Molecular Rotors as Simple Models to Study Amide NH−Aromatic Interactions and Their Role in the Folding of Peptide-like Structures

Abstract

The conformational behavior of designed macrocyclic naphthalenophanes (1a,b and 2a,b) derived from amino acids (Phe and Val) has been used for studying NH...pi interactions. The cycles having 16- and 17-membered rings showed a dynamic process within the NMR time scale, produced by the flipping of the aromatic naphthalene moiety with respect to the macrocyclic main plane. We used the temperature dependence of 1H NMR to obtain activation parameters of the energetic barrier for the process (variable temperature NMR and line shape analysis). The rate of the movement clearly depends on the macrocyclic ring size and, more interestingly, on the nature of the peptidomimetic side chain, the energetic barrier being higher for the compounds bearing aromatic side chains. A largely negative entropic contribution to the free energy of activation was observed, with clear differences due to the side chain nature. Molecular modeling studies suggest that the aromatic rings interact with intramolecularly H-bonded amide NH groups, protecting them from solvation and thus leading to a larger unfavorable activation entropy. This NH...pi interaction has been exploited for the preparation of new systems (1c and meso-1b) with designed conformational preferences, in which aromatic rings tend to fold over amide NH groups. Thus, these minimalistic molecular rotors have served us as simple model systems for the study of NH...pi interactions and their implication in the folding of peptide-like molecules.