Halogen Bond‐Tuning of Responsive Supramolecular Amino Acid Hydrogels

XB strongly influences both solid-state packing and rheological properties of hydrogels of a tailored halogenated Fmoc-amino acid in biomimetic environments. Interestingly, the addition of effective XB-acceptors (Nu) to the gelation medium increased gel stiffness, preluding to the possible future development of XB-responsive amino acid hydrogels in anion sensing, or for the encapsulation of specific guest molecules.

Abstract

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.

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