Parr Functions Research Articles

Chemical synthesis, spectroscopic studies, chemical reactivity properties and bioactivity scores of an azepin-based molecule

Azepines derived molecules are of great interest because of their multi-drug like properties and thus advantageous in biomedical field. Herein, a novel route is described for the synthesis of an azepine-based molecule, 10,11-Dibromo-10,11-dihydro- 5H-dibenzo[b,f]azepine-5-carbonyl chloride (DACC) by using dibutyltin dilaurate (DBTDL) as catalyst. The structure of DACC was elucidated by using FT-IR, NMR, and mass spectroscopic techniques. Several density functionals were considered for the study of the molecular properties of the synthesized compound. The global and local reactivity descriptors were estimated by using Conceptual Density Functional Theory (CDFT). The active sites suitable for the nucleophilic and electrophilic attacks were selected by linking them with the Fukui indices, Parr functions and condensed Dual Descriptor Δf(r). Finally, the bioactivity scores for the studied molecule were predicted through different methodologies.

Synthesis, crystal structure, DFT studies and biological activity of (Z)-3-(3-bromophenyl)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxyprop-2-en-1-one

BackgroundNowadays, is emerging a new generation of highly promising inhibitors bearing the β-ketoenol functionality. The present work relates to the first synthesis, the structure determination, the DFT studies and the use of a new biomolecule designed with a β-ketoenol group bounded to a pyrazolic moiety.ResultA novel β-ketoenol-pyrazole has been synthesized, well characterized and its structure was confirmed by single crystal X-ray diffraction. The electron densities and the HOMO–LUMO gap have been calculated using the DFT method with BLYP, PW91, PWC functionals and 6-31G* basis set. An evaluation of the molecule stability is provided by a NBO analysis and the calculated Fukui and Parr functions have been used to locate the reactive electrophile and nucleophile centers in the molecule. The synthesized compound, screened for its in vitro antifungal behavior against the Fusarium oxysporum f.sp. albedinis FAO fungal strains, shows a moderate activity with an inhibition percentage of 46%. The product was also tested against three bacterial strains (Escherichia coli, Bacillus subtilis and Micrococcus luteus), but no significant effect was observed against these organisms.ConclusionsDensity functional calculations are used to evaluate the HOMO–LUMO energy gap, the molecular electrostatic potential and to provide a natural bond orbital analysis. The measured antimicrobial activities encourage us to continue searching for other structures, likely to be good antifungal candidates.

Reactivity of β-Substituted Phosphoenol Pyruvates towards Alkoxides: A Theoretical and Experimental Study

A new, practical, synthesis of pyruvic orthoesters relying on the conversion of β-substituted phosphoenol pyruvates by the action of alkoxides is described. Our study of the reaction mechanism was done experimentally and also theoretically. Density functional theory calculations were used to explain the major reaction products found experimentally. Geometry optimisations and atomic charges obtained using different population analyses and the global and local reactivity indices, namely global electrophilicity and the Parr function, were obtained at the B3LYP/6-311G(d) level of theory. The experimental reactivity was correctly reproduced using the Parr function.

Chemical Reactivity Properties, pKa Values, AGEs Inhibitor Abilities and Bioactivity Scores of the Mirabamides A⁻H Peptides of Marine Origin Studied by Means of Conceptual DFT.

The MN12SX density functional, in connection with the Def2TZVP basis set, was assessed, together with the SMD solvation model (Solvation Model based on the Density), for calculation of the molecular properties and structure of a group of peptides of marine origin named Mirabamides A–H. All the chemical reactivity descriptors for the systems were calculated via Conceptual Density Functional Theory (CDFT). The active sites suitable for nucleophilic, electrophilic, and radical attacks were chosen by linking them with the Fukui function indices, nucleophilic and electrophilic Parr functions, and condensed Dual Descriptor , respectively. Additionally, the p values for the different peptides are predicted with great accuracy as well as the ability of the studied molecule in acting as an efficient inhibitor of the formation of Advanced Glycation Endproducts (AGEs), which constitutes a useful knowledge for the development of drugs for fighting Diabetes, Alzheimer and Parkinson diseases. Finally, the bioactivity scores for the Mirabamides A–H are predicted through different methodologies.

Local Molecular Reactivity of the Colored Dansylglycine in Water and Dioxane Studied through Conceptual DFT

This study evaluated a fixed long-range corrected range-separated hybrid (RSH) density functional associated with the Def2TZVP basis set alongside the SMD solvation model for the computation of the structure, molecular properties, and chemical reactivity of the M8 intermediate melanoidin pigment in the presence of water and dioxane. The preference of the active sites pertinent to radical, nucleophilic, and electrophilic attacks is made through linking them with the electrophilic and nucleophilic Parr functions, Fukui function indices, and condensed dual descriptor which are chemical reactivity descriptors that arise from conceptual density functional theory. The study confirmed the results from previous works showing that the MN12SX density functional is the most appropriate in predicting the chemical reactivity of this molecule in both solvents.

A theoretical investigation on the mechanism of cycloaddition reactions of fulvenes with tetrazine and diazacyclopentadienone derivatives

The mechanism of cycloaddition reactions for 6-dimethylaminofulvene and 6,6-diphenylfulvene with tetrazine and diazacyclopentadienone are studied by DFT at the MPWB1K/cc-pVDZ level of theory. The energy results indicated that the [6 + 4] cycloaddition reaction of 6-dimethylaminofulvene with tetrazine and diazacyclopentadienone derivatives proceeds in a stepwise fashion, while the [2 + 4] cycloaddition reaction of 6,6-diphenylfulvene might proceed in a one-step fashion. Our calculations showed some unfavorable processes with unstable cycloadducts arising from [4 + 2] cycloaddition reactions which are unobserved in the experimental results. Also, an analysis of the Parr functions for the reactants allows us to provide an explanation of the selectivity of these cycloaddition reactions.

Solvent effects on cycloaddition reactions of potent spin-trapping probe N-tert-butylmethanimine N-oxide: A DFT study

[Formula: see text]-tert-butylmethanimine [Formula: see text]-oxide is a potent spin-trapping probe for biologically important radicals, and this nitrone undergoes complete regioselective cycloadditions to less electron-deficient monosubstituted olefins. In the present study, solvent effects on the cycloaddition of this nitrone to styrene have been theoretically studied in terms of the global properties of the reactants, electrophilic and nucleophilic Parr function analysis and the activation and reaction energies of located transition states and products. Formation energies of optimized radical adducts were computed to determine their stabilities in different solvents. The cycloaddition is predicted to be completely ortho regioselective which is in complete agreement with experiments and involved earlier C–C bond formation owing to the insufficient depopulation of [Formula: see text]-conjugated carbon atom in styrene and shows varying asymmetry indices in different solvents. Decrease in activation parameters and increase in stability of cycloadducts are predicted with decreasing solvent polarity. Aqueous media destabilize the radical adducts as predicted from the calculated formation energy, enthalpy and free energy of reaction. Hydroxyl as well as methyl radical adducts are predicted to be more stable than superoxide anion radical adducts. These predictions are in complete agreement with the experiments.

Blue M2: an intermediate melanoidin studied via conceptual DFT.

In this computational study, ten density functionals, viz. CAM-B3LYP, LC-ω PBE, M11, M11L, MN12L, MN12SX, N12, N12SX, ω B97X, and ω B97XD, related to the Def2TZVP basis sets, are assessed together with the SMD solvation model for calculation of the molecular properties and structure of blue-M2 intermediate melanoidin pigment. All the chemical reactivity descriptors for the system are calculated via conceptual density functional theory (DFT). The active sites suitable for nucleophilic, electrophilic, and radical attacks are selected by linking them with the Fukui function indices, electrophilic Parr functions, and condensed dual descriptors Δf(r), respectively. The prediction of the maximum absorption wavelength is considerably accurate relative to its experimental value. The study reveals that the MN12SX and N12SX density functionals are the most appropriate density functionals for predicting the chemical reactivity of the molecule under study.

Computational study of the chemical reactivity of the Blue-M1 intermediate melanoidin

Abstract This study assessed eight density functionals that include CAM-B3LYP, LC- ω PBE, M11, MN12SX, N12SX, ω B97, ω B97X, and ω B97XD related to the Def2TZVP basis sets together with the SMD solvation model. These are assessed in calculating the molecular properties and structure of the Blue-M1 intermediate melanoidin pigment. Notably, the chemical reactivity descriptors for the system are calculated via the Conceptual Density Functional Theory. The choice of active sites applicable to nucleophilic, electrophilic as well as radical attacks is made by linking them with Fukui functions indices, electrophilic Parr functions, and condensed dual descriptor Δ f ( r ) . The predicted maximum absorption wavelength tends to be considerably accurate relative to the experimental value. The study found the MN12SX and N12SX density functionals to be the most appropriate in predicting the chemical reactivity of the molecule under study.

Conceptual DFT Study of the Local Chemical Reactivity of the Colored BISARG Melanoidin and Its Protonated Derivative.

This computational study assessed eight fixed RSH (range-separated hybrid) density functionals that include CAM-B3LYP, LC-ωPBE, M11, MN12SX, N12SX, ωB97, ωB97X, and ωB97XD related to the Def2TZVP basis sets together with the SMD solvation model in the calculation the molecular structure and reactivity properties of the BISARG intermediate melanoidin pigment (5-(2-(E)-(Z)-5-[(2-furyl)methylidene]-3-(4-acetylamino-4-carboxybutyl)-2-imino-1,3-dihydroimidazol-4-ylideneamino(E)-4-[(2-furyl)methylidene]-5-oxo-1H-imidazol-1-yl)-2-acetylaminovaleric acid) and its protonated derivative, BISARG(p). The chemical reactivity descriptors for the systems were calculated via the Conceptual Density Functional Theory. The choice of active sites applicable to nucleophilic, electrophilic as well as radical attacks were made by linking them with Fukui functions indices, electrophilic and nucleophilic Parr functions, and the condensed Dual Descriptor Δf(r). The study found the MN12SX and N12SX density functionals to be the most appropriate in predicting the chemical reactivity of the molecular systems under study starting from the knowledge of the HOMO, LUMO, and HOMO-LUMO gap energies.

Conceptual DFT study of the local chemical reactivity of the dilysyldipyrrolones A and B intermediate melanoidins

This computational study assessed 11 density functionals related to Def2TZVP basis sets, namely CAM-B3LYP, LC- $$\omega $$ PBE, M11, M11L, MN12L, MN12SX, N12, N12SX, $$\omega $$ B97, $$\omega $$ B97X, and $$\omega $$ B97XD, and the SMD solvation model for calculating the molecular properties and structures of the intermediate melanoidin pigments, dilysyldipyrrolone A (XL-W1) and dilysyldipyrrolone B (XL-W2). The global and local chemical reactivity descriptors for the systems were calculated via conceptual density functional theory (DFT). The active sites applicable to nucleophilic, electrophilic, and radical attacks were chosen by connecting them with Fukui function indices, electrophilic Parr functions, and condensed dual descriptor $$\varDelta {f}({\mathbf {r}})$$ over the atomic sites. The predicted maximum absorption wavelength obtained directly from the HOMO–LUMO was more accurate relative to the experimental values of the MN12SX and N12SX density functionals than those obtained with TDDFT calculations. This study found the MN12SX and N12SX density functionals to be most appropriate for predicting the chemical reactivity of the molecules under study.

Molecular Reactivity and Absorption Properties of Melanoidin Blue-G1 through Conceptual DFT.

This computational study presents the assessment of eleven density functionals that include CAM-B3LYP, LC-wPBE, M11, M11L, MN12L, MN12SX, N12, N12SX, wB97, wB97X and wB97XD related to the Def2TZVP basis sets together with the Solvation Model Density (SMD) solvation model in calculating the molecular properties and structure of the Blue-G1 intermediate melanoidin pigment. The chemical reactivity descriptors for the system are calculated via the conceptual Density Functional Theory (DFT). The choice of the active sites related to the nucleophilic, electrophilic, as well as radical attacks is made by linking them with the Fukui function indices, the electrophilic Parr functions and the condensed dual descriptor f. The prediction of the maximum absorption wavelength tends to be considerably accurate relative to its experimental value. The study found the MN12SX and N12SX density functionals to be the most appropriate density functionals in predicting the chemical reactivity of the studied molecule.

3+2] cycloaddition reaction between CF3-substituted thiocarbonyl ylides and thioketones: Exploration of regioselectivity and mechanistic aspects using Molecular Electron Density Theory

A CF3-containing thiadiazole derivative, TDA1, participates in a domino process initialized with a thermal N2 extrusion experienced at TDA1 within a retro- [3+2] cycloaddition (32CA) reaction to yield CF3-substituted thiocarbonyl ylide TCY3. Then, TYC3 is trapped over the course of a subsequent 32CA reaction toward thioketone TBP4 to generate dithiolane derivative CA5. This domino process was studied through Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d) computational level. Exploration of the relative Gibbs free energies obviously indicates that this domino process needs to overcome high barriers justifying why the harsh conditions (100 °C for 24h in toluene) is experimentally requested. In excellent agreement with the experimental findings, an entirely C1–C5 regioselective, polar, and pmr-type 32CA reaction of in situ generated TCY3 toward TBP4 leads to the formation of cycloadduct CA5 as the sole product along a quite irreversible pathway. While the high global electrophilicity ω index of TBP4 together with the high global nucleophilicity N index of TCY3 are responsible for the considerable polar character of the mentioned 32CA reaction, analysis of the electrophilic Pk+ and nucleophilic Pk− Parr functions at the reactive sites of reactants allows to rationalize C1–C5 regioselectivity observed experimentally. In terms of quantum topological analysis of the electron localization function (ELF) over some relevant points located along the IRC profile connecting separate TCY3 and TBP4 to CA5, a non-concerted two-stage one-step molecular mechanism is established for this polar pmr-type 32CA reaction. Such ELF analysis evidently shows that formation of the first C1–C5 and second C3–S4 single bonds is a direct consequence of coupling C1- to –C5 and C3- to –S4 pseudoradical centers, respectively.

A molecular electron density theory study of the chemo- and regioselective [3 + 2] cycloaddition reactions between trifluoroacetonitrile N-oxide and thioketones

The [3 + 2] cycloaddition (32CA) reaction between trifluoroacetonitrile N-oxide (NO 7) and 2,2,4,4-tetramethyl-3-thioxocyclobutan-1-one (THK 12) as well as the self-dimerization of NO 7 as a competitive pathway were studied within the Molecular Electron Density Theory (MEDT) using several DFT functionals together with def2-TZVP basis set. Taking CCSD(T)/TZVP activation energies as reference, among the employed functionals, just the B2PLYP-D3(BJ) one is able to portray complete predominance of 32CA reaction over self-dimerization process in excellent agreement with the experimental outcomes. Analysis of the global reactivity indices permits to characterize NO 7 and THK 12 as a strong electrophile and a strong nucleophile, respectively, while analysis of the Parr functions allows explaining the chemo- and regioselectivity observed experimentally. The electron localization function (ELF) analysis of several points along the IRC profile associated with the energetically most favorable reaction channel permits to establish a non-concerted two-stage one-step molecular mechanism for this polar pmr-type 32CA reaction.

Insights into the isothiourea-catalyzed asymmetric [4 + 2] annulation of phenylacetic acid with alkylidene pyrazolone.

A density functional theory (DFT) study was performed to explore the possible reaction mechanisms and the origin of stereoselectivity for the isothiourea-catalyzed [4 + 2] annulation reaction of in situ activated phenylacetic acid with alkylidene pyrazolone. The computed results reveal that the reaction contains several steps, including complexation of isothiourea with substrate, dissociation of the t-BuCO2- group, α-C-H deprotonation of the acyl ammonium intermediate, stepwise [4 + 2] cycloaddition processes, and the dissociation of isothiourea. The C-C bond formation involved in the [4 + 2] cycloaddition process was identified as the stereoselectivity-determining step, in which the two chiral carbon centers emerge. The pathway associated with the RR configurational isomer is calculated to be most energetically favorable, which is consistent with the experimental observations. The origin of stereoselectivity was further studied through analyses of distortion/interaction and non-covalent interaction (NCI), and the role of isothiourea was discovered by the analyses of the global reaction index (GRI) and Parr functions. By analyzing the activity of different isothiourea catalysts, it was found that a stronger nucleophilicity of the center N atom of the isothiourea catalysts would result in a lower energy barrier of the reaction. The novel insights obtained in the present study would be useful for the rational design of more efficient catalysts for this kind of reaction.

Chemical Reactivity Theory (CRT) Study of the Melanoidin M8: Local Conceptual Density Functional Theory Descriptors

This study evaluated a fixed long-range corrected range-separated hybrid (RSH) density functional associated with the Def2TZVP basis set alongside the Solvation Model based on Density (SMD) for the computation of the structure, molecular properties and chemical reactivity of the M8 intermediate melanoidin pigment. The preference of the active sites pertinent to radical, nucleophilic and electrophilic attacks is made through linking them with the electrophilic and nucleophilic Parr functions, Fukui function indices, and condensed Dual Descriptor. This study showed that the MN12SX density functional is the most suitable one for predicting the chemical reactivity of this system.

Evaluation of non-covalent interactions of chlorambucil (monomer and dimer) and its interaction with biological targets: Vibrational frequency shift, electron density topological and automated docking analysis

Chlorambucil is a well-known chemotherapy drug that is being used to treat chronic myelogenous leukemia. As it contains ten flexible rotational bonds, the possible spatial conformations have been identified theoretically. The spectral signatures of monomer and dimer structures of chlorambucil and the frequency shifts due to non-covalent interactions (NCIs) have been illustrated using FT-IR and FT-Raman spectra. The bond correlation between carbon and hydrogen nuclei of chlorambucil has been obtained using 2D-HSQC NMR spectrum. The assignments of harmonic normal modes have been done in order to find the vibrational contributions of each functional group. Besides the spectroscopic studies, the electron density based quantum topological atoms in molecule analysis have been performed to explore the possible interactions between the non-bonded atoms. The reduced density gradient and isosurface plots have been used in this study to understand the strength of NCIs. The charge delocalization patterns of monomer and dimer structures were explained so as to investigate the chemical stability profile. The active sites for the electrophilic and nucleophilic attack on the monomer conformers have been determined by applying Hirshfeld charges and atomic spin densities into Fukui and Parr functions, respectively. From the automated docking analysis, it is found that chlorambucil interacts with the aldo-keto reductase family 1 (AKR1B1, AKR1B10, AKR1B15) and FAD-linked sulfhydryl oxidase ALR proteins through strong hydrogen bonds and shows a potential inhibition. In order to take into account the interactions ranging from short to long range, the modern density functionals viz. M06-2X, wB97XD, B97D which includes dispersion-corrected repulsion terms have been employed and the theoretical results were found coincide with the experimental observations.

Theoretical Study on DBU-Catalyzed Insertion of Isatins into Aryl Difluoronitromethyl Ketones: A Case for Predicting Chemoselectivity Using Electrophilic Parr Function.

The possible mechanisms of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed chemoselective insertion of N-methyl isatin into aryl difluoronitromethyl ketone to synthesize 3,3-disubstituted and 2,2-disubstituted oxindoles have been studied in this work. As revealed by calculated results, the reaction occurs via two competing paths, including α and β carbonyl paths, and each path contains five steps, that is, nucleophilic addition of DBU to ketone, C–C bond cleavage affording difluoromethylnitrate anion and phenylcarbonyl–DBU cation, nucleophilic addition of difluoromethylnitrate anion to carbonyl carbon of N-methyl isatin, acyl transfer process, and dissociation of DBU and product. The computational results suggest that nucleophilic additions on different carbonyl carbons of N-methyl isatin via α and β carbonyl paths would lead to different products in the third step, and β carbonyl path associated with the main product 3,3-disubstituted oxindole is more energetically favorable, which is consistent with the experimental observations. Noteworthy, electrophilic Parr function can be successfully applied for exactly predicting the activity of reaction site and reasonably explaining the chemoselectivity. In addition, the distortion/interaction and noncovalent interaction analyses show that much more hydrogen bond interactions should be responsible for the lower energy of the transition state associated with β carbonyl path. The obtained insights would be valuable for the rational design of efficient organocatalysts for this kind of reactions with high selectivities.

A computational mechanistic study on the chemo-, regio- and stereoselectivity of cycloaddition reactions leading to γ-dihydropyran and tetrahydrocarbazol compounds

The reaction mechanisms of Danishefsky’s diene (1) with 3- and 2-substituted indoles (2 and 3) were investigated using the DFT method. Two possible approaches of the carbonyl and carbon-carbon double bond of the dienophile to Danishefsky’s diene (1) yield two types of compound, arising from the sequential [4+2] cycloaddition reaction. and hydrolysis of the silyl enol ether. Also, an acyclic hydroxyl product indicates that a stepwise mechanism of the Mukaiyama-type may be involved, when the reaction takes place in the presence of zinc chloride catalyst. In the cycloaddition reactions, while 3-substituted indole (2) tended to participate as the dienophile, 2-substituted indole (3) can react through a hetero Diels-Alder reaction. Then the chemoselectivity completely reverse in 2- and 3- substituted indoles, which energetical aspects and analysis of the Parr functions explained the chemoselectivity experimentally observed. The reactions were completely ortho regioselective with endo stereoselectivity in the zinc chloride catalyzed process. The Mukaiyama aldol reaction, as a stepwise mechanism, had a low activation energy relative to the concerted cycloaddition reactions. Moreover, analysis of the conceptual DFT reactivity indices allows the explanation of the reactivity, and the chemo- and regioselectivity.

Prediction of the Regioselectivity of 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides with 2(5H)-Furanones Using Recent Theoretical Reactivity Indices

The regioselectivity of a series of 16 1,3-dipolar cycloaddition reactions of nitrile oxides with 2(5 H)-furanones has been analysed by means of global and local electrophilic and nucleophilic reactivity indices using density functional theory at the B3LYP level together with the 6-31G(d) basis set. The local electrophilicity and nucleophilicity indices, based on Fukui and Parr functions, have been calculated for the terminal sites, namely the C1 and O3 atoms of the 1,3-dipole and the C4 and C5 atoms of the dipolarophile. These local indices were calculated using both Mulliken and natural charges and spin densities. The results obtained show that the C5 atom of the 2(5 H)-furanones is the most electrophilic site whereas the O3 atom of the nitrile oxides is the most nucleophilic centre. It turns out that the experimental regioselectivity is correctly reproduced, indicating that both Fukui- and Parr-based indices are efficient tools for the prediction of the regiochemistry of the studied reactions and could be used for the prediction of new designed reactions of the same kind.