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Definition of a Nucleophilicity Scale
Abstract
This work deals with exploring some empirical scales of nucleophilicity. We have started evaluating the experimental indices of nucleophilicity proposed by Legon and Millen on the basis of the measure of the force constants derived from vibrational frequencies using a probe dipole H-X (X = F,CN). The correlation among some theoretical parameters with this experimental scale has been evaluated. The theoretical parameters have been chosen as the minimum of the electrostatic potential V(min), the binding energy (BE) between the nucleophile and the H-X dipole, and the electrostatic potential measured at the position of the hydrogen atom V(H) when the complex nucleophile and dipole H-X is in the equilibrium geometry. All of them present good correlations with the experimental nucleophilicity scale. In addition, the BEs of the nucleophiles with two other Lewis acids (one hard, BF(3), and the other soft, BH(3)) have been evaluated. The results suggest that the Legon and Millen nucleophilicity scale and the electrostatic potential derived scales can describe in good approximation the reactivity order of the nucleophiles only when the interactions with a probe electrophile is of the hard-hard type. For a covalent interaction that is orbital controlled, a new nucleophilicity index using information of the frontier orbitals of both, the nucleophile and the electrophile has been proposed.
... In this study, a glutaraldehyde solution (25% v) was used as a crosslinking agent. Glutaraldehyde is a clear, oily 5-carbon dialdehyde and has received much attention due to its high reactivity and reasonable price [30,31]. The reaction between the amine groups of gelatin and the aldehyde group in glutaraldehyde leads to the reduction in hydrophilic groups and thereby reduces the hydrophilicity of the scaffold (Scheme 1) [32]. ...
... The presence of hydrophilic groups, i.e., -COOH and -NH2, in the gelatin structure reduces the contact angle of the scaffold and increases the wettability of the scaffold surface. However, the consumption of the amine groups during the crosslinking process increases the contact angle of the crosslinked scaffold [30,31]. ...
... The presence of hydrophilic groups, i.e., -COOH and -NH 2 , in the gelatin structure reduces the contact angle of the scaffold and increases the wettability of the scaffold surface. However, the consumption of the amine groups during the crosslinking process increases the contact angle of the crosslinked scaffold [30,31]. ...
A coaxial nanofibrous scaffold of poly (ε-caprolactone) and gelatin/cellulose acetate encapsulating anti-inflammatory and antibacterial drugs was co-electrospun for skin tissue regeneration. Indomethacin and ciprofloxacin as model drugs were added to the core and the shell solutions, respectively. The effect of the drugs' presence and crosslinking on the scaffold properties was investigated. TEM images confirmed the core-shell structure of the scaffold. The fiber diameter and the pore size of the scaffold increased after crosslinking. The tensile properties of the scaffold improved after crosslinking. The crosslinked scaffold illustrated a higher rate of swelling, and a lower rate of degradation and drug release compared to the uncrosslinked one. Fitting the release data into the Peppas equation showed that Fickian diffusion was the dominant mechanism of drug release from the scaffolds. The results of biocompatibility evaluations showed no cytotoxicity and suitable adhesion and cell growth on the prepared core-shell structure. The antibacterial activity of the scaffolds was studied against one of the most common pathogens in skin wounds, where the existence of ciprofloxacin could prevent the growth of the Staphylococcus aureus bacteria around the scaffold. The obtained results suggested a new coaxial nanofibrous scaffold as a promising candidate for simultaneous tissue regeneration and controlled drug release.
... Since there are much less studies dealing with the calculations of nucleophilicity indexes than with all other chemical descriptors, it was interesting to test if they could be suitable to describe SN AR reactions since they were first developed in the context of standard SN 2 reactions. 33 To this end, we computed the nucleophilicity index recently proposed by Jaramillo et al. 33 Table II) for the whole series of phenol derivatives. As reported in Figure 3, one can note that this intermolecular descriptor correlates very well with the experimental reaction rates (R = 0 988). ...
... Since there are much less studies dealing with the calculations of nucleophilicity indexes than with all other chemical descriptors, it was interesting to test if they could be suitable to describe SN AR reactions since they were first developed in the context of standard SN 2 reactions. 33 To this end, we computed the nucleophilicity index recently proposed by Jaramillo et al. 33 Table II) for the whole series of phenol derivatives. As reported in Figure 3, one can note that this intermolecular descriptor correlates very well with the experimental reaction rates (R = 0 988). ...
... Taking into account that most probably DFT approaches slightly overestimate the delocalisation at the TS, one can indeed reasonably conclude from the analysis of the NBO based charge Table II) the latter appears to be always smaller (between 0.14e − and 0.19e − ) and smaller than the transferred charge predicted using the same descriptor (N ) in the case classical SN2 reactions (between 0.22e − and 0.36e − ). 33 In any case, and contrary to the expectations, the transferred charged (both predicted, N , and at the TS) does not correlate well with the experimental reaction rates thus suggesting that the leading interaction for the formation of the sigma bond is not ruled only by simple electrostatic interactions. ...
The reactivity of 4-Chloro-7-nitrobenzofurazan (NBD-Cl) with a serie of nucleophiles (4-substituted phenols) has been investigated using Density Functional Theory (DFT) and interpreted using chemical reactivity descriptors. A good correlation between chemical descriptors, such as Ionisation Potential and nucleophilicity, and reaction rates was found for 4-substituted phenols. To get further insights on the mechanism, the transition state corresponding to the rate determining step was characterized for each reaction and the barrier heights related to the experimental reaction rates and the computed chemical descriptors.
... Electronegativity is an important concept that has been widely used to correlate a number of physico-chemical properties of atoms and molecules (Kaya and Kaya 2015;Miranda-Quintana et al. 2016;Rahm et al. 2018;Accorinti 2019;Tandon et al. 2019b). Similarly, the rationalization of chemical reactivity concerning reaction pathways, substituent effects, selectivity, and solvent interactions and so on has been possible due to the accessibility of empirical scales of nucleophilicity and electrophilicity (Legon and Millen 1987;Mayr and Patz 1994;Parr et al. 1999;Campodónico et al. 2006;Jaramillo et al. 2006;Ndassa et al. 2017;Ranjan and Chakraborty 2019). The knowledge pertaining to distribution of electrons in any species is elementary in elucidating the physico-chemical properties of species, and electronegativity stands as a significant tool in explaining the static distribution and dynamic rearrangement of electrons in various species (Coulson 1951;Fukui 1982). ...
... As apparent from literature, electronegativity (χ) and nucleophilicity index (N) both are important periodic descriptors of reactivity Legon and Millen 1987;Mayr and Patz 1994;Campodónico et al. 2006;Jaramillo et al. 2006Jaramillo et al. , 2008Pérez et al. 2009;Kaya and Kaya 2015;Cárdenas et al. 2016;Miranda-Quintana et al. 2016;Ruthenberg and González 2017;Politzer and Murray 2018a;Rahm et al. 2018;Accorinti 2019;Qteish 2019). Electronegativity has a direct relationship with electrophilicity while nucleophilicity demonstrates an inverse relationship with it (Tandon et al. 2019c;Chattaraj and Maiti 2001). ...
Electronegativity (χ) is an important physico-chemical concept to study the chemical structure and reactivity. Although, the conundrum related to measurement of electronegativity still persists. In view of this fact, a simple yet rigorous scale of electronegativity (χ), invoking an inverse relationship with atomic nucleophilicity index (N), has been proposed for 103 elements of the periodic table. The computed data follows periodicity distinctly satisfying all the sine qua non of a standard scale of electronegativity. Further, electronegativity values display a sound similarity with the standard electronegativity scales validating the suitability of the proposed model. Molecular electronegativities of some polyatomic molecules have also been calculated using the proposed scale of electronegativity.
Graphic Abstract
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... ), [67,68] local electrophilicity [69][70][71] etc. are some commonly used local reactivity descriptors. Global reactivity descriptors such as chemical potential [72] (i.e., the negative of electronegativity [73]), chemical hardness (g) [49], global electrophilicity index, [74,75] nucleophilicity, [76][77][78] electrofugality and nucleofugality, [79,80] etc. are mainly used for intermolecular reactivity study. Very recently Saha et al. [81] have proposed two new local reactivity descriptors (known as 'variants of hardness potential' or 'hardness potential derivatives') which have the prospect to be used as intermolecular reactivity descriptors. ...
... Several other global reactivity indices, e.g., nucleophilicity [76,88], electrofugality and nucleofugality [77,78] are also conceptually related to w. In a recent study Bagaria et al. [83] extended the above concept of stabilization energy to explain the thermodynamics and kinetics of chemical interactions. ...
... Electrophilicity knowledge is also necessary for providing adequate information on aromaticity, toxicity, substituents, interactions with solvents and other interactions with atoms and molecules. [31][32][33] Parr et al. [34,35] proposed that an equation could be created by combining the squared chemical potential and the hardness (g) to be connected with the electrophilicity index (x). According to Ayers et al. [36,37], an electrophilic molecule is one with a low chemical potential. ...
To maximize the solvent solubility and charge density of future battery systems, LiPF6 might serve as a reference standard for screening and similar analysis. This work is focused on finding a more effective electrolyte to enhance the lithium-ion battery's overall characteristics and performance such as including their toxicity, ionic conductivity, explosiveness, corrosion inhibitor, electrochemical stability and low electrolyte oxidation. Using computational tools, a solution for these kinds of issues has been evaluated. The core idea is to simulate and evaluate by changing molecular symmetries and the molecular descriptors used include non-covalent interactions, band structure, density of states, electrostatic potential, Fukui indices and others. A comparative study with other derivatives has also been carried out for comparison.
Graphical Abstract
Electrolytes evaluated model as ‘LiMF6, NaMF6 and KMF6’ where ‘M’ is N, P, As, Sb, Bi, Na, Mg, Al, Si, P, S, Cl, Ar, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Br, Kr with LiM1-29F6, NaM1-29F6, KM1-29F6
... Predicting electrophilic and nucleophilic attacks for biological interactions by using MEP (Molecular electrostatic potential) as an important tool was shown [26,27]. The geometry of dipic (pyridine-2, 6-dicarboxylic acid) and monomer of (1) were optimized using the B3LYP method 6-311G (2d, 2p). ...
... Nucleophilicity of molecular have been evaluated in many ways 46 . Domingo introduced nucleophilicity N-index for closed-shell molecules based on HOMO energies 28,47 . ...
The mechanism of silver-catalyzed hydroamidation of siloxy-alkynes reaction remains controversial. Using density functional theory (DFT), we revealed that the reaction takes place through a silylium ion migration mediated hydroamination (SMH) pathway. The SMH pathway goes through two steps, the first step is Ag+ promoted proton and silylium ion exchange between siloxy-alkynes and amide, leading to ketene and silyl-imines, the second step is Ag+ catalyzed nucleophilic addition between ketene and silyl-imines, following with a silylium ion migration afford the final product. In this reaction, Ag+ activates the siloxy-alkyne into silylium ion (TIPS+) and silver-ketene through the p-π conjugate effect, the silylium ion then catalyzes the reaction. According to our calculation, the scopes of alkynes in this reaction may be extended to silyl-substituted ynamines or silyl-substituted ynamides. The scopes of amide may be extended into the p-π conjugate system such as diazoles, diazepines, etc. Our calculations also reveal a concise way to construct enamides through Ag+ catalyzed nucleophilic addition between substituted-ketenes and silyl-substituted p-π conjugate system.
... Several such descriptors have been rigorously defined and modeled within the framework of Conceptual Density Functional Theory (CDFT) [2] . There are numerous empirical scales [3][4][5][6][7][8][9] , quantitative mathematical models and principles [10][11][12] that facilitate in the understanding of chemical, biochemical, physicochemical and related phenomenon occurring in nature. These descriptors along with principles provide a significant insight into the feasible reaction pathway based on the reaction energetics and atomic/molecular characteristics of the system in the ground state. ...
Chemical reactivity descriptors are significant tools to study various systems and processes. In order to explore their role in the prediction of catalytic activity, we have presented a Quantitative Structure-Activity Relationship (QSAR) model based on some of these descriptors for a broad set of Ruthenium (14-electron) complexes for olefin metathesis reaction. The complexes are of the type LCl2Ru=CH2 where L corresponds to varied dative ligands. It is observed that the multivariate QSAR model is able to correlate descriptors with the catalytic activities of the selected complexes nicely. The study is hasty, cost-effective and mimics the experimental activity trends for Grubbs Ru-catalysts. Chemically, it is noted that complexes with a bulky ligand present an increased catalytic activity as they lead towards the formation of an intermediate (metallacyclobutane) with lower steric crowding. Hence, it is suggested that employing chemical reactivity descriptors in multivariate models together with other crucial descriptors can offer a realistic means for activity prediction and catalyst development in case of olefin metathesis or any other organometallic reaction.
... where μ is the electronic chemical potential 47 and η is the chemical hardness. 48 The local electrophilicity index (ω rc + ) 49 and the nucleophilicity index (ω − ) 50 are calculated according to eqs 6−8, respectively. The Fukui function for nucleophilic attack, f + (r), 51 makes use of ρ N+1 and ρ No , which are the atomic charges in cationic and neutral species condensed to radical centers respectively; the atomic populations with the NPA methodology have been used. ...
The thiol-ene reaction is one of the fundamental reactions in biochemistry and synthetic organic chemistry. In this study, the effect of polar media on the reaction kinetics is taken into account by using the transition state theory, the reactivities of the car-bon and sulfur radicals have also been rationalized by using conceptual DFT. The results have shown that the solvents have more impact on hydrogen atom transfer reactions and the chain transfer rate constant, kCT, can be increased by using non-polar sol-vents, while propagation reactions are less sensitive to media. Similarly, the kP/kCT ratio can be manipulated by changing the environment in order to obtain tailor-made polymers. Regarding the DFT descriptors, the local and global electrophilicity indices are well correlated with the propagation rate constant kP, whereas global electrophilicty index is associated with the chain trans-fer rate constant kCT. Overall, electrophilicy indices can be used with confidence to predict the kinetics of thiol-ene reactions.
... For example the general equation proposed in the article of Phan et al [193] involves 2 parameters related to the electrophile and two others to the nucleophile. In the context of conceptual DFT, the nucleophilicity index proposed by Jaramillo et al [194] is expressed in terms of the chemical potentials and hardnesses of the electrophile and nucleophile, i. e.: ...
The concept of secondary bond covers a wide range of non-covalent interactions involving an acceptor (or electrophilic) molecule and an electron donor (or nucleophilic) one. It involves triel, tetrel, pnictogen, chalcogen, halogen, and aerogen bonds as well as hydrogen bonds. Such interactions yield complexes in which the internuclear distance of the electrophilic and nucleophilic centers is intermediate between the sums of the covalent and van der Waals radii of these atoms. These complexes can be considered as precursors of hypothetical nucleophilic substitution or addition reactions. As a consequence of the least motion principle, in the complex, the arrangement of the ligands around the electrophilic center should look like that of the hypothetical transition state or addition product. In a same fashion, the geometry around the nucleophilic center is determined by the location of the lone pair or of the bond involved in the interaction. In this picture of secondary bonding, the structure of the valence shell of the electrophilic atoms determines the geometry of the complex rather than the group to which belongs the elemental atom. The reorganization of the complexes in terms of the arrangement of the bonding and non-bonding electronic domains around the electrophilic center enables to rationalize the geometries in a systematic fashion. A set of VSEPR inspired rules enabling the building up of secondary bonded isomers are proposed and checked by quantum chemical calculations performed on representative test systems of the AX4−nEn type.
An example of secondary interaction: FClO\(^{...}\textit {FCH}_{3}\)
... Among the most widely used chemical concepts in chemistry textbooks as well as in the literature are the reactivity descriptors such as regioselectivity, electrophilicity and nucleophilicity [1][2][3][4][5][6]. Regioselectivity is the preference of reacting with one atom in a molecule over all other possible atoms, whereas electrophilicity (nucleophilicity) is the capability of atoms in molecules to accept (donate) electrons [7][8][9]. ...
Chemical reactivity properties such as regioselectivity, electrophilicity and nucleophilicity are important chemical concepts, yet their understanding and quantification are still far from being accomplished. Applying density functional theory (DFT) to appreciate these properties is one route to pursue in the literature. In this work, we present a comparative study to benchmark two approaches in DFT to predict regioselectivity, electrophilicity and nucleophilicity: one with the Hirshfeld charge and the other with the Fukui function. We also examine the impact of 15 different ways to compute atomic charges on the performance of their predictions about these chemical reactivity properties. Our results show that the Hirshfeld charge is able to reliably determine regioselectivity and simultaneously accurately quantify both electrophilicity and nucleophilicity. The Fukui function behaves reasonably well for the prediction of electrophilicity but performs poorly for nucleophilicity. Among all other atomic charges examined in this study, it is only the Voronoi deformation density charge that yields the similar result as the Hirshfeld charge. As the first systematic benchmark study in the literature to compare the two available approaches in DFT about reactivity predictions, this work should fill in the needed knowledge gap and provide an impetus for the future development of chemical reactivity theory using DFT language.
... [27] Ethyl nitroacetate incorporates an additional a-EWG group and differs from the previous nucleophiles. With reference to the Mayr nucleophilicity scale, [29] which quantitatively describes the reaction rates of various nucleophiles and electrophiles with equation log k = s(N + E), nucleophilicity parameter N = 15.74, and specific slope parameter s = 0.74 were found for ethyl nitroacetate. [30] For nitromethane, reported values of N = 20.71 and s = 0.60 in DMSO indicate it to be a better nucleophile. ...
Stereoselective addition of nitromethane to conjugated en‐ynones was performed through the application of chiral squaramides. Three non‐classical approaches to promote the addition reaction were tested, including activation of the nucleophile by inorganic base in a biphasic aqueous system, thermal activation, and ball‐milling. Hydrogen‐bonding catalysis was effective in all these methods, providing 1,4‐addition products in high yields and stereoselectivities of up to 98% requiring 1–5 mol% of Cinchona alkaloid squaramide.
... The electrophilicity (ω + ) and nucleophilicity (ω − ) concepts (Ingold, 1929(Ingold, , 1933(Ingold, , 1934 are related to electron-deficient (electrophile) and electron-rich (nucleophile) species (Jaramillo et al., 2006). These concepts were early introduced by Ingold in 1934 and they are based on the valence electron theory of Lewis (Lewis, 1923) and the general acid-base theory of Brönsted and Lowry (Brönsted, 1923;Lowry, 1923;Cedillo et al., 2007). ...
Nucleophilic aromatic substitution reactions of 4-chloroquinazoline toward aniline and hydrazine were used as a model system to experimentally show that a substrate bearing heteroatoms on the aromatic ring as substituent is able to establish intramolecular hydrogen bond which may be activated by the reaction media and/or the nature of the nucleophile.
... Im Fokus der Untersuchung steht dabei die Nukleophilie der B-B-Bindung. Im Gegensatz zur absoluten Definition der Elektrophilie von Parr et al. über das chemische Potential µ und die Härte nach Pearson η konnte noch keine adäquate Definition für die Nukleophilie gefunden werden.[241][242][243][244] Die in Gleichung (1) gezeigte erste Nukleophilie-Definition von Swain und Scott basiert auf einem rein kinetischen Ansatz und beinhaltet keine Korrelation zwischen Nukleophilie und Basizität einer Verbindung.[245] ...
Die Chemie des Bors wird fast ausschließlich von seinem elektrophilen Charakter geprägt. Daher lassen sich viele der seit Jahrzehnten etablierten Hydroborierungs- und Borylierungs-Reaktionen lediglich auf ungesättigte organische Substrate anwenden. Eine der größten Herausforderungen der Bor-Chemie ist deshalb die Darstellung von nukleophilen Bor-Reagenzien. Trotz großer Fortschritte der letzten Jahre ist die Anzahl der isolierbaren nukleophilen Bor-Verbindungen überschaubar. Durch die starke Lewis-Basizität bizyklischer Guanidinate wird ein außerordentlich hoher Elektronenreichtum der Diborane erreicht. Zusätzlich wird durch den verbrückenden Bindungsmodus der Schritt der Dehydrokupplung über eine Vororientierung der Boratome begünstigt. Das doppelt guanidinatstabilisierte Diboran(4) verfügt über eine einzigartige Reaktivität, die durch den nukleophilen Charakter der B–B-Bindung bestimmt wird. In der vorliegenden Arbeit gelang durch Einführung neuer Substituenten die Isolierung und Charakterisierung einer Reihe von nukleophilen Diboran(4)-Verbindungen. Bei diesen und bereits literaturbekannten Diboranen wurde der Einfluss der Substituenten auf die Eigenschaften der B–B-Bindung auf Basis experimenteller und theoretischer Methoden systematisch untersucht. Dabei konnte gezeigt werden, dass eine hohe Nukleophilie des Moleküls nicht zwingend eine nukleophile B–B-Bindung zur Folge hat. Die Substituenten der beiden Diborane [HB(μ-hpp)]2 und [nBuB(μ-hpp)]2 verfügen über keinen +M-Effekt und weisen nach eingehender Analyse quantenchemisch berechneter Parameter ausschließlich die B–B-Bindung als nukleophile Position auf. Im Gegensatz dazu wird die Nukleophilie von [(Me2N)B(μ-hpp)]2 primär von den freien Elektronenpaaren der Amin-Gruppen geprägt. Weiterhin wurden mehrere Synthesemöglichkeiten asymmetrischer Diboran(4)-Verbindungen untersucht. Dabei erwies sich die Darstellung von [(PhCC)B(μ-hpp)2BH] über das phosphoniumstabilisierte Diboranyl-Kation [HB(μ-hpp)2B(PCy3)]+ als die beste Methode. Zusätzlich konnte durch die Darstellung von [(PhCC)B(μ-hpp)2B(PCy3)]+ die Bildung des intermediären Diboranyl-Kations [(PhCC)B(μ-hpp)2B]+ bestätigt werden. Oxidationsexperimente an [HB(μ-hpp)]2 führten zum Dimerisierungsprodukt [H4B4(μ-hpp)4]2+. Als Mechanismus zur Bildung wurde eine Einelektronen-Oxidation der B–B-Bindung mit Umlagerung zu einem Bor-zentrierten Radikal-Kation postuliert, welches anschließend über Radikalkupplung dimerisiert. Das intermediär auftretende Radikal-Kation [HB(μ-H)(μ-hpp)2B]•+ konnte mit TEMPO abgefangen werden. Die gewonnen Erkenntnisse gewähren ein grundlegendes Verständnis des nukleophilen Charakters von B–B-Bindungen. Dadurch wird die Basis für weitere Folgeexperimente geschaffen, mit denen der nukleophile Charakter der Diborane(4) weiter ausgebaut und für breitere Anwendungsgebiete geöffnet werden kann.
... In vitro incubation with various peptides containing nucleophilic residues was used to determine if only free thiols are modified by PhNHOH or NOB. To this end, the synthetic peptides PAAKAA, PAACAA, and PAAHAA, in addition to human acetyl ACTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and acetyl γ-endorphin were subject to adduction. The latter two peptides contain no Cys residues but do include potentially reactive Lys and His residues. ...
1. Conjugation with the tripeptide glutathione (GSH) is a common mechanism of detoxification of many endogenous and exogenous compounds. This phenomenon typically occurs through the formation of a covalent bond between the nucleophilic free thiol moiety of GSH and an electrophilic site on the compound of interest.
2. While GSH adducts have been identified for many licit drugs, there is a lack of information on the ability of drugs of abuse to adduct GSH. The present study utilized a metabolic assay with GSH as a nucleophilic trapping agent to bind reactive drug metabolites formed in situ.
3. Extracted ion MS spectra were collected via LC-QqQ-MS/MS for all potentially significant ions and examined for fragmentation common to GSH-containing compounds, followed by confirmation of adduction and structural characterization performed by LC-QTOF-MS/MS.
4. In addition to the two positive controls, of the 14 drugs of abuse tested, 10 exhibited GSH adduction, with several forming multiple adducts, resulting in a total of 22 individual identified adducts. A number of these are previously unreported in the literature, including those for diazepam, naltrexone, oxycodone, and Δ⁹-THC.
... In vitro incubation with various peptides containing nucleophilic residues was used to determine if only free thiols are modified by PhNHOH or NOB. To this end, the synthetic peptides PAAKAA, PAACAA, and PAAHAA, in addition to human acetyl ACTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and acetyl γ-endorphin were subject to adduction. The latter two peptides contain no Cys residues but do include potentially reactive Lys and His residues. ...
MS-based proteomic analysis was combined with in silico quantum mechanical calculations to improve understanding of protein adduction by N-phenylhydroxylamine (PhNHOH) and nitrosobenzene (NOB), metabolic products of aniline. In vitro adduction of model peptides containing nucleophilic sidechains (Cys, His, and Lys) and selected proteins (bovine and human hemoglobin and β-lactoglobulin-A) were characterized. Peptide studies identified the Cys thiolate as the most reactive nucleophile for these metabolites, a result consistent with in silico calculations of reactivity parameters. For PhNHOH, sulfinamides were identified as the primary adduction products, which were stable following tryptic digestion. Conversely, reactions with NOB yielded an additional oxidized adduct, the sulfonamide. In vitro exposure of human whole blood to PhNHOH and NOB demonstrated that only sulfinamides were formed. In addition to previously reported adduction of β⁹³Cys of human Hb, two novel sites of adduction were found; α¹⁰⁴Cys and β¹¹²Cys. We also report CD and UV-Vis spectroscopy studies of adducted human Hb that revealed loss of α-helical content and deoxygenation. The results provide additional understanding of the covalent interaction of aromatic amine metabolites with protein nucleophiles.
... Density functional theory (DFT) (Parr and Yang 1989;Koch and Holthausen 2000) provides a powerful framework to explore and study the chemical reactivity through their conceptual approach (Geerlings et al. 2003;Chermette 1999). In this article, we will focus our attention on the chemical hardness (Parr and Pearson 1983) and nucleophilicity (Jaramillo et al. 2006) chemical reactivity descriptors. ...
In this article, we employed density functional theory calculation methods to determine the relationship between the chemical hardness, intermolecular chemical hardness, and nucleophilicity chemical
reactivity descriptors, as well as the energy of the occupied frontier orbitals (Ea1g), and the electrocatalytic activity of different metallophthalocyanines [MPc’s with M=Cr(II), Mn(II), Fe(II), Co(I), Ni(II), and Cu(II)] for the oxygen reduction reaction. Our results suggest that gDA, N, and Ea1g are appropriate parameters to estimate the electrocatalytic activity. On the other hand, the type of the metallic center determines the strength of the oxygen-binding energy, where a strong electronic interaction promotes the efficient electro-reduction of the oxygen molecule, which is observed experimentally as a high catalytic activity.
... [12][13][14][15] The advantage of conceptual DFT over wavefunction-based approaches is that in DFT, the number of electrons is treated as a continuous parameter. This makes it possible to treat charge transfer as a continuous thermodynamic process, which makes conceptual DFT ideally suited to acid/base chemistry, 16,17 electrophilic/nucleophilic substitutions/ eliminations, [18][19][20][21][22][23][24][25][26] and redox chemistry. [27][28][29][30] In this paper, we use the maximum hardness principle 13,[31][32][33][34] to establish a link between the electronegativity and the oxidation potential (Section II). ...
Using the maximum hardness principle, we show that the oxidation potential of a molecule increases as its electronegativity increases and also increases as its electronegativity in its oxidized state increases. This insight can be used to construct a linear free energy relation for the oxidation potential, which we train on a set of 31 organic redox couples and test on a set of 10 different redox reactions. Better results are obtained when the electronegativity of the oxidized/reduced reagents are adjusted to account for the reagents' interaction with their chemical environment.
... The nucleophilic character of the studied anions nucleophile in the presence of a cation was evaluated by the x À index which has been recently proposed by Jaramillo et al. [62] in the framework of the Density Functional Theory of chemical reactivity (so-called Conceptual DFT). This index is defined as follows: ...
Among industrial applications of CO2, the formation of cyclic carbonates from epoxides offers relevant chemical potentialities. Here, various N,N-dimethyl-N-cetyl-N-(2-hydroxyethyl)ammonium salts (HEA16X) associated with different counter-anions (X-) have been investigated as catalysts of the cycloaddition of carbon dioxide to styrene oxide. Most of these salts were characterized by reasonable catalytic activities in benzonitrile at 120 °C and under 15 bar of CO2 compared to choline chloride and cetyltrimethylammonium bromide. The influence of three parameters has been studied: (i) the polar head group, (ii) the anion (I-, Br-, Cl- for halogens and HCO3-, mesylate (Ms-), triflate (Tf-)) in the HEA16X series, as well as (iii) the chain length. The higher conversion and selectivity obtained with HEA16Br, compared to CTABr, pointed out the beneficial contribution of the hydroxylated polar head. The role of the compensation anion or more exactly of its nucleophilicity on the catalyst activity was also shown. However, unexpected results with HCO3-, affording styrene oxide conversions up to 95% (better than with HEA16Cl), were also obtained. DFT calculations supported the beneficial influence of the 2-hydroxyethyl substituent and the unexpected reactivity of the ammonium hydrogenocarbonate, HEA16HCO3. The reaction profiles allowed to draw some correlations (i) between styrene oxide conversion and the relative energy of the first intermediate and (ii) between the styrene carbonate selectivity and the energy of the first transition state. A new and original mechanism was also proposed for the reaction catalyzed by ammonium hydrogenocarbonate.
... It needs to be noted that a ranking of nucleophiles is not absolute and often depends on the nature of the electrophile, solvent and other reaction factors [for example, [65,66]. The claim of increased nucleophilicity for RSSH/RSS À over RSH/RS À , in the context of this paper, refers to simple biochemical reactions with typical electrophiles known to react with thiols in aqueous solution (e.g., peroxides, electrophilic nitrogen oxides, oxidized sulfur species, alpha-beta unsaturated carbonyls, alkyl halides, etc.). ...
... A lot of properties known from experimental chemistry, such as chemical potential, electronegativity, polarizability or hardness and softness, can be given strict definitions on the ground of conceptual DFT. Other reactivity descriptors, e.g., Fukui function [35] or various electrophilicity/nucleophilicity indices [36][37][38] can also be defined. They have been successfully applied in modeling various reactions [33,39], and lately also chemical toxicity [40]. ...
In the present study, nucleophilic properties of adenine and guanine are examined by means of density functional theory. H+ is used as a model electrophile. Two modes of H+ attack on the bases are considered: on the neutral molecule and on the anion. Solvent effects are modeled by means of polarizable continuum model. Regioselectivity of attack is studied by analyzing two contributions. The first one is the energetic ordering of the tautomers. The second is the relative inherent reactivity of nucleophilic sites in the bases. Atomic softnesses calculated by means of charge sensitivity analysis are employed for this purpose. The most reactive sites in various tautomers are identified on the ground of Li-Evans model. For adenine, it is demonstrated that both in basic and in neutral pH N7 atom possesses the most nucleophilic character. In polar solvents, N7 substitution is also most favored energetically. In basic pH and nonpolar solvents as well as in the gas phase, N9 substitution is slightly more probable. For guanine, a mixture of N7- and N9-substituted products can be expected in basic pH. In neutral pH, inherent reactivity and energy trends are opposite to each other; therefore, the substitution does not occur. Experimentally observed products of reactions with various electrophiles and in various conditions confirm the results obtained in this study.
... Finally, we would like to emphasize that within the current framework of rationalizing electronic aspects of electrophilicity and nucleophilicity responses [21][22][23][24][25], the correct choice of the chemical potential value for the electronic bath would further widen the scope of applicability. As has been recently shown [26], the explicit incorporation of the chemical potential (and hardness) of the reactive partner to simulate the surrounding environment of a given chemical species, provides a useful way to properly categorize the relative electrophilicity/ nucleophilicity responses when building theoretical electronic analogues of the well-known experimental scales of Mayr and coworkers [27][28][29][30]. ...
We present a critical discussion related to the recent definition of the intrinsic reactivity index, IRI, (Tetrahedron Lett. 2013, 54, 339-342; Tetrahedron 2013, 69, 4247-4258) formulated to describe both, electrophilicity (charge acceptance) and nucleophilicity (charge donation) reactivities. We here stress that such an IRI model, based on the quantity μ/η, should be properly related to theoretical approximations associated to the change in the global electronic energy of a given chemical system under interaction with a suitable electron bath (Gazquez JL et al. J Phys Chem A 2007, 111, 1966-1970). Further, the limitations of the IRI model are presented by emphasizing that the intrinsic relative scales of electrophilicity and nucleophilicity within a second-order perturbation approach must account for the further stabilization of the two interacting species (Chamorro E et al. J Phys Chem A 2013, 117, 2636-2643).
... The Li and Evans [26] minimum Fukui function criterion correctly describes the protonation process in systems presenting a unique protonation site embedded in different chemical environments, yet it markedly fails in polyfunctional systems, presenting more than one site for protonation. The reactivity descriptors [30][31][32][33][34][35][36][37][38][39][40][41][42] defined in the framework of density functional theory (DFT) are widely used to study reactivity of chemical species such as chemical potential (l), chemical hardness (g), softness (S), nucleophilicity index (N), and electrophilicity index (x). The hardness was first defined within the density function theory (DFT) and a large amount of work has been devoted to the derivation of operational definitions and scales for different atomic systems [43][44][45][46][47]. ...
The global and local quantum chemical reactivity descriptors of a series of thiazole derivatives substituted at 2, 4, and 5 positions with different groups including electron-donating and electron-withdrawing substituents, have been calculated at the B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of theory. The substituents have been selected to cover a wide range of electronic effects. Considering the calculated Fukui functions, thiazole derivatives are found to be suitable nucleophilic sites in the gas-phase. For the most substituents, it was observed that the calculated Fukui function \({\mathbf{\it f}}_{k }^{ - }\) values at the N-site are small in the case of electron-attracting substituents indicating a preferred N-site for hard reactions. In contrast, large \({\mathbf{\it f}}_{k }^{ - }\) values in case of electron-releasing groups indicate a preferred N-site for soft reactions. These two local descriptors predicted the reactivity of the electron-rich thiazoles and sequence to be 2-substituted thiazoles >5-substituted thiazoles >4-substituted thiazoles, where reactivity toward electrophilic attack at the pyridine nitrogen atom is enhanced by electron-donor substituents elsewhere in the molecule, due to resonance effect.
Graphical Abstract
... Nucleophilicity on the other hand cannot be derived within the same model leading to the definition of the electrophilicity index [30,50,51]. This problem arises because, for the right-hand side of the parabola model used by Parr et al., the electronic chemical potential becomes positive semidefinite. ...
Theoretical scales of reactivity and selectivity are important tools to explain and to predict reactivity patterns, including reaction mechanisms. The main achievement of these efforts has been the incorporation of such concepts in advanced texts of organic chemistry. In this way, the modern organic chemistry language has become more quantitative, making the classification of organic reactions an easier task. The reactivity scales are also useful to set up a number of empirical rules that help in rationalizing and in some cases anticipating the possible reaction mechanisms that can be operative in a given organic reaction. In this review, we intend to give a brief but complete account on this matter, introducing the conceptual basis that leads to the definition of reactivity indices amenable to build up quantitative models of reactivity in organic reactions. The emphasis is put on two basic concepts describing electron-rich and electron-deficient systems, namely, nucleophile and electrophiles. We then show that the regional nucleophilicity and electrophilicity become the natural descriptors of electrofugality and nucleofugality, respectively. In this way, we obtain a closed body of concepts that suffices to describe electron releasing and electron accepting molecules together with the description of permanent and leaving groups in addition, nucleophilic substitution and elimination reactions.
This work is focused on finding a more effecient electrolyte to enhance the lithium-ion battery's overall characteristics and performance under Molecular Ortbital Theory (MOT) approach. As lithium-based electrolytes are now widely employed in all battery-operated portable devices, their use must be done with caution owing to a number of issues, including their toxicity, limited ionic conductivity, explosiveness, corrosiveness and hydrolysability creating harmful gasses. Using computational tools, a solution for these kinds of issues has been evaluated. The core idea is to simulate and evaluate by changing molecular symmetries. The molecular descriptors used include non-covalent interactions, band structure, density of states, electrostatic potential and fukui indices. Following our findings, a soft molecule with a smaller energy gap will be more polarizable and capable of charge transfer, making it more chemically reactive and less non-corrosivity than lithium hexafluoroarsenate (LiAsF6) and lithium hexafluorophosphate (LiPF6). For comparison, we also examined the electronic properties of electrolytes using first-principles calculations based on the DFT in the material design software MedeA® computational environment and also carried out Band structure and DOS calculation, which indicate the significance of band gap of between 1.41 to 2.91 eV. Since, soft molecules lead to good conductivity, chemically reactive and electron transport. A relative study with sodium and potassium-based electrolytes was also performed.
Within the context of Density Functional Theory (DFT), Conceptual DFT (CDFT) has proven its merit for the analysis and interpretation of both experimental and theoretical studies of chemical phenomena, especially the thermodynamics and kinetics of chemical reactions. In the first part of this chapter, CDFT is introduced from a perturbative perspective. This approach exposes the machinery necessary to approximate reactivity indicators, computationally. Starting from an (approximate) energy model, E=E[v(r);N], a reference state is chosen which is usually the reactant molecule of interest. Its change in energy upon interaction with a second reactant, caused by changes in the number of electrons, N, and external potential, v(r), can then be written as a Taylor series where the expansion coefficients are partial derivatives with respect to N and/or functional derivatives with respect to v(r). These coefficients are only dependent on the (first) reactant, whereas the characteristics of the second reactant are reflected in the changes in N and v(r). The coefficients or response functions therefore characterize the intrinsic reactivity of the reactant molecule and can be considered reactivity indicators. These indicators are introduced up to third order in the expansion, and identified with chemical concepts, both in the canonical ensemble, characterized by the E=E[v(r);N] state function and in other Legendre-transformed ensembles. The Grand Canonical Ensemble with its associated Grand Potential Ω=Ω[v(r);µ] turns out to be more suitable for systems where the number of electrons is not easily controlled, paving the way to the description of open systems.
The second part highlights well-known rules of thumb, explains the limitations of CDFT, and discusses some pitfalls in its application. The focus on the onset of a chemical reaction or, in a comparative context, on different reactions, as advocated in the perturbative approach, is discussed via general considerations on reaction paths. Klopman’s non-crossing rule is highlighted, leading to the avoidance of late transition states or multi-step reactions. The limitations of several principles where CDFT is often used, e.g., the Hard and Soft Acids and Bases principle, are highlighted scrutinizing the proviso in Pearson’s formulation “all other things being equal, hard acids prefer binding to hard bases and soft acids prefer to bind to soft bases”. The selection of adequate reactivity descriptors among the Taylor expansion coefficients is discussed within the context of the one-reactant approach. The influence of the nature of the second reactant on this choice is paramount, leading to more general-purpose reactivity indicators, containing for example a mix of hard and soft components. This part closes by addressing the conundrum of how negative electron affinities should be regarded when evaluating both electronegativity and hardness.
The final part addresses important issues regarding the dissemination of CDFT-tools to help both specialists and non-specialists (including experimentalists) analyze their results and even, perchance, predict chemical reactivity. This requires user-friendly and well-documented software packages, like ChemTools, offering a unified approach to the evaluation of as many response functions as possible. ChemTools can post-process outputs of essentially any Gaussian basis-set-based quantum-chemistry code. A further advantage as compared to the variety of in-house research codes is the consistent use of various energy models. One thereby avoids the piecemeal approach to calculating response functions in existing codes. Starting from a chosen energy-model, a straightforward evaluation of the functional derivatives of the energy with respect to the external potential is then possible; all other reactivity indicators can readily be obtained by differentiating these descriptors with respect to the number of electrons.
An efficient and catalyst-free multicomponent sequence for synthesizing fused new polyheterocyclic pyrene-grafted dispiro-pyrrolidine oxindolines through 1,3-dipolar cycloaddition reaction mediated by non-stabilized azomethine ylides is reported herein. The regio- and stereochemistry of the cycloadducts were determined on the basis of one-dimensional (1D) and two-dimensional (2D) homonuclear and heteronuclear correlation NMR spectroscopy. The mechanism of the cycloaddition reaction, as well as regioselectivity were discussed by evaluating global and local electrophilicity and nucleophilicity descriptors at B3LYP/6-31G level of theory. The findings suggested that the polarity and charge transfer flow between azomethine ylides (dipole) and 5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones (dipolarophiles) was consistent with the global reactivity descriptors and substitutional pattern. These outcomes based on local descriptors Parr functions proposed by Domingo were found to be quite promising indices for the study of organic reactivity and to explain the regioselectivity of cycloaddition processes.
Computational-experimental analysis has allowed determining that the stereochemistry of the Staudinger reaction between ketenes and imines is strongly associated with the nature of the imine, which affects the two steps of the reaction. The first step, namely the nucleophilic attack of the sp2-hybridized nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene, is affected by the energetically accessible in situ isomerization patterns of the imine. The second step consists of a conrotatory electrocyclization of the zwitterionic intermediate formed in the previous step. This latter pericyclic step depends on the inward/outward torquoelectronic effects generated by the substituents of the imine. The impact of these factors on the stereochemistry of this reaction has been analyzed kinetically by numerical methods. The results of these simulations are compatible with the experimental results and support these conclusions.
Density functional theory (DFT) has proved to be an effective and fruitful framework for the detailed exploration of useful concepts and reactivity principles in chemistry. The DFT framework offers a formal mathematical structure for the interpretation/prediction of experimental/theoretical chemical reactivity patterns on the basis of a series of responses of state functions to changes or perturbations in basic ground-state variables. The generalized spin-polarized (SP)-DFT framework properly describe spin-dependent reactivity, as involved in free radical chemistry. The universal matrix-vector notation for conceptual DFT enables easy transfer of results to any formulation of spin-resolved DFT and even to spin-free conceptual DFT, offering a unifying perspective on conceptual DFT as a whole. One important quantity to be further explored is the role of electrophilicity and nucleophilicity indices within a SP-DFT perspective and its impact on the rationalization of free radical reactivity. Most free-radical chemical reactions feature electron transfer.
Sulfur hexafluoride (SF6) is considered as a potent greenhouse gas, whose effective degradation is challenging. Here we reported a computational study on the nucleophilic activation of sulfur hexafluoride by N‐heterocyclic carbenes and N‐heterocyclic olefins. The result shows that the activation of SF6 is both thermodynamically and kinetically favorable at mild condition using NHOs with fluoro‐substituted azolium and sulfur pentafluoride anion being formed. The Gibbs free energy barrier during the activation of SF6 has a linear relationship with the energy of HOMO of substrates, which could be a guideline for applying those compounds that feature higher energy in HOMO to activate SF6 in high efficiency.
Chemo- and site-specific modifications in oligonucleotides have wide applicability as mechanistic probes in chemical biology. However, methods that label specific sites in nucleic acids are scarce, especially for labeling DNA/RNA from biological or enzymatic sources rather than synthetic ones. Here we have employed a classical reaction, reductive amination, to selectively functionalize the N²-amine of guanosine and 2′-deoxyguanosine monophosphate (GMP/dGMP). This method specifically modifies guanine in DNA and RNA oligonucleotides, while leaving the other nucleobases unaffected. Using this approach, we have successfully incorporated a reactive handle chemoselectively into nucleic acids for further functionalization and downstream applications.
Theory on the molecular characteristic contour (III)——the indication of molecular regioselectivity and stereoselectivity via the molecular face
A kinetic study of the reactions of potentially bioactive 2-amino-4-arylthiazoles with highly reactive 4,6-dinitrobenzofuroxan (DNBF) is reported herein in acetonitrile solution. The complexation reaction was followed by recording the UV-vis spectra with time at λmax = 482 nm. Electronic effects of substituents influencing the rate of reaction have been studied using structure-reactivity relationships. It is shown that the Hammett plot relative to the reaction of DNBF with 2-amino-4-(4-chlorophenyl)thiazole exhibit positive deviation from the log k1 versus σ correlation, while it showed excellent linear correlation in terms of Yukawa–Tsuno equation. It has be noticed that the nonlinear Hammett plot observed for 2-amino-4-(4-chlorophenyl) thiazole is not attributed to a change in rate-determining step but is due to nature of electronic effect of substituent caused by the resonance of stabilization of substrates. The second-order rate constant (k1) relating to the bond C–C and C-N forming step of the complexation processes of DNBF with 4-substituted-aminothiazoles and 2-amino-5-methyl-4-phenylthiazole, respectively, is fit into the linear relationship log k = sN (N+ E), thereby permitting the assessment of the nucleophilicity parameter (N) of the 2-amino-4-arylthiazoles of the range (4.90 < N < 6.85). 2-amino-4-arylthiazoles is subsequently ranked by positioning its reactivity on the general nucleophilicity scale developed recently by Mayr and coworkers (2003) leading an interesting and a direct comparison over a large domain of π-,σ-, and n-nucleophiles. The global electrophilicity/nucleophilicity reactivity indexes of the 2-amino-4-arylthiazoles have been investigated by means of a density functional theory (DFT) method. .
The prediction of the nature of a reactivity descriptor is of paramount importance to theoretical chemists and thus, much work has been carried out in this area. The electrophilicity index (ω), an important theoretical construct of chemistry, is a measure of the electron acceptor affinity to gain an additional electronic charge from the environment. It is quantified in terms of the maximum energy stabilization in species, which arises due to accepting a charge. The electrophilicity concept is being extensively used in modern chemistry, although the finest measurement scale of the electrophilicity index is yet to be designed. In this study, a new scale of the electrophilicity index invoking the force concept based on the effective nuclear charge (Zeff) and absolute atomic radii (r) is proposed for 97 elements of the periodic table, which is determined through the regression analysis. The computed data follows the periodicity very well satisfying the sine qua non of the standard scale of the electrophilicity index. The electrophilicity equalization principle is also established in terms of the computed data. To test the model in the real field, the internuclear bond distance of some molecules is calculated in terms of the computed electrophilicity index. A comparative study of the theoretical vis-à-vis experimental internuclear bond distance reveals the efficacy of the proposed scale.
A new ansatz is suggested for computing the atomic nucleophilicity index (N) for atoms of 103 elements of the periodic table resting upon the mutual action of two periodic properties that is, atomic polarizability (α) and effective nuclear charge (Zeff). The ansatz is expressed as N = a (α/Zeff) + b, where a and b are constants, evaluated by regression analysis. The effectiveness of the model is illustrated by the explicit periodic behaviour. In addition, molecular nucleophilicity (NAM) is being proposed as arithmetic mean of the atomic nucleophilicities of the constituent atoms of the given molecule. Due to the nonexistence of benchmark for atomic nucleophilicity, molecular nucleophilicity is evaluated and a comparative analysis is made with the existing data as a validity test which reveals a close conformity between the two demonstrating the potency of the model as well as appropriateness of the molecular nucleophilicity concept. Furthermore, computed density functional theory (DFT) based reactivity descriptor, atomic nucleophilicity index, has been employed to construct a quantitative structure–activity relationship (QSAR) model, using regression analysis, to study the biological activities of testosterone derivatives. The predicted biological activities show high resemblance with the observed activities. High values of coefficients of determination (r2) indicate the usefulness of proposed QSAR model.
The neutral oxime reactivator RS194B with a seven-membered ring has shown better efficacy towards the tabun-inhibited AChE than that of RS69N with a six-membered ring and RS41A with a five-membered ring. The difference in the efficacy of these reactivators has remained unexplored. We report here the origin of the difference of efficacy of these reactivators based on the conformational analysis, quantum chemical calculations and steered molecular dynamics (SMD) simulations. The conformational analysis using B3LYP/6-31G(d) level of theory revealed that RS41A and RS194B are more stable in gauche conformation due to the gauche effect (–N–C–C–N– bonds) whereas RS69N prefers anti-conformation. The SMD simulations show that RS194B retains in more stable gauche conformation inside the active gorge of AChE during different time intervals that experiences more hydrogen bonding, hydrophobic interactions with the catalytic anionic site (CAS) residues and weaker interactions with the peripheral anionic site (PAS) residues compared to RS41A and RS69N. In an effort to design an even superior reactivator, RS194B-S has been chosen with a subtle change in the geometry of RS194B by replacing the carbonyl oxygen with the sulfur atom. The newly designed reactivator RS194B-S can also be a promising candidate to reactivate tabun-inhibited AChE.
Computational approaches based on density functional theory (DFT) combined with polarizable continuum model (PCM) of solvation have been used to probe the likelihood of complexation in water between oxo-vanadium(IV) and various medicinal cysteamine-based ligands. The experimental electronic spectra of a complex formed by oxo-vanadium(IV) and penicillamine in water agree well with the theoretical spectra based on the time-dependent density functional theory (TD-DFT) calculations. Among all density functionals adopted, CAM-B3LYP outperforms the others in predicting both structural and spectroscopic properties of oxo-transition metal complexes of cysteamine-based ligands. A variety of chelation behaviors have been found for the ligands tested, depending on the choice of substituent added to the cysteamine backbone. Solvation has a great impact on the thermodynamic driving force for cysteine and its derivatives to undergo complexation. In all cases, the thiolate sulfur atom forms stronger coordination bond than either the amine nitrogen or carboxylate oxygen atoms. Based on the thermodynamic and nucleophilicity index calculations, penicillamine has the highest potential to form complex with oxo-vanadium(IV).
The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono- (G-mec and A-mec) and dialkylated (AA-mec, GG-mec and AG-mec) adducts has been studied using density functional theory (DFT). In order to have a complete overview of DNA-alkylation processes, direct chloride substitution and formation through activated aziridinium species were considered as possible reaction paths for adduct formation. Our results confirm that DNA alkylation by nitrogen mustard mechlorethamine (mec) occur via aziridine intermediates instead of direct substitution. Consideration of explicit water molecules in conjunction with polarizable continuum model (PCM) was shown as an adequate computational method for a proper representation of the system. Moreover, Runge-Kutta numerical kinetic simulations including the possible bisadducts have been performed. These simulations predicted a product ratio of 83:17 of GG-mec and AG-mec diadducts, respectively.
The reaction mechanism associated with the synthesis of phosphorus-based heteropolyaromatic architectures by intramolecular SEAr have been investigated by DFT calculations at the B3LYP-D3/6-311+G(D) level of theory. The purpose of this study is to provide essential information for the future development of improved polycyclic organophosphorus materials. To that end, we have studied the impact of the initial reactant and/or the intermediates' structure into the mechanistic features and energetic profiles of the phosphorus cyclization process. Moreover, we have analysed in detail the reactivity parameters within a conceptual DFT framework and extracted underlying reactivity trends. Thus, our findings provide important insights for a rational design of polycyclic phosphorus compounds.
Exposure to diacetyl and related α-diketones causes respiratory-tract damage in humans and experimental animals. Chemical toxicity is often associated with covalent modification of cellular nucleophiles by electrophilic chemicals. Electrophilic α-diketones may covalently modify nucleophilic arginine residues in critical proteins and, thereby, produce the observed respiratory-tract pathology. The major pathway for the biotransformation of α-diketones is reduction to α-hydroxyketones (acyloins), which is catalyzed by NAD(P)H-dependent enzymes of the short-chain dehydrogenase/reductase (SDR) and the aldo-keto reductase (AKR) superfamilies. Reduction of α-diketones to the less electrophilic acyloins is a detoxication pathway for α-diketones. The pyruvate dehydrogenase complex may play a significant role in the biotransformation of diacetyl to CO2. The interaction of toxic electrophilic chemicals with cellular nucleophiles can be predicted by the hard and soft, acids and bases (HSAB) principle. Application of the HSAB principle to the interactions of electrophilic α-diketones with cellular nucleophiles shows that α-diketones react preferentially with arginine residues. Furthermore, the respiratory-tract toxicity and the quantum-chemical reactivity parameters of diacetyl and replacement flavorant α-diketones are similar. Hence, the identified replacement flavorant α-diketones may pose a risk of flavorant-induced respiratory-tract toxicity. The calculated indices for the reaction of α-diketones with arginine support the hypothesis that modification of protein-bound arginine residues is a critical event in α-diketone-induced respiratory-tract toxicity.
The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a CuI or AgI catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4-aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3-dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism.
The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a CuI or AgI catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4-aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3-dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism.
The solvent effect on the nucleophile and leaving group atoms of the prototypical F- + CH3Cl → CH3F + Cl- backside bimolecular nucleophilic substitution reaction (SN2) is analyzed employing the reaction force and the atomic contributions methods on the intrinsic reaction coordinate (IRC). Solvent effects were accounted for using the polarizable continuum solvent model. Calculations were performed employing eleven dielectric constants, ε, ranging from 1.0 to 78.5, to cover a wide spectrum of solvents. The reaction force data reveals that the solvent mainly influences the region of the IRC preceding the energy barrier, where the structural rearrangement to reach the transition state occurs. A detailed analysis of the atomic role in the reaction as a function of ε reveals that the nucleophile and the carbon atom are the ones that contribute the most to the energy barrier. In addition, we investigated the effect of the choice of nucleophile and leaving group on the ΔE0 and ΔE↕ of Y- + CH3X → YCH3 + X- (X,Y= F, Cl, Br, I) in aqueous solution. Our analysis allowed us to find relationships between the atomic contributions to the activation energy and leaving group ability and nucleophilicity.
In the present work we calculate structural parameters, vibrational spectra (IR, 1H NMR and UV–Visible Absorption) and corresponding mode of vibrational assignments of two ligands derived from benzoxazole; L1: 2-(5-(trifluoromethylpyridin-2-yl)-benzoxazole and L2: 2-(5-methylpyridin-2-yl)-benzoxazole at B3LYP/6-311++G** level, in the gas phase. The HOMO and LUMO study is used to determine the charge transfer within the molecules. Reactivity descriptors such as ionization energy, electronic affinity, global hardness, global softness, electrophilicity, nucleophilicity and condensed Fukui functions using NBO population analysis are also determined to predict the reactivity of L1 and L2. The calculated geometrical parameters are in good agreement with those of similar benzoxazole derivatives. Theoretical frequencies assignments confirmed the experimental ones of these benzoxazole derivatives.
Qualitative explorations of elementary mechanisms of chemical reactions are outlined and simple modeling of reactivity preferences is summarized. The familiar energy profiles along the reaction intrinsic coordinate can be analyzed by examining the associated changes in the reaction force and the information content of the electron probability distributions in elementary collisions. Such Shannon and Fisher information “signatures” of the reaction mechanism in both the position and momentum spaces, respectively, have recently been examined for the representative disconcerted (abstraction) and concerted (nucleophilic substitution) reactions. The momentum-space entropy/information data have been shown to identify regions where the bond-breaking and bond-forming processes really occur. These features are not revealed by the MEP energy profile and the density of electrons at the Transition-State complex alone.
In the present study, we have rationalized the effect of variation in the symmetry of relatively smaller fullerene (C32) on the mode of its interaction with semi-conducting Single-Walled Carbon Nanotubes (SWCNTs) in the process of formation of stable hybrid carbon NanoBuds. Thermodynamic and kinetic parameters, along with the charge transfer values associated with the interaction between fullerene and SWCNTs, have been evaluated using an un-conventional and computationally cost–effective method based on density functional reactivity theory (DFRT). In addition to this, conventional DFT based studies are also performed to substantiate the growth of NanoBud structures formed by the interaction between fullerene and SWCNTs. The findings of the present study suggest that the kinetic, thermodynamic and structural aspects of hybrid carbon NanoBuds are significantly influenced by both the symmetry of C32 fullerene and its site of covalent attachment to the SWCNT.
Two nucleophilicity indices were evaluated for a series of N-nucleophiles. The first index is the one defined by Jaramillo et al. in 2006 while the second is a new index proposed for the first time in this paper. Both indices are based on information concerning the frontier molecular orbital of the nucleophile and its electrophilic partner. The models based on these indices were validated against existent kinetic data for the nucleophilic substitution of benzhydrylium cations with primary and secondary amines in water at 20C. The predictive character of the models was also tested.
A study on the nucleophilic reactivity of silyl enol ethers and ketene silyl acetals has been carried out using conceptual density functional theory based reactivity descriptors. Silyl enolates having substituents of both electron releasing and electron withdrawing nature at various key positions of the molecules have been considered for the study. While intramolecular reactivity towards elctrophilic attack is studied on the basis of local philicity index, the intermolecular reactivity is assessed using group philicity. Role of Dmethyl substituents are found to be crucial for nucleophilic reactivity of these systems.
The understanding in science implies insights from several different points of view. Alternative modern outlooks on electronic structure of atoms and molecules, all rooted in quantum mechanics, are presented in a single text. Together these complementary perspectives provide a deeper understanding of the localization of electrons and bonds, the origins of chemical interaction and reactivity behavior, the interaction between the geometric and electronic structure of molecules, etc. In the opening two parts the basic principles and techniques of the contemporary computational and conceptual quantum chemistry are presented, within both the wave-function and electron-density theories. This background material is followed by a discussion of chemical concepts, including stages of the bond-formation processes, chemical valence and bond-multiplicity indices, the hardness/softness descriptors of molecules and reactants, and general chemical reactivity/stability principles. The insights from Information Theory, the basic elements of which are briefly introduced, including the entropic origins and Orbital Communication Theory of the chemical bond, are the subject of Part IV. The importance of the non-additive (interference) information tools in exploring patterns of chemical bonds and their covalent and ionic components will be emphasized. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.
The efficiency of certain additives like tryptophan (TRP), adenosine monophosphate (AMP) and phenethylamine (PEA) on polyamide membrane (PA) surface for better salt rejection is studied through density functional theory. The interaction energies of monovalent (Na+, K+) and divalent (Ca2 +, Mg2 +) cations with pure PA and modified PA surfaces are calculated and a stronger binding of divalent cations over monovalent cations is noticed. The increasing order of binding of PA surfaces with metal-ions is PA_PEA < PA < PA_AMP < PA_TRP. The two major factors influencing the binding of metal ions to the surfaces are cation–π interactions between the metal ion and the π-cloud of the additive and the nucleophilic character of the membrane surface. The increasing order of metal ion binding to any of the PA surface is K+ < Na+ < Ca2 + < Mg2 +. Both gas phase and solvent phase interaction energies follow the same trend of metal ion binding to the PA surface. The findings from the interaction studies are supported by conceptual density functional descriptors. TRP and AMP bound PA surfaces with polar functional groups are relatively presented as an effectual membrane surface for salt rejection than the pure polyamide surface.
An empirical local hardness index is introduced and tested. The usefulness of this new quantity as an intramolecular selectivity descriptor is illustrated for a set of 49 molecules. The proposed local hardness index appears as a good descriptor of the orientation of the electrophilic aromatic substitution, the selectivity of addition reaction as well as the alkylation and acylation of lithium enolates. The sites for the attack by hard species seem to be correctly predicted by the proposed index.
Based on ab initio calculations at MP2 and MP4 levels, a chemically intuitive π-type hydrogen-bond model is proposed to illustrate and interpret the small deviations from a strictly linear hydrogen bond X⋯H-Y in the dimers (HF)2, (H2O)2, and H2O-HF. The computational results show that π-type hydrogen-bond interaction is secondary and is an attraction between the H atom of the H-X bond and lone pair on Y. In particular, the orientations of lone pairs are detected, by the energy scan at the MP2/6-311+G (2df, 2p) level with a probing point charge of q = -1, which is important to show the existence of the π-type hydrogen bond. Furthermore, the interaction energy of π-type hydrogen bond, Dπ, and stabilized energy of bent hydrogen bond, ΔEsb, are also calculated and discussed.
The zero-point and equilibrium dissociation energies (D0 and De) of the hydrogen-bonded dimers CH3CN-HF and HCCCN-HF are determined experimentally on the basis of absolute intensity measurements of selected rotational transitions. A Stark-modulated microwave spectrometer is employed with the cooled absorption cell described by Legon et al. (1980). The results are presented in tables and analyzed. Energies determined are D0 = 26.1(0.6) kJ/mol and De = 29.0(0.9) kJ/mol for CH3CN-HF and D0 = 20.4(0.7) kJ/mol and De = 23.4(0.9) kJ/mol for HCCCN-HF. Theoretical De values calculated using the Morse potential function are found to be in much better agreement with the experimental results than those calculated with the Lennard-Jones potential function.
Based on ab initio calculations at MP2 and MP4 levels, a chemically intuitive π-type hydrogen-bond model is proposed to illustrate and interpret the small deviations from a strictly linear hydrogen bond X···H−Y in the dimers (HF)2, (H2O)2, and H2O−HF. The computational results show that π-type hydrogen-bond interaction is secondary and is an attraction between the H atom of the H−X bond and lone pair on Y. In particular, the orientations of lone pairs are detected, by the energy scan at the MP2/6-311+G (2df, 2p) level with a probing point charge of q = −1, which is important to show the existence of the π-type hydrogen bond. Furthermore, the interaction energy of π-type hydrogen bond, Dπ, and stabilized energy of bent hydrogen bond, ΔEsb, are also calculated and discussed.
Statistical models for the study of solvent effects on the endo/exo selectivity of Diels–Alder reactions using molecular surface electrostatic potentials was obtained. The models show that hydrogen bond interactions of solvent molecules favor the predominance of the endo isomer for the reaction of methyl acrylate, methyl methacrylate and methyl trans-crotonate with cyclopentadiene whereas the effect of solvophobicity seems to be negligible.
The electrophilicity of tricarbonyl(cycloalkadienylium)iron complexes like 1 was determined by measuring the rates of their reactions with nucleophiles like 2 to give the neutral complexes 3 [Eq. (a)]. This enables the integration of the electrophilicity scale of organometallic cations with that of carbenium ions. Counterion BF; R is, for example, Ph.
The addition of carbenium ions to CC double bonds, a key step in many syntheses in organic and macromolecular chemistry, is analyzed using the Lewis acid promoted reactions of alkyl chlorides with alkenes as an example. Stereochemical and kinetic experiments suggest that the transition state is slightly bridged and product-like. Rearrangements of the carbenium ions that result from the electrophilic attack can be minimized by adding salts with nucleophilic counter ions. The thermodynamics of the addition reactions are analyzed, and the conditions necessary in order to observe the back reaction (i.e. the Grob fragmentation) are discussed. Multiparameter equations that predict rate constants are derived from kinetic studies on the reactivities of carbenium ions and alkenes. Reactivity-selectivity relationships over a reactivity range that covers eight orders of magnitude show that the structure of the transition state is only changed by variation of substituents in the immediate vicinity of the reaction center.
Contrary to widely held opinion, for many reactions in organic and organometallic chemistry it is possible to define nucleophilicity and electrophilicity parameters that are independent of the reaction partners. This phenomenon, discovered by Ritchie during the early 1970s for reactions of highly stabilized carbenium and diazonium ions with n-nucleophiles, also occurs with reactions of carbenium ions with aliphatic and aromatic π-electron systems and in hydride transfer reactions. With the aid of the scales of nucleophilicity and electrophilicity set out here, which extend over eighteen orders of magnitude, forecasts can be made about the feasibility and rate of a given CC bond formation, ionic reduction, or diazo coupling. Linkage with the reactivity scales of Ritchie and Sweigart/Kane-Maguire enables a unified treatment of a large number of polar reactions.
A technique which employs high resolution Fourier transform infrared spectroscopy is demonstrated for evaluation of hydrogen bond dissociation energies D0 and De. Results for HCN‐‐HF give a D0=20.77(22) and De =28.77(45) kJ/mol which are compared with previously determined values obtained from microwave absolute intensity measurements and ab initio molecular orbital calculations. Rovibrational band information available for HCN‐‐HF also permits evaluation of thermal functions of dimer formation in kJ/mol: ΔU○298.2 =20.1(2), ΔH○298.2 =22.6(2), ΔG○298.2 =59.4(2), ΔS○298.2 =−0.1235.
The DFT-based reactivity descriptors “local softness” and “local hardness” are used as reactivity indices to predict the reactivity sequences (both intramolecular and intermolecular) of carbonyl compounds toward nucleophilic attack on them. The finite difference approximation is used to calculate local softness, whereas local hardness is approximated by −Vel/2N, where Vel is the electronic part of the molecular electrostatic potential. Both aldehydes and ketones, aliphatic and aromatic, have been selected as systems. Critical cases, e.g., C6H5CHCHCHO, CH3CHCHCHO, and CH2CHCHO, where a CC double bond is in conjugation with the CO group, are also considered. Two new reactivity descriptors are proposed, “relative electrophilicity” (sk+/sk-) and “relative nucleophilicity” (sk-/sk+), which will help to locate the preferable reactive sites. Our results show that local hardness can be used as a guiding parameter when constructing intermolecular reactivity sequences.
In this paper we describe a method to obtain estimates of the relative nucleophilicity for a series of neutral and charged electron donors from their solution phase ionization potential (Is). The relationship between nucleophilicity and the solution phase ionization potentials is first tested for experimental Is values in aqueous solution. On the basis of the meaningful relationship found, the method is then applied to the theoretical solution phase Is obtained at the IPCM-MP2/6-311G(2d,p) level of theory. The comparison between the experimental nucleophilicity as given by Ritchie's N+ scale and the solution phase ionization energy for a series electron donors split out into two families: a first group of marginal and moderate nucleophiles that mainly contains atoms of the first row (H2O, NH2CONHNH2, CF3CH2NH2, NH3, CH3ONH2, NH2OH and CH3O-), with nucleophilicity number N+ < 6.0; a second group of strong nucleophiles, mainly including second-row sulfur atom (CH3CH2S-, CH3CH2CH2S-, OHCH2CH2S-, C6H5S-) and the first-row electron donors piperidine and morpholine, with nucleophilicity number N+ > 7.0. An approximate expression for a local nucleophilicity index is proposed. The results show that the nucleophilicity power of the electron donors is consistently shown at the expected nucleophilic sites in these molecules. The solvent effect on the predicted nucleophilicity is also discussed.
Dynamical behavior of chemical reactivity indices like electronegativity, hardness, polarizability, entropy, electrophilicity and nucleophilicity indices and uncertainty product is studied within a quantum fluid density functional framework for the interactions of a helium atom in its ground and excited electronic states with monochromatic and bichromatic laser pulses with different intensities. Time dependent analogues of various electronic structure principles like the principles of electronegativity equalization, maximum hardness, minimum polarizability and maximum entropy have been found to be operative. Insights into the variation of intensities of the generated higher order harmonics on the color and intensity of the external laser field are obtained.
In the work described in this paper we have studied the adsorption of gaseous molecules inside the zeolite lattice using recently developed different reactivity descriptors. In particular, we have used Fukui function-based descriptors and local hard−soft acid−base (HSAB) principle for a quantitative and qualitative analysis. This represents the first case in which local HSAB principle has been used for quantitative description of weak adsorption cases.
The most negative-valued molecular electrostatic potential (MESP) minimum (Vmin) observed over the benzene ring is proposed as a sensitive quantity for the analysis of the electronic perturbations due to the substituents attached to it. MESP topography of 45 doubly substituted benzenes is mapped at HF/6-31G** level for an appraisal of this proposition. The Vmin values are seen to clearly reflect the changes due to the different orientations (para, meta, and ortho) and conformations of the substituents and different mechanisms of electron donation or withdrawal. Good linear correlations are obtained with Vmin and the experimentally determined σ values of the ortho- and meta-disubstituted benzenes. New quantities, Dp, Dm, and Do, introduced in this work as the substituent pair-constants respectively for the para, meta, and ortho arrangements, provide a quantitative measure of the simultaneous effect of two substituents over the aromatic nucleus. The predictive power of these quantities is checked in the case of some triply substituted benzenes using an equation Vmin = Vben + ∑ΔVmin(mono) − ∑Dp − ∑Dm − ∑Do where Vben is the MESP minimum of benzene and ΔVmin(mono) is the difference between the monosubstituted benzene Vmin and Vben. These predicted values are in fairly good agreement with the MESP values obtained at HF/6-31G** level.
A new equation, which is a combination of a nucleophilic scale and a basicity scale, is presented for the correlation of the reactions of electron donors. A new nucleophilic scale for donors, based on electrode potentials, is devised. Data used to test the equation and the scale include rates of displacement reactions of carbon, oxygen, hydrogen and sulfur, and equilibrium constants for complex ion associations, solubility products and iodine and sulfur displacements. The results are good for most of the correlations, and are especially encouraging for those cases, such as complex ion constants, which have been treated heretofore only qualitatively. Advantages and consequences of a double basicity scale for electron donors are discussed briefly.
A two-parameter equation is found to correlate the relative rates of 47 reactions (11 new, 36 from the literature) of various nucleophilic reagents (water, chloride ion, hydroxide ion, aniline, etc.) with various organic substrates (alkyl halides, esters, epoxides, acyl halides and a sulfonium ion) in water solution with a mean median deviation of only a factor of 1.5, although the mean variation in relative rates from water to the most nucleophilic reagent measured for each substrate is more than a factor of 105. This equation is log(k/k0) = sn where k0 is a rate constant for reaction with water, k is the corresponding rate constant for reaction with any other nucleophilic reagent, s (the substrate constant) is characteristic of only the substrate and defined as 1.00 for methyl bromide in water at 25° and n (the nucleophilic constant) is characteristic of only the nucleophilic reagent and defined as 0.00 for water. Typical nucleophilic constants are 2.7 for acetate ion, 3.0 for chloride ion, 4.0 for azide ion, 4.2 for hydroxide ion, 4.5 for aniline, 5.0 for iodide ion and 6.4 for thiosulfate ion. Typical substrate constants are 0.66 for ethyl tosylate, 0.77 for β-propiolactone, 0.95 for β-chloroethylethylenesulfonium ion, 1.00 for 2,3-epoxypropanol, and 1.43 for benzoyl chloride. Contrary to previous belief, the nucleophilic reactivity of hydroxide ion toward epoxides or acyl halides is not abnormally low (based on methyl bromide as a standard substrate). A four-parameter equation allows for variations in the electrophilic reagent (water, phenol, hydrogen ion, mercuric bromide, etc.) as well. The Brönsted catalysis laws, Grunwald-Winstein correlation and the two-parameter equation are corollaries of the four-parameter equation.
The rates of reaction of a number of nucleophiles with methyl iodide and trans-[Pt(py)2Cl2] have been measured in methyl alcohol at 25°. Relative nucleophilic reactivity parameters, nCH3I and nPt, have been calculated. It was not found possible to correlate these numbers with each other or with other extra-kinetic data. Equations in the literature for predicting nucleophilic reactivity have only a limited range of usefulness.
Three important factors determining the reactivity of nucleophilic reagents are considered. These are basicity, polarizability and the presence of unshared pairs of electrons on the atom adjacent to the nucleophilic atom, the alpha effect. The theoretical bases for these three factors are discussed. Experimental data for a number of substrates are given which make it clear that the reactivities of some substrates depend almost entirely on basicity of the nucleophile, and some substrate reactivities depend entirely on the polarizability. Substrates which resemble the proton in having a high positive charge and a low number of electrons in the outer orbitals of the central atom depend on basicity. Substrates with a low positive charge and with many electrons in the outer orbitals of the central atom depend on polarizability. The alpha effect appears to be general for all substrates.
The energy decomposition analysis of Morokuma et al. within the ab initio SCF-MO theory has been applied to the study of the origin of hydrogen bonding. An examination of interaction energy components, electrostatic, polarization, exchange repulsion, charge transfer, and their coupling, for (H2O)2, (HF)2, H3N-HF, and other complexes in which the proton donor is HF, H2O, NH3, or CH4 and the proton acceptor is HF, H2O, and NH3, as functions of geometric parameters, indicates these hydrogen-bonded complexes can be qualitatively called "electrostatic > charge transfer" or "electrostatic" complexes. The energy analysis of substituent effects in hydrogen bonding has been carried out for two examples, H3N-HOZ where Z = H, CH3, NH2 and F, and RH2N-HOH where R = H and CH3, and is compared with those in electron donor-acceptor complexes and protonation complexes. A comparison of energy components with lithium complexes has been performed in two cases: (LiF)2, (LiH)2 with (HF)2, and RH2N-Li+ with RH2N-H+. Based on these and our previous studies, the following questions concerning the origin of hydrogen bonding are discussed: (1) factors determining the geometrical parameters, in particular, the X-Y distance, the hydrogen bond directionality, and linearity, (2) energy components in hydrogen bond energy, (3) charge transfer and charge redistribution, (4) substituent effects, and (5) what makes hydrogen bonding unique?
Hydrogen-bond stretching force constants (kσ) determined from the rotational spectra of dimers B⋯HX have been used to establish the nucleophilicities (N) of B for B = N2, CO, PH3, H2S, HCN, CH3CN, H2O, and NH3 and the electrophilicities (E) of HX for X = F, Cl, CN, Br, C≡CH, and CF3. Values of E and N have been used to predict kσ for a number of dimers as yet unobserved.
Rate coefficients have been measured for the gas-phase reactions of methyl, ethyl, n-propyl, isopropyl, tert-butyl, and neopentyl chlorides and bromides with the following set of nucleophiles, listed in order of decreasing basicity: HO-, CH3O-, F-, HO- (H2O), CF3CH2O-, H2NS-, C2F5CH2O-, HS-, and Cl-. For methyl chloride the reaction efficiency first falls significantly below unity with HO- (H2O) as the nucleophile and for methyl bromide with HS- as the nucleophile; in both cases the overall reaction exothermicity is about 30 kcal mol-1. Earlier conclusions that these halides react slowly with stronger bases are shown to be in error. In the region where the rates are slow oxygen anions react with the alkyl chlorides and bromides by elimination while sulfur anions of the same basicity react by substitution. This difference is due to a slowing down of elimination with the sulfur bases; sulfur anions show no increased nucleophilicity as compared to oxy anions of the same basicity. Rate coefficients have also been measured for reaction of methyl fluoride with HO- and CH3O- and ethylene oxide with HO-, CH3O-, and F-. All of these rates are slow but measurable; combining the results of these experiments with those of the alkyl chlorides and bromides suggests that the gas-phase barrier to the symmetrical SN2 reaction of F- with methyl fluoride is lower than previous estimates. We have also measured rates for reaction of allyl chloride with F-, H2NS-, and HS-, chloromethyl ether with H2NS- and HS-, chloroacetonitrile with F-, H2NS-, HS-, and 37Cl-, bromoacetonitrile with Cl- and 81Br-, and α-chloroacetone with H2NS-, HS-, and 37Cl-. Our results also imply that the gas-phase SN2 barrier for Br- reacting with methyl bromide is nearly equal to the ion-dipole attraction energy of the reactants, in agreement with previous estimates.
Quantum mechanical calculations at the MP2/TZ2P level of theory predict geometries and bond energies of donor-acceptor complexes of the Lewis acids BH3, BF3, BCl3, AlCl3, and SO2 which are in very good agreement with experimental gas-phase values. Strong donor-acceptor bonds are calculated for the boron complexes OC-BH3 (D-0(298) = 25.1 kcal/mol), H3N-BH3 (D-0(298)= 30.7 kcal/mol), Me(3)N-BH3 (D-0(298) = 41.1 kcal/mol), H3N-BF3 (D-0(298) = 22.0 kcal/mol), Me(3)N-BF3 (D-0(298) = 32.9 kcal/mol), H3N-BCl3 (D-0(298) = 29.7 kcal/mol), and Me(3)N-BCl3 (D-0(298) = 40.5 kcal/mol). Weakly bound van der Waals complexes are predicted for OC-BF3 (D-0(298) = 4.7 kcal/mol), HCN-BF3 (D-0(298) = 7.2 kcal/mol), MeCN-BF3 (D-0(298) = 9.1 kcal/mol), OC-BCl3 (D-0(298) = 4.0 kcal/mol), and MeCN-BCl3 (D-0(298) = 6.4 kcal/mol). Intermediate dissociation energies are calculated for the BF, complexes with Me(2)O (D-0(298) = 17.3 kcal/mol), benzaldehyde (D-0(298) = 13.0 kcal/mol), and 2-methylacrolein (D-0(298) = 12.8 kcal/mol). The strongest donor-acceptor bond is calculated for Me(3)N-AlCl3, (D-0(298) = 49.3 kcal/ mol). A strong bond is also predicted for EtCClO-AlCl3 (D-0(298) = 24.8 kcal/mol), while the complex Me(3)N-SO2 is more weakly bound (D-0(298) = 15.5 kcal/mol). The bond lengths of the Lewis acids are longer in the complexes than in the isolated molecules. A good correlation is found between the calculated bond strengths of the BF3 complexes and the lengthening of the B-F bond. The NBO partitioning scheme suggests that there is no correlation between the charge transfer and the bond strength. The topological analysis of the electron density distribution shows that the donor-acceptor bonds of the strongly bound boron complexes have significant covalent contributions, while the weakly bound boron complexes are characterized by electrostatic interactions between the Lewis acid and base. However, the nature of the strongly bound AlCl3 complexes is different from that of the strongly bound boron complexes. The strongest donor-acceptor bond calculated for Me(3)N-AlCl3 is characterized by electrostatic interactions and very little covalent contributions. The bond shortening of the donor acceptor bonds between the gas phase and the solid state is calculated to be mainly due to short-range dipole-dipole interactions. The geometry-optimized dimer and tetramer of H3N-BH3 and the dimer of H3N-BF3 have significantly shorter B-N bonds than the monomer.
The chemical potential equalization principle is used to define the fukui function of the kth atom in a molecule A with NA. electrons, fAk-= qAK(NA) - qAk(NA - 1), for electrophilic attack, and fAk+ = qAk(NA + 1) - qAk(NA), for nucleophilic attack, the softness of an atom in a molecule, S±Ak = S±Af±Ak, where SA. is the global softness, and the hardness of an atom in a molecule η±Ak = 1/S±Ak (qAk is the charge of the kth atom in the molecule). With these definitions it is shown that, in general, the reactive site of a molecule is located at the atom with the largest value of the fukui function (the softest atom), however, the interaction between two chemical species will not necessarily occur through their softest atoms, but rather through those whose fukui functions are approximately equal.
In the density-functional theory of the ground state of an electronic system there arise the concepts of softness, hardness, local softness, and local hardness. Definitions of these quantities are reviewed, and then local softness and local hardness are discussed in some detail. The local softness of a species, the derivative
, is a measure of the chemical reactivity of a site in the molecule. From it can be obtained the total global absolute softness in the sense of Pearson and a normalized chemical reactivity index of frontier type. Several formulas for s(r) are obtained, including new fluctuation formulas, and its determinative role in chemisorption, catalysis, and frontier-controlled charge-transfer processes is briefly discussed. Local hardness is a corresponding appropriately defined functional derivative η(r) = [δμ/δp(r)]v(r). Difficulties associated with ambiguities in this definition are discussed and resolved. It is concluded that for most purposes the best working formula for local hardness is
, where η(r, r′) is the hardness kernel;
, where F[p] is the usual Hohenberg-Kohn functional and f(r) is the Fukui function. With this definition, η(r) = η, a constant which is the global hardness. Just as the chemical potential equalizes in the ground state, so does the hardness. It is demonstrated that hardness can be taken to be an average of orbital contributions.
The N,N-dimethylmethyleneammonium ion 1 reacts regio- and stereoselectively with the 1,3-dienes 2a−2f to yield the 1,2,5,6-tetrahydropyridinium ions 3. The kinetics of these hetero Diels−Alder reactions, which have been followed by dilatometry and 1H-NMR spectroscopy, obey second-order rate laws. Since the observed rate constants are only 30−300 times larger than those calculated for the stepwise process by the linear free-enthalpy relationship lg k = s (E + N), it is concluded that these cycloadditions proceed in a stepwise manner or through pericyclic transition states that are not significantly stabilized by the concerted formation of two new σ-bonds. In contrast, the reaction of the iminium ion 1 with cyclopentadiene (2g) yields 2,2-dimethyl-2-azoniabicyclo[2.2.1]hept-5-ene (3g) 2×104 times more rapidly than predicted for the stepwise cycloaddition process, indicating a free enthalpy of concert of 27 kJ mol−1.
The selectivities of stabilized carbanions towards electron-deficient π-electron systems are nearly independent of their reactivities, as shown by the rate constants of the reactions of nine carbanions 2 with four quinone methides 1. These constant selectivity relationships may constitute the basis of a nucleophilicity scale for carbanions.
Rate constants for the reactions of the iminium ions Me2N+CH2 (1), iPr2N+CH2 (2), Ph(Me)N+CH2 (3), and Me2N+C(Cl)H (4) with nucleophiles were determined by 1H-NMR spectroscopy. By correlation, the electrophilicity parameters E(1) = −7.0, E(2) = −8.0, E(3) = −4.8, and E(4) = −5.8 were obtained, which allow to define scope and limitation of aminomethylations.
The paper reviews results from computational studies by molecular orbital and density functional theories on several series of hydrogen bonded complexes. These studies aim at quantifying the reactivity of molecules for the complexation process. Excellent linear relationships are found between the electrostatic potential values at the sites of the electron donor and electron accepting atoms and the energy of hydrogen bond formation (ΔE). The series studied are: (a) complexes of R–CHO and R–CN molecules with hydrogen fluoride; (b) complexes of mono-substituted acetylene derivatives with ammonia; (c) (HCN)n hydrogen bonded cluster for n=2–7. All 22 studied complexes of carbonyl and nitrile compounds with hydrogen fluoride fall in the same dependence between the energy of hydrogen bond formation and the electrostatic potential at the atomic site of the carbonyl oxygen and nitrile nitrogen atoms, with linear regression correlation coefficient r=0.979. In the case of complexes of mono-substituted acetylene and diacetylene derivatives with NH3, the correlation coefficient for the dependence between the electrostatic potential at the acidic hydrogen atom and ΔE equals 0.996. For the series of hydrogen bonded (HCN)n clusters, the correlation coefficient for the relationship between the electrostatic potential at the end nitrogen atom and ΔE is r=0.9996. Similarly, the analogous relationship with the electrostatic potential at the end hydrogen atom has a regression coefficient equal to 0.9994. The dependencies found are theoretically substantiated by applying the Morokuma energy decomposition scheme. The results show that the molecular electrostatic potential at atomic sites can be successfully used to predict the ability of molecules to form hydrogen bonds.
Prompted by a recent paper by Maynard and co-workers (Maynard, A. T.; Huang, M.; Rice, W. G.; Covel, D. G. Proc. Natl. Acad. Sci. U.S.A. 1998. 95, 11578), we propose that a specific property of a chemical species. the square of its electronegativity divided by its chemical hardness, be taken as defining its electrophilicity index. We tabulate this quantity for a number of atomic and molecular species, for two different models of the energy-electron number relationships, and we show that it measures the second-order energy change of an electrophile as it is saturated with electrons.
The H bonds in H2O–HF and H2O–HCl are studied and compared using abinitio molecular orbital methods and the results compared to experimental data. Basis sets used are: (i) triple valence 6-311G** and (ii) double &zgr; with two sets of polarization functions. Electron correlation, included via second- and third-order Mo&slash;ller–Plesset perturbation theory, is found to have profound effects on both systems, particularly H2O–HCl. Both H bonds are strengthened substantially with a concomitant reduction in length. H-bond energies and geometries calculated at correlated levels are in excellent accord with available experimental information. In both systems, all levels of theory indicate the equilibrium geometry contains a pyramidal arrangement about the oxygen atom. However, the difference in energy between this structure and a C2v planar arrangement is found to be small enough that consideration of probability amplitudes in the ground vibrational level leads to nearly equal likelihood of observing either geometry. Agreement between experimental vibrational frequencies in H2O–HF and those calculated at correlated levels and involving quadratic, cubic, and quartic force constants is quite good. An explanation is offered for the increase in HX bond length which occurs at SCF and correlated levels upon H-bond formation based upon nearly linear relationships between this length on one hand and subunit dipole moment and polarizability on the other. The dispersion energy is found to be a very sensitive, almost exactly linear function of the increase of H–X bond length. This energy contributes substantially to the weakening of the HX bond upon complexation.
Two classical tools, the intermolecular stretching force constants of H-bonded complexes and the molecular electrostatic potential are used to propose a nucleophilicity index evaluated for a series of pyridines. The model is validated against kinetic data recorded for the aminolysis of S-methyl 2,4-dinitrophenyl thiocarbonate.
Calculations of the electrostatic potentials were made around yeast elongator phenylalanine, aspartate tRNAs, and yeast initiator methionine tRNA in aqueous solution at physiological ionic strength. The calculations were carried out with a finite difference algorithm for solving the nonlinear Poisson-Boltzmann equation that incorporates the screening effects of the electrolyte, the exclusion of ions by the molecule, the molecular shape, and the different polarizabilities of the solvent and the tRNA. The initiator tRNA is surrounded by uniformly spaced contours of negative potential. The elongator tRNAs are also surrounded by a similar contour pattern except in the anticodon region where there is a pronounced "hole" in the potential surface. This hole is caused by an invagination of the potential contours, which also results in an increase in the local field strength. The effect of this hole is that the anticodon region in the elongator tRNAs is the least negative, or conversely the most positive, region of the molecule. This hole, which is not found when simple Coulombic potentials are used, is due both to the structure of the elongator tRNA anticodon loops and to the different polarizabilities of the solvent and tRNA. The existence of the potential hole in elongator tRNAs may account in part for their ability to associate with other negatively charged macromolecules, in particular mRNA. Moreover, it suggests that the anticodon loop of elongator tRNAs is the energetically most favorable point of approach of mRNA to tRNA.
The reaction of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein p7 (NCp7) with a variety of electrophilic agents was investigated by experimental measurements of Trp37 fluorescence decay and compared with theoretical measures of reactivity based on density-functional theory in the context of the hard and soft acids and bases principle. Statistically significant correlations were found between rates of reaction and the ability of these agents to function as soft electrophiles. Notably, the molecular property that correlated strongest was the ratio of electronegativity to hardness, chi2/eta, a quantity related to the capacity of an electrophile to promote a soft (covalent) reaction. Electronic and steric determinants of the reaction were also probed by Fukui function and frontier-orbital overlap analysis in combination with protein-ligand docking methods. This analysis identified selective ligand docking regions within the conserved zinc finger domains that promoted reaction. The Cys49 thiolate was found overall to be the NCp7 site most susceptible to electrophilic attack.
Twenty-three diarylcarbenium ions and 38 pi-systems (arenes, alkenes, allyl silanes and stannanes, silyl enol ethers, silyl ketene acetals, and enamines) have been defined as basis sets for establishing general reactivity scales for electrophiles and nucleophiles. The rate constants of 209 combinations of these benzhydrylium ions and pi-nucleophiles, 85 of which are first presented in this article, have been subjected to a correlation analysis to determine the electrophilicity parameters E and the nucleophilicity parameters N and s as defined by the equation log k(20 degrees C) = s(N + E) (Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957). Though the reactivity scales thus obtained cover more than 16 orders of magnitude, the individual rate constants are reproduced with a standard deviation of a factor of 1.19 (Table 1). It is shown that the reactivity parameters thus derived from the reactions of diarylcarbenium ions with pi-nucleophiles (Figure 3) are also suitable for characterizing the nucleophilic reactivities of alkynes, metal-pi-complexes, and hydride donors (Table 2) and for characterizing the electrophilic reactivities of heterosubstituted and metal-coordinated carbenium ions (Table 3). The reactivity parameters in Figure 3 are, therefore, recommended for the characterization of any new electrophiles and nucleophiles in the reactivity range covered. The linear correlation between the electrophilicity parameters E of benzhydryl cations and the corresponding substituent constants sigma(+) provides Hammett sigma(+) constants for 10 substituents from -1.19 to -2.11, i.e., in a range with only very few previous entries.
Molecular electrostatic potentials (MESP) surrounding the pi-region of several substituted ethylenes (CH(2)CHR) have been characterized by locating the most negative-valued point (V(min)) in that region. The substituents have been classified as electron donating and withdrawing on the basis of the increase or decrease in the negative character of V(min) in these systems as compared to ethylene. The values of V(min) show a good linear correlation with the Hammett sigma(p) constants, suggesting that the substituent electronic effects in substituted ethylenes and substituted benzenes are basically similar. With electron-donating substituents, the position of MESP minimum is closer to the unsubstituted carbon facilitating the pi-complex formation of it with HCl at this site. Such a regiospecific pi-complex formation is found to favor the formation of Markovnikov-type transition state for the addition of HCl to CH(2)CHR. For the electron-withdrawing substituents, the V(min) location is almost equidistant and farther from the ethylenic carbon atoms. This and the less negative V(min) values account for the less regiospecific CH(2)CHR...HCl pi-complexes as well as the transition states for the HCl addition to CH(2)CHR when R is an electron-withdrawing group. The interaction energy (E(int)) between CH(2)CHR and HCl for the formation of the CH(2)CHR...HCl pi-complex shows a good linear correlation with the corresponding V(min) value.
In the past 25 years, a tremendous amount of work has been published on the ion/molecule reactions of organic species. This review provides an overview of the areas where gas phase ion chemistry has made a contribution to our understanding of fundamental organic reaction processes. It is clear that the gas phase work can provide insights into subtle features of reaction mechanisms that could not be addressed by conventional condensed phase methods. The study of ion/molecule reactions has already had a major impact on the way that organic chemists think about reaction mechanisms and interpret substituent effects. Moreover, it has heightened our awareness of the importance of solvation effects and how they can alter not only absolute rates but also relative rates, leading in some cases to complete reversals in reactivity patterns. A large body of work could not be included in this review due to space limitations. For example, the study of thermochemistry in the gas phase (i.e., acidities, basicities, bond strengths, binding energies, etc.) has provided a wealth of data that has been exceptionally useful in interpreting organic reaction mechanisms. This has spilled over into the study of organometallic systems, and several groups are making major headway in using mass spectrometry to probe the stability and reactivity of transition metal species. Finally, work involving chemical ionization has provided abundant information on gas phase reaction mechanisms. The future appears to be very promising for the study of gas phase organic reaction mechanisms. In particular, the emergence of new ionization techniques and more powerful mass analyzers will allow chemists to explore a wider range of species. Although still at an early stage, the gas phase study of biochemical transformations offers great promise and has been facilitated by electrospray and matrix assisted laser desorption ionization methods. In addition, these techniques provide a means for introducing important, metal-centered catalytic species into the gas phase and exploring the details of their reactivity. Finally, mass spectrometry continues to play a major role in the study of atmospheric ion chemistry and is providing important kinetic as well as mechanistic data.