Side-chain halogen effects on self-assembly and hydrogelation of cationic phenylalanine derivatives

Low molecular weight (LMW) supramolecular hydrogels have great potential as next-generation biomaterials for drug delivery, tissue engineering, and regenerative medicine. The design of LMW gelators is complicated by the lack of understanding regarding how the chemical structure of the gelator correlates to self-assembly potential and emergent hydrogel material properties. The fluorenylmethyloxycarbonyl-phenylalanine (Fmoc-Phe) motif is a privileged scaffold that is prone to undergo self-assembly into self-supporting hydrogel networks. Cationic Fmoc-Phe-DAP derivatives modified with diaminopropane (DAP) at the C-terminus have been developed that self-assemble into hydrogel networks in aqueous solutions of sufficient ionic strength. We report herein the impact of side-chain halogenation on the self-assembly and hydrogelation properties of Fmoc-Phe-DAP derivatives. A systematic study of the self-assembly and hydrogelation of monohalogenated Fmoc-Phe-DAP derivatives with F, Cl, or Br atoms in the ortho, meta, or para positions of the phenyl side chain reveal significant differences in self-assembly and gelation potential, nanoscale assembly morphology, and hydrogel viscoelastic properties as a function of halogen identity and substitution position. These results demonstrate the profound impact that subtle changes to the chemical scaffold can have on the behavior of LMW supramolecular gelators and illustrate the ongoing difficulty of predicting the emergent self-assembly and hydrogelation behavior of LMW gelators that differ even modestly in chemical structure.