Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Molecules. 2021 Oct 29;26(21):6543. doi: 10.3390/molecules26216543.
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: NO, Cl, and NH. For this reason, the energetic descriptor of global substituent effect (), 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 NO, Cl, and NH groups are thoroughly discussed.
各种取代的 N-杂环化合物在生物和药物化学中广泛存在。本工作旨在通过计算评估 N-杂环化合物的类型和取代位置对三种模型取代基（NO、Cl 和 NH）性质的影响。为此，考虑了全局取代基效应的能量描述符（）、取代基的几何形状以及电子描述符（cSAR、pEDA、sEDA），并讨论了这些特性之间的相关性。此外，环内 N 原子的存在可能会引起特定取代基的近程效应。因此，使用各种量子化学方法来评估它们：原子在分子中的量子理论（QTAIM）、使用约化密度梯度（RDG）函数分析非共价相互作用以及静电势图（ESP）。研究表明，与取代相关的能量效应高度依赖于杂环中 N 原子的数量和位置。此外，对于与一个以上的内 N 原子（例如嘧啶中的）相互作用的这种效应，可以通过添加对于取代吡啶中与一个内 N 原子相互作用计算的效应，以合理的精度来评估。最后，彻底讨论了 NO、Cl 和 NH 基团的所有可能的近程相互作用情况。
