Nucleophilicity Index Research Articles

Modeling of Toxicity-Relevant Electrophilic Reactivity for Guanine with Epoxides: Estimating the Hard and Soft Acids and Bases (HSAB) Parameter as a Predictor.

According to the electrophilic theory in toxicology, many chemical carcinogens in the environment and/or their active metabolites are electrophiles that exert their effects by forming covalent bonds with nucleophilic DNA centers. The theory of hard and soft acids and bases (HSAB), which states that a toxic electrophile reacts preferentially with a biological macromolecule that has a similar hardness or softness, clarifies the underlying chemistry involved in this critical event. Epoxides are hard electrophiles that are produced endogenously by the enzymatic oxidation of parent chemicals (e.g., alkenes and PAHs). Epoxide ring opening proceeds through a SN2-type mechanism with hard nucleophile DNA sites as the major facilitators of toxic effects. Thus, the quantitative prediction of chemical reactivity would enable a predictive assessment of the molecular potential to exert electrophile-mediated toxicity. In this study, we calculated the activation energies for reactions between epoxides and the guanine N7 site for a diverse set of epoxides, including aliphatic epoxides, substituted styrene oxides, and PAH epoxides, using a state-of-the-art density functional theory (DFT) method. It is worth noting that these activation energies for diverse epoxides can be further predicted by quantum chemically calculated nucleophilic indices from HSAB theory, which is a less computationally demanding method than the exacting procedure for locating the transition state. More importantly, the good qualitative/quantitative correlations between the chemical reactivity of epoxides and their bioactivity suggest that the developed model based on HSAB theory may aid in the predictive hazard evaluation of epoxides, enabling the early identification of mutagenicity/carcinogenicity-relevant SN2 reactivity.

Comparison of reactivity of Pt(II) center in the mononuclear and binuclear organometallic diimineplatinum complexes toward oxidative addition of methyl iodide

The reactivities of Pt(II) center in a series of organometallic mononuclear Pt(II), binuclear Pt(II) and binuclear mixed-valence Pt(II)–Pt(IV) complexes toward oxidative addition of MeI have been compared from a theoretical point of view. The nucleophilicity index and electron-donation power were calculated for each of these complexes. The energies of HOMO and dZ2 orbital were determined for these complexes. Very good correlations were found between logk2 (k2 is the experimentally determined second order rate constant for the oxidative addition of MeI on these complexes) and nucleophilicity index or electron-donation power for these complexes. The correlation between logk2 and the energy of HOMO or the energy of dZ2 orbital were also very good. The condensed-to-atom Fukui functions for electrophilic attack on these complexes showed that the Pt(II) center is the preferred site for the oxidative addition of MeI. All of these observations are in agreement with the proposed SN2 type mechanism in the oxidative addition of MeI on the Pt(II) center in these complexes.

1,3-Dipolar cycloaddition of nitrones to transition metal-bound isocyanides: DFT and HSAB principle theoretical model together with analysis of vibrational spectra

The hard and soft acids and bases (HSAB) principle together with the density functional theory (DFT) calculations were used to analyze the driving forces of the hypothetical 1,3-dipolar cycloaddition (CA) of the nitrone CH2N(Me)O to the uncomplexed CNMe and to isocyanide ligands in various transition metal complexes. The calculated activation (ΔGs≠) and reaction (ΔGs) energies depend from the electronic chemical potential (μ), the global electrophilicity (ω) and nucleophilicity (N) indexes of the dipolarophiles, the static charge transfer “nucleophile → electrophile” (ΔN0), and the maximum amount of electronic charge that the electrophile system may accept (ΔNmax). Thus, the HSAB principle may be successfully apply for the study of reactivity of such compounds. The ΔGs≠ and ΔGs and the calculated stretching vibration frequencies ν(CN) of isocyanides well correlated with each other, i.e. higher values of ν(CN) correspond to lower values of ΔGs≠ and ΔGs. The application of the reactivity descriptors discussed in this work is a possible alternative and a complement addition to the estimates based on the classical frontier molecular orbital (FMO) theory.

Moving toward Ylide-Stabilized Carbenes.

The effect of ylide substitution at the α position to the carbene carbon (Cc ) atom on the stability and σ-donating ability of a number of cyclic carbenes has been studied theoretically. The stabilities of all of the carbenes were investigated from an evaluation of their singlet-triplet energy gaps and stabilization energies. All carbenes were found to have a stable singlet state. The energy of the σ-symmetric lone-pair orbital at the Cc atom increases as a result of the introduction of ylide centers near to the Cc atom. This indicates an enhanced σ-donating ability of the ylide-containing carbenes. The calculated carbonyl-stretching frequencies of the corresponding rhodium complexes, proton affinities, and nucleophilicity index values correlate well with the σ basicity of the carbenes.

Understanding the Regioselectivity and Reactivity of Friedel–Crafts benzoylation Using Parr Functions

A theoretical study of the reactivity and regioselectivity of some aromatic compounds in electrophilic aromatic substitution is carried out at the B3LYP/6-31G(d) computational level. The relative reactivity of these systems is rationalized by means of the global nucleophilicity index proposed by Domingo’s group. The positional selectivity, namely o, m or p, is predicted by means of the local nucleophilicity indices [Parr fonctions]. The present study shows that the experimental trends of the relative reactivities and regioselectivities of these reactions are correctly predicted using Parr fonctions.

An experimental and quantumchemical study of [2+3] cycloaddition between (Z)-C-(m,m,p-trimethoxyphenyl)-N-(p-methyphenyl)-nitrone and (E)-3,3,3-trichloro-1-nitroprop-1-ene: mechanistic aspects

Article history: Received May 6, 2014 Received in revised form October 02, 2014 Accepted 21 October 2014 Available online 21 October 2014 Analysis of addent interactions with respect to the theory of electrophilicity and nucleophilicity indexes and kinetic studies shows the polar nature of [2+3] cycloaddition of (Z)-C-(m,m,ptrimethoxyphenyl)-N-(p-methylphenyl)-nitrone to (E)-3,3,3-trichloro-1-nitroprop-1-ene. However, PES exploration results do not confirm any zwitterion on the reaction paths. On the other hand, the nature of the solvent effect and the experimentally determined activation parameter values do not exclude a scenario in which one-step and stepwise processes occur simultaneously. © 2015 Growing Science Ltd. All rights reserved.

Molecular Design of Indolizine Derivative as Sensitizers for Organic Dye-Sensitized Solar Cells

Nine new D-π-A metal-free sensitizers INI1–INI9 with indolizino [3,4,5-ab] isoindole(INI) as electronic donor were investigated using the density functional theory(DFT) and time-dependent DFT calculations. Compared to D5 and D9, some major factors affecting the performance of the cell, including light harvesting, electron injection, dye regeneration, and charge recombination are taken into consideration.Calculations show that these novel INI-based sensitizers have an absorption maximum at 440–500 nm whenπ conjugated bridge attached at different position of aromatic ring and an excellent charge separation characters. INI2 shows better performance than that of D9 due to the theoretical maximum short-circuit current density of 13.26 m A cm–2. Fortunately, condensed Fukui function calculation suggested that the INI2 be easiest to obtain due to a largest nucleophilic index at 2 position of INI aromatic ring. Based on the calculations of dyes adsorption on Ti O2 cluster, indirect electron injection may be the main path from dye to Ti O2 for INI2 and D5. Our calculations indicate that the INI dyes will be promising candidates for fabrication of the high performance dye-sensitized solar cells.

The spectroscopic (FT-IR, UV–vis), Fukui function, NLO, NBO, NPA and tautomerism effect analysis of (E)-2-[(2-hydroxy-6-methoxybenzylidene)amino]benzonitrile

A new o-hydroxy Schiff base, (E)-2-[(2-hydroxy-6-methoxybenzylidene)amino]benzonitrile was isolated and investigated by experimental and theoretical methodologies. The solid state molecular structure was determined by X-ray diffraction method. The vibrational spectral analysis was carried out by using FT-IR spectroscopy in the range of 4000–400cm−1. Theoretical calculations were performed by density functional theory (DFT) method using 6-31G(d,p) basis set. The results of the calculations were applied to simulated spectra of the title compound, which show excellent agreement with observed spectra. The UV–vis spectrum of the compound was recorded in the region 200–800nm in several solvents and electronic properties such as excitation energies, and wavelengths were calculated by TD-DFT/B3LYP method. The most prominent transitions were corresponds to π→π∗.Hybrid density functional theory (DFT) was used to investigate the enol-imine and keto-amine tautomers of titled compound. The titled compound showed the preference of enol form, as supported by X-ray and spectroscopic analysis results. The geometric and molecular properties were compaired for both enol-imine and keto-amine forms. Additionally, geometry optimizations in solvent media were performed with the same level of theory by the integral equation formalism polarizable continuum (IEF-PCM). Stability of the molecule arises from hyperconjugative interactions, charge delocalization and intramolecular hydrogen bond has been analyzed using natural bond orbital (NBO) analysis. Mulliken population method and natural population analysis (NPA) have been studied. Also, condensed Fukui function and relative nucleophilicity indices calculated from charges obtained with orbital charge calculation methods (NPA). Molecular electrostatic potential (MEP) and non linear optical (NLO) properties are also examined.

DFT study of nucleophilicity of organometallic (2,2′-bipyridine)platinum(II) complexes

The structures of [Pt(bpy)R2] complexes (bpy = 2,2′-bipyridine, R = Me, Ph, 4-MeC6H4, 4-MeOC6H4, 3-MeOC6H4, 4-NMe2C6H4, 4-FC6H4, 3-FC6H4, 4-ClC6H4, CCH, CCPh, CF3, CN) were optimized. Energy of neutral, cationic and anionic forms of these complexes were calculated at the B3LYP/6-311G(d,p) level of theory. Nucleophilicity indexes and electron-donating powers were calculated for these complexes. A relatively good correlation for nucleophilicity index and a very good correlation for electron-donating power were found between these descriptors and logk2 (when available) (k2 is the second order rate constants for oxidative addition of methyl iodide on these complexes). Also a good correlation was found between the energy of platinum dZ2 orbital and logk2. The condensed-to-atom Fukui functions for nucleophilic and electrophilic attacks on these complexes show that in all of these complexes, Pt center is the especially preferable site for electrophilic attack. These observations support the mechanism of SN2 type for oxidative addition of polar organic reagents on organoplatinum(II) complexes.

Quantitative study by the Electrophilic and Nucleophilic indexes of chemical reactivity for the intramolecular Diels-Alder reaction of the Triene-Amide Molecule. DFT investigation

In this study, we proposed to examine the reactivity of the intramolecular cycloaddition Diels-Alder (IMDA) reaction of the molecule triene amide by chemical descriptors established globally in the intermolecular reactions (DA), such as of electrophilic index ω and the nucleophilic index N. In order to provide the power releasing or withdrawing of electrons of the diene (D) and dienophile (Dp) fragments in the intramolecular molecule, the polarity of the reaction can be evaluated by the application of these two factors, applied locally to the diene (D) and dienophile (Dp) fragments, other parameters have been introduced to enrich these results, such as transferability index γ and charge transfer (CT) in a transition state. During our study we used density functional theory (DFT) in the hybrid B3LYP and basis set level 6-31G (d, p), the geometries are optimized for the reactants, transition states as well for products, the calculation of the charge transfer is carried out using the natural population analysis (NPA), the results obtained show that the diene (D) fragment is donor of electrons in the IMDA reaction.

The singlet–triplet energy splitting of π-nucleophiles as a measure of their reaction rate with electrophilic partners

The recently introduced nucleophilicity index (N) of unsaturated compounds, which are typical π-nucleophiles, correlates (R=0.9229) with their singlet–triplet energy splitting (ΔS–T) between the ground singlet and the excited 3(ππ∗) state. The latter quantity is proposed for the activation barrier (Ea) determination of the nucleophile–electrophile addition reactions. A new approach for calculation of the Ea value is developed for reactions between alkenes and the p-methoxybenzhydryl cation. This scheme involves some simple DFT parameters, namely, the ΔS–T of the reactants and products. The experimentally available Ea values for the above reaction correlate well (R=0.9944) with the calculated data.

Can hydroxylamine be a more potent nucleophile for the reactivation of tabun-inhibited AChE than prototype oxime drugs? An answer derived from quantum chemical and steered molecular dynamics studies.

Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ∼1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (ω(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective π-π interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometry and the orientation of the drug candidates, the hydroxylamine is suggested to orchestrate the reactivation process better than TMB4. Furthermore, the calculated log P values show the effective penetration of the neutral drug candidate through the blood-brain barrier. The toxicity measurements and the IC50 values (a measure of the intrinsic affinity toward AChE) suggest that the pyridinylhydroxylamine compound could have similar toxic behavior compared to the prototype oxime antidotes used for reactivation purposes. The newly designed pyridinylhydroxylamine drug candidate can be an effective antidote both kinetically and structurally to reactivate the tabun-inhibited enzyme.

ChemInform Abstract: Recent Progress in Quantifying Substituent Effects

AbstractReview: 152 refs.

1, 3-dipolar cycloaddition of C-phenyl carbamoyl-N-phenyl nitrone with some dialkyl-substituted 2-benzylidenecyclopropane-1,1-dicarboxylates: theoretical analysis of mechanism and regioselectivity

The regiochemistry of 1,3-dipolar cycloaddition reactions of C-phenyl carbamoyl-N-phenyl nitrone with some dialkyl-substituted 2-benzylidenecyclopropane-1,1-dicarboxylates as dipolarophile was investigated using density functional theory-based reactivity indexes and activation energy calculations at B3LYP/6-31G(d) level of theory. Analysis of the geometries and bond orders at the TS structures associated with the different reaction pathways shows that these 1,3-dipolar cycloaddition reactions occur via an asynchronous concerted mechanism. Analysis of the local electrophilicity and nucleophilicity indexes based on Parr functions only for reaction between 1 + 2a and based on Fukui functions only for 1 + 2b gives correct regioselectivity. The theoretical results obtained in the work clearly predict the regiochemistry of the isolated cycloadducts and agree to experimental results.

DFT study of the mechanism and stereoselectivity of the 1,3-dipolar cycloaddition between pyrroline-1-oxide and methyl crotonate

A theoretical study of the regio- and stereoselectivities of the 1,3-dipolar cycloaddition reaction between methyl crotonate and pyrroline-1-oxide has been carried out using density functional theory (DFT) at the B3LYP/6-31G(d) level of theory. The reaction has been followed by performing transition state optimization, calculations of intrinsic reaction coordinate and activation energies; the molecular mechanism of the reactions is concerted and asynchronous. The regio- and exo/endo-selectivity have been explained in terms of frontier molecular orbital interactions, local and global electrophilicity and nucleophilicity indices and an analysis of the Wiberg bond indices in the transition state. The FMO analysis and DFT-based reactivity indices showed that the regioselectivity of this reaction is controlled by the HOMOdipole–LUMOdipolarophile interaction. The activation parameters indicated favoured endo approach along the meta-pathway in agreement with the experimental results. The molecular mechanism of the 1,3-dipolar cycloaddition reaction between pyrroline-1-oxide and methyl crotonate is theoretically investigated by DFT method at the B3LYP/6-31G* level. The transition states corresponding to the possible stereoisomeric pathways along regioisomeric reaction channels were searched, localized and optimized. The cycloaddition is favored along the reaction channel with the meta-endo adduct as major diastereomer in agreement with experiment.

ChemInform Abstract: Structure‐Reactivity Relationships for Aromatic Molecules: Electrostatic Potentials at Nuclei and Electrophile Affinity Indices

AbstractReview: 91 refs.

Prediction of the chemo- and regioselectivity of Diels–Alder reactions of o-benzoquinone derivatives with thiophenes by means of DFT-based reactivity indices

Global and local reactivity indices derived from density functional theory were used to elucidate the regio- and chemoselectivity of Diels–Alder reactions of masked o-benzoquinones with thiophenes acting as dienophiles. The polarity of the studied reactions is evaluated in terms of the difference of electrophilicity powers between the diene and dienophile partners. Preferential cyclisation modes of these cycloadditions are predicted using Domingo's polar model based on the local electrophilicity index, ωk, of the electrophile and the local nucleophilicity index, Nuk, of the nucleophile. The theoretical calculations, carried out at the B3LYP/6-311G(d,p) level of theory, are in good agreement with experimental findings.

Recent progress of quantifying substituent effects

This paper summarizes significant progresses of quantifying organic substituent effects in recent 20 years. The main content including: (1) The principle of electronegativity equalization was widely accepted, and used to calculate the intramolecular charge distribution and inductive effect of groups. A valence electrons equilization method was proposed to compute the molecular electronegativity on the basis of geometric mean method, harmonic mean method, and weighted mean method. This new calculation method further extended the application of the principle of electronegativity equalization. (2) A scale method was established for experimentally determining the electrophilic and nucleophilic ability of reagents, in which benzhydryliumions and quinone methides were taken as the reference compounds, and the research field was extended to the gas phase conditions, organometallic reaction and radicals system. Moreover, the nucleophilicity parameters N and electrophilicity parameters E for a series of reagents were obtained. The definition and quantitative expression of electrophilicity index ω and nucleophilicity index ω - were proposed theoretically, and the correlation between the parameters from experimental determination and the indexes from theoretical calculation was also deeply investigated. (3) The polarizability effect parameter was initially calculated by empirical method and further developed by quantum chemistry method. Recently, the polarizability effect index of alkyl (PEI) and groups (PEIX) were proposed by statistical method, and got wide applications in explaining and estimating gas-phase acidity and basicity, ionization energy, enthalpy of formation, bond energy, reaction rate, water solubility and chromatographic retention for organic compounds. (4) The excited-state substituent constant σCCex which was obtained directly from the UV absorption energy data of substituted benzenes, is different from the polar constants in molecular ground state and the radical spin-delocalization effects constants in molecular radical state. The proposed constant R s correlated well with the UV absorption energy of many kinds of organic compounds, such as 1,4-disubstituted benzenes, substituted stilbenes, and disubstituted N -benzylidenebenzenamine. (5) The presence of the steric shielding effect distinguished three traditional steric effects. The stereoselectivity index Ci was proposed to quantify the stereoselectivity in addition reaction of carbonyl with nucleophilic reagent. The shielding parameter R S′ was defined to quantitatively express the specific surface of the reaction center screened by a group. Further, the topological steric effect index (TSEI) of a group based on the relative specific volume of reaction center screened by the atoms of substituents was proposed. These parameters have good applications in estimating the intramolecular dihedral angles, stereoselectivity of reaction, enthalpies of formation of alkene and alkylbenzene, acidity of substitutedimidazolium ionic liquid, and the reaction rate of alkane and hydroxyl free radical. In addition, some suggestions and prospects for further studies on quantifying the organic substituent effects were presented in this paper.

MM/QM study: Interactions of copper(II) and mercury(II) with food dyes in aqueous solutions

In this work we studied four azo dyes which are proposed for synthetic colorants in foods applications and named L 1 : Sunset Yellow, E110, L 2 : Tartrazin, E102, L 3 : Amaranth, E123, L 4 : Red Ponceau 4R, E124. In addition, electron density analysis has been carried out to highlight the possible strengths of interaction of these four azo dyes with metal ions. Density Functional Theory (DFT) was utilized, using the B3LYP functional and the 6-31G(d) basis set. This level of calculation was used to find the optimized molecular structure and to predict the molecular orbitals energies, dipole moment, Fukui function values f − k , locals nucleophilicity indexes N k and the chemical reactivity parameters that arise from Conceptual DFT. Also, the steric energies values from the four complexes were calculated with the EMO program using MM2 method. Complexes forms with mercury are easier to form and more stable than copper. These show that the mercury intoxication is faster than the copper, knowing that mercury is toxic even with low dose. For that, the men who carry amalgams, we advise may be avoid to eat food and drugs which contain azo dyes because there exists a high trend between these azo dyes and the metal ions which released by the amalgams.

Recent progress in quantifying substituent effects

This paper summarizes significant progress in quantifying organic substituent effects in the last 20 years. The main content is as follows: (1) The principle of electronegativity equalization has gained wide acceptance, and has been used to calculate the intramolecular charge distribution and inductive effect of groups. A valence electrons equalization method was proposed to compute the molecular electronegativity on the basis of geometric mean method, harmonic mean method, and weighted mean method. This new calculation method further extended the application of the principle of electronegativity equalization. (2) A scale method was established for experimentally determining the electrophilic and nucleophilic ability of reagents, in which benzhydryliumions and quinone methides were taken as the reference compounds, and the research field was extended to the gas phase conditions, organometallic reaction and radicals system. Moreover, the nucleophilicity parameters N and electrophilicity parameters E for a series of reagents were obtained. The definition and quantitative expression of electrophilicity index ω and nucleophilicity index ω - were proposed theoretically, and the correlation between the parameters from experimental determination and the indexes from theoretical calculation was also investigated. (3) The polarizability effect parameter was initially calculated by empirical method and further developed by quantum chemistry method. Recently, the polarizability effect index of alkyl (PEI) and groups (PEIX) were proposed by statistical method, and got wide applications in explaining and estimating gas-phase acidity and basicity, ionization energy, enthalpy of formation, bond energy, reaction rate, water solubility and chromatographic retention for organic compounds. (4) The excited-state substituent constant σccex obtained directly from the UV absorption energy data of substituted benzenes, is different from the polar constants in molecular ground state and the radical spin-delocalization effects constants in molecular radical state. The proposed constant σccex correlated well with the UV absorption energy of many kinds of organic compounds, such as 1,4-disubstituted benzenes, substituted stilbenes, and disubstituted N -benzylidenebenzenamine. (5) The establishment of the steric shielding effect distinguished the three traditional steric effects. The stereoselectivity index Ci was proposed to quantify the stereoselectivity of the addition reaction of carbonyl with nucleophilic reagent. The shielding parameter was defined to quantitatively express the specific surface of the reaction center screened by a group. Further, the Topological Steric Effect Index (TSEI) of a group was proposed on the basis of the relative specific volume of reaction center screened by the atoms of substituents. These parameters can be applied in estimating the intramolecular dihedral angles, stereoselectivity of reaction, enthalpies of formation of alkenes and alkylbenzene, acidity of substitutedimidazolium ionic liquid, and the reaction rate of alkane and hydroxyl radical. In addition, some suggestions and prospects for further studies on quantifying the organic substituent effects were presented in this paper.