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.
Keywords: heterocyclic compounds; pyridine; substituent effect; substituent energy.