Complete assignment of NMR data of 22 phenyl-1H-pyrazoles' derivatives

Article abstract of DOI:10.1002/mrc.2773

Complete assignment of ¹H and ¹³C NMR chemical shifts and J(¹H/¹H and ¹H/¹⁹F) coupling constants for 22 1-phenyl-1H-pyrazoles' derivates were performed using the concerted application of ¹H 1D and ¹H, ¹³C 2D gs-HSQC and gs-HMBC experiments. All 1-phenyl-1H-pyrazoles' derivatives were synthesized as described by Finar and co-workers. The formylated 1-phenyl-1H-pyrazoles' derivatives were performed under Duff's conditions. Copyright

Full text of DOI:10.1002/mrc.2773

MRC Letters
Received: 2 March 2011
Revised: 29 April 2011
Accepted: 10 May 2011
Published online in Wiley Online Library: 14 July 2011
(wileyonlinelibrary.com) DOI 10.1002/mrc.2773
Complete assignment of NMR data of 22
phenyl-1H-pyrazoles’ derivatives
Aline Lima de Oliveira,a∗ Carlos Henrique Alves de Oliveira,b
Laura Maia Mairink,b Francine Pazini,a,b Ricardo Menegattib
a
˜
and Luciano Morais Liao
Complete assignment of 1H and 13C NMR chemical shifts and J(1H/1H and 1H/19F) coupling constants for 22 1-phenyl-1H-
pyrazoles’ derivates were performed using the concerted application of 1H 1D and 1H, 13C 2D gs-HSQC and gs-HMBC
experiments. All 1-phenyl-1H-pyrazoles’ derivatives were synthesized as described by Finar and co-workers. The formylated
c
1-phenyl-1H-pyrazoles’ derivatives were performed under Duff’s conditions. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: NMR; 1H NMR; 13C NMR; 2D NMR; 1-phenyl-1H-pyrazoles
Introduction
measurements were done using a Bruker Avance III 500 instru-
ment (operating at 500.13 MHz for 1H) equipped with a 5-mm
tuneable multinuclear triple resonance probehead equipped with
z gradient. To acquire 1H and 13C experiments, samples containing
20 mg of substances (Fig. 1) typically in CDCl3 (or DMSO-d6) and
1% tetramethylsilane as internal standard were used. Following
1D and 2D pulse sequences from the Bruker User Library were
used for the NMR experiments:
1H 1D (500.13 MHz): π/2 pulse for 1H 9.9 µs, spectral width
7500 Hz, acquisition time 4.37 s, relaxation delay 1.0 s and the
16 transient free-induction decay were collected with 64K data
points.
HSQC (500.13/125.76MHz): 2D 1H/13C correlation via double
inept transfer, using the phase-sensitive Echo/Antiecho-TPPI
gradient selection, with decoupling during acquisition, using trim
pulses in inept transfer: π/2 pulse for 1H 9.9 µs, spectral width
in F2 7.5 kHz, acquisition time 0.27 s, relaxation delay 1.0 s, 16
transients per increment, 256 complex data points in F1, spectral
width in F1 21 kHz and linear prediction in F1 up to 1 K complex
data points.
HMBC (500.13/125.76MHz): 2D 1H/13C correlation via heteronu-
clear zero and double quantum coherence, optimized for long-
range couplings, no decoupling during acquisition, using gradient
pulses for selection: π/2 pulse for 1H 9.9 µs, spectral width in F2
7.5 kHz, acquisition time 0.27 s, relaxation delay 1.0 s, 32 transients
per increment, 256 complex data points in F1, spectral width in F1
28 kHz, linear prediction in F1 up to 1 K real data points.
Simple nitrogen-containing heterocycles are compounds which
receive a lot of attention as a consequence of their extensive
properties. This structural motif appears as a component in
a large number of products either as a bioactive agent in
the pharmaceutical and herbicidal area[1–4] or in the dyestuff
industry.[5] Among these heterocycles, pyrazoles’ derivates have
demonstrated promising properties for developing drugs for
the treatment of neurological disorders, diabetes, as an anti-
inflammatory, analgesic and antipyretic.[6–9]
Recently, the synthesis and pharmacological evaluation of
new derivates of N-phenylpiperazine were described as multi-
target compounds potentially useful for the treatment of
schizophrenia.[10] The synthetic route planned to achieve these
compounds explored 1-phenyl-1H-pyrazoles’ derivates as inter-
mediary. The 1-phenyl-1H-pyrazole derivates were synthesized
through the classical method described by Finar and Godfrey.[6]
On the other hand, chemoselective and regiospecific formylations
of1-phenyl-1H-pyrazoles’derivativeswereperformedunderDuff’s
conditions.[11–13]
In this paper, we present a detailed compilation of NMR
spectroscopic data for 22 phenyl-1H-pyrazoles’ derivatives. In
addition to chemical shift analyses, our data carefully highlight the
signal’s multiplicities by measuring as many coupling constant as
possible, providing clues for reference purposes for synthetic
researchers. Currently, data clarifying J-coupling are limited
and, in most cases, the information is simplistic, especially for
aromatic compounds with nucleus magnetically nonequivalent.
In fact, to eliminate doubts regarding multiplicities and constants
values and to confirm our data, computational simulator was
used.
∗
Correspondence to: Aline Lima de Oliveira, Laborato´rio de Ressonaˆncia
´
´
Magnetica Nuclear, Instituto de Química, Universidade Federal de Goias,
ˆ
CP 131, 74001-970 Goiania/GO, Brazil. E-mail: aline.alo@gmail.com
´ ˆ ´
Laboratorio de Ressonancia Magnetica Nuclear, Instituto de Química,
a
´
ˆ
Universidade Federal de Goias, CP 131, 74001-970 Goiania/GO, Brazil
Experimental
´ ˆ
Laboratorio de Química Farmaceutica Medicinal (LQFM), Faculdade de
b
All 1-phenyl-1H-pyrazoles’ derivates were synthesized as de-
scribed by Finar and Godfrey[6] (Scheme 1). The 1H, 13C NMR
´
´
ˆ
Farmacia, Universidade Federal de Goias, CP 131, 74001-970 Goiania/GO,
Brazil
c
Magn. Reson. Chem. 2011, 49, 537–542
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

A. L. de Oliveira et al.
Scheme 1. Synthetic route to the studied compounds.
Figure 1. Structures of the studied compounds.
Figure 2. HMBC cross-peaks of the compound 1-(3-chlorophenyl)-1H-pyrazole (6). 1J couplings was not assigned.
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wileyonlinelibrary.com/journal/mrc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2011, 49, 537–542

Complete assignment of NMR data of 22 phenyl-1H-pyrazoles’ derivatives
c
Magn. Reson. Chem. 2011, 49, 537–542
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

A. L. de Oliveira et al.
c
wileyonlinelibrary.com/journal/mrc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2011, 49, 537–542

Complete assignment of NMR data of 22 phenyl-1H-pyrazoles’ derivatives
Table 2. 13C NMR chemical shifts (ppm) for 1-phenyl-1H-pyrazoles derivates in CDCl3
Position (δ of 13C)
4ꢁ 5ꢁ
Compounds
3
4
5
1ꢁ
2ꢁ
3ꢁ
6ꢁ
CHO
CF3
Me (2ꢁ)
Me (4ꢁ)
Me (5ꢁ)
1
141.1
140.8
139.7
142.7
142.3
141.3
141.6
140.7
141.7
141.8
140.8
142.6
141.5
141.7
141.9
141.7
141.7
140.6
141.5
141.2
142.0
142.0
107.7
107.2
105.8
109.2
108.8
107.8
107.9
107.4
125.6
125.6
124.6
126.9
125.8
125.7
125.7
125.8
125.6
125.2
125.0
125.0
125.9
125.9
126.6
126.8
130.2
126.9
126.8
126.5
126.7
130.5
130.0
130.1
133.9
130.6
133.0
129.8
129.9
130.2
130.0
136.2
135.5
135.1
130.1
130.0
140.1
138.0
139.2
144.3
141.0
140.7
141.4
124.6
139.0
136.9
138.5
143.5
139.6
139.9
137.6
140.3
135.3
124.0
133.7
138.9
139.9
138.1
119.2
119.3
130.3
118.5
113.5
119.2
114.2
153.6
119.8
119.9
130.2
119.7
113.5
120.0
120.8
107.6
121.6
154.2
122.2
118.3
123.2
121.3
129.3
129.8
130.8
125.4
148.9
134.9
163.3
105.0
129.8
130.3
131.0
125.6
148.4
135.6
129.7
163.0
116.5
105.2
129.1
134.2
122.7
133.0
126.4
129.3
119.2
119.3
126.5
118.5
124.3
116.7
106.6
125.5
119.8
119.9
126.4
119.7
124.6
117.3
120.8
115.0
121.6
126.8
127.3
128.3
118.1
121.3
–
–
–
–
–
–
20.8
–
–
–
2
136.2
128.8
145.3
120.6
126.2
112.9
160.7
127.9
138.4
130.3
146.8
121.6
127.7
133.7
114.8
161.8
161.4
130.1
130.9
131.1
121.6
129.8
136.4
125.4
130.3
130.1
130.6
111.9
129.8
130.3
136.8
125.6
130.9
130.4
129.7
131.0
116.5
112.2
133.3
128.6
131.2
133.0
–
3
–
–
17.4
–
20.5
–
4
–
–
–
5
–
–
–
–
–
6
–
–
–
–
–
7
–
–
–
–
–
8
–
–
–
–
–
9
184.2
184.2
184.2
183.7
184.9
183.9
183.9
184.0
184.0
183.9
183.8
184.2
183.8
183.8
–
–
–
–
10
11
12
13a
14
15
16
17
18a
19
20
21
22
–
–
21.1
–
–
–
17.3
–
20.6
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
126.7
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
a Spectra in DMSO-d6.
chemical shift, but different couplings constants, showing an
AAꢁBBꢁ splinting system. As a result of this effect, the intensity
of the signal did not fit the rules of the intensity for first-order
systems.
As expected, noticeable differences in 1H and 13C chemical
shift values were observed in the pyrazole ring of carbaldehyde
compounds because of CHO anisotropic effects. Once this group
deshields the nucleus of 1H in positions 3 and 5, the chemical shift
values change from an average of 7.7 to 8.2 ppm. A similar effect
is also observed with carbon in position 4 which is deshielded by
approximately 20 ppm.
Results and Discussion
The 1-phenyl-1H-pyrazoles’ derivates were synthesized with
fluorine, bromide, chlorine, nitro or methyl groups, mono- or
di-substituted in the ortho-, meta- and para-positions (Fig. 1). The
structures of the molecules were investigated and confirmed by
NMRspectroscopy,combiningthe1H,HSQCandHMBCcorrelation
spectra, as shown in an example of Fig. 2. H and 13C chemical
1
shifts, together with J-coupling constants (1H/1H and 1H/19F),
for all 1-phenyl-1H-pyrazoles’ derivates were assigned and are
summarized in Tables 1 and 2.
In the phenyl ring, the chemical shift values were mainly
dependent on the substituent pattern. In the 13C NMR data,
differences were more pronounced in the atoms directly attached
to the substituent group. The most pronounced effect is
observed in aromatic carbons directly attached to the fluorine
deshieldedbyapproximately33 ppm,followedbycarbonsdirectly
attached to the NO2 group deshielded approximately by 19 ppm,
carbons attached to the CH3 group deshielded by 7–10 ppm,
and those attached to chlorine that were deshield by 5 ppm.
Finally, the carbons attached to bromide were shielded by
7 ppm.
A careful analysis was undertaken of the expansions of multiple
signals from the 1H NMR spectra, measuring as many coupling
constants as possible and clarifying the multiplicities. Doubts
concerning multiplicities and J-coupling constants values were
eliminated using spectral simulations with the software first-
order multiplet simulator/checker (FOMSC3)[14] which calculates
and plots NMR first-order multiplets starting from information
about coupling constants values. The similarity observed from the
comparison between the experimental and simulated spectra,
as shown in Fig. 3, served as the basis for confirmation of
1H/1H and 1H/19F J-coupling constants and strongly suggests
that the coupling constant values and the multiplicities shown
in Table 1 are correct. The displaying of coupling patterns was
valuable for the assignment of proton signals since the coupling
patterns of aromatic protons differ greatly depending on the
number of protons involved in the spin system. In particular, the
para-substituted aromatic systems presented a typical pattern
splitting. As known, these protons are chemically equivalent,
but magnetically nonequivalent; therefore, they have the same
1
In the H spectra, no significant differences were detected in
halides, and the greatest effect is observed in the NO2 group which
increases the chemical shift values in the range of 0.9 ppm in ortho
position, 0.3 ppm in meta position and 0.6 ppm in para position.
All chemical shifts were compared with the parent compound.
Acknowledgements
TheauthorsaregratefultoCAPES, CNPqandFINEP forthefinancial
support.
c
Magn. Reson. Chem. 2011, 49, 537–542
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

A. L. de Oliveira et al.
H6’
H3’
J = 7.7 Hz
J = 7.7 Hz
J = 1.5 Hz
J = 0.5 Hz
J = 1.5 Hz
J = 0.5 Hz
J = 0.5 Hz
J = 0.5 Hz
J = 0.5 Hz
J = 0.6 Hz
J = 0.6 Hz
J = 0.6 Hz
7.870
7.865
7.860
7.855
7.850
7.845
ppm
7.585
7.580
7.575
7.570
7.565
7.560
7.555 ppm
Figure 3. Comparison between the experimental (lower panel) and simulated spectra by FOMSC3 (upper panel) of 6ꢁ (left) and 3ꢁ (right) 1H from
1-(2-trifluoromethyl)-1H-pyrazole-4-carbaldehyde (19).
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Magn. Reson. Chem. 2011, 49, 537–542