Theoretical study of the structure and rotational flexibility of diacylhydrazines: Implications for the structure of nonsteroidal ecdysone agonists and azapeptides

High-level ab initio calculations have been used to determine the minimum energy structures of N,N'-diformylhydrazine, N-methyl-N,N'-diformylhydrazine, and N,N'-dimethyl-N,N'-diformylhydrazine. These calculations show that the global minimum is a nonplanar structure in which the nitrogen lone pairs are essentially perpendicular to one another. However, the energy required for (Z,Z)-diformylhydrazine to adopt a planar structure is less than 1 kcal/mol (MP2/6-31+G**). This is due to attractive intramolecular hydrogen bonds between the N-hydrogens and the carbonyl oxygens in the planar geometry. When one or both amide configurations are inverted (Z,E; E,E), or when the nitrogens are substituted, with methyl for example, these hydrogen bonds are lost and the planar structure becomes much less stable relative to the twisted rotamer. Thus, we conclude from these calculations that diacylhydrazines are intrinsically nonplanar with respect to the CO-N-N-CO torsion, and that with the exception of (Z,Z)-diformylhydrazine the rotational barriers are large. The observation of a planar crystal structure for diformylhydrazine is due to additional intermolecular hydrogen bonds which are available to planar diformylhydrazine in the crystal lattice. Finally, these calculations have significant implications for the structure and dynamical properties of nonsteroidal ecdysone agonists, azapeptides, and azatides which incorporate the diacylhydrazine structure.