EFFECTS OF BACKBONE RIGIDIFICATION ON INTRAMOLECULAR HYDROGEN-BONDING IN A FAMILY OF DIAMIDES

In an effort to gain insight on the balance of noncovalent forces that controls the adoption of folded conformations in small molecules, we have examined intramolecular hydrogen bond formation in a series of diamides containing a variety of conformational constraints. The intramolecularly hydrogen-bonded state of flexible diamide 2 was previously shown to be enthalpically favored by about 1.5 kcal/mol relative to the non-hydrogen-bonded state in methylene chloride. For flexible diamide 1, however, the enthalpic preference for the intramolecularly hydrogen-bonded state is only about 0.4 kcal/mol in this solvent. We describe here the synthesis and behavior of diamides 3-9, in which eight- or nine-membered-ring N-H...O=C hydrogen bonds occur in rigidified frameworks. Thermodynamic parameters were determined spectroscopically for the two-state equilibrium, non-hydrogen-bonded vs intramolecularly hydrogen-bonded, for diamides 3 and 4 in methylene chloride. The intramolecularly hydrogen-bonded state of 3 is enthalpically favored by ca. 1.6 kcal/mol. The enhanced enthalpic favorability of the internally hydrogen-bonded state of 3, relative to 1, is consistent with the MM2/MacroModel prediction that formation of an optimal hydrogen bond by 1 requires an eclipsed torsion angle in the linking segment. The intramolecularly hydrogen-bonded state of 4 is enthalpically favored by about 1.1 kcal/mol. The diminished enthalpic favorability relative to 3 may result from the poorer hydrogen-bond-accepting ability of the lactam carbonyl, relative to the acyclic tertiary carbonyl of 3. The extent of intramolecular hydrogen bonding in 5 is less than or equal to the extent in 2 at all temperatures in methylene chloride. Among the olefinic series 6-8, the addition of methyl substituents to the alkene carbons is found to promote hydrogen bond formation so effectively that 8 is predominantly hydrogen bonded in acetonitrile at room temperature, conditions under which little or no intramolecular hydrogen bonding can be detected for 1 or 6. X-ray diffraction data show that the intramolecular hydrogen bond is maintained by 8 in the solid state.