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

N , N '-diacylhydrazines (R 1 CO-NR 3 -NR 4 -COR 2 ) 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 conformations 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 ∼ 180°), 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 ).