Substituent Effects on the Self-Assembly/Coassembly and Hydrogelation of Phenylalanine Derivatives

Supramolecular hydrogels derived from the self-assembly of organic molecules have been exploited for applications ranging from drug delivery to tissue engineering. The relationship between the structure of the assembly motif and the emergent properties of the resulting materials is often poorly understood, impeding rational approaches for the creation of next-generation materials. Aromatic π–π interactions play a significant role in the self-assembly of many supramolecular hydrogelators, but the exact nature of these interactions lacks definition. Conventional models that describe π–π interactions rely on quadrupolar electrostatic interactions between neighboring aryl groups in the π-system. However, recent experimental and computational studies reveal the potential importance of local dipolar interactions between elements of neighboring aromatic rings in stabilizing π–π interactions. Herein, we examine the nature of π–π interactions in the self- and coassembly of Fmoc-Phe-derived hydrogelators by systematically varying the electron-donating or electron-withdrawing nature of the side chain benzyl substituents and correlating these effects to the emergent assembly and gelation properties of the systems. These studies indicate a significant role for stabilizing dipolar interactions between neighboring benzyl groups in the assembled materials. Additional evidence for specific dipolar interactions is provided by high-resolution crystal structures obtained from dynamic transition of gel fibrils to crystals for several of the self-assembled/coassembled Fmoc-Phe derivatives. In addition to electronic effects, steric properties also have a significant effect on the interaction between neighboring benzyl groups in these assembled systems. These findings provide significant insight into the structure–function relationship for Fmoc-Phe-derived hydrogelators and give cues for the design of next-generation materials with desired emergent properties.由有机分子自组装得到的超分子水凝胶已被应用于从药物递送到组织工程等诸多领域。然而，组装基元的结构与所得材料的涌现性质之间的关联往往尚不明确，这阻碍了下一代先进材料的理性开发路径。芳香π-π相互作用在诸多超分子水凝胶因子的自组装过程中发挥着重要作用，但这类相互作用的确切本质仍有待清晰界定。传统描述π-π相互作用的模型多基于π体系中相邻芳基之间的四极静电相互作用。不过，近期的实验与计算研究表明，相邻芳香环片段间的局域偶极相互作用在稳定π-π相互作用方面可能具有关键意义。本文通过系统性调控侧链苄基取代基的给电子/吸电子特性，并将这些效应与体系的组装及凝胶化涌现性质相关联，探究了Fmoc-Phe衍生水凝胶因子自组装与共组装过程中的π-π相互作用本质。研究结果表明，组装体系中相邻苄基之间的稳定偶极相互作用发挥着重要作用。此外，我们通过数种自组装/共组装Fmoc-Phe衍生物的凝胶原纤维向晶体的动态转变获得了高分辨率晶体结构，为特定偶极相互作用提供了进一步的实验证据。除电子效应外，空间位阻性质同样对这类组装体系中相邻苄基间的相互作用具有显著影响。本研究成果为阐明Fmoc-Phe衍生水凝胶因子的构效关系提供了重要见解，并为设计具备预期涌现性质的下一代先进材料提供了指导思路。