Direct spectroscopic evidence of hyperconjugation unveils the conformational landscape of hydrazides

Article abstract of DOI:10.1002/anie.201407801

The stereochemistry of hydrazides makes them especially interesting as building blocks for molecular design. An exhaustive conformational analysis of three model hydra-zides was conducted in a conformer-selective approach by using a combination of high-level quantum chemistry calculations and vibrational spectroscopy in the gas phase and in solution. The NH stretch frequency was found to be highly sensitive to hyper conjugation, thus making it an efficient probe of the conformation of the neighboring nitrogen atom. This property greatly assisted the identification of the isomers observed experimentally in the conformer pool. A rationalization of the hydrazide conformational landscape is proposed, therefore paving the way for a better characterization of secondary structures in larger systems.

Full text of DOI:10.1002/anie.201407801

Angewandte
Chemie
DOI: 10.1002/anie.201407801
Structure Elucidation
Direct Spectroscopic Evidence of Hyperconjugation Unveils the
Conformational Landscape of Hydrazides**
Eric Gloaguen,* Valꢀrie Brenner, Mohammad Alauddin, Benjamin Tardivel, Michel Mons,
Anne Zehnacker-Rentien, Valꢀrie Declerck, and David J. Aitken*
Abstract: The stereochemistry of hydrazides makes them
especially interesting as building blocks for molecular design.
An exhaustive conformational analysis of three model hydra-
zides was conducted in a conformer-selective approach by
using a combination of high-level quantum chemistry calcu-
lations and vibrational spectroscopy in the gas phase and in
solution. The NH stretch frequency was found to be highly
sensitive to hyperconjugation, thus making it an efficient probe
of the conformation of the neighboring nitrogen atom. This
property greatly assisted the identification of the isomers
observed experimentally in the conformer pool. A ration-
alization of the hydrazide conformational landscape is pro-
posed, therefore paving the way for a better characterization of
secondary structures in larger systems.
A
cylated hydrazines (Figure 1) are a widely used family of
hydrazides with applications in diverse fields ranging from
pharmaceuticals to industrial products and materials.[1,2] Since
these building blocks combine the physical and chemical
features of hydrazines and peptides, they have generated
considerable interest as peptidomimetics,[3] potentially yield-
ing drug candidates with enhanced pharmacological pro-
files.[4] In monoacylated hydrazines, one nitrogen atom is
reminiscent of a planar amide nitrogen atom (N3), whereas
the other nitrogen atom (N4) has a free lone pair of electrons,
which leads to distinct conformational and physicochemical
characteristics. An example of a therapeutic in this compound
class is the protease inhibitor atazanavir, which has provided
Figure 1. Top: A representative monoacylated hydrazine of the hydra-
zides investigated herein. Middle: the four intrinsic conformers of the
hydrazide group. Bottom: the three hydrazide molecules investigated
herein.
[*] Dr. E. Gloaguen, Dr. V. Brenner, Dr. M. Alauddin, B. Tardivel,
Dr. M. Mons
CNRS, CEA, LIDyL, Laboratoire Francis Perrin URA 2453
91191 Gif-sur-Yvette (France)
E-mail: eric.gloaguen@cea.fr
a simplified antiretroviral treatment for human immunodefi-
ciency virus since its introduction a decade ago.[5] Other
examples include immunogenic[6] and antimicrobial[7] agents,
while in the area of foldamer design, predictions of regular
secondary structures for hydrazino peptides[8] have been
borne out experimentally.[9–11]
Homepage: http://iramis.cea.fr/Pisp/70/eric.gloaguen.html
Dr. A. Zehnacker-Rentien
CNRS, ISMO, Bꢀt. 210, Universitꢁ Paris Sud
UMR 8214, 91405 Orsay (France)
Although the conformational preferences of hydrazides
are primordial for their biological activities and an under-
standing of their origins is of equal importance, appropriate
studies have been somewhat limited. Combined theoretical
and experimental gas-phase investigations on model com-
pounds are rare.[12] Some solution studies have focused on
specific cases, such as the hydrazino turn phenomenon[13–15] or
the behavior of cyclic aza-b3-peptides.[16] It has been suggested
that a combination of steric and electronic effects are at play
in the conformational preferences of the core Na-acylated
Nb,Nb-disubstituted hydrazide feature.[2,17,18] Given the impor-
tance of this central structural feature for the behavior of
Dr. V. Declerck, Prof. D. J. Aitken
Universitꢁ Paris Sud, ICMMO, UMR 8182, Bꢀt 420
15 rue Georges Clꢁmenceau, 91405 Orsay cedex (France)
E-mail: david.aitken@u-psud.fr
Homepage: http://www.icmmo.u-psud.fr/Labos/LSOM/cv/da.php
[**] This work was supported by the inter-Labex PALM-CHARMMMAT
project Lalifold 2013-0272I. We would like to acknowledge Dr.
Michel Broquier for energy calculations on NDMPA and NIA at the
QCISD(T) level, and Adrien Fredon for energy calculations on NIA at
the RI-B97-D level. This work was granted access to the HPC
resources of CCRTat CEA under the allocation CCRT2014-p606bren.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407801.
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numerous other derivatives, we decided to study it in more
detail.
ꢀ
Two stereocenters are involved (Figure 1): the C2 N3
bond, which leads to E or Z geometries, and the N4 atom,
which enables synclinal or anticlinal (sc or ac) C2-N3-N4-C5
torsional angles (ꢁ 608 or ꢁ1208, respectively). This leads to
a potential energy surface with eight wells, which is reduced to
four when R’ = R’’, labeled E-ac, E-sc, Z-ac, and Z-sc.
Hydrazides are often observed as a mixture of two con-
formers[2,12,17–19] attributed to E/Z isomerism, although the
puzzling appearance of two very different free N3-H stretch
frequencies (3424 and 3303 cmꢀ1) in the IR spectra remains
unexplained.[19] To better understand this observation and
gain deeper insight into the interactions which shape hydra-
zides, a comprehensive conformational analysis was carried
out on three model compounds through a combination of
solution and conformer-selective gas-phase IR spectral anal-
ysis of the NH stretch region with high-level quantum
chemistry calculations of the isolated species.
First, N’,N’-dimethylacetohydrazide (NDMA) was stud-
ied since it is one of the simplest hydrazides which bears only
one NH moiety; thus if several transitions appear in the
spectral region of the NH stretch, a conformational mixture is
implicated. The FTIR spectrum in chloroform indeed shows
three transitions (Figure 2): a weak band at 3430 cmꢀ1 and two
intense bands at 3301 and 3334 cmꢀ1. To conclude that these
result from three conformations is not straightforward,
however. While the first transition is consistent with an NH
group not engaged in a hydrogen bond, the 3300–3350 cmꢀ1
range, where the intense doublet lies, is more typical of NH
groups engaged in strong hydrogen bonds.[20] It therefore
needs to be ascertained whether self-association of NDMA
through hydrogen bonding is responsible for this doublet, and
if not, why monomers would lead to such unusually red-
shifted transitions for nonbonded NH groups.
Figure 2. IR spectra of the three hydrazides recorded in solution (FTIR,
10 mm, in CHCl3) and in the gas phase (IR/R2PI-UV). The intensities
correspond to absorbance in solution (IA, ꢂ10ꢀ3) or depletion in the
gas phase (ID, %).
In this respect, obtaining IR spectra of isolated monomers
in the gas phase is of primary interest. To this end, IR/UV
double-resonance spectroscopy, a mass-resolved conformer-
selective technique,[21] is particularly suitable to record
separately the IR spectrum of each conformer of a conforma-
tional mixture, provided the system possesses a near-UV
chromophore (see the Supporting information). N’,N’-
dimethyl-2-phenylacetohydrazide (NDMPA) and N-(isoindo-
lin-2-yl)acetamide (NIA) were designed for such studies.
Figure 2 presents both their solution and gas-phase IR
spectra. First, their spectra in solution comprise three bands
resembling the pattern already described for NDMA. This
gives a first indication that the
vation for isolated molecules in a vacuum proves that the free
N3-H group is intrinsically able to reach a transition range
normally reserved for strongly hydrogen-bonded NH
groups.[20] Transitions of conformer B appear in the usual
range for a free NH group[20,22] (3456 and 3466 cmꢀ1
respectively).
,
To understand these observations, quantum chemistry
calculations on the isolated molecules were conducted on the
four conformers expected for NDMA, NDMPA, and NIA. In
the case of the latter two, the theoretical results can be
directly compared to gas-phase data. Energetics and NH
stretch frequencies are presented in Table 1. A first point is
aromatic ring has little interference
on the hydrazide function of these
systems. Gas-phase experiments
reveal that monomers have two
conformers, A and B, with A dom-
inating the UV spectrum (see the
Supporting information). For both
NDMPA and NIA, A is character-
ized by a narrow band in the 3300–
Table 1: Energetics and scaled harmonic frequency of the NH stretch.
NDMA
NDMPA
NIA
DG(300 K)[a]
n(NH)[b]
DG(300 K)[b]
n(NH)[b]
DG(300 K)[a]
n(NH)[b]
E-ac
Z-sc
Z-ac
E-sc
0
5
11
25
3306
3444
3283
3406
0
3
8
29
3294
3440
3305
3404
0
3
10
21
3303
3436
3285
3400
[a] In kJmolꢀ1. Electronic energies were calculated at the QCISD(T)/TZVPP level on MP2/TZVPP-
optimized geometries; thermodynamic corrections at 300 K were calculated at the RI-B97D/TZVPP level
on geometries optimized at the same level. [b] In cmꢀ1. A scaling function determined for amide groups
3350 cmꢀ1
range
(3320
and
3330 cmꢀ1, respectively). This obser- was used (see the Supporting Information).
2
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Table 2: NBO analysis.
NDMA
Z-ac
NDMPA
Z-sc Z-ac
NIA
E-ac Z-sc Z-ac E-sc
E-ac
Z-sc
E-sc
E-ac
E-sc
[a]
n(sN3-H
)
1.954 1.952 1.948 1.951
0.056 0.038 0.058 0.041
1.952 1.951 1.947 1.953
0.057 0.039 0.058 0.042
1.955 1.953 1.948 1.952
0.056 0.039 0.058 0.043
[a]
n(s*N3-H
lpN4!s*N3-H
lpN4!s*C2-N3
)
[b]
[b]
51
12
23
53
52
7
29
57
51
11
20
53
49
11
29
58
54
14
24
54
54
8
31
57
[a] Occupancies were analyzed at the MP2/TZVPP level. [b] Stabilization energies (kJmolꢀ1) between donor and acceptor orbitals were calculated at
the HF/TZVPP level (see the Supporting Information).
that the conformational energetics of all three compounds are
very similar, thus validating NDMPA and NIA as good model
systems for the characterization of the hydrazide conforma-
tional landscape. The results demonstrate that conformers can
be classified into two categories according to their NH stretch
frequency: conformers Z-sc and E-sc have frequencies
predicted above 3400 cmꢀ1, while Z-ac and E-ac have
frequencies below 3306 cmꢀ1. It appears that the unusual
red-shifted signature for the free NH group is associated to
the ac character of the C2-N3-N4-C5 angle, and not to the E
or Z character of the amide group. Consequently, A must be
assigned to an ac conformer, and B to an sc conformer. As the
lowest energy conformers are expected to be the most
populated in the experiment, E-ac and Z-sc are the most
reasonable assignments for A and B, respectively.
It now has to be explained why conformer A has a weaker
NH bond than B, as evidenced by the considerable red-shift of
136 cmꢀ1 in both NDMPA and NIA, and how this is related to
the sc or ac character of the C2-N3-N4-C5 angle. Natural
bond orbital (NBO) analyses were carried out and the most
significant results are presented in Table 2. For all the
conformers of all three systems, the occupancy of the NH
bonding orbital (sN3-H) does not vary significantly. However,
the occupancy of the NH antibonding orbital (s*N3-H
)
dramatically increases by about 40% in ac conformers
relative to sc conformers. It then follows that the red-shift
of the predicted NH stretch frequency of the ac conformers
relative to the sc conformers can be ascribed to an increase of
the occupancy of the s*N3-H orbital. Stabilization energies
(Table 2) reveal that this increase in occupancy correlates
with an increase in the interaction between s*N3-H and the N4
lone pair of electrons (lpN4). This hyperconjugation occurs
mostly when the overlap between the s*N3-H and lpN4 orbitals
is optimum, that is, in the ac conformers (Figure 3). Another
hyperconjugation effect was also revealed between the lpN4
and s*C2N3 orbitals by the same analysis, and occurs mostly in
the sc conformers. A spectral signature of this latter hyper-
conjugation should be expected in the CN stretch region, but
no effect has been clearly evidenced by harmonic frequency
calculations because of strong couplings of the CN stretch
with other vibrational modes.
The energetics of hydrazides can be rationalized by
comparison with amides. (Z)-N-methylacetamide is intrinsi-
cally more stable than the E conformer by 13 kJmolꢀ1 (see the
Supporting Information). This energetic order is preserved in
sc hydrazides (E-sc and Z-sc), with an energy gap even raised
to more than 20 kJmolꢀ1 because of steric clashes in E-sc
between C5-H2 and C6-H2 on one side, and C1-H2 on the
Figure 3. Energetics of NDMA, NDMPA, and NIA conformers. The
conformational landscape of hydrazides is mainly governed by hyper-
conjugation effects between s*NH (green) and lpN4 (red), lpN4 and
s*C2N3 (blue), the electronic repulsion between lpO (gray) and lpN4 in
Z-ac, and a steric clash in E-sc (see text for details).
other side.[17] Surprisingly, this order is totally reversed for the
ac pair, with Z-ac being less stable than E-ac by about
10 kJmolꢀ1. The analysis of conformer geometry reveals that
all NDMA conformers except Z-ac have a plane of symmetry
(C2N3N4 plane). The loss of symmetry in Z-ac is due to the
rotation around the NN bond caused by the electronic
repulsion between the lone pair of electrons on the oxygen
atom (lpO) and lpN4 (Figure 3).[17,18] Therefore, Z-ac is shifted
about 20 kJmolꢀ1 higher relative to E-ac than is expected for
a E/Z pair. Without this repulsion, Z-ac would be expected to
be 13 kJmolꢀ1 lower in energy than E-ac (E/Z amide energy
gap), and all the ac conformers would be far more stable than
their sc counterparts by at least 15 kJmolꢀ1 (Table 2). The
differential hyperconjugation effect between lpN4!s*N3-H
stabilizing the ac conformers, and lpN4!s*C2-N3 stabilizing
the sc conformers must contribute to this intrinsic energy
difference between the ac and sc conformers, although it is
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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employed. Finally, while E-sc and Z-ac are too energetically
penalized to be observed in the gas phase, solvent effects may
bring the energy of Z-ac low enough to be observed in
solution, as revealed by FTIR spectra.
In conclusion, this study reveals that hyperconjugation
between the s*N3-H and lpN4 orbitals has a huge impact on the
NH stretch frequency in model hydrazides. Large red-shifts
(ca. 130 cmꢀ1) relative to the habitual free NH stretch range
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1,1,1,3,3,3-hexafluoro-2-propanol in CCl4[23]). This phenom-
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The reason why the vibrational signature of hyperconjugation
is too often neglected might come from its general occurrence
in spectral regions that become easily crowded in large
species. The present demonstration of the value of direct
spectroscopic evidence of hyperconjugation may be expected
to foster both experimental and theoretical developments
leading to a better characterization of such effects through
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Received: July 31, 2014
Published online: && &&, &&&&
´
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Keywords: hydrazides · hyperconjugation · IR spectroscopy ·
laser spectroscopy · structure elucidation
.
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4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Angewandte
Chemie
Communications
Structure Elucidation
Neighborhood watch: IR spectroscopy of
hydrazides in the gas phase and in
solution has proved to be an efficient
probe of the conformation of the neigh-
boring nitrogen atoms. The large hyper-
conjugation-induced spectral shifts in the
NH stretch region enabled a series of
hydrazide model molecules to be con-
formationally characterized.
E. Gloaguen,* V. Brenner, M. Alauddin,
B. Tardivel, M. Mons,
A. Zehnacker-Rentien, V. Declerck,
D. J. Aitken*
&&&& — &&&&
Direct Spectroscopic Evidence of
Hyperconjugation Unveils the
Conformational Landscape of Hydrazides
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!