Comparison of the Self-Assembly Behavior of Fmoc-Phenylalanine and Corresponding Peptoid Derivatives

Fluorenylmethoxycarbonyl-protected phenylalanine (Fmoc-Phe) derivatives are a privileged class of low molecular weight amino acid hydrogelators that undergo spontaneous self-assembly in water to form one-dimensional (1D) fibril networks. Structural studies indicate that these fibrils feature unidirectional hydrogen bonding and parallel pi-pi interactions (Fmoc-Fmoc and side chain benzyl-benzyl), which stabilize the 1D fibrils. However, the relative contribution of hydrogen bonding vs pi-pi interactions in these assemblies is not understood. Herein, we compare the self-assembly of Fmoc-Phe amino acids with corresponding Fmoc-protected peptoid derivatives. The N-benzyl glycine-derived peptoid analogues exhibit altered hydrogen bonding ability and benzyl side chain presentation geometry relative to the parent Fmoc-Phe molecules. We found that Fmoc-peptoid analogues preferentially assemble into two-dimensional (2D) nano- and microsheets that ultimately adopt crystalline states, whereas the Fmoc-Phe amino acids assemble into 1D nanofibrils. Crystal diffraction analysis suggests that hydrogen bonding of the carbamate group within Fmoc-Phe assemblies may be crucial for directing unilateral 1D growth of fibrils, while alteration of these interactions in the peptoid analogues removes the possibility for hydrogen bonds involving the carbamate moiety and limits intermolecular interactions to pi-pi bonding, which favors assembly into 2D architectures.