The strengths of hydrogen bonding interaction between formamide (FA) and thioformamide (TFA) were investigated at the B3LYP level with the 6-311G(d,p), 6-31+G(d,p), and 6-311++G(2d,2p) basis sets. The 18 minimum energy structures of FA-FA, TFA-TFA, and TFA-FA dimers were examined. The average strength of the OCN-H---OdC, SCN-H---SdC, OCN-H---SdC, and SCN-H---OdC hydrogen bonds at the B3LYP/6-311++G(2d,2p) level was -6.1 ( 0.3, -5.0 ( 0.1, -4.8 ( 0.3, and -7.3 ( 0.4 kcal/mol, respectively, when the basis set superposition error (BSSE) was corrected. The results show that TFA is a good hydrogen bond donor but a poor hydrogen bond acceptor as compared to FA. For the OC-H---OdC, SC-H---SdC, OC-H---SdC, and SC-H---OdC hydrogen bonds, the average strength has been predicted to be -2.2 ( 0.3, -2.2 ( 0.2, -1.0 ( 0.3, and -3.1 ( 0.3 kcal/mol, respectively. It is remarkable that the thioformyl hydrogen atom of TFA has a strong hydrogen bonding ability as compared to that of FA. The abilities of the hydrogen bond donor have a good correlation with the proton affinities of the deprotonated anion.

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The conformational properties of azapeptide derivatives, Ac-azaGly-NHMe (1), Ac-azaAla-NHMe (2), Ac-NMe-azaGly-NHMe (3), Ac-NMe-azaAla-NHMe (4), Ac-azaGly-NMe(2) (5), Ac-azaAla-NMe(2) (6), Ac-NMe-azaGly-NMe(2) (7), and Ac-NMe-azaAla-NMe(2) (8), were systematically examined by using ab initio MO and DFT methods. Structural perturbations in azapeptides resulting from cyclic substitution of a methyl group at three N-positions of an azaamino acid were studied on the basis of the structure of the simplest model azapeptide, 1. Potential energy surfaces were generated at the HF/6-31G level for 1-4 and at the HF/6-31G//HF/3-21G level for 5-8 by rotating two key dihedral angles (phi, psi) in increments of 30 degrees. The backbone (phi, psi) angles of the minima for 1-4 are observed at the i + 2 position to form the betaI(I')-, betaII(II')-, betaVI-turns or the polyproline II structure according to the orientation of the acetyl group and the positions of the N-methyl groups. Compounds 5-8 coupled to a secondary amine were found to preferentially adopt polyproline II, betaI(III)-turn, or alpha-helical structure or even extended conformations depending on the orientation of the acetyl group and the positions of the N-methyl groups. Furthermore, N-methyl groups, depending on their positions, were found to affect the orientation of the amide group in the lowest energy conformations, the pyramidality of the N2 atom, and the bond length in azapeptide derivatives. These unique theoretical conformations of N-methyl azapeptide derivatives could be utilized in the definite design of secondary structure for peptides and proteins, and in the development of new drugs and molecular machines.