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 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.

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.

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).

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.

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.