Evidence of an n_N(amide) → π*_Ar Interaction in N-Alkyl-N,N′-diacylhydrazines

Abstract

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

Understanding the n → π* non-covalent interaction using different experimental and theoretical approaches

“…Hence, the increase in the strength of the np* interaction makes the nitrogen lone-pair less available for the -NH-C(QO)-conjugation, and thus, the N-H stretching frequency gets red-shifted. 81 It has been found from the NBO analysis that the E (2) energy for this interaction decreases as the distance between the nitrogen atom and carbon increases from EWGs to EDGs (Fig. 12(a)).…”

“…Thus, the importance of the np* interaction in stabilizing the t-c configuration of N,N 0 diacylhydrazine was established. 81 Sarma and co-workers also tuned the strength of the np* interaction by modifying various electronic substituents at the para position (21-26 in Fig. 11(e)) and observed the spectroscopic signature of this interaction.…”

“…11(c)), and the t-c configuration was still favored. 81 However, when the nitrogen atom (np* donor) was replaced with the -CH 2 group (Fig. 11(d)), a mixture of 70% trans and 30% cis configurations was observed.…”

“…11(b)). 81 The probability of stabilization of this configuration due to the N-HÁ Á Áp hydrogen bond was ruled out when the second N-H was also methylated (Fig. 11(c)), and the t-c configuration was still favored.…”

“…Moving from the EWGs to the EDGs, the strength of this interaction decreases, and thus, the N-H stretching frequency gets blue-shifted. 81 Based on NMR spectroscopy, the chemical shift values of the N-H and -CH 3 protons of the hydrazine compounds were found to show upfield shifts. 81 The conjugation in the -NH-C(QO)group, which decreases with the increment of the np* interaction, weakens the anisotropic effect of the -NQC-double bond and leads to the upfield of the chemical shift of the N-H and -CH 3 protons (Fig.…”