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.

Paweł A Wieczorkiewicz,Halina Szatylowicz,Tadeusz M Krygowski

doi:10.3390/molecules26216543

Paweł A Wieczorkiewicz, Halina Szatylowicz + Show 1 more

Open Access

https://doi.org/10.3390/molecules26216543

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Abstract

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.

Highlights

The problem of substituent effects is mainly related to approaches that analyze their influence on the physical or chemical properties of the substituted systems
That energetic descriptor of global substituent effect (Erel) is a global descriptor of the substituent effect, i.e., it is calculated for the entire molecule
One of them corresponds to the ortho systems, while the second to other systems

Summary

Introduction

The problem of substituent effects is mainly related to approaches that analyze their influence on the physical or chemical properties of the substituted systems. This parameter evaluates the energetic effect of interactions between the substituent and the substituted system. ∆pEDA(X) and ∆sEDA(X) indicate changes in the pEDA(X) and sEDA(X) values of substituent X with respect to their values in substituted benzene (in the case of six-membered rings: pyridine, pyrimidine, pyrazine, triazine) or 2-X-naphthalene (for quinoline). It should be stressed, that Erel is a global descriptor of the substituent effect, i.e., it is calculated for the entire molecule. Analysis of RDG isosurfaces is frequently used [28,29] to visualize the non-covalent interactions between groups of atoms. For visualization of ESP maps and RDG isosurfaces, the VMD program was used [33]

Results and Discussion

Energetic Characteristics of Substituents

Conclusions