Evaluation of catalytic activity of imidazolo[1,2-a] pyridine derivatives: Oxidation of catechol

Article abstract of DOI:10.1007/s11164-012-0561-6

A series of heterocyclic compounds possessing imidazolo[1,2-a]pyridine moiety, namely, ethyl 7-methylimidazolo[1,2-a] pyridine-2-carboxylate L1; 2-(3-nitrophenyl)imidazo[1,2-a]pyridine L2; 3-(imidazo[1,2-a]pyridine-2-yl) aniline L3; 2-phenylimidazolo[1,2-

Full text of DOI:10.1007/s11164-012-0561-6

Res Chem Intermed (2012) 38:2457–2470
DOI 10.1007/s11164-012-0561-6
Evaluation of catalytic activity of imidazolo[1,2-a]
pyridine derivatives: oxidation of catechol
•
R. Saddik M. Khoutoul N. Benchat
•
•
•
B. Hammouti S. El Kadiri R. Touzani
•
Received: 15 March 2012 / Accepted: 10 April 2012 / Published online: 4 May 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A series of heterocyclic compounds possessing imidazolo[1,2-a]pyri-
dine moiety, namely, ethyl 7-methylimidazolo[1,2-a] pyridine-2-carboxylate L1;
2-(3-nitrophenyl)imidazo[1,2-a]pyridine L2; 3-(imidazo[1,2-a]pyridine-2-yl)aniline
L3; 2-phenylimidazolo[1,2-a]pyridine-3carbaldehyde L4; and 2-phenylimidazo
[1,2-a]pyridine L5 were synthesized. The in situ generated copper (II), iron (II), and
zinc (II) complexes of these compounds (L1–L5) were examined for their catalytic
activities and were found to be effective catalysts for the oxidation of catechol to
o-quinone with the atmospheric oxygen. The present study reveals that the rate of
oxidation depends on four parameters: the nature of the ligand, transition metals, ion
salts, and the concentration of the complex. The combination L2(Cu(CH3COO)2)
gives the highest rate.
Keywords Imidazolo[1,2-a]pyridine Á Catechol Á Oxidation Á
Transition metal salts
Introduction
Catalysis is an interesting and ever-growing branch with useful applications in
synthetic chemistry. We were interested in this work to discover the efficiency of
copper (II)—imidazolo [1,2-a] pyridine complexes in the oxidation of catechol,
R. Saddik Á M. Khoutoul Á N. Benchat Á B. Hammouti Á S. El Kadiri Á R. Touzani
´
Laboratoire de Chimie Appliquee et Environnement, LCAE-URAC18; COSTE,
´
Faculte des Sciences, Universite Mohamed Premier, BP 524, 60 000 Oujda, Morocco
e-mail: n_benchat@yahoo.fr
´
R. Touzani (&)
´
Faculte Pluridisciplinaire de Nador, Universite Mohamed Premier, BP 300,
62700 Selouane, Nador, Morocco
´
e-mail: touzanir@yahoo.fr
123

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R. Saddik et al.
which presents a major challenge both in biology and in medicine. The reason
behind the interest in these complexes is their resemblance to biological systems,
capable of activating the catalyst for many chemical reactions. The in situ
preparation of complexes allowed us to easily vary the nature of the ligands and the
anions.
We examined a series of five heterocyclic compounds based on imidazolo[1,2-a]
pyridine moiety, namely, ethyl 7-methylimidazolo[1,2-a] pyridine-2-carboxylate
L1 [1]; 2-(3-nitrophenyl)imidazo[1,2-a]pyridine L2 [2, 3]; 3-(imidazo[1,2-a]pyri-
dine-2-yl)aniline L3 [4]; 2-phenylimidazolo[1,2-a]pyridine-3carbaldehyde L4 [5];
and 2-phenylimidazo[1,2-a]pyridine L5 [6].
Results and discussion
Experimental
In this study, kinetic measurements were made spectrophotometrically on a UV-Vis
spectrophotometer (UV-1650 PC Shimadzu) at the COSTE (Centre de l’Oriental des
Sciences and Technologies de l’Eau) following the appearance of o-quinone over
time at 25 °C (390-nm absorbance maximum, e = 1,600 M-1 cm-1 in methanol).
The metal complex (prepared in situ [7–15] by mixing 0.15 mL of a solution of ligand
(2 9 10-3 M) and 0.15 mL of a solution of metal salt (2 9 10-3 M) namely, Cu
(CH3COO)2, CuSO4, Cu (NO3)2, CuCl2, FeCl2, and ZnCl2 and a 2-mL solution
(10-1 M methanol solution) of catechol was added together in the spectrophotometric
cell. We follow the evolution of absorbance at 390 nm versus time after setting to
zero. So for each ligand, we varied the nature of the anion. The different kinetic
parameters were determined by the method of the initial velocity (Table 1).
Chemistry
The synthesis and biological activities based on imidazolo[1,2-a]pyridine against
many diseases have been reported [16–23]. The most potent scaffold was selected
for further optimization leading to a series with potent Gram-positive antibacterial
activity and a low resistance frequency (Scheme 1).
These ligands are known compounds [24]. For the synthesis of compound L1 [1]:
the 7-methyl imidazo [1,2-a] pyridine-2-ethyl carboxylate was provided by Benchat
Table 1 The rates of oxidation of catechol in the presence of L1–L5 (nmol L-1 s-1
)
Ligand/salt
Cu(CH3COO)2
CuSO4
Cu(NO3)2
CuCl2
FeCl2
ZnCl2
L1
L2
L3
L4
L5
55.7
68.5
64.1
26.4
65.0
2.98
7.43
23.8
15.3
12.1
5.55
6.87
15.1
2.15
5.90
5.55
4.65
1.18
1.25
7.30
6.46
4.79
4.16
–
1.25
0.97
1.30
1.53
1.87
2.01
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Evaluation of catalytic activity
2459
H3C
O
N
N
OC2H5
L1
N
N
N
N
NO2
N
L2
L5
N
N
N
N
N
CHO
NH2
L3
L4
Scheme 1 Structure of tested ligands
and coworkers [24] by the following method: The synthetic strategy involves
condensation of 7-methyl 2-amino pyridine (37.64 g; 0.4 mol) with ethylbromo-
pyruvate (48.75 g; 0.25 mol) in boiling ethanol for 5 h, after cooling the solution
the mixture was neutralized at 0 °C with Na2CO3; the product was extracted with
dichloromethane. The organic layer was dried over sodium sulphate and the
dichloromethane was removed under reduced pressure. The crude product was
purified on a silica gel column and a colorless solid was obtained. The 7-methyl
imidazo [1,2-a] pyridine-2-ethyl carboxylate compound was obtained with a good
yield 70 % with mp = 144 °C. For the synthesis of compound L2 [2, 25]:
Condensation of 2-aminopyridine with 1-(2-bromo-3-nitro-phenyl)-ethanone in
boiling ethanol for 4 h, after cooling the solution the mixture was neutralized at
0 °C with Na2CO3, the product was extracted with dichloromethane. The organic
layer was dried over sodium sulphate and the dichloromethane was removed under
reduced pressure. The crude product was purified on a silica gel column and a
colorless solid was obtained. The 2-(metanitrophenyl) imidazo [1,2-a] pyridine
compound was obtained with a good yield 65 % with mp = 200 °C. For the
synthesis of compound L3 [4]: The 2-(3-nitro-phenyl)-imidazo[1,2-a]pyridine was
dissolved in methanol, a solution of tin in methanol was added drop-wise after the
123

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R. Saddik et al.
residue was agitated for 3 h, the 2-(metaaminophenyl)imidazopyridine was obtained
with a good yield 65 % with mp = 212 °C.
For the synthesis of compound L4 [5, 26–30]: 1 mol of the 2-phenylimidazo
[1,2-a]pyridine was dissolved in DMF, a solution of POCl3 (2 mol) was added
slowly, after the addition, the solution was stirred for 7 h and the DMF was removed
under reduced pressure; the was residue extracted with dichloromethane and
purified on silica gel to give a white solid, 2-phenyl imidazo[1,2-a]pyridine-2-
carbaldehyde was obtained in good yield with mp = 150 °C. For the synthesis of
compound L5 [20, 31–37]: condensation of 2-aminopyridine with acetophenone-2-
bromide in boiling ethanol for 4 h, after cooling the solution, the mixture was
neutralized at 0 °C with Na2CO3, the product was extracted with dichloromethane.
The organic layer was dried over sodium sulphate and the dichloromethane was
removed under reduced pressure. The crude product was purified on a silica gel
column and a colorless solid was obtained. The 2-phenyl imidazo[1,2-a]pyridine
compound was obtained with a good yield 80 % with mp = 340 °C.
Scheme 2 depicts the oxidation of catechol to o-quinone:
Catechol oxidases: catechol in the absence of the catalyst
This study focuses on the catalytic activity of copper complexes to oxidize catechol
along with a comparison of copper chloride with iron and zinc. Before starting the
study, we verified that under the experimental conditions used, catechol does not
undergo oxidation in the absence of copper catalyst. Figure 1 shows an almost zero
absorbance with time in the absence of the catalyst under experimental conditions.
Figure 2 shows that the ligand alone does not allow oxidation.
Thus the ligands alone do not have a catalytic effect on the oxidation of catechol.
Figure 3 shows the evolution in absorbance of o-quinone with time for the
following metal salts: Cu(CH3COO)2, CuSO4, Cu (NO3)2, CuCl2, FeCl2 and ZnCl2.
From Fig. 3, it is clear that the absorbance is very low, when the metal salts alone
are used for oxidation except Cu(CH3COO)2, which shows a remarkable catalytic
activity.
Oxidation of catechol in the presence of complexes formed with L1–L5
The results obtained for compound L1 show that the oxidation rate for CH3COO-
anion is much more important (55.7 nmol L-1 s-1) compared to other anions.
OH
O
OH
O
Cat
2H2O
2
2
O2
+
+
(MX2) / (L)
M: Cu, Fe and Zn
o-quinone
catechol
Scheme 2 Reaction model
123

Evaluation of catalytic activity
2461
Fig. 1 Oxidation of catechol in absence of catalyst
Fig. 2 Oxidation of catechol in the presence of ligands L1–L5
123

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R. Saddik et al.
Fig. 3 Oxidation of catechol in the presence of metal salts
The oxidation rates for compound L2 are low except CH3COO- anions, which
presents a high rate of 68.5 nmol L-1 s-1
The complex formed with CH3COO- and L3 shows a remarkable oxidation rate
.
2-
-
it is about (64.1 nmol L-1 s-1), whereas with SO4 and NO3 with the same
ligand shows average speeds (23.8 and 15.1 nmol L-1 s-1). These complexes with
ligand L4 and the tested metals have not shown remarkable speeds, the best is the
one with CH3COO- (26.4 nmol L-1 s-1). Regarding the complex of L5, the best
rate is by acetate (CH3COO-) with a value of 65.0 nmol L-1 s-1, very low speeds
shown in the case of other anions (Figs. 4, 5, 6, 7, 8).
The effect of the nature of the ligand on the kinetics of oxidation of catechol
to o-quinone
The purpose of present study is to compare the catalytic effect of complexes of
copper (II) formed by different ligands for the same anion. The following figure
shows the oxidation of catechol by complexes of the ligands and copper (II) acetate
(Figs. 9, 10, 11, 12, 13, 14).
We note that L2 has a higher catalytic effect, the ligands L1, L3, and L5 show a
remarkable effect and almost identical, against L4, which gives a small effect. The
labile bond between CH3COO- and the copper make this coordination very easy to
displace, so the substrate has no problem to coordinate with the metal because it can
easily replace the weakly bonded anion. It is found that the presence of an electron
withdrawing group (–C=O) (such as in L4) decreases the electron density on the
nitrogen (position 1) and does not allow it to co-ordinate well with the metal. In the
case of SO42-, L3 and L4 dominate (Fig. 10). For NO3-, L3 and L4 give a
123

Evaluation of catalytic activity
2463
Fig. 4 Oxidation of catechol in the presence of complexes formed with L1
Fig. 5 Oxidation of catechol in the presence of complexes formed with L2
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R. Saddik et al.
Fig. 6 Oxidation of catechol in the presence of complexes formed with L3
Fig. 7 Oxidation of catechol in the presence of complexes formed with L4
123

Evaluation of catalytic activity
2465
Fig. 8 Oxidation of catechol in the presence of complexes formed with L5
Fig. 9 Oxidation of catechol in the presence of copper II acetate
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R. Saddik et al.
2-
Fig. 10 Oxidation of catechol in the presence of SO4
-
Fig. 11 Oxidation of catechol in the presence of NO3
123

Evaluation of catalytic activity
2467
Fig. 12 Oxidation of catechol in the presence of CuCl2
Fig. 13 Oxidation of catechol in the presence of FeCl2
123

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R. Saddik et al.
Fig. 14 Oxidation of catechol in the presence of ZnCl2
dominant low absorbance (Fig. 11). In both cases, the absorbance remains low. This
is due to very strong links formed by these anions with copper. Chlorides do not
show remarkable activities (Figs. 12, 13, 14), only the chlorides of zinc and iron
revealed significant absorbance with L3, while those that bind chlorides strongly
with the metal does not exhibit catalytic activity with this type of ligands.
In summary, as observed in the IR spectrum figures, the presence of catechol and
the production of o-quinone caused significant changes in the IR spectrum with time
in the case of the combination of L2(Cu(CH3COO)2). Other testes are in progress to
understand exactly what is happening during this catalytic reaction. We tried to
evaluate the catalytic activity of complexes prepared in situ from the ligands
imidazo [1,2-a] pyridine, in the oxidation reaction of catechol to o-quinone by
oxygen. The studied complexes have catalytic capabilities, which vary with the
ligand and the anion. It is found that the presence of donor groups can enrich the
coordination properties of the ligand and promotes stability of the complex, whereas
the presence of an electron-withdrawing group is a disadvantage for complex
formation due to a decrease in electron density on the sites of coordination. The
anion used and its nature plays an important role in the catalytic efficiency of
complex anions that bind tightly to the metal cannot be easily displaced by the
substrate, thereby reducing the catalytic power. While the anions are less strongly
attached with the metal ion, the substrate cannot find any difficulty to coordinate
with the metal because it can easily replace the weakly bonded anions.
Consequently, the oxidation reaction of catechol is favored and significant oxidation
rates are observed.
123

Evaluation of catalytic activity
2469
Conclusions
While the preparation of these complexes in situ allowed us to easily vary the nature
of the ligands and anions, the results show that the complexes exhibit catalytic
activity for oxidation of catechol under very mild conditions at room temperature
(25 °C) using air oxygen as an oxidant. Spectrophotometric monitoring of
absorbance versus time shows that the different complexes catalyze the oxidation
reaction of catechol with different speeds. The anions that are weakly attached with
metal ion, the substrate finds no difficulty to coordinate with the metal because it
can easily replace the weakly linked anions as in the case of acetate, while the
anions that bind tightly to the metal cannot be easily moved by the substrate, thereby
reducing the catalytic ability. The presence of donor groups enriches the
coordination properties of the ligand and gives stability to the complex, whereas
the presence of an electron-withdrawing group is a disadvantage for complex
formation by decreasing the electron density on the sites of coordination (such as
in L4).
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