Chen Liang-Yu, Chaudhury Udayan, Wei Shengkai, Li Junqi
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States.
J Org Chem. 2025 Jan 10;90(1):374-384. doi: 10.1021/acs.joc.4c02295. Epub 2024 Dec 17.
Understanding how changes in structure translate to changes in molecular shape is key to catalyst optimization and molecular design in medicinal chemistry and materials. One key contributor to the molecular shape is the relative orientation of substituents on a scaffold. Macrocyclic metacyclophanes display their two arenes in a parallel or antiparallel fashion, resulting in or conformations that lead to disparate relative orientations of the aryl substituents. This work reports the synthesis of new 14- and 16-membered metacyclophanes and the elucidation of their / preferences by H NMR and computational conformational analysis. Most metacyclophanes studied herein display a strong or preference and, thus, have well-defined substituent orientations. We propose that / conformational preferences arise from the minimization of torsional strain along the backbone of the macrocycle, which leads to the prediction that metacyclophanes with remote aryl substituents will adopt the same conformation as their unsubstituted counterparts. Exit vector analysis also reveals that -metacyclophanes project their substituents into regions in three-dimensional space that are not accessed by other common large scaffolds, e.g., [2.2]paracyclophanes and ferrocenes. This work also demonstrates how ring size and functional groups, two parameters commonly optimized in macrocycle design, can be used to tune molecular shape.
理解结构变化如何转化为分子形状变化是药物化学和材料领域中催化剂优化及分子设计的关键。分子形状的一个关键因素是支架上取代基的相对取向。大环间环芳烷以平行或反平行方式展示其两个芳环，从而产生 或 构象，导致芳基取代基的相对取向不同。本文报道了新型14元和16元间环芳烷的合成，以及通过核磁共振氢谱和计算构象分析对其 / 偏好的阐明。本文研究的大多数间环芳烷表现出强烈的 或 偏好，因此具有明确的取代基取向。我们认为 / 构象偏好源于大环主链上扭转应变的最小化，这导致预测带有远程芳基取代基的间环芳烷将采用与其未取代对应物相同的构象。出射向量分析还表明， -间环芳烷将其取代基投射到三维空间中其他常见大支架（如[2.2]对环芳烷和二茂铁）无法进入的区域。这项工作还展示了环大小和官能团这两个在大环设计中通常优化的参数如何用于调节分子形状。
