Wieczorkiewicz Paweł A, Krygowski Tadeusz M, Szatylowicz Halina
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.
Phys Chem Chem Phys. 2024 Jul 17;26(28):19398-19410. doi: 10.1039/d4cp01709a.
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 = NO, CN, Br, Cl, F, SH, OH, NH). 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 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-) 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.
五元氮杂环是许多在化学、生物化学或药物化学等各个领域具有至关重要意义的化合物的主要成分。因此，明确确定决定连接在杂环部分上特定基团的给电子/吸电子性质的结构因素，以及阐明取代诱导的环状和非环状电子离域变化，变得极为必要。因此，对吡咯、咪唑、吡唑、1,2,3 - 和1,2,4 - 三唑及其碳取代的单衍生物（X = NO、CN、Br、Cl、F、SH、OH、NH）进行了量子化学计算。所获得的数据集包含有关取代基性质（cSAR - 取代基活性区域电荷法）、离域（EDDB - 离域键的电子密度）和几何结构的信息。可以看出，环内氮原子相对于取代基的位置对其性质有着最深远的影响。特定位置的氮原子通过诱导作用显著增强给电子能力并减弱吸电子能力。另一个因素是从取代基到氮原子的共振电荷转移，然后与其他（非）氮原子进行诱导相互作用。虽然取代基常数正确地描述了它们性质的变化（包括连接到杂环上的那些），这证明了哈米特的卓越才能，但必须使用量子化学模型来量化确切的性质。在大多数杂环中，给电子取代基会阻碍环状离域，4 - 吡唑除外。所应用的最新EDDB方法能够详细研究这一现象。可以看出，芳香性的变化源于取代基对环键的π电子效应，以相关方式改变特定键的定位和离域。
