Conformation-directing effects of a single intramolecular amide-amide hydrogen bond: Variable-temperature NMR and IR studies on a homologous diamide series

Article abstract of DOI:10.1021/ja00004a016

We have studied intramolecular hydrogen bonding in a homologous series of diamides (compounds 1-6) in methylene chloride, 9:1 carbon tetrachloride/benzene, and acetonitrile. By correlating variable-temperature ¹H NMR and IR measurements, we have shown that the temperature dependence of the amide proton NMR chemical shift (Δδ/ΔT) can provide qualitative (and in some cases quantitative) information on the thermodynamic relationship between the intramolecularly hydrogen bonded and non-hydrogen-bonded states of flexible molecules. Among the hydrogen-bonded ring sizes represented in the diamide series, the intramolecular interaction is particularly enthalpically favorable in the nine-membered hydrogen-bonded ring (compound 4). Variable-temperature IR and NMR data indicate that the internally hydrogen bonded state of diamide 4 is 1.4-1.6 kcal/mol more favorable enthalpically than the non-hydrogen-bonded state, in methylene chloride solution; the non-hydrogen-bonded state is 6.8-8.3 eu more favorable entropically in this solvent. In contrast, there appear to be much smaller enthalpy differences between the internally hydrogen bonded and non-hydrogen-bonded states of diamides 2 and 3. Our findings are important methodologically because the temperature dependences of amide proton chemical shifts are commonly used to elucidate peptide conformation in solution. Our results show that previous "rules" for the interpretation of such data are incomplete. In non-hydrogen-bonding solvents, small amide proton Δδ/ΔT values have been taken to mean that the proton is either entirely free of hydrogen bonding or completely locked in an intramolecular hydrogen bond over the temperature range studied. We demonstrate that an amide proton can be equilibrating between intramolecularly hydrogen bonded and non-hydrogen-bonded states and still manifest a small chemical shift temperature dependence (implying that the hydrogen-bonded and non-hydrogen-bonded states are of similar enthalpy).