Structural and thermodynamic characterization of temperature-dependent changes in the folding pattern of a synthetic triamide

Article abstract of DOI:10.1021/ja00063a046

Variable-temperature ¹H NMR and IR studies of triamide 1 and related compounds indicate that 1 undergoes dramatic temperature-dependent conformational changes in relatively nonpolar solvents (methylene chloride and chloroform). The folding pattern favored at low temperatures in these chlorocarbons (1c) contains a single C=O?H-N hydrogen bond in a nine-membered ring, while a folding pattern containing only a six-membered-ring C=O?N-H interaction (1a) is favored at higher temperatures. Dimethyl sulfoxide, a very strong hydrogen-bond-accepting solvent, disrupts all internal hydrogen bonding in 1. Acetonitrile appears to disrupt the six-membered-ring hydrogen bond selectively and to promote nine-membered-ring interaction at room temperature, relative to chlorocarbon solvents. By treating the behavior of 1 as a two-state system, in which folding pattern 1c is considered to be the "native state" and all other folding patterns comprise the "denatured state", we have been able to carry out van't Hoff analyses of the temperature-dependent conformational changes. In methylene chloride, the native state is enthalpically preferred by 1.9-2.5 kcal/mol but entropically disfavored by 7.4-9.1 eu. Similar values are obtained in chloroform. This thermodynamic characterization demonstrates that, even in a relatively nonpolar environment, the relative enthalpic stabilities of alternative folding patterns cannot be predicted simply by maximizing the pairing of hydrogen-bond donors and acceptors.