Phenylalanine (Phe)-derived molecules have been exploited as low molecular weight hydrogelators. Perturbing the hydrophobic and p-p interactions that promote self-assembly and hydrogelation of these derivatives will facilitate improved understanding of hydrogelation phenomena and the design of small molecule hydrogelators with novel properties. The efficient self-assembly and hydrogelation of Fmoc-protected pentafluorophenylalanine (Fmoc-F 5 -Phe) are reported herein. Suspensions of Fmoc-F 5 -Phe in water undergo rapid self-assembly to entangled fibrillar structures within minutes, giving rise to rigid supramolecular gels. Self-assembly occurs at concentrations as low as 2 mM (0.1 wt%). Variation of the fluorinated aromatic side chain or N-terminal functionalization perturbs hydrogelation, implicating fluorous and p-p interactions as the primary determinants for molecular recognition and self-assembly. The hydrophobic and electronic properties of F 5 -Phe provide remarkable potential for functional self-assembly in a minimal amino acid scaffold.
Fmoc-protected aromatic amino acids, including Fmoc-phenylalanine (Fmoc-Phe), Fmoc-tyrosine (Fmoc-Tyr), and Fmoc-pentafluorophenylalanine (Fmoc-F 5 -Phe), have been shown to undergo efficient self-assembly and to promote hydrogelation in aqueous solvents. In order to probe the electronic and steric role of the benzyl side-chain in hydrophobic and p-p interactions during selfassembly, the hydrogelation behavior of monohalogenated (F, Cl, Br) Fmoc-Phe side-chain derivatives was assessed. Incorporation of single halogen substituents on the aromatic side-chain of Fmoc-Phe dramatically enhances the efficient self-assembly of these amino acid derivatives (relative to Fmoc-Phe) into amyloid-like fibrils that promote hydrogelation in aqueous solvents. The position of halogen substitution (ortho, meta, para) and the halogen itself (F, Cl, Br) exert a strong influence on the selfassembly rate and on the bulk rheological properties of the resultant hydrogel. These results demonstrate that minimal atomic substitutions can be used to tune self-assembly and gelation of small molecule hydrogelators.
The development of hydrogels resulting from the self-assembly of low molecular weight (LMW) hydrogelators is a rapidly expanding area of study. Fluorenylmethoxycarbonyl (Fmoc) protected aromatic amino acids derived from phenylalanine (Phe) have been shown to be highly effective LMW hydrogelators. It has been found that side chain functionalization of Fmoc-Phe exerts a significant effect on the self-assembly and hydrogelation behavior of these molecules; fluorinated derivatives, including pentafluorophenylalanine (F(5)-Phe) and 3-F-phenylalanine (3-F-Phe), spontaneously self-assemble into fibrils that form a hydrogel network upon dissolution into water. In this study, Fmoc-F(5)-Phe-OH and Fmoc-3-F-Phe-OH were used to characterize the role of the C-terminal carboxylic acid on the self-assembly and hydrogelation of these derivatives. The C-terminal carboxylic acid moieties of Fmoc-F(5)-Phe-OH and Fmoc-3-F-Phe-OH were converted to C-terminal amide and methyl ester groups in order to perturb the hydrophobicity and hydrogen bond capacity of the C-terminus. Self-assembly and hydrogelation of these derivatives was investigated in comparison to the parent carboxylic acid compounds at neutral and acidic pH. It was found that hydrogelation of the C-terminal acids was highly sensitive to solvent pH, which influences the charge state of the terminal group. Rigid hydrogels form at pH 3.5, but at pH 7 hydrogel rigidity is dramatically weakened. C-terminal esters self-assembled into fibrils only slowly and failed to form hydrogels due to the higher hydrophobicity of these derivatives. C-terminal amide derivatives assembled much more rapidly than the parent carboxylic acids at both acidic and neutral pH, but the resultant hydrogels were unstable to shear stress as a function of the lower water solubility of the amide functionality. Co-assembly of acid and amide functionalized monomers was also explored in order to characterize the properties of hybrid hydrogels; these gels were rigid in unbuffered water but significantly weaker in phosphate buffered saline. These results highlight the complex nature of monomer/solvent interactions and their ultimate influence on self-assembly and hydrogelation, and provide insight that will facilitate the development of optimal amino acid LMW hydrogelators for gelation of complex buffered media.
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