Evidence of an nN(amide) → π*ArInteraction in N-Alkyl- N, N′-diacylhydrazines

Article abstract of DOI:10.1021/acs.orglett.1c00834

1,2-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 nN(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.

Full text of DOI:10.1021/acs.orglett.1c00834

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Letter
Evidence of an nN(amide) → π*Ar Interaction in
N‑Alkyl‑N,N′‑diacylhydrazines
Jugal Kishore Rai Deka, Biswajit Sahariah, Sushil S. Sakpal, Arun Kumar Bar, Sayan Bagchi,*
and Bani Kanta Sarma*
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ABSTRACT: 1,2-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 nN(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-tert-
N,N′-Diacylhydrazines can have four amide bond rotamers
(Figure 1A). In a recent study, we discussed the role of
reciprocal carbonyl-carbonyl (CO···CO) n → π* interactions
in the stabilization of the trans−trans (t−t) conformations of
unsubstituted N,N′-diacylhydrazines (Figure 1A, R3 = R4 =
H).8 We also reported that when one of the nitrogen atoms
was methylated (1−3), there was a drastic conformational
change and their trans−cis (t−c) conformations became more
stable due to a noncovalent carbon-bonding (C-bonding)
nN(amide) → σ*C−X interaction (Figure 1C).9 Herein, we
show that incorporating a π-system such as a phenyl group at
R2 facilitates an nN(amide) → π*Ar interaction (Figure 1D)
and stabilizes the t−c conformations of N-alkyl-N,N′-
diacylhydrazines. For example, we show that the biologically
active t−c conformations of RH-5849 and its analogues that
are N-alkylated and contain phenyl rings at the acyl positions
(R1 and R2 of Figure 1A) are stabilized by nN(amide) → π*Ar
interactions. Understanding the noncovalent interactions that
stabilize the t−c rotamers of these molecules is crucial for the
N,N′-diacylhydrazine-based drug design. We provide spectro-
scopic evidence for the presence of this interaction in N-
methyl-N,N′-diacylhydrazines in solution, which is also
supported by X-ray crystallographic and computational studies.
Figure 1. (A) Amide bond rotamers of N,N′-diacylhydrazines. (B)
Chemical structure of RH-5849. (C) Noncovalent carbon-bonding
interactions in 1−3 and (D) proposed nN(amide) → π*Ar interactions
in N-alkyl-N,N′-diacylhydrazines.
butylhydrazine (RH-5849) (Figure 1B) analogues have been
commercialized as insecticides.1 In addition, many natural
products,2 azapeptides,3 azatides,4 and azapeptoids5 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
Received: March 10, 2021
https://doi.org/10.1021/acs.orglett.1c00834
© XXXX American Chemical Society
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A

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n → π* has emerged as an important noncovalent interaction
that can stabilize both small molecules and macromolecules.10
However, to the best of our knowledge, there is no report of n
→ π* interaction involving a nitrogen atom of amide character
in the literature.
To probe the presence of the proposed nN(amide) → π*Ar
interaction, we first investigated the crystal structures of RH-
5849 and its analogues from the Cambridge Structural
Database (CSD) (Figures S1 and S2). These molecules
(Figure 1B and 2A) crystallize in the t−c conformations in the
Table 1. Crystallographic Structural Parameters and NBO
Second-Order Perturbation Energies (E2) of nN(amide) →
σ*/π*Ar Interactions in 1−6, 4-NMe, and RH-5849
a
,
b
c
compd
ΔC1Ph (Å)
ΔC2Ph (Å)
E2 (kcal mol−1
)
d
1
0.000
−0.013
0.46
0.51
d
2
3
d
e
RH-5849
0.034
0.045
0.014
0.041
0.009
−0.004
−0.030
−0.005
−0.032
1.10
0.16
1.39
0.89
1.08
4
4-NMe
5
6
0.028
b
a
20 mM in CDCl3. We obtained single crystals of all these
compounds except 3. Crystal geometries were t−c. nN(amide) →
π*Ar interactions calculated using crystallographic coordinates.
c
d
e
Reference 9. RH-5849-conf2, data taken from ref 11 (R4 = tBu).
interaction (1.38 kcal mol−1) between the oxygen atom of
NH−amide CO and the carbon atom of the NtBu−amide CO
(O···C = 2.84 Å). The nN → π*Ar interaction is considerably
diminished in this molecule (0.16 kcal mol−1). In addition, the
cis NtBu−amide bonds in RH-5849 and its analogues are also
stabilized by nO → σ*C−C interactions between their NtBu
t
amide CO oxygen and the σ*C−CH orbital in the Bu group
3
(Table S1 and Figure S4).
RH-5849 and its analogues have a bulky tBu group in one of
the nitrogen atoms, which could force the NtBu−amide bond
to adopt cis geometry.12 To minimize the steric effect, we
substituted the tBu group with methyl (CH3), the smallest
alkyl group (4−6, Figure 3A). The rotameric populations of
Figure 2. (A) Chemical structures of other 1,2-diaroyl-1-tert-
butylhydrazines obtained from the CSD. (B) Crystal structure of
RH-5849 (conformer 2). (C) NBO nN(amide) → π*Ar orbital
interaction in RH-5849 (conformer 2). (D) Pyramidalities of C1Ph
carbon of RH-5849 and other 1,2-diaroyl-1-tert-butylhydrazines
(Figure 2A) are plotted against their NBO nN(amide) → π*Ar
second-order perturbation energy values.
1
the compounds were determined by H NMR, 1D-NOE, and
2D-NOESY experiments (see the Supporting Information).
We observed only the t−c rotameric form of 4−6 in CDCl3
and DMSO-d6, wherein the NH− and NMe−amide bonds
adopted trans and cis geometries, respectively. X-ray crystal
solid state with the NH−amide bonds in the trans and the
NtBu−amide bonds in the cis geometries, respectively (Figure
2B and Figure S2). We observed pyramidalization of the
phenyl carbon attached to the NtBu amide group (C1Ph−CO)
toward the NH nitrogen atom in these molecules (Figure 2C),
which is a crucial evidence for the presence of n → π*
interactions.10 Interestingly, no such trend of pyramidalization
was observed in the phenyl carbon atom attached to the NH
amide group [Δ(C2Ph), Table 1 and Table S1]. Natural Bond
Orbital (NBO) calculations also showed the presence of
nN(amide) → π*Ar interactions in these molecules (Figure 2D
and Figure S3 and Table 1 and Table S1). To take the HN →
CO resonance effect of the amide group into consideration, the
NBO second-order perturbation energies for the nN(amide) →
π*Ar interactions were taken as 60% of the values obtained
from NBO calculations as such calculations consider the amide
configuration as a CO double bond with an unconjugated
nitrogen lone pair (see the Supporting Information for details).
Interestingly, the stabilization energies due to the nN(amide)
→ π*Ar interactions in RH-5849 (1.10 kcal mol−1) and its
analogues are considerably higher compared to the C-bonding
interaction energies in 1 and 2 (Table 1 and Table S1). The
crystal structure of RH-5849 contains two molecules in the
asymmetric unit.11 In one of these molecules (RH-5849-
conf1), we also observed significant CO···CO nO → π*CO
Figure 3. (A) Chemical structures of 4−12, 4-CH2, and 4-NMe. (B)
Crystal geometry of 4. (C) NBO orbital overlap for nN(amide) →
π*Ar interactions in 4. (D) Crystal geometry of 4-NMe showing the
positive pyramidality (ΔN) of the donor amidic nitrogen atom toward
the Ph ring. (E) NBO orbital overlap for nN(amide) → π*Ar
interactions in 4-NMe.
B
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structures of 4−6 also confirmed their t−c conformations in
the solid state (Figure 3B and Figure S5, Tables S2 and S3).
N-Alkyl−amide bonds exist in a mixture of cis and trans
rotameric forms.13 Although the cis amide bond preference of
N-methylanilides is known, this is a special case that arises due
to the repulsion between the carbonyl oxygen lone pairs and
the π-electrons of the phenyl ring on the nitrogen atom in the
trans amide bond conformation.14 We were intrigued by the
complete reversal from trans (HNCO ∼ 180°) to cis
(MeNCO ∼ 0°) geometries of the hydrazide amide
bonds in 4−6 upon N-methylation. To probe this behavior, we
synthesized compound 4-CH2 (Figure 3A), wherein the NH
group in 4 was replaced with a CH2 isostere. Isosteric
replacement of NH with CH2 should eliminate the nN → π*Ar
interaction due to the absence of the electron donor lone pair
in 4-CH2 and should reveal the role of the nN → π*Ar
interaction in the conformational preference of 4−6. As
anticipated, we observed a mixture of cis and trans amide bond
rotamers in 4-CH2 (trans, 70%; cis, 30%). Therefore, it is clear
that the presence of the NH group is essential for the
stabilization of the cis conformations of the NMe−amide
bonds in 4−6. We ruled out any role of hydrogen bonding as
4-NMe (Figure 3A) also adopted a conformation similar to
that of 4 in solution and the solid state (Figure 3D). Inspection
of the crystal geometries of 4−6 and 4-NMe revealed positive
pyramidality of the phenyl carbon (CPh) toward the NH
nitrogen atom, and NBO analyses indicated the presence of
nN(amide) → π*Ar interactions in them (Table 1, Figure 3B−
E). Interestingly, in 4-NMe, we also observed pyramidalization
of the donor nitrogen atom (0.103 Å) toward the acceptor
carbon atom, indicating the presence of the nN(amide) → π*Ar
interaction (Figure 3D).
To systematically modulate the strength of nN(amide) →
π*Ar interactions and probe spectroscopic signature, we further
synthesized compounds 7−12 (Figure 3A) with various
substituents at the para-position of the phenyl ring. From
the solution NMR studies we confirmed the t−c rotamers to
be the most dominant rotamers of 7−12 in solution. A minor
c−c rotamer was also observed due to the isomerization of the
relatively smaller acetyl group to the cis form. As in 4−6, no
isomerization of the NMe−amide bond near the phenyl ring
was observed in 7−12. We could crystallize 7−10 and 12
(Figure 4C and Figures S5 and S6), all of which crystallized in
the t−c rotameric forms with positive pyramidalization of the
aromatic carbon atom (CPh) toward the amidic NH nitrogen
atom (Figure 4B). Interestingly, similar to RH-5849-conf1 and
RH-5849-conf2, we could crystallize 12 in two different forms
(12tc-conf1) and (12tc-conf2) (Figure 4C,D). We could also
locate two conformational forms (t−c-conf1 and t−c-conf2) of
the t−c rotamer of 7−12 using quantum chemistry calculations
(see the Supporting Information for details and Figure S7),
which showed the dominance of the nN(amide) → π*Ar
interaction in the t−c-conf2 and the dominance of the CO···
CO nO → π*CO interaction in the t−c-conf1 conformer,
respectively. This is also reflected in the higher pyramidality of
the acceptor CPh atoms in the optimized geometries of the t−c-
conf2 of 7−12 (Figure 4E, Table S7). We observed a good
correlation between the N···C distances and the corresponding
NBO nN(amide) → π*Ar interaction energies in 7−12 (Figure
4F and Figure S7D). However, the effect of the nN(amide) →
π*Ar interaction was not observed in the change in the CN
and CO bond lengths of the NH−amide group of 7−12
(Table S8).
Figure 4. (A) Bar diagram showing the percentage of the rotameric
populations of 7−12. (B) Pyramidality of the phenyl carbon (CPh)
[directly bonded to the CO group near the NMe group] observed in
the crystal geometries of 7−10 and 12. (C), (D) Crystal geometries
of 12 in two different forms. (E) Pyramidality of the phenyl carbon
(CPh) bonded to the NMe−amide group in the optimized t−c-conf1
and t−c-conf2 conformations of 7−12. (F) Correlation of the N···C
distances (Å) and the NBO nN(amide) → π*Ar interaction energies
(E2) of 7−12. The average of the N···C distances (Å) and E2 values of
the t−c-conf1 and t−c-conf2 of 7−12 were used for this plot (Table
S7).
Interestingly, stronger nO → π*CO interactions in 7−12
should weaken the nN(amide) → π*Ar interactions and vice
versa, and these two interactions should have opposite effects
on the CO and NH stretching frequencies. nO → π*CO
interactions should increase the HN→CO conjugation of the
donor amide and, therefore, shorten the N−H bond, and a
blue shift in the N−H vibrational frequency is expected. On
the other hand, nN(amide) → π*Ar interactions should weaken
the HN→CO conjugation of the donor amide and, therefore,
elongate the N−H bond and cause a red shift in the N−H
vibrational frequency. The NH stretch region of the IR spectra
of 7−12 consisted of three overlapping peaks (Figure 5A and
Figure S9A). The concentration dependent IR experiments
suggested that the lowest frequency NH peak belongs to an
NH that is involved in intermolecular NH···OC hydrogen
bonding (HB) (Figure 5A), but the highest frequency peak
(gray) and the middle peak (cyan) (Figure S9A) are for NH
groups not involved in intermolecular HB. On the basis of
NMR and IR spectroscopic observations, we assigned the
highest frequency peak to the t−c and the middle peak to the
c−c rotamers, respectively (see the Supporting Information for
details). Analyses of the N−H vibrational frequencies of the t−
c rotamers of 7−12 showed a gradual red shift from 7 to 12
(Figure 5B, Table S9), which indicates the dominance of
nN(amide) → π*Ar interactions in 7−12 in CDCl3 solution. A
strong correlation of the red shift in the N−H vibrational
C
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Figure 5. (A) Concentration dependent IR study of 9. The lowest
frequency population arises from intermolecular CO···NH hydrogen
bonds, and thereby a nonlinear increment with concentration is
observed. (B) NH vibrational frequencies of t−c rotamers of 7−12.
The peak positions correspond to the gray region of the peaks shown
in Figure S9A that were obtained by fitting the IR spectrum of each
compounds with a Gaussian + Lorentzian line shape. Details are
discussed in the Supporting Information.
Figure 6. Concentration-dependent changes in 1H NMR peaks of (A)
acetyl CH3 and (B) NH of 7−12 and acetohydrazide (C-1).
interactions in 7−12 to increase with the increase in
concentration. We observed a gradual upfield shift of the δ
values of the CH3 hydrogens with an increase in concentration
(Figure 6A), which can be correlated to the increase in the
nN(amide) → π*Ar interaction and decrease in the anisotropic
effect of the π-electron cloud of NC bond with the increase
in the NH···OC HB at higher concentration. Interest-
ingly, in acetohydrazide (C-1 in Figure 6A,B) that lacked the
nN(amide) → π*Ar interaction, no upfield shift of the acetyl
CH3 hydrogens was observed. Therefore, we conclude that the
upfield shift of acetyl CH3 hydrogens provides direct evidence
of nN(amide) → π*Ar interactions in 7−12.
In conclusion, we have discovered a hydrazide amide
nitrogen mediated nN(amide) → π*Ar interaction in the
insecticide RH-5849 and related N-alkyl-N,N′-diacylhydra-
zines, which stabilize their biologically active t−c rotameric
conformations. As the N-alkyl-N,N′-diacylhydrazine motifs are
found embedded in many natural products and aza-
peptidomimetics, we also anticipate a role of these interactions
in their stabilization.
frequencies with the Hammett constant (σp) of the para-
substituent (R) was observed in 7−12 (Figure S11A).
We also investigated the acetyl CO stretching frequencies of
7−12 for signatures of nO → π*
and nN(amide) → π*Ar
CO
interactions. nO → π* CO interactions should cause red shift of
both the donor and acceptor carbonyl CO stretching
whereas nN(amide) → π*Ar interactions would cause a blue
shift of the acetyl CO stretching due to weakening of the
HN→CO conjugation. Analyses of the acetyl CO stretching
frequencies of the t−c conformers indicated a gradual blue hift
with the increase in the electron withdrawing ability of the
para-substituent (σp), which is in agreement with the expected
decrease in the HN→O conjugation and increase in the CO
bond strength from 7 to 12 due to nN(amide) → π*Ar
interactions (Figure S11B, Table S9).
Investigation of the effect of nN(amide) → π*Ar interaction
on the vibrational stretching of the acceptor CC bonds
showed no gradual trend of red shift in 7−12, but we observed
a substantial red shift of the CC stretching vibrations in 12
compared to that of 7 (Figure S12), which supports stronger
nN(amide) → π*Ar interaction in 12 compared to 7 (see the
Supporting Information for details).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00834.
■
sı
Experimental details, 1D, 2D, and concentration
dependent NMR studies, IR studies and DFT results,
synthetic protocols, crystal data, energies, structures,
distance and energy graphs, NBO orbital overlaps,
chemical shifts, Hammett constants and frequencies,
NOESY spectra, and Cartesian coordinates (PDF)
Further, we investigated the NMR spectroscopic signature of
nN(amide) → π*Ar interactions in 7−12. In the absence of any
other factor, we expect the electron withdrawing effect of the
1
remote R group in the phenyl ring of 7−12 to shift the H
NMR signals of the NH and acetyl CH3 groups downfield.
Interestingly, however, we observed a gradual upfield shift of
Accession Codes
1
the H NMR signals of both the CH3 and NH protons of the
CCDC 1949085−1949087, 1956552, 2003213, 2003215−
2003216, 2050118, 2050120, and 2052664 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
t−c rotamers from 7 to 12 at all concentrations (1−150 mM)
tested, which is evident from the inspection of relative δ values
of CH3 and NH hydrogens of 7−12 at various concentration
points in Figure 6A,B (Table S10−S11). The Hammett
correlation of the upfield shifts of the δ values of the acetyl
CH3 and NH hydrogens at 20 mM concentration with the
increase in the electron withdrawing ability of the para-
substituent (R) in the aryl ring from 7 to 12 are shown in
Figure S13A,B. We reason that the increase in the nN(amide)
→ π*Ar interaction from 7 to 12 reduces the HN → CO
conjugation, which leads to decrease in NC double bond
character and, thus, reduces the anisotropic effect of the NC
bond π-electron cloud, thereby leading to an upfield shift of
the CH3 and NH hydrogen δ values from 7 to 12.
AUTHOR INFORMATION
Corresponding Authors
■
Sayan Bagchi − Physical and Materials Chemistry Division,
CSIR-National Chemical Laboratory, Pune 411008,
Maharashtra, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India; orcid.org/
0000-0001-6932-3113; Email: s.bagchi@ncl.res.in
As hydrogen bond (HB) donation makes an amide nitrogen
lone pair more available,9 we envisaged the nN(amide) → π*Ar
D
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(10), 558−564. (c) Sarma, B. K.; Liu, X.; Kodadek, T. Identification
of selective covalent inhibitors of platelet activating factor
acetylhydrolase 1B2 from the screening of an oxadiazolone-capped
peptoid−azapeptoid hybrid library. Bioorg. Med. Chem. 2016, 24 (17),
3953−3963.
Bani Kanta Sarma − New Chemistry Unit, Jawaharlal Nehru
Centre for Advanced Scientific Research (JNCASR),
Bangalore 560064, India; orcid.org/0000-0003-0830-
6007; Email: bksarma@jncasr.ac.in
(6) (a) Melton, S. D.; Brackhahn, E. A. E.; Orlin, S. J.; Jin, P.;
Chenoweth, D. M. Rules for the design of aza-glycine stabilized triple-
helical collagen peptides. Chem. Sci. 2020, 11 (39), 10638−10646.
(b) Zhang, Y.; Herling, M.; Chenoweth, D. M. General Solution for
Stabilizing Triple Helical Collagen. J. Am. Chem. Soc. 2016, 138 (31),
9751−9754. (c) Zhang, Y.; Malamakal, R. M.; Chenoweth, D. M.
Aza-Glycine Induces Collagen Hyperstability. J. Am. Chem. Soc. 2015,
137 (39), 12422−12425.
(7) (a) Bishop, G. J.; Price, B. J.; Sutherland, I. O. Torsional barriers
in N,N′-diacylhydrazines. Chem. Commun. 1967, 14, 672−674.
(b) Kalikhman, I. D.; Bannikova, O. B.; Medvedeva, E. N.;
Yushmanova, T. I.; Lopyrev, V. A. Conformational isomerism of
1,2-diformyl-, diacetyl-, and di(trifluoroacetyl) hydrazines and their
methyl analogs. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1982, 31 (6),
1275−1277. (c) Reynolds, C. H.; Hormann, R. E. Theoretical Study
of the Structure and Rotational Flexibility of Diacylhydrazines:
Implications for the Structure of Nonsteroidal Ecdysone Agonists and
Azapeptides. J. Am. Chem. Soc. 1996, 118 (39), 9395−9401.
(8) Rahim, A.; Saha, P.; Jha, K. K.; Sukumar, N.; Sarma, B. K.
Reciprocal carbonyl-carbonyl interactions in small molecules and
proteins. Nat. Commun. 2017, 8 (1), 78.
(9) Deka, J. K. R.; Sahariah, B.; Baruah, K.; Bar, A. K.; Sarma, B. K.
Conformational control of N-methyl-N,N’-diacylhydrazines by non-
covalent carbon bonding in solution. Chem. Commun. 2020, 56 (36),
4874−4877.
(10) (a) Newberry, R. W.; Raines, R. T. The n→π* Interaction. Acc.
Chem. Res. 2017, 50 (8), 1838−1846. (b) Singh, S. K.; Das, A. The
n→π* interaction: a rapidly emerging non-covalent interaction. Phys.
Chem. Chem. Phys. 2015, 17 (15), 9596−9612. (c) Sahariah, B.;
Sarma, B. K. Spectroscopic evidence of n→π* interactions involving
carbonyl groups. Phys. Chem. Chem. Phys. 2020, 22 (46), 26669−
26681.
Authors
Jugal Kishore Rai Deka − Department of Chemistry, School of
Natural Sciences, Shiv Nadar University, Dadri, Uttar
Pradesh 201314, India
Biswajit Sahariah − New Chemistry Unit, Jawaharlal Nehru
Centre for Advanced Scientific Research (JNCASR),
Bangalore 560064, India; orcid.org/0000-0001-6649-
892X
Sushil S. Sakpal − Physical and Materials Chemistry Division,
CSIR-National Chemical Laboratory, Pune 411008,
Maharashtra, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India
Arun Kumar Bar − Department of Chemistry, Indian Institute
of Science Education and Research (IISER) Tirupati,
Tirupati 501507, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00834
Author Contributions
All authors have approved the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
B.K.S. acknowledges the Science and Engineering Research
Board (SERB), India, for research grants (ECR/2015/000337
and CRG/2019/003299) and Jawaharlal Nehru Centre for
Advanced Scientific Research (JNCASR) and Shiv Nadar
University (SNU) for support. J.K.R.D thanks SNU for
research fellowship. S.B. acknowledges SERB (EMR/2016/
000576). S.S.S. acknowledges UGC for the research fellowship.
(11) Chan, T. H.; Ali, A.; Britten, J. F.; Thomas, A. W.; Strunz, G.
M.; Salonius, A. The crystal structure of 1,2-dibenzoyl-1-tert-
butylhydrazine, a nonsteroidal ecdysone agonist, and its effects on
spruce budworm (Choristoneurafumiferana). Can. J. Chem. 1990, 68
(7), 1178−1181.
(12) (a) Roy, O.; Dumonteil, G.; Faure, S.; Jouffret, L.; Kriznik, A.;
Taillefumier, C. Homogeneous and Robust Polyproline Type I
Helices from Peptoids with Nonaromatic α-Chiral Side Chains. J. Am.
Chem. Soc. 2017, 139 (38), 13533−13540. (b) Roy, O.; Caumes, C.;
Esvan, Y.; Didierjean, C.; Faure, S.; Taillefumier, C. The tert-Butyl
Side Chain: A Powerful Means to Lock Peptoid Amide Bonds in the
Cis Conformation. Org. Lett. 2013, 15 (9), 2246−2249.
REFERENCES
■
(1) (a) Wing, K. D. RH 5849, a nonsteroidal ecdysone agonist:
effects on a Drosophila cell line. Science 1988, 241 (4864), 467.
(b) Carlson, G. R.; Dhadialla, T. S.; Hunter, R.; Jansson, R. K.; Jany,
C. S.; Lidert, Z.; Slawecki, R. A. The chemical and biological
properties of methoxyfenozide, a new insecticidal ecdysteroid agonist.
Pest Manage. Sci. 2001, 57 (2), 115−119.
(2) Le Goff, G.; Ouazzani, J. Natural hydrazine-containing
compounds: Biosynthesis, isolation, biological activities and synthesis.
Bioorg. Med. Chem. 2014, 22 (23), 6529−6544.
(3) (a) Chingle, R.; Proulx, C.; Lubell, W. D. Azapeptide Synthesis
Methods for Expanding Side-Chain Diversity for Biomedical
Applications. Acc. Chem. Res. 2017, 50 (7), 1541−1556. (b) Zega,
A. Azapeptides as pharmacological agents. Curr. Med. Chem. 2005, 12
(5), 589−597. (c) Avan, I.; Hall, C. D.; Katritzky, A. R.
Peptidomimetics via modifications of amino acids and peptide
bonds. Chem. Soc. Rev. 2014, 43 (10), 3575−3594.
(4) (a) Han, H.; Janda, K. D. Azatides: Solution and Liquid Phase
Syntheses of a New Peptidomimetic. J. Am. Chem. Soc. 1996, 118
(11), 2539−2544. (b) Tonali, N.; Correia, I.; Lesma, J.; Bernadat, G.;
Ongeri, S.; Lequin, O. Introducing sequential aza-amino acids units
induces repeated β-turns and helical conformations in peptides. Org.
Biomol. Chem. 2020, 18 (18), 3452−3458.
(13) Sui, Q.; Borchardt, D.; Rabenstein, D. L. Kinetics and Equilibria
of Cis/trans Isomerization of Backbone amide bonds in peptoids. J.
Am. Chem. Soc. 2007, 129 (39), 12042−12048.
(14) (a) Yamasaki, R.; Tanatani, A.; Azumaya, I.; Saito, S.;
Yamaguchi, K.; Kagechika, H. Amide conformational switching
induced by protonation of aromatic substituent. Org. Lett. 2003, 5
(8), 1265−1267. (b) Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A.
Theoretical Studies on cis-amide preference in N-methylanilides. J.
Org. Chem. 1995, 60 (15), 4715−4720. (c) Itai, A.; Toriumi, Y.; Saito,
S.; Kagechika, H.; Shudo, K. Preference for cis-amide structure in N-
acyl-N-methylanilines. J. Am. Chem. Soc. 1992, 114 (26), 10649−
10650.
(5) (a) Kanta Sarma, B.; Yousufuddin, M.; Kodadek, T. Acyl
hydrazides as peptoid sub-monomers. Chem. Commun. 2011, 47 (38),
10590−10592. (b) Sarma, B. K.; Kodadek, T. Submonomer Synthesis
of A Hybrid Peptoid−Azapeptoid Library. ACS Comb. Sci. 2012, 14
E
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