Synthesis, structural, catecholase, tyrosinase and DFT studies of pyrazoloquinoxaline derivatives

Article abstract of DOI:10.1016/j.molstruc.2017.03.052

Six functional multidentate ligands: 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl) quinoxaline, L¹, 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-nitroquinoxaline, L², 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylquinoxaline, L³, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydrazinyl-6-nitroquinoxaline L⁴, 2-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylquinoxaline, L⁵, 2-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl) quinoxaline, L⁶, and a new copper (II) complex, were prepared and evaluated for their catecholase activities at aerobic conditions. We found that, the reaction rate depends on: The nature of the substituents in the quinoxaline ring, counter anion, metal, concentration of ligand and the used solvent. The complex obtained in-situ from reaction of one equivalent of ligand L¹ and two equivalents of Cu(CH₃COO)₂ in methanol showed the highest oxidation rate activity (V?=?33.48?μmol?L^?1. min^?1). In addition, geometry optimizations of the complexes in order to get better insight into the geometry and the electronic structure and chemical reactivity were carried out by means of DFT calculations.

Full text of DOI:10.1016/j.molstruc.2017.03.052

Accepted Manuscript
Synthesis, structural, catecholase, tyrosinase and DFT studies of
Pyrazoloquinoxaline derivatives
Zohra Bouanane, Mahmoud Bounekhel, Meriem Elkolli, Farid Abrigach, Mohamed
Khoutoul, Rabab Bouyala, Rachid Touzani, Abdelkader Hellal
PII:
S0022-2860(17)30323-X
10.1016/j.molstruc.2017.03.052
MOLSTR 23548
DOI:
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Revised Date:
Accepted Date:
25 January 2017
11 March 2017
11 March 2017
Please cite this article as: Zohra Bouanane, Mahmoud Bounekhel, Meriem Elkolli, Farid Abrigach,
Mohamed Khoutoul, Rabab Bouyala, Rachid Touzani, Abdelkader Hellal, Synthesis, structural,
catecholase, tyrosinase and DFT studies of Pyrazoloquinoxaline derivatives, Journal of Molecular
Structure (2017), doi: 10.1016/j.molstruc.2017.03.052
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ACCEPTED MANUSCRIPT
Graphical Abstract
R1
1/2 O2
H2O
R1
OH
O
O
R2
OH
Catechol
R1= R2 = H
1
6
R2
M/ (L - L )
M: CuCl2, CoCl2, Cu(CH3COO)2, CuSO4, CuNO3
Ni(CH3COO)2, Cd(CH3COO)2,, Co(CH3COO)2,
CdCl2 and Mn(CH3COO)2).
o-quinone
90nm
00nm
3
4
R1= R2 = tBu
H3C
CH3
Me
N
Me
N N L4: R3=NO2, R2=H, R1=NHNH2
N
N N
L1: R=H
L2: R=NO2
L3: R=CH3
R2
R3
L5: R3=H, R2=CH3, R1=Cl
N
N
L6: R3=R2=H, R1=Cl
R
N
N
R1
H3C
CH3

ACCEPTED MANUSCRIPT
Highlights






Syntheses and characterization of pyrazoloquinoxaline
Catecholase and tyrozinaze oxidation reaction
All prepared in-situ complexes catalyze the oxidation reaction of catechol
Oxidation reaction rate depends on four parameters.
1
−1
−1
The highest rate activity is given by L [Cu(CH COO) ] V= 33.48 μmolL min
3
2
Use of DFT for electronic structure elucidations.

ACCEPTED MANUSCRIPT
Synthesis, structural, catecholase, tyrosinase and DFT studies of Pyrazoloquinoxaline
derivatives
a,*
a
a
b
c
Zohra Bouanane , Mahmoud Bounekhel , Meriem Elkolli , Farid Abrigach , Mohamed Khoutoul , Rabab
c
b,c
d
Bouyala , RachidTouzani , Abdelkader Hellal
aLaboratoire des matériaux polymériques multiphasiques « LMPMP », Département de génie des procédés, Faculté de
technologie, Université Ferhat Abbas, Sétif-19000, Algérie.
.
b
Laboratoire de Chimie Appliquée et Environnement, Département de Chimie, Faculté des Sciences, Université
Mohamed Premier, BP 524, 60 000 Oujda, Maroc.
Faculté Pluridisciplinaire de Nador, Université Mohamed Premier, BP300, Selouane 62700, Nador, Maroc.
c
d
Laboratoire d’Electrochimie des Matériaux Moléculaires et des Complexes « LEMMC », Département de génie des
procédés, Faculté de technologie, Université Ferhat Abbas, Sétif-19000, Algérie.
Corresponding authors: E-mail: syntorg@hotmail.fr (Z. Bouanane) or haekpharm @yahoo.fr (A. Hellal).
Abstract
1
Six functional multidentate ligands: 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl) quinoxaline, L ,
2
2
,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-nitroquinoxaline, L , 2,3-bis(3,5-dimethyl-1H-pyrazol-1-
3
4
yl)-6-methylquinoxaline, L , 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydrazinyl-6-nitroquinoxaline L ,
-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylquinoxaline, L , 2-chloro-3-(3,5-dimethyl-1H-
pyrazol-1-yl) quinoxaline, L , and a new copper (II) complex, were prepared and evaluated for
their catecholase activities at aerobic conditions. We found that, the reaction rate depends on: The
nature of the substituents in the quinoxaline ring, counter anion, metal, concentration of ligand and
5
2
6
1
the used solvent. The complex obtained in-situ from reaction of one equivalent of ligand L and two
equivalents of Cu(CH COO) in methanol showed the highest oxidation rate activity (V= 33.48
3
2
−
1
−1
μmol.L .min ). In addition, geometry optimizations of the complexes in order to get better insight
into the geometry and the electronic structure and chemical reactivity were carried out by means of
DFT calculations.
Keywords: Multidentate ligands, Pyrazoloquinoxaline, Copper, Tyrosinase, Catecholase, DFT,
HOMO, LUMO.
1
. Introduction
Copper plays an important role in biological systems, where it is mainly bound in
metalloenzymes. These enzymes are involved in many processes such us hydroxylation, oxygen
transport, electron transfer, and catalytic oxidation [1-8]. Recently, many works have been devoted
to the copper complexes based on pyrazole ligands to mimic the function of catecholase [9-14]. In
fact, the imidazole ring of histidine residues is one of the most common ligands at the active sites of
metalloproteins, which guided us to use pyrazole which have a similar structure of imidazole to
mimic the function of catecholase active site. The pyrazole based ligands present important results
−
1
−1
in terms of oxidation rate, which sometimes attains 28.99 μmol.L .min [15].
1
6
In this study, six ligands L -L , were reported and examined for their catecholase activities at
1
6
ambient conditions. The metallic complexes formed in-situ from L -L and different metal salts
MX : CuCl , Cu(CH COO) , CuSO , Cu(NO ) , Ni(CH COO) , Cd(CH COO) , CdCl ,
(
2
2
3
2
4
3 2
3
2
3
2
2
Co(CH COO) , CoCl and Mn(CH COO) show significant catalytic influence pathway on the
3
2
2
3
2
1

ACCEPTED MANUSCRIPT
oxidation of catechol and 3,5-DTBC to the corresponding o-quinones via formation of dinuclear
species. To more understand the parameters influencing the catalytic activity of the studied
complexes and to understand the key properties of solvents which have a controlling role in the
catecholase activity, the effect of ligand concentration, the nature of substrate, and the effect of the
solvent are studied. The reaction follows Michaelis–Menten [16], enzymatic reaction kinetics to
determinate the kinetic parameters.
In the present investigation, common DFT-based reactivity descriptors are consequently included
for their importance during the actual study. The DFT cover systems between a few tens up to a few
hundreds of atoms. It is often of wide-ranging applicability and reasonably accurate in many cases.
The 1998 noble prize in chemistry recognized the convergence of traditional quantum chemical
methodology and DFT [17]. In fact, DFT has enjoyed an enormous popularity in this field over the
past two decades and has found many users that range from hardcore theoretical chemists to
experimentalists who wish to employ DFT along side with their experimental studies. Parallel with
the impressive development of computational hardware the quantum chemical software that is
required to perform DFT calculations has progressed to a state where calculations can be performed
with high efficiency and in a user friendly manner [18-21].
In the present study, the structure and the ground state energy of the molecules under
investigation have been analyzed employing gas phase using DFT/B3LYP (C, H, N and
O)/LanL2DZ (Cu) level calculations. The optimized geometry and their properties such as
equilibrium energy, frontier orbital energy gap, have also been used to understand the activity of
these compounds. Density functional theory has been found to be successful in providing insights
into the chemical reactivity and stability, the analysis of the frontier molecular orbitals is a crucial
way to obtain information on reactivity of molecules and to study electron excitation from the
highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO).
2
. Experimental section
2
.1. Instruments
1
13
The H NMR and C NMR spectra were recorded on a Bruker 300 spectrometer. Chemical
shifts are listed in ppm and are reported relatively to TMS. The Infra-red spectra were taken using
KBr discs on Mattson Genisis FTIR. The mass spectra have been obtained on a SHIMADZU
1
Axima-CFR MALDI-TOF. L has spectral data in accordance with the literature data [22]. A new
complex CP was synthesized and characterized by means of IR and UV by Z. Bouanane and co-
1
workers [23].
2
2
.2. Synthesis
2
3
.2.1. General method for synthesis of ligands L and L :
Acetylacetone (15mL, 25 mmol) was added to a suspension of 2,3-hydrazinoquinoxaline
2
b-c (3 mmol, 6,88g) in 250 ml of ethanol . The mixture was stirred under reflux for 4 hours, the
solvent was removed and the compounds were purified by column chromatography with
hexane/ethyl acetate(7/3:v/v).
2
-
2
,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-nitro quinoxalines, L . Yield: 83%. FTIR (KBr, cm
1)
: 2978, 2892, 1599, 1393. H NMR (300MHz, CDCl , δ, ppm): 9.00 (s, H , 1H); 8.56 (dd,
1
3
5
2

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1
3
H ,1H); 8.24 (dd, H ,1H); 6.01(s, H-pz, 2H); 2.42(s, pz-CH , 6H); 2.15 (s, pz-CH , 6H). C NMR
7
8
3
3
(
75MHz, CDCl , δ, ppm) : 151.4-138.5 (C); 130.1-124.0(CH); 108.4-108.1(CH pz); 13.5 (CH );
3
-
3
1
2.0 (CH ); MALDI-TOF (ES) m/z (%) = 364.17 (80) ; 363.14 (70) ; 362.21 (100).
3
3
2
,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl quinoxalines, L . Yield: 85%. FTIR (KBr,
-1
1
cm ):2940, 2850, 1595, 1384. H NMR (300MHz, DMSO, δ , ppm) :8.58 (dd, H , 1H); 8.25 (s,
8
H ,1H); 8.15 (dd, H ,1H); 6.09(s, H-pz, 2H); 2.53 (Aromatique-CH ); 2.42(s, pz-CH , 6H); 2.15 (s,
5
7
3
3
1
3
pz-CH , 6H). C NMR (75MHz, DMSO, δ, ppm): 149.9-138.0 (C); 130.2-124.3(CH); 108.0-107.8
3
(CH pz); 20.6 (Aromatique-CH ); 13.2 (CH ); 11.6 (CH ); MALDI-TOF (ES) m/z (%) = 334.24
- 3 3 3
(
35) ; 333.24(100) ; 332.22 (25) ; 331.23 (90).
.2.2.General method for synthesis of ligands, L -L :
Acetylacetone (0.11mL, 1.1mmol) was added to a suspension of 2-chloro-3-
4
6
2
hydrazinoquinoxaline 2b-c (0.27 g, 1 mmol) in 50 ml of ethanol . The mixture was stirred under
reflux for 18 hours, the solvent was removed and the compounds were purified by column
chromatography with hexane/ethyl acetate(7/3:v/v).
4
2
-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydrazinyl-6-nitroquinoxaline, L . Yield: 78%.FTIR
-1
1
(
KBr, cm ): 3448, 3281, 1629, 1552, 1487, 817. H NMR (300MHz, DMSO, δ , ppm) :8.91 (d, H ,
8
1
H); 8.50 (dd, H ,1H); 8.02 (d, H ,1H); 6.18(s, H-pz, 2H); 4.24 (hydrazine-NHNH ); 2.43(s, pz-
6 5 2
1
3
CH , 3H); 2.36 (s, pz-CH , 3H). C NMR (75MHz, DMSO, δ, ppm) : 149.9-138.0 (C); 130.2-
3
3
1
24.3(CH); 108.0-107.8 (CH pz); 20.6 (Aromatique-CH ); 13.2 (CH ); 11.6 (CH ); MALDI-TOF
- 3 3 3
(ES) m/z (%) = 334.24 (35) ; 333.24(100) ; 332.22 (25) ; 331.23 (90).
5
3
-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylquinoxaline, L , Yield: 92%.FTIR
-1
1
(
KBr, cm ): 2766, 1630, 802. H NMR (300MHz, DMSO, δ , ppm) :8.17-8.01 (m, H , H , 2H);
8 5
7
.87-7.78 (m, H , H ,2H); 8.15 (dd, H ,1H); 6.08(s, H-pz, 1H); 2.34 (Aromatique-CH ); 2.34(s, pz-
6 7 7 3
1
3
CH , 3H); 2.32 (s, pz-CH , 3H). C NMR (75MHz, DMSO, δ, ppm) : 149.9-138.0 (C); 130.2-
3
3
1
24.3(CH); 108.0-107.8 (CH pz); 20.6 (Aromatique-CH ); 13.2 (CH ); 11.6 (CH ).
- 3 3 3
6
-1
2
-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl)quinoxaline, L ,Yield: 89%.FTIR (KBr, cm ):
1
3
8
3
2
039, 2915, 1635, 770. H NMR (300MHz, DMSO, δ , ppm) :7.98 (d, H , 1H); 8.25 (s, H ,1H);
5
8
.15 (dd, H,1H); 6.10(s, H-pz, 2H); 2.60 (Aromatique-CH ); 2.35(s, pz-CH , 3H); 2.31 (s, pz-CH ,
3
3
3
H). 13C NMR (75MHz, DMSO, δ, ppm) : 150.9-139.8 (C); 142.0-127.7(CH); 107.5 (CH pz);
-
1.9(Aromatique-CH ); 13.7 (CH ); 11.7 (CH ).
3
3
3
2
.3.Catecholase Activity Measurements
Kinetic measurements were made spectrophotometrically on UV-Visible spectrophotometer
In the COSTE: Centre de l’Oriental des Sciences et Technologies de l’Eau), following the
(
-1
-1
appearance of o-quinone over time at 25°C (390 nm absorbance maximum, ε = 1600 M .cm in
methanol,ε = 1900 M .cm in THF and ε = 1600 M .cm in acetonitrile). The metal complex
solution (prepared in-situ: 1 mL of a 2.10 M ligand and metal salt solution) and a solution of
catechol (2 mL of a 10 M solution) were mixed in the spectrophotometric cell.
-1
-1
-1
-1
-3
-1
2
.4 Computational details
All calculations were performed using the GAUSSIAN 09 program package [24] with the
aid of the GaussView visualization program [25]. The ground state geometries of CP and CP2
1
3

ACCEPTED MANUSCRIPT
were fully optimized using the hybrid B3LYP functional methods [26-27] in combination with the
6
-31G (d) basis set for C, H, N and O, while for Cu, the LanL2DZ basis set with effective core
potential were used [28].
3
. Results and discussion
3
.1. Synthesis
1
6
The pyrazolyl derivatives, L -L , were prepared respectively by a three-step process
involving the synthesis of chloroquinoxaline 1a-c [29] and hydrazinoquinoxaline derivatives 2a-e
30]. Followed by a condensation of 2,4-pentanedione with hydrazinoquinoxaline derivatives in
[
1
13
anhydrous solvents (Scheme 1). All compounds were characterized by means of IR, H-NMR, C-
NMR and mass spectrometry techniques.
3
4
The new ligands L and L were obtained with good yield (85-90%). The absence of bands
-1
between 3200 and 3400 cm in IR spectra, demonstrated that the pyrazole compounds is formed.
The proton NMR spectra of the pyrazolic ligands revealed signals at 6.09-5.96 ppm corresponding
to the pyrazolic protons (-CH-pz). The influence of different R groups is visible on the chemical
1
shift in H NMR of the aromatic protons of quinoxaline.
The Complex CP was characterized by MALDI-TOF mass technique. The value M (m/z) =
1
5
17.16 on the Fig.1 corresponding to the mass of CP1 plus a molecule of water.
.2. Catalytic activity studies
3
The progress of the catechol oxidation reaction is conveniently followed monitoring the
strong absorbance peak of o-quinone in the UV/Vis spectrophotometer (Scheme 2). The metal
complex (prepared in situ from metal salt and the ligand) [31] and a solution of catechol were added
together in the spectrophotometric cell at 25°C. Formation of o-quinone was monitored by the
increase in absorbance at 390 and 400 nm as a function of time. In all cases, catecholase activity
was noted.
3
.2.1. Effect of ligand concentration on the catecholase activity
To understand the effect of ligand concentration to form the catalyst of the oxidation
reaction of catechol to o-quinone, we realized this reaction using different concentration of ligand
and metal ion (L/M: 1/1; 2/1; 1/2), after monitoring the absorbance of o-quinone for each proportion
(Fig. 2). The results obtained showed a change in absorbance at 390 nm as a function of time during
the first hour of the reaction, which can explains the combinations used as catalyst, catalyze the
reaction well studied, and it is clear that there to differences in the absorbance values for each
combination, according to these values, the combination formed by 2 mole of metal and one mole
ligand appears the best catalytic condition for this reaction. After comparison of results showed in
Tables 1, it appears that there is a difference in obtaining values of the oxidation rate; this difference
may be related to the effect of the ligand concentration, which can be explained by the nature of
coordination environment. Based on the information which confirms that the active site of the
enzyme catecholase contains two Cu (II) ions [32], so, our complexes must contain two cupric ions
Cu(II) to do its catalytic function, so we can propose that one molecule of ligand can participate in
coordination of two ions Cu(II).
3
.2.2. Effect of the nature of ligand
4

ACCEPTED MANUSCRIPT
The nature of the ligand particularly the electronic effect of substituent group could modify
2
3
coordination. The presence of donor and acceptor substituents in L and L , explain that the
complex with these ligands has the lowest value of catalytic activity. If we examine well the
1
6
structures of all ligands L –L and the obtained results (Fig.3) of catecholase activities of this
variety of complexes, we notice that the substituents on the pyrazole rings have a strong effect on
the oxidation reaction. As can be seen from Table 1, all of the complexes catalyze the oxidation
-1
-1
reaction of catechol to o-quinone with the rate varying from a higher one of 33.48 μmol.L .min
1
-1
-1
for the L [Cu(CH COO) ] complex to a weaker rate of 8.36 μmol.L .min
for
3
2
1
L [Cu(CH COO) ] complex. The catalytic activities depend strongly on both the form of the
3
2
ligand chains and the concentration of the metallic salt. The order of reactivity for the oxidation of
1
2
3
4
5
6
catechol by Cu (CH COO) complexes is L >L >L > L >L >L .
3
2
3
.2.3. Effect of the nature of the metal and the anion
The oxidation rate depends strongly on both the ligand and the type of metals. The nature of
the metals affects the geometry of the complex. This factor can contribute to the explanation of the
oxidation rate dependence in the oxidization of catechol in o-quinone.
In the case of Cl and NO3- anions (Fig. 4), the complex of the ligand L with metals Co(II)
-
1
-1
-1
and Cu(II) give an oxidation rate between 1.02 and 1.10 µmol.L .min which is higher than the
complexes with ligand containing nitro L and methyl L (Table 2),.We notice that most ligands
2
3
have low absorbance with all the anions except the case of the metals salt of Cu(II), Co (II) and
-1
-1
Mn(II), the oxidation rates vary from the highest value of 33.48 μmol.L .min for
1
-1
-1
3
4
6
L [Cu(CH COO) ] to the weaker value of 0.03 μmol.L .min forL , L and L [Cd(CH COO) ].
3
2
3
2
On other hand, the effect of the nature of the counter anion on the catalytic activity has been noted
Table 2), this allowed us to observe that the counter anion participates in the coordination
(
environment and its nature influences well the catalytic activity. 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 strongly
to the metal cannot be easily moved by the substrate, thereby reducing the catalytic ability.
3
.2.4. Effect of substrate
A study by the catecholase activity was performed using 3,5-di-tert-butyl catechol (3,5-
DTBC). The absorbance was continually monitored at =400 nm, in the presence of combinations
1
6
L -L / Cu(CH COO) (1L/2M) in methanol, the obtained results are in Fig.5. Lowest value of
3
2
catalytic activity was found. It appears to be much more difficult to oxidize 3,5-DTBC, owing to the
presence of bulky tertiary butyl substituents. The in situ complexes catalyze the oxidation reaction
-1
-1
of 3,5-DTBC to 3,5-DTBQ with the rate varying from a high of 20.56 μmol. L .min for the
1
-1
-1
2
L [Cu(CH COO) ] complex, 18.75 μmol L min for the L [Cu(CH COO) ] complex, 15.96
3
2
3
2
-1
-1
3
-1
-1
5
μmol.L .min for L [Cu(CH COO) ] complex, 12.77μmol.L .min for the L [Cu(CH COO) ]
3
2
3
2
-1
-1
4
-1
-1
complex, 7.29μmol.L .min for the L [Cu(CH COO) ] and rate of 5.34μmol.L .min
for
3
2
6
L [Cu(CH COO) ] complex.
3
2
3
.2.5. Effect of solvent
To understand better the effect of solvent on the catalysis of oxidation reaction of catechol,
we carried out the same experiments under same thermodynamic conditions, but by using the
5

ACCEPTED MANUSCRIPT
acetonitrile and THF as solvent, the absorbance of o-quinone are shown in Fig.6. The calculation of
1
6
catechol oxidation rate in the presence of the copper complexes with ligands L –L in the
acetonitrile and THF, led to results gathered in Table 3. From results obtained by the spectrometer
UV–vis and from reaction rates, we observed that the nature of used solvent has an important effect
on the catalytic activities of the studied complexes. Methanol, protic and polar solvent, appears a
better solvent than acetonitrile which is aprotic and polar solvent. If we consider that the commonly
known physical parameters of solvents like dielectric constant, dipole moment, polarity, etc., have
no significant role in changing the activity of the complexes toward the oxidation of catechol, it
should be the coordination power or protic nature of the solvents that play the key role in changing
the activity of the complexes [33].
3
.3. Kinetic study
The reaction kinetics was studied by observing the time dependent change in absorbance at a
1
1
-
wavelength of 390 nm for catalysis in MeOH with ligand L , concentration of L was fixed in 10
3
mol/L. 0.04 ml of the ligand solution, with a constant concentration of 1 M,was added to 2 ml of
catechol of a particular concentration (concentration varying from 1.10 M to 1.10 M) to achieve
the ultimate concentration of the ligand as 10 M. The conversion of catechol to o-quinone was
monitored with time at a wavelength of 390 nm. The rate versus concentration of substrate data
were analyzed on the basis of Michaelis–Menten approach of enzymatic kinetics to get the
Lineweaver–Burk (double reciprocal) plot as well as the values of the various kinetic parameters
-3
-2
-2
-1
-1
-1
(
Vmax=8.95 µmol.L min , K =0.0098 mol.L ).
M
1
The spectra of ligand L in methanol solution show dramatic changes immediately after
1
addition of o-quinone. Fig.8 shows the variation of the spectral behaviour for L as representative of
it followed up for 2 h. From the figure, it is clear that the bands at 268 and 355 nm vanishes
immediately after addition of catechol, and three new bands are developed at 400, 500 and 680 nm.
Also the d-d bands are retained even after 2 h of reaction, indicating the presence of Cu(II) species.
3
.3.1. Catecholase mechanism
The mechanism for the enzymatic reaction is primarily based on an earlier proposal derived
from spectroscopy and theoretical studies [34] and a recent series of crystal structures of the various
intermediates of the catechol oxidase [35]. Two catechol molecules are oxidized per cycle and
dioxygen is reduced to water.
In the first stage of the reaction, the dicopper (II) complex 1 reacts with dioxygen to form
II
2–
II
the oxy form (Cu –O –Cu ) species 2. This species oxidizes one equivalent of catechol in
2
stoichiometric reaction through a two-electron transfer from the catechol to the peroxide moiety.
II
II
After the quinone molecule is released, the complex 4 (Cu -OH-Cu , met) is generated, and the
catalytic cycle can continue, as shown in Scheme 3. Two equivalents of quinone are thus generated
per one catalytic cycle. This mechanism is in fact very similar to the mechanisms earlier proposed
by Wagner and coll. [36] and Rolff and coll.[37] for dinuclear Cu(II) complexes, and by Krebs and
co-workers for catechol oxidase [38,39]. Although the binding mode of the substrate to the dicopper
centers unfortunately remains unclear.
3
.3.2. UV–vis spectrophotometric study for catechol oxidase activity of the complex
6

ACCEPTED MANUSCRIPT
The catecholase activity of complex CP was studied in methanol–DMF (50:1, v/v). Fig.9
1
shows the change of spectral behavior of complex immediately after the addition of a solution of
catechol to the complex solutions the original bands vanish.
In MeOH, o-quinone shows maximum absorption at 390 nm (Fig.9). o-quinone obtained
was purified by column chromatography with yields 65.5%. This was characterized by determining
its melting point (75-80°C) which agreed well with that reported in literature [40].
3
.4. Oxidation of phenol: tyrosinase activities
1
The oxidation of phenol was realized by adding successively 0.334 mL of the ligand L
−
3
−3
−1
(
2×10 M) and 0.668 mL of metallic salt Cu(CH COO) (2×10 M) in 2 mL of phenol (10 M),
3 2
the spectrum of evolution of orthoquinone absorbance was registered according to time every 20
1
6
min. We have found that all ligand L –L have no tyrosinase activity.
3
.4. Theoretical calculations
To investigate the structure geometries, we performed full geometry optimization of CP1
and CP in the gas phase using DFT/B3LYP (C, H, N and O)/LanL2DZ (Cu) level calculations.
2
Additionally to the geometry optimization, density functional theory has been found to be
successful in providing insights into the chemical reactivity and stability, the analysis of the frontier
molecular orbitals is a crucial way to obtain information on reactivity of molecules and to study
electron excitation from the highest occupied molecular orbital (HOMO) to the lowest unoccupied
molecular orbital (LUMO). The LUMO represents the ability of the molecule to capture an electron
while the HOMO represents the ability to donate an electron.
The optimized structure (Fig.10) of CP display a coordination site of seven atoms that is
1
2
formed by the two pyrazolic rings, the distance between sp Nitrogen and Copper (N-Cu) are 1.96
Å, the two bonds (N-Cu) constitutes an angle of 102.65° (N-Cu-N) with Copper. For CP the
2
2
coordinated coppers are in small cavities (five atoms) formed by sp Nitrogen of pyrazole and
quinoxalin rings. The angles N-Cu-N were equal to 82.43° and the bond length N-Cu varies
from1.93 Å to 1.99 Å.
In CP , the occupied orbitals are mainly localized on the acetate fragment and the copper, while
1
the unoccupied orbitals have their major contribution from the ligand. These results suggest that the
transition involve charge transfer from the metal to ligand (MLCT). From MOs of CP it seems that
2
there is a metal-metal charge transfer (MMCT) (Fig.11).
By using HOMO and LUMO energy values for a molecule, the global chemical reactivity
descriptors of molecules such as hardness (η), softness (S),) can be measured by using Koopman’s
theorem for closed-shell molecules.
A molecule having high ionization potential (I) or electron affinity (A) loses or admits electron
hardly [41,42]. By Koopmans’ approximation [43.44], the ionization potential and electron affinity
of any molecule can be calculated using the relations,
I = -EHOMO
A = -ELUMO
(1)
(2)
Koopmans` theorem for closed-shell molecules [44] results in the hardness of the molecule;
η= (I-A)/2 (3)
7

ACCEPTED MANUSCRIPT
The softness of the molecule;
S= 1/2η (4)
The hardness of a molecule is a qualitative indication of how polarizable it is, that is how much
its electron cloud is distorted in an electric field. In this sense the terms hard, and its opposite soft,
were evidently suggested by D.H. Busch [45] by analogy with the conventional use of these words
to denote resistance to deformation by mechanical force. Absolute hardness, η, and softness, , are
important properties to measure the molecular stability and reactivity. A hard molecule has a large
energy gap and a soft molecule has a small energy gap. Soft molecules are more reactive than hard
ones because they could easily offer electrons to an acceptor.
Using the above relations we find the electro molecular characteristics for CP1 and CP2 has
been presented in Table 4.
Table 4 shows that CP2 has lower energy gap (0.404 a.u). Lower hardness (0.202a.u), the higher
softness (2.4752 a.u). The CP1 has the higher energy gap (2.514a.u), higher hardness (1.257a.u),
and a lower softness (0.3977a.u). A small energy gap are generally associated with a high chemical
reactivity, low kinetic stability and are also considered as soft entities, while those with large energy
gap have higher stability and are termed as hard molecules because they oppose charge transfer and
changes in their electron density and distribution. The results indicate that compound CP , with
2
smaller LUMO/HOMO gap, is softer, less stable and more reactive than CP The ionization
1
.
potential (I) of CP1 and CP2 molecules are 5.703a.u and 5.863a.u respectively. The electron
affinity (A) for both molecules is 3.189 a.u and 5.459a.u for CP1 and CP2, respectively, which
clearly indicates that the CP are very stable than CP
1
2.
4
. Conclusion
Six ligands and a new complex were synthesized, which show efficacity in the oxidation rate
1
of catechol in aerobic conditions. According to the obtained result ligand L exhibits a high rate of
−
1
−1
oxidation reaching to 33.48 μmol.L .min . At the same time, weak bonds of anions-metals
favorite the reaction of oxidation as in the case of copper acetate. The presence of an electron-
withdrawing group enrich the coordination properties of the ligands and gives stability to the
complex, whereas the presence of donor group is a disadvantage for complex formation by
3
decreasing the electron density on the sites of coordination (such as in L ). The study of various
metals salts shows that the catalytic activities are most controlled by the nature of metal too. From
the theoretical calculations, CP is more stable than CP and the charge transfer is from metal to
1
2
ligand (CP ) and metal-metal charge transfer for CP (MMCT).
1
2
References
[
[
[
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(1963).
1
0

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Figures and Schemes captions
Data: 15september\pk_JL_C2_nomat_ref_pos0001.3F2[c] 11 Sep 2015 16:25 Cal: 3 PEP MIX 11 Sep 2015 14:54
Shimadzu Biotech Axima CFR 2.8.3.20080616: Mode reflectron, Power: 134, P.Ext. @ 1200 (bin 108)
%Int.
1725 mV[sum= 208682 mV] Profiles 1-121 Unsmoothed
509.11
1
00
5
10.01
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
3
8.95
5
18.16
5
17.07
2
23.04
3
51.02
5
99.89
388.88
272.92
71.94
2
2.98
2
425.89
89.41
132.84
3
6
00.89
71.02
0
0
657.74
917.32
1058.89
1000
1239.06
1200
1381.92
1400
1
[c]
2
00
400
600
800
m/z
Fig.1. MALDI-TOF mass spectrum of CP1.

ACCEPTED MANUSCRIPT
1
1
1
2
L / 1 Cu(CH COO)
3
2
2
2
3,0
2,5
2,0
1,5
1,0
0,5
0,0
1
L / 2 Cu(CH COO)
3
1
L / 1 Cu(CH COO)
3
0
10
20
30
40
50
60
Time(min)
Fig.2. Oxidation of catechol by complexes of ligand L1.

ACCEPTED MANUSCRIPT
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
1
L / Cu(CH COO)
3
2
2
2
2
2
2
2
L / Cu(CH COO)
3
3
L / Cu(CH COO)
3
4
L / Cu(CH COO)
3
5
L / Cu(CH COO)
3
6
L / Cu(CH COO)
3
0
10
20
30
40
50
60
Time(min)
1
6
Fig.3. Oxidation of catechol by complexes of ligand L -L (1 equiv L / 2 equiv M).

ACCEPTED MANUSCRIPT
3,0
2,5
2,0
1,5
1,0
0,5
0,0
Cu(CH COO)2
3
Co(CH COO)2
3
Cu(NO3)2
Zn(CH COO)2
3
Cd(CH COO)2
3
CuSO4
3
Ni(CH COO)2
Mn(CH COO)2
3
CuCl2
CoCl2
0
10
20
30
40
50
60
Time(min)
1
Fig.4. Oxidation of catechol by complexes of ligand L (1 equiv L /2 equiv M).

ACCEPTED MANUSCRIPT
3
2
2
1
1
0
0
,0
,5
,0
,5
,0
,5
,0
1
L
2
L
3
L
4
L
5
L
6
L
0
10
20
30
40
50
60
Time ( min )
1
6
Fig.5. 3,5-DTBQ oxidation in presence of ligand L -L (1equiv L/2 equiv Cu(CH COO) ).
3
2

ACCEPTED MANUSCRIPT
Acetonitril
DMF
Methanol
3,0
2,5
2,0
1,5
1,0
0,5
0,0
0
10
20
30
40
50
60
Time(min)
1
Fig.6. Catechol oxidation in presence of L / Cu(CH COO) (1 equiv L /2 equiv M) in
3
2
different solvents.

ACCEPTED MANUSCRIPT
Vi
1
0
8
6
4
2
0
0
2
4
6
8
10
2
[
L1]. (10 (M/L))
Fig.7. Dependence of the reaction rates on the catechol concentrations for the oxidation
1
reaction from one equivalent of L and two equivalents of Cu(CH COO) (in methanol).
3
2

ACCEPTED MANUSCRIPT
Fig.8. (a) The variation of the spectral behavior after addition of catechol (1:100) to methanol
1
solution of ligand L followed up for 2 h. The spectra are recorded every 20 min. (b) final
1
spectrum of solution after 24 h. (c) spectrum of ligand L in methanol.

ACCEPTED MANUSCRIPT
Fig.9. (a) Variation of the spectral behaviour after addition of catechol (1:100) to methanol-
DMF (50/1, v/v) solution of complex CP followed up for 2 h. The spectra are recorded every
1
2
0 min.

ACCEPTED MANUSCRIPT
Fig.10. Optimized geometries of CP and CP .
1
2

ACCEPTED MANUSCRIPT
Fig.11. Orbitals frontiers of CP and CP .
1
2

ACCEPTED MANUSCRIPT
Cl
N
OH
OH
N
NHNH2
N
N
NH NH
2
SOCl 3h
2
2
,
N
EtOH, 78°C, 3h
N
DMF/ dioxane R
Cl
1a: R=H
R
Cl
R
a: R=H
2d: R=H
2
b: R=NO2
c: R=CH3
1b: R=NO2
1c: R=CH3
2e: R=CH3
H
N
C
2
CH3
°
H
8
N
O
7
,
H
O
O
t
NHNH2
CH3
E
N
N
O
O
CH3
H C
CH3
3
R
NHNH2
H C
h
8
R
N
N N
Cl
3
1
,
C
°
8
7
2a: R=H
2b: R=NO2
c: R=CH3
,
H
tO
E
N
2
6
H C
CH3
L : R=H
3
5
N
N N
L : R=CH
h
3
O
CH3
4
,
C
°
N
NHNH2
O
8
O N
7
2
,
4
H
O
L : R=NO2
H C
3
t
E
H C
3
CH3
H C
CH3
3
N
N
N N OCOCH3
Cu
,H2O
N
N N
N N
Cu(CH COO) .H O
OCOCH3
N N
3
2
2
N
CH3
R
MeOH
H C
3
Complex CP1
H C
CH3
3
1
L : R=H
2
L : R=NO2
3
L : R=CH3
1
2
3
4
5
6
Scheme 1. Reaction pathway for L , L , L , L , L and L .

ACCEPTED MANUSCRIPT
R1
1/ O
2
2
H O
2
R1
OH
OH
O
O
R2
R2
1
6
M/ (L - L )
M: CuCl2, CoCl , Cu(CH COO) , CuSO , CuNO
3
Catechol
R = R = H
R = R = tBu
2
3
2
4
o-quinone
Ni(CH COO) , Cd(CH COO) , Co(CH COO)
CdCl2 and Mn(CH COO) ).
3
2
3
2,
3
2,
1
2
390nm
400nm
3
2
1
2
H C
CH3
L1: R=H
L2: R=NO
L3: R=CH
3
Me
N
Me
4
N
N N
L : R =NO , R =H, R =NHNH
R2
R3
N N
R1
3
2
2
1
2
5
L : R =H, R =CH , R =Cl
3 2 3 1
2
N
6
R
N
N
L : R =R =H, R =Cl
N
3
2
1
3
H C
CH3
3
Scheme 2. Oxidation of catechol to o-quinone.

ACCEPTED MANUSCRIPT
CH3
(
H COOC) Cu
N
N
CH3
3
2
N
N
N
N
N
=
N
N
CH3
2
CH3
Equiv of Cu(COOCH3)2
N
N
Cu
(COOCH3)
N
N
CH(H COOC) Cu
3
3 2
N
(H COOC) Cu
CH3
3
2
N
N
1
CH
3
in-situ f ormed complex(CP )
2
1
Equiv L CH3
OH
OH
N
N N
CH COO-
N
N
N
2
N
3
N
(
H COOC)Cu
Cu(COOCH3)
3
(H COOC) Cu
Cu(COOCH3)2
O
3
2
O
H
5
O O
4
O
+
H O
2
O
O
2
CH COOH
2
H
CH COO
3
3
O
+
H O
2
N
N
N
N
N
Cu
N
(
H COOC) Cu
N
N
3
2
(COOCH3)2
O
O
1
(H COOC)Cu
Cu(COOCH3)
3
O2
O O
3
2
CH COOH
3
-
2
CH COO
3
N
N
N
N
OH
OH
O
(
H COOC)Cu
Cu(COOCH3)
II
3
O
2
II
1
Scheme 3. Proposed mechanism for the catechol oxidation using L / Cu(CH COO) system.
3
2

ACCEPTED MANUSCRIPT
Table captions
Table 1.
-1
-1
1
6
Oxidation rates (μmol.L .min ) of catechol in presence of Ligand L -L with Cu(CH OO) in MeOH.
3
2
Ligand / metallic salt 1equiv / 1 equiv 1 equiv / 2 equiv 2 equiv/ 1 equiv
L1
L2
L3
L4
L5
L6
20.04
25.08
23.15
18.35
17.98
12.41
33.48
31.95
26.58
24.08
20.16
17.02
8.36
15.83
18,31
10.79
12.75
18.07

ACCEPTED MANUSCRIPT
Table 2.
Oxidation rates (μmol. L . min ) of catechol.
-1
-1
L/M Cu(OAc)
2
Cu(NO
0.09
3
)
2
CuSO
2.45
6.08
2.14
2.22
0.53
2.21
4
Co(OAc)
6.92
2
Mn(OAc)
2
Cd(OAc)
0.04
2
Ni(OAc)
2
CoCl
1.02
0.06
0.30
0.04
0.04
0.06
2
CuCl
1.10
0.11
0.06
0.10
0.17
0.04
2
L1
L2
L3
L4
L5
L6
33.48
31.95
26.58
24.08
20.16
17.02
2.62
1.90
0.06
5.92
1.92
0.36
1.49
0.50
6.89
2.38
0.03
1.61
0.68
7.10
2.29
0.03
1.66
0.29
8.42
3.18
0.13
2.23
0.08
6.97
2.39
0.03
1.83

ACCEPTED MANUSCRIPT
Table 3.
Oxidation rates (μmol.L .min ) of catechol in presence of Ligand L -L with Cu(CH COO) (1 equiv L
-1
-1
1
6
3
2
/
2 equiv M) in different solvents.
Ligand / metallic salt DMF methanol Acetonitrile
L1
L2
L3
L4
L5
L6
1.38
33.48
31.95
26.58
18.53
17.98
17.02
3.65
1.04
1.53
0.36
0.94
-
-
-
-
-
-