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Herein, we report a mechanistic investigation of a recently developed electrochemical method for the deconstructive methoxylation of arylalcohols. A combination of synthetic, electroanalytical, and computational experiments have been performed to gain a deeper understanding of the reaction mechanism and the structural requirements for fragmentation to occur. It was found that 2-arylalcohols undergo anodic oxidation to form the corresponding aromatic radical cations, which fragment to form oxocarbenium ions and benzylic radical intermediates via mesolytic cleavage, with further anodic oxidation and trapping of the benzylic carbocation with methanol to generate the observed methyl ether products. It was also found that the electrochemical fragmentation of 2-arylalkanols is promoted by structural features that stabilize the oxocarbenium ions and/or benzylic radical intermediates formed upon mesolytic cleavage of the aromatic radical cations. With an enhanced understanding of the reaction mechanism and the structural features that promote fragmentation, it is anticipated that alternative electrosynthetic transformations will be developed that utilize this powerful, yet underdeveloped, mode of substrate activation.

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Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.

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An air-stable, inexpensive, and isolable cobalt(II) complex (C1) of N-((1-methyl-1H-imidazol-2-yl)methyl)-2-(phenylselanyl)ethan amine (L1) was synthesized and characterized. The complex was used to catalyze a one-pot cascade reaction between 2-(2-aminophenyl)ethanols and benzyl alcohol derivatives. Interestingly, 2-aryl-3-formylindole derivatives were formed instead of N-alkylated or C-3 alkylated indoles. A broad substrate scope can be activated using this protocol with only 5.0 mol % catalyst loading to achieve up to 87 % yield of 2-aryl-3-formylindole derivatives. The mechanistic studies suggested that the reaction proceeds through tandem imine formation followed by cyclization.

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Ethylene dimerization is an efficient industrial chemical process to produce 1-butene, with demanding selectivity and activity requirements on new catalytic systems. Herein, a series of monodentate phosphinoamine-nickel complexes immobilized on UiO-66 are described for ethylene dimerization. These catalysts display extensive molecular tunability of the ligand similar to organometallic catalysis, while maintaining the high stability attributed to the metal-organic framework (MOF) scaffold. The highly flexible postsynthetic modification method enables this study to prepare MOFs functionalized with five different substituted phosphines and 3 N-containing ligands and identify the optimal catalyst UiO-66-L5-NiCl2 with isopropyl substituted nickel mono-phosphinoamine complex. This catalyst shows a remarkable activity and selectivity with a TOF of 29 000 (molethyl/molNi/h) and 99% selectivity for 1-butene under ethylene pressure of 15 bar. The catalyst is also applicable for continuous production in the packed column micro-reactor with a TON of 72 000 (molethyl/molNi). The mechanistic insight for the ethylene oligomerization has been examined by density functional theory (DFT) calculations. The calculated energy profiles for homogeneous complexes and truncated MOF models reveal varying rate-determining step as ß-hydrogen elimination and migratory insertion, respectively. The activation barrier of UiO-66-L5-NiCl2 is lower than other systems, possibly due to the restriction effect caused by clusters and ligands. A comprehensive analysis of the structural parameters of catalysts shows that the cone angle as steric descriptor and butene desorption energy as thermodynamic descriptor can be applied to estimate the reactivity turnover frequency (TOF) with the optimum for UiO-66-L5-NiCl2. This work represents the systematic optimization of ligand effect through combination of experimental and theoretical data and presents a proof-of-concept for ethylene dimerization catalyst through simple heterogenization of organometallic catalyst on MOF.

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Vitamin D plays a crucial role in preventing atherosclerosis and in the regulation of macrophage function. This review aims to provide a comprehensive summary of the clinical evidence regarding the impact of vitamin D on atherosclerotic cardiovascular disease, atherosclerotic cerebrovascular disease, peripheral arterial disease, and associated risk factors. Additionally, it explores the mechanistic studies investigating the influence of vitamin D on macrophage function in atherosclerosis. Numerous findings indicate that vitamin D inhibits monocyte or macrophage recruitment, macrophage cholesterol uptake, and esterification. Moreover, it induces autophagy of lipid droplets in macrophages, promotes cholesterol efflux from macrophages, and regulates macrophage polarization. This review particularly focuses on analyzing the molecular mechanisms and signaling pathways through which vitamin D modulates macrophage function in atherosclerosis. It claims that vitamin D has a direct inhibitory effect on the formation, adhesion, and migration of lipid-loaded monocytes, thus exerting anti-atherosclerotic effects. Therefore, this review emphasizes the crucial role of vitamin D in regulating macrophage function and preventing the development of atherosclerosis.

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We report an unprecedented iron-catalyzed C-H annulation using readily available 2-vinylbenzofurans as the reaction pattern. The redox-neutral strategy, based on cheap, non-toxic, and earth-abundant iron catalysts, exploits triazole assistance to promote a cascade C-H alkylation, benzofuran ring-opening and insertion into a Fe-N bond, to form highly functionalized isoquinolones. Detailed mechanistic studies supported by DFT calculations fully disclosed the manifold of the iron catalysis.

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Fe and N co-doped walnut shell biochar (Fe,N-BC) was prepared through a one-pot pyrolysis procedure by using walnut shells as feedstocks, melamine as the N source, and iron (III) chloride as the Fe source. Moreover, pristine biochar (BC), nitrogen-doped biochar (N-BC), and α-Fe2O3-BC were synthesized as controls. All the prepared materials were characterized by different techniques and were used for the activation of peroxymonosulfate (PMS) for the degradation of sulfamethoxazole (SMX). A very high degradation rate for SMX (10 mg/L) was achieved with Fe,N-BC/PMS (0.5 min-1), which was higher than those for BC/PMS (0.026 min-1), N-BC/PMS (0.038 min-1), and α-Fe2O3-BC/PMS (0.33 min-1) under the same conditions. This is mainly due to the formation of Fe3C and iron oxides, which are very reactive for the activation of PMS. In the next step, Fe,N-BC was employed for the formation of a composite membrane structure by a liquid-induced phase inversion process. The synthesized ultrafiltration membrane not only exhibited high separation performance for humic acid sodium salt (HA, 98%) but also exhibited improved self-cleaning properties when applied for rhodamine B (RhB) filtration combined with a PMS solution cleaning procedure. Scavenging experiments revealed that 1O2 was the predominant species responsible for the degradation of SMX. The transformation products of SMX and possible degradation pathways were also identified. Furthermore, the toxicity assessment revealed that the overall toxicity of the intermediate was lower than that of SMX.

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A family of 4,4'-tBu2-2,2'-bipyridine (tBubpy) ligands with substituents in either the 6-position, 4,4'-tBu2-6-Me-bpy (tBubpyMe), or 6 and 6'-positions, 4,4'-tBu2-6,6'-R2-bpy (tBubpyR2; R = Me, iPr, sBu, Ph, or Mes), was synthesized. These ligands were used to prepare Ni complexes in the 0, I, and II oxidation states. We observed that the substituents in the 6 and 6'-positions of the tBubpy ligand impact the properties of the Ni complexes. For example, bulkier substituents in the 6,6'-positions of tBubpy better stabilized (tBubpyR2)NiICl species and resulted in cleaner reduction from (tBubpyR2)NiIICl2. However, bulkier substituents hindered or prevented coordination of tBubpyR2 ligands to Ni0(cod)2. In addition, by using complexes of the type (tBubpyMe)NiCl2 and (tBubpyR2)NiCl2 as precatalysts for different XEC reactions, we demonstrated that the 6 or 6,6' substituents lead to major differences in catalytic performance. Specifically, while (tBubpyMe)NiIICl2 is one of the most active catalysts reported to date for XEC and can facilitate XEC reactions at room temperature, lower turnover frequencies were observed for catalysts containing tBubpyR2 ligands. A detailed study on the catalytic intermediates (tBubpy)Ni(Ar)I and (tBubpyMe2)Ni(Ar)I revealed several factors that likely contributed to the differences in catalytic activity. For example, whereas complexes of the type (tBubpy)Ni(Ar)I are low spin and relatively stable, complexes of the type (tBubpyMe2)Ni(Ar)I are high-spin and less stable. Further, (tBubpyMe2)Ni(Ar)I captures primary and benzylic alkyl radicals more slowly than (tBubpy)Ni(Ar)I, consistent with the lower activity of the former in catalysis. Our findings will assist in the design of tailor-made ligands for Ni-catalyzed transformations.

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The temperature sensitivity (e.g. Q10) of night-time leaf respiratory CO2 efflux (RCO2) is a fundamental aspect of leaf physiology. The Q10 typically exhibits a dependence on measurement temperature, and it is speculated that this is due to temperature-dependent shifts in the relative control of leaf RCO2. Two decades ago, a review hypothesized that this mechanistically caused change in values of Q10 is predictable across plant taxa and biomes. Here, we discuss the most appropriate measuring protocol among existing data and for future data collection, to form the foundation of a future mechanistic understanding of Q10 of leaf RCO2 at different temperature ranges. We do this primarily via a review of existing literature on Q10 of night-time RCO2 and only supplement this to a lesser degree with our own original data. Based on mechanistic considerations, we encourage that instantaneous Q10 of leaf RCO2 to represent night-time should be measured: only at night-time; only in response to short-term narrow temperature variation (e.g. max. 10°C) to represent a given midpoint temperature at a time; in response to as many temperatures as possible within the chosen temperature range; and on still attached leaves.

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Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches. In this study, we describe the effect of bleomycin concentration on disease progression in the classical rat bleomycin model. In a dose-response study (1.5, 2, 2.5 U/kg i.t), we characterized lung fibrosis at day 14 after bleomycin challenge using endpoints including clinical signs, inflammatory cell infiltration, collagen content, and bronchoalveolar lavage fluid-soluble profibrotic mediators. Furthermore, we investigated fibrotic disease progression after 2 U/kg i.t. bleomycin administration at days 3, 7, and 14 by quantifying the expression of clinically relevant signaling molecules and pathways, epithelial mesenchymal transition (EMT) biomarkers, ECM components, and histopathology of the lung. A single bleomycin challenge resulted in a progressive fibrotic response in rat lung tissue over 14 days based on lung collagen content, histopathological changes, and modified Ashcroft score. The early fibrogenesis phase (days 3 to 7) is associated with an increase in profibrotic mediators including TGFß1, IL6, TNFα, IL1ß, CINC1, WISP1, VEGF, and TIMP1. In the mid and late fibrotic stages, the TGFß/Smad and PDGF/AKT signaling pathways are involved, and clinically relevant proteins targeting galectin-3, LPA1, transglutaminase-2, and lysyl oxidase 2 are upregulated on days 7 and 14. Between days 7 and 14, the expressions of vimentin and α-SMA proteins increase, which is a sign of EMT activation. We confirmed ECM formation by increased expressions of procollagen-1Aα, procollagen-3Aα, fibronectin, and CTGF in the lung on days 7 and 14. Our data provide insights on a complex network of several soluble mediators, clinically relevant signaling pathways, and target proteins that contribute to drive the progressive fibrotic phenotype from the early to late phase (active) in the rat bleomycin model. The framework of endpoints of our study highlights the translational value for pharmacological interventions and mechanistic studies using this model.

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Two applications of a radical trap based on a homolytic substitution reaction (SH2') are presented for the trapping of short-lived radical intermediates in organic reactions. The first example is a photochemical cyanomethylation catalyzed by a Ru complex. Two intermediate radicals in the radical chain propagation have been trapped and detected using mass spectrometry (MS), along with the starting materials, products and catalyst degradation fragments. Although qualitative, these results helped to elucidate the reaction mechanism. In the second example, the trapping method was applied to study the radical initiation catalyzed by a triethylboronoxygen mixture. In this case, the concentration of trapped radicals was sufficiently high to enable their detection by nuclear magnetic resonance (NMR). Quantitative measurements made it possible to characterize the radical flux in the system under different reaction conditions (including variations of solvent, temperature and concentration) where modelling was complicated by chain reactions and heterogeneous mass transfer.

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Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

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A tridentate ligand L with a P,NH,N donor motif was synthesized in few steps from commercially available precursors. Upon reaction with [MnBr(CO)5], an octahedral 18-electron complex [Mn(CO)3(L)]Br (1) is obtained in which L adopts a facial arrangement. After deprotonation of the NH group in the cationic complex unit, a neutral Mn(I) amido complex [Mn(CO)2(L-H)] (2) is formed under loss of CO. Rearrangement of L-H leads to a trigonal bipyramidal structure in which the P and N donor centers are in trans position. Further deprotonation of 2 results in a dep-blue anionic complex fragment [Mn(CO)2(L-2H)]- (3). DFT calculations and a QTAIM analysis show that the amido complex 2 contains a Mn-N bond with partial double bond character and 3 an aromatic MnN2C2 ring. The anion [Mn(CO)2(L-2H)]- reacts with Ph2PH to give a phosphido complex, which serves as phosphide transfer reagent to activated olefins. But the catalytic activity is low. However, the neutral amido complex 2 is an excellent catalyst and with loadings as low as 0.04 mol %, turn over frequencies of >40'000 h-1 can be achieved. Furthermore, secondary and primary alkyl phosphines as well as PH3 can be added in a catalytic hydrophosphination reaction to a wide range of activated olefins such as α,ß-unsaturated aldehydes, ketones, esters, and nitriles. But also, vinyl pyridine and some styrene derivatives are converted into the corresponding phosphanes.

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The hyperactivity of urease enzymes plays a crucial role in the development of hepatic coma, hepatic encephalopathy, urolithiasis, gastric and peptic ulcers. Additionally, these enzymes adversely impact the soil's nitrogen efficiency for crop production. In the current study 100 known drugs were tested against Jack Bean urease and Proteus mirabilis urease and identified three inhibitors i.e. terbutaline (compound 1), Ketoprofen (compound 2) and norepinephrine bitartrate (compound 3). As a result, these compounds showed excellent inhibition against Jack Bean urease i.e. (IC50 = 2.1-11.3 µM), and Proteus mirabilis urease (4.8-11.9 µM). Moreover, in silico studies demonstrate maximum interactions of compounds in the enzyme's active site. Furthermore, intermolecular interactions between compounds and enzyme atoms were examined using STD-NMR spectrophotometry. In parallel, molecular dynamics simulation was carried out to study compounds dynamic behavior within the urease binding region. Urease remained stable during most of the simulation time and ligands were bound in the protein active pocket as observed from the Root mean square deviation (RMSD) and ligand RMSD analyses. Furthermore, these compounds display interactions with the crucial residues, including His492 and Asp633, in 100 ns simulations. In the binding energy analysis, norepinephrine bitartrate exhibited the highest binding energy (-76.32 kcal/mol) followed by Ketoprofen (-65.56 kcal/mol) and terbutaline (-62.15 kcal/mol), as compared to acetohydroxamic acid (-52.86 kcal/mol). The current findings highlight the potential of drug repurposing as an effective approach for identifying novel anti-urease compounds.Communicated by Ramaswamy H. Sarma.

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ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain. AIM OF THE STUDY: To assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (KATP) mechanisms in its anti-nociceptive effects. MATERIAL AND METHODS: We employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1-, α2- and ß-adrenergic, potassium adenosine triphosphate (KATP), opioidergic and serotonergic systems, respectively. RESULTS: MO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception. CONCLUSIONS: MO contains biologically active compounds with potential anti-nociceptive properties that modulate KATP, opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.

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The size-dependent activity of catalysts has been researched for a long time in the field of catalysis. Positively charged small Pt clusters enhance catalytic activity than bigger clusters and bulk for propane dehydrogenation. We performed DFT calculations on small Pt clusters adsorbed on silica support. The planar structure of Pt clusters is present till 4 Pt atoms, after which three-dimensional structures are observed. AIMD and DFT calculations for silica showed that it has a high surface area and thermal stability suitable to conduct dehydrogenation reactions. The adsorption of Pt cluster on silica results in the formation of directional bonds which affects the properties of the adsorbed Pt catalysts by changing the redox properties. In the bulk phase, ethane and propane molecules undergo dehydrogenation reactions with 0.133 eV atom-1 and 0.244 eV atom-1 energies, respectively. NEB calculations showed that except for Pt-2/SiO2 , all the even Pt clusters require less activation energy than the neighboring odd Pt clusters. Ethane molecule interacting with Pt-4/SiO2 , Pt-5/SiO2 , Pt-6/SiO2 , and propane with Pt-3/SiO2, Pt-4/SiO2 , Pt-5/SiO2 , Pt-6/SiO2 , follows the reverse Horiuti-Polanyi mechanism during dehydrogenation, whereas non-reverse Horiuti-Polanyi mechanism (which requires comparatively lower activation energy) is followed for smaller Pt clusters.

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Herein, we have reported the synthesis of a macrocyclic organosulfur ligand (L1) having a seventeen-membered macrocyclic ring. Subsequently, the corresponding trans-palladium complex (C1) of bulky macrocyclic organosulfur ligand (L1) was synthesized by reacting it with PdCl2 (CH3 CN)2 salt. The newly synthesized ligand and complex were characterized using various analytical and spectroscopic techniques. The complex showed a square planar geometry with trans orientation of two ligands around the palladium center. The complex possesses intramolecular SCH…Cl interactions of 2.648 Šbetween the macrocyclic ligand and palladium dichloride. The potential energy surface (PES) for the rotational process of C1 suggested a barrier of ~23.81 kcal/mol for chlorine rotation. Furthermore, the bulky macrocyclic organosulfur ligand stabilized palladium complex (C1) was used as a catalyst (2.5 mol %) for α-olefination of nitriles by primary alcohols. The α,ß-unsaturated nitrile compounds were found to be the major product of the reaction (57-78 % yield) with broad substrate scope and large functional group tolerance. Notably, the saturated nitrile product was not observed during the reaction. The mechanistic studies suggested the formation of H2 and H2 O as only by-products of the reaction, thereby making the protocol greener and sustainable.

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Transition metal-catalyzed reactions have attracted much attention in synthetic organic chemistry due to their important role in the formation of C-heteroatom bonds. Ullmann coupling has risen in prominence in recent decades owing to its utilization in the synthesis of biaryl ethers found in a wide range of natural products together with biologically essential molecules, including antibiotics and major industrial polymers. In this article we provide the current understanding of the theoretical aspects of the underlying mechanism of the Ullmann-type O-arylation reaction.

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This report describes the synthesis of a new NNSe pincer ligand and its mono- and dinuclear palladium(II) pincer complexes. In the absence of a base, a dinuclear palladium pincer complex (C1) was isolated, while in the presence of Et3 N base a mononuclear palladium pincer complex (C2) was obtained. The new ligand and complexes were characterized using techniques like 1 H, 13 C{1 H} nuclear magnetic resonance (NMR), fourier transform infrared (FTIR), high-resolution mass spectrometry (HRMS), ultraviolet-visible (UV-Visible), and cyclic voltammetry. Both the complexes showed pincer coordination mode with a distorted square planar geometry. The complex C1 has two pincer ligands attached through a Pd-Pd bond in a dinuclear pincer fashion. The air and moisture-insensitive, thermally robust palladium pincer complexes were used as the catalyst for decarboxylative direct C-H heteroarylation of (hetero)arenes. Among the complexes, dinuclear pincer complex C1 showed better catalytic activity. A variety of (hetero)arenes were successfully activated (43-87 % yield) using only 2.5 mol % of catalyst loading under mild reaction conditions. The PPh3 and Hg poisoning experiments suggested a homogeneous nature of catalysis. A plausible reaction pathway was proposed for the dinuclear palladium pincer complex catalyzed decarboxylative C-H bond activation reaction of (hetero)arenes.

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Over the last decades, much effort has been devoted to the construction of protein and peptide-based metalloporphyrin catalysts capable of promoting difficult transformations with high selectivity. In this context, mechanistic studies are fundamental to elucidate all the factors that contribute to catalytic performances and product selectivity. In our previous work, we selected the synthetic peptide-porphyrin conjugate MnMC6*a as a proficient catalyst for indole oxidation, promoting the formation of a 3-oxindole derivative with unprecedented selectivity. In this work, we have evaluated the role of the metal ion in affecting reaction outcome, by replacing manganese with iron in the MC6*a scaffold. Even though product selectivity is not altered upon metal substitution, FeMC6*a shows a lower substrate conversion and prolonged reaction times with respect to its manganese analogue. Experimental and theoretical studies have enabled us to delineate the reaction free energy profiles for both catalysts, indicating different thermodynamic limiting steps, depending on the nature of the metal ion.

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