Catalytic and biological valorization of a supramolecular mononuclear copper complex based 4-aminopyridine

Article abstract of DOI:10.1002/aoc.4793

Hydrothermal reaction of copper bromide with 4-aminopyridine in DMF solution yields a new mononuclear copper complex [Cu(C₅H₆N₂)₄]2Br.2(C₃H₇NO) abbreviated Cu-4AP-Br. The product was characterized, structurally, by single-crystal X-ray diffraction analysis and, thermally, by DSC-ATG measurement. The inorganic–organic hybrid compound Cu-4AP-Br crystallizes in the centrosymmetric space group Pbcn, exhibiting a supramolecular network. Simultaneous DSC-ATG analysis shows that this compound remains stable up to 100?°C and then performs a successive decompositions accompanied with endothermic peaks. The complex Cu-4AP-Br was applied as a catalyst in the Heck coupling reaction under ultrasonic irradiation in various reaction conditions. The yields, obtained for a short period of time, allow us to consider this complex, generating selectivity on the external position of styrene with a preference of the trans form over cis, as an excellent catalyst for this type of reaction. Interestingly, Cu-4AP-Br displayed important antibacterial (Gram-positive and Gram-negative) and antioxidant activities (β-carotene bleaching inhibition, scavenging effect on DPPH free radical, and reducing power).

Full text of DOI:10.1002/aoc.4793

Received: 19 July 2018
DOI: 10.1002/aoc.4793
Revised: 17 December 2018
Accepted: 17 December 2018
F U L L P A P E R
Catalytic and biological valorization of a supramolecular
mononuclear copper complex based 4‐aminopyridine
1
2
3
4
2
Nabil Hfidhi | Intidhar bkhairia | Dhieb Atoui | Jaursup Boonmak | Moncef Nasri |
3
4
1
Ridha Ben Salem | Sujittra Youngme | Houcine Naïli
1
Laboratoire Physico‐chimie de l'Etat
Hydrothermal reaction of copper bromide with 4‐aminopyridine in DMF solu-
Solide, Département de Chimie, Faculté
des Sciences de Sfax, Université de Sfax, B.
P. 1171, 3000 Sfax, Tunisia
tion yields a new mononuclear copper complex [Cu(C H N ) ]2Br.2(C H NO)
5
6
2 4
3
7
abbreviated Cu‐4AP‐Br. The product was characterized, structurally, by
single‐crystal X‐ray diffraction analysis and, thermally, by DSC‐ATG measure-
ment. The inorganic–organic hybrid compound Cu‐4AP‐Br crystallizes in the
centrosymmetric space group Pbcn, exhibiting a supramolecular network.
Simultaneous DSC‐ATG analysis shows that this compound remains stable
up to 100 °C and then performs a successive decompositions accompanied
with endothermic peaks. The complex Cu‐4AP‐Br was applied as a catalyst
in the Heck coupling reaction under ultrasonic irradiation in various reaction
conditions. The yields, obtained for a short period of time, allow us to
consider this complex, generating selectivity on the external position of
styrene with a preference of the trans form over cis, as an excellent catalyst
for this type of reaction. Interestingly, Cu‐4AP‐Br displayed important
antibacterial (Gram‐positive and Gram‐negative) and antioxidant activities
2
Laboratory of Enzyme Engineering and
Microbiology, University of Sfax, National
School of Engineering of Sfax (ENIS),
Tunisia
3
Organic Chemistry Laboratory (LR17/
ES08), University of Sfax, Faculty of
Sciences of Sfax, Tunisia
4
Materials Chemistry Research Center,
Department of Chemistry and Center of
Excellence for Innovation in Chemistry,
Faculty of Science, Khon Kaen University,
Khon Kaen 40002, Thailand
Correspondence
Houcine Naïli, Laboratoire Physico‐
chimie de l'Etat Solide, Département de
Chimie, Faculté des Sciences de Sfax, B.P.
(
β‐carotene bleaching inhibition, scavenging effect on DPPH free radical,
1
171, 3000 Sfax, Université de Sfax,
and reducing power).
Tunisia.
Email: houcine_naili@yahoo.com
KEYWORDS
biological activities, crystal structure, heck coupling reaction, supramolecular, ultrasound
1
| INTRODUCTION
supramolecular materials are depending on both the
nature of the inorganic centre (geometry, electronic con-
Transition metal complexes with a pyridine derivative
ligand, as supramolecular hybrid inorganic–organic
materials, have been gaining momentum owing to their
enormous structural varieties and the accompanying
multitude of potential applications in various fields,
including catalysis, photochemistry, magnetism and
figuration, reactivity, coordination number, etc.) and the
structure of the organic molecule (shape, number and
type of reactive functional groups). The development of
new solid‐state structures, which involve the self‐
assembly of molecules into well‐defined supramolecular
via noncovalent, multiple intermolecular interactions,
showed the diversity of such materials in terms of struc-
[1–5]
biotechnology.
Their impressive compositional
[
6–10]
diversities and versatile applications have extensively
driven continuous interest in designing and making
novel transition metals complexes‐based functional
materials. It is now well established that the structure,
the dimensionality and the properties of these
ture, topology and composition.
The bonding in
these materials is just as diverse as their structures, with
covalent, ionic, and coordination bonds, hydrogen bond-
ing, van‐der Waals (vdW) forces, and π···π stacking,
being observed in a single compound. On the other
Appl Organometal Chem. 2019;e4793.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
1 of 14
https://doi.org/10.1002/aoc.4793

2
of 14
HFIDHI ET AL.
hand, copper (II) is a typical transition metal ion charac-
terized by its ability to form a wide range of coordina-
tion complexes, incorporating octahedral, tetrahedral
and square‐coplanar along with many kinds of irregular
coordination geometries and, thus offering a good
structure diversity. The geometry of the coordination
polyhedron around copper (II) is also influenced by
several subtle ligand factors, such as ligand constraints
and steric hindrance.
improving the evolution and the selectivity of the
chemical reaction.
2
| MATERIALS AND METHODS
.1 | Materials
2
All the solvents and chemicals were of reagent grade
quality. They were purchased from commercial sources
and used as received.
A large number of these complexes were applied as
catalysts that allow to synthesize new target molecules
such as natural products and pharmaceutical compounds.
Some current studies focus on examining copper owing to
its low cost and abundance compared to other transition
2.2 | Synthesis
[11]
metals.
These tests reveal that copper can have an
A mixture of CuBr (0.22 g, 1 mmol) and 4‐aminopyridine
2
excellent catalytic activity and better selectivity in
(
0.27 g, 3 mmol) in 5 ml of N,N‐Dimethylformamide
[12]
[13]
catalytic reactions such as oxidation,
epoxidation
In the same context, Kocovsky
reported that copper complexes with sterically
(
DMF) was transferred to a stainless steel autoclave,
[14]
and polymerization.
sealed and placed in a programmable stove. The temper-
ature was raised to 140 °C at 5 deg/min and held at that
temperature for 24 hr, then cooled at 0.1 deg/min to
[15]
et al.
hindered nitrogen ligands are excellent catalysts. These
complexes are stable and more active than those of
phosphine ligands.
90 °C and held for 12 hr; afterwards it was cooled at the
same rate to 70 °C and held for another 12 hr, and finally
cooled down to room temperature at 0.1 deg/min
On the other hand, the increasing interest of
researchers for chemical modification of biologically
active compounds by complexation with various metals
(
(
Figure 1). The resulting plate purple crystals of [Cu
C H N ) ]Br ·2(C H NO) were collected, washed with
5
6
2 4
2
3
7
[16]
is noteworthy.
New therapeutic strategies based on
ethanol and then air dried.
agents sharing antioxidant, anti‐microbial and anti‐
inflammatory properties should be helpful to counter
the development of chronic diseases. As an extension
of this study and in an attempt to establish structure–
activity relationships, it seemed of interest to further
investigate the biological aspects of the synthesized
compound. It is known that various substances,
containing pyridine derivatives molecules, exhibit anti-
2.3 | X‐ray data collection and structure
determinations
Details of crystallographic data collection and
refinement parameters for the complex Cu‐4AP‐Br are
shown in Table 1. A single crystal, of dimensions
0.37*0.31*0.25 mm, was mounted onto a MiTeGen
MicroLoops 200 μm. Diffraction intensities for complex
Cu‐4AP‐Br were collected on Bruker D8 Quest
[17]
bacterial activity.
Furthermore, metal ions of the first
transition series, such as copper, possess a certain degree
[
18]
of antioxidant,
which can provide an additional
[
19]
mechanistic pathway of its anti‐tumor action.
Recently Ji et al.
[20]
reported that a series of compounds
based on Copper (II) represent an important biological
activity and would be good candidates to be used for
medical practice. Some organically template copper
[
21]
have been used as inhibitors of HIV‐1 protease,
[22]
antibacterial and antioxidant activities,
and antitumor
[23]
properties.
With respect to our investigations pertaining to the
mononuclear copper complex, we report, herein, the
chemical preparation, the thermal behavior, the biologi-
cal activities, the crystallographic description and the
catalytic properties of [Cu(C H N ) ]2Br·2(C H NO) in
5
6
2 4
3
7
the Heck cross‐coupling reaction under ultrasonic
irradiation. This activation method proved to be
ecological, highly quick and efficient in terms of
FIGURE 1 The reaction scheme with the different steps to
synthesis the Cu‐4AP‐Br complex

HFIDHI ET AL.
3 of 14
TABLE 1 Crystallographic data of Cu‐4AP‐Br
2.4 | Thermal analysis measurements
Structural parameter
Compound (1)
2 3 7
[Cu(C ]Br ·2(C H NO)
DSC‐ATG measurements of Cu‐4AP‐Br were performed
Formula
5
H
6
N
2
)
4
using a ASDT Q600 instrument, under air flow (100 ml/
−
1
−1
Formula weight (g mol
Temperature (K)
Crystal system
Space group
A (Å)
)
746.02
298 K
min), with a heating rate of 5 °C min up to 900 °C.
Orthorhombic
Pbcn
2.5 | General procedure for the catalytic
activity studies
10.8139(11)
15.8635(15)
19.1580(12)
3286.5(6)
b (Å)
2.5.1 | Experimental
c (Å)
0.01 mmol of catalyst, 3 mmol of base, 2 mmol of aryl
3
Volume (Å )
halide, 2.5 mmol of styrene and 6 ml of the solvent were
introduced successively in the reactor (glass bottle) and
subjected to ultrasonic irradiation. After the reaction,
the resulting mixture was cooled and the organic phase
extracted by means of diethyl ether. Subsequently, the
reaction crude was purified by column of silica with
Z
4
Diffractometer
Bruker D8 Quest
PHOTON100 CMOS
−3
ρ
cal (mg m )
1.508
Absorption correction
Multi‐scan
0.37 x 0.31 x 0.25
Purple, Plate
3.14
80% of n‐hexane and 20% of dichloromethane as eluent
3
Crystal size (mm )
to yield the final product.
Crystal color/shape
−1
μ (mm
)
2.5.2 | Characterization
θ range (deg)
θmin = 2.8; θmax = 26.4
hkl range
−13 ≤ h ≤ 12
Gas chromatographic (GC) analyses were performed by a
Shimadzu GC‐2014 device, to which a WBI‐2014 injector
and a FID‐2014 detector were connected with a DB‐5
capillary column. The carrier gas was nitrogen. All
analyses were processed using GC‐solution software.
The H NMR and C NMR spectra of the synthesized
compounds were recorded on a Bruker AC 400 apparatus
with Fourier transform and a nominal frequency of
−
−
19 ≤ k ≤ 17
23 ≤ l ≤ 23
No. of reflections collected
3357
No. of independants reflections 1306
1
13
F (000)
1516.0
R1
0.0686
0.1438
0.983
wR2
100 MHz. Chemical shifts were expressed in parts per
GooF
million (ppm) relative to tetramethylsilane (TMS), used
as an internal reference. The spectra were recorded in
chloroform‐d.
Transmission factors
Largest difference map
Tmin = 0.769, Tmax = 0.837
Δρmin = −0.39; Δρmax = 0.43
−
3
hole (e Å
)
FT‐IR spectra were recorded by a PerkinElmer
Spectrum 100 apparatus. The absorption frequencies (υ)
−
1
were expressed in cm .
PHOTON100 CMOS diffractometer, equipped with
graphite‐monochromated MoKα radiation with radiation
wavelength 0.71073 Å by using the φ‐ω scan technique
at ambient temperature. Data collection, cell refinement,
data reduction and analysis were carried out by means of
The ultrasonic activation was affected by an ultra-
sonic device (model Sonopuls HD 3200, 20 kHz, 200 W)
coupled to an ultrasonic generator (Sonics VC 505,
300 W) and an ultrasonic probe (MS‐72, Φ = 2 mm).
[24]
the APEX2 program.
was applied to the data with the use of SADABS.
Analytical absorption correction
[
24]
The
2.5.3 | (E)‐stilbene
structure was solved by direct methods and refined with
−
1
the full‐matrix least‐squares technique, using SHELXS‐
IR (KBr, cm ) ν = 3128–2837 (CH aro), 1500 (C=C
[25]
1
9
7 and SHELXL‐97 programs.
Anisotropic thermal
ethyl), 1449 (C=C aro), 963 (CH ethyl); H NMR
parameters were assigned to all non‐hydrogen atoms.
The organic hydrogen atoms were generated geometri-
cally. All the figures were designed using DIAMOND
(400 MHz, CDCl ) δ (ppm) = 7.54 (d, 4H, J = 7.52 Hz),
3
7.40 (t, 4H, J = 7.39 Hz), 7.30–7.24 (m, 2H), 7.15
13
(s, 2H); C NMR (100 MHz, CDCl3) δ (ppm) = 137.36,
[26]
program.
128.72, 128.69, 127.63, 126.53.

4
of 14
HFIDHI ET AL.
2
.5.4 | (Z)‐stilbene
for 10 min at 10,000 × g. Finally, 2.5 ml of the superna-
tant solution from each sample mixture were mixed with
−
1
IR (KBr, cm ) ν = 3146–2843 (CH aro), 1537 (C=C
ethyl), 1361 (C=C aro), 1106 (CH ethyl); H NMR
2.5 ml of distilled water and 0.5 ml of FeCl (0.1% (w/v)).
3
1
After a 10‐min reaction time, the absorbance of the
resulting solutions was measured at 700 nm. The control
was conducted in the same manner, except that distilled
water was used instead of sample. BHA was used as
reference antioxidant. Values presented are the mean of
two analyses.
(400 MHz, CDCl ) δ (ppm) = 7.53 (d, 4H, J = 7.53 Hz),
3
7
.37 (t, 4H, J = 7.38 Hz), 7.32–7.21 (m, 2H), 7.13 (t, 2H,
13
J = 7.14 Hz);
C NMR (100 MHz, CDCl3) δ
(ppm) = 137.45, 128.82, 127.77, 126.65.
2
.6 | In vitro biological activities
.6.1 | Antioxidant activities
PPH radical‐scavenging assay
DPPH radical‐scavenging activity of Cu‐4AP‐Br was
determined as described by Bersuder et al.
2
[
29]
Sample
β‐carotene bleaching assay
The ability of Cu‐4AP‐Br to prevent the bleaching of β‐
carotene was assessed as described by Koleva et al.
(500 μl) at different concentrations (0.1 to 1 mg/ml) was
mixed with 375 μl of ethanol (99.5%) and 125 μl of DPPH
(0.02%) in ethanol (99.5%). The mixtures were then kept
at room temperature in the dark for 1 hr, and the reduc-
tion of DPPH radical was measured at 517 nm using a
UV–Visible spectrophotometer (T70, UV/VIS spectrome-
ter, PG Instruments Ltd., Beijing, China). When the
DPPH radical was scavenged, the color of the reaction
mixture changed from purple to yellow with the decrease
of absorbance. The control was conducted in the same
manner, except that DMSO was used instead of sample.
The DPPH radical scavenging activity was calculated as
follows:
[
27]
A
stock solution of β‐carotene/linoleic acid mixture was pre-
pared by dissolving 0.5 mg of β‐carotene, 25 μl of linoleic
acid and 200 μl of Tween 40 in 1 ml of chloroform. The
chloroform was completely evaporated under vacuum in
a rotatory evaporator at 40 °C, then 100 ml of bi‐distilled
water were added, and the resulting mixture was
vigorously stirred. The emulsion obtained was freshly
prepared prior to each experiment. Aliquots (2.5 ml) of
the β‐carotene/linoleic acid emulsion were transferred to
test tubes containing 0.5 ml of Cu‐4AP‐Br solution (0.1
to 1 mg/ml). The tubes were immediately placed in water
bath and incubated at 50 °C for 2 hr. Finally, the
absorbance of each sample was measured at 470 nm
using a UV–Visible spectrophotometer (T70, UV/VIS
spectrometer, PG Instruments Ltd., China). A blank was
conducted in the same manner, except that distilled water
was used instead of sample. The BHA was used as posi-
tive control. Three replicates were conducted for each test
sample. The antioxidant activity was determined by:
DPPH radical − scavenging activity ð%Þ
Acontrol
Asample
¼
× 100
Acontrol
where Acontrol is the absorbance of the control reaction
and Asample is the absorbance of sample reaction. BHA
was used as a positive control. The test was carried out
in duplicate and the results are mean values.
A0 At
A0’ At’
Antioxidant activity ð%Þ ¼ 1 −
× 100
2.6.2 | Antibacterial activity
Microorganisms
’
where A and A are the absorbances of the sample and
Antibacterial activity of Cu‐4AP‐Br was tested against
Gram positive and Gram negative bacterial strains. The
bacteria used were Staphylococcus aureus (ATCC 25923),
Bacillus cereus (ATCC 11778), Enterococcus faecalis
0
0
the blank, respectively, measured at time zero, and At
and A are the absorbances of the sample and the blank,
respectively, measured after incubation for 2 hr.
′
t
(
ATCC 29212), Micrococcus luteus (ATCC 4698), Salmo-
Reducing power assay
nella enterica (ATCC 43972) and Klebsiella pneumoniae
The ability of Cu‐4AP‐Br to reduce iron (III) was
(ATCC 13883).
[
28]
determined according to the method of Yildirim et al.
Sample (1 ml) at different concentrations (0.1 to
mg/ml) was mixed with 2.5 ml of 0.2 M phosphate
buffer (pH 6.6) and 2.5 ml of K Fe(CN) solution (1%
Agar‐well diffusion method
Antibacterial test was performed by agar‐well diffusion
method as described by Tagg and McGiven (1971).
fresh cell suspension (200 μl) adjusted to 10 cfu/ml for
bacteria was inoculated onto the surface of agar plates.
Thereafter, wells with 6 mm in diameter were punched
1
[30]
A
3
6
6
(
5
w/v)). The mixtures were incubated for 30 min at
0 °C. After incubation, 2.5 ml of TCA (10% (w/v)) were
added and the reaction mixtures were then centrifuged

HFIDHI ET AL.
5 of 14
in the inoculated agar medium with sterile Pasteur
pipettes and 50 μl of Cu‐4AP‐Br in dimethylsulphoxide
(DMSO) with a concentration of 2 mg/ml added to each
well. The plate was allowed to stand for 4 hr at 4 °C to
allow the diffusion of the extracts in the agar, followed
by incubation at 37 °C for 24 hr.
The antimicrobial activity was evaluated by measur-
ing the inhibition zone diameters (IZD) (including well
diameter of 6 mm).
Anti‐inflammatory activity
The anti‐inflammatory activity was assessed using the
spectrophotometric measurement of a conjugated diene,
the result of linoleic acid oxidation by the enzyme 5‐
[31]
LOX.
Briefly, 500 μL of buffer (pH = 7.4) (Na HPO ,
2 4
2
H O; KH PO ; NaCl) were mixed with 200 μL of protein
2
2
4
hydrolysate, 200 μL of linoleic acid and 100 μL of 5‐LOX
enzyme solution. The mixture was homogenized and
incubated for 10 min at 25 °C. The absorbance was
determined at 234 nm against a blank. Naprosyn (NAP)
was used as a standard.
FIGURE
Cu(C
2
Asymmetric
unit
representation
of
[
5
H
6
N
2
)
4
]2Br•2(C3H7NO) generated by the two‐fold rotation
axis along the crystallographic b axis
[
33]
3
3
| RESULTS AND DISCUSSION
.1 | Crystal structure of
Addison and coworkers for a four coordinated complex,
τ4 = [360°‐(α ± β)/141° (α and β as the two largest angles
(N5–Cu–N3 and N1–Cu–N1#) in the four‐coordinate
species). The values of τ4 range from 1 for a perfect tetra-
hedral geometry, since 360° − 2(109.5°) = 141°, to 0 for a
perfect square‐planar geometry, since 360° − 2(180°) = 0.
Calculated τ parameter for Cu‐4AP‐Br is 0.021 ≈ 0.00,
demonstrating that the cation [Cu(C H N ) ] , exhibits
a square planar (D ) geometry. In addition, the dihedral
angle between the planes N1CuN5 and N3CuN1# is equals
[Cu(C H N ) ]2Br·2(C H NO)
5 6 2 4 3 7
The new copper (II) complex Cu‐4AP‐Br crystallizes in
the orthorhombic system with the centrosymmetric space
group Pbcn. The lattice parameters are a = 10.8139(11) Å,
b = 15.8635(15) Å, c = 19.1580(12) Å and the volume of
4
2+
5
6 2 4
4h
3
the unit cell is V = 3286.5(6) Å . A complete list of the
structure factors is illustrated in Table 1. As demonstrated
in Figure 2, the complex Cu‐4AP‐Br is generated by a
two‐fold rotation axis and consists of isolated tetra‐
to 0° confirms the regular square‐planar geometry of the
CuN entity and the planarity of the five atoms (Cu and
4
the four Npyridine atoms). Indeed, copper atoms are sepa-
rated from each other along the a, b and c crystallographic
axis, with the shortest metal–metal distance equal to 9.599
(16) Å, 10.813 (11) Å and 11.192 (10) Å, respectively, sug-
gesting that they are very well isolated. This difference in
the metal–metal distance is likely assigned to the size
and the shape of the coordinated ligand.
2+
aminopyridine cuprate (II) cations [Cu(C H N ) ] , free
5
6 2 4
−
bromine anions [Br ] and uncoordinated solvent
dimethylformamide molecules (C H NO) which are all
3
7
connected by a complex hydrogen bond system to form
a periodic 0 dimensional structure.
In this complex, the copper atom is located in a spe-
cial position and coordinated by four nitrogen atoms of
the pyridine ligand with Cu—N bonds distance ranging
from 2.003 (5) to 2.035 (8) Å and N—Cu—N angles vary-
ing from 88.47 (15) to 180.000 (3)° (Table 2). These values
fall in the range reported previously for compounds
−
On the other hand, the free Br anions are located
2
+
above and below the square planar of [Cu(C H N ) ]
5
6 2 4
with the Cu‐‐‐Br distance equal to 3.537 (8) Å, being too
long to be considered as a coordinated bond. In fact, the
9
electronic subshell d of Cu (II) is responsible for the dis-
[32]
containing Cu—N bonds.
Visual inspection of the
tortion of the copper coordination polyhedron and conse-
quently generating an elongation of the Cu‐‐‐Br bond.
This phenomenon corresponds to the well‐known
Jahn‐Teller effect. Indeed, in an octahedral field the five
d‐orbitals of the Cu ion split into two sets, labeled by
molecular structure in Figure 2 reveals that the coordi-
nated copper complex deviates substantially from a
square‐planar geometry. Thus, the degree of distortion
2+
of [Cu(C H N ) ] coordination polyhedral was deter-
5
6 2 4
mined by the index of tetrahedrality introduced by
symmetry as t2g (d , d , d ) and e (d , d
z2
x2−y2
). The eg
xy
yz
xz
g

6
of 14
HFIDHI ET AL.
TABLE 2 Selected bond distances (Å) and angles (°) for Cu‐4AP‐
Indeed, they participate in strong hydrogen bonds as
Br
acceptor with the amino groups [N2‐‐‐Br01 = 3.5370
(
(
61) Å, N4‐‐‐‐Br01 = 3.5086 (41) Å and N6‐‐‐Br01 = 3.4908
40) Å].
Cu—N1
2.003 (5)
C5—C4
1.361 (9)
i
Cu—N1
Cu—N3
Cu—N5
N5—C10
N5—C10
N3—C7
2.003 (5)
2.013 (8)
2.035 (8)
1.338 (8)
1.338 (8)
1.333 (8)
1.333 (8)
1.331 (8)
1.352 (9)
1.203 (9)
1.366 (9)
1.384 (8)
1.337 (11)
176.9 (3)
88.47 (15)
88.47 (15)
91.53 (15)
91.53 (15)
180.000 (3)
116.9 (9)
121.6 (4)
121.6 (4)
116.1 (9)
121.9 (4)
121.9 (4)
115.3 (6)
122.4 (5)
122.3 (5)
120.7 (7)
122.1 (4)
122.1 (4)
C8—C7
C8—C9
1.361 (9)
1.394 (8)
1.394 (8)
1.354 (9)
1.352 (8)
1.393 (9)
1.395 (9)
1.384 (8)
1.344 (12)
1.343 (9)
1.441 (10)
1.451 (9)
121.8 (4)
121.8 (4)
116.4 (9)
125.1 (7)
124.2 (8)
122.8 (7)
121.2 (7)
116.0 (7)
120.7 (7)
119.2 (7)
123.9 (9)
121.3 (7)
121.9 (8)
116.7 (7)
123.8 (7)
122.9 (8)
119.6 (7)
115.8 (9)
In the title compound, the 4‐aminopyridine ligand
acts as a monodentate ligand by the ring nitrogen atom.
The C‐C and C‐N bond lengths vary from 1.354 (9) Å to
1.395 (9) Å and 1.331 (8) Å to 1.352 (9) Å, respectively.
The C‐C‐C and C‐N‐C bond angles fall in the range
i
C9—C8
C1—C2
C3—N2
C3—C4
C3—C2
C12—C11
N4—C9
N7—C13
N7—C15
N7—C14
i
1
15.8 (9)° to 120.7 (7)° and 118.7(7)° to 120.8(7)°, respec-
tively. The main inter atomic distances and angles in the
monodentate ligand are reported in Table 2. These values
are in agreement with those observed in similar com-
i
N3—C7
i
N1—C5
N1—C1
O1—C13
[
35]
pounds.
With regard the coordinated molecules are
not in the same plane. The dihedral angles formed
between these ligands in the trans position, are equal to
2
C11—C10
C11—C12
N6—C12
2.190 ° for N3—Cu—N5 and 59.718 ° for N1—Cu—N1#.
The crystal structure of Cu‐4AP‐Br is stabilized by the
N4—C9—C8
N4—C9—C8
hydrogen bonding interactions that involve the coordi-
nated lattice 4‐aminopyridine molecules as well as the
bromine anions and DMF molecules. Furthermore, the
supramolecular architecture of the title compound is built
from the alternatively arranged cationic and anionic
layers in wave forms along the crystallographic a axis
(Figure 3). Moreover, the arrangement of the different
species present in the lattice structure allows some
dominant interactions, calculated by CRYSTAL
i
i
N1—Cu—N1
i
N1—Cu—N3
C8—C9—C8
N1—C1—C2
N3—C7—C8
N2—C3—C4
N2—C3—C2
C4—C3—C2
C5—C4—C3
C1—C2—C3
i
N1 —Cu—N3
N1—Cu—N5
i
N1 —Cu—N5
N3—Cu—N5
i
C10 —N5—C10
[
36]
EXPLORER,
H‐‐‐Br/Br‐‐‐H (18%), O‐‐‐H/H‐‐‐O (7%)and N‐‐‐H/H‐‐‐N
5%) (Figure 4), and thus generating a supramolecular
being H‐‐‐H (47%), C‐‐‐H/H‐‐‐C (23%),
i
C10 —N5—Cu
C10—N5—Cu
(
i
C7—N3—C7
O1—C13—N7
C13—N7—C15
C13—N7—C14
C15—N7—C14
N1—C5—C4
network. These entities are interconnected significantly
through extensive N—H‐‐‐Br/O hydrogen bonding
between the anionic and cationic moieties (Table 3) and
C—H‐‐‐π stacking interactions between the aromatic
rings of the amine molecules themselves. The uncoordi-
nated bromide anion and DMF molecule play a signifi-
cant role in providing the supramolecular aspect and
form a connecting bridge between the isolated Cu‐square
planar themselves.
C7—N3—Cu
i
C7 —N3—Cu
C5—N1—C1
C5—N1—Cu
C1—N1—Cu
C10—C11—C12
N5—C10—C11
C7—C8—C9
i
i
N6—C12—C11
C11 —C12—C11
N6—C12—C11
Symmetry code: (i) − x, y, −z + 3/2.
3.2 | Thermal analysis of
[
Cu(C H N ) ]2Br·2(C H NO)
5
6
2 4
3
7
2
1
orbitals are occupied by three electrons ( dz
2
, d
x2−y2
),
giving rise to a doubly degenerate ground state and
consequently the symmetry decreases by Jahn‐Teller
elongation along the c axis containing the bromine
The thermal stability of Cu‐4AP‐Br crystal was studied by
means of a simultaneous thermogravimetric analysis
(TGA) and differential scaling calorimetric (DSC), carried
out with a heating rate of 5 °C/min between 25 and
900 °C. The results are depicted in Figure 5. The TG curve
illustrates that the compound is thermally stable up to
80 °C and the first mass loss starts above 80 °C due to
the decomposition of two DMF molecules (observed
weight loss, 18.8%; calculated weight loss, 19.58%). This
[34]
ions.
The presence of those halide atoms as a part of an
anionic sublattice leads to a total negative charge of (2‐)
on the framework which is equilibrated by the presence
2+
of the cation [Cu(C H N ) ] . The bromine atoms play
5
6 2 4
a subordinate role in the stabilization of the structure.

HFIDHI ET AL.
7 of 14
FIGURE 3 Projection of the structure along the crystallographic b‐axis for compound Cu‐4AP‐Br, showing the supramolecular character
and the alternation between the cationic and anionic parts in wave forms along the crystallographic a axis
the degradation of the organic molecules and one Br2
molecule (calculated weight loss, 71.86%). This transfor-
mation is accompanied by endothermic peak at
~206 °C. The last transformation starts at about 650 °C
and corresponds to the formation of copper oxide CuO
as final residue (calculated weight loss, 89.28%; observed
weight loss, 91.21%).
3.3 | Catalytic properties
The coupling reactions in the presence of complex based
on transition elements are very interesting. They allow
access to original syntheses of new compounds as
pharmaceutical intermediates that can be used as
medicaments. Generally, these reactions are carried out
[
37,38]
FIGURE 4 The pie chart of non‐covalent interactions in Cu‐4AP‐
with a palladium catalyst.
However, on account
Br
of their cost, toxicity and the instability of some
[
39,40]
palladium complexes,
new transition metals such
[
41]
[42]
[43]
[44]
phenomenon is accompanied by an endothermic peak on
the DSC curve after 80 °C. Furthermore, the second
weight loss of 70.42%, observed on the TG curve in the
temperature domain from 150 to 650 °C, is attributed to
as ruthenium,
nickel,
manganese,
cobalt,
[
45]
[46,47]
iron
and copper
have, recently, been examined.
In this work, we tested the complex Cu‐4AP‐Br as a
catalyst in the coupling reaction of bromobenzene with
TABLE 3 Hydrogen‐bond geometry (Å, °)
D—H···A
D—H
H···A
D···A
D—H···A
ii
N6—HN6B···Br
0.86
0.86
0.86
0.86
0.86
0.86
2.63
2.63
2.75
1.99
2.69
2.69
3.491(4)
3.491(4)
3.537(6)
2.841(8)
3.508(4)
3.508(4)
175.1
175.1
153.5
171.9
160.5
160.5
iii
N6—HN6A···Br
N2—HN2A···Br
iv
v
N2—HN2B···O1
v
N4—HN4B···Br
N4—HN4A···Br
vi
Symmetry codes: (ii) x − 1, y + 1, z; (iii) − x + 1, y + 1, −z + 3/2; (iv) x − 1, −y + 1, z − 1/2; (v) x − 1, y, z; (vi) − x + 1, y, −z + 3/2.

8
of 14
HFIDHI ET AL.
progress of the reaction, whose amplitude is less than 30%
(
Table 4, entry 1–3), and then by increasing to 40% the
yield decreases, which accounts for the threshold or the
physical limit of ultrasonic activation. Therefore, the
effect of ultrasound increases with the amplitude injected
to a maximum value, which has the cavitation threshold.
From this limit, cavitation becomes very intense. This
increases the percentage of gas in the medium that
decreases the effect of the ultrasonic waves since it is
[
50]
weakly driven by gas rather than a liquid.
The study of the pulsation period duration was
affected by varying the ON/OFF times. To prevent the
erosion of sonic emission surface horn, we relied on low
durations, i.e. one to three seconds. The pulsating time
FIGURE
5
Simultaneous thermogravimetric analysis and
in operation (t ) is the duration of the emission of
E
differential scaling calorimetric scan for Cu‐4AP‐Br. The scan was
performed in flowing air with a ramp rate of 5 °C/min
ultrasonic irradiation in the reaction medium during a
period. Therefore, the effect of ultrasound increases with
the creation of cavitations. On the contrary, the off pulsa-
styrene, in the presence of different bases in various
solvents (Figure 6) under ultrasonic irradiation using an
MS‐72 ultrasonic probe (diameter Φ = 2 mm) immersed
directly in the reaction mixture (Figure 7).
At first, we optimized the ultrasonic operating param-
eters. Thus, several parameters can be adjusted to influ-
ence the selectivity and the progress of the chemical
tion 6+ time (t ) designates the stop of the creation of the
A
irradiation within the reaction mixture. During this
period, the cavitations rate decreases, thus, decreasing
the effects of the ultrasonic activation.
Based on the results obtained previously in our labo-
[
51]
ratory,
we examined the bromobenzene coupling reac-
[
48,49]
reaction.
The results obtained did not display any
tion with styrene catalyzed by Cu‐4AP‐Br in different
FIGURE 6 Heck reaction between bromobenzene and styrene
FIGURE 7 Mounting of the coupling
reaction activated by ultrasonic irradiation

HFIDHI ET AL.
9 of 14
TABLE 4 Optimization of reaction parameters for Heck cross‐coupling reaction of bromobenzene with styrene in the presence of Cu‐4AP‐
Br
a
A
b
Entry
Amplitude (%)
t
E
‐ t
(s)
solvent
base
Time(min)
Yield (%) E/Z
1
2
3
4
5
6
7
8
9
15
20
25
30
35
40
35
35
35
35
35
35
35
35
35
2‐2
DMF
Na
Na
Na
Na
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
45
45
45
30
60
120
60
60
90
90
90
90
60
60
60
No reaction
No reaction
No reaction
trace
2–2
2–1
3–1
3–2
3–2
3–2
3–2
3–2
3–2
3–2
3–2
3–2
3–2
3–2
DMF
DMF
DMF
DMF
Na
99/<1
t
DMF
BuOK
65/<1
DMF
K
2
CO
3
99/<1
DMSO
MeCN
MeCN
MeCN
DMF
Na
2
CO
3
3
100/none
73/26
NaOH
10
11
12
13
14
15
K
2
CO
3
72/26
Na
2
CO
74/24
KOH
Et
68/31
DMSO
DMSO
DMF
3
N
82/16
K
2
CO
3
99/<1
NaOH
79/20
(
0.01 mmol) of catalyst, (2 mmol) of bromobenzene, (2.5 mmol) of styrene, (3 mmol) of base and 6 ml of the solvent under ultrasonic irradiation at 25 °C.
a
Period duration (t = t
E
+ t
A E A
); t :pulsation time ON, t : pulsation time OFF.
b
The yields were measured by GC using diethyl ether as solvent.
aprotic polar solvents. We chose DMF, DMSO and MeCN
due to their high boiling temperatures to prevent their
vaporization and to maintain the height (H) of reaction
mixture (Figure 7). The obtained results are summarized
in Figure 8.
Among the three solvents tested, DMSO was the best
solvent adapted to affect this type of coupling. Indeed,
for a very short period of time (60 min), the progress of
the reaction was almost total. In addition, an excellent
selectivity on external position of styrene was noticed.
In contrast, in the MeCN, the reaction time increases to
90 minutes with an average preference of the trans form
over cis.
This is well confirmed in the presence of different
bases such as NaOH, K CO and Et N. In addition, we
2
3
3
found that the reactivity of the reaction was increased
by the addition of carbonate base. However, the use of
NaOH or KOH increases the duration of the reaction
and improves the cis form. This can confirm that the
carbonate anions facilitate the reductive elimination step
−
much more than the (OH ) ions.
In order to elucidate these results, we proposed the
reaction mechanism presented in Figure 9. The proposed
catalytic cycle starts with an oxidative addition
accompanied by the release of one of four ligands
4
‐aminopyridine, which causes the formation of
[
52]
organocuprate (2).
During this step, the degree of
oxidation of copper increases by two units, according to
a concerted mechanism, since the halogenated derivative
is of Csp2‐X type. The second step is the syn‐insertion of
styrene to the last complex (2) which results in the
formation of a new C‐C bond followed by stilbene
removal and hydride (4). Finally, the corresponding base
decomposes this hydride by trapping the HBr acid and
II
the regeneration of Cu .
One of the most interesting advantages of this
complex is its stability for air and temperature, favoring
it to be a potential candidate for marketing; contrary to
FIGURE 8 Solvent and base effects on the evolution and
selectivity of the Heck reaction catalyzed by Cu‐4AP‐Br

10 of 14
HFIDHI ET AL.
antioxidant capacity of the new elaborated complex
Cu‐4AP‐Br. Its capacity was determined, in vitro, by
means of β‐carotene bleaching test, reducing power assay
and DPPH scavenging ability.
β‐carotene‐linoleic acid assay
In this antioxidant test, the oxidation of linoleic acid gen-
erates free radicals, such as hydroperoxides which attack
the highly unsaturated β‐carotene molecules. When this
reaction occurs and in the absence of antioxidants, the
β‐carotene molecule loses its conjugation and, therefore,
β‐carotene undergoes a rapid discoloration reaction.
Antioxidant activity was determined by measuring the
inhibition effects of Cu‐4AP‐Br and BHA to β‐carotene
bleaching. As shown in Figure 10, Cu‐4AP‐Br antioxi-
dant activities in β‐carotene‐linoleate model system
increased in a dose‐dependent manner, however, it was
lower than that of BHA. As noted in Figure 10, Cu‐
4
AP‐Br inhibits the oxidation of β‐carotene with a I% of
FIGURE 9 Cycle catalytic plausible of the Heck reaction
catalyzed by Cu‐4AP‐Br
72.86 ± 1.4%, at a concentration of 200 μg/ml. The antiox-
idant effect in the synthesized compound can reduce the
extent of β‐carotene destruction by neutralizing the
linoleate‐free radical and other free radicals formed in
the system.
phosphine ligand complexes that need specific conditions
[53]
during storage.
Furthermore, this complex does not
require any agent or additive to activate the reaction.
Besides, a very remarkable selectivity of external
arylation of styrene compared to complexes based on
phosphine or oxygenated ligands was used in
Free radical scavenging activity using DPPH assay
DPPH provides an easy and rapid method for the deter-
mination of antioxidant activity of synthesized com-
pounds, since DPPH can directly react with the
[54]
literature.
From an ecological perspective, this
complex verified certain principles of green chemistry.
The yields found reveal that Cu‐4AP‐Br can replace
palladium, the metal of choice for coupling reactions.
This allows reducing the cost of the reaction and avoiding
the paradox of synthesizing stilbene derivatives with
[
58]
antioxidant species.
The principle of the DPPH assay
is a single electron transfer (SET) reaction and a
[
59]
hydrogen‐atom removal.
In our study, the metal
complex compound showed good activities as a radical
scavenger (Figure 11). It can be inferred that free radical
scavenging activities of synthesized compound are
[
55]
anticancer activities
can cause cancer.
using palladium complexes that
[
56]
To sum up, this complex is endowed with a stability, a
reactivity and a well‐defined selectivity that allow it to be,
together with its ecological features, a new procedure in
fine chemistry.
3
.4 | Evaluation of in‐vitro biological
activity.
3.4.1 | Antioxidant activity
For many years, a large number of researches have
actively investigated copper compounds based on the
assumption that these endogenous metals may be less
toxic. It has been established that the properties of
copper‐coordinated compounds are largely determined
by the nature of ligands and donor atoms bound to the
FIGURE 10 β‐carotene bleaching activity of Cu‐4AP‐Br at
different concentrations. BHA was used as positive control. Each
experiment was executed in triplicate
[57]
metal ion.
Accordingly, we attempted to evaluate the

HFIDHI ET AL.
11 of 14
FIGURE 12 Reducing power of Cu‐4AP‐Br at different
concentrations. BHA was used as positive control. Each
experiment was executed in triplicate
FIGURE 11 Scavenging effect on DPPH free radical of Cu‐4AP‐
Br at different concentrations. BHA was used as positive For Peer
Review control. Each experiment was executed in triplicate
3
.4.2 | In‐vitro antimicrobial activity of u‐
concentration dependent. Correspondingly, Hazra
4AP‐Br synthesized compound
[60]
et al.
have indicated that all the metal complexes
showed comparable or slightly less activity compared to
that of standard. At concentrations range 10 to
From the industrial perspective, the organic compounds
used for the purpose of disinfection are limited due to
their toxicity towards healthy cells and instability at high
2
00 μg/ml, Cu‐4AP‐Br was able to scavenge DPPH radi-
cals and the value of the maximum inhibition was
3.91 ± 1.08%. The obtained results were in agreement
[
65]
temperatures and pressures.
Hence, we are at the cut-
6
ting edge stage of finding the alternative effective agent to
deactivate microorganisms. Correspondingly, the synthe-
sized compound Cu‐4AP‐Br is of high significance.
Antibacterial activity of Cu‐4AP‐Br complex was
assessed against five strains. The result was compared
with those of the standard (Bacitracin) and the mean
diameters of inhibition zones are shown in Table 5. Based
on the results, it can be concluded that the synthesized
Cu‐4AP‐Br has significant antibacterial action against
both of the Gram classes of bacteria. Cu‐4AP‐Br exhibits
intermediate to higher bioactivity against all organisms
and its activity is promising toward Salmonella enterica.
At a concentration of 200 μg/ml, antimicrobial activities
of Cu‐4AP‐Br against Micrococcus luteus, Salmonella
enterica, Staphylococus aureus, Escherichia Coli and Pseu-
domonas aeruginosa were about 10 mm, 14 mm, 8 mm,
8 mm and 10 mm, respectively. The high abundance of
amines on their cell surface enhances the affinity of Cu
with several works reported in the literature with regards
to the antioxidant potential of metal complexes. In a
[61]
recent study, Sulpizio et al.
have reported that the
metal complexes [Cu (ISO) ] and [Zn (ISO) ] show 72
2
2
and 88% inhibition of the DPPH radical.
[5]
According to results of Saïd et al., copper complex
displayed significantly higher DPPH activity. Konarikova
[62]
et al., (2013)
have also reported that, after complexa-
tion with metal ions, the antioxidant activity increases
due to the presence of positively charged meal ions as
well as electron donating groups present in the moiety.
Thus, the complex compound has a strong potential to
be applied as a scavenger to eliminate radicals.
Reducing power activity using FRAP assay
Reducing power also increased with the increase of Cu‐
4
AP‐Br and BHA concentration, and the values obtained
[
66]
for the synthesized compound were excellent, despite
ions towards these groups,
which gives rise to high
being about 69% of that of BHA (Figure 12). At
antimicrobial proficiency of synthesized Cu‐4AP‐Br com-
1
1
00 μg/ml, the absorbance value of Cu‐4AP‐Br is above
.0. This result was similar to a previous study reporting
pound. Similar results were previously reported by
[
67]
Samanta et al.
In fact, pyridine‐2‐carboxamide copper
that synthesized compounds (Itaconic anhydride (ITA))
complexes possess good antibacterial activity. Inspection
of the data given in Table 5 reveals that Cu‐4AP‐Br is
active towards the five tested strain. On the other hand,
bacitracin did not show inhibition against Salmonella
enterica. It was reported that the antibacterial activity of
the compound is affected by different factors such as the
[63]
exhibited high reducing power potential.
It has been
reported that the reducing properties are generally
associated with the presence of reductones, shown to
exert antioxidant action by donating a hydrogen atom
[64]
and breaking the free radical chain.

12 of 14
HFIDHI ET AL.
TABLE 5 Antibacterial activity of Cu‐4AP‐Br and Bacitracin (C) using agar disc diffusion
Micrococcus
luteus
Salmonella
enterica
Staphylococus
aureus
Escherichia
Coli
Pseudomonas
aeruginosa
IZD (Cu‐4AP‐Br)
10
19
14
8
8
9
10
9
IZD (C)
‐
25
nature of the chelating agent and its chelating sites, the
nature of the metal ion, the geometrical structure of the
activity, and accordingly this type of synthesized com-
pound should be considered as potential active agent for
drug delivery process.
[68]
complex, solubility and other factors.
Recently,
Saleemh et al. have reported that copper (II) complexes
have been found to exhibit prominent antimicrobial and
anticancer potential activity by inducing apoptosis.
4
| CONCLUSION
[
69]
Bacteria are very strong and have already developed
struggle to many regularly used antibiotics. This may
pave the way for the exploitation of new drugs.
In summary, the structural feature of the new mononu-
clear copper compound template 4‐aminopyridine was
investigated. The X‐ray diffraction of Cu‐4AP‐Br shows
the ideal square‐planar geometry of the copper atoms,
which are isolated from each other with a Cu‐‐‐Cu dis-
tance equal to 9.599 (16) Å. The structural arrangement
of the synthesized compound exhibits a supramolecular
network manifested by the hydrogen bonds type N—
H‐‐‐Br/O and C—H‐‐‐π, yielding their structural stability.
In particular, the bromine atoms play a crucial role in
constructing 0D supramolecular frameworks because
they extend acceptors hydrogen bonding as well as main-
tain the charge balance of the system. Cu‐4AP‐Br was
applied as a catalyst in the Heck coupling reaction under
ultrasonic irradiation in various reaction conditions. The
results found are very encouraging: the ultrasonic activa-
tion generates the selectivity on the external position of
styrene with a preference of the trans form over cis. The
yields obtained for a short period of time allow us to
consider this complex as an excellent catalyst for this type
of reaction. Overall, the present study emphasized the
significant role attributed to Cu‐4AP‐Br as a promising
source for antioxidant and antibacterial agents.
3.4.3 | Inhibitory effect of 5‐LOX
5‐LOX inhibition by Cu‐4AP‐Br was reported for the first
time in the literature, in this study. Naproxen (NAP) is
used as an anti‐inflammatory agent with analgesic and
antipyretic properties. NAP, known as a potent anti‐
inflammatory, was used as a standard. The effects of
Cu‐4AP‐Br and NAP on inhibition of 5‐LOX activity are
reported in Table 6. This pure compound has 4.6 times
stronger anti‐inflammatory activity, at a concentration
of 25 μg/ml, when compared to the synthesized
compound. The finding revealed that, at a test concentra-
tion of 100 μg/ml, Cu‐4AP‐Br exhibited high anti‐
inflammatory activity (IP = 54.2 ± 2.08%). A similar trend
[
70]
is observed for copper (II)‐ibuprofenato complex.
In
fact, inhibition of 5‐LOX may proceed via redox or
metal‐chelating mechanisms, apart from competitive
[71]
(non‐redox) enzyme inhibition.
Sorenson has reported
that Cu (II) complexes of clinically used nonsteroidal
anti‐inflammatory drugs (NSAIDs) are often more potent
anti‐inflammatory agents than either the parent NSAID
ORCID
[72]
drug or the uncomplexed Cu salt.
The synthesized
Houcine Naïli https://orcid.org/0000-0002-9224-5851
Cu‐4AP‐Br exhibited excellent anti‐inflammatory
TABLE 6 Anti‐inflammatory activity of Cu‐4AP‐Br and NAP at
various concentrations
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