Molecular Electron Density Research Articles

A molecular electron density theory study of the bimolecular nucleophilic substitution reactions on monosubstituted methyl compounds.

The nucleophilic substitution reactions involving methyl monosubstituted compounds have been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311+G(d,p) computational level in DMSO. This study aims to characterize the electronic nature of the transition state structures (TSs) involved in the so-called SN2 and SNi reactions. Both electron localization function and atom-in-molecules topological analyses indicate that the TSs involved in these nucleophilic substitutions can be described as a central methyl CH3+ carbocation, which is strongly stabilized by the presence of two neighbouring nucleophilic species through electron density transfer. This MEDT study establishes a significant electronic similarity between the so-called SN1 and SN2 reactions. Due to the weak electrophilic character of the methyl tetrahedral carbons, the departure of the leaving group should be expected with the approach of the nucleophile. However, while along the SN1 reactions, the strong stabilization of the tertiary carbocation does not demand the participation of the nucleophile, along the SN2 and SNi reactions involving primary tetrahedral carbons, the nucleophiles should participate in the reaction to stabilize the unstable methyl carbocation.

On the Question of Zwitterionic Intermediates in the [3+2] Cycloaddition Reactions between Aryl Azides and Ethyl Propiolate.

The molecular mechanism of the [3+2] cycloaddition reactions between aryl azides and ethyl propiolate was evaluated in the framework of the Molecular Electron Density Theory. It was found that independently of the nature of the substituent within the azide molecule, the cycloaddition process is realized via a polar but single-step mechanism. All attempts of localization as postulated earlier by Abu-Orabi and coworkers' zwitterionic intermediates were not successful. At the same time, the formation of zwitterions with an "extended" conformation is possible on parallel reaction paths. The ELF analysis shows that the studied cycloaddition reaction leading to the 1,4-triazole proceeds by a two-stage one-step mechanism. It also revealed that both zwitterions are created by the donation of the nitrogen atom's nonbonding electron densities to carbon atoms of ethyl propiolate.

A Spectroscopic Approach on Permanganate Oxidation of 1-[(4-Chlorophenyl)methyl]piperidin-4-amine in Presence of Ruthenium(III) Catalyst with DFT Analysis on Reaction Mechanism Pathway

The kinetic oxidation of 1-[(4-chlorophenyl)methyl]piperidin-4-amine (CMP) using alkaline potassium permanganate in presence of Ru(III) as catalyst was conducted spectrophotometrically at 303 K. The Pseudo first-order reaction was maintained with regard to oxidant and substrate during the reaction at an ionic strength of 0.01 mol dm-3. The first-order kinetics has been depicted with respect to catalyst Ru(III) chloride and less than unit order with substrate and medium. For the slow step, different activation parameters including ΔH# (kJ mol-1), Ea (kJ mol-1), ΔG# (kJ mol-1) and ΔS# (J K-1 mol-1) were calculated. The effect of temperature, variation of substrate concentration, oxidant, ionic strength were studied. The stoichiometry ratio of the reaction to the substrate and oxidizing agent was found to be 1:4. The products of reaction were isolated and identified as chlorobenzene and L-alanine, N-(2-aminomethylethyl)-carboxylic acid by LC-MS spectra, a suitable mechanism has been proposed and the rate laws are derived. The frontier molecular orbital (FMO) and frontier electron density (FED) of piperidiamine and the oxidative products were studied using density functional theory (DFT). The results of the theoretical calculations supported the suggested reaction pathways.

MEDT Study, hemisynthesis via regioselective ring opening of α-Himachalene-Epoxides, ADME survey and docking studies designed to target coronavirus and HIV-1

The ring-opening reaction of the two diepoxides, α-himachalenes 6 and 7, with aluminum lithium hydride (LiAlH4) in ether produced the title compounds C15H24O2 sesquiterpene alcohol. Both experimentally and conceptually, the regio- and stereospecificity of this ring opening reaction were investigated using the Molecular Electron Density Theory (MEDT). The Parr functions and the energy study correctly predicted the best interaction to be between the C13 carbon and the hydride, as evidenced by the attained regio- and stereo-specificity revealed through the experimental research. Moreover, the alcohol 8 is obtained from a kinetic and thermodynamic control while the alcohol 9 is obtained only by a kinetic control, in the maximum conformity with the findings of the experiments. In addition, the performed docking calculations to examine the coronavirus and HIV-1 activities of the products 1–9 revealed that alcohol 9 has a higher affinity against coronavirus while β-himachalene 1 against the HIV-1.

Theoretical investigation of electronic, energetic, and mechanical properties of polyvinyl alcohol/cellulose composite hydrogel electrolyte

Hydrogels are a new class of electrolytic materials employed in zinc-air batteries due to their significant on the battery's performance. However, the effectiveness of electrolytic hydrogel is affected by factors such as water content, temperature, additives, etc. Using DMol3 and molecular dynamics modeling techniques, this research aimed at investigating the electronic properties, effect of water content, and temperature on the binding energy, cohesive energy, and the mechanical properties of polyvinyl alcohol/cellulose-based composite hydrogel at the molecular level. The electronic optimized structures of the polymeric materials and parameters such as frontier molecular orbitals, band gap and electron density were analyzed. The results revealed that the binding energies of hydrogel polymer composite increased as the number of water molecules in the composite increased up to 60 % after which the binding energy decreased. In addition, the temperature increase led to a decrease in the binding energy of the composite. The cohesive energy density of the composite was highest at 40 % water content while higher temperatures decreased the cohesive energy density of the hydrogel. As the number of water molecules increased from 29 to 256, the tensile modulus increased from 0.707 × 10−3 to 2.821 × 10−3 Gpa; while the bulk modulus (K) increased in the order of K 40 > 50 > 30 > 20 > 10 respectively. These results serve as a theoretical enlightenment and a guide for experimental works in the field of energy conversion and storage devices.

Vibrational spectra, molecular level solvent interaction, stabilization, donor- acceptor energies, thermodynamic, non-covalent interaction and electronic behaviors of 6-Methoxyisoquinoline- anti tubercular agent

The present research is a theoretical examination of 6-methoxyisoquinoline implementing Density Functional Theory quantum mechanical approach. Structural optimization was performed to achieve a stable molecular structure with the least amount of energy. Several protic and aprotic solvent interactions were performed using the IEF polarization continuum model to examine the reactivity and stability of the molecules. Molecular interactions with solvents were investigated using UV–Visible, HOMO-LUMO, MEP, NBO, and NLO properties, which shows some changes in the compound activity at solvent phases against gas phase. The molecular interaction of π*C1–N2 to π*C5 - C10 shows the higher stabilizing energy. DMSO solvent exhibits a very low band gap energy, favors the molecule's high stability. Molecular reactivity, interactions, and optical behavior were all readily apparent. The chemical reactivity of the compound was found good in water. The percentage of PED contributions was evaluated for each mode of vibrations using vibrational spectral investigation. Topological surface analysis was used for better understanding of molecular electron density, reactive center, and steric effect. ELF, LOL, and RDG was generated for compounds with different solvents. The distance of transition and the overlapping of electron and hole were calculated using electron hole analysis. Pharmacological assessments include drug likeness, ADME, toxicity, and a pre-ADMET online tool, which supports the biological capability of the compound. Finally, molecular docking with anti-tubercular protein was performed, and a Ramachandran plot of chosen protein was shown to explore stability.

New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost‐effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

Diastereoselective green synthesis of pyrrolo[1,2-a]quinolines via [3+2] cycloaddition reaction: insights from molecular electron density theory

Diastereoselective green synthesis of pyrrolo[1,2-a]quinolines via [3+2] cycloaddition reaction: insights from molecular electron density theory

Unveiling the mechanism, regiochemistry and substituent effects of the [3 + 2] cycloaddition reactions of C, N-diaryl nitrile imine to ethylene derivatives from the molecular electron density theory perspective

The [3 + 2] cycloaddition (32CA) reactions of C-(4-methoxyphenyl)-N-phenyl nitrile imine (NI) with a series of ethylene derivatives of increased electrophilic character have been studied within the framework of Molecular Electron Density Theory (MEDT). These 32CA reactions are kinetically controlled with activation Gibbs free energies between 14.8 and 24.0 kcal mol−1, and with the preferred regioselectivity involving the nucleophilic attack of the carbenoid carbon of NI on the non-substituted carbon of the electrophilic ethylenes in agreement with the experimental outcomes. The presence of electron-withdrawing substituents in the ethylene makes the 32CA reaction of forward electron density flux (FEDF) more quickly, relative to that with nucleophilic propene, showing the highest activation parameters and non-polar character. Electron localization function (ELF) and atom-in-molecules (AIM) topological analysis of the electron density at the transition state structures characterize the non-concerted nature of these one-step cb-type 32CA reactions.

Stereoselective Synthesis of a Novel Series of Dispiro-oxindolopyrrolizidines Embodying Thiazolo[3,2-a]benzimidazole Motif: A Molecular Electron Density Theory Study of the Mechanism of the [3 + 2] Cycloaddition Reaction

A one-pot multi-component reaction was employed for the stereoselective synthesis of a novel set of dispiro-oxindolopyrrolizidines analogs incorporating a thiazolo[3,2-a]benzimidazole scaffold based on the [3 + 2] cycloaddition (32CA) reaction approach. The desired novel dispiro-oxindolopyrrolizidines 9a–d were achieved using the 32CA reaction of new ethylene derivatives based on thiazolo[3,2-a]benzimidazole moiety seven with thiazolidine derivatives eight and different substituted isatin compounds 5a–d (R = H, Cl, NO2, and Br). The final dispiro-oxindolopyrrolizidines cycloadducts were separated, purified, and fully characterized by means of a set of spectroscopic tools including IR, HNMR, CNMR, and MS. The Molecular Electron Density Theory (MEDT) was applied to explain the mechanism and stereoselectivity in the of the key 32CA reaction step. The reactive pseudo(mono)radical electronic structure of the in situ generated azomethine ylides and the high polar character of the corresponding 32CA reactions account for the low computed activation Gibbs free energies and total endo stereoselectivity of this kinetically controlled exergonic reaction. The computed relative Gibbs free activation energies of competitive reaction paths and regioisomers ratio distribution of 80:20 justify the major formation of 9a via the most favorable ortho/endo reaction path.

Insights into the mechanism of [3+2] cycloaddition reactions between N-benzyl fluoro nitrone and maleimides, its selectivity and solvent effects.

We present a theoretical study of the [3+2] cycloaddition (32CA) reactions of N-benzyl fluoro nitrone with a series of maleimides producing isoxazolidines. We use the Molecular Electron Density Theory at the MPWB1K/6-311G(d) level. We focus on the reaction mechanism, selectivity, solvent, and temperature effects. In addition, we perform topological analyses at the minimal and transition states to identify the intermolecular interactions. Electron Localization Function approach classifies the N-benzyl fluoro nitrone as zwitterionic (zw-) three-atom components (TACs), associated with a high energy barrier. The low polar character of the reaction is evaluated using the Conceptual Density Functional Theory analysis of the reactants, confirmed by the low global electron density transfer computed at the transition states. Computations show that these 32CA reactions follow a one-step mechanism under kinetic control, with highly asynchronous bond formation and no new covalent bond is formed at the TS. Besides, the potential energy surfaces along the reaction pathways in gas phase and in solvent are mapped. The corresponding Gibbs free energy profiles reveal that the exo-cycloadducts are kinetically and thermodynamically more favored than endo-cycloadducts, in agreement with the exo-selectivity observed experimentally. In particular, we found that solvent and temperature did not affect this selectivity and mainly influence the activation energies and the exothermic character of these 32CA reactions.

Chromone-isoxazole hybrids molecules: synthesis, spectroscopic, MEDT, ELF, antibacterial, ADME-Tox, molecular docking and MD simulation investigations

A mechanistic study was performed within the molecular electron density theory at the B3LYP/6-311G (d,p) computational level to explain the regioselectivity observed. An electron localization function analysis was also performed, and the results confirm the zwitterionic-type (zw-type) mechanism of the cycloaddition reactions between nitrile oxide and alkylated 4H-chromene-2-carboxylate derivatives and shed more light on the obtained regioselectivity experimentally. In silico studies on the pharmacokinetics, ADME and toxicity tests of the compounds were also performed, and it was projected that compounds 5a, 5b, 5c and 5d are pharmacokinetic and have favorable ADME profiles. Moreover, docking and molecular dynamics investigations were conducted to evaluate the interactions, orientation and conformation of the target compounds on the active sites of four distinct enzymes. The results of this investigation showed that two compounds, 5a and 5c, interacted effectively with the S. aureus active site while maintaining acceptable binding energy. Communicated by Ramaswamy H. Sarma

Revealing the influence of tether length on the intramolecular [3 + 2] cycloaddition reactions of nitrones from the molecular electron density theory perspective

AbstractThe influence of ethylene substitution and the tether length between the two reacting counterparts on the selectivity and reactivity of the intramolecular [3 + 2] cycloaddition (IM32CA) reactions of cyclic nitrones leading to tricyclic isoxazolidines have been studied within the Molecular Electron Density theory at the MPWB1K/6‐311G(d,p) computational level. These zw‐type IM32CA reactions follow one‐step mechanism, and the activation barrier decreases with the introduction of electron withdrawing (EW) substituent at the alkene moiety in both the intramolecular and intermolecular versions. The IM32CA reactions involving unsubstituted alkene have non‐polar character with minimal electron density flux classified as null electron density flux type, while that involving the EW nitro substituted ethylene is more facile with a strong electron density flux from the nitrone to the ethylene moiety, classified as forward electron density flux type. The increase in the polar character of the IM32CA reaction decreases the activation Gibbs free energies associated with these intramolecular processes, while the highly polar IM32CA reactions are disfavored with respect to the intermolecular ones. Interestingly, the preferred regioselectivity observed in low polar IM32CA reactions having three methylene units between the nitrone and ethylene frameworks is reversed to that in nitrones separated with four methylene units, in conformity with the experimental outcome. Finally, electron localization function and quantum theory of atoms‐in‐molecules studies reveal that, in general, these IM32CA reactions involve early transition state structures in which the formation of new C‐C and C‐O single bonds have not yet started.

Study of a smooth interpolation between Hirshfeld and iterative Hirshfeld population analyses

A smooth interpolation between the Hirshfeld and the iterative Hirshfeld isolated atomic densities used to determine the weight function that distributes the molecular electronic density among the atoms is proposed to analyze the effect of the Fukui function on the atomic charges obtained. The interpolation makes use of a parameter α, that leads to the Hirshfeld weight function when α=0, and to the iterative Hirshfeld weight function when α=1. Through the calculation of the correlation coefficient R2 between these charges and those corresponding to fits of the electrostatic potential, it is found that R2 presents a maximum when α is equal to 0.95, and is almost constant for values of α between 0.85 and 1.0. The second main correlation was found with the atomic dipole moment corrected Hirshfeld charges that leads to a maximum when α lies between 0.5 and 0.6. Thus, the additional parameter that results from the interpolation may be used to obtain charges similar to those found through schemes that only assign charges, to obtain at the same time the atomic densities that add up to the molecular electron density, or the additional parameter may be used to find a set of charges in a molecule aimed to give a better description of a specific property, delivering at the same time a set of atomic densities that may be very important to derive other properties of the atoms in a molecule.

Construct exchange-correlation functional via machine learning.

Density functional theory has been widely used in quantum mechanical simulations, but the search for a universal exchange-correlation (XC) functional has been elusive. Over the last two decades, machine-learning techniques have been introduced to approximate the XC functional or potential, and recent advances in deep learning have renewed interest in this approach. In this article, we review early efforts to use machine learning to approximate the XC functional, with a focus on the challenge of transferring knowledge from small molecules to larger systems. Recently, the transferability problem has been addressed through the use of quasi-local density-based descriptors, which are rooted in the holographic electron density theorem. We also discuss recent developments using deep-learning techniques that target high-level abinitio molecular energy and electron density for training. These efforts can be unified under a general framework, which will also be discussed from this perspective. Additionally, we explore the use of auxiliary machine-learning models for van der Waals interactions.

Chromatography Scrutiny, Molecular Docking, Clarifying the Selectivities and the Mechanism of [3 + 2] Cycloloaddition Reaction between Linallol and Chlorobenzene-Nitrile-oxide.

Employing the Molecular Electron Density Theory, [3 + 2] cycloaddition processes between 4-chlorobenzenenitrileoxide and linalool, have been applied using the DFT/B3LYP/6-311(d,p) method, activation, reaction energies and the reactivity indices are calculated. In an investigation of conceptual DFT indices, LIL-1 will contribute to this reaction as a nucleophile, whilst NOX-2 will participate as an electrophile. This cyclization is regio, chemo and stereospecific, as demonstrated by the reaction and activation energies, in clear agreement with the experiment's results, in addition, ELF analysis revealed that the mechanism for this cycloaddition occurs in two steps. Furthermore, a docking study was conducted on the products studied, and the interaction with the protein protease COVID-19 (PDB ID: 6LU7), our results indicate that the presence of the -OH group increases the affinity of these products, moreover, adsorption study by chromatography was made on silica gel as support; our outcome reveals that the -OH group creates an intramolecular hydrogen bond in the product P2, while in the product P3 will create a hydrogen bond with the silica gel which makes the two products P2 and P3 are very easy to separate by chromatography, this result is in excellent agreement with the Rf retention value. The study might provide a fundamental for developing natural anti-viral compound in promoting human health.

A molecular electron density theory study of asymmetric Diels-Alder [4 + 2] reaction's mechanism of furan with three substituted alkynes (5-R substituted-3-(3-(phenylsulfonyl)-propioloyl)-oxazolidin-2-one).

The [4 +2 ] cycloaddition reactions between furan and three substituted alkynes (5-R-substituted-3-(3-(phenylsulfonyl)-propioloyl)-oxazolidin-2-one) have been investigated using the MEDT approach. Reactivity indices, reaction pathways, and activation energies are calculated. In an investigation of conceptual DFT indices, furan acts as a nucleophile, while the three substituted alkynes (5-R-substituted-3-(3-(phenylsulfonyl)-propioloyl)-oxazolidin-2-one) function as electrophiles in this reaction. The cycloaddition is regioiselective, as demonstrated by the activation and reaction energies, in clear agreement with the experiment's results. Hetero Diels-Alder [4 + 2] cycloadditions occur following a non-concerted two stages one-step molecular mechanism. For the purpose of this study, all calculations were performed using the Gaussian 09 software. Optimization was achieved through Berny's computational gradient optimization method, employing the B3LYP functional and the 6-31G(d) basis set. Analysis of both local and global reactivity indices provided insights into the reactivity tendencies of the reactants, distinguishing between electrophilic and nucleophilic characteristics via Parr functions. Frequency calculations were employed to identify and characterize stationary points, with transition states indicated by a single imaginary frequency and positive values of all frequencies for reactants and product. The electron localization function (ELF) was investigated using the Multiwfn software within the context of topological analyses.

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

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

Investigation of the molecular mechanism and diastereoselectivity in the [3 + 2] cycloaddition reaction between acetonitrile oxide and Cis-3,4-Dichlorocyclobutene: Insights from MEDT and docking study

[3 + 2] cycloaddition (32CA) reactions involving acetonitrile oxide 1 and cis-3,4-dichlorocyclobutene 2 has been investigated via Molecular Electron Density Theory (MEDT) at B3LYP and M06-2X associated with the basis 6–311++G(d,p). The calculated energy profile demonstrates clearly that this reaction is considerably high diastereoselectivity, which is perfectly in accordance with the results of the experiments. The cycloaddition reaction's molecular mechanism has been examined in bonding evolution theory (BET) terms that displays several changes in electron densities along the reaction pathway and demonstrates a one-step process with highly asynchronous transition states. The acetonitrile oxide under study was classified as zwitter-ionic species from the topological analysis of the electron localization function (ELF). In addition, the optimum solvent for performing this cycloaddition is cyclohexane, which is followed by ether and then chloroform. In a further step, a docking survey was carried out for cycloadducts 3, 3-F, 4 and 4-F docked to the main protease of SARS-CoV2 (6LU7) in comparison with ribavirin, revealing that these cycloadducts have lower binding energies than ribavirin.

A novel alpha-amylase inhibitor-based spirooxindole-pyrrolidine-clubbed thiochromene-pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory.

A novel spirooxindole-pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene-based thiochromene and pyrazole scaffolds with the secondary amino-acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS-on is 13.9 kcal mol-1 below the separated reagent. This 32CA, which takes place through a non-concerted one-step mechanism, presents a total ortho regio- and endo stereoselectivity, which is controlled by the formation of two intramolecular H… O hydrogen bonds. The design of spirooxindole-pyrrolidines engrafted thiochromene and pyrazole was tested for alpha-amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole-pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).