Substituent and solvent effects on intermolecular interactions in crystals of N -acylhydrazone derivatives: Single-crystal X-ray, solid-state NMR, and computational studies

Article abstract of DOI:10.1021/cg401866x

New crystalline forms of hydrated and anhydrous N-acylhydrazones are reported. The studied crystal structures were determined by single-crystal X-ray diffraction at 90 or 100 K. Transferred aspherical atom model (TAAM) structure refinements were performed

Full text of DOI:10.1021/cg401866x

Article
pubs.acs.org/crystal
Substituent and Solvent Effects on Intermolecular Interactions in
Crystals of N‑Acylhydrazone Derivatives: Single-Crystal X‑ray, Solid-
State NMR, and Computational Studies
Liliana Mazur,*,† Katarzyna N. Jarzembska,‡,§ Radosław Kaminski,‡,§ Krzysztof Wozniak,‡
́
́
Edyta Pindelska,∥ and Monika Zielinska-Pisklak∥
́
†Department of Chemistry, Maria Curie-Skłodowska University, Maria Curie-Skłodowska Square 2, 20-031 Lublin, Poland
‡Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warszawa, Poland
§Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, United States
∥Department of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland
S
* Supporting Information
ABSTRACT: New crystalline forms of hydrated and anhydrous N-acylhydrazones are
reported. The studied crystal structures were determined by single-crystal X-ray diffraction
at 90 or 100 K. Transferred aspherical atom model (TAAM) structure refinements were
performed with the aid of the most recent version of the University at Buffalo Databank
(UBDB). The resulting crystal structures were analyzed in terms of molecular
conformations, intermolecular interaction energies, and crystal packing motifs. For this
purpose, solid-state NMR studies and theoretical calculations were conducted
supplementarily. It was found that all studied hydrazones adopt the E configuration around
the azine N−N bond and imino NC function in the solid state, whereas the hydrazide
N−N−CO moiety exhibits the E and Z arrangement in the N-acyl and N-aroyl
derivatives, respectively. The constrained energy scans confirmed the E conformation of the
hydrazide unit and the E arrangement of pyridine and hydrazone N atoms as the most stable
ones. The association modes in the studied crystals are dominated by strong hydrogen
bonds of the N−H···O or N−H···N-type involving the amide group as a proton donor. Consequently, as indicated by lattice
energy calculations, a significant increase in the crystal cohesive energy per asymmetric unit is observed when water molecules are
incorporated into the crystal structure, because this enables efficient saturation of the hydrogen bond acceptor and donor atoms.
On the other hand, a substantial contribution of π···π stacking interactions to the overall stabilization of the crystal nets was also
found. Thus, when more bulky phenyl substituents are introduced, the cohesive energy becomes more favorable.
hydrazones are organic compounds bearing the C2N2N1
lone electron pair of the terminal N1 atom. Both nitrogen
1. INTRODUCTION
moiety, where the double CN bond is conjugated with the
The chemistry of N-acyl- and N-aroylhydrazones (NAHs) has
been the subject of much interest in recent years. Many papers
atoms of the hydrazone group are nucleophilic, whereas the
and reviews concerning the use of hydrazone derivatives in
azine C2 atom has both electrophilic and nucleophilic character
and constitutes the most reactive center of the hydrazone
moiety. In the case of N-acyl- and N-aroylhydrazones, the
presence of an additional CO donor site induces an extended
π-electron delocalization along the whole C1(O)N1HN2
C2 fragment. These structural and electronic features determine
the physicochemical properties and biological activities of
NAHs to a large extent. Commonly, the acylhydrazone unit
adopts a planar geometry; however, the planarity might be
broken in the case of steric hindrance between substituents
around the CN bond.6 Due to presence of the double CN
bond, unsymmetrical hydrazones may appear in the form of E/
organic1 and organometallic2 syntheses, as well as their
potential applications in analytical chemistry3 and medicine,4
have been published. N-acylhydrazones, which can be readily
obtained by condensation of aldehydes or ketones with
acylhydrazines in the presence of acid catalysts,5 represent a
class of azomethine compounds (Scheme 1). In general,
Scheme 1. Possible Isomers of Acetyl- And Aroylhydrazone
Derivatives6,8
Received: December 14, 2013
Revised: March 18, 2014
Published: April 2, 2014
© 2014 American Chemical Society
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Z configurational isomers. Additionally, their N-acyl and N-
aroyl derivatives can exist in solution as a mixture of
conformational isomers, because of the hindered rotation
around the C−N amide bond. Therefore, in total four isomers
are possible. What is more, some aroylhydrazones can be
involved in keto−enol tautomeric interconversion.7 The E−Z
isomerization of hydrazones resulting from temperature and
solvent effects, pH value, or UV irradiation can occur. Different
tautomeric and isomeric forms have different physicochemical
and spectral properties and can be distinguished according to
the corresponding IR, UV−vis, and NMR spectra. On the basis
of quantum-chemical calculations, it was established that among
various conformational possibilities provided by the discussed
hydrazone derivatives, acylhydrazones exist mainly in the EE′
form (Scheme 1) with E configuration for both imine and
amide groups and s-trans junction between both functions. In
turn, in the case of aroylhydrazone crystal structures, the EZ′
form is commonly encountered.8 The conformational behavior
and E−Z isomerization of certain hydrazone derivatives was
studied in DMSO and CDCl3 solutions by NMR and HPLC
techniques.6a It was found that N-aroylhydrazones exist
primarily as the EZ′ isomers whereas a mixture of both forms
was found for acyl derivatives, with variable stoichiometric
ratios, depending on the solvent polarity.
Due to the capability of reacting with electrophilic and
nucleophilic reagents, hydrazones and their aldehyde deriva-
tives are widely used in organic chemistry, especially in
condensation, cyclization, and cycloaddition reactions for
synthesis of heterocyclic compounds.1a,5b N-Acylhydrazones
can serve as stable imine equivalents, which can react with
various nucleophiles. Chiral hydrazide products can be used as
building blocks and transformed into various chiral nitrogen-
containing compounds by cleavage of the N−N bond.1b,c The
N-acyl groups often play important roles as templates for metal
catalysis, which facilitate stereochemical control.1 Furthermore,
synthetic flexibility of hydrazones, selectivity, and sensitivity
toward transition metal ions make them attractive as ligands in
coordination chemistry.
will be explored. Experimental methods together with
theoretical computations shall shed some light on the preferred
conformations of the studied molecules as well as provide
qualitative and quantitative information about crystal architec-
ture and energetics, main molecular motifs, intermolecular
interactions, and water content contribution to the crystal
lattice stability. Finally, this work is enriched with solid-state
NMR spectroscopy, which is a complementary technique to X-
ray crystallography. Thanks to these experiments, the purity of
the studied solid systems was evaluated, and hence the relative
stability of selected crystals was established.
2. EXPERIMENTAL SECTION
2.1. Synthesis and Materials. All chemicals and solvents were
purchased from commercial sources (Sigma-Aldrich Co., USA, or
Polish Chemical Reagents, Poland) and used without further
purification. IR spectra (600−4000 cm−1) were recorded on a Nicolet
6700 FT-IR spectrophotometer (in the ATR mode, ZnSe crystal).
Elemental analyses (Table S1, Supporting Information) were
performed on a CHN PerkinElmer 2400 analyzer.
The considered hydrazones were prepared by condensation of 2-
pyridinecarboxaldehyde with the corresponding acid hydrazides in
methanolic solution (Scheme 2) following the procedure described in
the literature.5,9 Single crystals suitable for X-ray diffraction studies
were grown from the mother liquor by slow evaporation at room
temperature. Alternatively, they were obtained by recrystallization
from dry methanol or DMF solutions.
2.2. X-ray Crystallography. 2.2.1. X-ray Data Collection. Single-
crystal X-ray measurements of 1, 1·H2O, 2, 4·H2O, 4·2H2O, 5, and 5·
H2O were carried out on an Agilent Technologies Xcalibur CCD
diffractometer equipped with a molybdenum sealed X-ray tube (Mo
Kα radiation, λ = 0.71073 Å), graphite monochromator, and Oxford
Cryosystems nitrogen gas-flow device (Cobra Plus). The measurement
of 3·H2O was performed on a Bruker AXS Kappa APEX II Ultra
diffractometer equipped with a TXS rotating anode, multilayer optics,
and Oxford Cryosystems nitrogen gas-flow device (700 Series
Cryostream). In all the cases, single crystals of suitable sizes were
mounted on a goniometer head using Paratone N oil and cooled to
100 or 90 K. Data collection strategies, based solely on ω scans, were
optimized and monitored applying the appropriate algorithms
implemented within the CRYSALIS10 or APEX211 program suites,
respectively. Unit cell parameter determination, raw diffraction image
integration, Lorentz and polarization corrections, oblique incidence
effects, multiscan absorption corrections, and frame-to-frame scaling
were performed with the diffractometer software (CRYSALIS or
APEX2). Merging of reflections was carried out with the SORTAV
program.12 Final data collection parameters are summarized in Table
1.
2.2.2. Structure Solution and Refinement. All structures were
solved using direct methods implemented in the SHELXS program13
and refined with the SHELXL program13 within the independent atom
model (IAM) approximation. In all cases, the positions of hydrogen
atoms and orientations of methyl groups were determined from
Fourier residual maps. Subsequently, transferred aspherical atom
model (TAAM)14 refinements were performed in the MOPRO
package15 with the aid of the new version of the University at Buffalo
Databank (UBDB)16 and the LSDB program,16,17 based on the
Hansen−Coppens multipole model.18 During TAAM refinements, all
electron density parameters are kept fixed at the databank values,
whereas the scale factor, atomic positions, and atomic displacement
parameters (ADPs) are iteratively varied. Additionally, for the purpose
of this work the UBDB databank was extended with the atom types
specific for hydrazone molecules (Table S2, Supporting Information),
according to the literature procedure.19 The final refinement statistics
for all compounds are summarized in Table 1. The CIF files for each
refinement are available from the Supporting Information or can be
retrieved from the Cambridge Crystallographic Data Centre
(CCDC)20 (deposition numbers CCDC 974829−974836).
Given the scope of applications, it is not surprising that the
chemistry of N-acyl- and N-aroylhydrazones has attracted
particular attention in recent years. Many researchers have
synthesized these compounds as target structures and evaluated
their physicochemical and biological properties. However,
studies devoted to their crystal structures seem to be rather
limited. For these reasons and as a part of the wider project
devoted to structural, electronic, and antiproliferative properties
of selected 2-pyridinecarboxaldehyde hydrazones, a compre-
hensive single-crystal X-ray analysis and computational
investigations were performed. The aim of this work was to
gain insight into the influence of the type of C1-substituent on
the conformational preferences of 1−5 (Scheme 2) and the
intermolecular interaction patterns in their crystals. Addition-
ally, solvent aspects constitute an interesting subject and thus
Scheme 2. General Synthetic Route of Studied Hydrazones
(R = H (1), Me (2), Ph (3), 2-Cl-C6H5(4), 2-NH2-C6H5 (5))
and a Numbering Scheme
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Table 1. Crystal Data and TAAM Refinement Details Characterizing All Studied Hydrazone Crystals
cryst structure
chemical formula
formula weight
Tm, °C
1
1·H2O
C7H9N3O2
167.16
132
2
3·H2O
C13H13N3O2
243.25
124
C7H7N3O
149.14
122
C8H9N3O
163.17
133
cryst syst
space group
a, Å
monoclinic
P21/c
triclinic
monoclinic
P21/c
orthorhombic
Pbca
P1
̅
9.5229(9)
4.6958(5)
16.170(2)
90
6.4717(5)
7.9214(7)
8.6745(7)
72.412(8)
86.116(7)
69.625(8)
397.04(6)
2
5.3682(2)
8.0654(2)
18.5394(5)
90
6.978(1)
11.921(2)
29.198(6)
90
b, Å
c, Å
α, deg
β, deg
95.509(9)
90
92.938(3)
90
90
γ, deg
V, Å3
90
719.7(1)
4
801.64(4)
4
2429.0(8)
8
Z
F(000)
312
176
344
1024
d
calc, g·cm−3
1.377
1.399
1.352
1.331
completeness
(sin θ/λ)max, Å−1
θ range, deg
absorp coeff, μ,mm−1
cryst size, mm3
cryst color and form
T, K
97.5%
98.5%
96.7%
98.9%
1.13
0.70
0.66
0.85
3.47−29.82
0.098
2.87−27.97
0.106
3.35−37.16
0.094
2.79−53.23
0.093
0.54 × 0.15 × 0.12
colorless needle
100
0.42 × 0.18 × 0.06
colorless plate
100
0.65 × 0.38 × 0.10
colorless plate
90
0.25 × 0.22 × 0.17
colorless needle
90
Rint
2.75%
1.71%
2.24%
5.88%
reflns collected/unique
reflns with I ≥ 3σ(I)
params/restraints
R[F]
5730/2021
1446
2760/1883
1250
15459/3984
2873
119023/14445
10 443
128/14
145/18
145/18
215/26
a
b
b
b
a
b
b
b
a
b
b
b
a
b
b
b
3.15% /4.73%
2.65% /4.56%
2.76% /4.34%
2.48% /3.50%
a
a
a
a
R[F2]
6.67% /6.91%
3.96% /4.28%
6.38% /6.61%
4.42% /4.51%
a
a
a
a
wR[F]
3.60% /3.81%
2.81% /3.09%
3.00% /3.17%
3.05% /3.22%
a
b
a
b
a
b
a
b
S
1.57 /1.39
1.22 /1.08
1.57 /1.40
1.36 /1.25
ϱmresin/max, e·Å−3
−0.19/+0.22
−0.17/+0.15
−0.27/+0.34
−0.34/+0.19
cryst structure
chemical formula
formula weight
Tm, °C
4·H2O
C13H12N3O2Cl
277.69
4·2H2O
C13H14N3O3Cl
295.71
5
5·H2O
C13H14N4O2
258.26
128
C13H12N4O
240.25
155
131
118
cryst syst
space group
a, Å
orthorhombic
Pbca
hexagonal
monoclinic
P21/n
monoclinic
P21/c
R3
̅
7.0180(2)
11.8624(4)
31.332(1)
90
26.0229(3)
26.0229(3)
11.2044(2)
90
12.497(4)
5.8221(9)
16.191(2)
90
15.191(1)
6.8256(5)
12.215(1)
90
b, Å
c, Å
α, deg
β, deg
90
90
99.42(2)
90
98.478(6)
90
γ, deg
V, Å3
90
120
2608.4(2)
8
6571.0(2)
18
1162.1(4)
4
1252.8(2)
4
Z
F(000)
1152
2772
504
544
d
calc, g·cm−3
1.415
1.346
1.374
1.370
completeness
(sin θ/λ)max, Å−1
θ range, deg
absorp coeff, μ,mm−1
cryst size, mm3
cryst color and form
T, K
98.0%
99.3%
98.1%
0.66
99.1%
0.86
1.13
0.66
3.43−37.61
0.294
2.71−53.20
0.272
3.30−27.97
0.092
3.28−27.96
0.096
0.52 × 0.28 × 0.12
colorless needle
90
0.58 × 0.25 × 0.16
colorless needle
90
0.50 × 0.18 × 0.05
yellow plate
100
0.54 × 0.25 × 0.12
yellow needle
90
Rint
4.83%
4.40%
3.15%
1.51%
reflns collected/unique
reflns with I ≥ 3σ(I)
params/restraints
R[F]
48334/6809
4399
206261/17456
11 704
4849/2749
1599
5208/2971
2329
220/24
237/28
211/24
228/28
a
b
b
a
b
b
a
b
b
a
b
b
3.17% /6.32%
2.87% /4.58%
4.69% /7.84%
2.96% /3.96%
a
a
a
a
R[F2]
5.97% /6.68%
3.64% /3.87%
8.74% /9.86%
6.56% /6.78%
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Table 1. continued
a
b
a
b
a
b
a
b
wR[F]
3.84% /4.15%
3.14% /3.42%
5.23% /5.94%
3.36% /4.76%
a
b
a
b
a
b
a
b
S
1.83 /1.58
−0.37/+0.47
1.56 /1.46
−0.32/+0.41
1.81 /1.53
−0.27/+0.40
1.57 /1.94
−0.17/+0.24
ϱmresin/max, e·Å−3
a
b
Values given for reflections with I ≥ 3σ(I). Values given for all reflections.
2.3. NMR Studies. 13C and 15N spectra were recorded at room
temperature with a Bruker Avance 400 WB spectrometer at 9.4 T,
using 100.61 and 40.50 MHz resonance frequencies, respectively. A
Bruker 4.0 mm HX double-resonance magic-angle spinning (MAS)
probe was applied. The 13C and 15N experiments were performed
using cross-polarization (CP),21 high power decoupling, and MAS23
with 4 mm zirconia rotors driven by dry air. The MAS rates were 7.5
kHz and 3.5−5.0 kHz for 13C and 15N, respectively. The Hartmann−
Hahn conditions22 for 13C and 15N were matched with the aid of
adamantane and glycine-15N. Typical 13C acquisition parameters,
including a (π/2) pulse of 2.7 μs and a recycle delay of all hydrazones,
were optimized (30−250 s). Chemical shifts were referenced to TMS
using adamantane as an external secondary standard (δ = 38.3 ppm
from TMS for the high-frequency peak). The 15N CP/MAS spectra
were acquired under the following conditions: a (π/2) pulse of 4.1 μs
and a contact time of 5 ms. They have been referenced to liquid
nitromethane by setting the −345 ppm value to the peak of crystalline
glycine-15N. The NMR spectra were processed, and peaks were
deconvoluted with the ACD/SpecManager NMR program.23 In order
to verify the signal assignment, GIPAW calculations of shielding
constants based on X-ray structures of NAHs were performed using
the Cambridge Serial Total Energy Package (CASTEP) program24
implemented in the Materials Studio 6.1 software.25 The computation
details can be find in the Supporting Information.
2.4. Thermal Analysis. The thermal stabilities of the studied
hydrazones were examined using a Setsys 16/18 (Setaram) thermal
analyzer, recording the TG/DTG/DSC curves. Crystals obtained from
the crystallization batches had been air-dried before they were
subjected to DSC or TGA analysis. The samples (4−7 mg) were
heated in a ceramic crucible between 30−900 °C in a flowing air
atmosphere with a heating rate of 10 °C min−1. Loss of solvent from
the crystals was characterized by TG, and mass loss was calculated
based on the mass of the original sample. The temperatures of the
dehydration processes and temperatures and enthalpies of fusion
(Table S1, Supporting Information) were established on the basis of
the DSC curves.
computational analyses of the solid state,34 were used for the purposes
of the CRYSTAL calculations. The cohesive energy (Ecoh) was
calculated following the procedure described in the literature:35
1
Z
Ecoh
=
Ebulk − Emol
where Ebulk is the total energy of a system (calculated per unit cell) and
Emol is the energy of an isolated molecule extracted from the bulk
(with the same geometry as in the crystal phase). Z stands for the
number of molecules in the unit cell.
The CRYSTAL package was additionally used for the dimer
interaction energy estimation at the DFT(B3LYP)/6-31G** level of
theory. The supermolecular approach was applied with both Grimme
dispersion and BSSE corrections.
All CRYSTAL input files were prepared using the CLUSTERGEN
program.36
3. RESULTS AND DISCUSSION
3.1. Crystal Syntheses and Introductive Remarks. A
common feature of the studied compounds is their tendency to
crystallize as hydrates. The same propensity was previously
observed for some other N-aroylhydrazone derivatives.37
Among the compounds reported in this paper (Scheme 2),
crystallization only as an anhydrous form is restricted to 2,
whereas the remaining hydrazones form stoichiometric
hydrates (3·H2O, 4·H2O, 4·2H2O), or exist both in the
hydrated and solvent-free forms (1, 1·H2O, 5, 5·H2O). Most of
the studied compounds form well-shaped single crystals as a
result of solvent evaporation directly from the stock solution (1,
2, 3·H2O, 4·2H2O, 5·H2O). In turn, the crystals of 1·H2O, 4·
H2O, and 5 can be obtained by recrystallization from DMF or
dry methanol. It is worth noting that both forms of 5 actually
grow simultaneously from the latter solution. Crystallization
from other common organic solvents (e.g., ethanol, propan-1-
ol, propan-2-ol, acetone, acetonitrile, chloroform, tetrahydro-
furan, DMSO) leads most often to stoichiometric hydrates or
solvent-free powder solids but never to other solvated crystal
structures. Such observations suggest that the specific
intermolecular interactions between either hydrazones, or
more importantly hydrazones and water molecules, are crucial
in the aggregation and crystallization processes and, in
consequence, determine the structures and compositions of
the final products. Furthermore, the water incorporated into
crystal networks can be either associated with the solvent or
absorbed from the air. The size and hydrogen bond donor and
acceptor properties of water molecules seem to satisfy best
hydrazone-based crystal networks. Nevertheless, it should be
stressed that no systematic study dedicated either to solvato-
morphism or polymorphism screening has yet been under-
taken.
2.5. Computational Studies. 2.5.1. Isolated Molecule Calcu-
lations. All isolated molecule computations were performed using the
GAUSSIAN program package (GAUSSIAN09 version).26 Constrained
energy scans of the N2−C2−C3−N3 and, separately, the O1−C1−
C8−C9 dihedral angles were performed for selected model hydrazone
molecules at the DFT(B3LYP)/6-31G** level of theory.27,28 During
the scan procedure, solely the mentioned dihedral angle was
constrained in each case, and all the other parameters were fully
optimized. No symmetry constraints were applied during the
calculations. In the cases where discontinuous features were observed
in the trajectories (Figure S1, Supporting Information), only the
minimum energy conformations were optimized. These were done
both at the DFT(B3LYP)/ 6-31G** and at the MP2/aug-cc-pVDZ
level of theory.29,30
2.5.2. Periodic Calculations. All energy computations within the
CRYSTAL program package (CRYSTAL09 version)31 were performed
at the DFT(B3LYP) level of theory. The 6-31G** molecular all-
electron basis set was utilized for the purpose of the conducted
calculations. Both the Grimme dispersion correction32 and correction
for basis set superposition error (BSSE)33 were applied. Ghost atoms
were selected up to 5 Å distant from the studied molecule in a crystal
lattice and were used for the basis set superposition error estimation.
The evaluation of Coulomb and exchange series was controlled by five
thresholds, set to values of 10−7, 10−7, 10−7, 10−7, 10−25. The condition
for the SCF convergence was set to 10−7 on the energy difference
between two subsequent cycles. The TAAM refined crystal geometries,
which have previously been proven to be appropriate for sensible
The majority of the compounds under consideration
crystallize in centrosymmetric space groups (P1, P2 /c, or
̅
1
Pbca) with one hydrazone molecule in the asymmetric part of
the unit cell. The highest crystallographic symmetry was
observed for the 2-chlorophenyl derivative dihydrate, 4·2H2O
(R3 space group), which is isostructural with the previously
̅
reported 2-pyridinecarbaldehyde-2′-bromobenzoyl hydrazone
dihydrate38 (CSD refcode: HIGCOQ). Furthermore, a detailed
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a
Table 2. Selected Geometric Parameters for Studied Hydrazones after TAAM Refinement
d, Å
1
1·H2O
2
3·H2O
4·H2O
4·2H2O
5
5·H2O
C1−O1
C1−N1
N1−N2
N2−C2
C2−C3
C1−C8
θ, deg
1.225(1)
1.355(1)
1.371(1)
1.288(1)
1.468(1)
1.226(1)
1.344(1)
1.368(1)
1.279(1)
1.467(2)
1.2365(6)
1.3595(6)
1.3698(6)
1.2866(6)
1.4682(7)
1.4984(7)
2
1.2285(5)
1.3624(5)
1.3677(5)
1.2834(5)
1.4669(6)
1.4952(6)
3·H2O
1.225(1)
1.364(1)
1.371(1)
1.281(1)
1.470(1)
1.500(1)
4·H2O
1.2257(4)
1.3527(4)
1.3718(4)
1.2817(4)
1.4645(4)
1.5008(4)
4·2H2O
1.223(3)
1.377(3)
1.373(3)
1.278(3)
1.470(4)
1.491(4)
5
1.237(1)
1.369(1)
1.374(1)
1.287(1)
1.475(1)
1.493(1)
5·H2O
1
1·H2O
O1−C1−N1
O1−C1−C8
N1−C1−C8
C1−N1−N2
N1−N2−C2
N2−C2−C3
C2−C3−N3
τ, deg
123.2(1)
123.6(1)
119.06(5)
122.96(3)
121.60(3)
115.42(2)
118.24(1)
115.29(2)
120.50(2)
114.34(2)
3·H2O
123.6(1)
122.5(1)
113.9(1)
117.9(1)
115.7(1)
120.0(1)
114.6(1)
4·H2O
124.45(4)
122.31(4)
113.23(3)
118.99(3)
114.58(3)
120.42(3)
114.75(3)
4·2H2O
122.5(3)
122.8(2)
114.7(3)
119.4(2)
115.5(2)
121.8(3)
114.5(3)
5
121.7(1)
122.6(1)
115.8(1)
118.3(1)
115.4(1)
120.8(1)
114.5(1)
5·H2O
122.40(6)
118.54(4)
121.26(4)
115.33(5)
120.99(6)
115.22(4)
2
119.1(1)
114.9(1)
122.5(1)
113.8(1)
1
118.0(1)
116.0(1)
121.1(1)
114.7(1)
1·H2O
O1−C1−N1−N2
C1−N1−N2−C2
N1−N2−C2−C3
N2−C2−C3−N3
O1−C1−C8−C9
−176.8(1)
175.8(1)
178.9(1)
−176.5(1)
−178.8(1)
176.7(1)
179.13(5)
−1.70(2)
3.2(1)
0.65(3)
−8.0(2)
172.6(2)
176.5(2)
178.8(2)
−32.5(2)
2.2(1)
176.1(1)
−178.4(1)
176.2(1)
−23.4(1)
−175.29(4)
−179.37(4)
−178.40(4)
−176.88(2)
178.89(2)
−175.08(2)
22.48(2)
−179.7(1)
−176.9(1)
173.0(1)
−172.84(3)
−178.65(3)
−177.47(3)
68.18(3)
−179.0(1)
173.8(1)
−42.7(1)
a
d, bond distance; θ, bond angle; τ, torsion angle.
comparison of the studied structures with the closely related
hydrazone derivatives deposited in CSD indicated significant
similarity of the unit cell parameters, corresponding atom
coordinates, and hydrogen-bonding patterns of 2-pyridinecar-
boxaldehyde acetylhydrazone 2 with benzaldehyde39a and 2-
fluorobenzaldehyde39b acetylhydrazones (CSD refcodes: VUH-
MUG and KUTWEC).
In turn, the crystal structure of 3·H2O has been reported
previously by two groups,5d,e each time determined from
diffraction data collected at ambient temperature and refined
using the standard spherical atom model. In the course of the
present study, we have redetermined this structure from the
data measured at 90 K and refined using the transferable
aspherical atom model (TAAM) approach.14 In order to fully
characterize the crystal structure motifs and understand the
structural and energetic factors that control the packing of
molecules with a given functional group, it is essential to have a
wider overview of the solid-state arrangement of molecules
bearing that group. Therefore, comprehensive structural,
energetic, and Hirshfeld surface analyses of 3·H2O were carried
out and are included in our study. However, because the
molecular and crystal structure of this compound has been
described previously and the 3·H2O crystal is isostructural to 4·
H2O, only the latter structure is discussed in detail.
3.2. Molecular Structure and Cohesive Energy. The
relevant geometric parameters for all studied structures are
given in Table 2, whereas the molecular plots with the atom-
labeling schemes are presented in Figure 1. As indicated by the
X-ray data, all of the studied compounds appear in their keto−
imino tautomeric forms in the solid state with the trans
configuration around the C2N2 double bond of the
hydrazone bridge and s-trans junction between imine and
amide functions (Scheme 1).
The central C3−C2−N2−N1−C1−C8 spacer unit (Figure
1) in benzoyl derivatives, 3−5, as well as the C3−C2−N2−
N1−C1 moiety in the acyl hydrazones, 1 and 2, are effectively
planar with the all-trans extended-chain conformation, which is
supported by the appropriate torsion angles being close to 180°
(Table 2). The overall geometry of 2 is very similar to that
observed in some other closely related N-acetylhydrazones
(CSD refcodes: EYAQIF, KABHEC, KUTWEC, VABZOP,
XOZDIA). A common conformational feature for all
compounds is the trans arrangement of the pyridine N3 atom
with respect to the imine N2 atom as defined by the N2−C2−
C3−N3 torsion angles, deviating by no more than 7° from
180°. Such a conformation prevents potential repulsion
between the H atoms attached to the C2 and C4 carbon
atoms. In order to check the rotational freedom of the C2−C3
bond, an energy scan was also performed (Figure 2a). In the
case of model system 1, two minima, which correspond to trans
and cis conformations, differ energetically by about 22 kJ·mol−1.
In addition, the rotation barrier is rather high (system needs to
be activated by about 40 kJ mol−1 to rotate along the C2−C3
bond from trans to cis arrangement. Therefore, due to the
hampered rotation and significant conformational energy
difference, the more advantageous trans conformation is
observed in all the crystal structures of the studied hydrazones.
A small twist of the 2-pyridyl ring from the approximate plane
of the spacer unit, observed in the solid state, is naturally a
result of the crystal field effects.
In general, the most visible geometric difference between the
N-acyl- (1 and 2) and N-aroylhydrazones (3−5) is the
conformation of the hydrazide function, which adopts the
trans and cis arrangement, respectively. The energetic effects
accompanying rotation of the N1−C1 bond were examined
computationally. In the case of the model systems 1 and 3, two
local minima were found regarding the fixed O1−C1−N1−N2
torsion angle. In the case of 1, the more stable conformation is
the one where the O1 and N2 atoms are at the opposite sides
of molecule (EE′ conformation in Scheme 1; Table S3,
Supporting Information). This conformation is energetically
favored by about 12−16 kJ·mol−1, depending on the level of
theory used. In the compound 3, the bulky phenyl group leads
to diminishing of the energy differences, making the trans (EE′
conformation) orientation more energetically preferable by
only about 5−9 kJ·mol−1. It is worth mentioning that the
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Figure 1. Labeling of atoms and estimation of their thermal motion parameters as ADPs (50% probability level) after the final TAAM refinements.
Hydrogen and other selected atom labels are omitted for clarity.
molecule of 1 is flat in both of the most favorable
conformations, whereas in the case of 3, it deviates from
planarity (ca. 3° and 15°, for more and less stable minimum,
respectively). Interestingly, in the 3·H2O crystal structure, the
hydrazone molecule adopts the less stable conformation (EZ′)
with the O1−C1−N1−N2 torsion angle being equal to
−1.70(2)°, which seems to result from intermolecular
interactions in the crystal lattice.
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Figure 2. Torsion-angle-(τ)-constrained scans for (a) N2−C2−C3−N3 angle in compound 1 and O1−C1−C8−C9 angles in compounds (b) 3 and
(c) 4 (bold font denotes rotation along the respective bond).
In the solid state, a significant rotation of the phenyl ring is
also observed in the benzoyl derivatives 3−5 (Figure 1). The
degree of rotation depends on the substituent in the ortho-
position. The ortho-substituents in the hydrated and solvent-
free forms of the 5 compound exhibit the cis configuration with
respect to the amide O1 atom, and so does the chlorine atom in
both crystals of 4. Whereas in the former case an intramolecular
hydrogen bond is formed, in the latter one there is not much
interaction between the carbonyl oxygen atom and the chlorine
substituent (more details are provided in section 3.3.2). Thus,
in 4, due to the steric effects and electrostatic forces, the
rotation degree is obviously greater. To support the observed
features, C1−C8 bond rotation energy scans were also
performed (Figure 2b,c). In the model compound 3, the
minima indicate slight rotation of the phenyl ring (about 30°)
in the optimal structure. This is very well reflected in the 3·H2O
crystal structure. Compound 4 constitutes a more interesting
case, where two types of minima are observed. At both minima,
the phenyl ring is rotated by about 30°; however, in the more
advantageous conformation, the chlorine substituent is placed
on the opposite side of the molecule to the amide O1 atom
(“trans” conformation). Interestingly, in both hydrous crystal
structures of 4, the less stable conformation is observed
(compared with the computational results). In this case, such a
result can come from not taking into account dispersion
interactions while doing the scan but also from the
intermolecular interactions present in a crystal. Naturally, the
rotation barrier is highest for 5 (Figure S1, Supporting
Information), where the intramolecular hydrogen bond is
preferentially formed. Compound 5 adopts the close-to-optimal
conformation in its crystal structures.
Having a closer look at the geometrical parameters, bond
lengths and angles characterizing 1−5 (Table 2) are among
typical values for this class of compounds,5,37 with a clear
distinction between single and double bonds in the central
functional spacer. The C1−O1 (1.223(3)−1.237(1) Å) and
N2−C2 (1.278(3)−1.288(1) Å) interatomic distances can be
classified as double bonds, whereas the C1−N1 (1.344(1)−
1.377(3) Å) distances agree well with the mean values reported
for the amide Csp −N (about 1.34 Å) bonds.40 In turn, the N1−
2
N2 (1.368(1)−1.374(1) Å) distances are slightly shorter than
typical azine Nsp −Nsp (about 1.40 Å) single bonds;40 however,
they are in good agreement with those observed in some other,
closely related NAHs.37 Small deviations in the corresponding
bond lengths in different crystal forms result most probably
from different intermolecular interaction patterns. A common
2
2
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phenomenon for the 3−5 benzoyl derivatives is a significant
widening of the O1−C1−N1 and O1−C1−C8 angles (Table
2), accompanied by narrowing of the N1−C1−C8 angle. This
is caused by the repulsion between lone electron pairs at the O1
and N2 atoms and/or steric hindrance between carbonyl and
phenyl functional groups.
stabilization energies for the anhydrous crystal structures,
hydrated crystal structures, and those with the excluded water
content (for an example of a similar analysis, see ref 41).
The final structure is a balance between the hydrazone
conformational stability, intermolecular interactions, entropy,
and kinetics. Among the anhydrous structures, 1 is charac-
terized by the least advantageous cohesive energy. When more
bulky phenyl substituents are introduced, the cohesive energy
becomes more beneficial.
3.3. Supramolecular Structures and Intermolecular
Interactions. To obtain an overall picture of the studied
structures, a Hirshfeld surface approach42 was employed.
Hirshfeld surfaces are a useful tool in crystal engineering
because they allow for crystal packing investigations and some
quantification of contributions coming from different inter-
molecular contact types existing in a crystal lattice. Thus, here
we present the Hirshfeld surface fingerprint plots in Figure 3.
The percentage contributions of important intermolecular
interactions for each structure are given in Figure S2 in the
Supporting Information.
Although it is hard to distinguish sets of similar structures,
observations of a general nature can be easily drawn from the
analysis of fingerprint plots. The important feature of all the
plots is that they are rather asymmetric. This is clearly the result
of conformational flexibility of the molecules and the
anisotropic environment in the solid state, especially in the
case of hydrates. The asymmetry is most visible in the 1·H2O
crystal structure, where the double-spike feature is most
pronounced. The upper and middle spikes are associated
with the O···H contacts, whereas the bottom one is related to
the N···H interactions. This separation is also observed, though
to a lesser extent, for the 4·H2O, 4·2H2O, 5, and 5·H2O crystal
structures. Generally, the sharp spike features result from
hydrogen bonds present in the studied structures and show
their importance for structural stability. Another observation
that can be made on the basis of Figure 3 concerns more
efficient packing of the hydrated structures in comparison to
their anhydrous equivalents, as reflected in the plotted
interatomic distances.
On the other hand, the plot of percentage contributions of
selected interatomic contacts to the Hirshfeld surfaces of the
hydrazone molecules in the studied crystals (Figure S2,
Supporting Information) gives us an idea of the most common
interactions in the crystal lattices. Most important here are both
O···H (10−22%) and N···H (7−18%) contacts, which reflect
the hydrogen bond impact, and C···H (8−29%) interactions or
less emphasized C···C, C···N, etc., responsible for contacts
more dispersive in nature. In the case of anhydrous structures,
the percentage contributions of O···H and N···H contacts are
very comparable. Naturally N···H interactions are outnumbered
by O···H contacts in the hydrated structures. It is also worth
noting that the C···H contacts contribution is very substantial,
being most pronounced for 5 (29%) and least for 1·H2O (8%).
In the case of compound 4, a significant contribution from Cl···
H contacts, being around 14−15%, is also observed.
As mentioned previously, the largest geometrical deviations
are observed in the relative arrangement of the terminal units,
especially pronounced for the benzoyl derivatives, 4 and 5. In
the case of compound 1, the molecule is almost completely
planar in 1·H2O (Table 2), whereas in its anhydrous crystal a
small rotation (to within 6°) around N1−N2 and C2−C3
bonds is visible. The differences in the overall geometry of the
aroyl derivatives, 4 and 5, are mostly caused by rotation around
the C1−C8 bond. The displacement of the terminal phenyl
ring in the 2-chloro and 2-aminophenyl derivatives (com-
pounds 4 and 5) is more significant than that of the
nonsubstituted phenyl derivative in 3·H2O (Table 2). This is
driven by the steric hindrance and the nature of interactions
between C9-substituents and carbonyl O1-atoms. In the case of
5, the phenyl group is oriented in a way that assures a
reasonable geometry of the hydrogen bond, either intermo-
lecular (5) or inter- and intramolecular (5·H2O), formed
between the C9 amino group and the respective acceptor
atoms. What is more, the involvement of the water molecules in
intermolecular interactions with surrounding host molecules
forces further conformational changes in the hydrated
hydrazones. This is evidenced by the dihedral angle values
between the least-squares-fitted planes to the 2-pyridine and
phenyl rings. The angles equal 47.42(1)° and 80.05(1)° in 4·
H2O and 4·2H2O, whereas they are 51.00(1)° and 30.80(2)° in
5 and 5·H2O, respectively.
A careful examination of the molecular geometries of the
studied hydrazones in their hydrous and solvent-free forms
certainly reveals their ability to exist as different conformers in
the solid state. It seems that the imbalance in the total number
of hydrogen-bond donor and acceptor atoms in the systems,
spatial molecular flexibility and affinity for water make
hydrazones prone to inclusion of water molecules into their
crystal networks. Water molecules ensure the hydrogen bond
saturation of the host compounds. There is a visible gain in
energy per asymmetric part of the unit cell (ASU) content
(around 50 kJ·mol−1) when water molecules are incorporated
into the crystal (Table 3). Nevertheless, the whole crystal-
lization process also involves entropy changes and other factors.
Table 3 shows the differences in the hydrazone framework
Table 3. Cohesive Energy Values of the Studied Crystals in
a
Their Hydrous and Anhydrous Forms
anh
structure
ASU content
Ecoh, kJ·mol−1
E
coh
, kJ·mol−1
−75.0
1
1H
−110.6
−175.6
−115.4
−207.7
−218.1
−287.0
−168.7
−216.8
1·H2O
2
1H + 1W
1H
3·H2O
4·H2O
4·2H2O
5
1H + 1W
1H + 1W
1H + 2W
1H
−107.1
−115.6
−103.1
3.3.1. Anhydrous Hydrazone Crystal Structures. Among
the intermolecular interactions involved in stabilization of
solvent-free crystals, hydrogen bonds of the N−H···O and/or
N−H···N type play the dominant role, as is evident from the
Hirshfeld surface analysis. In all the studied cases, the amide
N1−H group acts as a donor, while the amide O1 atom or
pyridine N3 atoms function as hydrogen bond acceptors.
Geometrical parameters of the shortest intermolecular
5·H2O
1H + 1W
−116.1
a
Abbreviations: H, hydrazone molecule; W, water molecule; Ecoh
,
cohesive energy, Eaconhh, cohesive energy of structure with artificially
removed water.
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Figure 3. Hirshfeld surface fingerprint plots for all the studied hydrazone crystal structures (only hydrazone molecules are considered in the case of
hydrates). Characteristic features of fingerprint plots are depicted as red triangles (O···H interactions), blue squares (N···H), green circles (C···H),
and stars (Cl···H).
interactions found in all the studied systems are listed in Table
4.
In turn, the main motif in the crystal of 2 is based on N−H···
O hydrogen-bonding involving just amide groups. The
energetically favorable E configuration of the hydrazide moiety
enables the N1 and O1 atoms from the adjacent molecules to
interact via strong N1−H1N···O1#9 hydrogen bonds (Table 4,
Figure 5a). As a result, the cyclic amide−amide homosynthon A
(Scheme 3) involving an R22(8)43 hydrogen-bonded ring motif
with interaction energy equal to −65.5 kJ·mol−1 is formed. It is
worth noting that 2 is the only structure in the group where this
motif is observed and, what is more, it is the strongest stabilized
synthon among the studied structures. The centrosymmetric
dimers are linked further into the [210] molecular chains via
H···H44 interactions (Figures 5a,b). The H4···H5#33 and H8b···
H5#33 (symmetry code: (#33) −x + 2, −y + 1, −z + 1) contacts
are particularly interesting, because they are characterized by
interhydrogen distances smaller than the sum of VdW radii
(2.137 and 2.359 Å, respectively). It is, however, difficult to
estimate their actual contribution to the interaction energy of
the corresponding dimer (total interaction energy −8.8 kJ·
mol−1), where electrostatic interactions are also involved (C5−
H5···N2#33). The 3D framework in 2 can be analyzed in terms
of two 2D substructures. The first one utilizes weak C7−H7···
In the crystal of 1, the strongest interaction is formed by the
adjacent 21 axis related molecules, which are connected
together by relatively short N1−H1N···N3#1 (symmetry
codes as in Table 4) hydrogen bonds reinforced by weak
C2−H2···N3#1 interactions (the interaction energy of the
corresponding dimer is −37.8 kJ·mol−1, Table 4, Figure 4a).
This leads to the formation of helical chains (Figure 4b)
running down the Y axis. Additional stabilization of the motifs
is provided by weak C7−H7···O1#3 contacts of about −5.7 kJ·
mol−1 in strength (Figure 4c, Table S4, Supporting
Information). The neighboring chains, related one to another
by inversion and hence running antiparallel, are connected by
the combination of weak C4−H4···O1#2 and C1−H1···N2#2
hydrogen-bond type contacts (Table 4, Figure 4a). The head-
to-head oriented molecules, linked by those interactions, create
centrosymmetric dimers, characterized by an interaction energy
of −28.5 kJ·mol−1. The crystal packing is further supported by
relatively strong π-stacking interactions (Table S4, Supporting
Information, and Figure 4b), involving the amide, hydrazone,
and pyridyl ring fragments. Supplementary stabilization of the
3D structure is achieved by weak C5−H5···O1#4 interactions
(−6.7 kJ·mol−1 in total) and C7−H7···π contacts, present
between complex and significantly puckered (100) sheets
(Figure 4d).
O1#10, C6−H6···N3#11, and C8−H8b···π (d
=
C8···πcent(N3−C7)
3.550(3) Å, dH8B···π = 2.623 Å, θC8−H8B···π = 144°; symmetry
cent
cent
code: −x + 1, −y + 1, −z + 1) hydrogen bonds (Figure 5d),
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Table 4. Geometries of Hydrogen Bonds and Selected Short Contacts for All Studied Hydrazone Structures after TAAM
a
Refinement Together with Interaction Energy Values of Selected Hydrazone Dimers and Hydrazone−Water Contacts
b
compound
interaction
dD−H, Å
dH···A, Å
dD···A, Å
dD−H···A, deg
Eint, kJ·mol−1
1
N1−H1N···N3#1
1.027(1)
1.027(1)
1.082(2)
1.083(2)
1.083(2)
1.083(2)
1.027(1)
1.082(1)
0.958(1)
0.958(1)
1.082(1)
1.083(1)
1.083(1)
1.083(1)
1.026(2)
1.082(2)
1.077(2)
1.082(2)
1.025(1)
1.082(1)
1.083(1)
0.956(1)
0.956(1)
0.956(1)
1.082(1)
1.083(1)
1.083(1)
1.027(2)
1.082(2)
1.082(2)
0.958(2)
0.957(2)
0.957(2)
1.082(2)
1.082(2)
1.082(2)
1.082(2)
1.082(2)
0.957(2)
0.958(2)
0.957(2)
1.027(2)
1.082(2)
0.957(2)
1.082(2)
1.082(2)
1.082(2)
1.082(2)
1.024(2)
1.024(2)
1.024(2)
1.027(2)
1.083(2)
1.083(2)
1.083(2)
1.083(2)
1.010(2)
1.027(2)
1.083(2)
1.082(2)
1.940(3)
2.701(4)
2.520(4)
2.427(5)
2.706(4)
2.701(4)
1.877(4)
2.63(1)
2.957(2)
3.568(2)
3.582(2)
3.447(2)
3.644(2)
3.257(2)
2.869(5)
3.417(8)
2.835(4)
2.863(2)
3.463(5)
3.533(4)
3.219(7)
3.696(7)
2.864(1)
3.363(1)
3.590(1)
3.599(1)
2.827(1)
3.249(1)
3.277(1)
2.848(1)
3.000(1)
3.047(1)
3.450(1)
3.283(1)
3.170(1)
2.828(1)
3.269(1)
3.328(1)
2.862(1)
2.924(1)
3.137(1)
3.569(1)
3.249(1)
3.695(1)
3.596(1)
3.647(1)
2.737(4)
2.721(1)
2.789(1)
2.836(1)
3.352(1)
2.908(1)
3.733(1)
3.248(1)
3.282(1)
3.742(1)
2.821(3)
3.058(7)
3.219(3)
3.044(5)
3.331(5)
3.512(5)
3.578(8)
3.450(7)
2.712(1)
2.867(1)
3.278(2)
3.268(2)
169.9(3)
136.8(3)
166.7(3)
156.4(5)
144.8(5)
111.5(5)
161.4(4)
129(1)
−37.8
C2−H2···N3#1
C1−H1···N2#2
−28.5
C4−H4···O1#2
C7−H7···O1#3
−5.7
−6.7
C5−H5···O1#4
1·H2O
N1−H1N···O1W
C2−H2···O1W
−27.2
O1W−H1W···O1#5
O1W−H2W···N3#2
C1−H1···N3#6
1.900(5)
1.919(4)
2.635(8)
2.623(6)
2.46(1)
164.5(5)
167.9(4)
132.9(6)
141.2(4)
125.9(7)
152.2(7)
173.4(2)
154.1(3)
163.9(2)
149.1(3)
163.2(3)
135.0(3)
141.9(3)
162.9(3)
141.1(4)
133.0(4)
145.0(3)
131.5(3)
115.9(3)
154.3(7)
130.3(8)
121.9(8)
162.1(5)
149.1(7)
126.2(8)
149.3(5)
129.2(6)
149.1(5)
127.6(7)
135.3(7)
167.6(3)
177.5(2)
171.2(2)
169.9(2)
132.0(4)
164.6(3)
161.7(2)
169.1(2)
132.5(4)
133.8(4)
115(1)
−20.5
−20.1
−13.8
−23.9
−8.7
C4−H4···O1#7
C5−H5···O1#8
C6−H6···O1W#8
N1−H1N···O1#9
C7−H7···O1#10
2.71(1)
−7.9
2
1.842(2)
2.356(4)
2.543(2)
2.628(4)
1.830(2)
2.392(4)
2.356(4)
1.920(2)
2.195(5)
2.314(5)
2.558(4)
2.464(4)
2.545(4)
1.867(2)
2.464(9)
2.627(9)
1.935(4)
2.060(7)
2.470(9)
2.595(6)
2.454(9)
2.725(6)
2.83(1)
−69.5
−10.6
−19.2
−9.2
C8−H8C···O1#5
C6−H6···N3#11
3·H2O
N1−H1N···O1W
C2−H2···O1W
−21.3
−25.5
−25.7
C13−H13···O1W
O1W−H2W···N3#12
O1W−H1W···O1#13
O1W−H1W···N2#13
C4−H4···O1W#14
C13−H13···O1#13
C5−H5···O1#31
−27.6
−21.5
4·H2O
N1−H1N···O1W
C2−H2···O1W
−22.0
−25.6
−28.5
C13−H13···O1W
O1W−H2W···N3#15
O1W−H1W···O1#16
O1W−H1W···N2#16
C4−H4···O1W#18
C13−H13···O1#16
C5−H5···N3#17
−30.9
C7−H7···Cl1#19
C11−H11···Cl1#1
O1W−H1W···N3
O1W−H2W···O2W
O2W−H4W···O1W#20
N1−H1N···O1W#20
C2−H2···O1W#20
O2W−H3W···O1#21
C4−H4···O2W#25
C5−H5···O1#22
−29.8
−5.5
−19.0
−15.8
−15.1
2.79(1)
4·2H2O
1.794(2)
1.763(2)
1.840(2)
1.819(2)
2.531(5)
1.973(3)
2.68(2)
−28.4
−32.4
2.178(2)
2.452(5)
2.909(5)
2.23(3)
−14.2
−7.3
−32.6
C13−H13···O2W#23
C6−H6···Cl1#24
N4−H4A···O1
5
N4−H4A···O1#9
N4−H4B···O1#26
N1−H1N···N3#27
C2−H2···N3#27
2.21(1)
139(1)
−39.0
−50.2
2.22(1)
163(1)
2.07(1)
157(1)
2.56(1)
128(1)
−34.3
−23.1
C13−H13···N3#27
C4−H4···O1#7
2.69(1)
133(1)
2.57(1)
155(1)
C5−H5···N4#7
2.49(1)
147(1)
5·H2O
N4−H4A···O1
1.929(8)
1.873(4)
2.392(7)
2.414(7)
132(1)
N1−H1N···O1W
C13−H13···O1W
C2−H2···O1W
161.8(5)
138.0(6)
134.8(6)
−22.6
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Table 4. continued
b
compound
interaction
dD−H, Å
dH···A, Å
dD···A, Å
dD−H···A, deg
Eint, kJ·mol−1
−25.7
O1W−H2W···N3#7
O1W−H1W···O1#28
O1W−H1W···N2#28
C4−H4···O1W#30
C13−H13···O1#28
N4−H4B···N4#32
C5−H5···O1#29
0.958(2)
0.958(2)
0.958(2)
1.083(2)
1.083(2)
1.009(2)
1.082(2)
1.960(4)
2.143(7)
2.388(9)
2.622(7)
2.532(7)
2.67(1)
2.889(1)
2.965(1)
3.088(1)
3.563(2)
3.324(2)
3.278(3)
3.257(2)
162.9(4)
143.1(7)
129.6(7)
145.0(5)
129.2(5)
118.5(7)
122.7(6)
−27.9
−26.4
−15.6
−18.0
2.54(1)
a
b
Calculated at the DFT(B3LYP-D)/6-31G** level of theory with BSSE and Grimme corrections applied. Symmetry transformations: (#1) −x + 1,
y + 1/2, −z + 1/2; (#2) −x + 1, −y + 2, −z + 1; (#3) −x + 1, y + 3/2, −z + 1/2; (#4) x − 1, y − 1, z; (#5) x + 1, y, z; (#6) x − 1, y, z; (#7) −x, −y +
1, −z + 1; (#8) x + 1, y − 1, z + 1; (#9) −x, −y, −z + 1; (#10) x + 1, −y + 1/2, z + 1/2; (#11) −x + 2, y + 1/2, −z + 3/2; (#12) −x, 1 − y, −z;
(#13) −x + 1/2, y + 1/2, z; (#14) −x + 1/2, y − 1/2, z; (#15) −x + 1, −y + 1, −z; (#16) −x + 3/2, y + 1/2, z; (#17) −x + 1/2, y−3/2, z; (#18) −x
+ 3/2, y − 1/2, z; (19) x + 1/2, −y + 1/2, −z; (#20) −y + 2/3, x − y + 1/3, z + 1/3; (#21) y, −x + y, −z + 1; (#22) −y + 1/3, x − y + 2/3, z − 1/3;
(#23) −x + y + 1/3, −x + 2/3, z + 2/3; (#24) −x + 1/3, −y + 2/3, −z + 2/3;(#25) x − y, x, −z + 1; (#26) x, y − 1, z; (#27) −x − 1/2, y − 1/2, −z
+ 3/2; (#28) x, −y + 1/2, z − 1/2; (#29) −x, −y + 1, −z + 2; (#30) x, −y + 1/2, z + 1/2; (#31) −x, −y, −z; (#32) −x + 1, −y + 1, −z + 2.
Figure 4. (a) Hydrogen-bonding motifs, (b) π-stacked dimers and molecular chain helically extended along the 21 screw axis (green solid line), (c)
weak C−H···O and C−H···π interactions, and (d) (100) molecular layers in crystal 1, viewed down the Y axis. Dashed lines indicate hydrogen bonds
or π-stacking interactions.
which link the adjacent molecules into (102) layers. The
The crystal packing of 5 is dominated by strong N−H···O/N
hydrogen bonds involving amide, amine, or pyridine functional
groups and reveals a molecular chain arrangement typical for
this class of compounds, which further associates into layer
motifs. As in 1, the adjacent 21 screw-axis related molecules are
connected here by relatively short N1−H1n···N3#27 hydrogen
bonds, which together with the C2−H2···N3#27 contacts give
rise to molecular chains along the [010] crystallographic
direction with the cyclic hydrazone−pyridine R12(6) homo-
synthon B (Scheme 3, Figure 6a). The interaction energy of
̅
second one is based on π···π interactions between planar
molecular units (Figures 5b,c) and formed due to stacking of
the [210] molecular chains. As indicated by the interaction
energy values, the dispersive π-stacking interactions are
generally quite significant (e.g., −29.0 kJ·mol−1 for the dimer
created by the −x + 1, −y + 1, −z + 1 related molecules, Table
4, Table S4, Supporting Information). Nevertheless, the overall
crystal cohesive energy is comparable to that of 1 (Table 4).
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Figure 5. Part of the crystal structure of 2 showing (a) formation of [210] molecular ribbon via strong N−H···O hydrogen bonds (the total energy
of the dimer = −65.5 kJ·mol−1) and weak H···H contacts (−8.8 kJ·mol−1), (b) crystal packing viewed along the X axis, (c) molecular dimers
stabilized by C−H···O and π-stacking interactions, and (d) weak C−H···O/N and C−H···π intermolecular interactions.
Scheme 3. Supramolecular Synthons Observed in the Hydrazone Crystals
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Figure 6. Selected parts of the crystal structure of 5 showing (a, b) hydrogen-bonding motifs (dashed lines) and (c) crystal packing viewed along the
Y axis.
this motif is similar to that of the B synthon in 1 and is equal to
−34.3 kJ·mol−1. The assembly is reinforced by weak C13−
H13···N3#27 and C7−H7···πphen (−x − 1/2, y + 3/2, −z + 3/2)
interactions involving pyridine and phenyl rings (Figure 6b).
The most advantageous dimer, for which the interaction energy
amounts to about −50 kJ·mol−1, is created however with the
assistance of both N4−H4B···O1#26 hydrogen bond and the π-
stacking interactions (Figure 6b). Additionally, relatively strong
hydrogen bonds are formed between the head-to-head oriented
molecules from the adjacent chains, that is, N4−H4A···O1#9
(Figure 6a).
energetically favored than the remaining anhydrous crystal
structures of 1 and 2 (Table 4). This is surely due to the
additional π-electron-rich center, the phenyl substituent, which
at the same time contains an amino group eager to form
hydrogen bonds.
3.3.2. Hydrazone Hydrates. The incorporation of water
molecules into the crystal structure framework of the studied
compounds leads to quite different supramolecular arrange-
ments and hydrogen-bonding patterns. In general, in the
structures of 1·H2O−5·H2O, water molecules span the adjacent
units into the complex architectures. The energetic results
gathered in Table 3 clearly indicate a significant increase in
crystal cohesive energy per ASU when water molecules are
incorporated into the crystal structure. Water molecule size and
properties ensure saturation of the hydrogen bond donor and
acceptor centers, as well as much more favorable hydrogen
bond geometries, making the overall packing more energetically
advantageous. Also, comparing the fingerprint plots generated
for the water containing and anhydrous pairs of crystals, one
may notice that average interatomic contacts are becoming
shorter in the case of hydrated structures. This means that the
structure is more efficiently packed.
These interactions are characterized by an overall dimer
interaction energy of −39.0 kJ·mol−1. The mentioned contacts
are further accompanied by weak C4−H4···O1#7 and C5−H5···
N4#7 interactions (total energy of the corresponding dimer:
−23 kJ·mol−1; Table S4, Supporting Information), which
results in a 2D (101) layered network formation (Figure 6c).
The molecules are arranged in such a way that the hydrophilic
and hydrophobic parts are separated in the crystal lattice. The
neighboring layers are held together by C−H···π contacts
(dC10···π
= 3.374(3) Å, dH10···π
= 2.594 Å,
cent(C8−C13)
cent
θC10−H10···π = 128°). The richness of the electrostatic
cent
In the 1·H2O crystal structure, the two adjacent inversion-
related host units are connected by two water molecules, acting
as hydrogen-bonding acceptors for hydrazone N1 and C2
centers and as donors to pyridine N3 atoms (Figure 7a). As a
interactions, reinforced by the additional NH2 group in
contrast to the other studied molecules, and dispersive
interactions makes this crystal structure significantly more
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Figure 7. (a) Hydrogen-bonding pattern in crystal of 1·H O; (b) single (112) sheet motifs viewed along the Z axis; (c) weak C−H···O/N and π···π
̅
2
interlayer interactions; (d) crystal packing viewed along the [111] direction.
̅
result, a cyclic hydrazone−water−pyridine heterosynthon C
(Scheme 3) is formed. The water−hydrazone interactions
related to this motif are characterized by interaction energy
close to −27.2 kJ·mol−1 for the first kind of interactions,
whereas for the water−pyridine hydrogen bond, this is −20.1
kJ·mol−1 (Table 4, Table S4, Supporting Information). The
overall stabilization energy of this molecular arrangement
reaches −128.1 kJ·mol−1 (i.e., −64.0 kJ·mol−1 per each
hydrazone−water pair). These units are then linked by a
combination of weak C4−H4···O1#7 (corresponding dimer
interaction energy −23.9 kJ·mol−1) and C5−H5···O1#8 (−8.7
kJ·mol−1) interactions, which, in turn, lead to the centrosym-
metric hydrazone tetramers (Figure 7b). The tetramers
patterns in 3·H2O−5·H2O are very similar. While the
isostructural hydrates 3·H2O and 4·H2O crystallize in the
orthorhombic Pbca space group, the 2-aminophenyl (5·H2O)
derivative adopts monoclinic P21/c symmetry. However,
similarly to 1·H2O, in all the remaining crystal structures,
water species fill in the gaps between the adjacent inversion-
related hydrazone molecules and serve as hydrogen-bonding
supramolecular mediators. In general, the hydrazone−water
interaction energy is in the range from −20 to −30 kJ·mol−1
(Table 4). Within the selected asymmetric units, the two
independent molecular components are linked by short, almost
linear N1−H1N···O1W hydrogen bonds, enhanced by two
weak C2−H2···O1W and C13−H13···O1W contacts (Figure
8a, Table 4). These bimolecular units are further connected via
strong bifurcated O1W−H1W···(O1,N2)#13/16/28 hydrogen
bonds (heterosynthon D) and weak C4−H4···O1W#14/18/30
contacts into molecular chains, propagating along the [010] (3·
H2O, 4·H2O) or [001] (5·H2O) crystallographic directions
(Figure 8b). At the same time, each water molecule is engaged
in an additional strong O−H···N hydrogen bond to the
pyridine N3#12/15/7 atom from the adjacent inversion-related
molecule leading to a cyclic hydrazone−water−pyridine
heterosynthon C. The combination of both chain and ring
motifs is sufficient to create a 2D layered architecture.
Interlayer stabilization is provided by CAr−H···πAr contacts
(3·H2O) or C11−H11···Cl1#1 (4·H2O, −5.5 kJ·mol−1, Figures
associate further into the (112) molecular sheets via the C6−
̅
H6···O1W#8 (−7.9 kJ·mol−1) interactions. The layers are
stabilized by strong water−carbonyl O1W−H1W···O1#5 and
weak formyl−pyridyl C1−H1···N3#6 (Figure 7c) hydrogen
bonds (corresponding dimer interaction energies −20.5 and
−13.8 kJ·mol−1, respectively). Water molecules appear in the
crystal structure so as to fasten together hydrazone species,
leading to a complex 3D network (Figure 7d). It is also worth
mentioning that π-stacking interactions cannot be neglected in
the case of 1·H2O since, as in the anhydrous structures, they
contribute noticeably to the overall cohesive energy (e.g., −27.5
kJ·mol−1 for the −x + 1, −y + 1, −z + 1 dimer, Figure 7c).
Despite the differences in molecular compositions and
internal symmetries of the studied crystals, the supramolecular
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Figure 8. (a) Hydrogen-bonding pattern in a crystal of 4·H2O; (b) [010] molecular chains in view along the X axis; (c) short Cl···π contacts in 4·
H2O; (d) crystal packing in view along the Y axis. The supramolecular arrangements of 3·H2O and 5·H2O are very similar.
8b,d) and N4−H4B···N4#32 (5·H2O,−15.6 kJ·mol−1) hydrogen
bonds.
It is noteworthy that the Cl atoms in crystal 4·H2O are
additionally engaged in short Cl1···C11#14 contacts (Figure 8c).
Given the geometry of these contacts (dCl1···C11) = 3.415(2) Å,
θC9−Cl1···C11 = 155°; −5.9 kJ·mol−1), they can be classified as
“edge-on” Cl···π interactions.45
In turn, incorporation of one additional water molecule, as in
the lattice network of 4·2H2O, induces considerable changes in
the lattice symmetry and the supramolecular pattern compared
with the orthorhombic monohydrate structure, 4·H2O.
bonding potential of a single water molecule is greater than
that, just to mention our latest studies of water clusters in the
ortho-boronic acid solvatomorphs and ice crystals.46 Therefore,
water should strongly interact with the neighboring hydrazone
molecules so as to saturate their remaining hydrogen bond
centers. Indeed, it seems that water chains constitute a kind of
“template” around which the hydrazone molecules are arranged
spirally. As mentioned above, one hydrogen atom of each water
molecule is involved in hydrogen bonding with the oxygen
atom of an adjacent symmetry-independent water molecule,
while its own oxygen atom is simultaneously hydrogen bonded
to another molecule of water to complete the motif (Figure 9a).
At the same time, the second hydrogen atom of O1W donates
to pyridyl N3 from the host molecule whereas the oxygen atom
serves as an acceptor in the three-center N1−H1N/C2−H2···
O1W#20 hydrogen bond. Then, each O2W water molecule
participates as a donor in the strong O2W−H3···O1#21
hydrogen bond with the host unit.
On the other hand, two different trigonal motifs (TA and TB
motifs; Figure 9c,d) created by host molecules can be
distinguished in the structure. The overall arrangement of the
motifs down the 3-fold screw axis is ···TATBTATB···.
Regarding the interactions between the host hydrazone
molecules, the C5−H5···O1#22 contact (−14.2 kJ·mol−1; Figure
9d) between the adjacent molecules forming the spiral TB
motif seems to be noticeable, as well as relatively strong C6−
H6···Cl1#24 and π···π stacking interactions between the
overlapping pyridyl−pyridyl (−32.6 kJ·mol−1, Figure 9a) and
pyridyl−phenyl rings (−20.5 kJ·mol−1), which hold the
molecules from TA and TB motifs together.
Interestingly, the dihydrate of 4 crystallizes in the trigonal R3
̅
space group, with a stoichiometric content of water molecules
occupying general positions. As indicated by Figure 9b,e, the
crystal structure is characterized by two types of channels along
the Z axis, the primary hydrophilic and secondary hydrophobic
ones in the ratio of 2:1, respectively. In general, the structure of
4·2H2O is governed by an extensive net of strong interactions
around the well-ordered guest water molecules, filling the
hydrophilic 1D channels (water constitutes over 50% of the
volume of free space (Vv) in the “anhydrous” 4·2H2O crystal
structure, Figure 9e), and consequently a second type of
channel with chlorophenyl ring walls is formed. The hydrogen-
bonded water polymeric structure created around the 31 axis is
characterized by about −65.8 kJ·mol−1 of stabilization energy
(per two symmetry-independent water molecules). This energy
value is equivalent to one strong hydrogen bond per water
molecule in such a water chain. The 1D water substructure is
created via O1W−H2W···O2W and then O2W−H4W···
O1W#20 directional hydrogen bonds. Clearly, the hydrogen
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Figure 9. (a) Hydrogen-bonding patterns in a crystal of 4·2H2O. (b) Crystal packing viewed along the Z axis. Two spiral host motifs viewed along
the Z axis, formed around the guest hydrogen-bonded chains: (c) motif TA; (d) motif TB. (e) Voids in real (left) and artificial “anhydrous” (right)
structures of 4·2H2O (viewed along the Z axis).47
3.4. NMR Studies. The 13C CP/MAS NMR spectra of the
studied crystalline N-acylhydrazone derivatives are shown in
Figure 10, whereas Table S5 (Supporting Information) presents
13C NMR chemical shifts of these compounds. The 13C CP/
MAS NMR experimental shifts are in good agreement with the
CASTEP calculated isotropic shielding (Supporting Informa-
tion). The number of signals in the 13C CP/MAS NMR spectra
of 1·H2O, 2, 4·2H2O, and 5 is in agreement with the number of
carbon atoms in the molecules, in contrast to the spectra of 1,
3·H2O, and 5·H2O. In the case of 1 an additional signal at
156.84 ppm can be observed. This signal comes from the
carbonyl group and proves that compound 1 was contaminated
by formic hydrazide. All attempts to purify 1 led to the
formation of the crystal structure of 1·H2O. In the cases of 3·
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(approximately 13 ppm). Moreover, the chemical shifts of the
N3 nitrogen atom in the structures 2 and 4·2H2O differ
significantly from the ones in the remaining N-acylhydrazone
derivatives. In the structure 2, the signals coming from nitrogen
atoms N2 and N3 overlap and form one broadened peak at
−56 ppm. In this case, the two discussed nitrogen atoms are
involved in weak interactions, namely, C6−H6···N3#11 and
C8−H8b/c···N2. In 4·2H2O, the position of the signal of
nitrogen atom N3 is shifted toward higher frequency (δ = −107
ppm). In this crystal structure, N3 is involved in a short linear
hydrogen bond, O1W−H1W···N3. Moreover, due to the short
distance between O1W and N3 (2.737(4) Å) and the higher
thermal motion during the solid-state NMR measurements,
proton transfer from the water molecule to the nitrogen atom
N3 is possible. In this case, the discussed shifting of the
nitrogen N3 signal would be a combination of two effects: a
very strong hydrogen bond and the N3−H+···OH− interaction.
As previously shown,48,49 solid-state NMR, combined with
quantum mechanical computations of NMR shielding, can be
successfully applied to characterize crystal structures. The solid-
state NMR method is also very useful in monitoring the
stability and purity of the studied compounds. Based on perfect
correlation between shielding constants calculated for the XRD
structure of 1 and the appropriate chemical shifts in the NMR
spectra, it can be concluded that the hydrazide form is only an
impurity (is not incorporated in the crystal lattice), and the
discussed spectrum is a superposition of two independent
components (Figure S3, Supporting Information). Moreover,
the results obtained for 4·H2O and 4·2H2O indicate that the
stable compound used for NMR experiments is the latter one,
because a better fit was obtained for the dihydrate structure (R2
value of 0.992 vs 0.953).
Figure 10. The 13C CP/MAS NMR spectra of the studied hydrazones
in two regions, 104−180 ppm and 10−30 ppm, acquired with a
contact time of 4 ms.
H2O and 5·H2O, the partial overlap of the signals hampers their
correct assignment. In the spectra of the studied hydrazones,
there is no signal splitting because each crystal form contains a
single molecule in the asymmetric part of the unit cell.
Furthermore, in the NMR spectra of most NAHs, no
significant differences in the chemical shifts of the individual
carbon atoms are observed. Only in the case of compound 2,
the signal of carbon atom C1 is shifted toward higher-frequency
(Δδ = 8−12.23 ppm). This effect results from the crystal
packing of 2 (Figure 5), mainly determined by the strong N−
H···O hydrogen-bonding leading to the cyclic amide−amide
homosynthon A.
In turn, the 15N CP/MAS NMR spectra were used to
characterize substituent effects and hydrogen bonds in the
studied derivatives. The 15N chemical shifts are given in Table
S6 (Supporting Information). Particular attention should be
paid to differences in chemical shift values of the nitrogen atom
N1. Its chemical shift in the case of 1, 1·H2O, and 2 is in all
cases less than 200 ppm, whereas for 3·H2O, 4·2H2O, 5, and 5·
H2O, it is always above this value. This effect is caused by the
substitution of carbon atom C1 with the phenyl ring. The N2
nitrogen atom in the structure 5 does not participate in the
hydrogen bond formation but is involved in the π-stacking
interactions described previously. These interactions lead to a
significant difference in the observed chemical shift of N2
3.5. Thermal Stability. The thermal stabilities were
assessed by both DSC and TGA. The melting point values
for the studied crystals and enthalpies of fusion for anhydrous
hydrazone crystals were determined from the DSC curves
(Figure 11 and Figure S4, Supporting Information).
The results of TGA/DSC studies of hydrazone hydrates
suggest significant differences in their behavior. The thermal
desolvation of 1·H2O and 3·H2O takes place via two stages and
is accompanied by two broad endotherms with the peak
maxima at 92 and 110 °C (1·H2O) and at 95 and 111 °C (3·
H2O). The total TGA weight loss of 10.89% (1·H2O) and
7.32% (3·H2O) is in accordance with the 1:1 host−guest ratio
Figure 11. DSC (red solid line), TG (blue solid line), and DTG (green solid line) plots showing mass loss of the studied crystals of (a) 5 and (b) 5·
H2O.
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as determined from the X-ray data. The weight loss of 5.52%
for 1·H2O and 3.79% in the case of 3·H2O, which corresponds
to the first stage of the dehydration process, may suggest
formation of semihydrates as intermediate forms. The final
melting of the desolvated products was observed at 132° and
124°, respectively. In contrast, the DSC thermograms of 4·
H2O, 4·2H2O, and 5·H2O show single, very broad desolvation
peaks starting at 49, 51 and 46 °C, respectively, overlapped by a
sharp endotherm of fusion. The corresponding TGAs indicate a
mass loss of 11.87% (calculated 12.17%) for 4·2H2O, 6.66%
(calculated 6.48%) for 4·H2O, and 6.72% (calculated 6.97%)
for 5·H2O, which confirms that they are 1:2, 1:1, and 1:1
hydrates, respectively.
The thermal behavior of the anhydrous hydrazones is quite
different compared with their hydrated forms. The single sharp
endothermic peaks at 122 °C (heat of fusion, ΔHf = 107.7 J·g−1
= 16.1 kJ·mol−1) for the formylhydrazine derivative 1, at 123 °C
(ΔHf = 113.5 J·g−1 = 18.5 kJ·mol−1) for 2, and at 155 °C (ΔHf
= 93.9 J·g−1 = 22.6 kJ·mol−1) for 5 (Table S1, Supporting
Information), corresponding to the melting points of these
compounds, were observed in the DSC experiment. At the
same time, no evidence indicating thermal decomposition of 1,
2, and 5 was found in their TG curves up to the melting
temperature.
capacity without significant changes in its molecular geometry.
Incorporation of water molecules to the crystals leads to visibly
shorter hydrogen bonds. In each case, water molecules play the
role of hydrogen-bonding linkages between the amide and
pyridine N or amide O atoms. The significant contribution of
water molecules to the total crystal lattice energy has been
confirmed by the theoretical calculations similarly to our
previous studies for hydrated boronic acid crystals.50 A single
water molecule incorporated into the hydrazone crystal leads to
a significant cohesive energy gain of over 50 kJ·mol−1 per ASU.
Small water molecules are effectively packed in the crystal
lattice and create well-directed hydrogen bonds with the host
molecules, which are characterized by energy ranging from
about −20 to −30 kJ·mol−1. The water−hydrazone interactions
are among the strongest ones in the analyzed crystals. Apart
from strong hydrogen bonding, there is an extensive net of
weak C−H···O, C−H···N, and C−H···π interactions and π···π
stacking contacts in all studied crystals. Significant contribution
of the latter ones to the total crystal lattice energy was
supported by the computational results.
ASSOCIATED CONTENT
* Supporting Information
■
S
Theoretical calculations of NMR shielding constants in
CASTEP, synthetic, physicochemical and spectral character-
istics of all studied crystals, multipolar parameters of the new
UBDB-like atom types utilized for TAAM refinement, relative
energies between two optimized minima for isolated molecules,
at two levels of theory, molecular motifs, symmetry codes and
interaction energy values, 13C NMR and 15N chemical shifts of
the studied hydrazones, torsion-angle-constrained scan for the
O1−C1−C8−C9 angle in compound 5, percentage contribu-
tions of selected interatomic contacts to the Hirshfeld surfaces
of hydrazone molecules, 13C CP/MAS NMR spectra of the
compound 1 and formic hydrazide, DSC, TG, and DTG plots
for 1·H2O, 1, 2, 3·H2O, 4·2H2O, and 4·H2O crystals, and
crystallographic information in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
In general, there is a clear correlation between the enthalpy
of fusion values and the melting point temperatures for
anhydrous hydrazones. Interestingly, one can also find some
correlation of the above-mentioned quantities with the cohesive
energies described earlier (Table 3). It is, however, important
to stress that generally there is no straightforward relation
between cohesive energy values and the two other physical
quantities, and due to the few data points, no significant
conclusions can be drawn.
4. SUMMARY AND CONCLUSIONS
In this contribution, we have reported a detailed structural
characterization of a series of simple N-acyl- and N-
aroylhydrazones, compounds that are widely used in chemical
synthesis. This study constitutes the first extensive investigation
of energetic features of the hydrazone crystal structures.
The studied hydrazones have been crystallized in their
solvent-free forms or as hydrates or both. In general, the
performed crystallization experiments confirmed the previously
reported37 hydrazone affinity for water and its inclusion into
their crystal networks. The crystallization conditions seem to
have minor influence on the phase that is formed. The water
molecules incorporated into the crystal can be derived either
from the crystallization solution or from the air. What is more,
in some cases both solvated and solvent-free forms can be
obtained simultaneously. This suggests that the crystallization
outcomes are driven by specific intermolecular interactions in
solution rather than the preparation regime.
AUTHOR INFORMATION
Corresponding Author
*Liliana Mazur. E-mail: lmazur2@op.pl.
■
Funding
L.M. thanks the Polish Ministry of Science and Higher
Education/National Science Centre for financial support
(Grant No. N N204 546839). K.N.J. and R.K. thank the
Wrocław Centre for a Networking and Supercomputing (Grant
No. 285) and also the Interdisciplinary Centre for Mathemat-
ical and Computational Modelling (Grant No. G33-14) for
providing computational facilities. K.N.J. thanks the Foundation
for Polish Science for financial support within the “START”
program.
The most striking conformational differences between N-
acyl- and N-aroylhydrazones concern their hydrazide moiety,
which adopts the trans and cis arrangement, respectively. The
less stable cis configuration observed in the latter group seems
to be imposed by intermolecular interactions involving the
amide function.
In turn, a common structural feature of all studied
hydrazones is the deficiency of proton-donor groups. The
imbalance between the hydrogen-bond donor/acceptor atoms
can be saturated via incorporation of a water molecule into the
crystal, which satisfies the host’s hydrogen-bond acceptor
Notes
The authors declare no competing financial interest.
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