Effect of Substituents on the Intramolecular n→π* Interaction in 3‑[2-(Dimethylamino) phenyl] propanal: A Computational Study

n→π*
non-covalent interaction (NCI) and hydrogen bond
have similarity in terms of delocalization of the electron density
between the two orbitals involved in the interaction. Hydrogen bond
(X–H···Y) involves delocalization of the lone
pair electrons (n) on the Y atom into the σ* orbital of the
X–H bond. In contrast, the n→π* interaction deals
with delocalizing the lone pair electrons (n) on the N, O, or S atom
into the π* orbital of a CO group or aromatic ring.
Herein, we have shown a resemblance of this weak n→π*
interaction with the relatively stronger hydrogen bond in terms of
folding the side chains in flexible molecules. This work reports the
study of folding of the flexible side-chain in 3-[2-(dimethylamino)
phenyl] propanal (DMAPhP) through a N···CO
n→π*
interaction using various computational approaches such as NBO, QTAIM,
and NCI analyses. The folding of the molecule by the n→π*
interaction observed in this study is found to be similar to that
present in the secondary structures of peptides or proteins through
hydrogen bonding interactions. Interestingly, the stabilization of
the global minimum conformer of DMAPhP by the n→π* interaction
demonstrates the importance of this NCI in providing conformational
preferences in molecular systems. Another important finding of this
study is that the theoretical redshift obtained in the CO
stretching frequency of the most stable conformer of the DMAPhP is
contributed mostly by the n→π* interaction as the CO
group is not involved in hyperconjugation with any neighboring heteroatom,
which is a common phenomenon in any ester or amide. We have also demonstrated
here that the strength of the intramolecular n→π* interaction
can be modulated by varying the electronic substituents at the para
position of the donor group involved in the interaction.

n→π*相互作用与非共价相互作用（non-covalent interaction, NCI）及氢键在相互作用所涉及的两个轨道间的电子密度离域特性上具有相似性。氢键（X–H···Y）的本质是Y原子上的孤对电子（n）离域至X–H键的σ*轨道。与之相对，n→π*相互作用则是指N、O或S原子上的孤对电子（n）离域至CO基团或芳香环的π*轨道。本研究证实了这类弱n→π*相互作用与强度更高的氢键在柔性分子侧链折叠过程中存在相似性，本文针对3-[2-(二甲氨基)苯基]丙醛（3-[2-(dimethylamino)phenyl]propanal，DMAPhP）体系的柔性侧链折叠行为展开研究，通过自然键轨道（Natural Bond Orbital, NBO）、分子中原子量子拓扑理论（Quantum Theory of Atoms in Molecules, QTAIM）及非共价相互作用（NCI）分析等多种计算手段，探究了其中存在的N···CO型n→π*相互作用。本研究观测到，由n→π*相互作用诱导的分子折叠现象，与肽或蛋白质二级结构中由氢键相互作用介导的折叠过程高度相似。值得注意的是，n→π*相互作用对DMAPhP全局最低能量构象的稳定作用，彰显了该类非共价相互作用在赋予分子体系构象偏好性方面的重要价值。本研究另一项关键发现为：DMAPhP最稳定构象的CO伸缩振动频率出现理论红移，其主要贡献源于n→π*相互作用——由于该CO基团未与相邻杂原子发生超共轭作用，这一现象与酯或酰胺中的常见情况截然不同。此外，本研究还证实，通过改变参与相互作用的给体基团对位的电子取代基，可以对分子内n→π*相互作用的强度进行调控。