Catecholase activity investigation for pyridazinoneand thiopyridazinone- based ligands

Article abstract of DOI:10.1007/s11164-012-0520-2

A series of seven heterocyclic compounds based on pyridazinone and thiopyridazinone moieties: 5-(2-chlorobenzyl)-6-methylpyridazin-3-one L1; 5-[(2-chlorobenzyl)hydroxyl)methyl]6-methylpyridazin-3-one L2; 5-(2-chlorobenzyl)-2,6-dimethylpyridazin-3-one L3; 5-(2-chlorobenzyl)-2- (hydroxyethyl)-6-methylpyridazin-3-one L4; ethyl-4-(2-chloro-benzyl)-3-methyl-6- oxopyridazin-1(6H)-yl) acetate L5; 5-(2-chlorobenzyl)-2-(hydroxyethyl)-6- methylpyridazin-3-thione L6, and ethyl-4-(2-chloro-benzyl)-3-methyl-6- thioxopyridazin-1(6H)-yl)acetate L7 were tested for the oxidation of catechol to o-quinone for miming microorganism in the O₂ activation for electrophilic non substituted aromatic. The in situ generated Cu(II), Fe(II) and Zn(II) complexes of these ligands (L1-L7) were examined for such catalytic activities. We found that all these substrates catalyze the oxidation reaction of catechol to o-quinone with the presence of atmospheric dioxygen. The rates of this oxidation depend on two parameters: the nature of the ligand and the nature of ion salts. We found that the combination of L7 [Cu(CH ₃COO)₂] leads to the fastest catalytic processes. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0520-2

Res Chem Intermed (2012) 38:1987–1998
DOI 10.1007/s11164-012-0520-2
Catecholase activity investigation for pyridazinone-
and thiopyridazinone-based ligands
•
R. Saddik F. Abrigach N. Benchat S. El Kadiri
•
•
•
•
B. Hammouti R. Touzani
Received: 19 January 2012 / Accepted: 26 February 2012 / Published online: 20 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A series of seven heterocyclic compounds based on pyridazinone and
thiopyridazinone moieties: 5-(2-chlorobenzyl)-6-methylpyridazin-3-one L1; 5-[(2-
chlorobenzyl)hydroxyl)methyl]6-methylpyridazin-3-one L2; 5-(2-chlorobenzyl)-
2,6-dimethylpyridazin-3-one L3; 5-(2-chlorobenzyl)-2-(hydroxyethyl)-6-methylpy-
ridazin-3-one L4; ethyl-4-(2-chloro-benzyl)-3-methyl-6-oxopyridazin-1(6H)-yl)
acetate L5; 5-(2-chlorobenzyl)-2-(hydroxyethyl)-6-methylpyridazin-3-thione L6,
and ethyl-4-(2-chloro-benzyl)-3-methyl-6-thioxopyridazin-1(6H)-yl)acetate L7 were
tested for the oxidation of catechol to o-quinone for miming microorganism in the O2
activation for electrophilic non substituted aromatic. The in situ generated Cu(II),
Fe(II) and Zn(II) complexes of these ligands (L1–L7) were examined for such cata-
lytic activities. We found that all these substrates catalyze the oxidation reaction of
catechol to o-quinone with the presence of atmospheric dioxygen. The rates of this
oxidationdepend on two parameters: the nature of the ligand and the nature of ion salts.
We found that the combination of L7 [Cu(CH3COO)2] leads to the fastest catalytic
processes.
Keywords Nitrogen ligand Á Pyridazinone Á Thiopyridazine Á Oxidation Á
Transition metal salts Á O2 activation
R. Saddik Á F. Abrigach Á N. Benchat (&) Á S. El Kadiri Á B. Hammouti Á R. Touzani
´
Laboratoire de Chimie Appliquee et Environnement, LCAE-URAC18, COSTE,
´
Faculte des Sciences, Universite Mohamed Premier, BP524, 60000 Oujda, Morocco
e-mail: n_benchat@yahoo.fr
´
R. Touzani (&)
´
Faculte Pluridisciplinaire de Nador, Universite Mohamed Premier, Selouane, BP300, 62700 Nador,
Morocco
´
e-mail: touzanir@yahoo.fr
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R. Saddik et al.
Introduction
Copper and other elements of the first transition series such as iron and zinc are
important in many biochemical processes. These metals are present in metallo-
enzymes that involve the coordination of a metal ion as an active site and in which
the metal plays the role of catalyst [1]. They also participate in the electron transport
of O2, and the degradation of the superoxide ion O2- [2–4]. Copper dioxygen is well
known for its participation in (bio)inorganic chemistry such as the reversible O2
binding via coupled binuclear Cu like hemocyanin [5–10], the O2 activation for
H-atom via non-coupled binuclear Cu like peptidylglycine-a-hydroxylation mono-
oxygenase DbM [11–15], the O2 reduction to H2O using trinuclear Cu cluster
[16–20], the O2 activation for methane oxygenation for preparing methanol [21–25],
and the O2 activation for electrophilic aromatic substitution like tyrosinase and
catechol oxidase which are important dioxygen-processing proteins [26–30]. These
metallo-enzymes, which use molecular oxygen from air as the primary oxidant, are
generally considered as very sophisticated catalysts. Their reactions are very fast
and highly efficient while operating under mild conditions with high substrate
specificity, regio-selectivity and yield, and having mostly water as the only ‘waste’
product [31–37]. To understand more about this biological process and to search for
new ligands that are able to contribute with other metals miming bio-organism
puzzles, we examined a series of seven heterocyclic compounds L1–L7 based on
pyridazinone and thiopyridazinone. These compounds show many properties such
as anticorrosion, as does L2 which inhibited the corrosion of copper [38] and as
antimicrobial, as does L4 [39]. In this work, we focused on the study of catecholase
activity by using these seven ligands with Cu(II), Fe(II) and Zn(II) metals towards
oxidation of catechol to o-quinone.
Experimental
Kinetic measurements were made spectrophotometrically on UV–Vis spectropho-
tometer (in the COSTE: Centre de l’Oriental des Sciences et Technologies
de l’Eau), following the appearance of o-quinone over time at 25 °C (390 nm
absorbance maximum, e = 1,600 L mol-1 cm-1 in methanol [40]). The complexes
were prepared in situ by successively mixing 0.15 mL of a solution (2 9 10-3 M)
of CuX2, nH2O (X = Cl–, NO3-, CH3COO- or SO42-), FeCl2 and ZnCl2 with
0.15 mL of a solution (2 9 10-3 M) of ligand, then adding 2 mL of a solution of
catechol at a concentration of 10-1 M.
Results and discussion
Chemistry
Many natural and synthetic heterocyclic compounds bearing pyridazinone ring
derivatives are known for having different biological activities [41–50]. The
123

Catecholase activity investigation
1989
Cl
OH
CH
3
N
NH
Cl
CH
3
Cl
CH
3
L2
O
N
N
N
O
CH
3
N
O
CH
3
S
O
L7
L3
Cl
CH
3
N
NH
L1
O
Cl
CH
3
Cl
CH
3
N
N
N
N
L6
L4
S
O
Cl
CH
HO
3
HO
N
O
N
O
CH
3
O
L5
Scheme 1 Structures of tested pyridazinone and thiopyridazinone ligands
pyridazine moiety is an important structural feature of many biologically active
compounds and shows diverse pharmacological properties. Pyridazines hold consid-
erable interest relative to the preparation of organic intermediates and physiologically
active compounds. However, on the basis of the literature, pyridazinone derivatives
have not been reported to be used as catalysts for oxidation reaction. In this paper, we
study their catalytic activities via the oxidation of the catechol to give o-quinone. We
have also chosen seven pyridazinone compounds by the variation of their skeletons
(Scheme 1).
Synthesis
–
The compound L1 was prepared in two steps. The first step is to synthesize
levulinic-chlorobenzylidene acid (2) by reacting levulinic acid (1) with
chlorobenzaldehyde in the presence of a gaseous stream of hydrochloric acid.
The second step is the action of hydrazine hydrate on the compound (3), then we
obtained L1 [39] (Scheme 2).
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R. Saddik et al.
Cl
Cl
H
CHO
H3C
COOH
COOH
HCl (gas)
+
COCH3
O
(2)
(1)
NH2NH2,H2O
EtOH, reflux
Cl
CH3
N
NH
L1
O
Br(CH2)2OH
K2CO3/BTBA
reflux
/THF
Cl
CH3
Cl
CH3
N
N
N
N
P2S5
Pyridine
reflux
O
S
OH
OH
L6
L4
Scheme 2 Pathways for the preparation of the some tested pyridazinone and thiopyridazinone ligands
–
–
The compounds L2 and L3 were prepared by the action of hydrazine hydrate
(for L2) and methyl hydrazine (for L3) on 3-acetyl-4-butanolide [51, 52].
The compounds L4 and L5 were obtained by the alkylation of L1 by
bromoethanol (for L4) or ethyl bromoacetate (for L5) in the presence of
potassium carbonate and tetrahydrofuran or by using microwaves [52–58].
The thiopyridazinones L6 and L7 are prepared from the sulfurization of their
counterpart’s pyridazinones L4 and L5, respectively [39, 52, 59, 60].
–
Catecholase studies
The progress of the catechol oxidation reaction is conveniently followed by
monitoring the strong absorbance peak of quinone in the UV/Vis spectrophotometer
(Scheme 3). The formation of quinone was monitored by the increase in absorbance
at 390 nm as a function of time. In all cases, catecholase activity was noted.
Figures 1, 2, 3, 4, 5, 6, and 7 show the absorbance versus time spectrum for the first
60 min of the reaction for the Cu(II), Fe(II) and Zn(II) complexes, while the
oxidation rates are shown in Table 1.
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Catecholase activity investigation
1991
1/2O 2
H O
2
O
O
OH
RT
Ligand/ Metals
OH
L
1
L
2
L
3
L
4
L
5
L
6
L
7
Cu
Zn
Fe
Catechol
O-quinone
Scheme 3 The oxidation model reaction of the catechol to o-quinone
Fig. 1 Oxidation of catechol by complexes of ligand L1
Fig. 2 Oxidation of catechol by complexes of ligand L2
From these figures, all the ligand has an absorbance but with variable portions.
Indeed, most ligands have a low absorbance with all the anions except in the case of
acetate anions where the values of the absorbance are high. Also, as can be seen
from Table 1, the oxidation rates vary from the highest value of 138 nmol L-1 s-1
for L7 [Cu(CH3COO)2] to the weaker value 0.86 nmol L-1 s-1 for L5 [ZnCl2].
Therefore, we can conclude that the catalytic activities strongly depend on both the
structure of the ligand and the action of the anion.
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R. Saddik et al.
Fig. 3 Oxidation of catechol by complexes of ligand L3
Fig. 4 Oxidation of catechol by complexes of ligand L4
Fig. 5 Oxidation of catechol by complexes of ligand L5
The study of the effect of the ligand on the kinetics oxidation reaction
In this study, we want to make a comparison between the catalytic activity of
complexes of Cu(II), Fe(II) and Zn(II) formed by different ligands for the same
favorable anion acetate. The figures reported below show the results of this study.
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Catecholase activity investigation
1993
Fig. 6 Oxidation of catechol by complexes of ligand L6
Fig. 7 Oxidation of catechol by complexes of ligand L7
Table 1 Oxidation rates (nmol L-1 s-1) of catechol
Ligand/salt
Cu(CH3COO)2
CuSO4
Cu(NO3)2
CuCl2
ZnCl2
FeCl2
L1
L2
L3
L4
L5
L6
L7
48.50
69.30
69.30
103.00
87.50
88.70
138.00
6.93
4.85
7.50
2.50
24.90
1.45
8.62
2.08
4.16
3.00
2.00
3.90
2.08
4.68
4.68
1.21
7.25
6.25
8.62
–
1.81
1.45
1.09
1.87
0.86
0.87
1.25
–
–
–
–
–
1.50
–
3.05
(1) In the CH3COO- (Fig. 8) case, L7 and L5 show high values of absorbance in
time, the other ligands show average values but ligand L6 shows low values
which are close to zero. Thus, the values of oxidation rates observed with this
anion are the highest compared with other anions, which reach
138 nmol L-1 s-1 for L7, 103 nmol L-1 s-1 for L4, and 88.7 nmol L-1 s-1
for L6.
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R. Saddik et al.
Fig. 8 Oxidation of catechol in presence of acetate
Fig. 9 Oxidation of catechol in presence of sulfate
Fig. 10 Oxidation of catechol in presence of nitrate
(2) In the case of SO42- (Fig. 9), the high value observed is that of L5 with a rate
-
of 24.9 nmol L-1 s-1, whereas in the case of NO3 (Fig. 10), the values
observed for all ligands are located in the same gap but are still very low; also,
the speeds achieved are very low within the range of 2.00 nmol L-1 s-1 (L4)
to 4.68 nmol L-1 s-1 (L7). With respect to chlorides of copper, zinc or iron
(Figs. 11, 12 and 13), the values found are very low.
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Catecholase activity investigation
1995
Fig. 11 Oxidation of catechol in presence of copper chloride
Fig. 12 Oxidation of catechol in presence of zinc chloride
Fig. 13 Oxidation of catechol in presence of iron chloride
It is found that the catalytic activity of our ligands influenced by:
–
Nature of the core group supported by pyridazine (the nitrogen atom 2), in fact,
the donor group can increase the complexing properties of the ligand and
promote stability in the complex. By the presence of an electron withdrawing
123

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R. Saddik et al.
group, a disadvantage complex formation occurs by reducing the electron
density on the sites of chelation and, therefore, reducing the rate of
correspondence between the substrate and the complex.
-
–
Nature of cons-ion. If it is strongly bonded to the metal as in the case of NO3
ions and Cl-, the binding of the substrate on the metal will be difficult, therefore
reducing the catalytic power of the corresponding complex. Otherwise, the
bonds formed between the metal and its cons-ion are not as strong (case of the
CH3COO- anion), so the substrate can be replaced easily, which positively
affects the speed of the reaction.
Conclusion
The seven compounds studied, L1–L7, showed catalytic activity of varying
intensity of one compound to another. This study highlighted the high catalytic
activity of our compounds mainly the compound L7 [Cu (CH3COO)2]. We also
demonstrated that the nature of the group carried by the core pyridazine has a large
effect on the oxidation reaction rate. The study of various Cu(II), Fe(II) and Zn(II)
salts showed that the catalytic activities are also mostly controlled by the nature of
anion. It seems interesting to continue this work on the synthesis of these complexes
and to test their reactivity as metallo-enzymes in the field of biomimetic catalysis.
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