Complexation-induced unfolding of heterocyclic ureas. Simple foldamers equilibrate with multiply hydrogen-bonded sheetlike structures

The synthesis and conformational studies of heterocyclic ureas (amides) 1-7 and their concentration-dependent unfolding to form multiply hydrogen-bond ed complexes are described. Ureas 1 and 7 were prepared by reacting 2-amino pyridine and aminonaphthyridine 25, respectively, with triphosgene and 4-(d imethylamino)pyridine (DMAP). Amine 25, in turn, was synthesized by a Knorr condensation of 2,6-diaminopyridine and 4,6-nonanedione. Heterocyclic urea s 3, 4, and 16 were prepared by treating their corresponding amino precurso rs with butylisocyanate, whereas bisureido naphthyridines 6 and 17 were pre pared by heating 2,7-diamino-1,8-naphthyridine (13) with butylisocyanate an d 3,4,5-tridodecyloxyphenyl isocyanate, respectively. The hydrogen-bonding modules 2 and 5 were synthesized by reacting 13 and 2-amino-1,8-naphthyridi ne with valeric anhydride. X-ray crystallographic analyses were performed o n ureas 1, 3, 16, and 17, indicating that these ureas are intramolecularly hydrogen-bonded in the solid state. Moreover, detailed H-1 NMR solution stu dies of 1, 3, 4, 6, and 7 indicate that similar folded structures form in c hloroform. In addition, naphthyridinylureas 3 and 7 unfold and dimerize by forming four hydrogen bonds at high concentrations, and ureas I and 4 unfol d in the presence of their hydrogen-bonding complements, amides 2 and 5, to form complexes with three and four, hydrogen bonds, respectively. Likewise , the mixing of 6 and 7 results in a mutual unfolding and formation of a ro bust, sheetlike, sextuply hydrogen-bonded complex. The hydrogen-bonding mod ules described are useful building blocks for self-assembly, and the unfold ing process represents a very primitive mimicry of the helix-to-sheet trans ition shown by peptides and potentially shown by the hypothetical naphthyri dinylurea 8.