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

Abstract

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 ).

Stereochemical Analysis of Trifluoroacetamide Derivatives Based on Through-Space 1H–19F Spin–Spin Couplings

“…It is worth mentioning that the coupling constants ( 5 J HF = 1.4−1.8 Hz) (Table 1) associated with through-space coupling in compounds 1 and 2 are smaller than those in 2′-fluorosubstituted acetophenones ( 5 J HF = 3.2−5.0 Hz), as reported in our previous study (Figure 1). 5 The TBC constants ( 5 J HF ) of most compounds are generally less than 1 Hz, which is similar in magnitude to those observed for compounds 1 and 2. However, it should be noted that, although 1 H− 19 F coupling was observed in one of the diastereotopic protons (H 6ad ′ and H 4ad ′ in compounds 1 and 2, respectively), no such couplings were observed for other diastereotopic protons (H 6b in compound 1 and H 4b in compound 2), which are both five bonds apart from the F in CF 3 group.…”

“…Two nuclei, such as 19 F/ 19 F, 19 F/ 1 H, and 19 F/ 13 C, can exchange spin information when in van der Waals contact through space, regardless of the number of chemical bonds separating them. 4 In the course of our studies on the syntheses of bioactive compounds, 5 we accidentally observed TSCs with significant magnitudes ( 5 J HF = 3.2−5.0 Hz) in the 1 H NMR spectra of 2′fluoro-substituted acetophenone derivatives. These TSCs revealed that 2′-fluoro-substituted acetophenone derivatives in solution exclusively form s-trans conformers (Figure 1).…”

“…These TSCs revealed that 2′-fluoro-substituted acetophenone derivatives in solution exclusively form s - trans conformers (Figure ). Additionally, the principles of TSC have been used to distinguish between amide conformations in recent years …”

“…These TSCs revealed that 2′-fluoro-substituted acetophenone derivatives in solution exclusively form s-trans conformers (Figure 1). 5 Additionally, the principles of TSC have been used to distinguish between amide conformations in recent years. 6 These studies prompted us to elucidate the conformational properties of trifluoroacetamides based on their TSCs.…”

Synergistic n → π* and nN → π*Ar interactions in C-terminal modified prolines: effect on Xaa–Pro cis/trans equilibrium

“…The choice of the N , N ′-diacylhydrazine unit at the C-terminus of Pro was inspired by our recent observations that an n N → π* Ar interaction between the NH nitrogen lone pair and the π* Ar orbitals of the aryl ring at the acyl position of the NMe amide locked these molecules in trans – cis ( t – c ) geometries, wherein the NH and NMe amides adopted trans and cis geometries, respectively. 17 Based on these observations, we designed Pro-DAH compounds ( 1–6 ) (Fig. 1c) that should have n → π* interaction from the N-terminal CO to the central CO and n N → π* Ar interaction from the central amide's NH lone pair to the terminal aromatic ring (Fig.…”