Abstract
The conformational study on N‐methoxycarbonyl‐L‐proline‐N′‐methylamide (Moc‐Pro‐NHMe, prolylcarbamate) is carried out using ab initio HF and density functional B3LYP methods with the self‐consistent reaction field method in the gas phase and in solution (chloroform, acetonitrile, and water). The replacement of the N‐acetyl group by the N‐methoxycarbonyl group results in the changes in conformational preferences, populations for backbone and prolyl puckering, and barriers to cis‐trans isomerization of the prolyl residue in the gas phase and in solution, although there are small changes in the geometry of the prolyl peptide bond and the torsion angles of backbone and prolyl ring. The cis population increases with the increase of solvent polarity, as found for Ac‐Pro‐NHMe (prolylamide), but it is amplified by 9% in the gas phase and about 17% in solution for prolylcarbamate compared with those for prolylamide. It is found that the cis‐trans isomerization for prolylcarbamate proceeds through the clockwise rotation with ω′ ≈ +120° about the prolyl peptide bond in the gas phase and in solution, as found for prolylamide. However, the rotational barriers to the cis‐trans isomerization for prolylcarbamate are calculated to be 3.7–4.7 kcal/mol lower than those of prolylamide in the gas phase and in solution, and are found to be less sensitive to the solvent polarity. The calculated rotational barriers for prolylcarbamate in chloroform and water are in good agreement with the observed values. The shorter hydrogen‐bond distance between the prolyl nitrogen and the amide H (H~NHMe~) of the NHMe group, the decrease in electron overlap of the prolyl CN bond, and the favorable electrostatic interaction between the ester oxygen and the amide H~NHMe~ for the transition state seem to play a role in lowering the rotational barrier of prolylcarbamate. The smaller molecular dipole moments of the ground‐ and transition‐state structures for prolylcarbamate in the gas phase and in solution seem to be one of factors to make the rotational barrier less sensitive to the solvent polarity. As the solvent polarity increases (i.e., from the gas phase to chloroform to acetonitrile), the value of Δ__H__ decreases and the magnitude of Δ__S__ increases for prolylcarbamate, which results in a nearly constant value of the rotational barrier. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009