New Ag(I) and Pd(II) complexes derived from symmetrical and asymmetrical NHC precursors: Synthesis, Characterization, Antibacterial activity, and Theoretical calculations

Article abstract of DOI:10.1016/j.molstruc.2021.131254

New symmetric and asymmetric imidazolium salts namely 1-methyl-3-(2,5-dimethylphenyl)-acetamideimidazolium chloride (2), 1-benzyl-3-(2,5-dimethylphenyl)-acetamideimidazolium chloride (3) and 1,3-bis-(2,5-dimethylphenyl)-acetamideimidazolium chloride (4) w

Full text of DOI:10.1016/j.molstruc.2021.131254

Journal of Molecular Structure 1245 (2021) 131254
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
New Ag(I) and Pd(II) complexes derived from symmetrical and
asymmetrical NHC precursors: Synthesis, Characterization,
Antibacterial activity, and Theoretical calculations
Mohammed Z. Ghdhayeba, Karem J. Sabaha, Abbas Washeel Salmanb,∗
,
Mustafa Mohammed Kadhimc,d
a Department of Chemistry, Faculty of Science, University of Kufa, Kufa, P.O.BOX(21), Najaf, Iraq
b Department of Production, College of Agriculture, Wasit University, Kut, Wasit, 52001, Iraq
c Department of Dentistry, Kut College University, Kut, Wasit, 52001, Iraq
d College of technical engineering, The Islamic University, Najaf, Iraq
a r t i c l e i n f o
a b s t r a c t
Article history:
New symmetric and asymmetric imidazolium salts namely 1-methyl-3-(2,5-dimethylphenyl)-
acetamideimidazolium chloride (2), 1-benzyl-3-(2,5-dimethylphenyl)-acetamideimidazolium chloride
(3) and 1,3-bis-(2,5-dimethylphenyl)-acetamideimidazolium chloride (4) were synthesized. In situ de-
protonation technique was employed to synthesize Ag(I)-NHC complexes (5-7) from the reaction of
Ag2O with the abovementioned ligand precursors. Subsequent reactions of Ag(I)-NHC complexes with
[PdCl2(MeCN)2] resulted the Pd(II)-NHC complexes (8-10) via transmetallation method. All the synthe-
sized compounds were characterized using various techniques such as 1H and 13 C NMR, FTIR and CHN
analysis. The antibacterial activity of all the compounds was evaluated against bacterial strains E. coli
as gram-negative and S. aureus as gram-positive bacteria using azithromycin as a standard antibiotic.
The density functional theory (DFT) method was used to optimize the structures of the synthesized
compounds using Gaussian 09 and Molecular Graphic Laboratory (MGL). Electronic energy, HOMO,
LUMO, and dipole moment were calculated as well. Further, the estimated anticancer activity of the
compounds was determined using docking calculations.
Received 25 May 2021
Revised 2 August 2021
Accepted 4 August 2021
Available online 6 August 2021
Keywords:
Silver
Palladium
Acetamide
NHCs
E. coli
S. aureus
Docking
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
may easily be modified by the introduction of various substituents
on the heterocycle [11,12].
Since its first isolation by Arduengo in 1991, and due to its re-
markable applications particularly in catalytic and biological ones,
N-heterocyclic carbene (NHC) chemistry has undergone incredi-
ble expansion [1-6]. NHCs have a strength highly favored forming
complexes with a series of metals than heterocycles that have a
P, N, O, and S atoms, also the metal-carbene bond is more reac-
tive than the other types of metal-complexes such as phosphine
complexes [7]. Two important factors can affect the stabilization of
NHCs, the first is π-bonding by a resonance effect, and the second
is σ-bonding by an inductive effect [8]. The bonding properties of
NHC may be better as σ-donors compared to those of known tri-
alkyl phosphines, makes them good candidates for the stabilization
of transition-metal catalysis in various oxidation states during bi-
ological activities [9,10]. In addition, the shape and size of NHCs
The interest in the chemistry of Ag(I)-NHC complexes has
greatly expanded during the last two decades. This is because of
different strength points including; synthetic strategies, structural
diversity, and their usefulness in several applications. So, many re-
search articles and reviews focusing on the structure and appli-
cations of silver(I)-NHC complexes have been published [13-19].
So far, the carbene transfer method which is used in the synthe-
sis of different transition metal-NHC complexes is the most sig-
nificant application for Ag(I)-NHCs. This method was discovered
by Lin and co-workers and used to synthesize palladium(II)- and
gold(I)-NHC complexes [20]. Later, it has been applied successfully
in the synthesis of many NHC complexes with a variety of metals,
such as nickel, ruthenium, rhodium, platinum, gold, iridium and
..etc [12,21,22]. In this context, silver(I)–NHC complexes are impor-
tant for the preparation of active species in homogeneous catalysis
by transmetallation to other transition metal–NHC complexes [23].
Furthermore, silver-NHC complexes showed another significant ap-
plications includes their potential use as antifungal [24,25], an-
∗
Corresponding author.
E-mail addresses: mohammed.alhallaqi@uokufa.edu.iq (M.Z. Ghdhayeb),
aws.chem@gmail.com (A.W. Salman).
https://doi.org/10.1016/j.molstruc.2021.131254
0022-2860/© 2021 Elsevier B.V. All rights reserved.

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Fig. 1. Energy levels HOMO and LUMO orbitals of compounds 2-4.
timicrobial [18,19,26], and anti-cancer agents [18,21,22,26,27-29].
Recently, according to theoretical calculations, some imidazolium
salts and Ag-NHC complexes showed activity against the novel
COVID-19 and could act as potential inhibitors for the virus [30,31].
The chemistry of Pd(II)-NHC complexes is still considered very re-
cent, despite it has a history of two decades or some more. The po-
tential of catalytic properties of this class of complexes particularly
in coupling reactions was recognized by Herrmann and co-workers
[7]. Later, this field has grown widely into different types of cataly-
sis research. So, these complexes are studied extensively in cataly-
sis ranging from C-C coupling to olefin polymerizations [11,32,33].
Biological applications of Pd(II)-NHC complexes are reported
first time by Ray and co-workers in 2007 [34], as some of Pd(II)-
NHC complexes are examined for their potency as anticancer
agents and found to be active against various cancer cell lines. Af-
ter that, various studies focused on the biological applications of
these complexes, especially in the field of anticancer agents be-
ing these complexes are mimics to the platinum complexes that
have such activity [18,22,35]. In the present work, we report the
synthesis and characterization of new symmetrical and asymmet-
rical NHC precursors derived from 1,3-disubstituted imidazole and
their corresponding mononuclear Ag(I) and Pd(II) complexes. All
the prepared compounds were examined for their in-vitro antibac-
terial activity against bacterial strains E. coli and S. aureus. Further,
DFT and docking studies were used to have a deep insight into
more properties for the prepared compounds.
2. Experimental
2.1. Materials and instrumentation
All chemicals and solvents were of high analytical grade and
used as it is without further purification. Nuclear magnetic reso-
nance (NMR) spectra were recorded using Bruker 400 MHz spec-
trometers at ambient temperature. 1HNMR chemical shifts were
referenced to the solvent signals. FT-IR spectra were recorded with
a Shimadzu FTIR-8400s spectrophotometer. The elemental analysis
(CHN) was carried out on PerkinElmer series II, 2400 microana-
lyzer. Palladium chloride PdCl2 was converted to its corresponding
[PdCl2(MeCN)2] using a reported method. [36].
2.2. Syntheses of ligand precursors
2.2.1. Preparation of 2-chloro-N-(2,5-dimethylphenyl)-acetamide (1)
2-chloro-N-(2,5-dimethylphenyl)acetamide was synthesized ac-
cording to a reported procedure [37], by mixing (5 ml, 40 mmol)
of 2,5-dimethylaniline in benzene (10 ml) then 1.5 ml of trimethy-
lamine was added. The mixture was stirred for 20 min then
chloroacetyl chloride (3 ml, 40 mmol) was added dropwise. The
stirring was continued for another 30 min at room temperature.
After completion of the reaction, the resulted white precipitate was
filtered and washed with distilled water and then recrystallized us-
ing ethanol. Yield (5.9 g, 75 %), (m.p = 140-142 °C).
2

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Fig. 2. TED maps of compounds 2-4.
ꢀ
2.2.2. 1-methyl-3-(2,5-dimethylphenyl)acetamide imidazolium
chloride (2)
zolium H2 ), 7.93 (2H, d, J = 7 Hz, Ar-H), 7.64 (H, d, J = 8 Hz, imi-
ꢀ
ꢀ
dazolium H5 ), 7.42-7.25 (7H, m, Ar-H, imidazolium H4 ), 5.62 (2H,
s, CO-CH2N), 5.35 (2H, s, benzylic CH2), 2.55 (3H, s, CH3-Ar) and
2.53 (3H, s, CH3-Ar). 13CNMR (100 MHz, d6-DMSO) δppm: 158.6
In a 50 mL round bottom flask, 1-methylimidazole (1 g, 12.1
mmol) in 10 ml of dioxane was placed, then 2-chloro-N-(2,5-
dimethylphenyl)acetamide (2.4 g, 12.1 mmol) dissolved in 20 ml of
dioxane was added dropwise. The mixture was refluxed with stir-
ring at 90 °C for 24 hrs. After completion of the reaction, the sol-
vent was evaporated under reduced pressure and the crude prod-
uct was washed with diethyl ether and dichloromethane to get
the product as a white powder. Yield: (2.4 gm 82%), (m.p = 157-
159°C). FT-IR cm−1: 3268 m ν(N-H), 1667 m ν(C=O), 1583 m ν(C-
N). 1HNMR (400 MHz, d6-DMSO) δppm: 9.96 (1H, s, N-H), 8.12 (1H,
ꢀ
(N-CO), 138.8 (imidazolium C2 ), 136.2, 135.1, 134.4, 133.6, 129.3,
128.5, 127.6, 125.4, 124.2, 123.1 (Ar-C), 122.8, 121.6 ((imidazolium
ꢀ
ꢀ
C5 & and C4 ), 54.9 (CO-CH2N), 52.2 (benzylic C), 21.3 (Ar-CH3),
17.9 (Ar-CH3). Anal. Calc. for C20H22N3OCl: C, 67.50; H, 6.23; N,
11.81. Found. C, 67.32; H, 6.12; N, 11.68.
ꢀ
s, imidazolium H2 ), 7.72 (2H, d, J = 7 Hz, Ar-H), 7.62 (1H, d, J = 8
ꢀ
idazolium H4 ), 5.52 (2H, s, COCH2N), 4.0 (3H, s, N-CH3), 2.52 (3H,
Hz, imidazolium H5 ), 7.31 (1H, s, Ar-H), 7.24 (1H, d, J = 8 Hz, im-
ꢀ
s, CH3Ar) and 2.51(3H, s, CH3Ar). 13CNMR (100 MHz, d6-DMSO)
2.2.4. 1,3-(bis[3-N-2,5-dimethylphenylacetamide])imidazolium
chloride (4)
ꢀ
δppm: 158.3 (N-CO), 139.3 (imidazolium C2 ), 135.4, 133.2, 129.1,
ꢀ
C4 ), 55.8 (CO-CH2N), 37.2 (N-CH3), 20.8 (Ar-CH3), 18.3 (Ar-CH3).
This compound was synthesized in a similar method to that
for 3, but using 2 mole of 1. White powder product. Yield: (2.5
gm, 89%), (m.p = 250-252 °C). FT-IR cm−1: 3266 w ν(N-H), 1658
s ν(C=O), 1584 s ν(C-N). 1HNMR (400 MHz, d6-DMSO), δppm: 9.3
128.5, 125.6, 123.3 (Caromatic), 124.7, 121.9 ((imidazolium C5 & and
ꢀ
Anal. Calc. for C14 H18 N3OCl: C, 60.10; H, 6.49; N, 15.02. Found. C,
60.35; H, 6.99; N, 15.19.
ꢀ
(2H, s, 2 × N-H), 8.3 (1H, s, imidazolium H2 ), 7.8 (2H, s, imida-
ꢀ
ꢀ
2.2.3. 1-benzyl-3-(2- N-2,5-dimethylphenylacetamide)imidazolium
chloride (3)
zolium H5 & H4 ), 7.2 (4H, d, J = 7 Hz, Ar-H), 7.16 (2H, s, Ar-H),
5.3 (4H, s, 2 × CO-CH2N), 2.3 (6H, s, CH3Ar) and 2.2 (6H, s, CH3Ar).
13CNMR (100 MHz, d6-DMSO) δppm: 162.2 (N-CO), 138.9 (imida-
This compound was synthesized in a similar method to that
for 2, except using of benzylimidazole instead of methylimidazole.
White gummy product. Yield: (1.8 gm, 72%), (m.p= 165-166 °C).
FT-IR cm−1: 3287 m ν(N-H), 1647 s ν(C=O), 1589 s ν(C-N). 1HNMR
(400 MHz, d6-DMSO) δppm: 10.12 (1H, s, N-H), 9.33 (1H, s, imida-
ꢀ
zolium C2 ), 136.5, 135.3, 129.6, 128.2, 125.1, 114.3 (Ar-C), 123.7,
ꢀ
ꢀ
122.9 ((imidazolium C5 & and C4 ), 53.8 (CO-CH2N), 21.6 (Ar-CH3),
20.2 (Ar-CH3). Anal. Calc. for C23H27N4O2Cl: C, 64.70; H, 6.37; N,
13.12. Found. C, 64.67; H, 6.61; N, 13.31.
3

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Fig. 3. ESP maps of the compounds 2-4.
ꢀ
ꢀ
2.3. Synthesis of silver (I)-NHC complexes (5-7)
(imidazolium C5 & and C4 ), 55.2 (CO-CH2N), 37.5 (N-CH3), 21.2
(Ar-CH3), 18.8 (Ar-CH3). Anal. Calc. for C28H34AgN6O2Cl: C, 53.39;
H, 5.44; N, 13.34. Found. C, 53.07; H, 5.12; N, 12.98.
2.3.1.
Bis(1-methyl-3-(2,5-dimethylphenyl)-acetamideimidazolium)silver
chloride (5)
Excess of silver oxide (0.7g, 2.1 mmol) was added to compound
2 (0.5 g, 2.1 mmol) in 20 ml of acetonitrile. The mixture was
stirred for 8 h in glassware wrapped with aluminum foil at 50 °C.
The black suspension was filtered through a pad of celite to re-
move the excess Ag2O, and the solvent was removed under vac-
uum. The resulted white solid washed twice with fresh diethyl
2.3.2.
Bis(1-benzyl-3-(2,5-dimethylphenyl)-acetamideimidazolium)silver
chloride (6)
This compound was synthesized in a similar method to that
for 5, but using 2 mole of compound 2. White solid. Yield: (1.25
gm, 73 %), (m.p = 150-152 °C). FT-IR cm−1: 3279 m ν(N-H), 1664
s ν(C=O), 1594 m ν(C-N). 1HNMR (400 MHz, d6-DMSO) δppm:
9.83 (2H, s, 2 × NH), 7.84 (4H, d, J = 7 Hz, 2 × Ar-H), 7.47 (2H,
ether. Yield = (0.84 gm, 65 %), (m.p= 130-132 °C). FT-IR cm−1
:
3265 s ν(N-H), 1668 s ν(C=O), 1590 w ν(C-N). 1HNMR (400 MHz,
ꢀ
d6-DMSO) δppm: 9.93 (2H, s, 2 × N-H), 7.82 (2H, d, J = 7 Hz, Ar-H),
d, J = 8 Hz, 2 × imidazolium H5 ), 7.28-7.21 (14H, m, 2 × Ar-H,
ꢀ
ꢀ
7.25 (1H, s, Ar-H), 7.25-7.20 (2H, m, 2 × imidazolium H5 ), 6.99-
2 × imidazolium H4 ), 5.2 (4H, s, 2 × benzylic CH2), 5.3 (4H, s,
ꢀ
6.90 (2H, m, 2 × imidazolium H4 ), 5.3 (4H, s, 2 × CO-CH2N), 4.2
2 × CO-CH2N), 2.3 (6H, s, 2 × Ar-CH3) and 2.2 (6H, s, 2 × Ar-CH3).
13CNMR (100 MHz, d6-DMSO) δppm: 177.8 (Ccarbene-Ag), 158.2 (N-
CO), 136.6, 135.3, 133.9, 133.7, 129.7, 128.8, 127.3, 125.6, 123.8,
(6H, s, 2 × N-CH3), 2.3 (6H, s, 2 × Ar-CH3), and 2.2 (6H, s, 2 × Ar-
CH3). 13CNMR (100 MHz, d6-DMSO) 178.4 (Ccarbene-Ag), 158.8 (N-
CO), 135.8, 134.3, 131.2, 129.7, 126.5, 124.8 (Caromatic), 123.6, 122.8
ꢀ
ꢀ
123.2 (Ar-C), 122.5, 121.3 (imidazolium C5 & and C4 ), 55.1 (CO-
CH2N), 52.6 (benzylic C), 21.5 (Ar-CH3), 18.4 (Ar-CH3). Anal. Calc.
4

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Fig. 4. Molecular interactions between LDH-5 and compounds 2-4.
13CNMR (100 MHz, d6-DMSO) δppm: 178.9 (Ccarbene-Ag), 161.1 (N-
CO), 135.9, 135.0, 128.8, 128.3, 124.7, 113.6 (Ar-C), 123.8 (imida-
for C40H42N6AgO2Cl: C, 61.43; H, 5.41; N, 10.75. Found. C, 61.67; H,
6.02; N, 10.44.
ꢀ
ꢀ
zolium C5 & and C4 ), 52.4 (CO-CH2N), 21.9 (Ar-CH3), 20.8 (Ar-
CH3). Anal. Calc. for C46H52N8AgO4Cl: C, 59.78; H, 5.67; N, 12.12.
Found. C, 59.97; H, 5.88; N, 12.41.
2.3.3.
Bis[1,3-(bis[3-N-2,5-dimethylphenylacetamide])imidazolium]silver
chloride (7)
This compound was synthesized in a similar method to that for
5, but using 2 mole of compound 3. White solid. Yield: (1.37 gm,
72 %), (m.p = 150-152 °C). FT-IR cm−1: 3271 m ν(N-H), 1662 s
ν(C=O), 1597 s ν(C-N). 1HNMR (400 MHz, d6-DMSO), δppm: 9.6
2.4. Synthesis of Palladiun(II)-NHC complexes (8-10)
2.4.1. Bis(1-methyl-3-(2,5-dimethylphenyl)-
acetamideimidazolium)Palladium dichloride
(8)
ꢀ
ꢀ
(4H, s, 4 × N-H), 7.7 (4H, s, 2 × imidazolium H5 & H4 ), 7.42
(8H, d, J = 7 Hz, 2 × Ar-H), 7.08 (4H, s, 2 × Ar-H), 5.2 (8H, s,
2 × CO-CH2N), 2.3 (12H, s, 4 × CH3Ar) and 2.2 (12H, s, 4 × CH3Ar).
Palladium complex [Pd(CH3CN)2Cl2] (0.04 gm, 0.15 mmol) dis-
solved in methanol (7.5 ml) add dropwise to complex 5 (0.13 gm,
5

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Fig. 4. Continued
0.15 mmol) that dissolved in methanol (7.5 ml), then the mix-
ture was stirred for 6 hrs at room temperature . The mixture was
filtered using celite to remove silver particles. The resulted solu-
tion was minimized to 1 ml using reduced pressure and 10 ml
of petroleum ether was added to give the complex as a pale-
brown precipitate which was filtered and dried at ambient tem-
2.4.3. Bis[1,3-(bis(2-N-2,5-
dimethylphenylacetamide)imidazolium]Palladium(II) dichloride
(10)
This complex was prepared in similar method, except using
complex 7 instead of 5. The complex resulted as a pale-brown
solid. Yield: (0.11 gm, 79 %), (m.p = 170-174 °C). FT-IR cm−1: 3269
m ν(N-H), 1663 s ν(C=O), 1599 s ν(C-N). 1HNMR (400 MHz, d6-
DMSO), δppm: 9.5 (4H, s, 4 × N-H), 7.9 (4H, s, 2 × imidazolium
perature. Yield: (0.13 gm, 82 %), (m.p = 170-174 °C). FT-IR cm−1
:
3267 m ν(N-H), 1663 s ν(C=O), 1592 s ν(C-N). 1HNMR (400 MHz,
d6-DMSO) δppm: 9.96 (2H, s, 2 × N-H), 8.20 (4H, d, J = 7 Hz,
H5 & H4 ), 7.32 (8H, d, J = 7 Hz, 2 × Ar-H), 7.04 (4H, s, 2 × Ar-H),
5.3 (8H, s, 4 × CO-CH2N), 2.3 (12H, s, 4 × CH3Ar) and 2.1 (12H, s,
ꢀ
ꢀ
ꢀ
4 × Ar-H), 7.84 (2H, d, J = 8 Hz, 2 × imidazolium H5 ), 7.37 (2H,
ꢀ
s, 2 × Ar-H), 7.32 (2H, d, J = 8 Hz, 2 × imidazolium H4 ), 5.5
4 × CH3Ar). 13CNMR (100 MHz, d6-DMSO) δppm: 168.6 (Ccarbene
-
(4H, s, 2 × CO-CH2N), 4.0 (6H, s, 2 × N-CH3), 2.3 (6H, s, 2 × Ar-
CH3) and 2.1 (6H, s, 2 × Ar-CH3). 13CNMR (100 MHz, d6-DMSO)
168.12 (Ccarbene-Pd), 156.9 (N-CO), 135.4, 133.9, 132.1, 129.5, 127.2,
Pd), 159.7 (N-CO), 135.7, 134.5, 128.2, 127.8, 124.6, 112.9 (Ar-C),
ꢀ
ꢀ
123.4 (imidazolium C5 & and C4 ), 53.0 (CO-CH2N), 21.3 (Ar-CH3),
19.6 (Ar-CH3). Anal. Calc. for C46H52N8PdO4Cl2: C, 57.66; H, 5.47;
N, 11.69. Found. C, 57.84; H, 5.68; N, 11.93.
ꢀ
ꢀ
125.2 (Caromatic), 124.8, 123.3 (imidazolium C5 & and C4 ), 55.6
(CO-CH2N), 36.8 (N-CH3), 22.1 (Ar-CH3), 19.3 (Ar-CH3). Anal. Calc.
For C28H34Cl2N6O2Pd: C, 50.65; H, 5.16; N, 12.66. Found. C, 50.39;
H, 5.08; N, 12.41.
2.5. Calculations Models
In the current study, The software Gaussian (Gauss View 0.9)
and Molecular Graphic Laboratory (MGL) tools were used [38-40].
The geometrical optimization for the complexes was suggested by
Density Functional Theory (DFT) with LanL2DZ basis set [41]. Phys-
ical properties such as Total energy, Dipole moment, bond lengths,
HOMO-LUMO energies, ESP, and TED are included in DFT calcu-
lation. Docking calculations were done for the studied complexes
as inhibitors for colon cancer cell LDH-5. (Research Collaboratory
for Structural Bioinformatics) RCSB [42] was used to download the
protein structure (1T2F). For each component, LDH-5 and coor-
dinates of drugs have been selected using Autodock tools (ADT,
version 1.5.6). The structures of protein and complexes are trans-
formed into a recognized format ADT (∗.pdbqt files).
2.4.2.
Bis(1-benzyl-3-(2,5-dimethylphenyl)-acetamideimidazolium)Palladium
dichloride (9)
This complex was prepared in similar method, except using
complex 6 instead of 5. The complex resulted as a pale-brown
solid. Yield: (0.16 gm, 85 %), (m.p = 108-110 °C). FT-IR cm−1: 3280
m ν(N-H), 1667 s ν(C=O), 1596 s ν(C-N). 1HNMR (400 MHz, d6-
DMSO) δppm: 9.63 (2H, s, 2 × NH), 7.94 (4H, d, J = 7 Hz, 2 × Ar-
ꢀ
H), 7.36 (2H, d, J = 8 Hz, 2 × imidazolium H5 ), 7.24-7.18 (14H,
ꢀ
m, 2 × Ar-H, 2 × imidazolium H4 ), 4.95 (4H, s, 2 × benzylic
CH2), 4.73 (4H, s, 2 × CO-CH2N), 2.27 (6H, s, 2 × Ar-CH3) and 2.16
Gasteiger charges and polar hydrogen atoms were taken into
consideration in the calculations as well. The Autodock also tries
to identify the root of the molecule if the consumer does not indi-
cate it. The root was selected automatically Autodock. The atomic
affinity maps were calculated with the support of Autogrid (ver-
sion 4.2.6) for all ligand atomic groups and electrostatic [43]. DSV
software gives the interactions of the cell with the complexes.
(6H, s, 2 × Ar-CH3). 13CNMR (100 MHz, d6-DMSO) δppm: 167.8
(Ccarbene-Pd), 158.32 (N-CO), 136.2, 135.7, 133.6, 133.3, 130.1, 128.9,
ꢀ
127.5, 125.4, 123.6, 123.4 (Ar-C), 122.8, 121.2 (imidazolium C5
&
ꢀ
and C4 ), 55.3 (CO-CH2N), 52.7 (benzylic C), 21.7 (Ar-CH3), 19.2 (Ar-
CH3). Anal. Calc. for C40H42N6PdO2Cl2: C, 58.87; H, 5.19; N, 10.30.
Found. C, 58.98; H, 5.42; N, 10.61.
6

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Scheme 1. Synthesis of 1.
Scheme 2. Synthesis of NHC precursors (2-4), and their coresponding Ag(I)-NHC (5-7), and Pd(II)-NHC (8-10) complexes.
2.6. Antibacterial activity
terial drug. Each bacteria isolate was inoculated onto the Muller-
Hinton Agar (sterilize in autoclave) by dipping a cotton swab into
the suspension and streaking it over the surface of the agar plates.
Then, in the solidified medium, four holes were made. These holes
were filled with (0.5 ml) of the prepared compounds ((100 μg/ μL
and 200 μg/ μL) of the compound dissolved in 1ml of DMSO sol-
The compounds 2, 3, 5, 6, 9, and 10 were screened for their an-
tibacterial activity against Escherichia coli and Staphylococcus au-
reus in Muller Hinton agar by measuring the inhibition zone, using
Azithromycin (AZ,100 μg/ μL and 200 μg/ μL) as a standard antibac-
7

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
vent). These plates were incubated at 37 °C and measured zone of
3.3. NMR spectroscopy
inhibition after 48 hours.
All NMR spectra of imidazolium salts and their corresponding
Ag(I)- and Pd(II)-NHC complexes were collected in d6-DMSO over
the scan range of δ 0-12 and δ 0-200 for 1H and 13C, respectively
(Figs SI2 and SI3). NMR spectra of all the synthesized compounds
showed the expected signals for this class of compounds. In 1H
NMR of the imidazolium salts 2-4, a singlet peak appeared at the
range of δ 9.3-10.12 is assigned to the proton of N-H. The signif-
3. Results and discussion
3.1. NHC precursors and complexes
The compound 2-chloro-(2,5-dimethyl phenyl) acetamide (1)
was prepared according to a reported procedure (Scheme 1), which
was then used to prepare compounds 2, 3, and 4.
ꢀ
icant signal of imidazolium H2 was observed at the range of δ
8.12-9.33 as a singlet peak. The arene protons Ar-H appeared at
Compounds
1-methyl-3-(2,5-dimethylphenyl)-
the range of δ 6.8-7.4 as multiplet peaks. While the imidazolium
acetamideimidazolium chloride (2), and 1-benzyl-3-(2- N-2,5-
dimethylphenylacetamide)imidazolium chloride (3), were prepared
by reaction of 1 with 1-methy- or 1-benzylimidazole in 1:1 mole
ratio, in dioxane and the mixture was refluxed with stirring
at 90 °C for 24 hrs. While the compound 1,3-(bis[3-N-2,5-
dimethylphenylacetamide])imidazolium chloride (4), was prepared
by the reaction of imidazole with 2 moles of 1 at the same condi-
tions). The prepared compounds resulted in their solid form after
evaporation of the solvent and washing with diethyl ether. More-
over, they were stable to air and moisture, and soluble in common
solvents such as ethanol, methanol, acetonitrile, dichloromethane,
DMSO, and DMF, but insoluble in some solvents such as benzene,
dioxane, and diethyl ether, and partially in the water.
ꢀ
ꢀ
H5 /H4 protons appeared at the range of δ 7.39-8.2 as variable
ꢀ
peaks. In 13C NMR, the most important signal is for C2 , which ap-
peared at the range of δ 138-139.
In both synthesized Ag(I) and Pd(II) complexes, 1H NMR
ꢀ
showed a full absence of H2 signals, the characteristic one in imi-
dazolium salts. According to the literature, this is attributed to the
successful coordination with the metals used [19,22,25]. The Ar-
H protons appeared at the range of δ 6.8-7.5 as multiplet peaks,
ꢀ
ꢀ
while the imidazolium H5 /H4 protons appeared at the range of
δ 7.7-8.1. In 13C NMR, the characteristic signals of Ccarbene-Ag and
Ccarbene-Pd appeared at the ranges δ 177.8-178.9 for Ag(I)-NHC
complexes, and δ 167.8-168.6 for Pd(II)-NHC complexes. All these
observations are in good agreement with the data of the reported
analogs imidazolium salts and complexes [47-49].
Silver complexes 5-7 were prepared according to a reported
procedure [20], by in situ reaction of silver oxide with correspond-
ing imidazolium salts 2-4, respectively. In glassware wrapped with
aluminum foil to exclude the light, the reaction of excess silver ox-
ide with imidazolium salt in refluxed acetonitrile for 8-10 h pro-
duced the complexes in good yields after appropriate treatment. In
all reactions, a resulted black suspension was filtered off using a
pad of celite to remove the excess of Ag2O. Then, the solvent was
removed under reduced pressure to give a white solid after wash-
ing with diethyl ether.
3.4. The antibacterial activity test
The antibacterial activity of substituted imidazolium salts and
their Ag(I) and Pd(II) complexes were evaluated against the bacte-
rial strains E. coli as gram-negative and S. aureus as gram-positive
using azithromycin as a standard antibiotic. In comparing with
azithromycin, all the imidazolium salts and their respective Ag(I)
and Pd(II) complexes showed good activity against the tested bac-
teria (Table 1). According to the tabulated results, the antibacterial
activity of Ag(I) complex 5 is the highest, while, the lowest was for
imidazolium salt 2. Also, Pd(II) complex 9 showed good activity but
less than 5. Other compounds showed moderate activity, and there
are no vast differences observed. The variance in the results is may
be due to the changing of N-substituents on the NHC, which leads
to a complete change in the stability of the complexes. This could
enhance a slow sustained release of Ag+ ions, which is significant
in the inhibition of bacterial growth [18,19]. Further, The sensitiv-
ity of the gram-negative bacteria increases as the volume of the
complex suspensions increases.
Palladium complexes 8-10 were synthesized by the transmet-
allation method [20]. The reaction of [PdCl2(MeCN)2] with cor-
responding Ag(I)-NHC complexes in stirring methanol for 6 h at
room temperature resulted in the Pd(II)-NHC complexes after suit-
able treatment in good yields. The black suspension resulted was
filtered off using a pad of celite to remove AgCl precipitate. Then,
the solvent was minimized under reduced pressure, followed by
the addition of petroleum ether to give the complexes as pale
yellow solids. Both Ag(I)-NHC and Pd(II)-NHC complexes were
soluble in organic solvents such as ethanol, methanol, acetoni-
trile, dichloromethane, DMSO, and DMF but insoluble in water, di-
ethyl ether, and benzene. Synthesis of compounds 2-10 shown in
Scheme 2.
3.5. Ground state of compounds
˚
The bond/interaction distances (A) of compounds 2-10 at the
3.2. FT-IR Spectroscopy
equilibrium (Table 2) were calculated using the DFT method. De-
peneding on the tabulated results, there are some differences in
lengths. Also, a decrease found in total energy in the order 2< 3<
4< 8< 5< 6< 9<10< 7, which is directly proportional to the size
of the geometrical and molecular structure of the studied com-
pounds. The coordination bonds give more stability to compounds
5-10, while the low stability of compounds 2, 3, and 4 reveals the
high activity of these compounds.
There is some good information that could be deduced by us-
ing the FT-IR spectrum when comparing the ligands and their cor-
responding metal complexes. Infrared spectra were obtained for all
imidazolium salts and their Ag(I) complexes using KBr disk method
(Figs SI1). In the imidazolium salt, the bands observed at the range
3266-3287 cm-1 are assigned to the stretching of N-H. The stretch-
ing bands of C=O were observed at the range 1667-1647 cm-1.
Another band was observed at the range 1583-1489 cm-1, which
was assigned to the stretching of C-N. In Ag(I)- and Pd(II)-NHC
complexes, most of the above-mentioned bands are shifted up or
down, and this could be considered as a primary indicator for suc-
cessful complexation with Ag and Pd, respectively [44]. The most
important band which is showed a significant shifting is C-N. This
band is shifted up at the range 5-15 cm-1. This shifting can be at-
tributed to the back bonding of Ag and Pd electrons [45,46].
3.6. Activity and molucular orbitals
In this part, some physical properties are studied to refer to the
activity [50,51] of the synthesized compounds (Table 3). There is
a decrease in ELUMO in the order 3< 2< 5< 9< 6< 10< 7< 8< 4,
(Figs. 1 and SI4). The energy gap, the difference between HOMO
and LUMO orbitals was in the order 3> 2> 7> 5> 8> 9> 6> 4>
8

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Table 1
Antibacterial activities of compounds 2, 3, 5, 6, 9, and 10 against E.coli. and S. Aureus.
E.coli.
S. aureus
Inhibition zone (mm)
Inhibition zone (mm)
Compound
100 μg ml−
¹
200 μg ml−
¹
100 μg ml−
¹
200 μg ml−
¹
2
15
20
25
20
25
20
30
20
30
35
20
25
25
40
0
10
25
30
25
25
15
30
3
15
25
20
20
15
20
5
6
9
10
AZ
Table 2
molecule.
IE − EA
˚
Bond/interaction distances (A) and total energy
of the studied compounds.
η =
(3)
2
2
N-Cl
1.87
N-Cl
1.88
N-Cl
2.02
Ag-Cl
2.32
Ag-Cl
2.32
Ag-Cl
1.72
Pd-Cl
2.24
Pd-Cl
2.25
Pd-Cl
2.25
C=O
1.20
C=O
1.25
C=O
1.20
Ag-C
2.11
Ag-C
2.10
Ag-C
1.59
Pd-C
2.03
Pd-C
2.05
Pd-C
2.03
N-C
Etotal (a.u)
-1244.06
-1474.64
According to η, the order is as follows:
3> 2> 7> 5> 8> 9> 6> 4> 10
1.36
N-C
3
1.46
N-C
The global softness (S) is the inverse of the global hardness.
Softness is one of the important properties that measure molec-
ular stability and reactivity.
4
-1722.56
-1726.67
-2188.65
-2682.15
-1722.56
-2184.56
-2679.12
1.36
C=O
1.20
C=O
1.20
C=O
1.20
C=O
1.20
C=O
1.20
C=O
1.20
5
1
S =
(4)
6
η
7
According to S, the order is:
3> 2> 7> 5> 8> 9> 6> 4> 10
8
In a covalent bond, the electronegativity (χ) is the ability of an
atom to attract shared electrons.
9
IE + EA
10
X = −μ =
(5)
2
If χ decreases, the efficiency of inhibition increases, and the or-
der will be:
3> 5> 9> 10> 2> 6> 8> 4> 7
10, which also represents the order of activity. The ionization en-
ergy (IE) is the amount of energy required for removing the elec-
tron of an atom. Low ionization energy gives high efficiency for
inhibition.
For the dipole moment (μ), the high value of μ is proportional
to the efficiency for inhibition. So, the order will be as follows:
8> 6> 10> 7> 9> 2> 5> 4>3
According to the above-mentioned parameters, the significant
activity was for compounds 2,3 and 4. So, they will take into con-
sideration in the next part.
IE = −EHOMO
According to the IE, the activity of the studied compounds or-
dered as:
(1)
3.7. TED and ESP maps
2> 7> 3> 8> 5> 6> 4> 9> 10
Electronic affinity (EA) is the amount of energy released when
an electron is added to a neutral atom. The higher value of electron
affinity, the less stability and gives high efficiency for inhibition.
The present compounds in this part 2, 3, and 4 are the more ac-
tive among the studied compounds. The electron density is known
as the total electron density (TED). In Figs. 2 and SI5, the red color
represents the negative sites, which refers to N and O, the more
electronegative atoms in the molecules. while the blue color indi-
cates the more positive sites (metal), that could accept electrons
from the donor [52].
EA = −ELUMO
According to EA, the activity of the studied compounds is as
follows:
(2)
4> 8> 7> 10> 6> 9> 5> 2> 3
Hardness (η) is defined as the second derivative of the E,
which gives an indicator for both the stability and reactivity of the
The electrostatic surface potential (ESP) shows the direction of
the adsorption of the molecule on the metal surface (Figs. 3 and
Table 3
Quantum chemical parameters for the studied molecules calculated in vacuum using DFT method.
a
a
a
Comp.
EHOMO
ELUMO
IEa
EAa
Egap
ηa
Sb
μc
χa
2
-3.9258
-4.2752
-4.9694
-4.8429
-4.8538
-4.8538
-3.5318
-4.4954
-5.1879
-1.2365
-1.9472
0.0971
3.9258
4.2752
4.9694
4.8429
4.8538
3.5318
4.4954
5.0203
5.1879
1.2365
1.9472
-0.0971
0.9222
0.1303
0.0593
-0.0884
0.3992
0.1058
2.6893
2.3279
5.0666
3.9207
4.7234
3.4725
4.5838
4.6211
5.0821
1.3446
1.1639
2.5333
1.9603
2.3617
1.7362
2.2919
2.3105
2.5410
0.7436
0.8591
0.3947
0.5101
0.4234
0.5759
0.4363
0.4327
0.3935
6.09
3.91
4.40
5.70
11.2
7.13
14.4
6.12
9.63
2.5811
3.1112
2.4361
2.8825
2.4920
1.7955
2.2034
2.7097
2.6469
3
4
5
-0.9222
-0.1303
-0.0593
0.0884
6
7
8
9
-0.3992
-0.1058
10
a: in eV, b: in eV−1, c: in Debye.
9

M.Z. Ghdhayeb, K.J. Sabah, A.W. Salman et al.
Journal of Molecular Structure 1245 (2021) 131254
Table 4
Declaration of Competing Interest
Binding energy values and efficiency of the
studied compounds.
The authors declare that no conflict of interest.
Comp.
Eb
LE
Best position
CRediT authorship contribution statement
2
-4.36
-4.70
-5.70
-3.68
-2.90
-3.68
-3.24
-2.07
-2.82
-0.23
-0.19
-0.14
-0.10
-0.06
-0.10
-0.08
-0.04
-0.11
L7
L2
L6
L8
L4
L8
L10
L3
L2
3
4
Mohammed Z. Ghdhayeb: Supervision, Methodology. Karem J.
Sabah: Visualization, Investigation. Abbas Washeel Salman: Writ-
ing – review & editing. Mustafa Mohammed Kadhim: Methodol-
ogy, Software.
5
6
7
8
9
10
Acknowledgements
M. Z. Ghdhayeb and K. J. Sabah thank the university of Kufa for
their support.
SI6), which is the same direction of the carbonyl group and chlo-
ride atoms in some double bonds [53].
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131254.
3.11. Docking results
All the synthesized compounds 2-10 were investigated for their
anticancer activity. Increasing glucose uptake in tumor cells leads
to increasing glycolytic activity, which in turn elevating the levels
of lactate production [54,55]. Lactate release is regulated by lactate
dehydrogenase-5 (LDH-5) found in tumor cells [56]. Recently, LDH-
5 inhibitors have been reported as potential antitumor agents [57].
Confirming that inhibition of LDH-5 is a significant target to obtain
new candidates with improved anticancer activity.
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