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 (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 differen...

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Published in:Journal of organic chemistry 2024-08, Vol.89 (15), p.10419-10433
Main Authors: Rai Deka, Jugal Kishore, Sahariah, Biswajit, Sarma, Bani Kanta
Format: Article
Language:English
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Summary: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 R3 and R4 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 R3 and R4 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 (R1-R4).
ISSN:0022-3263
1520-6904
1520-6904
DOI:10.1021/acs.joc.2c01891