Understanding the Cis-Trans Amide Bond Isomerization of N,N & PRIME;-Diacylhydrazines to Develop Guidelines for A Priori Prediction of Their Most Stable Solution Conformers

N,N '-diacylhydrazines (R1CO-NR3-NR4-COR2) are a class of small molecules with a wide range of applications in chemistry and biology. They are structurally unique in the sense that their two amide groups are connected via a N-N single bond, and as a result, these molecules can exist in eight different isomeric forms. Four of these are amide isomers [trans-trans (t-t), trans- cis (t-c), cis-trans (c-t), and cis-cis (c-c)] arising from C-N bond restricted rotation. In addition, each of these amide isomers can exist in two different isomeric forms due to N-N bond restricted rotation, especially when R(3 )and R-4 groups are relatively bigger. Herein, we have systematically investigated the conforma-tions of 55 N,N '-diacylhydrazines using a combination of solution NMR spectroscopy, X-ray crystallography, and density functional theory calculations. Our data suggest that when the substituents R(3 )and R-4 on the nitrogen atoms are both hydrogens. These molecules prefer twisted trans-trans (t-t) (> 90%) geometries (H-N- C=O similar to 180 degrees), whereas the N-alkylated and N,N '-dialkylated molecules prefer twisted trans-cis (t-c) geometries. Herein, we have analyzed the stabilization of the various isomers of these molecules in light of steric and stereoelectronic effects. We provide a guideline to a priori predict the most stable conformers of the N,N '-diacylhydrazines just by examining their substituents (R-1-R-4).