Acid-induced Conformational Switching of Helical Foldamers Containing Imidazole Amide

Abstract

N-Alkylated oligo- and poly(p-benzamide)s exist as dynamic helical structures with all-cis amide conformation. Imidazole N-alkylated amides also show cis conformational preference, but their major conformer is changed from cis to trans by addition of acid. Here, based on those findings, we designed and synthesized aromatic triamides 3 and hexaamides 4 containing an imidazole ring as candidate foldamers anticipated to exhibit acid-induced conformational change. X-Ray structure analysis of oligomer 3c showed that it takes all-cis conformation in the crystal. In solution, all the oligoamides examined existed as an equilibrium mixture of four conformers, among which the major conformer was the folded all-cis structure as judged from the low-temperature 1H NMR spectra. When trifluoroacetic acid-d was added to a solution of the oligoamides in methylene chloride-d2, only two conformers were observed in the low-temperature 1H NMR spectra, and the major conformer was the (trans, cis) form with respect to the amide bonds of the imidazole at the 4 and 2 positions. Experimental and theoretical analysis of the CD spectra indicated that the conformation of hexaamides 4 changes upon addition of acid. Our results suggest that N-alkylated imidazoleamide can serve as a key structural motif for the construction of foldamers with acid-switchable conformation.