A series of small, unsymmetrical pyridine-2,6-dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @-type folding pattern resembled the oxyanion-hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen-bonding patterns and aryl-aryl interactions. In the solid state, the foldamers adopted either the globular @-type fold or the more extended S-type conformers, which were very similar to those foldamers obtained computationally. In some cases, the same foldamer molecule could even crystallize into two different folding patterns, thus confirming that the different folding patterns are very close in energy in spite of their completely different shapes. Finally, the best match for the observed NOE interactions in the liquid state was a conformation that matched the computationally characterized helix-type fold.
33 crystal structures (11 unsolvated and 22 solvates) of a series of seven oligoamide foldamers were analysed. The crystal structures revealed that despite the structural and environmental differences the series of foldamers prefer only two general conformations, a protohelical @-conformation and a sigmoidal S-conformation. Both conformations also have preferred crystal packing motifs and solvate forming tendencies. Hydrogen bonding was found to be the most decisive factor in conformational preference, but steric properties, the type of the peripheral substituents, as well as solvent and aromatic interactions were also found to have an effect on the conformational details and crystal form.
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