Nucleophilic Centers Research Articles

Ultrasonic Promoted Regioselective Reactions of the Novel Spiro 3,1-Benzoxazon-Isobenzofuranone Dye Toward Some Organic Base Reagents

Ultrasonic and solvent-free condensation of 2-aminobenzoic acid with 4-bromoisobenzofuran-1,3-dione to construct the 4′-bromo-3′H-spiro[benzo[d][1,3]-oxazine-2,1′-isobenzofuran]-3′,4(1H)-dione dye (1) under basic reaction conditions. The spiro product 1 exhibited both electrophilic and nucleophilic centers. A series of nitrogen nucleophiles such as hydrazine, glycine, 2-aminopyridine, pyridin-2-ylmethanamine, 4-methoxyaniline, 4-aminoacetophenone, morpholine, piperidine or 1-ethylpiperazine and carbon electrophiles such as oxiranylmethylchloride, ethyl chloroacetate, chloroacetyl chloride can be treated with 2-benzoxazine-2-yl benzoic acid (BBA) via multicomponent reaction. The fluorescence of the spiro product dyes decreases proportionally to the initial chloride concentration in the solution. The chemical structures of the synthesized compounds can be confirmed by microanalytical, spectral data and optimized by quantum chemical parameters. Biological evaluation showed that these synthesized spiro compounds exhibited moderate to good cytotoxic activity. Among them, compounds 2, 5, and 11 displayed the best cytotoxic activity against MCF7 and Wl-38 cell lines.

Mechanistic Investigations of the Synthesis of Lactic Acid from Glycerol Catalyzed by an Iridium–NHC Complex

In the present work, the reaction pathways and the origin of catalytic activity for the production of lactic acid from glycerol catalyzed by an iridium–heterocyclic carbene (Iridium-NHC) complex at 383.15 K were investigated by DFT study at the M06-D3/6-311++G (d, p)//SDD level. Compared to the noncatalytic reaction pathway, the energy barrier sharply decreased from 75.2 kcal mol−1 to 16.8 kcal mol−1 with the introduction of the iridium–NHC complex. The catalytic reaction pathway catalyzed by the iridium–NHC complex with a coordinated hydroxide included two stages: the dehydrogenation of glycerol to 2,3-dihydroxypropanal, and the subsequent isomerization to lactic acid. Two reaction pathways, including dehydrogenation in terminal and that in C2-H, were studied. It was found that the formation of dihydroxyacetone from the H-removal in C2-H was more favorable, which might have been due to the lower energy of LUMO, whereas dihydroxyacetone could be easily transferred to 2,3-dihydroxypropanal. The analyses of electrostatic potential (ESP), hardness, and f- Fukui function also confirmed that the iridium–NHC complex acted as a hydrogen anion receptor and nucleophilic reaction center to highly promote the conversion of glycerol to lactic acid.

Bipolar CoSe2 nanocrystals embedded in porous carbon nanocages as an efficient electrocatalyst for Li-S batteries

The confinement and catalysis properties of orthorhombic CoSe2 as a host material for Li-S battery are studied by theoretical and experimental methods. First-principles calculations show that the (111) surface of CoSe2 possesses adjacent nucleophilic and electrophilic centers. This bi-polar surface can easily bond the polysulfide molecules and catalyze their conversion reactions. As a result, the decomposition energy barriers of polysulfides are greatly decreased from ∼3.0 eV to 0.2–0.4 eV. Following theoretical prediction, CoSe2 nanocrystals with specific (111) surface are prepared and embedded in porous carbon nanocages using ZIF-67 metal organic framework as a template. Benefited from the advantages of porous C and CoSe2 (111) surface, the shuttling of polysulfides is suppressed and their conversion kinetics is facilitated. The Li-S cell using this host material exhibits high capacity and remarkable cycle stability, showing a discharge capacity of 1199 mA·h·g−1 at 0.2C and 400 stable cycles at 1.0C.

Designing Electrophilic and Nucleophilic Dual Centers in the ReS2 Plane toward Efficient Bifunctional Catalysts for Li-CO2 Batteries.

Two-dimensional transition metal dichalcogenides (TMDCs) show great potential as efficient catalysts for Li-CO2 batteries. However, the basal plane engineering on TMDCs toward bifunctional catalysts for Li-CO2 batteries is still poorly understood. In this work, density functional theory calculations reveal that nucleophilic N dopants and electrophilic S vacancies in the ReS2 plane tailor the interactions with Li atoms and C/O atoms in intermediates, respectively. The electrophilic and nucleophilic dual centers show suitable adsorption with all intermediates during discharge and charge, resulting in a small energy barrier for the rate-determining step. Thus, an efficient bifunctional catalyst is produced toward Li-CO2 batteries. As a result, the optimal catalyst achieves an ultrasmall voltage gap of 0.66 V and an ultrahigh energy efficiency of 81.1% at 20 μA cm-2, which is superior to those of previous catalysts under similar conditions. The introduction of electrophilic and nucleophilic dual centers provides new avenues for designing excellent bifunctional catalysts for Li-CO2 batteries.

New styrylquinoxaline: synthesis, structural, biological evaluation, ADMET prediction and molecular docking investigations

The organic compound (E)-3-(4-methylstyryl)quinoxalin-2(1H)-one (SQO) with molecular formula C17H14N2O was synthesized and analyzed using single crystal X-ray diffraction, 1H, 13C NMR and FTIR spectroscopic techniques. The geometric parameters of the molecule was optimized by density-functional theory (DFT) choosing B3LYP with 6-31++G(d,p) basis set. For compatibility, the theoretical structure and experimental structure were overlapped with each other. Frontier molecular orbitals of the title compound were made, and energy gap between HOMO and LUMO was calculated. Molecular electrostatic potential map was generated finding electrophilic and nucleophilic attack centers using DFT method. Hirshfeld surface analysis (HSA) confirms active regions at the circumference of N1 atoms and O1 atoms that form intermolecular N1—H1···O1 hydrogen bond. The acute oral toxicity study was carried out according to OECD guideline, which approve that the compound SQO was non-toxic. In addition, this quinoxaline derivative was evaluated for its in vitro antidiabetic activity against α-glucosidase and α-amylase enzymes and for antioxidant activity by utilizing several tests as 1,1-diphenyl-2-picryl hydrazyl, (2,2′-azino-bis(3-ethyl benzthiazoline-6-sulfonicacid), reducing power test (FRAP) and hydrogen peroxide activity H2O2. The molecular docking studies were performed to investigate the antidiabetic activity of SQO and compared with the experimental results. SQO is a potent antidiabetic from both the experimental and molecular docking results. Finally, the physicochemical, pharmacokinetic and toxicological properties of SQO have been evaluated by using in silico absorption, distribution, metabolism, excretion and toxicity analysis prediction.

TELLURO-INDUCED CYCLIZATION OF 2-ALLYLTHIOQUINOLINECARBALDEHYDE

It is known that thiazolopyrimidines with an exocyclic aryl tellurium moiety exhibit antimalarial activity against the deadliest strain of Plasmodium falciparum. For expanding the number of potentially biologically active compounds with an exocyclic aryl tellurium moiety, a study of tellurium-induced heterocyclization of 2-allylthioquinoline-3-carbaldehyde with p-methoxyphenylteltur trichloride was performed. The selection of this synton is motivated by the fact that quinoline derivatives are used as drugs in the treatment of malaria.
 The starting compound 2-allylthioquinoline-3-carbaldehyde contains several nucleophilic centers for passing tellurium-induced cyclization, namely the multiple bond of the allyl moiety and the endocyclic nitrogen atom of quinoline. Thus cyclization reaction can lead to the formation of both addition and cyclization products. The reaction of the allyl thioether with p-methoxyphenyltelluriumtrichloride was performed in glacial acetic acid and under stirring the reagents at room temperature for 8 hours. It was found that the tellurium-induced cyclization of 2-allylthioquinoline-3-carbaldehyde with p-methoxyphenyltellurium trichloride leads to the formation of angular thiazoloquinoline with an exocyclic aryltellurium fragment ― 1-(dichloro(4-methoxyphenyl)-tellanyl)methyl)-4-formyl-1,2-dihydrothiazolo[3,2-a]quinolin-10-ium chloride. Based on the spectral data, it is proved that the reaction produces a complex of 1-(dichloro(4-methoxyphenyl)-tellanyl)methyl)-4-formyl-1,2-dihydrothiazolo[3,2-a]quinolin-10-ium chloride with p-methoxyphenyltellturium trichloride with composition 1: 1. It should be noted that the formation and composition of this complex does not depend on the ratio of starting reagents.
 In order to evaluate the biological activity of 1-(dichloro(4-methoxyphenyl)-tellanyl)methyl)-4-formyl-1,2-dihydrothiazolo[3,2-a]quinolin-10-ium chloride, the theoretical bioscreening was performed using online resource Way2Drug. Analysis of the obtained bioactivity data showed the potential antioxidant, antibacterial and antiviral activity of exotellurofunctionalized thiazolo[3,2-a]quinoline-10-ium.
 Keywords: 2-allylthioquinoline-3-carbaldehyde; p-methoxyphenyltellurium trichloride; electrophilic heterocyclization; annulation, thiazolo[3,2-a]quinolinium chloride.

EFFECTIVE SYNTHESIS OF 5-IODOMETHYL-2-PHENYLIMINOTHIAZOLIDINE

Thioamides and thioureas are interesting building blocks for the synthesis of azaheterocycles with valuable biological properties. The electrophilic cyclization of N-alkenylthioamides and N-alkenylthioureas is one of the methods of their synthesis. It is known that halogen-induced cyclization of N-alkenylthioamides and thioureas leads to the annealing of 5- or 6-membered cycles. In particular, the cyclization of allylthioamides in the presence of halogen gives halomomethylthiazolines. N-allyl-N-arylthioureas react with halogens, arylselenyl chloride or aryl tert-trichloride to form thiazolidine rings.
 The three-component reaction between unsaturated amine, isocyanate or isothiocyanate and halogen is the one of the methods for the synthesis of halogenated oxazolines or thiazolines. This reaction considered the using of propargyl amine, isocyanate and halogen, which leads to the formation of halomomethylidenoxazolidine or halomomethylidenethiazolidine. The formed vinyl halides are universal building blocks in organic synthesis due to their ability to modify. The aim of this work is to study the course of the three-component reaction between allylmethylamine, phenylisothiocyanate and iodine. The use of allylamine will allow to introduce a halogenomethyl group into the azaheterocycle, which will greatly facilitate its functionalization.
 The reaction of equimolar amounts of phenylisothiocyanate, allylmethylamine and iodine was performed in acetonitrile. This led to an increase in the yield of the target reaction product. Increasing the reaction temperature from room to 50 ° C also increased the yield. The 5-iodomethyl-3-methyl-2-phenylimino-1,3-thiazolidine was isolated as a light brown oil after treatment of the reaction mixture with potassium carbonate. Obviously, the process of iodocyclization is preceded by the formation of N-allyl thiourea, which effectively enters into the electrophilic heterocyclization reaction with the participation of an additional nucleophilic center - a sulfur atom.
 Thus, the resulting three-component reaction of phenylisothiocyanate, allylmethylamine and iodine is an effective method for the synthesis of bioperspective iodomethylthiazolidine, submitted for further functionalization.
 Keywords: electrophilic cyclization; allylmethylamine, three-component reaction; iodomethylthiazolidine.

Solvent Influence on Absorption Spectra and Tautomeric Equilibria of Symmetric Azomethine-Functionalized Derivatives: Structural Elucidation and Computational Studies.

A new series of azomethine‐functionalized compounds was synthesized from the condensation of 2‐hydroxy‐1,3‐propanediamine and 2‐thienylcarboxaldehydes in the presence of a drying agent. The derivatives were spectroscopically characterized by NMR, LC‐MS, UV/Vis, IR and elemental analysis. Variable temperature 1H‐NMR (−60 to +60 °C) was performed to investigate the effect of solvent polarity; the capability of solvent to form H‐bond was found to dramatically influencing the tautomerization process of the desired structures. The calculated thermochemical parameters (ΔH298, ΔG298 and ΔS298) at DFT and MP2 levels of theory explained that 3 b exists in equilibrium with two tautomers. The basis of the electronic absorptions was pursued through Time‐Dependent Density‐Functional Theory (TD‐DFT). Analysis of the structural surfaces was inspected and the molecular electrostatic potential (MEP) demonstrated that the three functionalized compounds were relatively analogous in the electronic distributions. Furthermore, the electrophilic and nucleophilic centers lying on the molecular surfaces were probably playing a key‐role in stabilizing the compounds through the nonclassical C−H⋅⋅⋅π interactions and hydrogen bonding. The impact of solvent polarity on absorption spectra were investigated via solvatochromic shifts. For instance, compound 3 c displayed a gradual shift of the maximum absorption to the red area when the solvent polarity was increased, recording a 21 nm of bathochromic shift. In contrast, no significant solvent‐effect on 3 a and 3 b was observed. The solvation relation was pursued between Gutmann's donicity numbers the experimental λmax; exhibited almost positive linear performance with a minor oscillation, that ascribe to the possible weak interface between the molecules of solute and designated solvents. The bandgap energy of all products were assessed experimentally using optical absorption spectra following Tauc approach, giving −4.050 (3 a), −3.900 (3 b) and −3.210 (3 c) eV. However, the ΔE were computationally figured out from TD‐DFT simulation to be −4.258 (3 a), −4.022 (3 b) and −3.390 (3 c) eV.

Insights into Thiourea-Based Bifunctional Catalysts for Efficient Conversion of CO2 to Cyclic Carbonates.

The bifunctional thiourea catalyst system with both electrophilic and nucleophilic centers has been certified to be effective for fixing CO2 under mild reaction conditions; however, many questions remain, especially concerning the relationship between structure and performance. Herein, we systematically studied a series of such bifunctional catalysts with different chain lengths, nucleophilic anions, and substituents, which impact obvious influence on the catalytic performance. The activation energies of catalysts with different chain lengths are calculated via in situ IR. On this basis, we disclosed for the first time that the spacer length of tetramethylene -(CH2)6- is the optimal spatial effect for the coupling of epoxides and CO2. Particularly, the single crystal X-ray diffraction analysis of the molecular structures of the bifunctional catalyst C8 indicated the discovery of the existence of interaction force between the sulfur atom on the thiourea group and one hydrogen atom on the benzene ring, as well as the intermolecular hydrogen bonding interaction of the bromide (Br-) and two NH groups on the thiourea group. The catalyst structure performance, direct observation of the crystal structure, the thermodynamic study, and a wide range of substrates (12 examples) should be informative on the optimization of the existing catalysts or the design of new catalysts in the future.

Solid-Phase Synthesis of Boranophosphate/Phosphorothioate/Phosphate Chimeric Oligonucleotides and Their Potential as Antisense Oligonucleotides.

In this study, we successfully synthesized boranophosphate (PB), phosphorothioate (PS), and phosphate (PO) chimeric oligonucleotides (ODNs) as a candidate for the antisense oligonucleotides (ASOs). The PB/PS/PO-ODNs were synthesized utilizing H-boranophosphonate, H-phosphonothioate, and H-phosphonate monomers. Each monomer was condensed with a hydroxy group to create H-boranophosphonate, H-phosphonothioate, and H-phosphonate diester linkages, which were oxidized into PB, PS, and PO linkages in the final stage of the synthesis, respectively. As for condensation of an H-phosphonothioate monomer, regulating chemoselectivity was necessary since the monomer has two nucleophilic centers: S and O atoms. To deal with this problem, we used phosphonium-type condensing reagents, which could control the chemoselectivity. In this strategy, we could synthesize PB/PS/PO oligomers, including a 2′-OMe gapmer-type dodecamer. The physiological and biological properties of the synthesized chimeric ODNs were also evaluated. Insights from the evaluation of physiological and biological properties suggested that the introduction of suitable P-modification and sugar modification at proper sites of ODNs would control the duplex stability, nuclease resistance, RNase H-inducing ability, and one base mismatch discrimination ability, which are critical properties as potent ASOs.

Semibiocatalytic Approach toward Regioisomerically Enriched Ethyl Dimethylpyrazines Important in Flavor Industries.

Alkylpyrazines are important heterocyclic compounds used as flavorants in food and beverage industries. In this study, a regioselective semibiocatalytic process was developed to synthesize 2-ethyl-3,5-dimethylpyrazine (235-EDMP) over its 3-ethyl-2,5-dimethyl pyrazine (325-EDMP) isomer and vice versa. We initially explored how sterics could direct the coupling orientations between diamines and diketones to access 235- or 325-EDMP selectively. Also, the physical parameters of the reaction conditions were changed, such as reduced temperature, the order-of-addition of the reactants, and supplementation with chiral zeolites to template the orientation of the coupling partners to direct the reaction regiochemistry. Each reaction trial resulted in 50:50 mixtures of the EDMP isomers. An alternative approach was explored to control the regioselectivity of the reactions; α-hydroxy ketones replaced the diketones as the electrophilic coupling reactant used in previous trial experiments. The hydroxy ketone reactants were made biocatalytically with pyruvate decarboxylase. The coupling reaction between 2-hydroxypentan-3-one and propane-1,2-diamine resulted in the desired 235-EDMP at >70% (∼77 mg) relative to 325-EDMP in the mixture. The 3-hydroxypentan-2-one congener was biocatalyzed and reacted with propane-1,2-diamine as a proof of principle to synthesize 325-EDMP (∼60% relative abundance, ∼73 mg) over 235-EDMP. These results suggested a mechanism that was directed by the hydroxy ketone electrophilicity and the sterics at the diamine nucleophilic centers.

Novel cucurbit[6]uril-based [3]rotaxane supramolecular ionic liquid as a green and excellent corrosion inhibitor for the chemical industry

The corrosion of steel materials in alkaline-saline media is the largest problem in industry. Economical and environmentally friendly corrosion inhibitors are crucial for corrosion protection. The present work is the first to introduce a novel cucurbit[6]uril-based [3]rotaxane supramolecular ionic liquid (CB6-based [3]rotaxane) as a green and efficient corrosion inhibitor for the chemical industry. The correlation between the supramolecular ionic liquid system and inhibition behavior was studied first. The inhibition characteristics of CB6-based [3]rotaxane in 1 M OH– + 1 M Cl– solution were first fully investigated by thermodynamic, gravimetric, electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PDP), electrochemical noise (EN), cyclic voltammetry (CV), density functional theory (DFT), molecular dynamics (MD) simulation, scanning electron microscopy (SEM) and energy dispersive X-ray spectrometry (EDX) methods. The experimental results confirmed that CB6-based [3]rotaxane exhibited excellent corrosion resistance, and its inhibition efficiency was 97.97% at 100 mg/L and 0.032 mM. The electrochemical results suggested that (i) CB6-based [3]rotaxane was a mixed-type corrosion inhibitor with anodic dominance; (ii) the supramolecular part of selected ionic liquid is responsible for notably blocks the charge transfer process on the metal surface. The theoretical findings correlated well with the experimental results and revealed that the protonated form of this supramolecular structure exhibited better performance than its neutral form. MD simulations results suggested that the bond length of the Fe(surface)-inhibitor (3.127 Å) is less than 3.5 Å, which indicates that chemisorption is dominant in the investigated adsorption system. Molecular electrostatic potential analysis confirmed that the studied ionic liquid-supramolecular system contained most favorable nucleophilic centers, which are responsible for excellent inhibition performance.

Copper‐Catalyzed Aza‐Sonogashira Cross‐Coupling To Form Ynimines: Development and Application to the Synthesis of Heterocycles

AbstractNitrogen‐substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper‐catalyzed synthesis of ynimines from readily available O‐acetyl ketoximes and terminal alkynes. A wide range of O‐acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross‐coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.

Copper-Catalyzed Aza-Sonogashira Cross-Coupling To Form Ynimines: Development and Application to the Synthesis of Heterocycles.

Nitrogen‐substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper‐catalyzed synthesis of ynimines from readily available O‐acetyl ketoximes and terminal alkynes. A wide range of O‐acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross‐coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.

Copper(II) Prevents the Saccarine-Dialkylcyanamide Coupling by Forming Mononuclear (Saccharinate)(Dialkylcyanamide)copper(II) Complexes

The reaction in the system CuII/sacNa(H)/NCNR2 (sacNa(H) = sodium saccharinate (saccharin); R = Me, Et) results in the formation of the complexes [Cu(sac)2(NCNR2)(H2O)2] (R = Me 1, Et 2) instead of the expected products derived from the saccharin–cyanamide coupling. Complexes 1, 2, and hydrate 1·2H2O were characterized by IR, AAS (Cu%), TGA, and also by single-crystal X-ray diffraction for 1 and 1·2H2O. An integrated computational study of model structure 1 in the gas phase demonstrates that the Cu–Ncyanamide and Cu–Nsac coordination bonds exhibited a single bond character, polarized toward the N atom and almost purely electrostatic, with the calculated vertical total energies for the Cu–Ncyanamide and Cu–Nsac of 43.6 and 156.4 kcal/mol, respectively. These data confirmed that the copper(II) completely blocks the nucleophilic centers of ligands via coordination, thus preventing the saccharin–cyanamide coupling.

Reactivity of a Gold-Aluminyl Complex with Carbon Dioxide: A Nucleophilic Gold?

A gold-aluminyl complex has been recently reported to feature an unconventional gold nucleophilic center, which was revealed through reactivity with carbon dioxide leading to the Au-CO2 coordination mode. In this work, we computationally investigate the reaction mechanism, which is found to be cooperative, with the gold–aluminum bond being the actual nucleophile and Al also behaving as electrophile. The Au–Al bond is shown to be mainly of an electron-sharing nature, with the two metal fragments displaying a diradical-like reactivity with CO2.

Regio- and chemoselectivity in S- and O- difluoromethylation reactions using diethyl (bromodifluoromethyl)phosphonate

The effective difluoromethylations of various S- and O- based- nucleophiles, presenting a wide range of pKa values, using diethyl(bromodifluoromethyl) phosphonate (1) under basic conditions is described. These reactions, which rely on the quantitative generation of difluorocarbene formed through the hydrolysis of 1, were found to be effective only once the starting materials had pKa values of less than ca. 11. Importantly, in cases in which the substrates held two or three nucleophilic centers this feature was successfully implemented to achieve a high chemo- or regioselective difluoromethylation of the center exhibiting the lowest pKa value and the highest polarizability.

Synthesis, structural properties and potent bioactivities supported by molecular docking and DFT studies of new hydrazones derived from 5-chloroisatin and 2-thiophenecarboxaldehyde

New hydrazones were synthesized by employing a convergent synthetic methodology involving condensation of N-alkyl 5-chloroisatins with hydrazone derived from 2-thiophenecarboxaldehyde. The synthesized compounds were fully characterized using UV/Vis., Infrared, 1H and 13C NMR spectroscopies as well as single crystal X-rays diffraction analysis. Bader's theory of ‘atoms in molecules’ confirmed the existence of all nonbonding interactions. Connectivity between isomers of synthesized compounds was characterized by the distribution of critical points, isatin surfaces, and bond paths. The presence of electrostatic potential on oxygen and hydrogen atoms was evaluated by means of MEP calculations, which showed that the oxygen atom acts as nucleophilic center for electrophilic hydrogen atom. Compound 6 exhibited potent anti-oxidant potential (DPPH, ABTS, NBT) with IC50 values of 46 ± 0.72 μM/mL. These compounds were also screened for in vitro cholinesterases inhibition, where compound 6 presented effective inhibition against AChE and BChE in comparison to the standard drugs; allanzanthane and galanthamine in a dose reliant mode. The IC50 values of both compounds (6 and 7) against AChE were determined to be 20.21 ± 0.06 & 16.22 ± 0.18 μM and against BChE, as 28.01 ± 0.01 & 20.11 ± 0.12 μM, respectively. Molecular docking studies supported these results and helped to establish structure activity relationship. The results reported in this manuscript are anticipated to be beneficial for understanding the solid-state architecture of the X-ray structures of new hydrazone conjugates of 5-chloroisatin & 2-thiophenecarboxaldehyde. On the other hand their intriguing biological potentials can create quest among scientific community to further analyze such molecules for drug discovery purposes.

Origin of the α‐Effect in SN2 Reactions

AbstractThe α‐effect is a term used to explain the dramatically enhanced reactivity of α‐nucleophiles (R−Y−X:−) compared to their parent normal nucleophile (R−X:−) by deviating from the classical Brønsted‐type reactivity‐basicity relationship. The exact origin of this effect is, however, still heavily under debate. In this work, we have quantum chemically analyzed the α‐effect of a set of anionic nucleophiles, including O‐, N‐ and S‐based normal and α‐nucleophiles, participating in an SN2 reaction with ethyl chloride using relativistic density functional theory at ZORA‐OLYP/QZ4P. Our activation strain and Kohn–Sham molecular orbital analyses identified two criteria an α‐nucleophile needs to fulfill in order to show α‐effect: (i) a small HOMO lobe on the nucleophilic center, pointing towards the substrate, to reduce the repulsive occupied–occupied orbital overlap and hence (steric) Pauli repulsion with the substrate; and (ii) a sufficiently high energy HOMO to overcome the loss of favorable HOMO–LUMO orbital overlap with the substrate, as a consequence of the first criterion, by reducing the HOMO–LUMO orbital energy gap. If one of these two criteria is not fulfilled, one can expect no α‐effect or inverse α‐effect.

Origin of the α-Effect in SN 2 Reactions.

The α‐effect is a term used to explain the dramatically enhanced reactivity of α‐nucleophiles (R−Y−X:−) compared to their parent normal nucleophile (R−X:−) by deviating from the classical Brønsted‐type reactivity‐basicity relationship. The exact origin of this effect is, however, still heavily under debate. In this work, we have quantum chemically analyzed the α‐effect of a set of anionic nucleophiles, including O‐, N‐ and S‐based normal and α‐nucleophiles, participating in an SN2 reaction with ethyl chloride using relativistic density functional theory at ZORA‐OLYP/QZ4P. Our activation strain and Kohn–Sham molecular orbital analyses identified two criteria an α‐nucleophile needs to fulfill in order to show α‐effect: (i) a small HOMO lobe on the nucleophilic center, pointing towards the substrate, to reduce the repulsive occupied–occupied orbital overlap and hence (steric) Pauli repulsion with the substrate; and (ii) a sufficiently high energy HOMO to overcome the loss of favorable HOMO–LUMO orbital overlap with the substrate, as a consequence of the first criterion, by reducing the HOMO–LUMO orbital energy gap. If one of these two criteria is not fulfilled, one can expect no α‐effect or inverse α‐effect.