Quinoline-Directed Folding in Anilide-Quinoline Hybrids: Length-Controlled Three-Dimensional Conformational Diversity

Quinoline-based aromatic oligoamide foldamers composed of anilide (A) and quinoline (Q) units, in which amide-bond formation at the quinoline 8-position provides access to cyclic and acyclic architectures, exhibit distinct folding behaviors. The cyclic series A-(n)-Q-(n) (n = 2-6) was obtained by one-pot cyclooligomerization or by stepwise assembly followed by intramolecular amidation. Structural analyses revealed a pronounced ring-size dependence of conformation and symmetry, ranging from symmetric macrocycles to unsymmetric, partially helical folds. In particular, the hexamer A6Q6 exhibits an unusual two-state conformational equilibrium in solution and was isolated in the solid state as both a partially helical unsymmetric conformer and a highly symmetric S ₆ cubic conformer featuring a hydrophobic internal cavity. In parallel, the corresponding acyclic oligomers NH ₂ -A-(n)-Q-(n)-CO ₂ H (n = 3-6) adopt well-defined helical structures in the solid state and retain compact folded conformations in solution, as supported by NMR, H/D-exchange, and NOE analyses. The helical fold generates a confined cavity comparable in size to that of a 12-membered ring. These findings establish anilide-quinoline hybrids as a versatile platform for size-programmed macrocycles, stable aromatic helices, and functional foldamer architectures.