Gutiérrez-Flores Jorge, H Huerta Eduardo, Cuevas Gabriel, Garza Jorge, Vargas Rubicelia
Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, Iztapalapa, C.P. 09340 Ciudad de México, México.
Insituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Alcaldía Coyoacán C.P. 04510 Ciudad de México, México.
J Org Chem. 2024 Jan 5;89(1):257-268. doi: 10.1021/acs.joc.3c02016. Epub 2023 Dec 15.
Tricyclic orthoamides are valuable molecules with wide-ranging applications, including organic synthesis and molecular recognition. Their structural properties make them intriguing, particularly the eclipsed all- conformer, which is typically less stable than the alternated conformation and is a rare phenomenon in organic chemistry. However, it gains stability in crystalline and hydrated settings, challenging the existing theoretical explanations. This study investigates which factors make eclipsed conformers more stable using experimentally reported anhydrous (ATO) and hydrated (HTO) crystal structures. Employing the quantum theory of atoms in molecules, noncovalent interaction index, and pairwise energy decomposition analysis, we delve into the noncovalent interaction environment surrounding the molecule of interest. In ATO, dispersive interactions dominate, whereas in HTO, both dispersive and electrostatic contributions are observed due to the presence of water molecules. Anchored to the lone pairs of the nitrogen atom in the orthoamide tricycle, water molecules prompt the methyl group's eclipsing through intermolecular and intramolecular interactions. This work resolves the long-standing conflict behind why tricyclic orthoamide has an eclipsed conformation by establishing the stabilization factors. These insights have implications for crystal engineering and design, enhancing our understanding of structural behavior in both crystalline and hydrated environments.
三环原酰胺是具有广泛应用的重要分子，包括有机合成和分子识别。它们的结构特性使其颇具吸引力，特别是重叠全构象，这种构象通常比交替构象更不稳定，在有机化学中是一种罕见现象。然而，它在晶体和水合环境中获得了稳定性，这对现有的理论解释提出了挑战。本研究利用实验报道的无水（ATO）和水合（HTO）晶体结构，研究了哪些因素使重叠构象更稳定。采用分子中的原子量子理论、非共价相互作用指数和成对能量分解分析，我们深入研究了目标分子周围的非共价相互作用环境。在ATO中，色散相互作用占主导，而在HTO中，由于水分子的存在，观察到色散和静电贡献。水分子锚定在原酰胺三环中氮原子的孤对上，通过分子间和分子内相互作用促使甲基重叠。这项工作通过确定稳定因素，解决了三环原酰胺为何具有重叠构象这一长期存在的矛盾。这些见解对晶体工程和设计具有启示意义，增进了我们对晶体和水合环境中结构行为的理解。
