Synthesis, characterization, theoretical, and antimicrobial studies of indenoquinoxalin-based ligands and their reactions with CuBr(PPh3)3

Article abstract of DOI:10.1016/j.molstruc.2021.130309

A series of three ligands were derived from the condensation of indeno[1,2-b]quinoxalin-11-one and hydrazines (L1 from hydrazine, L2 from phenylhydrazine and L3 from thiosemicarbazide). The three ligands were stirred with CuBr(PPh₃)₃ in dichloromethane; no reaction was observed except in the case of L3, providing a complex with the formula CuBr(PPh3)2(κ^S-L3) (Cu-L3). Crystal structure of the complex revealed that the central copper atom in the molecule is coordinated to two triphenylphosphine groups, a bromine atom and to the indeno[1,2-b]quinoxalin-11-ylidenecarbothioamidohydrazide (L3) ligand via S atom; forming a distorted tetrahedral geometry around it. In general, Cu-L3 complex has shorter Cu-P bond lengths compared to the parent complex which suggest less steric hindrance in Cu-L3. None of the three ligands were able to use the nitrogen atoms as donating atoms due to their highly engagement in hydrogen-bonding as observed in the crystal structure of Cu-L3 as well as the theoretical calculations. Moreover, theoretical calculation indicated that Cu-N interactions were weak with long distances beyond the typical bonding distances. Antimicrobial screening against a range of strains showed selective inhabitations of indeno[1,2-b]quinoxalin-11-one, L1 and L3 against S. aureus strain. Moreover, the introduction of the copper fragment to L3 did not cause any significant improvements to the antimicrobial properties of L3.

Full text of DOI:10.1016/j.molstruc.2021.130309

Journal of Molecular Structure 1238 (2021) 130309
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, characterization, theoretical, and antimicrobial studies of
indenoquinoxalin-based ligands and their reactions with CuBr(PPh3)3
a,∗
a
a
b
Bandar A. Babgi , Musab Bawazeer , Najah A. Alzaidi , Muhammad N. Arshad ,
Abdesslem Jedidi , Noor M. Bataweel , Ahmed M. Al-Hejinc,d, Mostafa A. Hussiena,e
a
c,d
a
Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
b
Centre of Excellence for Advanced Materials Research, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
c
Department of Biological Science, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
d
King Fahd Medical Research Centre, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
e
Department of Chemistry, Faculty of Science, Port Said University, Port Said 42521, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of three ligands were derived from the condensation of indeno[1,2-b]quinoxalin-11-one and hy-
drazines (L1 from hydrazine, L2 from phenylhydrazine and L3 from thiosemicarbazide). The three ligands
were stirred with CuBr(PPh3)3 in dichloromethane; no reaction was observed except in the case of L3,
Received 9 February 2021
Revised 7 March 2021
Accepted 14 March 2021
Available online 4 April 2021
S
providing a complex with the formula CuBr(PPh3)2(κ -L3) (Cu-L3). Crystal structure of the complex re-
vealed that the central copper atom in the molecule is coordinated to two triphenylphosphine groups,
a bromine atom and to the indeno[1,2-b]quinoxalin-11-ylidenecarbothioamidohydrazide (L3) ligand via S
atom; forming a distorted tetrahedral geometry around it. In general, Cu-L3 complex has shorter Cu-P
bond lengths compared to the parent complex which suggest less steric hindrance in Cu-L3. None of the
three ligands were able to use the nitrogen atoms as donating atoms due to their highly engagement in
hydrogen-bonding as observed in the crystal structure of Cu-L3 as well as the theoretical calculations.
Moreover, theoretical calculation indicated that Cu-N interactions were weak with long distances beyond
the typical bonding distances. Antimicrobial screening against a range of strains showed selective inhab-
itations of indeno[1,2-b]quinoxalin-11-one, L1 and L3 against S. aureus strain. Moreover, the introduction
of the copper fragment to L3 did not cause any significant improvements to the antimicrobial properties
of L3.
Keywords:
Cu(I)
Phosphine
Indeno[1,2-b]quinoxaline
Antimicrobial activity
Theoretical calculations
©
2021 Elsevier B.V. All rights reserved.
1
. Introduction
pounds exhibit biological significance which attracted intensive
structural-properties correlation studies to identify key require-
ments to design new drugs [4,5]. A series of 2,9,10-trisubstituted-
6-oxo-7,12-dihydro-chromeno[3,4-b]quinoxalines was synthesized
and the result of the antimicrobial screening showed moderate
to high inhabitation zone with the compound containing two
methyl and a methoxy groups being the most effective one [6].
The antimicrobial studies of 3-methyl-2-quinoxalinecarboxamide-
1,4-dioxide and related compounds revealed good activity against
Quinoxalines (also called benzopyrazines) are nitrogen contain-
ing heterocyclic compounds composed of benzene and a pyrazine
ring fused together. Quinoxalines scaffolds are encountered in a
family of antibiotics such as echinomycin, triostin A and lev-
omycin, which are well-known inhibitors of Gram-positive bac-
teria [1]. The two quinoxaline units act as the intercalating
parts (bis-intercalator) into DNA with preference for CG sites on
the minor groove of a double helix [2,3]. The naturally occur-
ring antibiotics encouraged the synthesis of several quinoxaline-
based compounds and examine their biological activities. Syn-
thesis of quinoxaline can be established easily by the conden-
sation of o-phenylenediamine derivatives with 1,2–dione com-
pound [4,5]. These substituted quinoxalines and their related com-
large number of strains studied such as E. coli [7].
A set
ꢀ
ꢀ
of thiadiazolo[2 ,3 :2,3]imidazo[4,5-b]quinoxaline was screened
against gram positive and Gram-negative bacteria. All the com-
pounds found to possess good antibacterial with further enhance-
ment provided by electron donating groups [8]. More examples on
the biological activities of quinoxaline can be reviewed in the ref-
erences [9,10] and [11].
Recently, tetracyclic systems containing quinoxaline moieties
have been synthesized form the condensation of ninhydrin
∗
Correspondence author.
E-mail address: bbabgi@kau.edu.sa (B.A. Babgi).
https://doi.org/10.1016/j.molstruc.2021.130309
0
022-2860/© 2021 Elsevier B.V. All rights reserved.

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Table 1.
Crystal data and structure refinement for Cu-L3.
and o-phenylenediamine derivatives, generating indenoquinoxalin
compounds with anticancer and/or anti-inflammatory properties
[
12,13]. Incorporating those indenoquinoxalin as ligands in the for-
Empirical formula
C70H56N5P3SCuBr (Cu-L3.PPh3)
mation of metal complexes are rare but prove to be a good strategy
to combine the biological activities of both chromophore (the lig-
and and the metal center) [14]. Motivated by this recent article, the
current work will be dedicated to design ligands with quinoxaline-
containing tetracyclic systems and incorporate them in the synthe-
sis of copper(I) complexes. Biological activities will be evaluated
for the ligands and their corresponding copper(I) complexes.
Formula weight
Temperature/K
Crystal system
1235.61
296(2)
Triclinic
Space group
a/A˚
b/A˚
c/A˚
P-1
13.6459(6)
14.2147(6)
18.0564(10)
α/°
β/°
γ /°
93.846(4)
98.404(4)
116.760(5)
2. Experimental section
˚ 3
Volume/A
3058.5(3)
Z
2
calcg/cm3
1.342
2
.1. Chemicals and reagents
ρ
μ/mm-1
F(000)
Crystal size/mm3
1.169
1272.0
Solvents were obtained commercially and used without any
0.27 × 0.19 × 0.16
MoKα (λ = 0.71073)
5.696 to 58.286
further purification. Hydrazine hydrate, phenylhydrazine and
thiosemicarbazide were obtained commercially. Synthesis of
CuBr(PPh3)3 was achieved as described in literature by stirring
copper(II) bromide with ca. four molar equivalents of triph-
enylphosphine in refluxing ethanol under inert gas atmosphere.
The product was precipitated in few minutes and collected by
filtration as a white powder [15]. Indeno[1,2-b]quinoxaline-11-
one was synthesized following the literature procedure by reflux-
ing equimolar amounts of ninhydrin and o-phenylenediamine in
ethanol; the product was obtained as a yellow precipitation that
was collected by filtration [16].
Radiation
2θ range for data collection/°
Index ranges
−18 ≤ h ≤ 18, -19 ≤ k ≤ 19, -24 ≤ l ≤ 23
34,733
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
14,597 [Rint = 0.0717, Rsigma = 0.1036]
14,597/0/742
0.999
R1 = 0.0751, wR2 = 0.1749
R1 = 0.1485, wR2 = 0.2221
1.27/−0.75
Largest diff. peak/hole / e A˚
−
3
added, forming a yellow precipitation. The precipitation was col-
lected by filtration and dried, affording the product as a yellow
2
.2. Instruments
1
powder (0.823 g, 78%). H NMR δ, (850 MHz, CDCl3): δ 7.48–7.50
Infrared spectra were recorded for KBr discs of the compounds,
(
t,1H, Harom), 7.50–7.57 (t,1H, Harom), 7.76–7.77 (t, 1H, Harom), 7.79–
using a Bruker Alpha FT-IR; peaks are reported in cm 1. 1H
−
7
.85 (t, 1H, Harom), 7.85 (d, J = 6.8 Hz, 1H, Harom), 8.11–8.12 (d, 1H,
NMR (600 MHz) spectra were recorded using a Bruker Avance
−1
Harom), 8.30–8.34(m, 2H, Harom). IR spectrum, ν, cm : 3411, 3310
6
00 MHz spectrometer. Electrospray ionization (ESI) mass spec-
+
(
NH2), 1600 (C=N), 1587 (C=N arom). ESI MS [C15H10N ] : calcd
4
tra were recorded using an Agilent Q-TOF 6520 instrument; all
mass spectrometry data are reported as m/z. Crystals of L3-Cu
suitable for analysis were obtained by vapor diffusion of hex-
ane into a solution of the reaction mixture in dichloromethane
at 5 °C. Crystals were observed under a microscope, selected and
mounted on an Agilent SuperNova (Dual source) Agilent Technolo-
gies Diffractometer, equipped with microfocused Cu/Mo Kα radi-
ation for data collection. The data collection was undertaken us-
ing CrysAlisPro software [17] at 296 K with Mo Kα radiation. The
structure was solved using SHELXS–97 [18] and refined by full–
matrix least–squares methods on F2 using SHELXL–97 [18], in-
terfaced with WinGX [19] (Table 1). The refinement of all non–
hydrogen atoms were acheived anisotropically by full–matrix least
squares methods [18]. The figures were produced through PLATON
2
46.1, found 246.1. Anal. Calcd for C15H N : C, 73.16; H, 4.09; N,
10 4
2
2.75%; found: C, 72.79; H, 3.72; N, 22.38%.
Synthesis of L2:
Into a conical flask, a solution of Indeno[1,2-b]quinoxaline-11-
one (0.940 g, 4.0 mmol), phenylhydrazine (0.4 ml, 4.0 mmol) and
Magnesium Sulphate (0.487 g, 4.0 mmol in a mixture of ethanol
2
8
0 mL and chloroform 10 ml was stirred at room temperature for
h. A precipitate orange was formed. The solvent was evaporated
through rotatory. 10 ml dichloromethane was added to precipitate
before filtering the solution by filtration paper, and evaporating the
filtrate to afford the wanted orange precipitate (1.021 g, 78%). 1
H
NMR δ, (400 MHz, CDCl3): δ 3.71–3.74(s, 1H, Harom), 7.06–7.09 (t,
H, Harom), 7.26 (s, 1H, Harom), 7.39–7.48 (dd, 4H, Harom), 7.57–
.62 (m, 2H, Harom), 7.68–7.72 (m, 4H, Harom), 12.80(s, 1H, NH).
1
7
[
20] and ORTEP [21] interfaced with WinGX. All hydrogen atoms
IR spectrum, ν, cm–1 3200 (NH), 1600(C=N), 1252 (N-Ph). ESI MS
were arranged geometrically and treated as riding atoms with C–
˚
for all carbon atoms. Crys-
eq(C)
+
[
C21H14 N ] : calcd 322.1, found 322.1. Anal. Calcd for C
H
21 14
N : C,
4
4
H = 0.93 A and U
= 1.2U
iso(H)
7
8.24; H, 4.38; N, 17.38%; found: C, 78.39; H, 4.19; N, 17.21%.
Synthesis of L3:
solution of Indeno[1,2-b]quinoxaline-11-one (0.510 g,
.2 mmol) and NH CSNHNH2 (2.000 g, 2.2 mmol) in a mix-
tal data are summarized in Table 1 and can be obtained free of
charge under the deposition number 2061538 from CCDC, 12 Union
Road, Cambridge CB21 EZ, UK (Fax: (+44) 1223 336–033; e-mail:
data_request@ccdc.cam. ac.uk).
A
2
2
ture of ethanol 15 mL and chloroform 10 mL was stirred at
reflux for 8 h in the presence of an excess amount of anhydrous
magnesium sulfate. The reaction mixture was cooled down and
filtered. The yellow filtrate was reduced in volume to ca. 10 mL
and 40 mL ethanol were added, forming yellow precipitation. The
precipitation was collected by filtration, washed with petroleum
spirit (40–60 °C fraction) and dried, affording the product as a
yellow powder (0.522 g, 74%). 1H NMR δ, (400 MHz, CDCl3): δ
2
.3. Synthesis and characterization of the compounds
Synthesis of L1:
To
a solution of Indeno[1,2-b]quinoxaline-11-one (1.000 g,
4
.3 mmol) and N H .H O (0.420 ml, 8.6 mmol) in 20 mL toluene,
2
4
2
anhydrous magnesium sulfate (ca. 1 g) was added and the mix-
ture was stirred at reflux for 8 h. The reaction mixture was cooled
down and the filtered. The yellow filtrate was reduced in volume
to ca. 10 mL and 40 mL petroleum spirit (40–60 °C fraction) was
7.66 (t, J = 7.6 Hz, 1H, Harom), 7.79–7.84 (t, 2H , Harom), 7.87–7.91
2
(t, 1H, Harom), 7.96 (d, J = 7.6 Hz, 1H, Harom), 8.28–8.37 (m, 3H,
Harom). IR spectrum, ν, cm–1: 3262 (NH), 3375, 3416 (NH ), 1630
2
2

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Scheme 1. Synthesis of L1-L3 and Cu-L3.
Fig. 1. Overlaid IR spectra of the L1 and the precursor (Left), showing the Schiff base formation and overlaid IR spectra of L3 and Cu-L3 (right).
(
C=N), 1618 (C=Narom), 1618, 1560, 1500 (C=Carom). 1256 (C=S),
chloroform. The mixture was stirred for eight hours under a ni-
trogen gas atmosphere at room temperature, no reaction was de-
tected by using Thin Layer Chromatography technique (TLC).
The reaction of L3 and CuBr(PPh3)3 (Cu-L3):
+
002(C–N). ESI MS [C1
H N S] : calcd 305.1, found 305.1. Anal.
6 11 5
1
Calcd for C16 H11 N S: C, 62.93; H, 3.63; N, 22.93%; found: C, 63.11;
5
H, 3.49; N, 22.51%.
The reaction of L1 and CuBr(PPh ) :
In a two-neck round bottom flask, L3 (0.250 g, 0.8 mmol) was
added into a solution of CuBr(PPh3)3 (0.726 g, 0.7 mmol) in 20 mL
chloroform. An instant orange solution was formed, and the solu-
tion was stirred for five hours under nitrogen gas atmosphere. The
orange solution was reduced in volume to ca. 10 mL and 40 mL
petroleum spirit (40–60 °C fraction) was added under nitrogen at-
mosphere, forming an orange precipitation. The precipitation was
collected by filtration and dried, affording the product as an orange
powder of Cu1-L3 (0.450 g, 58%). 1H NMR δ, (600 MHz, CDCl3):
3
3
In a two-neck round bottom flask, L1 (0.250 g, 1.0 mmol) was
added into a solution of CuBr(PPh3)3 (0.944 g, 1.0 mmol) in 20 mL
chloroform. The mixture was stirred for eight hours under a ni-
trogen gas atmosphere at room temperature, no reaction was de-
tected by using Thin Layer Chromatography technique (TLC).
The reaction of L2 and CuBr(PPh ) :
3
3
In a two-neck round bottom flask, L2 (0.250 g, 0.8 mmol) was
added into a solution of CuBr(PPh3)3 (0.721 g, 0.8 mmol) in 20 mL
3

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
N, P, Br, Cl and H [25], and the SDD basis set for Cu [26]. No sym-
metry constraints were used in the geometry optimizations, and
the final geometries were confirmed to be the minimum potential
energy structures through frequency calculations. Weak interac-
tions have been included in the energy evaluations using Grimme
D3 corrections [27]. The vibrational frequency calculations for all
ligands and complexes were performed to show the IR spectra in
comparison with experimental data. The delocalization interactions
of the proposed complexes were estimated by using Natural Bond
Orbital (NBO) program (Version 3.1) [28].
Fig. 2. Proposed hydrogen-bonding in L1 (left) and observed hydrogen-bonding in
Cu-L3 single crystal (right).
2
2
.5. Antimicrobial studies
0
-
.92−0.96 (dd), 1.34 −1.46 (m), 1.70–1.72 (t), 4.23 - 4.27 (m), 7.28
.5.1. The agar disk-diffusion method (DDM)
7.32 (dd), 7.38 - 7.45(m), 7.50 - 7.52 (dd), 7.58–7.60 (t), 7.68–
The tested microorganisms Escherichia coli, Pseudomonas aerug-
7
.70 (dd), 7.88 - 7.97 (m), 8.29 - 8.31 (d), 8.44 - 8.47 (d), 13.01(S,
inosa (Gram negative bacteria), Staphylococcus aureus (Gram posi-
tive bacteria) as well as the fungus Candida albicans were pure iso-
lates and taken from the culture collection of King Fahd Medical
Research Center (KFMRC) at King Abdulaziz University. Sabouraud
broth and nutrient were utilized for cultivating bacteria and the
fungus like yeast (C. albicans) respectively. The activity of lig-
ands L1, L2 and L3 as well as Cu-L3 against different pathogenic
microorganisms was done, using gentamicin and dimethylsulfox-
ide (DMSO) as positive and negative controls respectively [29].
Overnight cultures of the bacterial and C. albicans indicators were
prepared in nutrient and sabouraud broths. The amounts of 0.5 mL
(about 105 cells/mL) were speared over plate of corresponding
sterilized media. In seeded agar plate, the paper disks (6 mm in
diameter) placed and containing 30 μL of the solution previously
prepared of the different ligands and the complex. The plates were
NH). IR spectrum, ν, cm–1: 3262 (NH), 3419 (NH ), 1596 (C=Narom),
2
1
620, 1506, 1480 (C=Carom), 1261 (C=S), 841 (Cu-S), 540 (C-P), 490
+
(
Cu-N). ESI MS [M-Br] : calcd 892.2, found 892.2. Anal. Calcd for
C52H41BrCuN P S: C, 64.16; H, 4.25; N, 7.19%; found: C, 63.78; H,
5
2
3
.88; N, 6.83%.
2
.4. Theoretical studies
All the calculations have been performed using the Gaussian09
suites [22]. Preparation of models and analysis of the results was
made by Gaussview Software [23]. We applied the density func-
tional theory (DFT) method with the B3LYP functional [24] with
a split-valence double-zeta basis set (6–31 G) and five d-type
Cartesian-Gaussian polarization functions on each of the atoms C,
Fig. 3. Structures of the considered complexes: (a) complex 1 (b) CuBrPPh3-L1 (c) CuBrPPh3-L2 (d) CuBrPPh3-L3.
4

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Fig. 4.. ORTEP diagram of Cu-L3 where probability of thermal ellipsoids were drawn at 20% probability level.
then incubated at 30 °C for 24 h, after which the diameters of inhi-
bition zones were determined to approximate its inhibitory effects.
lowest concentration of solution that prevented this color change.
Eventually, the minimum inhibitory concentration (MIC) was de-
termined against Staphylococcus aureus (Gram positive bacteria).
2
.5.2. The minimal inhibitory concentration method (MIC)
Indeno[1,2-b]quinoxaline-11-one, L3 and Cu-L3 were chosen to
3. Results and discussions
be tested by MIC method. The selected compounds were dissolved
in DMSO the different concentrations and three-fold serial dilution
was carried out to ensure reproducibility. In the sterile dilution
assay, 100 μL of culture from an incubated was taken into 96-
well- plate, from starting concentration of dispensed in columns
and 50 μL added of the solution previously prepared of the differ-
3.1. Synthesis and characterizations
The work was directed toward the synthesis of
indenoquinoxlaine-based ligands and their copper (I) complexes.
Stirring ninhydrin and o-phenylenediamine in refluxing ethanol
provided Indeno[1,2-b]quinoxalin-11-one which is the precursor
to synthesize the three ligands. The compound was confirmed
1H NMR and IR spectroscopic techniques. Then, Indeno[1,2-
b]quinoxalin-11-one reacted with hydrazine hydrate (in toluene),
phenylhydrazine (in chloroform/ethanol mixture) and theosemi-
carbazide (in chloroform/ethanol), producing L1, L2 and L3 respec-
tively (Scheme 1). In case of L1, the use of toluene was made after
several attempts in different solvents. The benefit of the toluene
is that it was able to evaporate water out of the system, allowing
the formation of the C=N bond and the progress of the reaction to
ent ligands and Cu-L3 were dissolved in DMSO into each well of
9
6-well-plate containing nine different concentrations (25 × 10 3,
−
−3
−3
−3
−3
−3
1
2.5 × 10 , 6.25 × 10 , 3.12 × 10 , 1.56 × 10 , 0.78 × 10
−3
−3
and 0.39 × 10 , and 0.19 × 10 M respectively) [30,31]. A change
in the color from blue to pink indicates the presence of biological
material or bacteria due to the presence of Resazurin. Resazurin in
the negative control give blue color indicating the absence of bio-
logical materials. In contrast, the positive control turns into pink
color. The reaction between Resazurin and solution determined
the minimal inhibitory concentration (MIC) and was noted as the
5

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Table 2
Table 4.
Energies of the two possible structures of L2.
Some selected second-order perturbation (E(2)) estimation of the hyperconjuga-
tive energies (kcal/mol) of four complexes, obtained by employing B3LYP-D3/6-
Structure
H-bonding
Energy (a.u)
Energy (kcal/mol)
31G(d)/SDD//3-21G level of theory.
L2
no
−1027.687
−1027.709
−0.022
–
No.
Transition
CuBr(PPh3)(phen)
Cu-L1
Cu-L2
Cu-L3
L2
yes
–
Difference
−13.7
1
n(1)N1 → n∗(6)Cu
23.88
24.43
13.54
23.14
20.01
16.01
127.61
102.65
13.09
16.49
3.56
15.87
13.97
3.55
0.50
∗
∗
∗
∗
2
n(1)N1 → n (8)Cu
0.25
3
n(1)N1 → n (9)Cu
3.75
4
n(1)N2 → n (6)Cu
21.49
5.91
1.64
0.43
Table 3
5
n(1)N2 → n (8)Cu
0.45
0.08
Different distances and angles of the interaction between different ligands and
∗
6
n(1)N2 → n (9)Cu
14.30
138.56
69.33
0.76
0.06
the fragment CuBr(PPh3) as calculated by DFT B3LYP/6–31G(d)/SDD level of the-
ory.
∗
7
n(1)P → n (6)Cu
127.37
22.38
124.66
49.09
11.69
10.72
∗
8
n(1)P → n (7)Cu
Bond lengths ( A˚ )
Angles (°)
∗
∗
9
n
(
1)P
→ n
(8)Cu
L + CuBr(PPh3)
10
n(1)P → n
ꢀ
(9)Cu
∗
∗
∗
Cu-N1
Cu-N2
Cu-Br
Cu-P
Cu-S
PCuBr
1
1
n(1)Br → n (6)Cu
9.68
13.45
22.81
13.41
11.97
9.28
Phenanthroline
2.20
2.41
3.16
–
2.16
2.26
2.39
–
2.34
2.35
2.30
2.35
2.25
2.21
2.21
2.22
–
120
133
145
117
12
13
14
15
n(1)Br → n (8)Cu
31.19
102.19
45.97
42.37
97.59
34.07
33.05
82.00
38.50
16.76
12.63
14.74
15.54
56.92
466.30
L1
L2
L3
–
n(4)Br → n (6)Cu
∗
–
n(4)Br → n (8)Cu
∗
2.41
n(1)S → n (7)Cu
∗
1
1
1
1
6
7
8
9
n(1)S → n (8)Cu
∗
n(1)S → n (6)Cu
∗
n(1)S → n (8)Cu
∗
n(1)S30 → n (6)Cu
completion. The reactions of Indeno[1,2-b]quinoxalin-11-one with
Total
540.30
334.90
218.34
the different hydrazines were confirmed clearly by IR spectrometry
−1
as there were clear shifts for the band at 1730 cm
(stretching
frequency for C=O) to 1580–1630 cm− due to the formation of
1
phenanthroline is able to establish Cu-N interactions with dis-
tances within the bonding range, however, the other ligands have
Cu-N interactions with long distances that are not normally ob-
served for Cu-N bonds or no interaction at all (Table 3). One
more indication from the calculation is the geometrical structure
adopted by the central atom which deviated from the preferred
tetrahedral geometry of d10-configuration copper(I) as can been
seen in Fig. 3. This indicates that the nitrogen atoms in L1–L3 are
not soft enough to establish stable bonding interactions. L3 was
azomethine bond (C=N) (Fig. 1).
Ligands L1, L2 and L3 were stirred with CuBr(PPh ) into
3
3
dichloromethane, at room temperature and under nitrogen atmo-
sphere; there was no reaction in the case of L1 and L2 while L3
provided an orange compound (Scheme 1). L1 and L2 although
contain several N-donating atoms, they are still not soft enough
to coordinate to replace the phosphine ligands in the copper com-
plex [32]. Moreover, the nitrogen atoms were engaged in forming
hydrogen-bonding (Fig. 2), disabling the process of complexing lig-
ands (L1) and (L2) to copper center. L3 contains five N-donating
atoms and one S-donating atom with many possibilities for chela-
tion. The orange compound was recrystallized and crystal struc-
ture of the complex was obtained, showing that sulfur is the only
atom coordinating. Although, the preference of the copper to phos-
phorus is more than the sulfur-containing ligands, the steric hin-
drance (caused by the three triphenylphosphine groups) enhanced
the progress of the reaction. Unfortunately, the chelate effect was
not enough to stabilize the replacement of another phosphine by
one of the four nitrogen donating atoms in L3 due to the presence
of hydrogen bonding as indicated by the crsyatl structure (Fig. 4)
and possibly by the basic nature (hard Lewis bases) of the nitrogen
atoms in the ligands [33].
able to interact with CuBr(PPh ) through sulfur-atom with a dis-
3
˚
tance of 2.41 A which is close from that observed in the crystal
˚
structure (2.37 A).
The Natural Bond Orbitals (NBO) are used to calculate electron
densities (distributions) in atoms and bonds between atoms [37–
3
9]. The Natural Bond Orbital (NBO) analysis has been conducted
through studying the second order perturbation energies (E ) as
2
shown in the following equation:
ꢁ
ꢂ
2
Fij
E(2) = ꢀEij = qi
ꢀ
ε
where q is the occupancy of the donor orbital (i), F is the NBO
i
ij
Kohn-Sham off-diagonal matrix elements and ࢞ε is difference be-
tween the energies of the donor orbital (i) and an acceptor orbital
(j). Table 4 lists the relevant second order perturbation energies
Theoretical studies were carried out to rationalize the findings
of the experimental work. The optimization of three different lig-
ands (L1, L2 and L3) as shown in Scheme 1 have been performed
on various orientations. Results showed that the optimized struc-
tures are the ones possessing hydrogen bonding which are clearly
more stable. Furthermore, L2 was chosen to perform the energy
calculation because it has only two possible orientations: one con-
tains hydrogen bonding and the other one has not (The other two
ligands have several possible orientations involving different num-
ber of hydrogen bonding). The energy difference is pronounced
as the structure with H-bond is less in energy by 13.7 kcal/mol
(E ) for the different studied complexes illustrated in Fig. 3. The
2
calculations were estimated by employing B3LYP-D3/6-31G(d)//3-
21 G (NBO single point calculations) level of theory and summa-
rized in Table 4.
The natural charges of the Cu atom decrease on
CuBr(PPh )(phen) by 0.4e when the Phenanthroline is con-
3
nected to Cu by its N atoms which also become more negative
(moved from −0.45e on the ligand alone to −0.65e on the ligand
connected to Cu complex). However, slight change has been no-
ticed for the complexes Cu-L1 and Cu-L2 (moving from −0.63e to
−0.66e and from 0 to 0.52e to −0.54e for N1 and N2). The same
behavior is shown on the Cu-L3 with slight decrease of the natural
charges of N atoms additional to have the natural charges of S
atom more positive.
(
Table 2).
The reaction of CuBr(PPh3)3 proceeds almost immediately with
bipyridine, phenanthroline and their derivatives, producing com-
plexes with the general formula CuBr(PPh )(N^N) [34–36]. How-
ever, the imines in L1-L3 were unable to establish any bond-
3
ing with CuBr(PPh ) in a similar manner to that of the bipyri-
The most important hyperconjugative interactions include the
3
∗
dine, phenanthroline or their derivatives. Therefore, we sought to
investigate this reactions theoretically by evaluating the interac-
ligand nonbonding to metal antibonding orbital (n → n ). Com-
L
M
plex 1 shows higher value of E(2) for all bonds with Cu-P, Cu-Br
and also with Cu-N1 and Cu-N2 (540 kcal/mol for all bonds and
tion of each ligand and phenanthroline with CuBr(PPh ) (Table 3).
3
6

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Table 5
Assignment of the IR spectra peaks by matching the experimental against calculated IR spectra of
Cu-L3 and L3.
Cu-L3
L3
Assignment
Calculated (cm 1)
−
Observed (cm
−1
)
Calculated (cm
−1
)
−1
Observed (cm )
NH2
3702, 3554
3358
3192
1685
1677
1663
1661
1620
1603
1504
1436
1340
1247
837
3419,3222
3260
2921
1716
1660
1660
1659
1572
1596
1506
1480
1338
1261
841
3731, 3581
3219
3189,
1619
1669
1657
1641
1624
1563
1547
1497
1319
1246
–
3416,3375
3262
3171
1630
1634
1650
1642
1618
1600
1560
1500
1338
1256
–
NH
CH(Ar’)
C=N
C=C
C=N aliph.
C=N
C=C arom.
C=N arom.
C=C arom.
C=C arom.
NH–C–NH2
C=S
Cu-S
C-P
716
725
708
713
Cu-P
518
540
–
–
Cu-N
480
490
–
–
Cu-Br
456
458
–
–
roughly 121 kcal/mol for N1 and N2). Comparing with Cu-L1, Cu-L2
and Cu-L3, Cu-N interactions are 74.8, 36.2 and 5 kcal/mol, respec-
tively. However, Cu-L3 showed, in addition, Cu-S interaction which
made the total hyperconjugative interactions approaching the com-
plex1 interaction (466.3 kcal/mol for Cu-L3).
Although, we were lucky enough to obtain crystal structure of
Cu-L3, we decided to carry out detailed IR peaks’ assignment for
Cu-L3 against L3 as a benchmark for complexes with the general
formula [CuX(PPh ) (S-donating ligands)]. The theoretically pre-
3
2
dicted IR spectra have been used as a guideline to identify the
peaks in the experimentally obtained IR spectra (Table 5). The most
important peaks to highlight are those of Cu-Br and Cu-P which
showed signals at 456 and 490 cm-1 respectively while Cu-S is out
of the measurement range of our spectrometer.
3
.2. Crystallographic studies
Fig. 5.. Dimer formation in compound 1, where dashed lines are showing co-
The central copper atom in the molecule is coordinated to two
ordination or hydrogen bonding.
triphenylphosphine groups, a bromine atom and to the indeno[1,2-
b]quinoxalin-11-ylidenecarbothioamidohydrazide (L3) ligand via S
atom (Fig. 4). The coper atom is four coordinated and hence form-
ing a distorted tetrahedral geometry around it trigonal pyramid
N1-H(1a/1b)…Br interactions, where N1 is acting as donor atom
while Br is acting as acceptor atom following the symmetry code
-x + 2, -y + 2, -z + 1 (Fig. 5).
based on the geometry index value (τ ) of 0.85 [40]. This value
4
is less than that of the parent complex CuBr(PPh3)3 which has
geometry index value equal to 0.90 (less distorted tetrahedral
structure) [41]. In general, Cu-L3 complex has shorter Cu-P bond
lengths compared to the parent complex [41] which suggest less
steric hindrance in Cu-L3. Different angles around the Cu atoms
are 124.76(5)°, 115.02(4)°, 108.45(4)°, 105.28(4)° and 98.18(5)°. The
ligand indeno[1,2-b]quinoxalin-11-ylidenecarbothioamidohydrazide
3.3. Antimicrobial studies
The antimicrobial properties of the indeno[1,2-b]quinoxaline
containing compounds has been evaluated, using Agar disk-
diffusion method (Table 6). In general, Indeno[1,2-b]quinoxalin-11-
one has inhabitation zones ranging from 13 to 15 mm against the
three tested strains. While this values approaching 75% of that of
well-known antibiotic agent “gentamicin” against S. aureus strain
(positive gram), the effectiveness is around 50% when compared
to gentamicin against negative gram bacteria. Replacing the ketone
group (C=O) with the hydrazone group “C=N–NHR” leads to an
enhancement in the activity against the positive gram bacteria in
case of L2 and L3 but reduced or canceled the antimicrobial ac-
tivity against the negative gram bacteria. The copper containing
compound (L3-Cu) showed no antimicrobial activity in this method
possibly due to solubility problem which prevent the diffusion of
the compound to the Agar disk (Fig. 6). All the ligands and the cop-
(
C1-C16/N1-N5/S1), is nonplanar with the root mean square devi-
˚
˚
ation of 0.0802 A where the N5 = −0.2476 (4)A and N1 = 0.0844
˚
4)A are the most deviating atom from the plane produced from
(
the fitted atoms of the compound. The dihedral angle between
the hydrazinecarbothioamide (C1/N1/N2/N3/S1) and indeno[1,2-
b]quinoxaline (C2-C16/N4/N5) is 10.72(3)° which is indicating the
nonplanar behavior of this ligand molecule. The availability of N–H
bonds produces the intra and intermolecular hydrogen bonding. In-
tramolecular hydrogen bonding from N–H…N produces 5 and 6
membered ring motifs S(5) & S(6) while intermolecular hydrogen
bonding produced dimers with the formation of 8 membered ring
motifs R42(8). Intermolecular hydrogen bonding are produced from
7

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Fig. 6. The zone of inhibition of S. aureus with disk diffusion method for (1) Indeno[1,2-b]quinoxaline-11-one, (2) L3 and (3) Cu-L3.
Fig. 7. The antimicrobial activities of selected compounds against S. aureus bacteria evaluated by the MIC method.
Table 6
4. Conclusion
Inhabitation zones of L1-L3 and Cu-L3 as evaluated by Agar disk-diffusion method.
S. aureusa
P. aeruginosab
E. colib
In the current work, three ligands were derived from the con-
densation of indeno[1,2-b]quinoxalin-11-one and hydrazines (L1
from hydrazine, L2 from phenylhydrazine and L3 from thiosemi-
carbazide). The three ligands reacted with CuBr(PPh ) ; L3 is the
Gentamicin
21 mm
15 mm
27 mm
13 mm
28 mm
14 mm
Indeno[1,2-
b]quinoxaline-11-one
3
3
L1
0 mm
0 mm
0 mm
0 mm
0 mm
0 mm
11 mm
0 mm
0 mm
only one was able to react, providing a complex with the formula
L2
18 mm
20 mm
0 mm
S
CuBr(PPh3)2(κ -L3). None of the three ligands were able to use the
L3
nitrogen atoms as donating atoms due to their highly engagement
in hydrogen-bonding as observed in the crystal structure of Cu-L3
as well as the theoretical calculations. Moreover, theoretical cal-
culation indicated that Cu-N interactions were weak, and the dis-
tances are longer than the typical bonding distances. Antimicro-
bial screening against a range of strains showed selective inhabita-
tions of indeno[1,2-b]quinoxalin-11-one, L1 and L3 against S. aureus
strain. Moreover, the introduction of the copper fragment to L3 did
not cause any significant improvements to the antimicrobial prop-
erties of L3.
Cu-L3
agram positive bacteria.
bgram negative bacteria.
per complex exhibit no antifungal effect on the yeast-like candida
albicans strain.
To gain better judgment on the antimicrobial activities of the
copper complex against S. aureus strain, indeno[1,2-b]quinoxalin-
1
1-one, L3 and Cu-L3 were evaluated by the minimum in-
hibitory concentration method (Fig. 7). Solutions with concentra-
tions 0.2 μM of indeno[1,2-b]quinoxline-11-one and L3 were able
to reduce the bacterial growth significantly (ca. 50%). Testing more
concentrated solutions (up to 250-fold increase) of L3 cause in-
significant inhabitation, however, increasing the concentration of
the parent compound reduced the bacterial growth up to 91%. The
coordination of the CuBr(PPh3)2 moiety to L3 reduce the antimi-
crobial activity of L3; 125-fold increase in the concentration of Cu-
L3 was necessary to induce similar growth inhabitation to that of
L3 at 0.2 μM.
Author statements
BAB conceived of the presented idea. BAB, MB and NAA syn-
thesized and characterized the compounds. NAA, NMB and AMA
investigated the antimicrobial properties. MNA did the XRD mea-
surements and write the structures description. AJ performed the
computational studies. BAB supervised the findings of this work.
BAB and MAH discussed the results and contributed to the final
manuscript.
8

B.A. Babgi, M. Bawazeer, N.A. Alzaidi et al.
Journal of Molecular Structure 1238 (2021) 130309
Declaration of Competing Interest
tives and Tryptanthrin-6-oxime: synthesis, characterization, cytotoxicity, and
catalytic transfer hydrogenation of aryl ketones, ACS Omega
1167–11179.
5 (2020)
1
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
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