Annular tautomerism of 3(5)-disubstituted-1H-pyrazoles with ester and amide groups

Article abstract of DOI:10.3390/molecules24142632

A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups, as well as ester (a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (1a, 1b) and amino (2b) groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (3b, 4), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl₃, DMSO-d₆, and CD₃OD solvents. However, tautomer equilibrium was observed for 2b in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.

Full text of DOI:10.3390/molecules24142632

molecules
Article
Annular Tautomerism of
3
(5)-Disubstituted-1H-pyrazoles with Ester and
Amide Groups
Anna Kusakiewicz-Dawid, Monika Porada, Bła z˙ ej Dziuk and Dawid Siodłak *
Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland
*
Correspondence: dsiodlak@uni.opole.pl
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 6 July 2019; Accepted: 17 July 2019; Published: 19 July 2019
Abstract: A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups,
as well as ester (
was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment
in the crystal state showed for the compounds with methyl (1a 1b) and amino (2b) groups the
tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group
3b ), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl3,
a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism
,
(
, 4
DMSO-d6, and CD OD solvents. However, tautomer equilibrium was observed for 2b in DMSO.
3
The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to
conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring.
Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile,
and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds,
the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity
and intra- and inter-molecular interactions, seem to have a considerable influence on the choice
of tautomer.
Keywords: pyrazole; tautomer; conformation; X-ray; NOE; FT-IR; NICS; DFT
1
. Introduction
Pyrazole is a five-membered aromatic heterocycle with two adjacent nitrogen atoms, classified as
azole. Pyrazole derivatives have broad application, from engineering and polymers [
activity [ ]; thus, new synthetic strategies are constantly developed [10 17]. Among them, there are
H-pyrazoles with substituents at positions 3 and 5, which reveal interesting applications [18–25],
1–8], to biological
9
–
1
and some of them are depicted in Figure 1. The substitution at positions 3 and 5 by amide, ester,
or generally a carbonyl linkage makes a convenient structural building block of potentially broad usage.
For example, a non-natural 1H-pyrazole amino acid was investigated as a building block of short peptides
designed to act as
of the 1H-pyrazole residue result from a specific hydrogen bonding pattern, in which hydrogen bond
donors and acceptors can be aligned on one side of the residue [26 28]. To get more detailed information
β-sheet ligands, which prevent protein aggregation. The distinguishing properties
–
about these properties, the conformational properties of the 3-amino-1H-pyrazole-5-carboxylic acid
residue were investigated. It was found that the observed conformational preferences were clearly
related to the presence of intramolecular interactions formed within the studied residue [29]. This shows
that the N-unsubstituted 1H-pyrazole moiety is able to create a specific type of hydrogen interaction
and, then, association, which can be crucial for biological properties, or even broader for materials
science. However, these properties strictly depend on the position of the hydrogen atom. Therefore,
annular tautomerism of the 1H-pyrazoles is the subject of interest.
Molecules 2019, 24, 2632; doi:10.3390/molecules24142632
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2632
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Figure 1. Examples of 1H-pyrazole compounds with the 3(5)-carbonyl group.
The majority of the literature data is concerned with various 3(5)-substituted pyrazole compounds,
investigated mostly using X-ray structure analysis and NMR spectroscopy, such as 3(5)-phenyl- and
5
(3)-methyl-3(5)-phenylpyrazole [30], single aryl substituents [31], 3(5)-amino-5(3)-arylpyrazoles [32],
3-nitropyrazole [33], 3(5)-aminopyrazoles [34], 1H-pyrazole-3-(N-tertbutyl)-carboxamide [35],
or 3(5)-trifluoromethyl-1H-pyrazoles [36]. Various monosubstituted pyrazoles were studied using
theoretical methods on isolated molecules [37 38]. However, there is still insufficient data concerning
(5)-substituted pyrazole with an amide or ester linkage.
In this work, we present a study on the annular tautomerism of 3(5)-disubstituted-1H-pyrazoles,
,
3
with an ester/amide bond and methyl, amine, and nitro substituents (Figure 2). Assuming that intra-
and inter-molecular interactions can be important factors, not only the position of the hydrogen atom
at the pyrazole nitrogen atom, but also the conformation of the carbonyl linkage are considered.
Figure 2. Schematic representation of tautomers in 3(5)-1H-pyrazoles, conformation of the 3(5)-carbonyl
group, and numeration of the series of studied compounds.

Molecules 2019, 24, 2632
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2
. Results and Discussion
2
.1. X-Ray Results
Molecular structures of the studied molecules 1a
,
1b
,
2b
,
3b, and
4
in the crystal state are presented
in Figure 3. Molecular interactions are presented in Figure 4. The X-ray experimental details are
presented in Table 1 and selected geometric parameters in Tables S1–S6.
Figure 3. Molecular structures of the studied molecules in the crystal structure in the asymmetric part
of the unit cell. Displacement ellipsoids are drawn at the 50% probability level.
Figure 4. Molecular interactions of the studied molecules with visualization of the hydrogen bonds.

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Table 1. Crystal data and structure refining for the studied compounds.
1
a
1b
C H N O
2b
C H N O
3b
C H N O
4
Chemical formula
C H N O
C H N O
5 8 4 4
6
9
3
7
10
2
2
5
7
3
2
5
5
3
4
Mr
Crystal system, space
group
139.16
Monoclinic,
154.17
Monoclinic,
141.14
171.12
188.15
Monoclinic,
Monoclinic, P2 /n
Monoclinic, P2 /m
1
1
P2 /c
P2 /n
P2 /n
1
1
1
1
4.7736 (4),
7.2104 (2),
3.6295 (4)
90.800 (3)
1451.72 (7)
8
9.7186 (7),
6.0828 (4),
13.4976 (11)
102.810 (7)
778.07 (10)
4
3.7803 (1),
22.9836 (7),
9.0425 (3)
98.082 (3)
777.85 (4)
4
1
0.8040 (5), 13.6444 (5),
5.5232 (3), 6.1484 (3),
10.8318 (5)
a, b, c (Å)
1
3.8883 (6)
1
◦
β ( )
110.173 (5)
1921.74 (15)
12
0.12
0.4 × 0.3 × 0.2
102.679 (5)
358.87 (3)
2
0.14
0.5 × 0.4 × 0.2
3
V (Å )
Z
µ (mm 1)
Crystal size (mm)
No. of measured,
independent and
observed [I > 2σ(I)]
reflections
−
0.09
0.1
0.14
0.5
×
0.4
×
0.2 0.5
×
0.3
×
0.1
0.4
×
0.3
×
0.2
9524, 2826,
2196
5041, 1523,
1130
5234, 1530,
1186
9
264, 3742, 2660
2439, 776, 685
Rint
0.024
0.617
0.037
0.616
0.027
0.617
0.013
0.617
0.027
0.617
(
sin θ/λ)max (Å 1)
−
Refinement
0
.037, 0.103,
0.038, 0.103,
0.88
0.029, 0.070,
0.95
2
2
2
R[F > 2σ(F )], wR(F ), S
0.034, 0.085, 0.77
0.027, 0.076, 1.11
1.08
No. of reflections
No. of parameters
2826
185
1523
102
3742
292
776
79
1530
120
H atoms treated by a
mixture of
independent and
H atoms treated by a
mixture of
independent and
H-atom
parameters
constrained
H-atom
parameters
constrained
H-atom
parameters
constrained
H-atom treatment
constrained refinement constrained refinement
−
∆
ρmax, ∆ρmin (e Å 3)
0.26, −0.26
0.20, −0.27
0.17, −0.25 0.29, −0.19
0.24, −0.24
In the crystal structure of N-methyl 5-methyl-1H-pyrazole-3-carboxylamide (1a), CH -Pz-CONH
3
CH , there are two types of molecules with slightly different geometries. In both cases, the amide group
3
is at position 3 in relation to the N-H group of the pyrazole ring. Therefore, the tautomer denoted as
◦
T3 is present. The torsion angle N2-C1-C5-N3 has a value of
−
15.42(3) . This shows that the nitrogen
atoms of the amide group and pyrazole ring are at the same side, and the cisoidal conformation (T3c) is
obtained. The low value of torsion angle indicates that -electron conjugation between the pyrazole
ψ
π
ring and amide group is possible. Some deformation results from the intermolecular hydrogen bonds.
Two molecules of a slightly different geometry create a centrosymmetric dimer stabilized by two N-H
.
. . N hydrogen bonds (Table S6), in which the donor is the N-H group of the amide bond and the
acceptor is the nitrogen atom at positon 2 of the pyrazole ring. Additionally, each molecule creates
two N-H . . . O hydrogen bonds involving the C=O group as an acceptor and the N-H group of the
pyrazole ring as a donor.
In the crystal structure of ethyl 5-methyl-1H-pyrazole-3-carboxylate (1b), CH -Pz-COOCH CH ,
3
2
3
the ester group is also at position 3 in relation to the N-H group of the pyrazole ring, which means that
◦
the tautomer T3 is presented. The ester group is almost coplanar with the pyrazole ring (
ψ
= -5.84 ),
and thus, the same tautomer and conformer (T3c) are obtained as in the case of the amide analogue.
In contrast, the molecules are arranged in a linear association, which is stabilized by the N-H . . .
N
hydrogen bonds created between the pyrazole nitrogen atoms. Additionally, the carbonyl oxygen
of the ester group creates a short contact with the methyl group at position 2 of the pyrazole ring,
whereas the oxygen atom of the alkoxy group is involved in the contact with the pyrazole N-H group.
In the crystal state of methyl 5-amino-1H-pyrazole-3-carboxylate (2b), H N-Pz-COOCH ,
2
3
three independent molecules are present in the asymmetric unit. Again, the tautomer T3 is adopted.
◦
In the case of the ester group, the torsion angle
ψ
is close to a value of 180 . This means that in contrast
to compounds 1a and 1b, the transoidal conformation is adopted (T3t), in which the oxygen atom
of alkoxy group is in the trans position to the nitrogen atom of the pyrazole ring. Three molecules
of slightly different geometry create a trimer stabilized by six hydrogen bonds. Inside the trimer,
three N-H . . . N hydrogen bonds are created by the pyrazole nitrogen atoms, where each pyrazole

Molecules 2019, 24, 2632
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ring assumes a donor and acceptor function. Three N-H . . . O hydrogen bonds are created by the NH2
groups and carbonyl oxygens of neighboring molecules.
For the molecules of methyl 3-nitro-1H-pyrazole-5-carboxylate (3b), O N-Pz-COOCH , in the
2
3
crystal state, the ester group is at positon 5 of the pyrazole ring. Thus, in contrast to previous
compounds, the tautomer denoted as T5 is adopted. The ester group is coplanar with the pyrazole
◦
ring (
ψ
= 0 ), and the cisoidal conformation (T5c) is present. A linear association is formed, stabilized
by the N-H . . . O hydrogen bonds created by the N-H group of the pyrazole ring and carbonyl ester
group. There is also a short C-H . . . N contact between the C2-H and N2 of the pyrazole ring.
), O N-Pz-COO MeNH3+,
–
The crystal of methylammonium 3-nitro-1H-pyrazole-5-carboxylate (
4
2
shows that the ester group is at position 5 of the pyrazole ring. Therefore, the tautomer T5 is present.
Both the nitro and carboxylate groups are coplanar with the pyrazole ring. In comparison to previous
compounds, the association model is more complex. The pyrazole ring creates two hydrogen bonds:
+
as the acceptor in the N -H . . . N hydrogen bond with the methylammonium cation and as a donor in
the N-H . . . O hydrogen bond with the carboxylate group of another molecule. Additionally, each
+
carboxylate group creates three N -H . . . O hydrogen bonds with methylammonium cations. The nitro
groups are involved in C-H . . . O contacts with the methyl group of the ammonium cation and the
C2-H group of the pyrazole ring of the neighboring molecule.
As can be seen, the studied compounds reveal various association patterns. They create the N-H
.
. . N and N-H . . . O hydrogen bonds, involving both the N-H group of the pyrazole ring and the C=O
and N-H groups of ester/amide moieties. Nevertheless, a trend can be seen, for CH -Pz-CONHCH
3
3
(
1a), CH -Pz-COOCH CH (1b), and H N-Pz-COOCH (2b): the amide/ester group is at position 3 of
3 2 3 2 3
–
+
the pyrazole ring (the tautomer T3), whereas in O N-Pz-COOCH (3b) and O N-PzCOO MeNH (
4
),
2
3
2
3
the ester group is at position 5 (the tautomer T5).
Additional information was obtained by searching the Crystal Structure Database and analysis
of the structures containing three and five disubstituted pyrazole rings (Table 2, Table S7). For the
methyl substituent, only the structures of tautomer 3 are present with the value of the torsion angle
close to 0 (T3c). In contrast, the structures with the alkyl substituent, but with the fluorine atom at the
ψ
◦
α
carbon, adopt solely tautomer 5. This also occurs for the structures with the nitrile and hydroxyl
groups. When the phenyl group is present, all possible structures are adopted, but with preferences
towards tautomer 3. It seems that for the choice of tautomer, the type of substituent is important, that is
the
adopted. The introduction of the fluorine atom results in the
therefore, tautomer 5 is adopted. The nitrile substituent with both the
σ
/
π
-donating/-withdrawing character. When the
σ
donating methyl group is present, tautomer 3 is
-withdrawing character of the substituent;
and -withdrawing character
σ
σ
π
results solely in tautomer 5. The data for 3(5)-carboxy-1H-pyrazole-5(3)-carboxylate monohydrate
shows an interesting balance. The carboxy and carboxylate groups are structurally similar; thus,
both tautomers are present, but the negative charge of the carboxylate group results in tautomer
T3 being preferred, in which the N-H group of the pyrazole ring is closer to the electron donating
substituent (or the pyrazole nitrogen atom with a lone electron pair closer to more electron-withdrawing
substituents). This corroborates the result obtained in the case of the structure of
4. The data in Table S7
show that the amide and ester groups have a similar effect, at least in the solid state.

Molecules 2019, 24, 2632
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Table 2. Tautomers/conformers of the 1H-pyrazole residue (-Pz-CO-) with carbonyl at position 3(5)
found in the solid state.
X-Pz-CO-
Tautomer (T3/5)/Conformer (c/t)
X-
Me-
H-
T3c
7
2
T3t
T5c
T5t
3
1
5
Ph-
12
3
1
1
6
2
2
3
2
1
OOC-Pz-COOH 11
NC-
-CF-
HO-
2
.2. Theoretical Calculations
In order to get more detailed information, theoretical calculations were performed. Table 3
and Figure S1 present the local minima of the studied compounds in relation to their tautomers
position 3 or 5 of the carbonyl substituent) and rotation of the carbonyl substituent (the torsion angle
1–3
(
ψ
◦ ◦
close to a value of 0 or 180 ). Each studied compound has two tautomers (T3 or T5), and each
◦ ◦
ψ ~ 0 or 180 , respectively). Therefore, for each compound,
tautomer has two conformations (Tc or Tt,
four local minima (T3c, T3t, T5c, T5t) were analyzed. Thus, the information about the relative energy
between tautomers, conformers, and amide/ester substituent can be obtained. The calculations were
performed for isolated molecules (in vacuo), as well as mimicking an increase of environment polarity
(chloroform, acetonitrile, water).
As can be seen in Table 3, the results obtained for the most polar water-mimicking environment
corresponded fairy well with those for the X-ray structures. For CH -Pz-CONHCH3
(
1a),
3
CH -Pz-COOCH CH (1b), and H N-Pz-COOCH (2b) the lowest energy structure is adopted
3
2
3
2
3
in the crystal state, T3c for 1a and 1b and T3t for 2b. For O N-Pz-COOCH (3b), the second structure
2
3
in the predicted energy order is adopted (T5c), but the difference in relative energy from the lowest
energy structure (T5t) is small.
The influence of the environment is different for each structure. For more clear visualization,
the diagrams of the change of relative energy are given in Figure S2. For the pyrazole substituted
by the nitro group (3a and 3b), the environment does not seem to have an influence on the choice of
tautomer and conformation. The structure T5t is adopted with the ester/amide group in position 5
◦
and the torsion angle
ψ
~ 180 . The preferences of the pyrazole ring substituted by the methyl and
amide groups (1a) also seem to be independent of the polarity of the environment. In this case, the
◦
structure T3c is adopted with the amide group in position 3 and the torsion angle
ψ
~ 0 . A difference
is seen when the ester group is present instead of amide (1b). Although the structure in the crystal
state and solvent-mimicking environment is the same (T3c), for the isolated molecule 1b, the structure
T5t is predicted. This difference results from the presence of intramolecular hydrogen bonds. As is
depicted in Figure S1, in the structure T3c with the amide substituent (1a), there are two hydrogen
bonds: N-H . . . N between the amide N-H and pyrazole N2, as well as C-H . . . O, between the pyrazole
C4-H and amide O. The concomitant existence of these forces results in the highest stability of the
structure T3c. It should be noticed that for the isolated molecule 1a, the second in energy order is the
structure T5t, which can be explained by the presence of the N-H . . . O hydrogen bond (between the
pyrazole N-H and amide O). The remaining structures, T3t and T5c, undergo unfavorable H . . .
H
repulsion, which for T5c is seen by a deviation of the torsion angle . All this together explains why
ψ
the structure T3c is favorable. However, for the analogue with the ester substituent (1b), the structures
T5c and T5t have two hydrogen bonds, where the donors are the pyrazole N-H and C-H groups and
the acceptors are two oxygen atoms of the ester. The structure T5t prevails in an isolated molecule, and
its lowest energy can be explained by the presence of a stronger N-H . . . O hydrogen bond involving
the carbonyl oxygen atom.

Molecules 2019, 24, 2632
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Table 3. Local minima and the selected thermodynamic properties of the studied compounds 1–3 with reference both to tautomers and the rotation of the
carbonyl group.
In Vacuo
Energy
(Ha)
Chloroform
Energy
(Ha)
Acetonitrile
Energy
(Ha)
Water
Energy
(Ha)
ψ
∆E
ψ
∆E
ψ
∆E
ψ
∆E
◦
◦
◦
◦
Conformer Code↓
( )
(kcal/mol)
( )
(kcal/mol)
( )
(kcal/mol)
( )
(kcal/mol)
(
1a) CH -Pz-CONHCH
3 3
T3c
T3t
T5c
T5t
0.0
180.0
24.4
−473.322883
−473.312263
−473.314249
−
473.321441
0.00
6.66
5.42
0.90
0.0
180.0
24.1
−
−
−
−
473.340504
0.00
3.97
4.58
1.82
0.0
180.0
17.6
−
473.344429
473.340706
473.338227
473.341534
0.00
2.34
3.89
1.82
0.0
180.0
18.4
−
−
−
−
473.344742
473.342131
473.339003
473.341632
0.00
1.64
3.60
1.95
473.334178
473.333208
473.337598
−
−
−
180.0
180.0
180.0
180.0
(
1b) CH -Pz-COOCH CH
3
2
3
T3c
T3t
T5c
T5t
0.0
180.0
0.2
−
−
−
−
532.474789
532.473347
532.477188
532.477703
1.83
2.73
0.32
0.00
0.0
180.0
0.4
−
532.492603
0.00
0.50
0.69
0.52
0.0
180.0
0.3
−
−
−
−
532.496648
532.496280
532.494031
532.494172
0.00
0.23
1.64
1.55
0.0
180.0
0.0
−
−
−
−
532.494392
532.494119
532.490849
532.490747
0.00
0.17
2.22
2.29
−
−
−
532.491806
532.491509
532.491767
180.0
180.0
180.0
180.0
(
−
−
−
−
2a) H N-Pz-CONHCH
2 3
T3c
T3t
T5c
T5t
0.0
−489.374774
−489.365033
−489.371558
−
489.376759
1.25
7.36
3.26
0.00
0.0
−180.0
25.3
489.397950
489.392782
489.393897
489.397510
0.00
3.24
2.54
0.28
0.0
−180.0
18.1
−489.404669
−489.402127
−489.400630
−
489.403626
0.00
1.59
2.53
0.65
0.0
−
−
−
−
489.405337
489.404202
489.401874
489.404197
0.00
0.71
2.17
0.72
−179.9
−180.0
24.2
5.1
−180.0
180.0
180.0
−180.0
(
2b) H N-Pz-COOCH
2 3
T3c
T3t
T5c
T5t
0.0
180.0
0.0
−
−
−
−
509.246751
509.245885
509.253108
509.254195
4.67
5.21
0.68
0.00
0.0
180.0
0.4
−
−
−
−
(
−
−
−
−
509.267576
509.267586
509.270059
509.270450
1.80
1.80
0.25
0.00
0.0
180.0
0.4
−
−
−
−
509.274622
509.275108
509.275012
509.275315
0.43
0.13
0.19
0.00
0.0
180.0
0.2
−179.9
−
−
−
−
509.273901
509.274337
509.273864
509.273994
0.27
0.00
0.30
0.22
180.0
179.9
179.8
3a) O N-Pz-CONHCH
2 3
T3c
T3t
T5c
T5t
0.0
−155.5
26.8
−638.517709
−638.508452
−638.510067
−
638.518707
0.63
6.43
5.42
0.00
0.0
638.535327
638.529928
638.533577
638.538973
2.29
5.68
3.39
0.00
0.0
−174.3
22.6
−638.539811
−638.536869
−638.541327
−
638.545531
3.59
5.44
2.64
0.00
0.0
−
−
−
−
638.538274
638.536671
638.540059
638.544350
3.81
4.82
2.69
0.00
−174.4
−170.8
24.8
20.4
180.0
−177.3
180.0
−179.9
(
3b) O N-Pz-COOCH
2 3
T3c
T3t
T5c
T5t
0.0
180.0
0.0
−658.389922
−658.389303
−658.393160
−
658.394621
2.95
3.34
0.92
0.00
0.0
180.0
0.0
−
−
−
−
658.404657
658.404464
658.409513
658.410447
3.63
3.75
0.59
0.00
0.0
180.0
0.0
−658.409316
−658.409578
−658.414409
−
658.415251
3.72
3.56
0.53
0.00
0.0
180.0
0.0
−
−
−
−
658.405911
658.406313
658.411099
658.411725
3.65
3.40
0.39
0.00
180.0
180.0
180.0
180.0

Molecules 2019, 24, 2632
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A similar explanation can be deduced for the pyrazole with the amine substituent (2a and 2b).
For isolated molecules, preference towards the tautomer T5 can be explained by the lack of H . . . H
repulsion between the hydrogen atoms of the amine group and those of the pyrazole ring. The presence
of solvent results in the tendency towards the structure T3c for 2a. However, for 2b with the ester
bond, the increase of environment polarity decreases the gap of energy amongst the structures, which
predicts possible equilibrium of the tautomers.
The analysis of the relative differences in energy between the structures for the studied compounds
(Figure S2) clearly shows the influence of the environment. In general, the increase of environment
polarity lowers the energy of the structure T3t, regardless of the type of substituent. The structure T3t is
not stabilized by intramolecular hydrogen bonds; thus, both donor and acceptor groups can be involved
in the intermolecular interactions. A similar effect is observed for the structure T5c for the amide
compounds 1–3a. In contrast, for the ester compound 1b, the structures T5c and T5t are stabilized
by N-H...O and C-H...O intramolecular hydrogen bonds. Therefore, they are not effectively used in
intermolecular interactions, and the relative energies of these structures increase with environment
polarity. For the compound 2b, the environment decreases the relatively energy of the tautomer 3
structures, but for the tautomer 5 structures, the relative energy is maintained, which can be explained
by the advantageous interaction of the solvent with the amine substituent. For the compounds with
the nitro group, 3a and 3b, the tautomer 3 structures are not stabilized much by interactions with the
solvent. Even an increase of energy is observed for the structure T3c for 3a. This can be explained by
the presence of N-H...O and C-H...O intramolecular hydrogen bonds with oxygen atoms of the nitro
group as acceptors. In contrast, the tautomer 5 structures gain stabilization from both intra-, as well as
inter-molecular interactions. Therefore, it can be concluded that both the intra- and inter-molecular
interactions play a considerable role. However, the type of substituent determines this influence.
To determine the influence of the substituent on the aromaticity of the pyrazole ring,
Nucleus-Independent Chemical Shifts (NICS) were calculated, both for the 3(5)-monosubstituted
pyrazole ring (Table 4) and the compounds 1–3 (Table 5). As can be seen, the effect is rather small.
Therefore, the relatively differences, in particular for the z-component NICS(1)zz obtained 1 Å above
the molecular plane, were analyzed, as it turned out to be a more sensitive parameter to the electronic
structure [39]. Table 4 shows that the aromaticity of 3(5)-monosubstituted pyrazole compounds
decreases as compared to non-substituted pyrazole. Interestingly, regardless of the substituent, this
tautomer is preferred, in which the distance between the N-H pyrazole and substituent is longer.
The rotation of the amide or ester group has an insignificant influence on aromaticity. Table 5 shows
that for all studied compounds 1–3, the tautomer 5 is favored, that is the carbonyl group is closer to the
pyrazole N-H group. The tautomer 3 is disfavored in particular for the structure T3c, regardless of the
substituent and amide/ester group. It should be noted however that this effect is relatively small for
the structures (1a and
b) with the methyl substituent, whereas it is considerable for the structures 2
and 3 with the amino and nitro groups, respectively.

Molecules 2019, 24, 2632
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Table 4. NICS parameters for 3(5)-monosubstituted pyrazole.
Compound
NICS(0)
NICS(1)
NICS(1)zz
Pyrazole
-Methyl-1H-pyrazole
-Methyl-1H-pyrazole
H-pyrazol-3-amine
3-Aminopyrazole)
H-pyrazol-5-amine
5-Aminopyrazole)
−13.51
−12.57
−12.13
−11.37
−13.22
−12.12
−8.93
−33.87
−31.38
−30.52
−26.42
3
5
1
−11.97
(
1
−11.94
−8.72
−10.63
−10.36
−25.71
−29.74
−28.76
(
3
5
-Nitro-1H-pyrazole
-Nitro-1H-pyrazole
−13.50
−12.43
N-Methyl-1H-pyrazole-3-carboxamide
−12.81
−12.95
−12.61
−12.28
−12.88
−12.88
−12.29
−12.21
−10.89
−10.99
−10.90
−10.86
−10.98
−11.03
−10.89
−10.88
−30.98
−31.00
−32.07
−30.69
−31.14
−31.16
−30.85
−30.68
◦
(
ψ = 0 )
N-Methyl-1H-pyrazole-3-carboxamide
◦
(
ψ = 180 )
N-Methyl-1H-pyrazole-5-carboxamide
◦
(
ψ = 0 )
N-Methyl-1H-pyrazole-5-carboxamide
◦
(
ψ = 180 )
Methyl 1H-pyrazole-3-carboxylate
◦
(
ψ = 0 )
Methyl 1H-pyrazole-3-carboxylate
◦
(
ψ = 180 )
Methyl 1H-pyrazole-5-carboxylate
◦
(
ψ = 0 )
Methyl 1H-pyrazole-5-carboxylate
◦
ψ = 180 )
(
Table 5. NICS parameters for the studied compounds 1–3.
Code
NICS(0)
NICS(1)
NICS(1)zz
∆NICS(1)zz
(
1a) CH -Pz-CONHCH
3
3
T3c
T3t
T5c
T5t
−11.57
−10.08
−10.12
−10.05
−10.23
−27.86
0.00
−11.68
−11.57
−11.35
−27.88
−27.94
−28.09
−0.02
−0.08
−0.23
(1b) CH -Pz-COOCH CH
3
2
3
T3c
T3t
T5c
T5t
−11.61
−11.65
−11.37
−11.33(
−10.06
−10.19
−10.76
−10.29
−27.93
0.00
−28.02
−28.3
−0.08
−0.36
−0.18
−28.12
2a) H N-Pz-CONHCH
2
3
T3c
T3t
T5c
T5t
−11.48
−11.64
−11.45
-8.45
-8.56
-8.95
-23.36
-23.44
-25.81
-24.01
0.00
-0.08
-2.44
-0.65
−11.09(
-8.75
2b) H N-Pz-COOCH
2
3
T3c
T3t
T5c
T5t
−11.70
−11.72
−11.43
−11.40(
−8.61
−8.63
−9.08
−9.10
−23.60
−23.71
−24.84
−24.86
0.00
−0.11
−1.24
−1.26
3a) O N-Pz-CONHCH
2
3
T3c
T3t
T5c
T5t
−12.12
−12.50
−13.06
−10.00
−10.28
−10.29
−26.33
−27.40
−27.99
−27.16
0.00
−1.07
−1.66
−0.82
−12.72(
−10.33
3b) O N-Pz-COOCH
2
3
T3c
T3t
T5c
T5t
−12.30
−12.36
−12.77
−12.76
−10.17
−10.22
−10.33
−10.35
−26.60
−26.72
−27.28
−27.22
0.00
−0.12
−0.68
−0.62

Molecules 2019, 24, 2632
10 of 17
2
.3. Study in Solution
To determine the type of tautomer in solution, a series of NMR spectra in solvents of various
polarities (chloroform, dimethyl sulfoxide, methanol), as well as the NOE experiments were performed
(
Figures S3–S21). The main differences between the compounds
1
–
3
are presented in Figure 5. For the
1
compounds 1b and 3b, the H NMR spectra show that in each case, only one tautomer is present,
regardless of the polarity of the environment studied. However, the NOE experiments show that
these tautomers are different. For the compound 1b, both pyrazole hydrogen atoms (C-H
δ 6.49 and
H
N-H
δ
13.22) show proximity to the methyl substituent ( H
δ
2.25), which indicates the tautomer 3.
The case is similar for the amide analogue 1a. In contrast, for the compound 3b, the NOE experiment
shows the proximity of both pyrazole hydrogen atoms (C-H 7.53 and N-H 15.24) to the ester
H
δ
H
δ
H
methyl group (
δ 3.96). This indicates the tautomer 5. The results are in agreement with X-ray data,
H
as well as theoretical calculations predictions. Interestingly, for the compound 2b with the amine
substituent, a tautomer equilibrium is present in DMSO solution. As can be seen in Table 3, theoretical
calculations predicted the smallest differences between the energy of tautomers and conformers for
2
b. Furthermore, the equilibrium is not present in less polar (chloroform) and more polar (methanol)
solvents. This shows that the environment has an influence on the choice of tautomer.
Figure 5. NMR-NOE spectra in DMSO-d for the compounds 1b and 3b, which show the preferred
6
1
tautomer and H spectrum for 2b, which shows the equilibrium of the tautomers.
Figure 6 shows the
the solutions of the studied molecules
In chloroform, the spectra for 1b and 2b show single bands (at 1720 and 1725 cm , respectively),
whereas for 3b, the band shows a small shoulder on the side of higher frequencies, which after
deconvolution was resolved on the main band at 1734 cm and a much smaller band at 1751 cm .
ν
S(C=O)-stretching mode of the Fourier Transform Infrared (FT-IR) spectra for
3b in weakly-polar chloroform and more polar acetonitrile.
1
–
−1
−1
−1

Molecules 2019, 24, 2632
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The calculated stabilities of the structures presented in Table 3 together with the analysis of the
−
1
theoretical frequencies presented in Table 6 enable assigning for 1b the band at 1720 cm to the
−
1
structure T3c, for 2b the band at 1725 cm to the structure T5t, and for 3b the bands at 1734 and
751 cm to the structures T5t and T5c, respectively. In acetonitrile, the spectra for all compounds
show two bands; clearly seen for 1b (at 1730 and 1718 cm ) and after deconvolution for 2b (at 1731
and 1721 cm ) and 3b (at 1747 and 1739 cm ). Table 6 shows that these can be assigned to the
structures T3c and T3t for 1b and T5c and T5t for 3b. In the case of the compound 2b, all structures are
possible. The presented results show that FT-IR spectra show rather conformational changes involving
the rotation of the carbonyl substituent and its position in relation to the pyrazole ring.
−
1
1
−1
−1
−1
Figure 6. Selected FT-IR spectra of the studied molecules 1–3b in the ν (C=O) region.
S
Table 6. Calculated and measured frequencies of the studied molecules 1–3b in the νS(C=O) region in
chloroform and acetonitrile.
Code
Chloroform
Scaled a
Acetonitrile
Scaled b
Calc.
Measured
Calc.
Measured
(
1b) CH -Pz-COOCH CH
3 2 3
T3c
T3t
1803.76
1824.47
1715
1735
1720
1799.13
1814.27
1716
1731
1718
1730
(
2b) H N-Pz-COOCH
2 3
T3c
T3t
T5c
T5t
1807.09
1826.99
1827.74
1808.87
1718
1737
1737
1720
1801.77
1818.40
1820.13
1805.58
1719
1735
1736
1723
1721
1731
1731
1721
1725
(
3b) O N-Pz-COOCH
2
3
T5c
T5t
1840.61
1824.01
1750
1734
1751
1734
1831.87
1822.54
1748
1739
1747
1739
a
scaling factor 0.951. b scaling factor 0.954.

Molecules 2019, 24, 2632
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3
. Experimental Section
3
.1. Synthesis
N-Methyl 5-methyl-1H-pyrazole-3-carboxyamide (1a). Ethyl 5-methyl-1H-pyrazole-3-carboxylate (0.154 g,
mM) was dissolved in methanol (1 mL), and methylamine (0.08 mL, 1 mM) was added. The mixture
1
was left for 3 days, and then, the solvents were removed. The product was washed by ethyl acetate
1
(
3
×
1 mL); crystallized from a mixture of methanol/diethyl ether. Yield: 40%. H NMR (400 MHz,
DMSO-d ) δ (ppm): 12.76 (1H, s, N–H ), 8.04 (1H, s, CON–H), 6.36 (1H, s, C–H ), 2.72 (3H, s, CH -Pz),
Pz Pz 3
6
◦
.23 (3H, s, CH ). Melting point: 162–172 C. TLC CHCl /MeOH (9:1) R = 0.23.
3 3 f
2
Ethyl 5-methyl-1H-pyrazole-3-carboxylate (1b). The compound was purchased from Trimen Chemicals;
◦
1
crystallized from diethyl ether/hexane at about 5 C. H NMR (40 0MHz, DMSO-d )
δ
(ppm): 13.19
6
(
1H, s, N–H ), 6.49 (1H, s, C–H ), 4.24 (2H, q, J = 7.2, CH ), 2.25 (3H, s, CH -Pz), 1.27 (3H, t, J = 7.2,
Pz
Pz
2
3
◦
CH ) (Figure S9). Melting point by DSC: 80 C (Figure S22). TLC CHCl /MeOH (9:1) R = 0.44.
3
3
f
Methyl 5(3)-amino-1H-pyrazole-3(5)-carboxylate (2b). Methyl 3-nitro-1H-pyrazole-5-carboxylate (1.71 g
,
1
0 mM) was dissolved in methanol (40 mL), and 10% Pd/C (0.26 g) was added. Hydrogenation was
carried out in a Paar apparatus under 5 bar. After 24 h, the catalyst was filtered off and washed
by methanol. The solvent was evaporated by reduced pressure, and the residue was crystallized
◦
from ethanol (10 mL). Yield: 1.14 g, 81%. Melting point by DSC: 116 and 142 C (Figure S23). TLC:
CHCl /MeOH/AcOH (90:8:2) R = 0.43. Elemental analysis for C H N O : calculated C, 42.55%; H,
3
f
5
7
3
2
1
4
.96%; N, 29.79%; found: C, 42.70%; H, 5.00%; N, 29.71%. H NMR (400MHz, DMSO-d )
δ
(ppm):
6
tautomer T5; 12.16 (1H, s, N–H ), 5.68 (1H, s, C–H ), 5.19 (2H, s, NH ), 3.75 (3H, s, CH ), tautomer
Pz
Pz
2
3
13
T3; 12.60 (1H, s, N–H ), 5.92 (1H, s, C–H ), 4.81 (2H, s, NH ), 3.75 (3H, s, CH ) (Figure S15).
C
Pz
Pz
2
3
NMR (400 MHz, DMSO-d6)
δ (ppm): tautomer T5; 159.65 (C=O), 148.85 (C-NH ), 132.54 (C-C=O),
2
8
9.04 (C -H), tautomer T3; 162.87 (C=O), 156.20 (C-NH ), 142.35 (C-C=O), 94.27 (C -H).
4 2 4
Methyl 3-nitro-1H-pyrazole-5-carboxylate (3b). Commercial 3-nitro-1H-pyrazole-5-carboxylic acid (99.6%
purity, Aldrich) (1.54 g, 10 mM) was dissolved in methanol (15 mL), and 95% H SO (0.14 mL) was added.
2
4
The mixture was refluxed for 5 h. The solvent was evaporated under reduced pressure. A precipitate
was dissolved in ethyl acetate and washed with 5% NaHCO (2
×
10 mL) and water (1 × 10 mL).
3
The organic layer was dried with MgSO , and the ethyl acetate was evaporated. The residue was
4
dissolved in dichloromethane and purified on a silica-gel column (60H Merck 1.05553) eluted with
DCM:MeOH, from 2%–6% of MeOH; crystallization from a mixture of diethyl ether/hexane. Yield:
1
1
.28 g, 93%. H NMR (400MHz, DMSO-d )
δ
(ppm): 15.25 (1H, s, N–H ), 7.54 (1H, s, C–H ), 3.91 (3H,
6
Pz
Pz
◦
s, CH ) (Figure S19). Melting point by DSC: 148 C (Figure S24). TLC CHCl /MeOH/AcOH (90:8:2)
3
3
R = 0.74.
f
Methylammonium 3-nitro-1H-pyrazole-5-carboxylate (
4). Methyl 3-nitro-1H-pyrazole-5-carboxylate
(0.154 g, 1 mM) was dissolved in methanol (1 mL), and methylamine (0.08 mL, 1 mM) was added.
After 6 days, the white precipitate was filtered. During washing, the part of the precipitate with
◦
methanol dissolved. After several days, salt crystals appeared. Melting point: 195–210 C.
3
.2. X-Ray
The single-crystal X-ray diffraction experiments were performed at 100.0(1) K on the Xcalibur
diffractometer, equipped with a CCD area detector and a graphite monochromator for the MoK
radiation. The reciprocal space was explored by scans with detector positions at a 60-mm distance
from the crystal. The diffraction data processing of the studied compounds (Lorentz and polarization
corrections were applied) was performed using CrysAlis CCD [40 41]. All structures were solved in
the monoclinic crystal system, P2 /c, P2 /n, and P2 /m space groups, respectively (Table 1), by direct
α
ω
,
1
1
1
methods and refined by a full-matrix least squares method using the SHELXL14 program [42
,43]. The H
atoms were located by the difference Fourier synthesis. In both structures, H atoms were refined using

Molecules 2019, 24, 2632
13 of 17
a riding model. The structure drawings were prepared using the SHELXTL and Mercury programs [44].
The crystallographic data for the compounds were deposited at the Cambridge Crystallographic
Data Centre as Supplementary Publication Nos. CCDC 1,825,064 ( ), CCDC 1,825,062 ( ), CCDC
,825,063 ( ), CCDC 1,825,061 ( ), and CCDC 1,844,066 ( ). These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre,
2 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk.
1–5
1
2
1
3
4
5
1
3
.3. Computational Procedures
The Gaussian09 package was used to perform the calculations [45]. The M06-2X/6-311++G(d,p)
meta-hybrid level of theory [46] and the solvation model [47] were applied. The model compounds
1–3
(Figure 1) were analyzed. For each molecule, both tautomers were calculated, in which the carbonyl
linkage (ester or amide) was at position 3 or 5. Shortcuts, T3 and T5, were introduced. The flatness of
molecules, that is the co-planarity of the pyrazole ring with the ester or amide bond, was assumed.
◦ ◦
In this case, the torsion angle
ψ was close to a value of 0 or 180 . Thus, two possible conformations,
cisoidal (T3c, T5c) and transoidal (T3t, T5t), were considered for each tautomer. The ester and amide
bonds in the trans configuration were calculated.
The isolated molecules (in the gas phase) or in the environment of three solvents (chloroform,
acetonitrile, and water) were calculated. Thus, the influence of increased environment polarity was
considered. The energy minima were checked by full geometry optimization of the selected structures
at the M06-2X/6-311++G (d,p) level of theory in the gas phase, as well as in the solvent-mimicking
environment using the solvation model based on the density model. Frequency analyses were carried
out to calculate the zero-point vibrational energies and to verify the nature of the minimum state of all
the stationary points obtained.
NICS [48,49] was calculated using molecules optimized at the M06-2X/6-311++G (d,p) level of
theory. The NICS probes (ghost atoms that are called bq’s in the Gaussian program) were placed at
the center of the molecular plane for NICS(0) and 1 Å above the molecular plane for NICS(1) and its
z-component NICS(1)zz.
3
.4. NMR Spectroscopy
A Bruker NMR Spectrometer Ultrashield 400 MHz (2005) together with the Bruker TopSpin
1
13
Version 1.3 software were applied for data acquisition and processing. The H and C NMR spectra
were recorded at room temperature in DMSO-d with an internal TMS standard. The NOE difference
6
method (mixing time of 300 ms) within the standard programs was applied to determine the tautomer.
The spectra were recorded by using 5000 scans.
3
.5. FT-IR Spectroscopy
A Nicolet Nexus spectrometer with a deuterated triglycine sulfate detector, flushed with dry
nitrogen, was applied. Measurement at room temperature, KBr liquid cell (1.00 mm), concentrations
−3
−1
were obtained (3.9–10.9 10 mol/L), resolution (1 cm ) averaged by using 100 scans. The spectra
were obtained by subtraction of the solvent from the sample solutions. GRAMS/A1 Version 9.2
(Thermo Fisher Scientific) was applied to analyze the spectra. Fourier self-deconvolution techniques
and the second derivative as an “initial guess” were used to determine the number and position of
component bands. The quantum mechanical calculations were also taken into account to determine
the number of component bands. The curve-fitting procedure with a mixed (Gauss–Lorentz) profile
was applied to determine the accurate band position.
4
. Conclusions
The general concept, which arose from the presented studies, indicated that the tendency to adopt
a given tautomer is connected with the substituents at the pyrazole ring. The preferred tautomer
has nitrogen with a lone pair closer to a more electron-withdrawing substituent. When the methyl

Molecules 2019, 24, 2632
14 of 17
group was present, the lone pair at the pyrazole ring was closer to the ester/amide group. Thus,
the tautomer 3 was preferred. When the nitro group was present, the lone pair at the pyrazole ring
was further from the ester/amide group. Thus, the tautomer 5 was preferred. The same was the case
of 3-nitro-1H-pyrazole-5-carboxylate, which revealed tautomer 5 in the crystal state. The analysis of
the compounds in the Cambridge Crystallographic Data, which also have phenyl, nitrile, carboxy,
hydroxyl, and fluoroalkyl substituents, further confirmed this tendency. The theoretical methods
showed that at least three factors had an influence on the annular tautomerism of pyrazole substituted
by the ester/amide group: the pyrazole ring aromaticity determined by the second substituent,
internal hydrogen bonds, and intermolecular interactions, including the polarity of the environment.
The preferences towards the specific tautomer and conformation seem to depend on a balance between
these factors. The influence of these factors was depicted by the compound with the amino substituent.
Theoretical calculations on isolated molecules predicted the preference of tautomer 5. However,
the increase of the environment polarity diminished the gap in energy; thus, the NMR spectrum
in DMSO solution showed the equilibrium of tautomers. In the crystal state, the tautomer 3 was
present, as determined by the X-ray method. The FTI-IR analysis also showed equilibria, but they
were connected rather with the conformational arrangement of the ester/amide carbonyl group and
pyrazole ring.
Supplementary Materials: Supplementary Materials are available online. Tables S1–S7; Figures S1–S24.
Author Contributions: Conceptualization, A.K.-D. and D.S.; Formal Analysis, M.P. and B.D.; Investigation, M.P.,
A.K.-D., and D.S.; Writing-Original Draft Preparation, D.S.; Writing-Review & Editing, D.S.; Visualization, M.P.,
B.D., and D.S.
Funding: This research received no external funding.
Acknowledgments: This research was supported by PL-Grid Computational Infrastructure. The authors
gratefully acknowledge the Academic Computer Centre CYFRONET AGH in Krak
ów for the calculation facilities
and software.
Conflicts of Interest: The authors declare no conflict of interest.
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