ABSTRACT: We carried out a detailed computational investigation of an earlier experimentally observed, unusual, regioselective, electrophilic halogenation in helically folded quinoline oligoamides. In the experimental studies, halogenation occurred selectively at a given monomer of a foldamer substituted with electron-withdrawing groups at the N terminus, although apparently identical reactive sites were available to react with the incoming electrophile. On the other hand, the selectivity was lost with weakly electron-donating groups. To gain an insight into the regioselective preference of bromination in quinoline foldamers, conceptual DFT was used to calculate the local nucleophilicity index of various foldamers of different sizes and with different substituents, and it was found that the predicted reaction centers were in line with the experimental results. Frontier molecular orbital analysis was used to understand this behavior. A detailed study of the hypothetical linear conformation of the tetramer for comparison with the folded conformation was carried out. In the case of a linear conformer, the HOMO is localized on specific monomers irrespective of substitution, but upon folding delocalization is observed, which is larger for the weakly electron-donating groups when compared with the electron-withdrawing groups. In the case of strongly donating groups there is no delocalization, even upon folding. The behavior remains the same when the size of the helix is increased (octamer). Thus, it is clearly seen in this work that the combined effects of conformations and substituents dictate the regioselectivity in the folded oligoamides; this knowledge will have a profound effect on the field of foldamer chemistry.
ChemPhysChem 08/2012; 13(15):3526-34. · 3.41 Impact Factor