Encoding stability and dynamics in hydrogen-bonded octameric capsules through amino acid α-position design

How local molecular determinants encode stability and dynamics in supramolecular assemblies remains a central challenge in adapting biological design principles for synthetic systems. Here, we systematically investigate eleven amino acid-functionalized benzene-1,3,5-tricarboxamides to elucidate how chirality, α-substitution, and side-chain architecture control the formation, stability and function of noncovalent octameric capsules. Achiral derivatives lacking an α-hydrogen exhibit poor solubility in noncompetitive solvents and preferentially form extended polymeric aggregates, highlighting the role of the α-H motif in mediating solvation and preorganization of hydrogen-bonding networks. In contrast, chiral analogues retaining the α-H group readily self-assemble into discrete, D ₂-symmetric octameric capsules. Substitution of the α-hydrogen with a methyl group disrupts solubility and capsular stability; however, introduction of long aliphatic side chains partially restores capsule formation, albeit with increased dynamics. Moreover, α-methylation profoundly affects capsule function, leading to a complete loss of fullerene encapsulation ability compared to the corresponding α-H-containing capsules. Overall, these results reveal how subtle variations at the α-position translate into emergent differences in stability, dynamics, function and architecture of hydrogen-bonded supramolecular capsules.