The interplay of hydrogen bonds in the solid state structure of NH-pyrazoles bearing cyano and amino substituents

Article abstract of DOI:10.1016/j.molstruc.2012.01.026

The annular tautomeric equilibrium of two 4-cyano-3(5)-aminopyrazoles having hydrogen atom or methyl group in position 5(3) was studied by X-ray crystallography for the solid compounds and by DFT B3LYP/6-31G and CBS-QB3 calculations for the free molecules. The 3-amino tautomer was found to be the more favorable form for the free molecules and the sole form in the solid state.

Full text of DOI:10.1016/j.molstruc.2012.01.026

Journal of Molecular Structure 1014 (2012) 63–69
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
The interplay of hydrogen bonds in the solid state structure of NH-pyrazoles
bearing cyano and amino substituents
a
b
a
Elena E. Emelina a, , Alexander A. Petrov , Alexandra O. Borissova , Dmitriy V. Filyukov ,
⇑
Mikhail Yu. Antipin b
a Department of Chemistry, St. Petersburg State University, Saint Petersburg 198504, Russia
b A.N. Nesmeyanov Institute of Organoelemental Compounds, Russian Academy of Sciences, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2011
Received in revised form 18 January 2012
Accepted 19 January 2012
Available online 28 January 2012
The annular tautomeric equilibrium of two 4-cyano-3(5)-aminopyrazoles having hydrogen atom or
methyl group in position 5(3) was studied by X-ray crystallography for the solid compounds and by
DFT B3LYP/6-31Gꢀꢀ and CBS-QB3 calculations for the free molecules. The 3-amino tautomer was found
to be the more favorable form for the free molecules and the sole form in the solid state.
Ó 2012 Elsevier B.V. All rights reserved.
Keywords:
Pyrazoles
Crystal structures
Hydrogen bonds
1. Introduction
1H-pyrazole (3A) and 5-amino-1H-pyrazole (5A). Elguero et al.
[18] have found that 5(3)-amino-3(5)-aryl-1H-pyrazoles with do-
3(5)-Aminopyrazoles are an important group of organic mole-
cules, because many of them exhibit a broad spectrum of biological
activity and are useful materials in drug synthesis [1–4]. For exam-
ple, numerous recent studies dealt with 3(5)-aminopyrazoles as
nor substituents at the aryl ring exist in the solid state as 3A forms.
Surprisingly, crystals of 5(3)-amino-3(5)-aryl-1H-pyrazoles with
acceptor substituents at the aryl ring appeared to exist as mixtures
of 3A and 5A tautomeric forms (4-Br) or as 5A form only (4-NO2)
[18].
potent and selective p38a inhibitors [5], calcium-sensing receptor
antagonists (CaSR) [6], selective Rafkinase inhibitors in melanoma
cells [7], or selective adenosine A1 receptor antagonists [8]. 3(5)-
Aminopyrazoles have been recognized as valuable synthons for
the construction of more complex structures, in particular, of bio-
logically active fused heterocycles (e.g., pyrazolopyrimidines, pyr-
azolopyridines) [9–13].
Recent studies showed that NH-pyrazoles and pyrazolines are
promising synthons in self-assembly. The metal coordination
modes of these compounds were described, and it was concluded
that the pyrazole ring can be considered as the most flexible ligand
group in coordination chemistry [14].
N-unsubstituted pyrazoles are very interesting objects from the
viewpoint of the N–Hꢁ ꢁ ꢁN hydrogen bonding in their crystals. The
1,2-arrangement of N atoms in pyrazoles makes possible formation
of at least four kinds of structures: dimers, trimers, tetramers, and
catemers [19] (Fig. 1).
However, in case of 3(5)-amino-4-cyanopyrazoles, a number of
additional species should be taken into account, because cyano and
amino groups can also participate in hydrogen bonding in crystals.
Here we report on a single crystal X-ray diffraction analysis and
theoretical studies of NH-pyrazoles bearing cyano and amino
groups directly bonded to the pyrazole core, aimed not only to
determine the position of the NH ring proton but also to under-
stand its effect on the formation of supramolecular assemblies.
Tautomerism in five-membered heterocyclic systems is an
intriguing phenomenon attracting attention for
a long time
[15–17]. Knowledge of the tautomeric preferences and of the factors
affecting the equilibrium is essential for understanding the reactiv-
ity of compounds in chemical processes and their influence on
biological systems. Due to annular prototropic tautomerism, 3(5)-
aminopyrazole a priori can exist in two forms, namely, 3-amino-
2. Results and discussion
For N-unsubstituted 3(5)-aminopyrazoles, two tautomeric
forms are really possible (Scheme 1) [15–17,20]. The predominant
tautomeric forms of 3(5)-amino-4-cyanopyrazole 1 and 3(5)-ami-
no-4-cyano-5(3)-methylpyrazole 2 have been examined by X-ray
crystallography for the solid state and by DFT B3LYP calculations
⇑
Corresponding author.
E-mail address: emelina@hotmail.ru (E.E. Emelina).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2012.01.026

64
E.E. Emelina et al. / Journal of Molecular Structure 1014 (2012) 63–69
H
N
N
N
N
N
N
N
H
N
H
N
H
N
N
N
N
H
N
N
H
N
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
H
H
dimer
catemer
tetramer
trimer
Fig. 1. Traditional hydrogen-bonded structures in crystals of pyrazoles.
the hybrid exchange–correlation functional B3LYP [22,23] with
6-31Gꢀꢀ basis set. Frequency analysis has shown that the optimized
structures correspond to the energy minima on the potential sur-
face. The thermodynamic characteristics (free energies, enthalpies
at 298.15 K) and dipole moments were computed on the optimized
geometries at the same theory level with subsequent CBS-QB3
complete basis set extrapolation [24,25]) full optimization runs
using the Gaussian03 package [26]. The results are given in Tables
N
C
N
C
R
NH2
R
NH2
N
N
N
N
H
H
1 and 2. Since CBS-QB3
DEtot, DG and DH values differ from those
obtained by B3LYP/6-31Gꢀꢀ by less than 0.7 kcal/mol having the
same sign, B3LYP/6-31Gꢀꢀ theory level can be considered suitable
for the qualitative comparison of the two tautomeric forms of 4-
cyanopyrazoles.
3А
5А
R = H (1), CH3 (2)
According to Table 1,
D
Etot values obtained by B3LYP/6-31Gꢀꢀ
Scheme 1. Tautomerism of N-unsubstituted 3(5)-amino-4-cyanopyrazoles.
and CBS-QB3 indicate that the tautomeric form 3A of a free mole-
cule is more favorable than 5A for both compounds 1 and 2. There-
fore, the tautomeric form 3A can be expected to prevail in the solid
state. It is significant that dipole moments of tautomeric forms 3A
of compounds 1 and 2 are lower than those of forms 5A. According
to the computational data, the dipole moment vector of the free
molecules of 1 and 2 is oriented along the bond between the N
atom of the pyrazole ring and the labile proton toward the proton.
The orientations of the dipole moment vectors computed by
B3LYP/6–31Gꢀꢀ and CBS-QB3 methods for each structure under
study are essentially the same. See Fig. 2.
with 6-31Gꢀꢀ basis set and CBS-QB3 calculations for the free
molecules.
2.1. Theoretical calculations
The quantum chemical calculations were performed for both
tautomeric forms 3A and 5A of pyrazoles 1 and 2. Geometry opti-
mizations were performed with GAMESS-US package [21] using
Table 1
Total energies (Etot), zero point energies (ZPE), free energies (G), enthalpies (H) (all in hartree), relative energies (
DEtot and DG), enthalpies (DH) (all in kcal/mol), and dipole
moments (
l
, debye) for the tautomeric forms 3A and 5A of the free molecules of 1 and 2, calculated by DFT B3LYP/6-31Gꢀꢀ and CBS-QB3 methods.
Compound
Etot
ZPE
G
H
D
Etot
D
G
D
H
l
B3LYP/6-31Gꢀꢀ
1–3A
1–5A
2–3A
2–5A
ꢂ373.60446
ꢂ373.60259
ꢂ412.90091
ꢂ412.89891
0.08694
0.08700
0.11450
0.11463
ꢂ373.54846
ꢂ373.54663
ꢂ412.82104
ꢂ412.81732
ꢂ373.50974
ꢂ373.50775
ꢂ412.77669
ꢂ412.77477
ꢂ1.17
ꢂ1.15
ꢂ1.25
4.224
5.167
4.309
4.802
0
0
0
ꢂ1.25
ꢂ2.34
ꢂ1.20
0
0
0
CBS-QB3
1–3A
1–5A
2–3A
2–5A
ꢂ373.22952
ꢂ373.22669
ꢂ412.46500
ꢂ412.46237
0.08588
0.08578
0.11298
0.11286
ꢂ373.26047
ꢂ373.25780
ꢂ412.49903
ꢂ412.49579
ꢂ373.22171
ꢂ373.21879
ꢂ412.45526
ꢂ412.45266
ꢂ1.78
ꢂ1.68
ꢂ1.83
4.385
5.296
4.584
4.817
0
0
0
ꢂ1.65
ꢂ2.03
ꢂ1.63
0
0
0
Table 2
0
Selected bond lengths (l, ÅA) and bond angles (
x
, °) for molecules of 1 and 2 obtained by X-ray diffraction analysis of the crystals and by B3LYP/6–31Gꢀꢀ and CBS-QB3 calculations
for free molecules.
Bonds
Bond lengths
Bond angles
Angles (X-ray)
1
2
1
2
X-ray
B3LYP/6–31Gꢀꢀ
CBS-QB3
X-ray
B3LYP/6–31Gꢀꢀ
CBS-QB3
N1–N2
N1–C5
N2–C3
C3–C4
C4–C5
C3–N6
N1–H1
1.384(1)
1.331(1)
1.340(1)
1.427(1)
1.388(3)
1.368(1)
0.911(16)
1.366
1.343
1.330
1.435
1.392
1.379
1.007
1.363
1.341
1.325
1.434
1.389
1.377
1.006
1.378(2)
1.332(2)
1.334(2)
1.415(2)
1.390(2)
1.381(2)
0.87(2)
1.369
1.346
1.328
1.434
1.398
1.380
1.008
1.367
1.345
1.323
1.434
1.395
1.378
1.007
N1–N2–C3
N1–N2–C5
N2–C3–C4
C3–C4–C5
C4–C5–N1
C4–C3–N6
N2–C3–N6
104.70(8)
112.66(9)
110.33(9)
105.27(9)
107.04(9)
127.34(10)
122.24(9)
103.82(13)
113.99(13)
110.82(14)
105.94(14)
105.42(14)
127.50(14)
121.56(15)

E.E. Emelina et al. / Journal of Molecular Structure 1014 (2012) 63–69
65
1-3A
1-5A
2-3A
2-5A
Fig. 2. The B3LYP/6-31Gꢀꢀ calculated dipole moment vectors of the free molecules of 1 and 2.
1-3A tautomer
2-3A tautomer
Fig. 3. A view of the molecules of 1 and 2 with atom numbering. Thermal vibration ellipsoids are drawn at the 50% probability level.
2.2. Crystal structure determination and refinement
compound 2, being stabilized more efficiently by stronger solva-
tion with the polar solvent. In addition, it is known that ethyl
5(3)-acetylamino-1H-pyrazole-4-carboxylate exists in the solid
state as form 3A [27].
In each molecule, the five-membered pyrazole ring is planar
with deviation of the N(1) atom from the least-squares plane by
0.002 Å for 1 and 0.005 Å for 2.
The cyano group lies close to the plane of the pyrazole ring. All
formally single bonds C(3)–C(4), C(5)–N(1) and N(1)–N(2) of the
pyrazole rings (Table 2) are significantly shortened compared to
The results of single crystal X-ray diffraction studies of pyra-
zoles 1 and 2 are shown in Figs. 3–5 and Table 4. The X-ray studies
showed that these compounds consist of single tautomeric form
3A, confirming the results of the theoretical calculations. It is inter-
esting that the 1H and 13C NMR spectra of a solution of compound 2
in DMSO-d6 contain signals of both tautomeric forms 3A (37%) and
5A (63%) [20]. It can be assumed that the more polar form 5A
(l
= 4.802 D, B3LYP/6-31Gꢀꢀ, Table 1) prevails in the solution of
Fig. 4. H-bonded associates in the crystal structure of 1 (dashed lines denote H-bonds).

66
E.E. Emelina et al. / Journal of Molecular Structure 1014 (2012) 63–69
Table 4
Crystal data and structure refinement for 1,2.
1
2
Empirical formula
Formula weight
Temperature
C4 H4 N4
108.11
100(2) K
C5 H6 N4
122.14
120(2) K
Wavelength
Crystal system
Space group
0.71073 Å
Monoclinic
P 21/c
0.71073 Å
Triclinic
P-1
Unit cell dimensions
a = 3.6925(7) Å
b = 6.4297(13) Å
c = 20.087(4) Å
a = 6.1435(10) Å
b = 7.1154(11) Å
c = 7.4732(12) Å
a
= 67.668(2)°
b = 92.14(3)°
b = 87.601(3)°
c
= 76.399(2)°
Volume
Z
476.58(16) Å3
4
293.29(8) Å3
2
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data
collection
1.507 Mg/m3
0.107 mmꢂ1
224
1.383 Mg/m3
0.095 mmꢂ1
128
0.40 ꢃ 0.20 ꢃ 0.20 mm3 0.20 ꢃ 0.05 ꢃ 0.01 mm3
3.33–28.99°
2.95–29.00°
Index ranges
ꢂ5 ꢄ h ꢄ 4, ꢂ8 ꢄ k ꢄ 7, ꢂ8 ꢄ h ꢄ 8, ꢂ9 ꢄ k ꢄ 9,
Fig. 5. A fragment of the crystal packing of 2 along the crystallographic plane bc.
ꢂ13 ꢄ l ꢄ 27
2537
ꢂ10 ꢄ l ꢄ 10
3241
Reflections collected
Independent reflections
Completeness to
theta = 28.99°
1248 [R(int) = 0.0134]
99.2%
1552 [R(int) = 0.0292]
99.4%
the typical single bond lengths (1.54, 1.47, and 1.45 Å, respectively
[18]), suggesting appreciable p- and n-electron delocalization. The
calculated bond lengths are in good agreement with the corre-
sponding experimental results (Table 2), with small differences
attributable to intermolecular interactions in the crystals. The
nitrogen atom of the amino group has a distorted sp3-hybridization
and in both compounds 1 and 2 is out of the pyrazole ring plane:
the maximum deviation is 0.054 Å for 1 and 0.083 Å for 2. The
hybridization of the N(6) atom, characterized by the sum of bond
angles around it, is 351.0° for compound 1 and 344.2° for com-
pound 2. The C–NH2 distance for compound 2 (1.381 Å) is slightly
longer than for 1 (1.368 Å) (Table 2). Apparently, substitution of
the C(3) hydrogen with methyl group decreases the conjugation
Max. and min.
transmission
0.9780 and 0.970
1248/0/89
1.004
0.998 and 0.990
1552/0/106
Data/restraints/
parameters
Goodness-of-fit on F2
1.008
R1 = 0.0471,
wR2 = 0.1040
Final R indices [for 1145 R1 = 0.0350,
rflns with
I > 2sigma(I)]
R indices (all data)
wR2 = 0.0751
R1 = 0.0380,
wR2 = 0.0766
R1 = 0.0752,
wR2 = 0.1118
Largest diff. peak and
hole
0.326 and ꢂ0.220 e Åꢂ3 0.288 and ꢂ0.270 e Åꢂ3
between the amino group and pyrazole ring
p system. According
to published data [18], in 3-amino-5-phenylpyrazole the sum of
the bond angles around N(6) is appreciably smaller (335(6)°),
and the C–NH2 distance is longer (1.393 Å) than those in com-
pounds 1 and 2. This may be due to the acceptor power of the cy-
ano group.
The crystal structures of compounds 1, 2 are mainly stabilized
by intermolecular hydrogen bonds (Table 3) which determine the
crystal packing mode (Figs. 4 and 5).
gen atoms and the cyano nitrogen atom (Fig. 6, dimer 1.1). It is
known that, in crystals of N-substituted 5-aminopyrazoles, mole-
cules are linked to form identical hydrogen-bonded dimers with
the Nꢁ ꢁ ꢁN distance of 3.147 Å for 5-amino-1-(2-chlorophenyl)pyra-
zole-4-carbonitrile [28] and 3.10 Å for 5- amino-1-tert-butyl-3-(4-
methoxyphenyl)pyrazole-4-carbonitrile [29]. Furthermore, hydro-
gen bonding between the unsubstituted nitrogen atom of the pyr-
azole ring and NH group of another ring with the Nꢁ ꢁ ꢁN distance of
2.934 Å leads to a catemer-like arrangement of molecules of 1
(Fig. 6, catemer 1).
In the crystal structure of 1, two molecules form a dimer via two
equal intermolecular N–Hꢁ ꢁ ꢁN hydrogen bonds with the Nꢁ ꢁ ꢁN dis-
0
tance of 3.080 ÅA. Each bond is formed by one of the amino hydro-
Table 3
Hydrogen bond geometries in crystals of compounds 1 and 2.
0
Compound
1
D–Hꢁ ꢁ ꢁN
Bond angles, °
Bond lengths, ÅA
D–H
Hꢁ ꢁ ꢁN
Dꢁ ꢁ ꢁN
2.934(13)
3.080
3.258 (15)
3.264(16)
D–Hꢁ ꢁ ꢁN
ꢂ0.73
ꢂ0.53
ꢂ0.38
ꢂ0.33
N(ring)ꢁ ꢁ ꢁHAN(ring)a
C„Nꢁ ꢁ ꢁHAN(amino)b
NAH(amino)ꢁ ꢁ ꢁN(ring)c
CAHꢁ ꢁ ꢁN„C
0.913(17)
0.864(16)
0.893(17)
0.965(13)
2.025(17)
2.221(16)
2.369(16)
2.422(14)
174.4 (15)
172.8(14)
174.3(13)
145.7(11)
2
ꢂ0.67
ꢂ0.55
ꢂ0.11
C„Nꢁ ꢁ ꢁHAN(ring)d
N(ring)ꢁ ꢁ ꢁHN(amino)e
C„Nꢁ ꢁ ꢁHN(amino)
0.87(2)
0.92(2)
0.89(2)
2.08 (2)
2.20(2)
2.64(2)
2.927(2)
3.090(2)
3.342
166 (2)
165.2(2)
136.8(16)
Symmetry transformations used to generate equivalent atoms.
a
ꢂx + 1, y ꢂ 1/2, ꢂz + 1/2.
b
ꢂx, ꢂy + 2, ꢂz + 1.
c
ꢂx, y + 1/2, ꢂz + 1/2.
d
x, y, z + 1.
e
ꢂx + 2, ꢂy, ꢂz + 2.

E.E. Emelina et al. / Journal of Molecular Structure 1014 (2012) 63–69
67
dimer 1.1
catemer 1
dimer 1.2
chain 1
Fig. 6. Motives of hydrogen-bonded structures in crystals of pyrazole 1.
dimer 2.2
dimer 2.1
chain 2
Fig. 7. Motives of hydrogen-bonded structures in crystals of pyrazole 2.
In the solid state, every two neighboring molecules of com-
pound 1 are interconnected through van der Waals contacts be-
tween cyano nitrogen atom and C–H hydrogen atom of the ring
(bond angles 145.7°) (Fig. 6, dimer 1.2). The amino hydrogen atom
is linked with the ring nitrogen atom (Fig. 6, chain 1).
Pyrazole 2 differs from 1 in the composition of units forming the
crystal lattice.
The dimers are formed by hydrogen bonds between the nitro-
gen atom of the pyrazole ring and one of the amino hydrogen
atoms (Fig. 7, dimer 2.1). Hydrogen bonds between the cyano

68
E.E. Emelina et al. / Journal of Molecular Structure 1014 (2012) 63–69
nitrogen atom and the NH group of the pyrazole ring link mole-
cules of 2 in chains (Fig. 7, chain 2). Also one can distinguish a di-
mer formed by weaker H-bonds (angle 136.8°) between the cyano
nitrogen and amino hydrogen atoms (Fig 7, dimer 2.2). It is worth
noting that 5-amino-1-tert-butyl-3-phenylpyrazole-4-carbonitrile
molecules are linked by the same H bonds and form not dimers
but chains [28].
ters are listed in Table 4. The molecular drawings were prepared
using ORTEP for Windows [33]. The crystallographic data have
been deposited at the Cambridge Crystallographic Data Center,
CCDC 836030 and 836031.
4.3. Computational methods
Thus, the formation of supramolecular assemblies in the crys-
tals of compounds 1 and 2 is determined by hydrogen bonding
with cyano, amino, and ring nitrogen atoms as well as by van der
Waals interactions with each of the nitrogen atoms mentioned
above.
The molecular geometries were first optimized at the HF/6-31G
computational level and then reoptimized at the DFT B3LYP/6-
31Gꢀꢀ computational level within the GAMESS-US package [21].
Frequency calculations at both levels were carried out to confirm
that the structures obtained correspond to energy minima. Ther-
modynamic characteristics were calculated with the B3LYP/6-
31Gꢀꢀ optimized geometries. CBS-QB3 complete basis set extrapo-
lation runs were done for additional geometry reoptimizations and
accurate energy calculations within Gaussian03 package [22].
3. Conclusions
Theoretical study of the free molecules of 3(5)-amino-4-cyano-
pyrazole and 3(5)-amino-4-cyano-5(3)-methylpyrazole molecules
showed that 3-amino tautomers of these compounds are
preferable.
Comparison of the total energy, free energy and enthalpy
differences between tautomeric forms of the free molecules of
Acknowledgements
The authors are grateful to the Russian Foundation for Basic Re-
search for the financial support (project no. 10-03-00600-a).
3(5)-amino-4-cyanopyrazole
and
3(5)-amino-4-cyano-5(3)-
methylpyrazole, calculated by DFT B3LYP/6-31Gꢀꢀ and CBS-QB3
methods, showed that both methods can be used for finding the
more stable tautomeric form of the free molecules of such
4-cyanopyrazoles.
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tautomers.
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