Unraveling the Push-Pull Effect in Acenes, Polyenes and Polyynes.

Substituent effects (SEs) are fundamental for predicting molecular reactivity, while polyene, polyyne and acene derivatives are precursors to compounds with diverse applications. Computations were performed for Y-R-X systems, where reaction sites Y=NO2 and O- , substituents X=NO2 , CN, Cl, H, OH, NH2 , and spacers R=polyene, polyyne (n=1-5, 10 repeating units) and acene (up to tetracene). The cSAR (charge of the substituent active region) approach allowed to present, for the first time, quantitative relations describing the spacer's electron-donating and withdrawing properties as a function of n and the spacer type. The electronic properties of the X substituents depend on the type of spacer, its length and the Y group, which is an example of the reverse SE. To describe how the SE between Y and X weakens with n, two approaches were compared: cSAR and SESE (SE stabilization energy). The EDDB (electron density of delocalized bonds) characterize changes in electron delocalization in spacers due to the SE. A new approach - EDDB differential maps - allow to extract the effect of X substitution on the electron delocalization. The charges at spacer's C atoms correlate with cSAR; changes in the slopes confirm the charge transfer by resonance.

Substituent effects and electron delocalization in five-membered N-heterocycles.

Five-membered N-heterocycles are principal constituents of many compounds of vital importance in various fields of chemistry, biochemistry or pharmaceutical chemistry. For this reason, unequivocal identification of structural factors determining electron donating/withdrawing properties of specific groups attached to the heterocyclic moiety becomes an utmost need together with elucidation of the substitution-induced changes in cyclic and noncyclic electron delocalization. Thus, quantum-chemical calculations were performed for pyrrole, imidazole, pyrazole, 1,2,3- and 1,2,4-triazole, and their C-substituted mono-derivatives (X = NO2, CN, Br, Cl, F, SH, OH, NH2). The obtained dataset contains information on substituent properties (cSAR - charge of the substituent active region method), delocalization (EDDB - electron density of delocalized bonds) and geometry. It follows that the positions of endocyclic N atoms relative to the substituent influence in the most profound manner its properties. N atoms in ortho positions significantly boost the electron-donation and weaken the electron-withdrawal by induction. Another factor is the resonance charge transfer from the substituents to N atoms, and then inductive interactions with further (non-ortho) N atoms. While substituent constants correctly describe the changes of their properties (including those attached to the heterocycles), a testimony to Hammett's genius, quantum chemical models must be used to quantify the exact properties. In most heterocycles, electron-donating substituents hinder the cyclic delocalization, except 4-pyrazole. The applied recent EDDB method allows to study this phenomenon in detail. It follows that changes in aromaticity originate from the π-electronic effects of substituents on the ring bonds, changing the localization and delocalization of particular bonds in a correlated manner.

Substituent Effects from the Point of View of Energetics and Molecular Geometry in Acene, Polyene, and Polyyne Derivatives.

The substituent effect (SE) is one of the most important topics in organic chemistry and related fields, and Hammett constants (σ) are commonly used to describe it. The results of the computational studies carried out for Y-R-X systems (reaction sites Y = NO2, O-; substituents X = NO2, CN, Cl, H, OH, NH2; spacers R = polyene, polyyne, acene with n = 1-5 repeatable units) show that the substituent properties depend significantly on n, the type of R, and Y. Results of the analysis of the substituent effect stabilization energy and geometrical parameters of the Y-R-X systems reveal that (i) the SE strength and its inductive and resonance components decay with the increase in spacer length, its weakening depends on the Y and R type; quantitative relations describing decay are presented; (ii) the ratio between inductive and resonance effect strength changes with n and depends on Y; (iii) differences in the substituents' properties are examples of reverse SE; (iv) in general, structural parameters are mutually well correlated as well as with the SE descriptors; (v) due to the strong O- resonance effect, the changes in π-electron delocalization within R are well correlated with the SE strength only for Y = O- systems.

Substituent Effect versus Aromaticity─A Curious Case of Fulvene Derivatives.

A computational study on amino- and nitro-substituted penta- and heptafulvenes reveals the interplay between the aromaticity and the substituent effect (SE). Ring substitution alone has little influence on the aromaticity, but in combination with an exo substituent of opposite properties, it substantially enhances the cyclic π-electron delocalization. Despite the SE being stronger for ß substitution, only γ substitution leads to higher aromaticity. An explanation is provided by the electron density of delocalized bonds (EDDB) method, which proves to be a valuable tool in analyzing both cyclic delocalization and the SE.

Influence of the Solvent on the Stability of Aminopurine Tautomers and Properties of the Amino Group.

Amino derivatives of purine (2-, 6-, 8-, and N-NH2) have found many applications in biochemistry. This paper presents the results of a systematic computational study of the substituent and solvent effects in these systems. The issues considered are the electron-donating properties of NH2, its geometry, π-electron delocalization in purine rings and tautomeric stability. Calculations were performed in ten environments, with 1 < ε < 109, using the polarizable continuum model of solvation. Electron-donating properties were quantitatively described by cSAR (charge of the substituent active region) parameter and π-electron delocalization by using the HOMA (harmonic oscillator model of aromaticity) index. In aminopurines, NH2 proximity interactions depend on its position and the tautomer. The results show that they are the main factor determining how solvation affects the electron-donating strength and geometry of NH2. Proximity with the NH∙∙∙HN repulsive interaction between the NH2 and endocyclic NH group results in stronger solvent effects than the proximity with two attractive NH∙∙∙N interactions. The effect of amino and nitro (previously studied) substitution on aromaticity was compared; these two groups have, in most cases, the opposite effect, with the largest being in N1H and N3H purine tautomers. The amino group has a smaller effect on the tautomeric preferences of purine than the nitro group. Only in 8-aminopurine do tautomeric preferences change: N7H is more stable than N9H in H2O.

Intramolecular Interactions in Derivatives of Uracil Tautomers.

The influence of solvents on intramolecular interactions in 5- or 6-substituted nitro and amino derivatives of six tautomeric forms of uracil was investigated. For this purpose, the density functional theory (B97-D3/aug-cc-pVDZ) calculations were performed in ten environments (1 > ε > 109) using the polarizable continuum model (PCM) of solvation. The substituents were characterized by electronic (charge of the substituent active region, cSAR) and geometric parameters. Intramolecular interactions between non-covalently bonded atoms were investigated using the theory of atoms in molecules (AIM) and the non-covalent interaction index (NCI) method, which allowed discussion of possible interactions between the substituents and N/NH endocyclic as well as =O/−OH exocyclic groups. The nitro group was more electron-withdrawing in the 5 than in the 6 position, while the opposite effect was observed in the case of electron donation of the amino group. These properties of both groups were enhanced in polar solvents; the enhancement depended on the ortho interactions. Substitution or solvation did not change tautomeric preferences of uracil significantly. However, the formation of a strong NO∙∙∙HO intramolecular hydrogen bond in the 5-NO2 derivative stabilized the dienol tautomer from +17.9 (unsubstituted) to +5.4 kcal/mol (substituted, energy relative to the most stable diketo tautomer).

Dependence of the substituent energy on the level of theory.

Most often, the substituent effects are described using rather troublesome Hammett constants. Quite recently, it has been proposed to use the so-called substituent energy, which is based on total energies of the X-substituted polycyclic aromatic hydrocarbon and phenyl. This article concerns the influence of the applied level of theory (i.e., both the basis set and the method) on the determined values of the substituent energies. For this purpose, the energies of the NH2 and NO2 groups in 16 unique positions of naphthalene, anthracene, tetracene, phenanthrene, and pyrene were calculated using 10 different basis sets and 23 various exchange-correlation functionals representing the entire Jacob's Ladder, from local, through gradient- and meta-gradient-corrected, to hybrid and double-hybrid ones. Additionally, using even larger 6-311++G(2df,2p) basis set, the energies of NH2 , NO2 , CN, and Cl were also computed. Both the basis set and the method used have little effect on the substituent energy if the substituent is in the benzene-like position. On the contrary, the effect of the level of theory is pronounced especially in the case of the most spatially crowded 4-substituted phenanthrene. Substituent energies have been shown to be very useful theoretical parameters describing the proximity effect in the substituted derivatives of polycyclic aromatic hydrocarbons.

Energetic and Geometric Characteristics of the Substituents: Part 2: The Case of NO2, Cl, and NH2 Groups in Their Mono-Substituted Derivatives of Simple Nitrogen Heterocycles.

Variously substituted N-heterocyclic compounds are widespread across bio- and medicinal chemistry. The work aims to computationally evaluate the influence of the type of N-heterocyclic compound and the substitution position on the properties of three model substituents: NO2, Cl, and NH2. For this reason, the energetic descriptor of global substituent effect (Erel), geometry of substituents, and electronic descriptors (cSAR, pEDA, sEDA) are considered, and interdependences between these characteristics are discussed. Furthermore, the existence of an endocyclic N atom may induce proximity effects specific for a given substituent. Therefore, various quantum chemistry methods are used to assess them: the quantum theory of atoms in molecules (QTAIM), analysis of non-covalent interactions using reduced density gradient (RDG) function, and electrostatic potential maps (ESP). The study shows that the energetic effect associated with the substitution is highly dependent on the number and position of N atoms in the heterocyclic ring. Moreover, this effect due to interaction with more than one endo N atom (e.g., in pyrimidines) can be assessed with reasonable accuracy by adding the effects calculated for interactions with one endo N atom in substituted pyridines. Finally, all possible cases of proximity interactions for the NO2, Cl, and NH2 groups are thoroughly discussed.

Changes in Electron Structure of the Triple Bond in Substituted Acetylene and Diacetylene Derivatives.

The substituent effect is usually considered by means of various Hammett-like substituent constants and is most often related to aromatic systems. Unlike this, we present results of our research on the influence of 27 substituents spanning a wide range of electronic properties, from strongly electron-withdrawing to strongly electron-donating, on the electron structure of X-substituted acetylenes and diacetylenes - thus the systems which until now have practically not been subject of any deeper studies. It is shown that the interaction through triple bond(s) is associated with a significant advantage of resonance effects and that the substituent effect transmitted by the C≡C-C≡C unit is about half of that transmitted by the C≡C unit alone. Substituent X mainly affects the closest carbon atom by means of proximity effect, hence changes of charge on this atom do not follow any substituent constants. The effect on further carbon atoms is much smaller. The presence of the C≡C-C≡C unit withdraws more charge from X than a triple bond alone, and hinders communication between X and the terminal H atom. Comparison of substituent effects to those present in X-substituted benzene derivatives shows that the electronic properties of the terminal hydrogen atom in acetylenes and diacetylenes are most similar to the electronic properties of ortho and para hydrogen atoms in X-substituted benzene derivatives.

Mutual Relations between Substituent Effect, Hydrogen Bonding, and Aromaticity in Adenine-Uracil and Adenine-Adenine Base Pairs.

The electronic structure of substituted molecules is governed, to a significant extent, by the substituent effect (SE). In this paper, SEs in selected nucleic acid base pairs (Watson-Crick, Hoogsteen, adenine-adenine) are analyzed, with special emphasis on their influence on intramolecular interactions, aromaticity, and base pair hydrogen bonding. Quantum chemistry methods-DFT calculations, the natural bond orbital (NBO) approach, the Harmonic Oscillator Model of Aromaticity (HOMA) index, the charge of the substituent active region (cSAR) model, and the quantum theory of atoms in molecules (QTAIM)-are used to compare SEs acting on adenine moiety and H-bonds from various substitution positions. Comparisons of classical SEs in adenine with those observed in para- and meta-substituted benzenes allow for the better interpretation of the obtained results. Hydrogen bond stability and its other characteristics (e.g., covalency) can be significantly changed as a result of the SE, and its consequences are dependent on the substitution position. These changes allow us to investigate specific relations between H-bond parameters, leading to conclusions concerning the nature of hydrogen bonding in adenine dimers-e.g., H-bonds formed by five-membered ring nitrogen acceptor atoms have an inferior, less pronounced covalent nature as compared to those formed by six-membered ring nitrogen. The energies of individual H-bonds (obtained by the NBO method) are analyzed and compared to those predicted by the Espinosa-Molins-Lecomte (EML) model. Moreover, both SE and H-bonds can significantly affect the aromaticity of adenine rings; long-distance SEs on π-electron delocalization are also documented.

Aromaticity of acenes: the model of migrating π-circuits.

In this work we extend the concept of migrating Clar's sextets to explain local aromaticity trends in linear acenes predicted by theoretical calculations and experimental data. To assess the link between resonance and reactivity and to rationalize the constant-height AFM image of pentacene we used the electron density of delocalized bonds and other functions of the one-electron density from conceptual density functional theory. The presented results provide evidence for migration of Clar's π-sextets and larger circuits in these systems, and clearly show that the link between the theoretical concept of aromaticity and the real electronic structure entails the separation of intra- and inter-ring resonance effects, which in the case of [n]acenes (n = 3, 4, 5) comes down to solving a system of simple linear equations.

Dependence of the Substituent Effect on Solvent Properties.

The influence of a solvent on the substituent effect (SE) in 1,4-disubstituted derivatives of benzene (BEN), cyclohexa-1,3-diene (CHD), and bicyclo[2.2.2]octane (BCO) is studied by the use of polarizable continuum model method. In all X-R-Y systems for the functional group Y (NO2, COOH, OH, and NH2), the following substituents X have been chosen: NO2, CHO, H, OH, and NH2. The substituent effect is characterized by the charge of the substituent active region (cSAR(X)), substituent effect stabilization energy (SESE), and substituent constants σ or F descriptors, the functional groups by cSAR(Y), whereas π-electron delocalization of transmitting moieties (BEN and CHD) is characterized by a geometry-based index, harmonic oscillator model of aromaticity. All computations were carried out by means of B3LYP/6-311++G(d,p) method. An application of quantum chemistry SE models (cSAR and SESE) allows to compare the SE in water solutions and in the gas phase. Results of performed analyses indicate an enhancement of the SE by water. The obtained Hammett-type relationships document different nature of interactions between Y and X in aromatic and olefinic systems (a coexistence of resonance and inductive effects) than in saturated ones (only the inductive effect). An increase of electric permittivity clearly enhances communications between X and Y for BEN and CHD systems.

The role of the long-range exchange corrections in the description of electron delocalization in aromatic species.

In this article, we address the role of the long-range exchange corrections in description of the cyclic delocalization of electrons in aromatic systems at the density functional theory level. A test set of diversified monocyclic and polycyclic aromatics is used in benchmark calculations involving various exchange-correlation functionals. A special emphasis is given to the problem of local aromaticity in acenes, which has been a subject of long-standing debate in the literature. The presented results indicate that the noncorrected exchange-correlation functionals significantly overestimate cyclic delocalization of electrons in heteroaromatics and aromatic systems with fused rings, which in the case of acenes leads to conflicting local aromaticity predictions from different criteria. © 2017 Wiley Periodicals, Inc.

The electron density of delocalized bonds (EDDB) applied for quantifying aromaticity.

In this study the recently developed electron density of delocalized bonds (EDDB) is used to define a new measure of aromaticity in molecular rings. The relationships between bond-length alternation, electron delocalization and diatropicity of the induced ring current are investigated for a test set of representative molecular rings by means of correlation and principal component analyses involving the most popular aromaticity descriptors based on structural, electronic, and magnetic criteria. Additionally, a qualitative comparison is made between EDDB and the magnetically induced ring-current density maps from the ipsocentric approach for a series of linear acenes. Special emphasis is given to the comparative study of the description of cyclic delocalization of electrons in a wide range of organic aromatics in terms of the kekulean multicenter index KMCI and the newly proposed EDDBk index.

Substituent Effect on the σ- and π-Electron Structure of the Nitro Group and the Ring in Meta- and Para-Substituted Nitrobenzenes.

An application of quantum chemical modeling allowed us to investigate a substituent effect on a σ and π electron structure of a ring and the nitro group in a series of meta- and para-X-substituted nitrobenzene derivatives (X = NMe2, NHMe, NH2, OH, OMe, Me, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, and NO). The obtained pEDA and sEDA parameters (the π- and σ-electron structure characteristics of a given planar fragment of the system obtained by the summation of π- and σ-orbital occupancies, respectively) of the NO2 group and the benzene ring allowed us to reveal the impact of the substituents on their mutual relations as well as to analyze them from the viewpoint of substituent characteristics. The decisive factor for dependence of pEDA on sEDA of the ring is electronegativity of the atom linking the substituent with the ring; in subgroups an increase of sEDA is associated with a decrease of pEDA. The obtained mutual relation between pEDA(NO2) and pEDA(ring) characteristics documents strong resonance interactions for electron-donating substituents in the para position. The observed substituent effect on the σ-electron structure of the nitro group, sEDA(NO2), is significantly greater (∼1.6 times) for meta derivatives than for the para ones.

Towards physical interpretation of substituent effects: the case of meta- and para-substituted anilines.

Quantum chemical modeling was used to investigate the electron-donating properties of the amino group in a series of meta- and para-X-substituted anilines (X = NMe2, NH2, OH, OMe, CH3, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, and NO). Different methods (HF, B3LYP, and M06-2X) and basis sets (6-31+G(d,p), 6-311++G(d,p), and aug-cc-pVDZ) were applied and compared with the MP2 approach. The B3LYP/6-311++G(d,p) method was chosen as the most appropriate one. The substituent properties were described by σ, cSAR(X) and SESE descriptors; the amino group was characterized by structural (dCN, dNH and ΣNH2) and electronic [δ(N) and cSAR(NH2)] parameters; whereas the transmitting moiety was characterized by aromaticity indices HOMA and NICS, as well as by QTAIM characteristics at the ring critical point. All the used parameters were found to be mutually interrelated with much better correlations for the para-derivatives than the meta-derivatives. It was numerically confirmed that sensitivity of the amino group to the substituent effect was greater by over three times when the substituent was located in the para-position. In the case of the meta-derivatives, variability of characteristics for both the reaction center and the substituent was small. The reverse substituent effect was clearly shown by comparison of the cSAR(X) characteristics for monosubstituted benzenes, and meta- and para-substituted anilines.

Toward a physical interpretation of substituent effects: the case of fluorine and trifluoromethyl groups.

The application of ab initio and DFT computational methods at six different levels of theory (MP2/cc-pVDZ, MP2/aug-cc-pVTZ, B3LYP/cc-pVDZ, B3LYP/aug-cc-pVTZ, M06/cc-pVDZ, and M06/aug-cc-pVTZ) to meta- and para-substituted fluoro- and trifluoromethylbenzene derivatives and to 1-fluoro- and 1-trifluoromethyl-2-substituted trans-ethenes allowed the study of changes in the electronic and geometric properties of F- and CF3-substituted systems under the impact of other substituents (BeH, BF2, BH2, Br, CFO, CHO, Cl, CN, F, Li, NH2, NMe2, NO, NO2, OH, H, CF3, and CH3). Various parameters of these systems have been investigated, including homodesmotic reactions in terms of the substituent effect stabilization energy (SESE), the π and σ electron donor-acceptor indexes (pEDA and sEDA, respectively), the charge on the substituent active region (cSAR, known earlier as qSAR), and bond lengths, which have been regressed against Hammett constants, resulting mostly in an accurate correspondence except in the case of p-fluorobenzene derivatives. Moreover, changes in the characteristics of the ability of the substituent to attract or donate electrons under the impact of the kind of moiety to which the substituent is attached have been considered as the indirect substituent effect and investigated by means of the cSAR model. Regressions of cSAR(X) versus cSAR(Y) for any systems X and Y allow final results to be obtained on the same scale of magnitude.

Tautomerisation of thymine acts against the Hückel 4N + 2 rule. The effect of metal ions and H-bond complexations on the electronic structure of thymine.

The stability and aromaticity of thirteen known thymine tautomers were studied in the gas phase at the B3LYP/6-311++G(2d,2p) computational level. It was found that they do not follow the Hückel 4N + 2 rule when the energetic criterion is considered, but they follow it when aromaticity indices, such as NICS, HOMA and the sum of the Wiberg bond indices, are applied. It was shown that the stability of a given tautomer is strongly dependent on the number of C[double bond, length as m-dash]O groups attached to the ring. The most stable tautomer i.e. with two carbonyl groups exhibits low π-electron delocalization (HOMA = 0.490, NICS(0) = -1.5). Its stability results from specific interactions between N(δ-)H(δ+) and C(δ+)O(δ-) bond dipoles. A qualitative rule, which implies an increase in stability and a loss of aromaticity with increasing number of C[double bond, length as m-dash]O groups, holds in the case of thymine tautomers. Effects of intermolecular interactions (H-bonding and metal ion complexation) on the geometry and π-electron structure were analyzed for the five most stable tautomers with the following partners: HF/F(-) and Li(+)/Na(+)/K(+). The magnitude of these effects strongly depends on the site and type of intermolecular interaction. The electronic structure of the most aromatic tautomers is more weakly influenced by external perturbations such as H-bonding and is almost entirely resistant to metal complexation.

Effect of H-bonding and complexation with metal ions on the π-electron structure of adenine tautomers.

Influence of H-bonding and interactions with metals via complexation (probed by HF, F(-), Li(+) and Na(+)) on structural and π-electronic changes in four of the most stable amino adenine tautomers has been studied in the gas phase using the B3LYP/6-311++G(2d,2p) computational level. It has been found that the presence of the amino group in adenine increases its energetic sensitivity to structural changes caused by tautomeric effects as compared to its analogue deprived of this group (purine). Furthermore, its shape depends not only on tautomerism but also on intermolecular interactions. The observed variability of its pyramidalizations caused by H-bonding indicates the dramatic changes of electron donating/accepting properties of -NH2 as a substituent, which results in a variation of aromaticity of particular rings in adenine tautomers. Bifurcated coordination of metal cations by two nitrogen atoms of adenine is also an important factor influencing aromaticity. The overall range of H-bond strengths is between -4.64 and -26.39 kcal mol(-1), whereas energies for Li(+) and Na(+) complexes are in the ranges -41.45 to -67.50 and -25.04 to -51.39 kcal mol(-1), respectively. However, the highest aromaticity changes, expressed by the HOMA index, have been found to be about 24% of the HOMA scale for all types of complexes depending on the location of the intermolecular interaction.

Complexes of 4-substituted phenolates with HF and HCN: energy decomposition and electronic structure analyses of hydrogen bonding.

We have computationally studied para-X-substituted phenols and phenolates (X = NO, NO(2), CHO, COMe, COOH, CONH(2), Cl, F, H, Me, OMe, and OH) and their hydrogen-bonded complexes with B(-) and HB (B = F and CN), respectively, at B3LYP/6-311++G** and BLYP-D/QZ4P levels of theory. Our purpose is to explore the structures and stabilities of these complexes. Moreover, to understand the emerging trends, we have analyzed the bonding mechanisms using the natural bond orbital scheme as well as Kohn-Sham molecular orbital (MO) theory in combination with quantitative energy decomposition analyses [energy decomposition analysis (EDA), extended transition state-natural orbitals for chemical valence (ETS-NOCV)]. These quantitative analyses allow for the construction of a simple physical model that explains all computational observations.