Conformational Stability of a Model Macrocycle Tetraamide: An ab Initio Study

Ab initio calculations are carried out to investigate the conformational stability of a model macrocyle tetraamide.
The four amide groups in the selected model are present in the sequence:  (OCNH)Ph(NHCO)CHCH(OCNH)Ph(NHCO)CHCH. In this sequence, two phenyl rings and two ethene groups
act as bridges between the amide units. Each amide motif bonds to a phenyl ring through its amide nitrogen
and to an ethene group through its amide carbon. Four clearly distinct minimum-energy conformations are
found upon full geometry optimization using the B3LYP/6-31+G(d) method. Frequency calculations using
the same method confirm that the four conformations are indeed minima in the macrocycle potential energy
surface. Relative to the most stable conformer, the other conformations are higher in energy by 0.86, 2.09,
and 9.17 kcal/mol, respectively, at the MP2/6-31+G(d,p) level. The stability of the macrocycle conformations
is correlated primarily to the existence and strength of intramolecular NH···OC hydrogen bonds. Additional
stability to the conformations is found to come from weak PhH···OC hydrogen bonding between a carbonyl
oxygen and a hydrogen atom of a phenyl group. Solvent effects play an important role in the relative energies
of the various conformations, as indicated by the simple SCRF = dipole model calculations for the case of
aqueous solution.