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

被引:55
作者
LIANG, GB [1 ]
DESPER, JM [1 ]
GELLMAN, SH [1 ]
机构
[1] UNIV WISCONSIN, DEPT CHEM, SM MCELVAIN LAB ORGAN CHEM, 1101 UNIV AVE, MADISON, WI 53706 USA
关键词
D O I
10.1021/ja00056a017
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
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页码:925 / 938
页数:14
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