Structural Studies on N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1Hpyrazole-1- carboxamide with antibacterial activity

Article abstract of DOI:10.2174/157017861101140113161101

The structure and tautomerism of N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H- pyrazole-1-carboxamide with antibacterial activity have been investigated with experimental approaches (X-ray studies, IR, 1H and 13C NMR spectra, including NOESY and N-HSQC spectr

Full text of DOI:10.2174/157017861101140113161101

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40
Letters in Organic Chemistry, 2014, 11, 40-48
Structural
Studies
on
N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-
pyrazole-1-carboxamide with Antibacterial Activity
Agnieszka A. Kaczor1, Tomasz Wróbel1, Zbigniew Karczmarzyk2, Waldemar Wysocki2,
Andrzej Fruzinski3, Malgorzata Brodacka2, Dariusz Matosiuk1 and Monika Pitucha4*
1Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab,
Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodꢀki St., PL-20093
Lublin, Poland and University of Eastern Finland, School of Pharmacy, Department of Pharmaceutical Chemistry,
Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland; 2Department of Chemistry, Siedlce University, 3 Maja 54
3
St., PL-08110 Siedlce, Poland; Institute of General and Ecological Chemistry, Technical University, ꢁeromskiego115
St., PL- 90924 ꢂódꢀ, Poland; 4Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical Analyt-
ics, 4A Chodꢀki St., PL-20093 Lublin, Poland
Received March 24, 2013: Revised August 16, 2013: Accepted September 04, 2013
Abstract: The structure and tautomerism of N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-pyrazole-1-carboxamide with
1
antibacterial activity have been investigated with experimental approaches (X-ray studies, IR, H and 13C NMR spectra,
including NOESY and N-HSQC spectra) and quantum chemical calculations. It is found that the tautomer with the keto
group in position 5 is energetically privileged in the crystalline state while in DMSO and water solution the equilibrium is
shifted towards the form with the hydroxyl group at this position. These findings are related to antibacterial activity of the
studied compound and are crucial for future molecular docking and structure-activity relationship studies.
Keywords: Antibacterial compounds, pyrazolones, quantum chemical calculations, tautomerism, X-ray structure
determination.
INTRODUCTION
Recently, we have focused on compounds with pyrazole
moiety. Pyrazole derivatives are known as herbicides, fungi-
cides, insecticides, MDR modulators and also antibacterial,
anti-inflammatory, anti-tumor, antihyperglycemic, antipy-
retic and analgesic agents [6-15]. Some compounds with the
pyrazole moiety exhibit HIV-1 reverse transcriptase and IL-1
synthesis inhibitory activity [15]. Here we present the
Elucidation of structure of organic compounds with bio-
logical activity is crucial in order to rationalize their activity,
to enable molecular docking studies, and for structure-
activity relationship analysis. In particular, structural studies
are important for compounds which can occur in different
tautomeric forms. The tautomerism and energetic prevalence
of a particular tautomer may determine biological activity of
a compound by promoting or preventing the formation of
hydrogen bonds with its molecular target. The best known
example of the significance of tautomerism for biological
activity includes nitrogen bases present in DNA in which the
stabilization of one tautomer ensures the possibility of for-
mation of hydrogen bonds which stabilize the double helix
structure.
1
experimental (X-ray studies, IR, H and 13C NMR spectra,
including NOESY and N-HSQC spectra) and computational
studies on the structure and tautomerism of N-(1-naphthyl)-
3-amino-5-oxo-4-phenyl-1H-pyrazole-1-carboxamide. We
find that although the keto tautomer is the one present in the
crystalline state, in DMSO and water solutions the
tautomeric equilibrium is shifted towards the tautomer with
the hydroxyl group.
The tautomeric equilibrium between the keto and hy-
droxyl form occurs in many organic compounds, including
heterocyclic compounds. Previously, we found that stabiliza-
tion of one tautomer is important for the activity of 1-aryl-
4,5-dihydro-1H-imidazol-2-amine derivatives towards opioid
receptors [1-4], and for the anticancer activity of 4-benzyl-3-
[(1-methylpyrrol-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-
5-one, probably acting through EGRF tyrosine kinase [5].
MATERIALS AND METHODS
Chemistry
N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-pyrazole-1-
carboxamide was obtained as reported earlier: a mixture of
1.75g (0.0l moles) of 1-cyanophenylacetic acid hydrazide
and 0.01 moles of 1-naphthyl isocyanate in 10 ml of acetoni-
trile was kept for 24 hours at room temperature [16]. After-
wards the compound formed was filtered off, washed with
acetonitrile and crystallized from a methanol-acetonitrile
(1:1) mixture (Scheme 1) [16].
*Address correspondence to this author at the Department of Organic
Chemistry, Faculty of Pharmacy with Division of Medical Analytics, 4A
Chodꢀki St., PL-20093 Lublin, Poland; Tel: 48-81-535-73-74;
E-mail: monikapit@wp.pl
1875-6255/14 $58.00+.00
© 2014 Bentham Science Publishers

Tautomerism of N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-pyrazole-1-carboxamide
Letters in Organic Chemistry, 2014, Vol. 11, No. 1 41
Scheme 1.
X-ray Structure Determination
technique with the spectrometer equipped with a diamond
Orbit stage. All solution measurements employed the
transmittance technique using rigorously dried DMSO. The
drying procedure was performed according to the standard
method, i.e. standing over freshly activated alumina, filtering
and distilling over CaH2 under reduced pressure [20]. All
manipulation with DMSO was conducted in Atmosbag filled
with nitrogen to exclude any moisture coming from the air.
The spectrum was run in a demountable cell (Pike
Technologies) with KBr windows adjusted to 0.015 mm
optical length. It consisted of 16 scans and spectral
resolution of 4 cm -1. First, the spectrum of the dried DMSO
was recorded. Next, the spectrum of 1 in dried DMSO was
taken and both spectra were overlapped for the correct
assignments of the signals of 1 and subtraction of the DMSO
signals.
X-ray data of 1 was collected on the Bruker SMART
APEX II CCD diffractometer; crystal sizes 0.42x0.05x0.04
mm, CuKꢃ (ꢄ = 1.54178 Å) radiation, ꢀ scans, T = 100 K,
absorption correction: multi-scan SADABS [17], Tmin/Tmax
=
0.9281/1.0000. The structure was solved by direct methods
using SHELXS97 [18] and refined by full-matrix
least-squares with SHELXL97 [18]. The N-bound H atoms
were located by difference Fourier synthesis and refined
freely. The remaining H atoms were positioned geometri-
cally and treated as riding on their parent C atoms with C-H
distances of 0.93 Å (aromatic). All H atoms were refined
with isotropic displacement parameters taken as 1.5 times
those of the respective parent atoms. All calculations were
performed using WINGX version 1.64.05 package [19].
CCDC 929744 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre (CCDC), 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336 033;
email: deposit@ccdc.cam.ac.uk].
Computational Details
The molecular structure of 1 in the ground state (in
vacuo) was optimized with the B3LYP DFT (the variant of
the DFT method using Becke’s three parameter hybrid func-
tional (B3) [21] with correlation functional such as the one
proposed by Lee, Yang, and Parr (LYP) [22]) using
6-31G(d,p) as included in Gaussian09 [23]. Furthermore,
Frontier Molecular Orbital (FMO) analysis was performed
with Gaussian09 on the 6-31G(d,p)/B3LYP level of theory.
The energy for both tautomers of 1 was calculated for iso-
lated molecules (gas phase) and molecules in DMSO and
water solutions. The population of both tautomeric forms
was estimated using non-degenerate Boltzman distribution.
6-31G(d,p)/B3LYP calculations with Gaussian09 were also
used to calculate the Continuous Set of Gauge Transforma-
Crystal data of 1: C20H16N4O2, M = 344.373, trigonal,
space group R3, a = 35.3607(4), c = 6.66720(10) Å, V =
7219.64(16) Å3, Z = 18, dcalc = 1.426 Mg m-3, F(000) = 3240,
ꢅ(Cu Kꢃ) = 0.775 mm-1, T = 100K, 3012 measured reflec-
tions (ꢆ range 2.50–69.80°), 3012 unique reflections, final R
= 0.032, wR = 0.084, S = 0.907 for 2928 reflections with
I>2ꢇ(I).
NMR Spectra
All NMR spectra were obtained on Bruker AVANCE III
600 MHz spectrometer with a BBO probe equipped with Z-
gradient. Solvents were used as received from a commercial
supplier. Tetramethylsilane was used as an internal standard
for proton and carbon NMR spectra.
1
tions (CSGT) [24-26] H and 13C NMR chemical shifts as
well as vibrational frequencies and infrared intensities. Cal-
culations were performed using the Polarizable Continuum
Model (PCM) [27]. This method creates a solute cavity via a
set of overlapping spheres.
IR Spectra
In the case of NMR chemical shifts DMSO was used as a
1
solvent. The H and 13C NMR chemical shifts were con-
IR spectra were recorded on a Thermo Nicolet 6700
FTIR spectrometer. Solids were measured utilizing the ATR
verted to the TMS scale by subtracting the calculated abso-

42 Letters in Organic Chemistry, 2014, Vol. 11, No. 1
Kaczor et al.
Fig. (1). A view of the X-ray molecular structure of 1 with the atomic labeling scheme (probability 50%).
Table 1. Hydrogen Bond Geometry of 1 (Å, °)
D-H...A
D-H
H...A
D...A
D-H...A
N22-H22...O3
C32-H32...O21
C38-H38...N22
C42-H42...O3
N1-H1...O21i
0.914(19)
0.93
1.87(2)
2.30
2.6804(16)
2.9213(17)
2.8509(17)
3.082(2)
146.2(15)
123
0.93
2.54
100
0.93
2.56
116
0.862(19)
0.890(16)
1.950(18)
2.030(18)
2.7956(15)
2.9050(13)
167(2)
167.6(6)
N5-H51...O3Aii
(i) = 2/3-x, 1/3-y, 4/3-z; (ii) = x, y, 1+z
lute chemical shielding of TMS. These are 31.74 ppm and
190.92 ppm for 6-31G(d,p)/B3LYP for hydrogen and carbon
atoms, respectively. The vibrational band assignments were
made using ChemCraft [28]. Pymol v. 0.99 [29], Discovery
Studio v. 3.1 [30], Yasara Structure [31], Mercury [32] and
ArgusLab [33] were also used for visualization of results.
as in the above-mentioned structures, the carbonyl group of
the carboxamide moiety adopts a cis conformation in respect
to N-N bond in pyrazole ring with the torsion angle N1-N2-
C2 -O21 of 13.86(15)°. This conformation is stabilized by
the intramolecular hydrogen bond N22-H22…O3 (Table 1).
The torsion angles C3-C4-C4 -C42 = -32.92(15)° and C21-
N22-C31-C32 = 5.60(17)° show that the phenyl and naphth-
yl substituents have the cis conformation in respect to the
pyrazole-carboxamide system forcing by the intramolecular
C-H... X (X = O, N) interactions (Table 1).
RESULTS AND DISCUSSION
X-ray and Computed Structure of 1
In the crystal structure of 1 the intermolecular N1-
H1...O21 hydrogen bond connects pairs of molecules into
molecular dimers being in equi-positions (x, y, z) and (2/3-x,
1/3-y, 4/3-z) of the unit cell. These dimers form molecular
chains parallel to c crystallographic axis via intermolecular
N5-H51...O3 hydrogen bond (Table 1). Moreover, the ꢁ-
electron systems of the pairs of pyrazole and benzene
(C31…C40) rings belonging to the molecules at equi-
positions (x, y, z) and (2/3-x, 1/3-y, 1/3-z) overlap each
other, with centroid-to-centroid separation of 3.5674(9) Å
and the angle between overlapping planes of 14.11(7)°.
X-ray analysis of compound 1 was performed in order to
confirm the synthesis pathway and identification of its
tautomeric form in the solid state. The structure and confor-
mation of the molecule 1 in the crystal are shown in (Fig. 1).
In the crystalline state, the molecule exists in N22-
amino/O21-keto tautomeric form, as evidenced by the C21-
O21 bond length of 1.2195(13) typical for the carbonyl
group and the positions of the H atom in the vicinity of N22
in the difference electron-density map. The geometry (bond
lengths, angles and planarity) of the pyrazole-carboxamide
system is very similar in 1 and the closely related structure
of N-ethoxycarbonylmethyl-3-amino-5-hydroxy-4-phenyl-
1H-pyrazole-1-carboxamide and N-butyl-3-amino-5-hydroxy
-4-phenyl-1H-pyrazole-1-carboxamide [16]. In 1, similarly
The structure of 1 computed with the B3LYP DFT ap-
proach and 6-31G(d,p) basis set of Gaussian 09 was aligned

Tautomerism of N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-pyrazole-1-carboxamide
Letters in Organic Chemistry, 2014, Vol. 11, No. 1 43
to the molecule of 1 from crystallographic studies. The
alignment on the pyrazolone system of both structures of 1 is
presented in (Fig. 2). It can be seen that the position of the
naphthyl group is different in the X-ray and computed struc-
ture, while the position of phenyl group is similar. Further
conformational analysis studies may help to obtain a more
accurate structure. HOMO and LUMO orbitals for 1 are
shown in (Fig. 3), whereas the distribution of electron den-
sity for 1 is depicted in (Fig. 4). Naturally, the highest elec-
tron density occurs on both oxygen atoms, and on the amino
nitrogen atom.
Boltzman Distribution Studies in Relation to Anti-
bacterial Activity
The energy for both the keto and hydroxyl tautomers of 1
was calculated for isolated molecules (gas phase) and mole-
cules in DMSO and water solutions. It was determined that
in the gas phase the keto form is more stable with the stabili-
zation energy of 15 kcal/mol whereas in DMSO solution the
hydroxyl tautomer is favored with the stabilization energy of
5.58 kcal/mol. The population of the hydroxy form estimated
using non-degenerate Boltzman distribution is less than
0.01% the crystalline form and about 99.99% in DMSO and
water at 25 °C. The results of the calculations are in good
agreement with the experimental data obtained from X-ray
analysis and NMR and IR spectra. It can be hypothesized
that antibacterial activity of 1 may be related to the greatest
stability of its hydroxy form as it would ensure the formation
of proper hydrogen bonds with bacterial enzymes.
Fig. (2). Overlap of crystal and computed structures of 1 on the
pyrazolone system. Hydrogen atoms not shown for clarity.
IR Spectra
IR spectra were recorded without a solvent and in DMSO
and also computed with the B3LYP DFT method. The ATR
IR spectrum indicates an absence of a hydroxyl group thus
suggesting that the molecule exists as a keto form in solid
state which is supported by a strong band at 1712 cm-1. Also,
a single spike at 3449 cm-1 can contribute to a secondary
amine (Fig. 5A).
In order to obtain a reliable spectrum of 1 in DMSO, the
solvent was dried as described in the Materials and Methods.
Next, the spectrum of dried DMSO was overlapped with the
spectrum of 1 in dried DMSO (Fig. 5B). The DMSO
spectrum (blue) exhibits no signals in the range of 3000 ꢀ
3600 cm-1, which would indicate the presence of OH groups.
Furthermore, this spectrum contains only signals which are
characteristic for the dried DMSO. The spectrum of 1
recorded after deduction of DMSO (measured in the
background) is the spectrum of 1 excluding those regions in
which the solvent absorbs strongly.
Fig. (3). HOMO (A) and LUMO (B) orbitals for the keto form of 1.
A widened band of 3428 cm-1 in the spectrum of 1 in the
dried DMSO represents a hydroxyl group. It is generally
known that the hydroxyl group exhibits a characteristic
absorption in the range 3000-3600 cm-1 [34, 35]. This
corresponds to the stretching vibration band of the hydroxyl
group. Furthermore, hydroxyl groups which do not undergo
this association, exhibit a relatively narrow band of 3580-
3670 cm-1. This band is observed in the spectra of the diluted
solutions of alcohols and phenols. The process of association
may lead to the formation of a network of hydrogen bonds in
Fig. (4). Electron density distribution in the keto form of 1.

44 Letters in Organic Chemistry, 2014, Vol. 11, No. 1
Kaczor et al.
Fig. (5). A - ATR IR spectrum of 1; B - IR spectrum of 1 in dried DMSO (red) overlapped with spectrum of dried DMSO (blue).
more concentrated solutions of compounds possessing
hydroxyl groups. This phenomenon affects the shape and
position of the absorption bands of the hydroxyl group
stretching vibration through the formation of dimers and
polymers resulting in the broad band in the range of 3200-
3400 cm-1. The observed value of hydroxyl group band for 1
indicates that the investigated compound may at least
partially undergo association in the DMSO solution. It
should also be pointed out that DMSO will bond extensively
with molecule NH or OH groups, having impact upon the
observed OH stretch. It can be thus seen from (Fig. 5B) that
in DMSO solution the tautomeric equilibrium is shifted to-
wards the form with the hydroxy group at position 5 which is
confirmed by the computational data discussed above.
The IR data for the frequencies connected with the
tautomerism of the investigated compounds are presented in
(Table 2). It can be concluded that IR spectroscopy is a reli-
able method to investigate tautomerism in organic com-
pounds. This confirms our earlier results [5, 36], and results
by other authors obtained with IR [37] and Raman spectros-
copy [38] approaches.

Tautomerism of N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-pyrazole-1-carboxamide
Letters in Organic Chemistry, 2014, Vol. 11, No. 1 45
Table 2. Experimental and Computed IR Frequencies Involved in the Tautomerism of Compound 1
NꢀH (cm-1)
C=O (cm-1)
OH (cm-1)
IR
Exp.
Calc.
Exp.
Calc.
Exp.
Calc.
ATR
3449
3486
1711
1741
ꢀ
ꢀ
DMSO
ꢀ
ꢀ
ꢀ
ꢀ
3428
3340
Table 3. Experimental and Computed Chemical Shifts of 1 in DMSO
H
C
Atom
Comp.
Comp.
Exp.
Exp.
Keto
Hydroxy
Keto
Hydroxy
3
4
-
-
-
-
-
156.19
86.70
163.93
148.16
-
150.57
90.46
158.25
141.42
-
148.09
92.37
148.57
145.71
-
-
5
-
-
-
6
-
-
-
8
6.86
-
4.52
-
3.69
-
9
132.08
127.21
128.73
125.39
-
127.41
120.66
122.94
120.09
-
126.97
120.38
122.90
119.68
-
10, 14
11, 13
12
15
16
17
18
19
20
21
22
23
24
25
26
7.66
7.40
7.20
10.94
12.00
-
7.85
7.61
7.41
-
7.77
7.59
7.39
11.17
8.99
-
7.80
-
-
-
-
133.44
116.78
126.46
124.09
134.17
129.17
126.73
127.07
120.78
125.38
129.12
111.74
120.69
118.98
128.21
123.89
120.44
120.54
114.71
119.81
127.34
112.52
120.46
120.53
128.36
123.99
120.77
121.00
115.02
120.16
8.24
7.55
7.72
-
8.77
7.71
7.75
-
8.44
7.74
7.84
-
7.99
7.60
7.67
8.11
-
8.00
7.77
7.81
8.10
-
8.05
7.79
7.86
8.19
-

46 Letters in Organic Chemistry, 2014, Vol. 11, No. 1
Kaczor et al.
NMR Spectra
unambiguously related to experimental NMR spectrum.
However, some values of calculated chemical shifts for the
hydroxyl tautomer are close to the experimental values.
The experimental and computed NMR data of 1 is pre-
sented in (Table 3). All proton and carbon resonances were
assigned by the combined application of standard 1D and 2D
NMR techniques (1H-decoupled 13C NMR, COSY with gra-
With resonances of exchangeable protons being not com-
pletely reliable we decided to investigate N-HSQC informa-
tion which would reveal how many nitrogen atoms are pro-
tonated. Using short pulse sequence hsqcetgp, it was re-
vealed that only two nitrogen atoms are connected directly to
protons (Fig. 6) hence suggesting that only enol form might
be present in solution. However taking into consideration the
13
1
dient pulses, H- C multiplicity edited HSQC with gradient
selection [39-44], H-13C HMBC with gradient selection us-
1
ing low pass J-filter, Phase sensitive NOESY [45-46] and
Phase sensitive 1H-15N HSQC). Computed 1H and 13C chemi-
cal shifts for the keto and the hydroxyl tautomer cannot be
Fig. (6). N-H HSQC spectrum showing only two nitrogens with protons.
Fig. (7). NOESY spectrum indicating clossenes of protons 25 and 16.

Tautomerism of N-(1-naphthyl)-3-amino-5-oxo-4-phenyl-1H-pyrazole-1-carboxamide
Letters in Organic Chemistry, 2014, Vol. 11, No. 1 47
broadness of 10.94 ppm signal it is also possible that the keto
form is also present but does not show the expected correla-
tion despite using short pulse sequence. On the other hand
this chemical shift is more likely to be that of enol rather
than imine. Moreover, it can be inferred from the NOESY
spectrum that naphthalene ring assumes position that places
its 25 hydrogen close to hydrogen 16 (Fig. 7).
FMO
=
Frontier Molecular Orbitals
HOMO = Highest Occupied Molecular Orbital
LUMO = Lowest Unoccupied Molecular Orbital
PCM
= Polarizable Continuum Model
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CONCLUSION
In this study we find that the tautomer with the keto
group in position 5 of N-(1-naphthyl)-3-amino-5-oxo-4-
phenyl-1H-pyrazole-1-carboxamide with antibacterial is en-
ergetically priviliged in the crystalline state, while in DMSO
and water solution, the equilibrium is shifted towards the
form with the hydroxyl group at this position. This finding is
hypothesized to be related to antibacterial activity of the
studied compound and is crucial for future molecular dock-
ing and structure-activity relationship studies.
[6]
[7]
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
[8]
[9]
ACKNOWLEDGEMENTS
[10]
[11]
The presented research was partially performed during
the postdoctoral stay of Agnieszka A. Kaczor at the Univer-
sity of Eastern Finland, Kuopio, Finland, under a Marie Cu-
rie fellowship. Calculations were performed under a compu-
tational grant from the Interdisciplinary Center of Mathe-
matical and Computational Modeling (ICM) in Warsaw,
Poland, grant number G30-18 and under resources of CSC
Finland. The paper was developed using equipment pur-
chased under the project “The equipment of innovative labo-
ratories doing research on new medicines used in the therapy
of civilization and neoplastic diseases” within the Opera-
tional Programme Development of Eastern Poland 2007-
2013, Priority Axis I Modern Economy, operations I.3 Inno-
vation promotion
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ABBREVIATIONS
[15]
CSGT
DFT
=
=
Continuous Set of Gauge Transformations
Density Functional Theory

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