, yielding satisfactory results. This approach effectively overcomes the stability limitations of enzyme-based fluorescent sensors, offering a robust and innovative solution for the detection of organophosphate pesticides. Full article

Amines and hydroxylamines are essential compounds in the synthesis of pharmaceuticals and other functionalized molecules. However, the synthesis of primary amines and particularly hydroxylamines remains a challenging task. The most common way to obtain amines and hydroxylamines involves the reduction of substances containing C-N bonds, such as nitro compounds, nitriles, and oximes. Among these, oximes are the most readily accessible substrates easily derived from ketones and aldehydes. However, oximes are much harder to reduce compared to nitro compounds and nitriles. The catalytic heterogeneous hydrogenation of oximes often requires harsh conditions and catalysts with high precious metal loadings, while hydroxylamines are hard to be obtained by this method. In this work, we showed that Pt supported on a porous ceria–zirconia solid solution enables the selective and atom-efficient synthesis of both hydroxylamines and amines through the hydrogenation of oximes, achieving yields of up to 99% under ambient reaction conditions in a “green” THF:H₂O solvent system. The high activity of the 1% Pt/CeO₂-ZrO₂ catalyst (TOF > 500 h⁻¹) is due to low-temperature hydrogen activation on Pt nanoparticles with the formation of a hydride, Pt-H. The strong influence of electron-donating and electron-withdrawing groups on the hydrogenation of aromatic oximes implies the nucleophilic attack of hydridic hydrogen from Pt to the electrophilic carbon of protonated oximes. Full article

Oligomerization of glyoxal (GL) and methylglyoxal (MG) plays a vital role in secondary organic aerosol (SOA) formation in aqueous aerosols. However, the influence of emerging contaminants on the oligomerization of GL and MG remains unclear. Therefore, using quantum chemical and kinetic calculations, we investigated the oligomerization of GL and MG in the presence of phthalate esters (PAEs), including dimethyl phthalate (DMP), diethyl phthalate (DEP), dipropyl phthalate (DPP), and dibutyl phthalate (DBP), and the role of PAEs in the oligomerization. Our findings indicate that the direct PAE-mediated oligomerization of GL and MG is hindered due to the lack of reactive sites. However, the oligomerization of GL and MG is readily mediated by the hydrolysates of PAEs, which are the preferred forms of PAEs in weakly acidic aerosols, attributable to the additional -OH groups. The mechanisms show that the indirect PAE-mediated oligomerization proceeds via three-step reactions, including nucleophilic attack on carbenium ions, hydration, and deprotonation, which are thermodynamically and kinetically favorable. Our results reveal that the role of PAEs in the GL/MG oligomerization needs to be emphasized, particularly in conditions with a pH value approaching neutrality. Full article

Catalysts with anionic metal centers have recently been proposed to enhance the performance of various chemical processes. Here, we focus on the reactivity of ${\mathrm{Co}\left(\mathrm{CO}\right)}_4^{-}$ for the polymerization of aziridine and carbon monoxide to form polypeptoids, motivated by earlier experimental studies. We used multi-reference and density functional theory methods to investigate possible reaction mechanisms and provide insights into the role of the negatively charged cobalt center. Two different reaction paths were identified. In the first path, ${\mathrm{Co}}^{-}$ acts as a nucleophile, donating an electron pair to the reaction substrate, while in the second path, it performs a single electron transfer to the substrate, initiating radical polymerization. The difference in the activation barriers for the two key steps is small and falls within the accuracy of our calculations. As suggested in the literature, solvent effects can play a primary role in determining the outcomes of such reactions. Future investigations will involve different metals or ligands and will investigate the effects of these two reaction paths on other chemical transformations. Full article

Phospholipase D (PLD) enzymes from Loxosceles spider venom mediate envenomation pathology by cleaving phospholipid headgroups. We revisited the crystal structure of Loxosceles intermedia PLD (PDB: 3RLH) to evaluate two alternative mechanisms—covalent and non-covalent—for headgroup cleavage. The covalent mechanism involves a nucleophilic attack on the substrate’s P atom by catalytic histidine, forming a phosphohistidine intermediate. It was originally suggested that this intermediate hydrolyzes, leading to linear phosphates. The non-covalent mechanism relies on the substrate’s hydroxyl group performing an intramolecular attack on the P atom, thereby generating a cyclic phosphate. Structural refinement of the crystal structure revealed a cyclic phosphate bound at the active site, replacing previously assigned PEG molecules. This cyclic product, stabilized by His12, His47, and Mg²⁺, provides structural evidence that supports phosphate cyclization. The results of computational analyses, including molecular dynamics and quantum mechanics/molecular mechanics simulations, further support the non-covalent mechanism as the energetically preferred pathway, with a significantly lower activation barrier. Our findings highlight the role of substrate orientation and of the catalytic His residues in transphosphatidylation, advancing our understanding of PLD enzymology and providing insights for the design of inhibitors against Loxosceles envenomation. Full article

In the 21st century, sustainable agriculture is expected to become a major contributor to food security and improved nutrition. Amine–epoxide-based materials have great potential for use in agriculture due to their tunable physicochemical features, which are dependent on the concentration and composition of the monomers. In this work, catalyst-free green synthesis, using only water as a solvent, was performed to obtain a nanocarrier (TGel) capable of transporting nutrients after seed priming. The synthesis was based on the opening of the epoxy ring by nucleophile attack, using an amine-terminated polyether. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) techniques showed the spherical morphology of the particles, which ranged in size from 80 nm (unloaded TGel) to 360 nm (zinc-loaded TGel), respectively. Theoretical bonding analysis revealed that Zn cation species from the ZnSO₄ source interact with the polymer via σ-bonds, whereas EDTA forms hydrogen bonds with the polymer, thereby enhancing noncovalent interactions. Micro X-ray fluorescence (μ-XRF) and energy-dispersive X-ray fluorescence spectroscopy (EDXRF) provided details of the distributions of Zn in the seed compartments and shoots of cucumber plants after seed priming and plant growth, respectively. The use of the Zn-loaded TGels did not affect the physiology of the cucumber plants, as indicated by the photosynthetic efficacy, chlorophyll, and anthocyanin indices. Full article