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.