Characterization of 2-aryl-1,3,4-oxadiazoles by 15N and 13C NMR spectroscopy

Article abstract of DOI:10.1002/mrc.1231

¹⁵N NMR chemical shifts of 2-aryl-1,3,4-oxadiazoles were assigned on the basis of the ¹H-¹⁵N HMBC experiment. Chemical shifts of the nitrogen and carbon atoms in the oxadiazole ring correlate with the Hammett σ-constants of substituents in the aryl ring (r² ≥ 0.966 for N atoms). ¹⁵N NMR data are a suitable and sensitive means for characterizing long-range electronic substituent effects. Additionally, ¹³C NMR data for these compounds are presented. Copyright

Full text of DOI:10.1002/mrc.1231

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2003; 41: 689–692
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1231
1
5
Characterization of 2-aryl-1,3,4-oxadiazoles by N and
1
3
C NMR spectroscopy
∗
Barbara Nowak-Wydra, Bła z˙ ej Gierczyk and Grzegorz Schroeder
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, PL-60 780 Pozna n´ , Poland
Received 8 March 2003; Revised 29 April 2003; Accepted 20 May 2003
1
5
1
15
N NMR chemical shifts of 2-aryl-1,3,4-oxadiazoles were assigned on the basis of the H– N HMBC
experiment. Chemical shifts of the nitrogen and carbon atoms in the oxadiazole ring correlate with the
2
15
Hammett s-constants of substituents in the aryl ring (r ꢀ 0.966 for N atoms). N NMR data are a suitable
and sensitive means for characterizing long-range electronic substituent effects. Additionally, C NMR
1
3
data for these compounds are presented. Copyright  2003 John Wiley & Sons, Ltd.
KEYWORDS: NMR; 15N NMR; 13C NMR; chemical shifts; Hammett correlations; 1,3,4-oxadiazole
INTRODUCTION
EXPERIMENTAL
Correlations between NMR chemical shifts and structure
are an important aspect of modern spectroscopy. As a
Synthesis
The compounds were prepared according to a modified
procedure described in the literature.
To a solution of the corresponding benzoic acid (0.01 mol)
in anhydrous methanol (25 cm ), freshly distilled thionyl
chloride (0.015 mol) was added dropwise over 1 h with
stirring. The solvent was evaporated and the ester formed
was used in the next step without purification. In the case of
cyanobenzoic acid, sulfuric acid was used (0.25 cm ꢁ instead
of SOCl and the solution was heated for 10 h.
2
1
–3
13
continuation of our investigations in this area,
we now
1
5
present an N NMR study of a series of para-substituted 2-
phenyl-1,3,4-oxadiazoles and a correlation of the nitrogen
and carbon chemical shifts with Hammett ꢀ-values of
substituents in the aryl ring.
3
The 1,3,4-isomers are the most extensively studied
oxadiazoles, because of their interesting electro-optical,
3
4
,5
4–8
electronic and biological activities.
The wide use of
these compounds in medicine, agriculture and industry has
stimulated investigations of their chemical properties.
To the crude ester, hydrazine hydrate (0.025 mol) was
added and this mixture was kept at room temperature until
a precipitate of acyl hydrazide was formed. The crystals were
filtered off and dried in vacuum.
The hydrazide was heated in trimethyl orthoformate for
10 h under reflux, then the solvent was evaporated and
the oily residue was distilled in vacuum. The product that
crystallized in the condenser was recrystallized from acetone
and hexane.
1
13
Although the H and C NMR spectra of some disub-
9
–11
stituted 1,3,4-oxadiazoles have already been published,
1
5
there has been no systematic study of their N NMR chemi-
cal shifts, which may be useful in predicting the mechanism
of their activity. To the best of our knowledge, only one paper
1
5
has reported the N NMR chemical shifts for unsubstituted
1
2
1
,3,4-oxadiazole.
Figure 1 shows the structure of the oxadiazoles studied
and the numbering of atoms.
NMR spectra
The NMR spectra were recorded at 298 K on a Bruker
Avance DRX 600 spectrometer operating at frequencies
4
N
3
N
1
13
of 600.055 MHz ( H), 150.899 MHz ( C) and 60.821 MHz
2'
3'
2
15
5
1'
6
( N) and equipped with a 5 mm triple-resonance inverse
4'
1
31
O
probehead f H/ P/BBg with a self-shielded z-gradient coil
1
R
'
1
13
15
°
H pulse width 9.0 µs, C pulse width 13.3 µs and
N
5'
(90
pulse width 19 µs).
Spectra were measured in CDCl
3
and the sample
1
a
1b
1c
1d
1e
1f
Ph
1g
1h
1i
1j
concentrations ranged from 10 to 60 mg per 600 µl of solvent.
Chemical shifts υ (ppm) were referenced to internal Me Si for
H and C. The N NMR chemical shifts were referenced to
the signal of external CH NO in a 1 mm diameter capillary
inserted coaxially in the 5 mm NMR tube.
R
NMe2 NH2 OMe Me
H
F
Br
CN NO2
4
1
13
15
Figure 1. The 2-aryl-1,3,4-oxadiazoles studied.
3
2
Ł
Correspondence to: Grzegorz Schroeder, Faculty of Chemistry,
Adam Mickiewicz University, Grunwaldzka 6, PL-60 780 Pozna n´ ,
Poland. E-mail: schroede@amu.edu.pl
1
13
Two-dimensional H, C gradient selected HSQC (het-
1
13
1
eronuclear single quantum coherence) and H, C and H,
Copyright  2003 John Wiley & Sons, Ltd.

690
B. Nowak-Wydra, B. Gierczyk and G. Schroeder
15N gradient selected HMBC (heteronuclear multiple bond
coherence) experiments were performed using standard
pulse sequences from the Bruker pulse-sequence library.
substituents in the aryl ring are larger than those
for N-4.
The protonated carbons could be assigned using correla-
1
15
1
13
In H, N HMBC measurements the delays for evolution of
multiple-bond couplings were set to 55–280 ms, which cor-
tion via one-bond coupling observed in the H, C HMQC
spectra. The quaternary carbons were distinguished on the
1
1
13
respond to 2–9 Hz coupling constant values. The H spectral
basis of H, C HMBC measurements. The C-2 atom shows
0
0
windows were used depending on the case and 1024 data
a strong coupling via three bonds with H-2 ,6 protons of
the aryl substituent and correlation via four bonds with H-5
points along the t
to 2048 points prior to Fourier transformation (FT); 32–128
scans for 512 t time increments were collected and zero-
2
-axis were collected and then zero-filled
0
0
(strong) and H-3 ,5 (weak, not for all compounds observed).
The C-2 chemical shift is very characteristic (ca 165 ppm),
1
2
filled to 1024 prior to FT. The chemical shift measurement
accuracy was better than 0.05 ppm.
typical for quaternary sp carbon, bonded to one oxygen
and one nitrogen atom. The non-protonated carbons of aryl
substituents could be distinguished on the basis of couplings
0
0
0
0
0
with H-2 ,6 and H-3 ,5 protons. C-1 shows coupling to H-
0
0
3
,5 only (via three bonds) and the correlation via two bonds,
to H-2 ,6 protons, is not observed in all cases. In contrast, C-4
correlates with H-2 ,6 only. In the case of proton-containing
substituents in the aryl ring, C-4 also shows a coupling to
RESULTS AND DISCUSSION
0
0
0
0
0
For the synthesized series of 2-aryl-1,3,4-oxadiazoles (1a–j),
1
5
0
the N chemical shift data are summarized in Table 1. The
assignments of N-3 and N-4 chemical shifts were made on
the substituent protons.
1
15
Table 2 shows the 13C NMR chemical shifts for 1a–j.
The chemical shift ranges for the carbon atoms of the
oxadiazole ring, C-2 and C-5, are very small, 2.38 and
3.55 ppm, respectively.
the basis of the two-dimensional H, N correlation HMBC
spectra.
In the 1H, 15N HMBC spectra both nitrogen atoms,
N-3 and N-4, correlate with H-5 (via three and two
bonds, respectively) and can be distinguished by correlation
Chemical shifts were correlated with single Hammett ꢀ-
constants (ꢀ ꢁ or inductive (ꢀ ꢁ and resonance (ꢀ ꢁ Hammett
p I R
0
0
of N-3 with H-2 ,6 (via four bonds), whereas that of
0
0
N-4 with H-2 ,6 is not observed (separation by five
values determined for the substituents in the aryl ring.
Correlation equations for regression coefficients using single
Hammett ꢀ-constants and both inductive and resonance
parameters, respectively, are the following: chemical shift D
2
15
1
bonds). For the N-4 atom J( N, H) was observed, and
its values, ca 10.5–11.0 Hz, do not depend on substituent
electronegativity.
An examination of the data in Table 1 shows that
the chemical shifts of both nitrogen atoms depend
on the electronic properties of the aryl substituent;
the electron-withdrawing groups cause high-wavenumber
shifts, whereas electron-donating groups cause low-wave-
number shifts. The range of chemical shifts for N-3
for the studied compounds is 18.07 ppm (from ꢀ96.28
to ꢀ78.21 ppm), whereas that for N-4 is only 5.18 ppm
ꢂꢀ
p
C intercept and chemical shift D ꢂ
I
ꢀ
I
C ꢂ
R
ꢀ
R
C intercept.
Chemical shift values of 10 compounds were used in
correlation studies.
Statistical data for Hammett analysis of chemical shifts
of some carbon and nitrogen atoms in 1a–j are summarized
in Table 3. Linear correlations between chemical shifts and
Hammett values of substituents in the aryl ring were
obtained for both nitrogen atoms N-3 and N-4 with the
2
(
from ꢀ75.21 to ꢀ70.24 ppm) and shows that changes
classical ꢀ
p
substituent constants (r ꢀ 0.966). The N-3
in electron density for N-3 under the influence of
atom in the 1,3,4-oxadiazole ring is about four times more
Table 1. Hammett values (ꢀi) for aryl substituents and 15N NMR chemical shifts for 1a–j
Compound
R
ꢀpa
ꢀIa
ꢀRa
N-3
N-4
Other N-atoms
b
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
NMe2
NH2
OMe
Me
H
Ph
F
Br
CN
NO2
ꢀ0.63
ꢀ0.57
ꢀ0.28
ꢀ0.14
0
0.05
0.15
0.26
0.70
0.06
0.12
0.27
ꢀ0.05
0
0.1
0.5
0.44
0.56
0.65
ꢀ0.55
ꢀ0.5
ꢀ0.42
ꢀ0.13
0
ꢀ0.1
ꢀ0.31
ꢀ0.16
0.08
ꢀ96.28
ꢀ94.66
ꢀ91.83
ꢀ88.57
ꢀ86.77
ꢀ86.15
ꢀ86.94
ꢀ84.64
ꢀ79.00
ꢀ78.21
ꢀ75.06
ꢀ75.17
ꢀ74.89
ꢀ73.67
ꢀ73.44
ꢀ72.71
ꢀ72.94
ꢀ72.39
ꢀ70.90
ꢀ70.24
ꢀ328.27
c
ꢀ321.41
d
ꢀ122.27
e
j
0.81
0.15
14.72
a
b
c
Ref. 14.
N(CH3ꢁ2.
NH2.
CN.
NO2.
d
e
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 689–692

15N and 13
C NMR of 2-aryl-1,3,4-oxadiazoles
691
Table 2. 13C NMR chemical shifts for 1a–j
0
0
0
0
0
0
Compound
C-2
C-5
C-1
C-2 ,6
C-3 ,5
C-4
Other C-atoms
40.67a
1
1
1
1
1
1
a
b
c
d
e
f
165.72
165.05
164.50
165.55
164.71
165.09
152.04
150.07
152.13
153.03
152.73
152.92
110.78
113.31
115.87
121.38
123.36
122.65
128.99
128.97
128.87
127.46
127.01
127.90
111.88
114.75
114.09
130.29
129.02
128.11
152.89
164.97
162.35
143.06
131.94
145.38
55.53b
20.01c
140.21d
e
1
1
1
27.65
29.38f
g
28.64
1
1
1
1
g
h
i
163.69
164.55
163.33
163.48
152.57
153.21
153.23
153.89
119.62
127.19
127.40
129.23
129.17
129.05
127.64
128.36
116.24
133.04
132.96
124.82
164.65
122.90
115.60
150.27
117.74h
j
a
b
c
d
e
f
N(CH3ꢁ2.
OCH3.
CH3.
00
C-1 .
00 00
C-2 ,6 .
00 00
C-3 ,5 .
g
h
0
C-4 .
CN.
Table 3. Statistical data for correlation between the chemical shifts and Hammett parameters of
carbon and nitrogen atoms in 1a–ja
Probe atom
ꢂ š sꢂ
Substituent constant
i š si
n
r2
N-3
N-3
12.35 š 0.55
ꢂI: 9,06 š 0.95
ꢂR: 18,96 š 1.00
3.47 š 0.23
ꢀp
ꢀ87.74 š 0.25
ꢀ86.03 š 0.43
10
10
0.984
0.990
ꢀI and ꢀR
N-4
N-4
ꢀp
ꢀ73.26 š 0.10
ꢀ72.97 š 0.25
10
10
0.966
0.958
ꢂI: 2.97 š 0.56
ꢂR: 4.02 š 0.59
ꢀ1.45š 0.35
ꢀI and ꢀR
C-2
C-2
ꢀp
164.62 š 0.16
165.12 š 0.23
10
10
0.686
0.865
ꢂI: ꢀ2.68 š 0.50
ꢂR: ꢀ0.80 š 0.52
1.72 š 0.47
ꢀI and ꢀR
C-5
C-5
ꢀp
152.52 š 0.21
153.04 š 0.45
10
10
0.629
0.652
ꢂI: 0.58 š 0.99
ꢂR: 3.16 š 1.04
12.12 š 1.68
ꢀI and ꢀR
0
C-1
C-1
ꢀp
120.65 š 0.76
123.85 š 1.25
10
10
0.866
0.924
0
ꢂI: 5.46 š 2.77
ꢂR: 21.77 š 2.90
ꢀI and ꢀR
a
ꢂ D regression coefficient for the single parameter; i D intercept; sꢂ and si D standard deviations;
n D number of points; r D correlation coefficient.
sensitive to the electronic effects of substituents in the
aryl ring than N-4 (ꢂ D 12.35 and 3.47 for N-3 and N-4,
respectively).
Carbon C-5 shows the expected electron density varia-
tions, whereas in the case of C-2 a reverse substituent effect is
observed (electron-withdrawing substituents promote low-
wavenumber shifts and vice versa).
of the substituent effect into its inductive and resonance
components, ꢀ and ꢀ , improves the correlation coefficient
I
R
slightly and shows that inductive effects of the substituent
are predominant. This can be explained by the redistribution
of electron density due to the polarization of the C N double
1
5,16
bond, as described previously.
As a result of this study, we can conclude that
(i) substituents in the aryl ring of the compounds stud-
ied are able to exert long-range electronic effects, affecting
the chemical shifts of both the N-3 and N-4 atoms in the
For both carbon atoms of the oxadiazole ring, no
1
3
correlation between the C chemical shifts and Hammett
parameter was found. In the case of C-2, a dissection
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 689–692

692
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oxadiazole ring, provide further insight into the structural
features which determine their biological and optoelectronic
activity.
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Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 689–692