NH-acidities and Hammett correlation of 3-para substituted phenyl-1,2,4-oxadiazol-5(4H)-ones and 1,2 λ43,5-oxathiadiazole 2-oxides in nonaqueous media

Article abstract of DOI:10.3906/kim-1303-46

NH acidities of some 3-(p-substitutedphenyl)-1,2,4-oxadiazol-5(4H)-ones and 4-(p-substitutedphenyl)-1,2 λ⁴3,5-oxathiadiazole 2-oxides were determined in methanol by means of potentiometric titration with sodium methoxide. pKa values of the titl

Full text of DOI:10.3906/kim-1303-46

Turk J Chem
Turkish Journal of Chemistry
(2014) 38: 56 – 62
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1303-46
Research Article
NH-acidities and Hammett correlation of 3-para substituted
phenyl-1,2,4-oxadiazol-5(4H)-ones and 1,2 λ4 3,5-oxathiadiazole 2-oxides in
nonaqueous media
∗
¨
Nedime DURUST, Ya¸sar DURUST , Emine Ozge GOZLUKAYA
¨
¨
¨
¨
¨
¨
˙
Department of Chemistry, Abant Izzet Baysal University, Bolu, Turkey
Received: 16.03.2013
•
Accepted: 09.09.2013
•
Published Online: 16.12.2013
•
Printed: 20.01.2014
Abstract: NH acidities of some 3-(p-substitutedphenyl)-1,2,4-oxadiazol-5(4H)-ones and 4-(p-substitutedphenyl)-1,2
λ4 3,5-oxathiadiazole 2-oxides were determined in methanol by means of potentiometric titration with sodium methoxide.
pKa values of the title compounds calculated from the potentiometric data were interpreted on the basis of structural
effects caused by para-substituted groups on the phenyl ring by plotting pKa values versus Hammett σp+ constants,
which gave excellent linear correlations.
Key words: Potentiometry, oxadiazol-5(4H)-one, oxathiadiazol 2-oxide, linear Hammett correlation
1. Introduction
1,2,4-Oxadiazol-5(4H)-ones and 1,2λ4 3,5-oxathiadiazole 2-oxides are typical acidic heterocycles that are clas-
sically used by medicinal chemists as carboxylic acid bioisosters.1 In particular, heterocyclic scaffold 1,2,4-
oxadiazol-5(4H)-ones are found in AT1 antagonists, COX inhibitors, PLA2 inhibitors, and modulators of
GluR,2−5 and they serve as precursors and protecting groups for amidines, which are utilized as an important
class with biological functionality and as antihypertensive drugs.6−10 Moreover, 3H -1,2λ4 3,5-oxathiadiazole
2-oxides have been reported to be used to control hyperglycemia associated with type 2 (noninsulin dependent)
diabetes mellitus, and they were clinically found to have advantages over 4 divergent classes of drugs that are
in use.11
Potentiometric titration in nonaqueous media is a standard method for the determination of the basicity
and acidity of various heterocyclic compounds, particularly in pharmaceutical analyses since many organic
compounds of pharmaceutical importance do not dissolve in water thoroughly. Furthermore, due to the
amphotericity of water, only a very limited range of acid and base strengths can be determined in this
solvent and in trying to compare the protonation and deprotonation tendencies of such heterocycles in alternant
solvents.12−15
In continuation of our studies on the acid-base equilibria of amidoximes and related heterocyclic compo-
unds,16−18 we report herein acidity measurements and Hammett correlations of a series of 3-(para-substituted
phenyl-1,2,4-oxadiazol-5(4H)-ones and 4-(para-substituted phenyl)-3H -1,2λ4 ,3,5-oxathiadiazole 2-oxides (Sche-
me 1) in methanol as nonaqueous medium.
∗Correspondence: yasardurust@ibu.edu.tr
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2. Experimental
1,2,4-Oxadiazol-5(4H)-ones (2a–l) and 1,2λ4 ,3,5-oxathiadiazol-2-oxides (3a–l) were prepared according to the
procedures described previously.19−24
2.1. Potentiometric titrations
Titrations were performed in a 50-mL glass vessel designed for this work and equipped with a combined pH
electrode (Ingold), argon inlet and outlet tubes, a magnetic stirrer, and an inlet for titrant (sodium methoxide)
addition. A microburette with 0.01-mL graduations was used to add titrant. A Thermo Scientific Orion 4 Star
pH/ISE meter equipped with a modified electrode (saturated KCl solution in anhydrous methanol instead of
aqueous KCl solution) was used to read out the cell EMF.
The concentrations of the oxadiazolones and oxathiadiazole 2-oxides were maintained as 10−3 M in dry
methanol. Potentiometric measurements were conducted with constant stirring of 30 mL of sample solution
(magnetic stir-bar) at 25.0 ꢀ 0.1 ◦ C. Titration curves were constructed by plotting the potential change (from
the initial baseline value) versus the concentration of the titrant solution added. In order to calculate the end
points the Kolthoff method was utilized. The half neutralization potentials (HNP) were then determined by
using fine sigmoidal curves. In calculations of the pKa values, mV value of a standard buffer solution and HNP
values from the sigmoidal curves of the samples were used, and 59 mV was taken as corresponding to 1 pH unit.
3. Results and discussion
3-Aryl-substituted 1,2,4-oxadiazol-5(4H )-ones 2a–l were synthesized following the literature procedure25,26 by
reacting monoamidoximes with 1,1’-carbonyldiimidazole (CDI) in the presence of 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU), and 3-aryl substituted 1,2λ4 ,3,5-oxathiadiazole 2-oxides 3a–l were prepared similarly to the
procedure27 described by the condensation of mono amidoximes 1a–l with thionyl chloride along with pyridine
(Schemes 1 and 2).
Scheme 1. Synthesis of 3-p-substituted phenyl-1,2,4-oxadiazol-5(4H)-ones (2a–l).
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Scheme 2. Synthesis of 3-p-substituted phenyl-3H -1,2λ4 ,3,5-oxathiadiazole 2-oxides (3a–l).
pKa values of aromatic heterocyclic compounds bearing oxygen and nitrogen in the same ring, namely
oxadiazolones and oxathiadiazole 2-oxides, were determined potentiometrically in nonaqueous medium, anhy-
drous methanol, by using sodium methoxide as titrant. Overall results are compiled in Table 1, indicating the
σp+ constants for each substituent encountered, and typical titration curves for each series of the compounds
are shown in Figures 1 and 2.
Figure 1. Representative titration curve of mL titrant vs.
∆mV of 4-p-nitrophenyl-1,2,4-oxadiazol-5(4H)-one (2k).
Figure 2. Representative titration curve of mL titrant vs.
∆mV of 3-p-nitro 3H -1,2 λ4 ,3,4,5-oxathiadiazole 2-oxide
(3k).
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Table 1. Experimental pKa values of oxadiazolones (2a–l) and oxathiadiazole 2-oxides (3a–l) in methanol.
pKa
pKa
+
p
Entry
Entry
R
R
(oxadiazolone)
(oxathiadiazole 2-oxide)
2a
2b
2c
2d
2e
2f
H
6.35 0.02
6.80 0.04
6.50 0.01
6.30 0.02
6.18 0.05
6.28 0.03
7.24 0.06
7.10 0.06
5.69 0.13
5.60 0.01
5.44 0.10
0.00
–0.31
–0.07
0.11
3a
3b
3c
3d
3e
3f
H
6.12 0.01
6.40 0.04
6.17 0.05
6.05 0.07
5.76 0.01
5.90 0.03
7.00 0.08
6.80 0.02
5.45 0.06
5.36 0.07
5.07 0.12
CH3
CH3
4-F
4-F
4-Cl
4-Cl
4-Br
0.15
4-Br
4-I
0.14
4-I
2g
2h
2i
4-CH3O
4-CH3S
4-CF3
4-CN
4-NO2
–0.78
–0.60
0.61
3g
3h
3i
4-CH3O
4-CH3S
4-CF3
4-CN
4-NO2
2j
0.66
3j
2k
2l
0.79
3k
3l
4-N(CH3)2 8.30 0.16
–1.70
4-N(CH3)2 8.04 0.15
Deprotonation of the oxadiazolones 2a–l by methoxide will take place on the sp3 -hybridized 4-amino
nitrogen. The resulting heterocyclic anion, oxadiazol-5-olate, is now stabilized due to the delocalization of
negative charge through exocyclic oxygen, thus producing an aromatic oxadiazole structure (Scheme 3).
Scheme 3. Deprotonation of 1,2,4-oxadiazol-5(4H)-ones and resonance structures of the anion.
Electron-withdrawing and electron-releasing substituents (R groups) existing on the para position of the
phenyl ring in the case of oxadiazolones will have a remarkable impact on the acidities of these heterocycles. In
this regard, electron-donating substituents like dimethylamino, methoxy, and thiomethoxy cause an increase in
pKa values as much as 8.30, 7.24, and 7.10, respectively, while electron-withdrawing ones, such as NO2 , CN,
and CF3 , give rise to much lower pKa values of 5.44, 5.60, and 5.69, respectively, which are in accord with the
decreasing values of Hammett sigma para constants.
In a similar manner, we can illustrate the deprotonation of oxathiadiazole 2-oxides, which further gives
4-aryl-1,2λ4 ,3,5-oxathiadiazol-2-olate with aromatic stability (Scheme 4).
Again we can observe the higher acidities of the oxathiadiazole 2-oxides compared to oxadiazolones in
the case of electron-withdrawing substituents and this tendency can be attributed to the higher polarization of
S=O bond than C=O bond, causing easier deprotonation of NH hydrogens of oxathiadiazole 2-oxides.
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Scheme 4. Deprotonation of 1,2λ4 ,3,5-oxathiadiazole 2-oxides and resonance structures of the anion.
pKa values obtained for the title compounds were correlated with Hammett σp+ constants,28 which
have also been used for para substituents interacting with the aromatic ring through resonance delocalization
of the lone pairs.29,30 In Figure 3, it can be clearly perceived that electron-releasing groups (ERGs), i.e.
dimethylamino, methoxy, and thiomethoxy, which have lower Hammett σp+ values with higher pKa values,
appeared on one end of the line (right lower end), and electron-withdrawing (EWG) substituents, i.e. NO2 ,
CN and CF3 , which have higher Hammett σp+ constants with lower pKa values, appeared on the other end of
the graph (left upper end). In general, the acidities measured experimentally in nonaqueous solvents such as
methanol, dimethyl sulfoxide, dimethoxyethane, and acetonitrile are expected to be lower than those obtained
in water due to the higher stabilization of the ionic species in water.31−35
A similar observation was made for oxathiadiazol-2-oxides (Figure 4).
1
1
p-NO 2
0.8
0.6
0.4
0.2
0
p- NO
2
p-CN
p-CF 3
0.8
0.6
0.4
0.2
0
p- CN
p- CF
3
p- Br
p- I
p- Cl
p- Br
p- I
p- Cl
H
H
p- F
p-F
-0.2
-0.4
-0.6
-0.8
-1
-0.2
-0.4
-0.6
-0.8
-1
p-Me
p- Me
p-MeS
p-MeO
p- MeS
p- MeO
-1.2
-1.4
-1.6
-1.8
-2
-1.2
-1.4
-1.6
-1.8
-2
y= -0.8553x+ 5.1995
R2 = 0.9928
y= -0.8714x+ 5.5642
R2 = 0.9974
p- NMe 2
p-NMe2
5
5.4 5.8 6.2 6.6
7
7.4 7.8 8.2 8.6
9
4.5 4.9 5.3 5.7 6.1 6.5 6.9 7.3 7.7 8.1 8.5
pK
pK
a
a
Figure 3. Hammett plot indicating linear correlation
between electronic parameter of the substituents on the
oxadiazol-5(4H)-ones (2a–l) and pKa values obtained in
anhydrous methanol.
Figure 4. Hammett plot indicating linear correlation
between electronic parameter of the substituents on the
oxathiadiazol-2-oxides (3a–l) and pKa values obtained in
anhydrous methanol.
These results are in good accordance with the expected behavior of these groups predicated on the
proticity of amino hydrogen of oxadiazolones. In this regard, when there are electron-releasing groups present
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on the phenyl ring there will be an increase in electron density, which may result in resonance delocalization of
the lone pairs on the N, O, and S atoms (N(CH3)2 , CH3 O, CH3 S) through the aromatic ring, thus reducing
their acidity to a remarkable extent. In the presence of electron-withdrawing groups (NO2 , CN, CF3) on the
phenyl ring, a reverse effect on pKa values is observed due to the substantial decrease in the electron density of
the amino nitrogen atom of the oxadiazolones mesomerically, thus causing an increase in the proticity of amino
hydrogens.
4. Conclusions
In this work, we clearly demonstrated the acidity measurements (pKa) of a series of oxadiazolones and 1,2,4,5-
oxathiadiazol-2-oxides potentiometrically in anhydrous methanol. In addition, excellent linear correlations
between pKa values and Hammett σp+ constants were established and the results were interpreted by taking
account of the electronic–mesomeric nature of the existing groups on the phenyl ring at the 3-position of the
title oxygen, nitrogen containing 5-membered heterocycles.
Acknowledgment
˙
We are grateful to Abant Izzet Baysal University Directorate of Research Project Commission for its financial
support (BAP Grant No: 2011.03.03.442).
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