In this paper, the reaction of aniline with ammonium persulphate and concentrated HCl was studied. As a result of our experimental studies, 2,4,6-trichlorophenylamine was identified as the main product. This shows that a high concentration of HCl does not favour oxidative polymerisation of phenylamine, even though the ammonium persulphate/HCl system is widely used in polyaniline synthesis. On the basis of the experimental data and density functional theory for reaction path modelling, we proposed a mechanism for oxidative chlorination of aniline. We assumed that this reaction proceeded in three cyclically repeated steps; protonation of aniline, formation of singlet ground state phenylnitrenium cation, and nucleophilic substitution. In order to confirm this mechanism, kinetic, thermochemical, and natural bond orbital population analyses were performed.
Mannich Synthesis Under Ionic Liquid [Et3NH][HSO4] CatalysisIOSRJAC
Ionic liquid [Et3NH][HSO4] was found to be a particularly efficient catalyst for the synthesis of β- amino carbonyl pyrimidines through the Mannich condensation reaction of substituted pyrimidin-2(1H)-ones, cyclohexanone and 4-fluro/chlorobenzaldehyde under ultrasonic irradiation at room temperature. The present methodology offers several advantages such as excellent yields, simple procedure and mild conditions.
OXIDATION OF POLYETHYLENE GLYCOL-200 BY POTASSIUM PERIODATE IN ALKALINE MEDIU...Ratnakaram Venkata Nadh
Kinetics of PEG-200 oxidation by potassium periodatewas studied in alkaline medium. First-order dependence of
reaction on periodate was observed. Rate of the reaction was found to be independent of substrate concentration.
An inverse fractional order with respect to alkaliwas shown. Arrhenius parameters were calculated. Rate law was
postulated taking into consideration of experimental results.
Mannich Synthesis Under Ionic Liquid [Et3NH][HSO4] CatalysisIOSRJAC
Ionic liquid [Et3NH][HSO4] was found to be a particularly efficient catalyst for the synthesis of β- amino carbonyl pyrimidines through the Mannich condensation reaction of substituted pyrimidin-2(1H)-ones, cyclohexanone and 4-fluro/chlorobenzaldehyde under ultrasonic irradiation at room temperature. The present methodology offers several advantages such as excellent yields, simple procedure and mild conditions.
OXIDATION OF POLYETHYLENE GLYCOL-200 BY POTASSIUM PERIODATE IN ALKALINE MEDIU...Ratnakaram Venkata Nadh
Kinetics of PEG-200 oxidation by potassium periodatewas studied in alkaline medium. First-order dependence of
reaction on periodate was observed. Rate of the reaction was found to be independent of substrate concentration.
An inverse fractional order with respect to alkaliwas shown. Arrhenius parameters were calculated. Rate law was
postulated taking into consideration of experimental results.
Mechanistic Aspects of Oxidation of P-Bromoacetophen one by Hexacyanoferrate ...IJERA Editor
The kinetics of oxidation of p-bromoacetophenone by hexacyanoferrate (III) has been studied in alkaline
medium. The order of reaction with respect of both acetophenone and hexacynoferrate (III) has been found to be
unity. The rate of reaction increases with increase in the concentration of sodium hydroxide.On addition of
neutral KCl, reaction rate increases. The effects of solvent and temperature have been also studied. The product
p-bromophenyl glyoxal have been characterized by IR studies.
Spectroscopic, Thermal, Magnetic and conductimetric studies on some 7-hydroxy...IOSR Journals
7-hydroxy-4-methyl-8-(p-methylphenylazo)coumarin (L1) and 7-hydroxy-4-methyl-8-(p-methoxyphenylazo)coumarin (L2) have been prepared and characterized by elemental analysis, infrared (IR), proton nuclear magnetic resonance (1H NMR) and mass spectra. The important infrared (IR) spectral bands corresponding to the active groups in the two ligands and the solid complexes under investigation were studied. Also the important fragments in the ligands and complexes were done using mass spectra and the main peaks were corresponding to the molecular weights of the ligands and complexes. The solid complexes have been synthesized and characterized by elemental and thermal analyses (TG and DTA) as well as by IR, 1H NMR, magnetic measurements, electronic transition, molar conductance, mass and electron spin resonance (ESR) spectra. The proposed steriochemical structures for the investigated metal complexes suggest octahedral geometry with respect to Mn, Co, Ni, Cu and Zn divalent metal ions with the investigated ligands 1:1 and 1:2 complexes and all of the formed complexes contain coordinated and hydrated water molecules. All of the prepared solid complexes behave as non-electrolytes in chloroform.
Mechanistic Aspects of Oxidation of P-Bromoacetophen one by Hexacyanoferrate ...IJERA Editor
The kinetics of oxidation of p-bromoacetophenone by hexacyanoferrate (III) has been studied in alkaline
medium. The order of reaction with respect of both acetophenone and hexacynoferrate (III) has been found to be
unity. The rate of reaction increases with increase in the concentration of sodium hydroxide.On addition of
neutral KCl, reaction rate increases. The effects of solvent and temperature have been also studied. The product
p-bromophenyl glyoxal have been characterized by IR studies.
Spectroscopic, Thermal, Magnetic and conductimetric studies on some 7-hydroxy...IOSR Journals
7-hydroxy-4-methyl-8-(p-methylphenylazo)coumarin (L1) and 7-hydroxy-4-methyl-8-(p-methoxyphenylazo)coumarin (L2) have been prepared and characterized by elemental analysis, infrared (IR), proton nuclear magnetic resonance (1H NMR) and mass spectra. The important infrared (IR) spectral bands corresponding to the active groups in the two ligands and the solid complexes under investigation were studied. Also the important fragments in the ligands and complexes were done using mass spectra and the main peaks were corresponding to the molecular weights of the ligands and complexes. The solid complexes have been synthesized and characterized by elemental and thermal analyses (TG and DTA) as well as by IR, 1H NMR, magnetic measurements, electronic transition, molar conductance, mass and electron spin resonance (ESR) spectra. The proposed steriochemical structures for the investigated metal complexes suggest octahedral geometry with respect to Mn, Co, Ni, Cu and Zn divalent metal ions with the investigated ligands 1:1 and 1:2 complexes and all of the formed complexes contain coordinated and hydrated water molecules. All of the prepared solid complexes behave as non-electrolytes in chloroform.
Study of the Influence of Nickel Content and Reaction Temperature on Glycerol...IJRESJOURNAL
ABSTRACT: La2O3-SiO2-supported nickel catalysts were evaluated in glycerol steam reforming. The samples (30wt% La and 5, 10 and 15wt% of Ni on 70wt% commercial SiO2), prepared by the simultaneous impregnation method, were characterized by EDX, nitrogen physisorption, XRD, in-situ XRD, XANES and TPR. The analyses revealed NiO species weakly interact with the support and the different metallic surface areas of the catalysts. Catalytic tests were performed in a fixed bed reactor at 600oC and 15Ni catalyst, which showed the best performance, was also evaluated at 500oC and 700oC. According to the results, the Ni content on the catalyst surface interferes in the distribution of gaseous products H2, CO, CO2 and CH4. The increase in the Ni content increases the carbon formation during reaction. The reaction temperature affected the catalytic performance and the best results were obtained with the 15Ni catalyst at 600oC, which was also tested for 20 hours for the analysis of its stability.
Studies on Nitration of Phenol over Solid Acid Catalyst | Crimson PublishersDanesBlake
Phenol was selectively nitrated in liquid phase to produce ortho-nitrophenol using dilute nitric acid (30%) at room temperature in presence of hydrochloric acid treated γ-alumina. Initially Al(NO3) and NH4HCO3 were reacted to prepare Al (OH)3 which on successive calcinations at 550 ᴼC for 5h produce γ-alumina. The γ-alumina was characterized by BET, XRD, SEM and NH3-TPD analysis. The XRD profile confirmed the crystalline structure of the solid acid catalyst γ-alumina. The NH3-TPD analysis showed the development of lewis acidity on the surface of hydrochloric acid treated γ-alumina. The effects of various parameters such as concentration of reactants, types of catalyst, weight of the catalyst, solvent, temperature and time of reaction have been studied. The kinetics of the reaction was also investigated.
Mixed Ligand, Palladium(II) and Platinum(II) Complexes of Tertiary Diphosphin...Karwan Omer
Palladium(II) and platinum(II) complexes containing the mixed ligands tertiary
diphosphinesdppm. dppp and dppf with Thioester ligand S-1H benzo[d] imidazole-2-yl benzothioate
(HSBIBT) have been prepared by the reaction of PdCl2 and PtCl2 with one equiv of tertiary
diphosphines ligands to form [Pd(k2-dppf)Cl2], [Pd(k2-dppp)Cl2] and [Pt(k2-dppmCl)Cl2] complexes
and then add the ligand HSBIBT to these complexes to form mixed ligand complexes. The prepared
complexes have been characterized by single-crystal X-ray diffraction, elemental analysis, magnetic
susceptibility, molar conductance, IR spectral data and UV-Visible. The results suggested that the
ligand HSBIBT bonded to the metal through N atom and square planner geometries were assigned
for the complexes.
A new Schiff base 4-chlorophenyl)methanimine
(6R,7R)-3-methyl-8-oxo-7-(2-phenylpropanamido)-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylate= (HL)= C23H20
ClN3O4S) has been synthesized from β-lactam antibiotic
(cephalexin mono hydrate(CephH)=(C16H19N3O5S.H2O) and 4-
chlorobenzaldehyde . Figure(1) Metal mixed ligand complexes
of the Schiff base were prepared from chloride salt of
Fe(II),Co(II),Ni(II),Cu(II),Zn(II) and Cd (II), in 50% (v/v)
ethanol –water medium (SacH ) .in aqueous ethanol(1:1)
containing and Saccharin(C7H5NO3S) = sodium hydroxide.
Several physical tools in particular; IR, CHN, 1H NMR, 13C
NMR for ligand and melting point molar conductance, magnetic
moment. and determination the percentage of the metal in the
complexes by flame(AAS). The ligands and there metal
complexes were screened for their antimicrobial activity against
four bacteria (gram + ve) and (gram -ve) {Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus}.
The proposed structure of the complexes using program, Chem
office 3D(2006). The general formula have been given for the
prepared mixed ligand complexes Na2[M(Sac)3(L)], M(II) = Fe
(II), Co(II) , Ni(II), Cu (II), Zn(II) , and Cd(II).
HL= C29H24 ClN3O4S, L= C29H23 ClN3O4S -.
Studies on Nitration of Phenol over Solid Acid Catalyst by Lipika Das, Koushi...crimsonpublisherspps
Phenol was selectively nitrated in liquid phase to produce ortho-nitrophenol using dilute nitric acid (30%) at room temperature in presence of hydrochloric acid treated γ-alumina. Initially Al (NO3) and NH4HCO3 were reacted to prepare Al (OH)3 which on successive calcinations at 550 0C for 5h produce γ-alumina. The γ-alumina was characterized by BET, XRD, SEM and NH3-TPD analysis. The XRD profile confirmed the crystalline structure of the solid acid catalyst γ-alumina. The NH3-TPD analysis showed the development of lewis acidity on the surface of hydrochloric acid treated γ-alumina. The effects of various parameters such as concentration of reactants, types of catalyst, weight of the catalyst, solvent, temperature and time of reaction have been studied. The kinetics of the reaction was also investigated
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Paladio soportado sobre hidrotalcita como un catalizador para la reacción de ...52900339
Resumen
Se estudió la eficacia de diversas sales de paladio como catalizador en la reacción de acoplamiento cruzado de Suzuki, y la influencia de la base y de temperatura utilizados en su conversión, El uso de PdCl2 soportado sobre hidrotalcita como catalizador en presencia de carbonato de potasio como se encontró base para proporcionar los mejores resultados. Las temperaturas de reacción superiores a 90 °C garantizarse niveles de conversión a la par con los de muchos catalizadores homogéneos.
Green Chemistry Catalysts for Transfer Hydrogenation Reactions: Synthesis, ch...Karam Idrees
The poster that I presented at the 253rd American Chemical Society National Meeting and Exposition in San Francisco,
CA. It highlights some of my research at Millersville University under the mentorship of Dr. Edward Rajaseelan.
Experimental and Machine-Learning-Assisted Design of Pharmaceutically Accepta...Maciej Przybyłek
Deep eutectic solvents (DESs) are commonly used in pharmaceutical applications as excellent solubilizers of active substances. This study investigated the tuning of ibuprofen and ketoprofen solubility utilizing DESs containing choline chloride or betaine as hydrogen bond acceptors and various polyols (ethylene glycol, diethylene glycol, triethylene glycol, glycerol, 1,2-propanediol, 1,3-butanediol) as hydrogen bond donors. Experimental solubility data were collected for all DES systems. A machine learning model was developed using COSMO-RS molecular descriptors to predict solubility. All studied DESs exhibited a cosolvency effect, increasing drug solubility at modest concentrations of water. The model accurately predicted solubility for ibuprofen, ketoprofen, and related analogs (flurbiprofen, felbinac, phenylacetic acid, diphenylacetic acid). A machine learning approach utilizing COSMO-RS descriptors enables the rational design and solubility prediction of DES formulations for improved pharmaceutical applications.
Effect of Nanohydroxyapatite on Silk Fibroin–Chitosan Interactions—Molecular ...Maciej Przybyłek
Fibroin–chitosan composites, especially those containing nanohydroxyapatite, show potential for bone tissue regeneration. The physicochemical properties of these biocomposites depend on the compatibility between their components. In this study, the intermolecular interactions of fibroin and chitosan were analyzed using a molecular dynamics approach. Two types of systems were investigated: one containing acetic acid and the other containing calcium (Ca2+) and hydrogen phosphate (HPO₄2−) ions mimicking hydroxyapatite conditions. After obtaining the optimal equilibrium structures, the distributions of several types of interactions, including hydrogen bonds, ionic contacts, and hydrophobic contacts, along with structural and energetical features, were examined. The calculated binding energy values for the fibroin–chitosan complexes confirm their remarkable stability. The high affinity of fibroin for chitosan can be explained by the formation of a dense network of interactions between the considered biopolymers. These interactions were found to primarily be hydrogen bonds and ionic contacts involving ALA, ARG, ASN, ASP, GLN, GLU, GLY, LEU, PRO, SER, THR, TYR, and VAL residues. As established, the complexation of fibroin with chitosan maintains the β-sheet conformation of the peptide. β-Sheet fragments in fibroin are involved in the formation of a significant number of hydrogen bonds and ionic contacts with chitosan.
Experimental and Theoretical Insights into the Intermolecular Interactions in...Maciej Przybyłek
Solubility is not only a crucial physicochemical property for laboratory practice but also provides valuable insight into the mechanism of saturated system organization, as a measure of the interplay between various intermolecular interactions. The importance of these data cannot be overstated, particularly when dealing with active pharmaceutical ingredients (APIs), such as dapsone. It is a commonly used anti-inflammatory and antimicrobial agent. However, its low solubility hampers its efficient applications. In this project, deep eutectic solvents (DESs) were used as solubilizing agents for dapsone as an alternative to traditional solvents. DESs were composed of choline chloride and one of six polyols. Additionally, water–DES mixtures were studied as a type of ternary solvents. The solubility of dapsone in these systems was determined spectrophotometrically. This study also analyzed the intermolecular interactions, not only in the studied eutectic systems, but also in a wide range of systems found in the literature, determined using the COSMO-RS framework. The intermolecular interactions were quantified as affinity values, which correspond to the Gibbs free energy of pair formation of dapsone molecules with constituents of regular solvents and choline chloride-based deep eutectic solvents. The patterns of solute–solute, solute–solvent, and solvent–solvent interactions that affect solubility were recognized using Orange data mining software (version 3.36.2). Finally, the computed affinity values were used to provide useful descriptors for machine learning purposes. The impact of intermolecular interactions on dapsone solubility in neat solvents, binary organic solvent mixtures, and deep eutectic solvents was analyzed and highlighted, underscoring the crucial role of dapsone self-association and providing valuable insights into complex solubility phenomena. Also the importance of solvent–solvent diversity was highlighted as a factor determining dapsone solubility. The Non-Linear Support Vector Regression (NuSVR) model, in conjunction with unique molecular descriptors, revealed exceptional predictive accuracy. Overall, this study underscores the potency of computed molecular characteristics and machine learning models in unraveling complex molecular interactions, thereby advancing our understanding of solubility phenomena within the scientific community.
Deep Eutectic Solvents as Agents for Improving the Solubility of Edaravone: E...Maciej Przybyłek
In this study, both practical and theoretical aspects of the solubility of edaravone (EDA) in Deep Eutectic Solvents (DESs) were considered. The solubility of edaravone in some media, including water, can be limited, which creates the need for new efficient and environmentally safe solvents. The solubility of EDA was measured spectrophotometrically and the complex intermolecular interactions within the systems were studied with the COSMO-RS framework. Of the four studied DES systems, three outperformed the most efficient classical organic solvent, namely dichloromethane, with the DES comprising choline chloride and triethylene glycol, acting as hydrogen bond donor (HBD), in a 1:2 molar proportion yielding the highest solubility of EDA. Interestingly, the addition of a specific amount of water further increased EDA solubility. Theoretical analysis revealed that in pure water or solutions with high water content, EDA stacking is responsible for self-aggregation and lower solubility. On the other hand, the presence of HBDs leads to the formation of intermolecular clusters with EDA, reducing self-aggregation. However, in the presence of a stoichiometric amount of water, a three-molecular EDA–HBD–water complex is formed, which explains why water can also act as a co-solvent. The high probability of formation of this type of complexes is related to the high affinity of the components, which exceeds all other possible complexes.
Predicting sulfanilamide solubility in the binary mixtures using a reference ...Maciej Przybyłek
Background. Solubility is a fundamental physicochemical property of active pharmaceutical ingredients. The optimization of a dissolution medium aims not only to increase solubility and other aspects are to be included such as environmental impact, toxicity degree, availability, and costs. Obtaining comprehensive solubility characteristics of chemical compounds is a non-trivial and demanding process. Therefore, support from theoretical approaches is of practical importance.
Objectives. This study aims to examine the accuracy of the reference solubility approach in the case of sulfanilamide dissolution in a variety of binary solvents. This pharmaceutically active substance has been extensively studied, and a substantial amount of solubility data is available. Unfortunately, using this set of data directly for theoretical modeling is impeded by noticeable inconsistencies in the published solubility data. Hence, this aspect is addressed by data curation using theoretical and experimental confirmations.
Materials and methods. In the experimental part of our study, the popular shake-flask method combined with ultraviolet (UV) spectrophotometric measurements was applied for solubility determination. The computational phase utilized the conductor-like screening model for real solvents (COSMO-RS) approach.
Results. The analysis of the results of solubility calculations for sulfonamide in binary solvents revealed abnormally high error values for acetone-ethyl acetate mixtures, which were further confirmed with experimental measurements. Additional confirmation was obtained by extending the solubility measurements to a series of homologous acetate esters.
Conclusions. Our study addresses the crucial issue of coherence of solubility data used for many theoretical inquiries, including parameter fitting of semi-empirical models, in-depth thermodynamic interpretations and application of machine learning protocols. The effectiveness of the proposed methodology for dataset curation was demonstrated for sulfanilamide solubility in binary mixtures. This approach enabled not only the formulation of a consistent dataset of sulfanilamide solubility binary solvent mixtures, but also its implementation as a qualitative tool guiding rationale solvent selection for experimental solubility screening.
Molecular dynamics simulations of the affinity of chitin and chitosan for col...Maciej Przybyłek
Chitosan and chitin are promising biopolymers used in many areas including biomedical applications, such as tissue engineering and viscosupplementation. Chitosan shares similar properties with hyaluronan, a natural component of synovial fluid, making it a good candidate for joint disease treatment. The structural and energetic consequences of intermolecular interactions are crucial for understanding the biolubrication phenomenon and other important biomedical features. However, the properties of biopolymers, including their complexation abilities, are influenced by the nature of the aqueous medium with which they interact. In this study, we employed molecular dynamics simulations to describe the effect of pH and the presence of sodium and calcium cations on the stability of molecular complexes formed by collagen type II with chitin and chitosan oligosaccharides. Based on Gibbs free energy of binding, all considered complexes are thermodynamically stable over the entire pH range. The affinity between chitosan oligosaccharide and collagen is highly influenced by pH, while oligomeric chitin shows no pH-dependent effect on the stability of molecular assemblies with collagen. On the other hand, the presence of sodium and calcium cations has a negligible effect on the affinity of chitin and chitosan for collagen.
Intermolecular Interactions as a Measure of Dapsone Solubility in Neat Solven...Maciej Przybyłek
Dapsone is an effective antibacterial drug used to treat a variety of conditions. However, the aqueous solubility of this drug is limited, as is its permeability. This study expands the available solubility data pool for dapsone by measuring its solubility in several pure organic solvents: N-methyl-2-pyrrolidone (CAS: 872-50-4), dimethyl sulfoxide (CAS: 67-68-5), 4-formylmorpholine (CAS: 4394-85-8), tetraethylene pentamine (CAS: 112-57-2), and diethylene glycol bis(3-aminopropyl) ether (CAS: 4246-51-9). Furthermore, the study proposes the use of intermolecular interactions as molecular descriptors to predict the solubility of dapsone in neat solvents and binary mixtures using machine learning models. An ensemble of regressors was used, including support vector machines, random forests, gradient boosting, and neural networks. Affinities of dapsone to solvent molecules were calculated using COSMO-RS and used as input for model training. Due to the polymorphic nature of dapsone, fusion data are not available, which prohibits the direct use of COSMO-RS for solubility calculations. Therefore, a consonance solvent approach was tested, which allows an indirect estimation of the fusion properties. Unfortunately, the resulting accuracy is unsatisfactory. In contrast, the developed regressors showed high predictive potential. This work documents that intermolecular interactions characterized by solute–solvent contacts can be considered valuable molecular descriptors for solubility modeling and that the wealth of encoded information is sufficient for solubility predictions for new systems, including those for which experimental measurements of thermodynamic properties are unavailable.
Finding the Right Solvent: A Novel Screening Protocol for Identifying Environ...Maciej Przybyłek
This study investigated the solubility of benzenesulfonamide (BSA) as a model compound using experimental and computational methods. New experimental solubility data were collected in the solvents DMSO, DMF, 4FM, and their binary mixtures with water. The predictive model was constructed based on the best-performing regression models trained on available experimental data, and their hyperparameters were optimized using a newly developed Python code. To evaluate the models, a novel scoring function was formulated, considering not only the accuracy but also the bias–variance tradeoff through a learning curve analysis. An ensemble approach was adopted by selecting the top-performing regression models for test and validation subsets. The obtained model accurately back-calculated the experimental data and was used to predict the solubility of BSA in 2067 potential solvents. The analysis of the entire solvent space focused on the identification of solvents with high solubility, a low environmental impact, and affordability, leading to a refined list of potential candidates that meet all three requirements. The proposed procedure has general applicability and can significantly improve the quality and speed of experimental solvent screening.
Intermolecular Interactions of Edaravone in Aqueous Solutions of Ethaline and...Maciej Przybyłek
Edaravone, acting as a cerebral protective agent, is administered to treat acute brain infarction. Its poor solubility is addressed here by means of optimizing the composition of the aqueous choline chloride (ChCl)-based eutectic solvents prepared with ethylene glycol (EG) or glycerol (GL) in the three different designed solvents compositions. The slurry method was used for spectroscopic solubility determination in temperatures between 298.15 K and 313.15 K. Measurements confirmed that ethaline (ETA = ChCl:EG = 1:2) and glyceline (GLE = ChCl:GL = 1:2) are very effective solvents for edaravone. The solubility at 298.15 K in the optimal compositions was found to be equal xE = 0.158 (cE = 302.96 mg/mL) and xE = 0.105 (cE = 191.06 mg/mL) for glyceline and ethaline, respectively. In addition, it was documented that wetting of neat eutectic mixtures increases edaravone solubility which is a fortunate circumstance not only from the perspective of a solubility advantage but also addresses high hygroscopicity of eutectic mixtures. The aqueous mixture with 0.6 mole fraction of the optimal composition yielded solubility values at 298.15 K equal to xE = 0.193 (cE = 459.69 mg/mL) and xE = 0.145 (cE = 344.22 mg/mL) for glyceline and ethaline, respectively. Since GLE is a pharmaceutically acceptable solvent, it is possible to consider this as a potential new liquid form of this drug with a tunable dosage. In fact, the recommended amount of edaravone administered to patients can be easily achieved using the studied systems. The observed high solubility is interpreted in terms of intermolecular interactions computed using the Conductor-like Screening Model for Real Solvents (COSMO-RS) approach and corrected for accounting of electron correlation, zero-point vibrational energy and basis set superposition errors. Extensive conformational search allowed for identifying the most probable contacts, the thermodynamic and geometric features of which were collected and discussed. It was documented that edaravone can form stable dimers stabilized via stacking interactions between five-membered heterocyclic rings. In addition, edaravone can act as a hydrogen bond acceptor with all components of the studied systems with the highest affinities to ion pairs of ETA and GLE. Finally, the linear regression model was formulated, which can accurately estimate edaravone solubility utilizing molecular descriptors obtained from COSMO-RS computations. This enables the screening of new eutectic solvents for finding greener replacers of designed solvents. The theoretical analysis of tautomeric equilibria confirmed that keto-isomer edaravone is predominant in the bulk liquid phase of all considered deep eutectic solvents (DES).
Collagen Type II—Chitosan Interactions as Dependent on Hydroxylation and Acet...Maciej Przybyłek
Chitosan–collagen blends have been widely applied in tissue engineering, joints diseases treatment, and many other biomedical fields. Understanding the affinity between chitosan and collagen type II is particularly relevant in the context of mechanical properties modulation, which is closely associated with designing biomaterials suitable for cartilage and synovial fluid regeneration. However, many structural features influence chitosan’s affinity for collagen. One of the most important ones is the deacetylation degree (DD) in chitosan and the hydroxylation degree (HD) of proline (PRO) moieties in collagen. In this paper, combinations of both factors were analyzed using a very efficient molecular dynamics approach. It was found that DD and HD modifications significantly affect the structural features of the complex related to considered types of interactions, namely hydrogen bonds, hydrophobic, and ionic contacts. In the case of hydrogen bonds both direct and indirect (water bridges) contacts were examined. In case of the most collagen analogues, a very good correlation between binding free energy and DD was observed.
Solubility Characteristics of Acetaminophen and Phenacetin in Binary Mixtures...Maciej Przybyłek
The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents and their mixtures prevents direct measurements of all possible combinations for finding environmentally friendly, operational and cost-effective solubilizers. That is why support from theoretical screening seems to be valuable. Here, a collection of acetaminophen and phenacetin solubility data in neat and binary solvent mixtures was used for the development of a nonlinear deep machine learning model using new intuitive molecular descriptors derived from COSMO-RS computations. The literature dataset was augmented with results of new measurements in aqueous binary mixtures of 4-formylmorpholine, DMSO and DMF. The solubility values back-computed with the developed ensemble of neural networks are in perfect agreement with the experimental data, which enables the extensive screening of many combinations of solvents not studied experimentally within the applicability domain of the trained model. The final predictions were presented not only in the form of the set of optimal hyperparameters but also in a more intuitive way by the set of parameters of the Jouyban–Acree equation often used in the co-solvency domain. This new and effective approach is easily extendible to other systems, enabling the fast and reliable selection of candidates for new solvents and directing the experimental solubility screening of active pharmaceutical ingredients.
Application of COSMO-RS-DARE as a Tool for Testing Consistency of Solubility ...Maciej Przybyłek
Coumarin is a naturally occurring lactone-type benzopyrone with various applications in the pharmaceutical, food, perfume, and cosmetics industries. This hydrophobic compound is poorly soluble in water but dissolves well in protic organic solvents such as alcohols. Despite the extensive use of coumarin, there are only a few reports documenting its solubility in organic solvents, and some reported data are incongruent, which was the direct impulse for this study. To resolve this problem, a theoretical congruency test was formulated using COSMO-RS-DARE for the determination of intermolecular interaction parameters, which allowed for the identification of outliers as suspicious datasets. The perfect match between back-computed values of coumarin solubility and the experimental ones confirms the reliability of the formulated theoretical approach and its adequacy for testing solubility data consistency. As the final approval, the temperature-related coumarin solubility in seven neat alcohols was determined experimentally. Four solvents (methanol, ethanol, 1-propanol, and 2-propanol) were used for reproducibility purposes, and an additional three (1-butanol, 1-pentanol, and 1-octanol) were used to extend the information on the homologous series. The consistency of this extended solubility dataset is discussed in terms of the comparison of remeasured solubility values with the ones already published and within the series of structurally similar solvents. The proposed procedure extends the range of applicability of COSMO-RS-DARE and provides a real and useful tool for consistency tests of already published solubility data, allowing for the approval/disapproval of existing data and filling gaps in datasets. Linear regressions utilizing a 2D molecular descriptor, SpMin2_Bhm, or the distance between solute and solvent in the Hansen solubility space, Ra, were formulated for the estimation of COMSO-RS-DARE integration parameters.
Albumin–Hyaluronan Interactions: Influence of Ionic Composition Probed by Mol...Maciej Przybyłek
The lubrication mechanism in synovial fluid and joints is not yet fully understood. Nevertheless,
intermolecular interactions between various neutral and ionic species including large
macromolecular systems and simple inorganic ions are the key to understanding the excellent lubrication
performance. An important tool for characterizing the intermolecular forces and their
structural consequences is molecular dynamics. Albumin is one of the major components in synovial
fluid. Its electrostatic properties, including the ability to form molecular complexes, are closely
related to pH, solvation, and the presence of ions. In the context of synovial fluid, it is relevant to
describe the possible interactions between albumin and hyaluronate, taking into account solution
composition effects. In this study, the influence of Na+, Mg2+, and Ca2+ ions on human serum
albumin–hyaluronan interactions were examined using molecular dynamics tools. It was established
that the presence of divalent cations, and especially Ca2+, contributes mostly to the increase of
the affinity between hyaluronan and albumin, which is associated with charge compensation in
negatively charged hyaluronan and albumin. Furthermore, the most probable binding sites were
structurally and energetically characterized. The indicated moieties exhibit a locally positive charge
which enables hyaluronate binding (direct and water mediated).
Effect of Chitosan Deacetylation on Its Affinity to Type III Collagen: A Mole...Maciej Przybyłek
The ability to form strong intermolecular interactions by linear glucosamine polysaccharides with collagen is strictly related to their nonlinear dynamic behavior and hence bio-lubricating features. Type III collagen plays a crucial role in tissue regeneration, and its presence in the articular cartilage affects its bio-technical features. In this study, the molecular dynamics methodology was applied to evaluate the effect of deacetylation degree on the chitosan affinity to type III collagen. The computational procedure employed docking and geometry optimizations of different chitosan structures characterized by randomly distributed deacetylated groups. The eight different degrees of deacetylation from 12.5% to 100% were taken into account. We found an increasing linear trend (R2 = 0.97) between deacetylation degree and the collagen-chitosan interaction energy. This can be explained by replacing weak hydrophobic contacts with more stable hydrogen bonds involving amino groups in N-deacetylated chitosan moieties. In this study, the properties of chitosan were compared with hyaluronic acid, which is a natural component of synovial fluid and cartilage. As we found, when the degree of deacetylation of chitosan was greater than 0.4, it exhibited a higher affinity for collagen than in the case of hyaluronic acid.
New Screening Protocol for Effective Green Solvents Selection of Benzamide, S...Maciej Przybyłek
New protocol for screening efficient and environmentally friendly solvents was proposed and experimentally verified. The guidance for solvent selection comes from computed solubility via COSMO-RS approach. Furthermore, solute-solvent affinities computed using advanced quantum chemistry level were used as a rationale for observed solvents ranking. The screening protocol pointed out that 4-formylomorpholine (4FM) is an attractive solubilizer compared to commonly used aprotic solvents such as DMSO and DMF. This was tested experimentally by measuring the solubility of the title compounds in aqueous binary mixtures in the temperature range between 298.15 K and 313.15 K. Additional measurements were also performed for aqueous binary mixtures of DMSO and DMF. It has been found that the solubility of studied aromatic amides is very high and quite similar in all three aprotic solvents. For most aqueous binary mixtures, a significant decrease in solubility with a decrease in the organic fraction is observed, indicating that all systems can be regarded as efficient solvent-anti-solvent pairs. In the case of salicylamide dissolved in aqueous-4FM binary mixtures, a strong synergistic effect has been found leading to the highest solubility for 0.6 mole fraction of 4-FM.
Experimental and theoretical solubility advantage screening of bi-component s...Maciej Przybyłek
A comprehensive experimental and theoretical screening was performed for identification of curcumin solubilizers. Experimental data led to formulation of a non-linear QSPR model correlating molecular descriptors with measured solubilities. The majority of synthesized binary systems exhibited a moderate enhancement of curcumin solubility, which was found to be the highest in the case of curcumin cocrystallized with pyrogallol. New excipients for curcumin were found by utilization of the model within its applicability domain. It appears that a five-fold rise of curcumin solubility is the upper limit for this kind of formulations what was inferred from the screened 230 thousand compounds. Finally, theoretical analysis was extended on naturally occurring curcumin analogues, including demethoxycurcumin, bisdemethoxycurcumin, α-, β- and Ar-turmerones. In all cases, a list of coformers suitable for binary solids preparation with potential enhanced solubility was obtained. They can be treated as first choice lists for further experimental exploration of solubility enhancement of curcumin and its analogues.
Predicting Value of Binding Constants of Organic Ligands to Beta-Cyclodextrin...Maciej Przybyłek
The quantitative structure–activity relationship (QSPR) model was formulated to quantify values of the binding constant (lnK) of a series of ligands to beta–cyclodextrin (β-CD). For this purpose, the multivariate adaptive regression splines (MARSplines) methodology was adopted with molecular descriptors derived from the simplified molecular input line entry specification (SMILES) strings. This approach allows discovery of regression equations consisting of new non-linear components (basis functions) being combinations of molecular descriptors. The model was subjected to the standard internal and external validation procedures, which indicated its high predictive power. The appearance of polarity-related descriptors, such as XlogP, confirms the hydrophobic nature of the cyclodextrin cavity. The model can be used for predicting the affinity of new ligands to β-CD. However, a non-standard application was also proposed for classification into Biopharmaceutical Classification System (BCS) drug types. It was found that a single parameter, which is the estimated value of lnK, is sufficient to distinguish highly permeable drugs (BCS class I and II) from low permeable ones (BCS class II and IV). In general, it was found that drugs of the former group exhibit higher affinity to β-CD then the latter group (class III and IV).
Natural Deep Eutectic Solvents as Agents for Improving Solubility, Stability ...Maciej Przybyłek
Purpose
Study on curcumin dissolved in natural deep eutectic solvents (NADES) was aimed at exploiting their beneficial properties as drug carriers.
Methods
The concentration of dissolved curcumin in NADES was measured. Simulated gastrointestinal fluids were used to determine the concentration of curcumin and quantum chemistry computations were performed for clarifying the origin of curcumin solubility enhancement in NADES.
Results
NADES comprising choline chloride and glycerol had the highest potential for curcumin dissolution. This system was also successfully applied as an extraction medium for obtaining curcuminoids from natural sources, as well as an effective stabilizer preventing curcumin degradation from sunlight. The solubility of curcumin in simulated gastrointestinal fluids revealed that the significant increase of bioavailability takes place in the small intestinal fluid.
Conclusions
Suspension of curcumin in NADES offers beneficial properties of this new liquid drug formulation starting from excreting from natural sources, through safe storage and ending on the final administration route. Therefore, there is a possibility of using a one-step process with this medium. The performed quantum chemistry computations clearly indicated the origin of the enhanced solubility of curcumin in NADES in the presence of intestinal fluids. Direct intermolecular contacts leading to hetero-molecular pairs with choline chloride and glycerol are responsible for elevating the bulk concentration of curcumin. Choline chloride plays a dominant role in the system and the complexes formed with curcumin are the most stable among all possible homo- and hetero-molecular pairs that can be found in NADES-curcumin systems.
Application of Multivariate Adaptive Regression Splines (MARSplines) for Pred...Maciej Przybyłek
A new method of Hansen solubility parameters (HSPs) prediction was developed by combining the multivariate adaptive regression splines (MARSplines) methodology with a simple multivariable regression involving 1D and 2D PaDEL molecular descriptors. In order to adopt the MARSplines approach to QSPR/QSAR problems, several optimization procedures were proposed and tested. The effectiveness of the obtained models was checked via standard QSPR/QSAR internal validation procedures provided by the QSARINS software and by predicting the solubility classification of polymers and drug-like solid solutes in collections of solvents. By utilizing information derived only from SMILES strings, the obtained models allow for computing all of the three Hansen solubility parameters including dispersion, polarization, and hydrogen bonding. Although several descriptors are required for proper parameters estimation, the proposed procedure is simple and straightforward and does not require a molecular geometry optimization. The obtained HSP values are highly correlated with experimental data, and their application for solving solubility problems leads to essentially the same quality as for the original parameters. Based on provided models, it is possible to characterize any solvent and liquid solute for which HSP data are unavailable.
Utilization of oriented crystal growth for screening of aromatic carboxylic a...Maciej Przybyłek
The possibility of molecular complex formation in the solid state of urea with benzoic acid analogues was measured directly on the crystallite films deposited on the glass surface using powder X-ray diffractometry (PXRD). Obtained solid mixtures were also analyzed using Fourier transform infrared spectroscopy (FTIR). The simple droplet evaporation method was found to be efficient, robust, fast and cost-preserving approach for first stage cocrystal screening. Additionally, the application of orientation effect to cocrystal screening simplifies the analysis due to damping of majority of diffraction signals coming from coformers. During validation phase the proposed approach successfully reproduced both positive cases of cocrystallization (urea:salicylic acid and urea:4-hydroxy benzoic acid) as well as pairs of co-formers immiscible in the solid state (urea:benzoic acid and urea:acetylsalicylic acids). Based on validated approach new cocrystals of urea were identified in complexes with 3-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid. In all cases formation of multicomponent crystal phase was confirmed by the appearance of new reflexes on the diffraction patterns and FTIR absorption band shifts of O–H and N–H groups.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
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This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
Reaction of aniline with ammonium persulphate and concentrated hydrochloric acid: Experimental and DFT studies
1. Chemical Papers 66 (7) 699–708 (2012)
DOI: 10.2478/s11696-012-0163-1
ORIGINAL PAPER
Reaction of aniline with ammonium persulphate and concentrated
hydrochloric acid: Experimental and DFT studies
Maciej Przybylek*, Jerzy Gaca
Department of Chemistry and Environmental Protection, Faculty of Chemical Technology and Engineering,
University of Technology and Life Sciences, 85-326 Bydgoszcz, Poland
Received 31 October 2011; Revised 11 February 2012; Accepted 14 February 2012
In this paper, the reaction of aniline with ammonium persulphate and concentrated HCl was
studied. As a result of our experimental studies, 2,4,6-trichlorophenylamine was identified as the
main product. This shows that a high concentration of HCl does not favour oxidative polymerisation
of phenylamine, even though the ammonium persulphate/HCl system is widely used in polyaniline
synthesis. On the basis of the experimental data and density functional theory for reaction path
modelling, we proposed a mechanism for oxidative chlorination of aniline. We assumed that this
reaction proceeded in three cyclically repeated steps; protonation of aniline, formation of singlet
ground state phenylnitrenium cation, and nucleophilic substitution. In order to confirm this mech-
anism, kinetic, thermochemical, and natural bond orbital population analyses were performed.
c 2012 Institute of Chemistry, Slovak Academy of Sciences
Keywords: oxidative chlorination, 2,4,6-trichloroaniline, DFT
Introduction
The presence of oxidants, Cl−
and many differ-
ent kinds of organic compounds in the reaction mix-
ture can contribute to the formation of chloro–organic
species. Oxidative chlorination reactions have a great
significance in modern organic synthesis and the nat-
ural environment (Sasson, 1995; Gribble, 2003). In
general, the mechanisms for the formation of chloro–
organic compounds are very diverse because there are
many kinds of chlorinating agents such as Cl−
, Cl2,
HCl, HOCl, Cl.. This is why so many organic species
can be converted into chloro–organic compounds.
The reaction mechanism can be quantitatively and
qualitatively described by means of experimental and
theoretical tools. Probably mainly due to the low com-
putation cost, density functional theory (DFT) calcu-
lations are very common in reaction path modelling.
Nevertheless, the results of studies of reactions ob-
tained with the use of DFT methods are often in very
good agreement with experimental data (Zheng et al.,
2010; Szaleniec et al., 2006; Dračínský et al., 2010).
When considering the reaction of aromatic amine
with peroxides and aqueous HCl (HClaq), two main
pathways should be generally taken into account:
oxidative chlorination and oxidative polymerisation.
It is commonly known that aniline is very unstable
in the presence of oxidants. The ammonium persul-
phate ((NH4)2S2O8)/HClaq system is widely used in
polyaniline synthesis (Chiang & MacDiarmid, 1986;
MacDiarmid et al., 1987, 1991; Mattoso et al., 1994).
However, some of the N- and C-substituted aniline
derivatives can be chlorinated by Cl−
in the pres-
ence of peroxides without yielding large amounts
of oxidation by-products, e.g. oxidative chlorina-
tion of N-phenylacetamide (acetanilide) is an effec-
tive method of obtaining 2,4,6-trichlorophenylamine
(2,4,6-trichloroaniline, 2,4,6-TCA) (Gaca & ˙Zak,
1997). It is worth noting that C-substituted pheny-
lamine (aniline) derivatives can be chlorinated with
a good yield (up to 80 %) in the presence of
HClaq and H2O2 (Vyas et al., 2003). Studies on
the oxidative chlorination of p-nitrophenylamine (p-
nitroaniline) with the use of many different peroxides
*Corresponding author, e-mail: przybylek@mail.utp.edu.pl
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2. 700 M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012)
like M2S2O8 (where M = NH4, Na, K) and H2O2
showed that the yield of chlorinated products is the
highest when the reaction proceeds in the presence of
(NH4)2S2O8 (Kowalska & Gaca, 2002).
It is commonly accepted that the oxidative poly-
merisation of aniline is usually carried out in diluted
HClaq (Chiang & MacDiarmid, 1986; MacDiarmid et
al., 1987, 1991; Mattoso et al., 1994). To the best of
our knowledge, there is no information in the litera-
ture about the reaction of non-substituted aniline with
(NH4)2S2O8 in the presence of concentrated HClaq.
The purpose of this paper is to contribute towards fill-
ing this gap by presenting the results of our empirical
and theoretical studies.
Theoretical
All DFT calculations reported in this paper were
performed with the use of a Gaussian03 computer
software package (Frisch et al., 2004). The natural
bond orbital (NBO) charge distribution and opti-
mised molecular structures presented here were visu-
alised using GaussView 3.0 program (Dennington et
al., 2003).
Geometry optimisation, single point, and frequen-
cies calculations for all reactants, intermediates, tran-
sition states, and product were performed using the
Becke three-parameter (B3) hybrid method (Becke,
1988, 1993) with the Lee–Yang–Parr (LYP) func-
tional (Lee et al., 1988) and 6-311++G(2d,p) basis
set (McLean & Chandler, 1980; Krishnan et al., 1980;
Frisch et al., 1984; Clark et al., 1983). In order to
evaluate the reliability of the B3LYP method, addi-
tional G3MP2 (Curtiss et al., 1998) calculations were
performed for selected steps of the aniline oxidative
chlorination process. Because the reaction studied pro-
ceeds in an aqueous environment, the self-consistent
reaction field (SCRF) method with the polarised con-
tinuum model (PCM) of solvation (Miertuš et al.,
1981; Miertuš & Tomasi, 1982) and Bondi-type atomic
radii were applied. Boys–Bernardi counterpoise cal-
culations (Boys & Bernardi, 1970), which are neces-
sary for ion pair species, cannot be combined with
the PCM model. Therefore, basis set superposition er-
ror (BSSE) corrections were calculated in vacuum for
structures optimised in the PCM model according to
the approach presented in the paper (Hunter & Wet-
more, 2007). Vibrational analysis was performed in
order to confirm that reactants, product and interme-
diates were local minima (zero imaginary frequencies)
and transitional states are saddle points on the po-
tential energy surface of the molecules (one imaginary
frequency). Furthermore, the structures of the tran-
sitional states were verified by intrinsic reaction co-
ordinate (IRC) calculations (Fukui, 1981; Gonzales &
Schlegel, 1990). Gibbs free energy changes (∆G), and
the pK values derived from them, were calculated for
the standard conditions of 101.325 kPa and 298.15 K.
In order to obtain accurate results in reactions involv-
ing protonation and deprotonation, Gibbs free energy
of hydrated H+
(∆G(H+
)aq) was calculated from the
Eqs. (1) and (2).
Ggas(H+
) = Hgas(H
+
)−T Sgas(H
+
) (1)
∆G(H
+
)aq=Ggas(H
+
)+∆Ghydr(H
+
) (2)
Where Hgas(H+
) = 2.5RT (6.19 kJ mol−1
) and
TSgas(H+
) = 32.47 kJ mol−1
(Tawa et al., 1998; Topol
et al., 2000; Pokon et al., 2001; Liptak & Shields,
2001), R is gas constant, T represent temperature,
Hgas(H+
) is gas-phase enthalpy of H+
, Sgas(H+
) is
gas-phase entropy of H+
, and Ggas(H+
) is gas-phase
Gibbs free energy of H+
We used the experimental
value of Gibbs free energy of hydration ∆Ghydr(H+
)
= –1104.58 kJ mol−1
, which is accepted as the most
accurate (Camaioni & Schwerdtfeger, 2005; Palascak
& Shields, 2004; Król et al. 2006).
Experimental
All reagents, standards and solvents were pur-
chased from commercial suppliers. Ammonium per-
sulphate (purity ≥ 97 %), hydrochloric acid (37 %),
benzene (purity ≥ 99.5 %), and hexane (purity
≥ 99.0) from POCH (Poland). Aniline (purity ≥
99.5 %), 2,4,6-TCA (purity ≥ 98.0 %), tetramethyl-
silane (TMS), and zinc powder from Sigma–Aldrich
(USA). Chloroform-d (purity 99.96 %) from Deutero
GmbH (Germany) and used without purification ex-
cept aniline which was purified by distillation over
zinc powder before use. 1
H NMR (200 MHz) and
13
C NMR (50 MHz) spectra were recorded on a Var-
ian Gemini 200 spectrometer (Varian, USA), the IR
spectrum on a Bruker Alpha-PFT-IR spectrometer
(Bruker, Germany) with a diamond attenuated total
reflection (ATR) crystal, and the MS (EI) spectrum
on a Bruker 320-MS spectrometer (Bruker, Germany).
Thin-layer chromatography (TLC) was performed on
silica-gel plates (Merck 60 F254, Merck, Germany).
The reaction of aniline with (NH4)2S2O8 and con-
centrated HClaq was carried out at ambient temper-
ature and under atmospheric pressure conditions, ac-
cording to the following procedure. First, a solution of
phenylammonium chloride was prepared by the addi-
tion of aniline (0.91 mL, 10.00 mmol) to concentrated
HClaq (50 mL, 37 %) with vigorous magnetic stirring.
Then, (NH4)2S2O8 (3.5 g, 15.35 mmol) was added to
this solution. The mixture was stirred for an hour and
then poured into 1500 mL of water. The precipitated
product was filtered and washed copiously with wa-
ter until the filtrate was colourless. After drying in
air, 2,4,6-TCA was obtained as a pinkish–white solid.
The yield was 20.1 %; m.p. 75◦
C. TLC, eluent ben-
zene/hexane (ϕr = 2 : 3); Rf = 0.88. IR, ˜ν /cm−1
:
A
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3. M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012) 701
Fig. 1. Oxidation reactions of aniline and 2,4,6-TCA.
3456 (NH), 3367 (NH), 3075 (CH), 1610 (NH2),
1571 (Ph), 1391 (Ph), 1296 (C—N), 1072 (NH2), 783
(C—Cl), 555 (C—Cl). 1
H NMR (CDCl3), δ: 7.19 (s,
2H, benzene ring), 4.43 (bs, 2H, NH2). 13
C NMR
(CDCl3), δ: 139 (Car—N), 127.6 (CH), 121.8 (C—Cl),
119.7 (C—Cl). UV-VIS/nm (methanol): 304, 242, 218.
MS (EI) signals of 2,4,6-TCA in the recorded spec-
trum, m/z (Ir/%): 48.6 (6), 52.0 (10), 61.8 (15), 65.0
(13), 73.3 (4), 79.5 (7), 87.8 (12), 96.8 (21), 106.8 (3),
124 (29), 133.1 (4), 158.7 (7), 167.3 (3), 194.9 (100),
198.5 (25), 200.9 (10). We also identified peaks of m/z
values greater than those characteristic of 2,4,6-TCA
(Stein, 2011; AIST, 2011), m/z (Ir/%): 274.7 (7) and
355.1 (4).
Results and discussion
At the first stage of our studies, we sought to
establish what type of reaction occurred under ex-
perimental conditions and to propose a mechanism
for the main product formation. The main goal of
the experimental part of this study was to resolve
whether the oxidative chlorination of aniline occurred
in the presence of reagents which are typical of aniline
polymerisation. We found that a high concentration
of HCl did not favour the oxidative polymerisation
of aniline. Furthermore, good agreement with avail-
able spectral data (Stein, 2011; AIST, 2011; Badawi
et al., 2009; Davis, 2009) indicates that, in the re-
action of aniline with (NH4)2S2O8 and concentrated
HClaq, 2,4,6-TCA is mainly produced. We found that
the yield of chlorination of aniline and the purity of
obtained 2,4,6-TCA was most satisfactory when the
reaction was carried out according to the procedure
presented in “Experimental”, i.e. in the presence of a
maximal concentration of chloride ions, in contrast to
polymerisation which was carried out in diluted HCl.
However, the pinkish-white colour of the precipitate
and some mass spectrum peaks suggest that 2,4,6-
TCA is probably contaminated with small amounts
of aniline trimerisation (m/z = 274.7) and 2,4,6-
TCA dimerisation (m/z = 355.1) by-products. The
first of these reactions (Fig. 1) can take place under
conditions of the oxidative polymerisation of aniline
(Wei et al., 1990, 1989; Gospodinova & Terlemezyan,
1998; ´Ciri´c-Marjanovi´c et al., 2008a). The product
of the latter reaction was identical with the prod-
uct obtained by electrochemical oxidation of 2,4,6-
TCA (Jaworski & Kalinowski, 2007; Pusztai et al.,
2004).
Studies on oxidative chlorination of p-nitroaniline
(Kowalska & Gaca, 2002) and anodic chlorination of
aniline (Matsuda et al., 1984) suggest that Cl−
is the
most probable chlorinating agent. It appears obvious
that, although Cl2 is formed under reaction condi-
tions, it cannot act as a chlorinating agent in o- and
p-chlorination of aniline. According to Henderson–
Hasselbalch equation:
pKa = pH + log([BH]/[B]) (3)
in the presence of concentrated HClaq (pH < 1) almost
all of aniline, pKa = 4.57 (Hall et al., 1972), exists in
a protonated form and NH+
3 substituent directs elec-
trophilic attack on the meta position.
According to many papers, the oxidation of ani-
line with (NH4)2S2O8 in an acidic medium leads
to the formation of phenylnitrenium cation (´Ciri´c-
Marjanovi´c et al., 2006, 2008a, 2008b; Kovaľchuk et
al., 2001; Kulkarni et al., 2011). This species may
react with various nucleophiles (McClelland et al.,
1996; Tordeux & Wakselman, 1995; Borodkin & Shu-
bin, 2005). It is worth emphasising that only the sin-
glet ground state phenylnitrenium cation exhibits elec-
trophilic properties in the reaction with Cl−
(McClel-
land et al., 1996). Based on these facts, we assumed
that the oxidative chlorination of aniline consisted
of three steps which were cyclically repeated; proto-
nation of aniline, formation of singlet ground state
phenylnitrenium cation, and nucleophilic substitution
(Fig. 2).
At the next stage of our studies, DFT reaction
path modelling was performed. The results of the ther-
mochemical analysis of p-chloroaniline (p-CA), 2,4-
A
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4. 702 M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012)
Fig. 2. Proposed mechanistic pathway for oxidative chlorination of aniline.
Table 1. Results of thermochemical analysis of proposed aniline oxidative chlorination steps: in the cases of K1, K5, K9, K13, pK
values are equal to negative logarithm of equilibrium constant of deprotonation reaction (pKa); values in parentheses are
calculated at G3MP2 level
∆G pK
Reaction
kJ mol−1 Calc. Exp.
C6H5NH+
3
K1
←→ C6H5NH2 + H+ 23.01 4.03
4.57a
(30.51) (5.35)
C6H5NH+
3 + S2O2−
8
K2
←→ C6H5NH+
+ 2HSO−
4
–117.07 –20.51 –
(–87.90) (–15.4) –
C6H5NH+
3 Cl−
+ S2O2−
8
K3
←→ C6H5NH+
Cl−
+ 2HSO−
4 –140.58 –24.63 –
C6H5NH+
3 Cl− K4
←→ p−CA –108.91 –19.08 –
p-CAH+ K5
←→ p-CA + H+
18.03 3.16 3.99a
p-CAH+
+ S2O2−
8
K6
←→ p-Cl-C6H4NH+
+ 2HSO−
4 –127.78 –22.39 –
p-CAH+
Cl−
+S2O2−
8
K7
←→ p-Cl-C6H4NH+
Cl−
+ 2HSO−
4 –125.56 –22.00 –
p-Cl-C6H4NH+
Cl− K8
←→ 2,4-DCA –122.93 –21.54 –
2,4-DCAH+ K9
←→ 2,4-DCA + H+ 6.07 1.06
2.05a
(17.35) (3.04)
2,4-DCAH+
+ S2O2−
8
K10
←→ 2,4-di-Cl-C6H3NH+
+ 2HSO−
4
–131.17 –22.98
–
(–100.50) (–17.60)
2,4-DCAH+
Cl−
+S2O2−
8
K11
←→ 2,4-di-Cl-C6H3NH+
Cl−
+ 2HSO−
4 –130.75 –22.91 –
2, 4-di-Cl-C6H3NH+
Cl− K12
←→ 2,4,6-TCA –124.93 –21.89 –
2,4,6-TCAH+ K13
←→ 2,4,6-TCA + H+
–9.54 –1.67 –0.03b
a) pKa value from (Hall et al., 1972); b) pKa value from (Angioi et al., 2005); Calc. – calculated, Exp. – experimental.
dichloroaniline (2,4-DCA), and 2,4,6-TCA formation
are given in Table 1.
In this paper we compared two different compu-
tational methods: B3LYP/6-311++G(2d,p) based on
the density functional theory and G3MP2 based on
second order M¨oller–Plesset perturbation theory. ∆G
values calculated at these two levels of computational
theory vary from each other. Nevertheless, the results
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5. M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012) 703
Fig. 3. Visual representation of optimised structures of ammonium cation/Cl−: C6H5NH+
3 Cl− (A); p-CAH+ Cl− (C); 2,4-DCAH+
Cl− (E) and phenylnitrenium/Cl−: C6H5NH+Cl− (B); p-Cl-C6H4NH+ Cl− (D); 2,4-di-Cl-C6H3NH+ Cl− (F); ion pair
intermediates.
obtained with both of these methods confirmed that
the process studied could proceed under experimen-
tal conditions. The theoretical values of pK for K1,
K5, K9, and K13 reactions are found to be close to
the experimental data (Hall et al., 1972; Angioi et
al., 2005). However, the pK1 value calculated by the
G3MP2 method is slightly less accurate than by the
DFT method. All acid–base equilibria except for K13
favour the phenylammonium cation. This is obvious
because 2,4,6-TCA has a very weak basic character
(pKa < 0), and hence a large amount of water added
to the reaction mixture leads to precipitation of the
neutralised product.
With a high concentration of Cl−
, phenylammo-
nium/Cl−
, and phenylnitrenium/Cl−
ion pairs forma-
tion seems to be probable and so it should be taken
into consideration. DFT calculations showed that the
K3 reaction was more thermodynamically favourable
than the K2 reaction, which meant that ion-pairing
was advantageous for the non-substituted aniline ox-
idation step. The same cannot hold true for the oxi-
dation of chlorinated anilines, because ion pair inter-
mediates do not affect the values of pK significantly.
The structures of complexes involved in the proposed
mechanism are summarised in Fig. 3.
Energy of interaction (Eint) (Krygowski et al.,
2005; Szatylowicz et al., 2007) of phenylammonium/
Cl−
A, C, and E adducts is –8.33 kJ mol−1
,
–8.95 kJ mol−1
, and –10.00 kJ mol−1
, respectively.
The negative values of Eint indicate that an ion pair
has lower energy than the sum of separate energies
of individual ions. It is worth noting that the forma-
tion of complex A was proved via various NMR spec-
troscopy techniques (Suezawa et al., 1991). Cl−
· · ·C
interaction in B, D, and F is the cause of the increased
tetrahedral character of orto- and para-carbon atoms
in phenylnitrenium/Cl−
complex. This loss of pla-
narity is probably due to charge transfer and can be il-
lustrated by the value of C-3 C-4 C-5 C-6 dihedral an-
gle in B (Fig. 3) which is equal to –0.346◦
. Eint values
calculated for B, D, F complexes are –39.29 kJ mol−1
,
–12.72 kJ mol−1
, –14.77 kJ mol−1
, respectively. This
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6. 704 M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012)
Fig. 4. NBO charges in phenylnitrenium cation and its chlorinated derivatives.
shows that the formation of phenylnitrenium/Cl−
ion pair intermediates is energetically favourable.
BSSE error calculated for A–F ion pair species
is 1.92 kJ mol−1
, 3.97 kJ mol−1
, 1.88 kJ mol−1
,
4.48 kJ mol−1
, 2.26 kJ mol−1
, 4.73 kJ mol−1
, respec-
tively. This means that the BSSE error is generally
higher for phenylnitrenium/Cl−
complexes than in the
case of phenylammonium/Cl−
ion pairs. Interaction
between phenylnitrenium cation and Cl−
seems to be
fundamental in K4, K8, and K12 substitution steps.
NBO charge distribution in phenylnitrenium cation
(Fig. 4) indicates that chloride ion would be likely
to interact with ortho- and para-carbon atoms. Be-
cause there is lower electron density in para-position
in C6H5NH+
than in ortho-position, our studies do
not include o-chlorination of non-substituted aniline,
as we sought to present only the most favourable path-
way for 2,4,6-TCA formation. It is worth noting that,
according to the similar mechanism of electrochemi-
cal oxidative chlorination proposed by Matsuda et al.
(1984), aniline is chlorinated to p-CA and then p-CA
is chlorinated to 2,4-DCA.
High negative values of pK indicate that all oxida-
tion and substitution steps equilibria favour the prod-
ucts (Table 1). This means that the formation of chlo-
rinated aniline derivatives is probable, as our thermo-
chemical modelling predicts but, in order to confirm
that the proposed mechanism can really take place, ki-
netic calculations were also performed. The values of
Gibbs free energy of activation and transitional state
(TS) decomposition are presented in Fig. 5.
Protonation of the nitrogen atom in the transi-
tional state plays a key role in the kinetics of the nu-
cleophilic attack on the phenylnitrenium cation (Mc-
Clelland et al., 1996). Our calculations showed that
Gibbs free energy barriers of proton addition to B
and D intermediates (Figs. 5a and 5b) were the lowest
in comparison with other reaction paths. It is worth
noting that 2,4-DCA and 2,4,6-TCA can be formed
Table 2. Geometrical parameters of selected intermediates and
transitional states
Cl—H Cl—H—N Cl—C
Structure
˚A ◦ ˚A
A 2.136 176.302 –
B – – 1.887
TS1 – – 1.815
D – – 1.890
TS2 – – 1.811
TS4 – – 1.859
E 2.104 175.929 –
in the inter-molecular and intra-molecular proton-
transfer steps. The high positive values of Gibbs free
energy of activation suggest that inter-molecular pro-
ton transfers in D and F intermediates (Figs. 5d and
5e) are kinetically unfavourable, hence the formation
of TS2 and TS3 (Figs. 5b and 5c) in the alternative
pathway is preferred. Although TS3 is formed with
a relatively high value of Gibbs free energy of acti-
vation, this barrier can be overcome by the energy
released in the TS2 decomposition step. Summarising
these considerations, in accordance with our DFT cal-
culations, the most reasonable reaction path consists
of the intra-molecular proton transfers presented in
Figs. 5a–5c.
The geometrical parameters of selected intermedi-
ates and transitional states are presented in Table 2.
C—Cl bond distances in transitional states are longer
than in intermediates. However, the differences be-
tween values in this geometrical parameter are not
significantly high. Interactions of phenylammonium
cation/Cl−
and phenylnitrenium cation/Cl−
interme-
diates can be characterised by Cl—H and Cl—C bond
distances. It is worth noting that Cl—H and Cl—C
values calculated for A–F are lower than the sum of
A
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7. M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012) 705
Fig. 5. Transitional states formation and decomposition in substitution steps of oxidative chlorination of aniline. Gibbs free energy
values are given in kJ mol−1.
the appropriate van der Waals radii. Moreover, the
Cl—H—N bond angle in these complexes is close to
180◦
. Both of the geometrical parameters referred to
above (bond distances and angles) suggest relatively
A
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8. 706 M. Przybylek, J. Gaca/Chemical Papers 66 (7) 699–708 (2012)
good stability of the ion pairs studied.
Conclusions
The reaction between aniline, (NH4)2S2O8, and
concentrated HClaq has never been studied before. As
a result of our experimental investigations, we found
that, in a large excess of concentrated hydrochloride
acid, nucleophilic attack of chloride anion to phenyl-
nitrenium cation was more probable than chemical
polymerisation of aniline, although (NH4)2S2O8 and
HClaq are reagents widely used in polyaniline syn-
thesis. Oxidative chlorination of aniline under exper-
imental conditions results in the formation of 2,4,6-
TCA. Unfortunately, the reaction studied is not a
very effective method of chlorination of aniline be-
cause 2,4,6-TCA is formed in rather low yield and
it is contaminated with small amounts of probably
oxidative dimerisation and trimerisation by-products.
In order to establish the mechanism of the chlori-
nation of aniline with the use of (NH4)2S2O8 and
HClaq, B3LYP/6-311++G(2d,p) reaction path cal-
culations were performed. The results of this study
showed that formation of 2,4,6-TCA by the proposed
pathway (protonation of aniline, formation of phenyl-
nitrenium cation/Cl−
ion pair intermediate, and nu-
cleophilic substitution involving intra-molecular pro-
ton transfer) appears to be thermodynamically and
kinetically feasible.
Acknowledgements. The authors gratefully acknowledge the
help received from the Academic Computer Centre in Gda´nsk
in providing its facility to perform all the calculations published
in this study.
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