Dibenzoyl-1-tert-butylhydrazine (RH-5849) and related N-alkyl-N,N′-diacylhydrazines are environmentally benign insect growth regulators. Herein, we show that an unusual n N (amide) → π* Ar interaction mediated by a hydrazide amide nitrogen atom plays a crucial role in stabilizing their biologically active trans−cis (t−c) rotameric conformations. We provide NMR and IR spectroscopic evidence for the presence of these interactions, which is also supported by X-ray crystallographic and computational studies.N,N′-Diacylhydrazines (Figure 1A) possess a wide range of biological activities. In particular, some 1,2-dibenzoyl-1-tertbutylhydrazine (RH-5849) (Figure 1B) analogues have been commercialized as insecticides. 1 In addition, many natural products, 2 azapeptides, 3 azatides, 4 and azapeptoids 5 contain N,N′-diacylhydrazine motifs embedded in their structure. Recently, hyperstable collagen mimetic peptides (CMPs) 6 were produced by incorporating N,N′-diacylhydrazine motifs via strategic substitution of glycines with aza-glycines in CMPs. Despite such high significance, the conformational properties of N,N′-diacylhydrazines remained poorly studied. The repulsion between the hydrazide amide nitrogen lone pairs is considered as the major driving force in determining their conformations. 7

Unusual N(amide)⋯C–X noncovalent carbon bonding interactions stabilize the trans–cis (t–c) amide bond rotamers of N-methyl-N,N′-diacylhydrazines over the expected trans–trans (t–t) rotamers in solution.

An unusual Namide···H–Namide hydrogen bond (HB) was previously proposed to stabilize the azapeptide β-turns. Herein we provide experimental evidence for the Namide···H–Namide HB and show that this HB endows a stabilization of 1–3 kcal·mol–1 and enforces the trans–cis–trans (t–c–t) and cis–cis–trans (c–c–t) amide bond conformations in azapeptides and N-methyl-azapeptides, respectively. Our results indicate that these Namide···H–Namide HBs can have stabilizing contributions even in short azapeptides that cannot fold to form β-turns.

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 ).

The facile one‐pot procedure allows the synthesis of 1,5‐benzodiazepines from o‐phenylenediamines, aldehydes, and β‐keto esters under mild reaction conditions.