Oxidative ring cleavage of 2,3-dihydrophthalazine-1,4-dione in aqueous and non-aqueous solutions: Electrochemical and kinetic studies

Article abstract of DOI:10.1007/s12039-014-0738-1

Electrochemical oxidation of 2,3-dihydrophthalazine-1,4-dione (DHP) has been investigated in aqueous and some amphiprotic and aprotic non-aqueous solvents by cyclic voltammetric and controlled-potential coulometric techniques. Our data shows that electroc

Full text of DOI:10.1007/s12039-014-0738-1

J. Chem. Sci. Vol. 126, No. 6, November 2014, pp. 1923–1928. ꢀc Indian Academy of Sciences.
Oxidative ring cleavage of 2,3-dihydrophthalazine-1,4-dione in aqueous
and non-aqueous solutions: Electrochemical and kinetic studies
a,∗
b
c
D NEMATOLLAHI , S S HOSSEINY DAVARANI , P MIRAHMADPOUR and
F VARMAGHANI
a
a
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran, 65178-38683
Department of Chemistry, Faculty of Science, University of Shahid Beheshti, Tehran 19835389, Iran
Department of Chemistry, Shahre-Qods Branch, Islamic Azad University, Tehran, Iran
b
c
e-mail: dnematollahi@yahoo.com
MS received 10 February 2014; revised 7 June 2014; accepted 11 June 2014
Abstract. Electrochemical oxidation of 2,3-dihydrophthalazine-1,4-dione (DHP) has been investigated in
aqueous and some amphiprotic and aprotic non-aqueous solvents by cyclic voltammetric and controlled-
potential coulometric techniques. Our data shows that electrochemically generated phthalazine-1,4-dione
(
PTD) in water and amphiprotic non-aqueous solvents participates in an oxidative ring cleavage (ORC) reac-
tion to form phthalic acid. The rate of this reaction is dependent. On autoprotolysis constant (KSH) and basicity
of the solvent. Therefore, in the aprotic non-aqueous solvents such as acetonitrile and DMSO, the rate of ORC
is too slow to be observed on the time-scale of cyclic voltammetry.
Keywords. 2,3-Dihydrophthalazine-1,4-dione; oxidative ring cleavage; aprotic and amphiprotic solvents;
cyclic voltammetry.
absence of indole derivatives.17 Cyclic voltammo-
grams of this compound in the absence of indole show
1
.
Introduction
2,3-Dihydrophthalazine-1,4-diones (phthalylhydrazides)
one anodic (A ) peak and its corresponding cathodic
1
(DHP) are commonly used as intermediates for
peak (C ). These peaks correspond to the transforma-
1
pharmaceuticals and synthesis of organic compounds
and drug molecules. Its unique biological activities
serving as anti-convulsant, anti-microbial, anti-
tion of 2,3-dihydrophthalazine-1,4-dione (DHP) to
phthalazine-1,4-dione (diazanaphthoquinone) (PTD)
and vice versa, within a quasi-reversible two-electron
process with a peak current ratio (IpC1/IpA1) less than
1
2
3
4
5
6
7
fungal, vasorelaxant, anti-HIV, anti-cancer activity,
PDE3/PDE4 inhibitory agents,8 anti-asthamatic,
9
17
unity. This confirms the instability of the generated
10
leishmanicidal and anti-diabetic have made synthetic
studies of the phthalazine ring system attractive over the
years. The chemical oxidation of 2,3-dihydrophthalazine-
PTD. The higher reactivity or instability of PTD can
be due to the simultaneous presence of both carbonyl
and azo moieties. On the other hand, the instability of
PTD depends on the experimental conditions, and so
the optimization of experimental parameters seems to
be important. It also seems that the kinetic evaluation
of the stability of PTD is interesting for all workers
who deal with these compounds.
The importance of DHP on the one hand and the lack
of electrochemical data on the other hand, prompted us
to investigate the electrochemical oxidation of DHP in
aqueous and a few non-aqueous solvents using cyclic
voltammetry. Our results show that the electrogener-
ated PTD undergoes oxidative ring cleavage and con-
verts to the phthalic acid. In this direction, we have also
investigated the electrochemical oxidation of DHP in a
few non-aqueous solvents to increase available data on
oxidative ring cleavage of DHP.
1,4-dione and its derivatives has previously been carried
out both in water and organic solvents for the synthesis
of some organic compounds via the nucleophilic
addition or Diels-Alder reactions.1
1–15
The results
of these studies show that the generated diazanaphtho-
quinone from the oxidation of 2,3-dihydrophthalazine-
1,4-dione is unstable. In addition, the electrochemical
oxidation of 1,2-dihydropyridazine-3,6-dione has
recently been studied and shown that electrochemically
generated diazaquinone is very reactive. Furthermore,
we recently studied the electrochemical oxidation of
16
2,3-dihydrophthalazine-1,4-dione in the presence and
∗
For correspondence
1
923

1
924
D Nematollahi et al.
2.
Experimental
I/µA
A1
2
.1 Apparatus and reagents
5
00
0
0
0
0
.9
.7
.5
.3
g
Cyclic voltammetry and preparative electrolysis were
carried out using a µAutolab potentiostat/galvanostat
type III. The working electrode used in the voltamme-
try experiment was a glassy carbon disc (1.8 mm diam-
eter) and platinum wire (2 mm diameter and 1.6 cm
length) was used as the counter electrode. The working
electrode potentials were measured versus the Ag/AgCl
I
f
e
I
300
d
c
50
2100
v /mV/s
4150
(
KCl, 3 M) as a reference electrode (all electrodes were
1
00
b
a
obtained from Metrohm). The working electrode used
in controlled-potential coulometry and macroscale elec-
trolysis was an assembly of three carbon rods (8 mm
diameter and 6 cm length). The pH was measured
using a Metrohm pH meter 744 with a combined glass
electrode.
-
-
100
300
2,3-Dihydrophthalazine-1,4-dione and other chemi-
cals were obtained from Sigma-Aldrich; these chem-
icals were used without further purification. The
solvents were kept over 0.3 nm molecular sieves for
C1
-0.2
0.1
0.4
0.7
1.0
1.3
4
8 h prior to use and then were used without further
E/V vs. Ag/AgCl
purification.
Figure 1. Typical cyclic voltammograms of DHP
(
5
1.0 mM) at various scan rates. Scan rates from a to g are:
0, 100, 400, 1800, 3400, 4200 and 5000mV s , respec-
−1
3.
Results and Discussion
tively, at a glassy carbon electrode in water (phosphate
buffer, c = 0.2 M, pH = 2.5)/acetonitrile mixture (80/20,
◦
3
.1 Electrochemical studies in water/acetonitrile
v/v). T = 25 ± 1 C. Inset: Variation of peak current ratios
(
IpC1/IpA1) versus scan rate.
mixture
The cyclic voltammograms of 2,3-dihydrophthalazine- oxidation reaction of DHP. The anodic peak potential
,4-dione (DHP) (1.0 mM) in water (phosphate buffer, (EpA1), is given by:
1
c = 0.2 M, pH = 2.5)/acetonitrile mixture (80/20, v/v)
at different potential scan rates are shown in figure 1.
In the low scan rate (50 mV/s) (curve a), the cyclic
voltammogram exhibits the feature of an irreversible
ꢁ
E
= EpA(pH = 0) − (2.303mRT /2F) pH
(1)
pA
where m is the number of protons involved in the reac-
tion and E
is the anodic peak potential at pH =
pA(pH=0)
electron-transfer process with an anodic peak (A ) at
1
0.85 V versus Ag/AgCl which corresponds to the trans-
formation of DHP to phthalazine-1,4-dione (PTD). The
subsequent chemical reaction is supported by the lack
of corresponding cathodic peak C during the reverse
1
scan in low scan rate. The height of IpC1 increases with
the scan rate. This could be indicative of the fact that
electrochemically generated PTD in the surface of elec-
trode via a fast chemical reaction is converted to an
electro-inactive compound.
The electrochemical oxidation of DHP in water
(buffered with various pHs)/acetonitrile (80/20, v/v)
mixture has been studied using cyclic voltammetry. It
was found that by increasing pH, the potential of peak
A (EpA1) is shifted to the negative potentials. This is Figure 2. Variation of oxidation potential (EpA1) of DHP
1
as a function of pH.
predictable due to the participation of protons in the

Oxidative ring cleavage of 2,3-dihydrophthalazine-1,4-dione
1925
electrolysis shows the decrease in the peak A . This
1
peak disappears when the charge consumption becomes
−
about 4e per molecule of DHP. Diagnostic criteria
of cyclic voltammetry, consumption of four electrons
O
O
-
2e -2H+
N
N
NH
NH
O
O
DHP
PTD
Scheme 1. Electrochemical oxidation of 2,3-dihydro-
phthalazine-1,4-dione (DHP) at various pHs.
+
-
2
H O
H O + OH
pK = 14.0
w
2
3
O
0.0, R, T , and F have their usual meanings. An E-pH
H
O
OH
diagram is constructed for oxidation of DHP by plotting
the EpA values as a function of pH (figure 2). The EpA–
pH diagram comprise two linear segments with differ-
ent equations and slopes around pH = 5.3. The first
segment (pHs < 5.3) represents a line with a slope of
N
N
1) +OH-
N
N
+H+
2
)
O
PTD
O
O
5
4 mV/pH and intercept of 0.94 V vs. Ag/AgCl and the
second segment (pHs > 5.3) shows a line with a slope of
3 mV/pH and intercept of 0.83 V vs. Ag/AgCl. On the
3
O
basis of the above mentioned slope, it can be concluded
that the electrode surface reaction occurring at the pH
1) +OH-
+H+
OH
OH
N
<
5.3, corresponds to the two-electron, two-proton pro-
N
2
)
NH
H
NH
cess (scheme 1, Eq. 1). Whereas, the electrode sur-
face reaction at pH > 5.3 is a two-electron, one-proton
process involving the oxidation of ‘anionic form’ of
HO
O
O
-
N H
−
2
2
DHP (DHP ) to the corresponding PTD (scheme 1,
Eq. 2). Also, the pK of acid/base equilibrium shown
in scheme 2 is 5.3. The hydrogen attached to nitrogen
a
O
in DHP is more acidic than 1,2-dihydropyridazine-3,6-
16
OH
OH
dione (pK = 5.58), due to the presence of electron
2e -2H+
a
-
withdrawing phenyl group.
N H
N2
2
2
Controlled-potential coulometry was carried out
in water (phosphate buffer, c = 0.2 M, pH =
O
Phthalic Acid
2
.5)/acetonitrile mixture (80/20, v/v) containing of
DHP (0.25 mmol) at EpA1 (0.85 V versus Ag/AgCl).
Cyclic voltammetric analysis carried out during the
The overall reaction:
O
O
O
+
2H O
OH
OH
NH
NH
2
+
-4e -4H -N2
O
DHP
Phthalic Acid
Scheme 2. Acid/base equilibrium of 2,3-dihydrophthalazine- Scheme 3. Proposed mechanism for the electrochemical
,4-dione (DHP).
oxidation of 2,3-dihydrophthalazine-1,4-dione (DHP).
1

1
926
D Nematollahi et al.
Table 1. Autoprotolysis constant and basicity of the studied solvents.20
Solvent
Water
14.0
Acetic acid
Methanol
Ethanol
Acetonitrile
DMSO
pKSH
14.45
±
17.2
±
19.1
±
33.3
–
33.3
±±
Basicitya
a
The symbol ± is for the case comparable with water, ±± for the case much stronger than water, ± for the case somewhat
weaker than water, and – for the case much weaker than water.
per molecule of DHP, and the mass spectrum of iso- PTD is a reactive electrophile and nucleophilic
lated product (m/z = 166) indicate oxidative ring addition of hydroxide ion (or water) to carbonyl group
cleavage of DHP. The electrochemically generated led to oxidative ring cleavage (scheme 3).
I/µA
I/µA
A1
A
1
7
5
3
1
9
6
3
0
Acetic acid
Ethanol
c
c
3
4
1
8
b
2
b
a
a
-13
-5
0
.1
0.4
0.7
1.0
1.3
0.1
0.4
0.7
1.0
1.3
E/V vs. Ag/AgCl
E/V vs. Ag/AgCl
I/µA
A1
Methanol
4
3
2
1
0
1
2
3
4
5
c
b
a
-
0.1
0.4
0.7
1.0
1.3
E/V vs. Ag/AgCl
Figure 3. Cyclic voltammograms of DHP (1.0 mM) at various scan rates in the presence
of tetrabutylammonium perchlorate (0.1 M), in methanol, ethanol and acetic acid, at a glassy
◦
carbon electrode. Scan rates from a to d are 10, 50 and 100 mV/s. T = 25 ± 1 C.

Oxidative ring cleavage of 2,3-dihydrophthalazine-1,4-dione
1927
I/µA
I/µA
A1
A1
310
dimethyl sulfoxide
190
Acetonitrile
d
d
c
c
195
b
b
a
90
a
80
-10
-35
C1
C1
-150
-110
-
0.1 0.3 0.6 0.9 1.2 1.5 1.8
E/V vs. Ag/AgCl
-0.1 0.3 0.6 0.9 1.2 1.5 1.8
E/V vs. Ag/AgCl
Figure 4. Cyclic voltammograms of 1.0 mM of DHP at various scan rates in 0.1 M tetra-
butylammonium perchlorate, in DMSO and AN, at a glassy carbon electrode. Scan rates
◦
from a to c are 100, 200, 400 and 500 mV/s. T = 25 ± 1 C.
3.2 Electrochemical studies in non-aqueous solutions process. At these conditions, the peak current ratio
(
IpC1/IpA1) at high potential scan rates is nearly unity.
The oxidative ring cleavage (ORC) rates are dependent
on the type of solvent.1 Therefore, the effect of some
amphiprotic and aprotic solvents such as acetic acid,
methanol, ethanol, acetonitrile and dimethylsulfoxide
This can be considered as a criterion for the relative sta-
bility of PTD produced at the surface of the electrode
under the experimental conditions. In other words, in
the acetonitrile and DMSO, the rate of ORC is too low
to be observed on the time scale of cyclic voltammetry.
This finding is related to the very low KSH of these sol-
vents compared to amphiprotic solvents (table 1). In the
case of DMSO as a solvent, although it is a basic sol-
8,19
(DMSO) on the oxidative conversion of DHP has been
examined. As shown in scheme 3, the rate of ORC
is dependent on the autoprotolysis constant (K ) and
SH
basicity character of the solvent and it is expected that
PTD would be unstable in amphiprotic solvents with
high KSH and basicity. The values of pKSH and basicity
of the studied solvents are shown in table 1.20
20
vent, but its autoprotolysis occurs slightly (table 1).
Thus, while the lyate ion of DMSO (CH SOCH , dim-
syl ion) is somewhat stable, its effect on the cyclic
−
3
2
The cyclic voltammograms of DHP recorded in
amphiprotic solvents; acetic acid, methanol and ethanol
are shown in figure 3. The cyclic voltammograms of
DHP in methanol and ethanol displayed an irreversible
feature due to the relatively high basicity and KSH of
these solvents. The basicity of these solvents is com-
voltammograms of DHP is negligible due to very low
K .
SH
4.
Conclusions
parable with water (table 1). Unlike the methanol and The results of this study support the previous reports
ethanol, in acetic acid, the peak current ratio (IpC1/IpA1 on the anodic oxidation of 1,2-dihydropyridazine-
)
16
increases slightly upon increasing the potential scan 3,6-dione, and show that 2,3-dihydrophthalazine-
rate. This confirms the relative stability of PTD in acetic 1,4-dione (DHP) is oxidized to phthalazine-1,4-dione
acid due to the low basicity of acetic acid compared to (PTD). PTD is unstable and participates in a fast fol-
water (table 1).
lowing chemical reaction (oxidative ring cleavage) to
These experiments were repeated in aprotic solvents form phthalic acid. The reaction mechanism for the
acetonitrile and DMSO (figure 4). The cyclic voltam- oxidative conversion of DHP is presented in scheme 3.
mograms of DHP in these solvents show one anodic The rate of this reaction is dependent on the solvent
peak (A ) and the corresponding cathodic peak (C ) autoprotolysis constant (K ) and basicity. Thus, PTD
1
1
SH
which correspond to the transformation of DHP to PTD is unstable in non-aqueous amphiprotic solvents with
and vice versa within a quasi-reversible two-electron high K , while PTD is more stable in aprotic solvents.
SH

1
928
D Nematollahi et al.
Moreover, it was found that the pH dependence of DHP
is about 55 mV/pH, in the pH range from 1.0 to 5.3 and
7. Mey M V, Bommele K M, Boss H, Hatzelmann A,
Slingerland M V, Sterk G J and Timmerman H 2003 J.
Med. Chem. 46 2008
33 mV/pH, in the pH range from 5.3 to 9.0.
8
. Yamaguchi M, Koga T, Kamei K, Akima M, Maruyama
N, Kuroki T, Hamana M and Ohi N 1994 Chem. Pharm.
Bull. 42 1850
Acknowledgement
9
. Olmo E, Armas M G, López-Pérez J L, Muñoz V,
Deharo E and Feliciano A S 2001 Bioorg. Med. Chem.
Lett. 11 2123
We acknowledge Bu-Ali Sina University Research
Council and Centre of Excellence in Development of
Environmentally Friendly Methods for Chemical Syn-
thesis (CEDEFMCS) for their support to carry out this
work.
1
1
0. Madhavan G R, Chakrabarti R, Kumar S K B, Misra
P, Mamidi R N V S, Balraju V, Kasiram K, Babu R
K, Suresh J, Lohray B B, Lohray V B, Iqbal J and
Rajagopalan R 2001 Eur. J. Med. Chem. 36 627
1. Merenyi G, Lind J and Eriken T E 1968 J. Am. Chem.
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2. Kealy T 1962 J. Am. Chem. Soc. 84 966
3. Lind J, Mereyi G and Eriksen T E 1983 J. Am. Chem.
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