Comprehensive Experimental Study of N<i>-</i>Heterocyclic π‑Stacking Interactions of Neutral and Cationic Pyridines

A comprehensive experimental study was carried out by measuring the relative strengths of parallel π-stacking interactions of N-heterocycles with nonheterocycles. A versatile and rigid model system was developed, which was in equilibrium between a “closed” conformation that forms an intramolecular π-stacking interaction and an “open” conformation that cannot form the interaction. First, the formation and geometries of the intramolecular N-heterocyclic π-stacking interactions were verified by X-ray crystallography. Next, the closed/open ratios were measured in solution via integration of the 1H NMR spectra, providing an accurate comparison of the N-heterocyclic π-stacking interactions. The synthetic versatility of this model system enabled the systematic and comprehensive comparison of the influences of position, charge, and substituent effects of the nitrogen atom of the N-heterocycles within a single model system. The π-stacking interactions of the neutral N-heterocyclic rings were slightly stronger than that of nonheterocyclic rings. Cationic N-heterocycles formed significantly stronger π-stacking interactions than neutral N-heterocycles. The position of the nitrogen atom also had a strong influence on the stability of N-heterocyclic π-stacking complexes. Interestingly, opposite stability trends were observed for neutral and cationic N-heterocycles. For neural N-heterocycles, geometries with the nitrogen away from the π-face of the opposing ring were the more stable. For cationic N-heterocycles, geometries with the nitrogen close to the π-face of the opposing ring were the more stable. Finally, N-methylated heterocycles consistently formed stronger π-stacking interactions than N-protonated heterocycles.本研究围绕氮杂环与非杂环的平行π堆积（π-stacking）相互作用相对强度开展了一项全面的实验探究。研究构建了一种通用且刚性的模型体系，该体系可在形成分子内π堆积相互作用的"闭合"构象与无法形成该相互作用的"开放"构象之间达成动态平衡。首先，通过X射线晶体学验证了分子内氮杂环π堆积相互作用的形成过程与几何构型。随后，通过对溶液中1H核磁共振（1H NMR）谱图进行积分，测定了闭合/开放构象的比例，以此实现氮杂环π堆积相互作用的精准对比。该模型体系具备良好的合成通用性，使得我们能够在单一模型体系内，系统且全面地对比氮杂环上氮原子的位置、电荷及取代基效应所带来的影响。中性氮杂环的π堆积相互作用略强于非杂环体系。带正电的氮杂环所形成的π堆积相互作用则显著强于中性氮杂环。氮原子的取代位置同样对氮杂环π堆积复合物的稳定性具有显著影响。值得注意的是，中性与带正电氮杂环的稳定性变化趋势恰好相反：对于中性氮杂环而言，氮原子远离对面芳环π面的几何构型更为稳定；而对于带正电的氮杂环，氮原子靠近对面芳环π面的几何构型则更稳定。最后，N-甲基化杂环所形成的π堆积相互作用始终强于N-质子化杂环。