Electrophilic Substitution Research Articles

Formation of halogenated chloroxylenols through chlorination and their photochemical activity.

Trace organic contaminants usually go through multiple treatment units in a modern water treatment train. Structural modification triggered by pretreatment (e.g., prechlorination) may influence the further transformation and fate of contaminants in downstream units. However, knowledge on this aspect is still limited. In this contribution, we investigated the chlorination of chloroxylenol (PCMX), an antimicrobial agent extensively used during COVID-19 pandemic, and the photoreactivity of its halogenated derivatives. Results indicate that chlorination of PCMX mainly proceeded through electrophilic substitution to give chlorinated products, including Cl- and 2Cl-PCMX. The presence of bromide (Br-) resulted in brominated analogues. Owing to the bathochromic and "heavy atom" effects of halogen substituents, these products show increased light absorption and photoreactivity. Toxicity evaluation suggest that these halo-derivatives have higher persistence, bioaccumulation, and toxicity (PBT) than the parent PCMX. Results of this contribution advance our understanding of the transformation of PCMX during chlorination and the photochemical activity of its halogenated derivatives in subsequent UV disinfection process or sunlit surface waters.

Nanocomposite Anion Exchange Membranes for Aems Electrolyzers: Ion Transport and Carbonation Studies

Anion-exchange membranes (AEMs) have received increased interest in recent years as the electrolyte separator in different electrochemical energy conversion and storage (EECS) devices. [1] AEM fuel cells and electrolyzers devices can reach the performance level required by applications with electrocatalysts that do not require a high loading of platinum-group metals (PGMs) due to the alkaline environment at the electrodes. However, the AEM based EECS development and implementation is significantly hindered by the anion exchange membrane (AEM) stability during cell operation, their low OH- conductivity and the low kinetics of the electrocatalysts. In fact, the electrolytic anion-exchange membrane (AEM) is a crucial component which should allow good charge and water transport, i.e. high ionic conductivity, but should also guarantee good chemical, thermal and mechanical stability and high durability. [2]In this work, nanocomposite AEMs based on Polysulfone ionomer (PSU) and two different nanoadditives, Layered Double Hydroxide (LDH) and Nanoscale Ionic Materials (NIM), have been developed and studied. [3] LDHs are mineral anionic clays with elevated ion exchange capacity (IEC). They consist of the positively charged metal hydroxide layers with anions located in the interlayer space. This allows strong hydration of the material together with a large number of hydroxyls on the host layers forming a dense network of hydrogen bonds along the two-dimensional surface, therefore facilitating OH- ion conduction by diffusion mechanism. NIMs have a nanostructure consisting of a spherical silica core functionalized with an ionic oligomeric corona. Due to the extremely high number of functional groups present, these materials are able to significantly increase the ionic conduction capacity of the resulting electrolyte. [4]PSU is a thermoplastic polymer with high thermal stability, good chemical resistance and mechanical properties. However, since it has two activated positions per repetition unit for electrophilic aromatic substitution, it can undergo high degrees of functionalisation, which reduce the mechanical properties. We developed a two steps procedure, with allow a functionalization degree between 60 and 80%, preserving its stability.Nanocomposites AEMs were investigated in both OH- and HCO3 - forms, comparing swelling capacity, ionic conductivity and water diffusion. The latter was studied by NMR spectroscopy, measuring the self-diffusion coefficient by the Pulse Field Gradient (PFG) NMR techniques. The nanocomposite membranes are able to maintain good hydration at high temperatures, and to create an adequate nanostructure with the polymer chains, which favour the Grotthuss diffusion mechanism for the OH- ions. Such feature is reflected in the ionic conductivity and in the alkali stability, where they demonstrated the highest conductivity and a reduced membrane degradation rate. Finally, electrolysis cell tests were conducted on MEAs based on these hybrid membranes, and preliminary results showed very promising performance.

A Molecular Electron Density Theory Study of the Domino Reaction of N-Phenyl Iminoboranes with Benzaldehyde Yielding Fused Bicyclic Compounds.

The reaction of N-phenyl iminoborane with benzaldehyde yielding a fused aromatic compound, recently reported by Liu et al., has been studied within the Molecular Electron Density Theory (MEDT). Formation of the fused aromatic compound is a domino process that comprises three consecutive reactions: (i) formation of a weak molecular complex between the reagents; (ii) an intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent of iminoborane; and (iii) a formal 1,3-hydrogen shift yielding the final fused aromatic compound. The two last steps correspond to a Friedel-Crafts acylation reaction, the product of the second reaction being the tetrahedral intermediate of an electrophilic aromatic substitution reaction. However, the presence of the imino group adjacent to the aromatic ring strongly stabilizes the corresponding intermediate, being the reaction product when the ortho positions are occupied by t-butyl substituents. This domino reaction shows a great similitude with the Brønsted acid catalyzed Povarov reaction. Although N-phenyl iminoborane can experience a formal [2+2] cycloaddition reaction with benzaldehyde, its higher activation Gibbs free energy compared to the intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent, 6.6 kcal·mol-1, prevents the formation of the formal [2+2] cycloadduct. The present MEDT study provides a different vision of the molecular mechanism of these reactions based on the electron density.

Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation.

One of the promising leads for the rapid discovery of alternative antimicrobial agents is to repurpose other drugs, such as nonsteroidal anti-inflammatory agents (NSAIDs) for fighting bacterial infections and antimicrobial resistance. A series of new carbazole derivatives based on the readily available anti-inflammatory drug carprofen has been obtained by nitration, halogenation and N-alkylation of carprofen and its esters. The structures of these carbazole compounds were assigned by NMR and IR spectroscopy. Regioselective electrophilic substitution by nitration and halogenation at the carbazole ring was assigned from H NMR spectra. The single crystal X-ray structures of two representative derivatives obtained by dibromination of carprofen, were also determined. The total antioxidant capacity (TAC) was measured using the DPPH method. The antimicrobial activity assay was performed using quantitative methods, allowing establishment of the minimal inhibitory/bactericidal/biofilm eradication concentrations (MIC/MBC/MBEC) on Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains. Computational assays have been performed to assess the drug- and lead-likeness, pharmacokinetics (ADME-Tox) and pharmacogenomics profiles. The crystal X-ray structures of 3,8-dibromocarprofen and its methyl ester have revealed significant differences in their supramolecular assemblies. The most active antioxidant compound was 1i, bearing one chlorine and two bromine atoms, as well as the CO2Me group. Among the tested derivatives, 1h bearing one chlorine and two bromine atoms has exhibited the widest antibacterial spectrum and the most intensive inhibitory activity, especially against the Gram-positive strains, in planktonic and biofilm growth state. The compounds 1a (bearing one chlorine, one NO2 and one CO2Me group) and 1i (bearing one chlorine, two bromine atoms and a CO2Me group) exhibited the best antibiofilm activity in the case of the P. aeruginosa strain. Moreover, these compounds comply with the drug-likeness rules, have good oral bioavailability and are not carcinogenic or mutagenic. The results demonstrate that these new carbazole derivatives have a molecular profile which deserves to be explored further for the development of novel antibacterial and antibiofilm agents.

Regioselective Direct C-H Bond Heteroarylation of Thiazoles Enabled by an Iminopyridine-Based α-Diimine Nickel(II) Complex Evaluated by DFT Studies.

Direct C-H bond arylation is a highly effective method for synthesizing arylated heteroaromatics. This method reduces the number of synthetic steps and minimizes the formation of impurities. We report an air- and moisture-stable iminopyridine-based α-diimine nickel(II) complex for direct C5-H bond arylation of thiazole derivatives. Under a low catalyst loading and performing the reactions at lower temperatures (80 °C) under aerobic conditions, we produced mono- and diarylated thiazole units. Competition experiments and density functional theory calculations revealed that the mechanism of C-H activation in 4-methylthiazole involves an electrophilic aromatic substitution.

Chemische Synthese mit Gasförmigen Molekularen Ionen: Gewinnung von [B12Br11N2]− aus einem Massenspektrometer

AbstractIn der Massenspektrometrie werden häufig kurzlebige Ionen in der Gasphase beobachtet, die zuvor nicht in Lösung oder in der Bulkphase synthetisiert worden sind. Diese schwer zugänglichen Ionen werden daher oft primär als analytisch wertvoll für grundlegende Gasphasenstudien angesehen. Hier wird der Nachweis erbracht, dass die Produkte von Ionen‐Molekül‐Reaktionen in Massenspektrometern auf Oberflächen gesammelt werden können, um kondensierte Materie zu erzeugen und somit als Bausteine für die Synthese neuer Verbindungen zu dienen. Das hochreaktive Fragmentanion [B12Br11]− wurde in einem Massenspektrometer erzeugt und in Anwesenheit von molekularem Stickstoff in [B12Br11N2]− umgewandelt, gefolgt von seiner Massenselektion und sanften Deposition auf Oberflächen. Die Molekularstruktur des bisher nie zuvor synthetisierten [B12Br11N2]− wurde mit konventionellen Methoden der Molekularanalyse, einschließlich magnetischer Kernresonanz‐ und Infrarotspektroskopie, bestätigt. Das [B12Br11N2]−‐Ion ist auf Oberflächen und in Lösung bei Raumtemperatur stabil, aber Erhitzen führt zur Abspaltung von N2 und ermöglicht den Zugang zu dem hochreaktiven Zwischenprodukt [B12Br11]− in der kondensierten Phase, das beispielsweise als Reagenz für elektrophile aromatische Substitutionen weiterverwendet werden kann. Die Isolierung von [B12Br11N2]− erweitert somit das Repertoire der verfügbaren Diazo‐Ionen, die als vielseitige Zwischenprodukte bei verschiedenen chemischen Umwandlungen eingesetzt werden können.

Chemical Synthesis with Gaseous Molecular Ions: Harvesting [B12 Br11 N2 ]- from a Mass Spectrometer.

Mass spectrometry frequently reveals the existence of transient gas phase ions that have not been synthesized in solution or in bulk. These elusive ions are, therefore, often considered to be primarily of analytical value in fundamental gas phase studies. Here, we provide proof-of-concept that the products of ion-molecule reactions in mass spectrometers may be collected on surfaces to generate condensed matter and thus serve as building blocks to synthesize new compounds. The highly reactive fragment anion [B12 Br11 ]- was generated in a mass spectrometer and converted to [B12 Br11 N2 ]- in the presence of molecular nitrogen followed by its mass-selection and soft-landing on surfaces. The molecular structure of [B12 Br11 N2 ]- , which has not been synthetically obtained before, was confirmed by conventional methods of molecular analysis, including nuclear magnetic resonance and infrared spectroscopy. The [B12 Br11 N2 ]- ion is stable on surfaces and in solution at room temperature, but thermal annealing induces elimination of N2 and provides access to the highly reactive intermediate [B12 Br11 ]- in the condensed phase, which can be further used as a reagent, for example, for electrophilic aromatic substitutions. Thus, isolation of [B12 Br11 N2 ]- expands the repertoire of the available diazo ions that can be employed as versatile intermediates in various chemical transformations.

Through-Space, Lone-Pair Promoted Aromatic Substitution: A Relay Mechanism Can Beat Out Direct Activation.

We report a detailed experimental and theoretical analysis of through-space arene activation with halogens, tetrazoles and achiral esters and amides. Contrary to previously assumed direct activation through σ-complex stabilization, our results suggest that these reactions proceed by a relay mechanism wherein the lone pair-containing activators form exothermic π-complexes with electrophilic nitronium ion before transferring it to the probe ring through low barrier transition states. Noncovalent interactions (NCI) plots and Quantum Theory of Atoms in Molecules (QTAIM) analyses depict favorable interactions between the Lewis base (LB) and the nitronium ion in the precomplexes and the transition states, suggesting directing group participation throughout the mechanism. The regioselectivity of substitution also comports with a relay mechanism. In all, these data pave the way for an alternate platform of electrophilic aromatic substitution (EAS) reactions.

One-Step Synthesis of Functionalized Pyrazolo[3,4-b]pyridines via Ring Opening of the Pyrrolinium Ion.

Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.

Selective nucleophilic α-C alkylation of phenols with alcohols via Ti=Cα intermediate on anatase TiO2 surface

C−C bond forming reaction by alkylation of aryl rings is a main pillar of chemistry in the production of broad portfolios of chemical products. The dominant mechanism proceeds via electrophilic substitution of secondary and tertiary carbocations over acid catalysts, forming multiple aryl alkylation products non-selectively through all secondary and tertiary carbons in the alkyl chains but producing little α-C alkylation products because primary carbocations are poorly stable. Herein, we report that anatase TiO2 (TiO2-A) catalyzes nucleophilic α-C alkylation of phenols with alcohols in high selectivity to simply linear alkylphenols. Experimental and computational studies reveal the formation of Ti=C− bond with the α-carbon of the alkyl group at oxygen vacancies of the TiO2-A surface. The subsequent α-C alkylation by selective substitution of phenol ortho-C−H bond is verified by deuterium exchanged substrate and DFT calculations.

Computational and photophysical probing interactions of newly synthesized benzothiazole azo-bonded molecules acting as potent antitubercular agents

In the present work, we have presented a very detailed study of unprecedented mono-azo benzothiazole derivatives. The targeted molecules were synthesized by a single-step involving diazotizing the primary aromatic amines followed by resultant diazonium salts coupling with N, N-Diethyl-m-toluidine (DEMT) through electrophilic substitution reaction influenced by positive mesomeric effect (+M effect) under suitable experimental conditions. The FT-IR, UV–vis, Photoluminescence (PL), 1H NMR, 13C NMR, and HRMS techniques were used to investigate the synthesized mono-azo benzothiazole dye derivatives. Additionally, for the first time, calculations based on density functional theory have been used to examine the ground state geometry, electronic structure, and molecular characteristics potential region maps of four benzothiazole mono-azo architectures (CR1-CR4). The effectiveness of the synthesized dye colourants against M. tuberculosis, H37Rv was assessed by utilizing the agar well diffusion assay method (ATCC 27,294), amongst the studied mono-azo derivatives, CR3 and CR4 exhibited a good zone of inhibition compared to CR1 and CR2. The compound CR1 demonstrated sensitivity at 20 µM, compared to 48.2 µM for the reference gentamicin. The antibacterial activity of the CR1 and CR4 compounds was revealed to have a 19 mm zone of inhibition. The derivative CR1 displayed 42.86 and CR3 displayed 38.75 of the concentration IC50 in 100 μl/ml, respectively, based on their cytotoxic potentiality.

Perborate accelerated copper-immobilized carbon nanofibers activating peroxymonosulfate process for sulfadiazine degradation: Performance and mechanisms understanding

In this work, perborate (BO3−) was applied to promote the degradation of sulfadiazine (SDZ) in copper-immobilized carbon nanofibers (Cu-CNF-x) activated peroxymonosulfate (PMS) system. Results showed that in BO3−/Cu-CNF-3/PMS ternary system, 100% of SDZ (40 μM) could be efficiently eliminated in 5 min with 0.1 g/L Cu-CNF-3, 1 mM BO3− and 1 mM PMS; while Cu-CNF-3/PMS and BO3−/PMS systems only achieved 58.4% and 47.3% degradation in 30 min. In initial pH range of 5.0–9.0, the ternary system removed over 92.6% of SDZ, and the treated solution pH maintained neutral, effectively relieving the water acidification introduced by PMS. Electron paramagnetic resonance analysis and radical scavenger tests evidenced the production of SO4−•, •OH, 1O2 and H2O2BO•O•−. Mechanisms analysis proposed the activation process as follows: initially, BO3− promptly activated PMS to generate H2O2BO•O•− via electrophilic substitution reaction, and H2O2 was produced due to the decomposition of BO3−; thereafter, PMS was activated by Cu-CNF-x to yield SO4−•, •OH and 1O2; the obtained H2O2 was then utilized by Cu-CNF-x to produce •OH and 1O2 as well. Density functional theory (DFT) calculations showed that the adsorption energy (Ead) between PMS and Cu-CNF-x was 0.43 eV. BO3− greatly increased the Ead of PMS on Cu-CNF-x by ten times to 4.75 eV, which extremely promoted the PMS activation. This work provided a novel strategy of BO3−/Cu-CNF-3/PMS for the efficient degradation of refractory organic pollutants, and managed to understand the synergistic role of BO3− to PMS based heterogeneous catalytic processes.

Pd(II) and Rh(I) Catalytic Precursors for Arene Alkenylation: Comparative Evaluation of Reactivity and Mechanism Based on Experimental and Computational Studies.

We combine experimental and computational investigations to compare and understand catalytic arene alkenylation using the Pd(II) and Rh(I) precursors Pd(OAc)2 and [(η2-C2H4)2Rh(μ-OAc)]2 with arene, olefin, and Cu(II) carboxylate at elevated temperatures (>120 °C). Under specific conditions, previous computational and experimental efforts have identified heterotrimetallic cyclic PdCu2(η2-C2H4)3(μ-OPiv)6 and [(η2-C2H4)2Rh(μ-OPiv)2]2(μ-Cu) (OPiv = pivalate) species as likely active catalysts for these processes. Further studies of catalyst speciation suggest a complicated equilibrium between Cu(II)-containing complexes containing one Rh or Pd atom with complexes containing two Rh or Pd atoms. At 120 °C, Rh catalysis produces styrene >20-fold more rapidly than Pd. Also, at 120 °C, Rh is ∼98% selective for styrene formation, while Pd is ∼82% selective. Our studies indicate that Pd catalysis has a higher predilection toward olefin functionalization to form undesired vinyl ester, while Rh catalysis is more selective for arene/olefin coupling. However, at elevated temperatures, Pd converts vinyl ester and arene to vinyl arene, which is proposed to occur through low-valent Pd(0) clusters that are formed in situ. Regardless of arene functionality, the regioselectivity for alkenylation of mono-substituted arenes with the Rh catalyst gives an approximate 2:1 meta/para ratio with minimal ortho C-H activation. In contrast, Pd selectivity is significantly influenced by arene electronics, with electron-rich arenes giving an approximate 1:2:2 ortho/meta/para ratio, while the electron-deficient (α,α,α)-trifluorotoluene gives a 3:1 meta/para ratio with minimal ortho functionalization. Kinetic intermolecular arene ethenylation competition experiments find that Rh reacts most rapidly with benzene, and the rate of mono-substituted arene alkenylation does not correlate with arene electronics. In contrast, with Pd catalysis, electron-rich arenes react more rapidly than benzene, while electron-deficient arenes react less rapidly than benzene. These experimental findings, in combination with computational results, are consistent with the arene C-H activation step for Pd catalysis involving significant η1-arenium character due to Pd-mediated electrophilic aromatic substitution character. In contrast, the mechanism for Rh catalysis is not sensitive to arene-substituent electronics, which we propose indicates less electrophilic aromatic substitution character for the Rh-mediated arene C-H activation.

Lewis acid/acetic acid-catalysed electrophilic amidation of simple arenes with O-acetyl acetohydroxamic acid

Electrophilic arene CH amination constitutes an intrinsically more atom- and step-economical pathway towards arylamines than CX → CN methods. However, most literature examples are restricted to arenes with extensive directing groups (DG) and/or nitrogen coupling partners with large leaving groups (LG). Moreover, only few cases of EAs using cheap metals (e.g., Fe) have been reported. Herein, we demonstrate the catalytic activity of various Lewis acids in the electrophilic amidation of simple arenes with O-acetyl acetohydroxamic acid in acetic acid. With 5 mol% FeIII(citrate)·H2O, up to 27 % yield was achieved, whereas 5 mol% BiCl3 gave up to 31 % yield. Instability of the amidation agent and product inhibition were identified as the yield-limiting factors. The observed regioselectivity, as well as kinetic and spectroscopic data suggest an electrophilic aromatic substitution mechanism, in which acetic acid and the Lewis acid generate a highly electrophilic species from AcNHOAc.

Reaction Mechanism and Kinetics Study of Wheat Polysaccharide via Modified Reductor Technique in Bead Making Process

The reaction mechanism and kinetics investigation of the substitution of titanium in wheat flour polysaccharide (referred to here as titaniumation) in aqua medium during bead making process was carried out. The use of the Modified Reductor Technique was implored to study the reaction kinetics. The study was carried out at varying temperatures between 25 – 70oC. The study showed that the titaniumation of the wheat polysaccharide molecules increased with time and temperature. Hence, at 25oC, the degree of titaniumation (DT) of the ring increased from 0.41 % to 0.49 % and at elevated temperature of 70oC, DT increased from 0.58 to 0.94 % as time progressed from 30 to 210 mins, respectively, while keeping both amount of wheat polysaccharide and TiO2 constant, and thus achieving >1.9-fold. This also implies that the titaniumation of wheat polysaccharide using TiO2 is favourable at elevated temperature. The study was able to reveal that the reaction mechanism of the titaniumation of the polysaccharide molecules is an electrophilic substitution reaction, favouring the ortho position, while the kinetics study showed that the titaniumation reaction is of first order reaction.

Reduction of byproduct formation and cytotoxicity to mammalian cells during post-chlorination by the combined pretreatment of ferrate(VI) and biochar

Ferrate [Fe(VI)] can efficiently degrade various pollutants in wastewater. Biochar application can reduce resource use and waste emission. This study investigated the performance of Fe(VI)/biochar pretreatment to reduce disinfection byproducts (DBPs) and cytotoxicity to mammalian cells of wastewater during post-chlorination. Fe(VI)/biochar was more effective at inhibiting the cytotoxicity formation than Fe(VI) alone, reducing the cytotoxicity from 12.7 to 7.6 mg-phenol/L. The concentrations of total organic chlorine and total organic bromine decreased from 277 to 130 μg/L and from 51 to 39 μg/L, compared to the samples without pretreatment. Orbitrap ultra-high resolution mass spectrometry revealed that the number of molecules of DBPs decreased substantially from 517 to 229 by Fe(VI)/biochar, with the greatest reduction for phenols and highly unsaturated aliphatic compounds. In combination with the substantial reduction of 1Cl-DBPs and 2Cl-DBPs, 1Br-DBPs and 2Br-DBPs were also reduced. Fluorescence excitation-emission matrix coupled with parallel factor analysis suggested that fulvic acid-like substances and aromatic amino acid was obviously reduce likely due to the enhanced oxidation of Fe(IV)/Fe(V) produced by Fe(VI)/biochar and adsorption of biochar. Furthermore, the DBPs generated by electrophilic addition and electrophilic substitution of precursors were reduced. This study shows that Fe(VI)/biochar pretreatment can effectively reduce cytotoxicity formation during post-chlorination by transforming DBPs and their precursors.

ProHSO4: An efficient catalyst for solvent-free synthesis of bis(indolyl)methanes and their in silico screening for potential biological activity

A simple, mild, and efficient protocol has been developed for the synthesis of 3,3′-bis(indolyl)methanes (BIMs) using prolinium hydrogen sulfate (ProHSO4) as a catalyst under solvent-free and support-free conditions. This mechanochemical method undergoes electrophilic substitution reaction of indole with diverse aldehydes to afford the desired BIMs in high yields at room temperature. Due to diverse pharmacological utility, the synthesized BIMs were subjected to in silico studies. The structure activity analysis of BIMs revealed their ability to bind Eg5 kinesin, Human p38 α MAP Kinase, and Human 3 alpha HSD type 3 as a potential protein target for anticancer activity. The compounds exhibited higher binding affinities with Eg5 kinesin having hydrophobic interactions with α2, α3 helices and loop5 amino acid residues. Moreover, molecular docking with Human p38 α MAP Kinase protein depicted compounds as ATP-competitive molecules interacting with hydrophobic region I, II and allosteric DFG motif. A total of 13 derivatives were synthesized and subjected for in silico screening for predicting potential biological activity. Among them,3b, 3d, 3f, 3 g, 3i, 3j, and 3 k compoundswere identified as potential inhibitors of Eg5 kinesin, Human p38 α MAP Kinase, and Human 3 alpha HSD type 3, and their evaluation in the biological experimental system is warranted.

PHARMACOLOGICAL APPLICATION OF THIOPHENE DERIVATIVES

Thiophene nucleus has been established as the potential entity in the largely growing chemical world of heterocyclic compounds processing promising pharmacological characteristics.The knowledge of various synthetic pathway and the diverse physicochemical parameters of such compounds draw the especial attention of medical chemist to produce combanitorial library and carry out exhaustive efforts in the search of lead molecules. Thiophene is a five membered , sulfur containing hetero aromatic ring generally used as building block in drugs. It is structural metabolism leads to the formation of reactive metabolites. This compounds are widely spread in nature & have diversified application in design of new drug molecule. Thiophene has been established as the potential entity in largely growing chemical world of heterocyclic compounds possessing a pharmacological characteristics. A series of thiophene compound can be synthesize through various routes with pharmacological activity. The simple five – membered heterocycle are thiophene, with sulphur atom. It also undergo electrophilic aromatic substitution very readily.Sulphur is the least electron donor as compare to nitrogen and oxygen.Thiophene is similar to benzene in reactivity. Thiophene is the least reactive of the three because the p orbital of the lone pair of electrons on sulphur that conjugates with the ring is a 3p orbital rather than the 2p orbital of N or O, so overlap with 2p orbitals on carbon is less good. Thiophene undergo more or less normal Friedel- Craft reactions, although the less reactive unhydrides( aceticunhydride, Ac2O ) are used instead of acid chlorides, and weaker Lewis acid than AlCl3 are preferred. The regioselectivity is the – the 2- position is more reactive than 3- position. The present review includes the properties, synthesis, and a wide spectrum of biological activities of thiophene based scaffolds, and summary of thiophene containing active pharmaceutical ingredients (APIs) available in the market. KEY WORDS :Thiophene, Medicinal Importance, Biological Importance, Reaction of thiophene

Copper‐Catalyzed Intramolecular SEAr Reaction–Oxidation under Aerobic Conditions: Synthesis of Styryl‐/Alkenyl‐Substituted Xanthone Derivatives

AbstractHerein, we report a copper‐catalyzed intramolecular electrophilic aromatic substitution (SEAr)−oxidation process to access a wide range of diversified xanthone derivatives using air as a sole oxidant. Specifically, this protocol affords hitherto unknown styryl‐/alkenyl‐substituted xanthone derivatives in moderate to high yields. The practicality of the method has been demonstrated by gram‐scale syntheses.

Ru(II)-Catalyzed Weakly Coordinating Carbonyl-Assisted Dialkynylation of (Hetero)Aryl Ketones.

Functionalized aryl(heteroaryl) ketones are present in many natural products as key structural components and serve as basic synthetic building blocks for various organic transformation reactions. Therefore, the development of an effective and sustainable route for making these classes of compounds remains challenging yet highly desirable. Herein, we report a simple and efficient catalytic system for dialkynylation of aromatic/heteroaromatic ketones via a double C-H bond activation in the presence of less expensive ruthenium(II)-salt as a catalyst using the weakly and native carbonyl group as the desired directing group. The developed protocol is highly compatible, tolerant, and sustainable toward various functional groups. The synthetic utility of the developed protocol has been demonstrated through the scale-up synthesis and functional group transformation. Control experiments support the involvement of the base-assisted internal electrophilic substitution (BIES) reaction pathway.