The goal of this investigation is to evaluate the influence of solvent on the barrier to rotate the amide C-N bond. Several stable amides are known in which structural features partially or completely prevent the lone pair on nitrogen from delocalizing into the carbonyl pi bond. Some of these """"""""twisted"""""""" amides will be used to explore solvent effects on a variety of amide conformations. While much is known about the solvent dependence on the amide rotational barrier, little is known about where on the reaction coordinate the differences in solvent/solute interactions are most significant, and why these differences exist. Is a rotational barrier lowered because the transition state is stabilized, the reactant is destabilized, or some combination? What are the absolute magnitudes of these energies, and what are the origins? How does hydrogen bonding change with amide conformation? The properties of an amide are highly dependent on the conformation of the C-N bond. A detailed analysis of the conformational profile in amides, especially as a function of environment, is important for several reasons. The ability of a protein to adopt and maintain a three-dimensional structure with specific biological activity is dependent on the ease of rotation of the amide bonds, highly influenced by medium. Rotated amides are more susceptible to hydrolysis, for example by serine proteases. Strained amides are intimately involved in the biological activity beta-lactam antibiotics, and the immunosuppressants FK-506 and rapamycin derive their activity from structural features which mimic a rotated amide. More fundamentally, better knowledge of structure - energy relationships in amides will test our theories of structure and bonding. Study of two or more """"""""twisted"""""""" amides is proposed herein, representing different points on the potential energy curve to C- N rotation. Enthalpies of solution will be measured in a variety of solvents by calorimetry to determine which solvent properties are most important in stabilizing and destabilizing the rotated amides, compared to normal planar tertiary amides. Also, free energies of solvation for the twisted amides will be calculated using known simulation methods and will be compared to experimental results.
| Morgan, Kathleen M; Ashline, David J; Morgan, Jessica P et al. (2014) Electrospray ionization (ESI) fragmentations and dimethyldioxirane reactivities of three diverse lactams having full, half, and zero resonance energies. J Org Chem 79:517-28 |
