Halogen Bond-Tuning of Responsive Supramolecular Amino Acid Hydrogels.

N-Fmoc-pentafluoro-L-phenylalanine (F5) forms stable supramolecular hydrogels, mainly through π-π stacking of its aromatic groups. Hydrogen bonding-driven co-assembly of F5 with suitable partner molecules has been reported to affect the gel's properties, in accordance with what is observed in their corresponding co-crystal structures. Herein, we extended this hydrogel modulation strategy to halogen bonding (XB) interactions by introducing an XB-donating iodine atom in the para-position of the F5 phenyl ring. Under conditions mimicking biological environments, both crystal packing and hydrogelation of the resulting N-Fmoc-4-iodo-tetrafluoro-phenylalanine (IF4), were significantly affected by iodine-π interactions. Slower fibril formation kinetics and reduced strength of IF4 hydrogels in phosphate buffer solution, compared to F5, mirrored iodine-induced changes in Fmoc stacking in the solid state. Notably, the addition of strong XB-acceptors - such as iodide anions or pyridine-containing substrates, like vitamin B3 - induced a significant increase in gel stiffness. These findings suggest the possibility of exploiting properly tailored Fmoc-amino acids as "XB-responsive" hydrogelators, useful for anion sensing applications or for trapping bioactive molecules.