Synthesis, antimicrobial properties, and theoretical analysis of benzimidazole-2-ylidene silver(I) complexes

Article abstract of DOI:10.1080/00958972.2020.1812587

A series of symmetrical and nonsymmetrical N,N-disubstituted benzimidazolium salts were synthesized as N-heterocyclic carbene precursors. These salts were treated with Ag₂O to afford their corresponding mononuclear Ag(I)-NHC complexes. These compounds were characterized by spectroscopy techniques and analyzed by DFT/TDDFT and docking methods. Also, the structures of 2a and 2e were determined by single-crystal X-ray crystallography. These new Ag–NHC complexes were screened for their antibacterial activities against Gram-positive, Gram-negative bacteria, fungi, and nosocomial agents.

Full text of DOI:10.1080/00958972.2020.1812587

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: https://www.tandfonline.com/loi/gcoo20
Synthesis, antimicrobial properties, and
theoretical analysis of benzimidazole-2-ylidene
silver(I) complexes
Serpil Demir Düşünceli, Dilek Ayaz, Elvan Üstün, Selami Günal, Namik
Özdemir, Muharrem Dinçer & İsmail Özdemir
To cite this article: Serpil Demir Düşünceli, Dilek Ayaz, Elvan Üstün, Selami Günal, Namik
Özdemir, Muharrem Dinçer & İsmail Özdemir (2020) Synthesis, antimicrobial properties, and
theoretical analysis of benzimidazole-2-ylidene silver(I) complexes, Journal of Coordination
Chemistry, 73:13, 1967-1986, DOI: 10.1080/00958972.2020.1812587
To link to this article: https://doi.org/10.1080/00958972.2020.1812587
View supplementary material
Published online: 10 Sep 2020.
Submit your article to this journal
Article views: 17
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gcoo20

JOURNAL OF COORDINATION CHEMISTRY
2020, VOL. 73, NO. 13, 1967–1986
https://doi.org/10.1080/00958972.2020.1812587
Synthesis, antimicrobial properties, and theoretical
analysis of benzimidazole-2-ylidene silver(I) complexes
a,b
b
c
d
€
€ €
€
€
Serpil Demir Dus¸unceli , Dilek Ayaz , Elvan Ustun , Selami Gunal , Namik
e
f
a,b
€
_
€
Ozdemir , Muharrem Dinc¸er and Ismail Ozdemir
a
b
_
€ €
Faculty of Science and Art, Department of Chemistry, Inonu University, Malatya, Turkey; Catalysis
c
_
€ €
Research and Application Centre, Inonu University, Malatya, Turkey; Faculty of Science and Art,
Department of Chemistry, Ordu University, Ordu, Turkey; Faculty of Medicine, Department of
Microbiology, Inonu University, Malatya, Turkey; Department of Mathematics and Science Education,
Faculty of Education, Ondokuz Mayıs University, Samsun, Turkey; Department of Physics, Faculty of
d
e
_
f
Arts and Sciences, Ondokuz Mayıs University, Samsun, Turkey
ABSTRACT
ARTICLE HISTORY
Received 5 April 2020
Accepted 8 August 2020
A series of symmetrical and nonsymmetrical N,N-disubstituted benzi-
midazolium salts were synthesized as N-heterocyclic carbene precur-
sors. These salts were treated with Ag2O to afford their
corresponding mononuclear Ag(I)-NHC complexes. These com-
pounds were characterized by spectroscopy techniques and ana-
lyzed by DFT/TDDFT and docking methods. Also, the structures of
2a and 2e were determined by single-crystal X-ray crystallography.
These new Ag–NHC complexes were screened for their antibacterial
activities against Gram-positive, Gram-negative bacteria, fungi, and
nosocomial agents.
KEYWORDS
Antimicrobial activity;
benzimidazolium salts;
N-heterocyclic carbene;
silver NHC complexes
_
€
CONTACT Ismail Ozdemir
ismail.ozdemir@inonu.edu.tr
Dedicated to P.H. Dixneuf for his outstanding
contribution to organometallic chemistry and catalysis.
Supplemental data for this article is available online at https://doi.org/10.1080/00958972.2020.1812587.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

1968
S. D. DÜŞÜNCELI ET AL.
1. Introduction
Carbenes, molecules with two unpaired electrons, are excellent nucleophiles and are
known to be strong Lewis bases with the ability to bind metals across the periodic
table to form highly stable complexes. Comparatively, they are more stable than phos-
phine complexes [1–6]. Organometallic complexes have well-defined stereochemistries,
allowing for rational ligand design and optimization. Moreover, carbene complexes are
relatively lipophilic, uncharged, and kinetically stable with a metal atom at its lowest
oxidation state. These features make them attractive as biologically active lead mole-
cules, making them useful starting points for conventional structure-based drug design
and optimization [7].
The chemistry of metal complexes with N-heterocyclic carbene (NHC) ligands, which
contain a carbene carbon incorporated in a nitrogen-containing 5-membered hetero-
cycle, has been extensively studied because many of these complexes are effective
catalysts of various chemical reactions [8, 9]. In recent years, bioactive properties have
been identified for these compounds (anticancer, antibacterial, etc.), suggesting new
biomedical perspectives [10–16]. Thus, the biological potential of NHC complexes is an
important research area in the field of organometallic chemistry. The main bioactive
NHCs incorporate gold, silver, copper, palladium, or platinum [17, 18]. Silver(I)-NHC
complexes not only have potential medicinal applications, but also are useful as car-
bene transfer agents. NHC complexes of other transition metals, including gold, cop-
per, palladium, nickel, and ruthenium, have been similarly prepared [19]. The first
structurally characterized silver NHC complex was made by using a free carbene and a
silver salt [20]. However, generation of the free carbene has been problematic for
some NHC systems. This led to the discovery, by several research groups, of silver
bases with which silver NHCs could be synthesized from imidazolium salts in-situ. In
1997, Bertrand and colleagues reported the synthesis of a silver-NHC from triazolium
salts using silver acetate [21]. Lin and Wang, in 1998, reported the syntheses of silver
NHCs using Ag2O [22]. Danopoulos and colleagues reported the syntheses of silver
NHC complexes using Ag2CO3 in 2000 [23]. These procedures, particularly Lin’s,
allowed NHC-complexes of silver to be readily available and have led to a diverse area
of research.
The efficacy of silver complexes against bacteria and cancer cells depends on a
number of factors: lipophilicity, redox proclivity, water solubility and stability, and
rate of release of the silver ions. These factors are strictly controlled by the char-
acteristics of the ligands and their requirements in both steric and electronic
properties [24]. Finally, in this paper, we reported the synthesis and characteriza-
tion of 1,3-disubstituted benzimidazolium salts and their silver complexes. The
optimization and the evaluation of electronic transitions of the silver complexes
were analyzed by DFT/TDDFT based calculation methods and the molecules were
analyzed by docking methods. However, the antimicrobial activities of five novel
NHC–silver complexes were tested against most commonly isolated bacteria and
fungi standard strains from community and as a causative agent of nosoco-
mial infection.

JOURNAL OF COORDINATION CHEMISTRY
1969
2. Experimental
2.1. Materials
All reactions were made under argon gas using standard Schlenk techniques. All pri-
mary chemicals were purchased commercially from the following suppliers: Merck
(Darmstadt, Germany), Sigma-Aldrich (Aldrich and Fluka, St. Louis, MO), Introgen
(Carlo-Erba, Val de Reuil, France and Acros Organics, Geel, Belgium), and Thermo
Fisher Scientific (Alfa-Aesar, Lancashire, UK). Prior to use, the solvents were further
purified through conventional methods: diethyl ether and hexane by distillation over
Na and dichloromethane by distillation over P4O10. Mueller-Hinton Broth was pur-
chased from HiMedia Laboratories Pvt. Ltd. (Mumbai, India) and RPMI 1640 broth was
purchased from Sigma-Aldrich (Chemie GmbH, Taufkirchen, Germany). The melting
points (m.p.) of compounds were performed on an Electrothermal 9200 melting point
apparatus. FT-IR analyses were done on a Mattson 1000 spectrophotometer. The NMR
spectra of the compounds were performed on a Bruker Avance III 400 MHz. Chemical
shifts (d) were given in ppm relative to tetramethylsilane.
2.2. Antibacterial screening
Samples were tested at a concentration of 1000–1,95 mg/mL against the standard cul-
ture collections of the most frequently isolated strains among the society and hospital
acquired infectious agents depending on the suggestions of Clinical Laboratory
Standards Institute (CLSI) with method of serial dilutions using sterile 96-well micro-
plate readers (PLT microtiter plate ESP). Ten milligrams of the sample was dissolved in
1000 mL of dimethylsulfoxide to obtain stock solution. Hundred microliters of the
€
Muller-Hinton Broth (Merck 110293, USA) was loaded to the test wells. Hundred micro-
liters of the stock solution of our material was taken and starting from 1st well to 10th
well, serial dilutions were performed and the last two wells were used as control
groups. Ten microliters of bacterial suspensions, which were prepared according to
the Mc Farland 0.5 turbidity threshold, were distributed to all samples including the
control wells. Orbital shaker (PST 60HL Thermo USA) was used for 5 min in order to
mix bacteria and our substance. Lid of the microplate was closed, and it was incu-
bated at 35 ꢀC for 18–20 h. In order to check bacterial growth, culture from each well
€
was streaked on Muller-Hinton Agar plate using sterile plastic loop and incubated at
the same conditions. A pre-dilution of growth was determined as minimal inhibitory
concentration (MIC) of that substance. Antifungal activity was determined using
Sabouraud Dextrose Broth and Agar (oxoid CM0147, CM0041, USA) under same condi-
tions. In addition to this, in our study, reference drugs for each group of bacteria and
fungi were tested under same conditions as our substances.
Bacterial strains: Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC
29212, Staphylococcus aureus MRSA ATCC 43300, Escherichia coli ATCC 25922, Klebsiella
pneumoniae ATCC 700603, Pseudomonas aeruginosa ATCC 27853, Acinetobacter bau-
mannii ATCC 19606.
Fungal strains: Candida glabrata ATCC 90030, Candida albicans ATCC 14053.

1970
S. D. DÜŞÜNCELI ET AL.
Table 1. Crystal data and structure refinement parameters for 2a and 2e.
Parameters
2a
2e
CCDC depository
Color/shape
2011287
Colorless/plate
[AgCl(C21H16Cl2N2)]
510.58
296(2)
0.71073 Mo Ka
2011288
Colorless/prism
[AgBr(C27H27N3)]
581.29
296(2)
0.71073 Mo Ka
Chemical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell parameters
a, b, c (Å)
Triclinic
Triclinic
ꢀ
ꢀ
P1 (No. 2)
P1 (No. 2)
9.1112(7), 9.4691(7), 12.2672(9)
106.823(6), 95.327(6), 92.982(6)
8.8627(4), 12.1006(5), 13.1259(5)
103.717(3), 105.402(3), 108.786(3)
a, b, c (ꢀ)
Volume (Å3)
Z
1005.22(13)
2
1.687
1201.86(9)
2
1.606
Dcalc (g/cm3)
l (mmꢁ1
)
1.410
2.520
Absorption correction
Tmin, Tmax.
Integration
0.6522, 0.9610
508
0.61 ꢂ 0.26 ꢂ 0.03
STOE IPDS II
x scan
Integration
0.3104, 0.7066
584
0.70 ꢂ 0.35 ꢂ 0.19
STOE IPDS II
x scan
F000
Crystal size (mm3)
Diffractometer
Measurement method
Index ranges
ꢁ10 ꢃ h ꢃ 10, ꢁ11 ꢃ k ꢃ 11,
ꢁ14 ꢃ l ꢃ 14
2.253 ꢃ h ꢃ 25.045
12127
ꢁ11 ꢃ h ꢃ 11, ꢁ15 ꢃ k ꢃ 15,
ꢁ17 ꢃ l ꢃ 17
2.523 ꢃ h ꢃ 27.629
35743
h range for data collection (ꢀ)
Reflections collected
Independent/observed
reflections
3549/2759
5573/4899
Rint.
0.1246
Full-matrix least-squares on F2
3549/0/244
0.0610
Full-matrix least-squares on F2
5573/0/289
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final Rindices [I > 2r(I)]
Rindices (all data)
1.314
1.307
R1 ¼ 0.0790, wR2 ¼ 0.1306
R1 ¼ 0.1091, wR2 ¼ 0.1417
0.71, ꢁ0.59
R1 ¼ 0.0551, wR2 ¼ 0.1051
R1 ¼ 0.0650, wR2 ¼ 0.1083
0.56, ꢁ0.77
Dqmax., Dqmin. (e/Å3)
2.3. Computational and docking methods
DFT calculations were carried out with ORCA version 3.0.3 using the BP86 functional
with the resolution-of-the identity (RI) approximation, a def2-TZVP/def2-TZVP/J basis
set, the tightscf and grid4 options [25, 26]. AutoDock 4.2 (MGL tools 1.5.6) was used
for all docking simulations. Topoisomerase II (PDB Code: 1JIJ) and DNA-gyrase subunit
B (PDB Code: 1KZN) crystal structures obtained from RCSB Protein Data Bank were
used for this study (https://www.rcsb.org/pdb). The target protein file was saved in
pdbqt format after heteroatoms, water molecules and cofactors were removed. The
receptor was considered as rigid and only polar hydrogen atoms were included in the
docking process. Gasteiger charges of all atoms in molecules were converted to AD4
type. The analyzed poses were visualized by Discovery Studio 4.1.0 [27].
2.4. X-ray analysis
Intensity data of the compounds were collected with a STOE IPDS II diffractometer at
room temperature using graphite-monochromated Mo Ka radiation by applying the
x-scan method. Data collection and cell refinement were carried out using X-AREA
[28] while data reduction was applied using X-RED32 [28]. The structures were solved

JOURNAL OF COORDINATION CHEMISTRY
1971
by SUPERFLIP [29] and refined by means of the full-matrix least-squares calculations
on F2 using SHELXL-2018 [30]. All H-atoms were located in difference maps and then
treated as riding atoms, fixing the bond lengths at 0.93, 0.97, and 0.96 Å for CH, CH2,
and CH3 atoms, respectively. The displacement parameters of the H atoms were fixed
at Uiso(H) ¼ 1.2 Ueq (1.5 Ueq for CH3). Crystal data, data collection and structure refine-
ment details are given in Table 1. Molecular graphics were generated using
OLEX2 [31].
2.5. Synthesis and characterization of benzimidazolium salts (1a-e)
The benzimidazolium salts were prepared as follows: KOH was added to benzimidazole
solution in ethyl alcohol and alkyl halide was added to this solution after 1 h. The solu-
tion was refluxed for 6 h then allowed to cool to room temperature. The precipitated
KCl was removed by filtering. The obtained N-alkylbenzimidazole was purified by
crystallization. Subsequently, alkyl halide was added to the DMF solution of synthe-
sized N-alkylbenzimidazole and stirred for 24 h at 80 ꢀC. Benzimidazolium salts were
synthesized and purified by crystallization in a mixture of ethyl alcohol-diethy-
lether (2:1).
2.5.1. 1,3-bis(4-chlorobenzyl)benzimidazolium chloride, 1a
Compound 1a was synthesized as described above from 1-(4-chlorobenzyl) benzimida-
zole and 4-chlorobenzyl chloride. The reaction produced 1a (0.35 g, 85%) as a solid.
1
M.p.: 183–184 ꢀC. IR (cmꢁ1): v(CN): 1552. H NMR (400 MHz, CDCl3), d (ppm): 5.89 (s,
4H, NCH2C6H4-Cl); 7.36–7.38 (m, 4H, Ar–H); 7.50–7.53 (m, 8H, Ar–H); 12.17 (s, 1H,
NCHN). 13C NMR (100 MHz, CDCl3), d (ppm): 51.6 (NCH2C6H4-Cl); 113.7, 127.3, 129.7,
129.8, 131.0, 131.2, and 135.5 (Ar–H); 140.9 (NCHN).
2.5.2. 1-(3,5-dimethylbenzyl)-3-(4-chlorobenzyl)benzimidazolium chloride, 1b
Compound 1b was synthesized as described above from 1-(3,5-dimethylbenzyl) benzi-
midazole and 4-chlorobenzyl chloride. The reaction produced 1b (0.38 g, 87%) as a
1
solid. M.p.: 173–174 ꢀC. IR (cmꢁ1): v(CN), 1562. H NMR (400 MHz, CDCl3), d (ppm): 2.52
(s, 6H, NCH2C6H3(CH3)2-3,5); 5.72 and 5.83 (s, 4H, NCH2C6H4–Cl and NCH2C6H3(CH3)2-
3,5); 7.08–7.99 (m, 11H, Ar–H); 10.17 (s, 1H, NCHN). 13C NMR (100 MHz, CDCl3), d (ppm):
21.3 (NCH2C6H3(CH3)2-3,5); 49.7 and 49.8 (NCH2C6H4–Cl and NCH2C6H3(CH3)2-3,5);
114.4, 114.5, 126.5, 127.3, 129.6, 130.6, 130.8, 131.4, 131.6, 133.5, 133.9, 134.2, and
138.7 (Ar–H); 143.6 (NCHN).
2.5.3. 1-(4-methylbenzyl)-3-(4-chlorobenzyl)benzimidazolium chloride, 1c
Compound 1c was synthesized as described above from 1-(4-methylbenzyl) benzimi-
dazole and 4-chlorobenzyl chloride. The reaction produced 1c (0.35 g, 82%) as a solid.
1
M.p.: 174–175 ꢀC. IR (cmꢁ1): v(CN), 1560. H NMR (400 MHz, CDCl3), d (ppm): 2.32 (s,
3H, NCH2C6H4(CH3)-4); 5.79 and 5.92 (s, 4H, NCH2C6H4–Cl and NCH2C6H4(CH3)-4);
7.14–7.19 (m, 2H, Ar–H); 7.34–7.39 (m, 4H, Ar ꢁ H); 7.49–7.57 (m, 6H, Ar–H); 12.11 (s,
1H, NCHN). 13C NMR (100 MHz, CDCl3), d (ppm): 21.2 (NCH2C6H4(CH3)-4); 50.8 and 51.6
(NCH2C6H4–Cl and NCH2C6H4(CH3)-4); 113.5, 113.8, 127.1, 127.6, 128.2, 129.6, 129.8,
129.9, 130.1, 131.3, 135.4, and 139.4 (Ar–H); 144.0 (NCHN).

1972
S. D. DÜŞÜNCELI ET AL.
Scheme 1. The synthetic route for new benzimidazolium salts and their silver(I) complexes.
2.5.4. 1-(4-methoxybenzyl)-3-(4-cyanobenzyl)benzimidazolium bromide, 1d
Compound 1d was synthesized as described above from 1-(4-methoxybenzyl) benzimi-
dazole and 4-cyanobenzyl bromide. The reaction produced 1d (0.40 g, 80%) as a solid.
M.p.: 246–247 ꢀC. IR (cmꢁ1): v(CN), 1672; v(CꢄN), 2226. 1H NMR (400 MHz, CDCl3), d
(ppm): 3.77 (s, 3H, NCH2C6H4(OCH3)-4); 5.77 and 6.12 (s, 4H, NCH2C6H4–CN and
NCH2C6H4(OCH3)-4); 7.48–7.62 (m, 8H, Ar–H); 7.74 and 6.88 (d, 4H, J ¼ 8 Hz, Ar-H); 11.83
(s, 1H, NCHN). 13C NMR (100 MHz, CDCl3), d (ppm): 50.7 and 51.6 (NCH2C6H4–CN and
NCH2C6H4(OCH3)-4); 55.4 (NCH2C6H4(OCH3)-4); 113.1, 113.5, 114.0, 114.9, 118.0, 124.2,
127.3, 127.4, 129.2, 130.0, 131.2, 131.3, 133.0, and 160.3 (Ar–H); 137.9 (NCH2C6H4–CN);
143.4 (NCHN).
2.5.5. 1-(2,3,4,5,6-pentamethylbenzyl)-3-(4-cyanobenzyl)benzimidazolium bromide, 1e
Compound 1e was synthesized as described above from 1-(2,3,4,5,6-pentamethylben-
zyl) benzimidazole and 4-cyanobenzyl bromide. The reaction produced 1e (0.46 g,
92%) as a solid. M.p.: 242–243 ꢀC. IR (cmꢁ1): v(CN), 1667; v(CꢄN), 2223. 1H NMR
(400 MHz, CDCl3), d (ppm): 2.26 (s, 6H, NCH2C6(CH3)-2,3,4,5,6); 2.29 (s, 6H, NCH2C6(CH3)-
2,3,4,5,6); 2.30 (s, 3H, NCH2C6(CH3)-2,3,4,5,6); 5.77 and 6.24 (s, 4H, NCH2C6H4–CN and
NCH2C6(CH3)-2,3,4,5,6); 7.48–7.66 (m, 8H, Ar–H); 10.81 (s, 1H, NCHN). 13C NMR
(100 MHz, CDCl3), d (ppm): 17.1, 17.3, and 17.4 (NCH2C6(CH3)-2,3,4,5,6); 48.2 and 50.6
(NCH2C6H4–CN and NCH2C6(CH3)-2,3,4,5,6); 112.8, 113.6, 113.8, 118.1, 124.3, 127.5,
127.6, 129.0, 131.5, 132.9, 133.5, 134.2, 138.4, and 162.5 (Ar–H); 137.7 (NCH2C6H4–CN);
142.5 (NCHN).
2.6. Synthesis and characterization of Ag–NHC complexes (2a–e)
The Ag(I)-NHC complexes were synthesized from benzimidazolium salts (1a–e)
(2 mmol) and Ag2O (1 mmol) in 20 mL dry dichloromethane (Scheme 1). Light was
avoided during the reaction by wrapping the reaction vessel with aluminum foil. Then
the reaction mixture was filtered through a Celite bed and the resulted filtrate was
concentrated to 3 mL under vacuum. The fine white precipitate was afforded by add-
ition of diethyl ether (30 mL). The precipitate was filtered, washed with diethyl ether

JOURNAL OF COORDINATION CHEMISTRY
1973
(30 mL), and dried under vacuum to yield pure (2a–e). The structures of the com-
1
pounds were confirmed by FT-IR, H, and 13C NMR.
2.6.1. Chloro[1,3-bis(4-chlorobenzyl)benzimidazole-2-ylidene] silver(I), 2a
Compound 2a was synthesized as described above from 1,3-bis(4-chlorobenzyl)benzi-
midazolium chloride (2 mmol) and Ag2O (1 mmol). The reaction produced 2a (0.38 g,
1
74%) as a solid. M.p.: 229–230 ꢀC. IR (cmꢁ1): v(CN), 1394. H NMR (400 MHz, CDCl3), d
(ppm): 5.77 (s, 4H, NCH2C6H4-Cl); 7.37–7.43 (m, 10H, Ar–H); 7.71–7.73 (m, 2H, Ar–H). 13C
NMR (100 MHz, CDCl3), d (ppm): 51.6 (NCH2C6H4-Cl); 112.9, 124.8, 129.3, 129.6, 133.1,
133.8, and 135.7 (Ar ꢁ H).
2.6.2. Chloro[1-(3,5-dimethylbenzyl)-3(4-chlorobenzyl)benzimidazole-2-ylidene] silver(I), 2b
Compound 2b was synthesized as described above from 1-(3,5-dimethylbenzyl)-3-(4-
chlorobenzyl)benzimidazolium chloride (2 mmol) and Ag2O (1 mmol). The reaction pro-
1
duced 2b (0.30 g, 60%) as a solid. M.p.: 188–189 ꢀC. IR (cmꢁ1): v(CN), 1385. H NMR
(400 MHz, CDCl3), d (ppm): 2.27 (s, 6H, NCH2C6H3(CH3)2-3,5); 5.55 and 5.64 (s, 4H,
NCH2C6H4 –Cl and CH2C6H3(CH3)2-3,5); 6.87–7.38 (m, 11H, Ar–H). 13C NMR (100 MHz,
CDCl3), d (ppm): 21.3 (NCH2C6H3(CH3)2-3,5); 52.8 and 53.5 (NCH2C6H4–Cl and
NCH2C6H3(CH3)2-3,5); 111.9, 112.3, 124.4, 124.5, 128.5, 129.3, 130.3, 133.4, 133.7, 134.0,
134.5, and 138.8 (Ar–H).
2.6.3. Chloro[1-(4-methylbenzyl)-3(4-chlorobenzyl)benzimidazole-2-ylidene] silver(I), 2c
Compound 2c was synthesized as described above from 1-(4-methylbenzyl)-3-(4-chlor-
obenzyl)benzimidazolium chloride (2 mmol) and Ag2O (1 mmol). The reaction produced
1
2c (0.32 g, 65%) as a solid. M.p.: 229–230 ꢀC. IR (cmꢁ1): v(CN), 1393. H NMR (400 MHz,
CDCl3), d (ppm): 2.32 (s, 3H, NCH2C6H4(CH3)-4); 5.60 and 5.62 (s, 4H, NCH2C6H4 –Cl and
NCH2C6H4(CH3)-4); 7.10–7.39 (m, 12H, Ar–H). 13C NMR (100 MHz, CDCl3), d (ppm): 21.1
(NCH2C6H4(CH3)-4); 52.9 and 53.4 (NCH2C6H4 –Cl and NCH2C6H4(CH3)-4); 111.9, 112.3,
127.2, 128.5, 129.3, 129.8, 131.6, 133.3, 133.7, 133.9, 134.5, and 138.5 (Ar–H).
2.6.4. Bromo[1-(4-methoxybenzyl)-3(4-cyanobenzyl)benzimidazole-2-ylidene] silver(I), 2d
Compound 2d was synthesized as described above from 1-(4-methoxybenzyl)-3-(4-cya-
nobenzyl)benzimidazolium bromide (2 mmol) and Ag2O (1 mmol). The reaction pro-
duced 2d (0.38 g, 70%) as a solid. M.p.: 175–176 ꢀC. IR (cmꢁ1): v(CN), 1391; v(CꢄN),
2233. 1H NMR (400 MHz, CDCl3), d (ppm): 3.77 (s, 3H, NCH2C6H4(OCH3)-4); 5.68 and
5.82 (s, 4H, NCH2C6H4 –CN and NCH2C6H4(OCH3)-4); 7.22–7.38 (m, 8H, Ar–H); 6.82 and
7.54 (d, 4H, J ¼ 8 Hz, Ar-H). 13C NMR (100 MHz, CDCl3), d (ppm): 52.9 and 52.9
(NCH2C6H4–CN and NCH2C6H4(OCH3)-4); 55.3 (NCH2C6H4(OCH3)-4); 111.4, 112.2, 114.4,
118.2, 124.3, 126.9, 127.7, 128.6, 132.7, 133.8, and 159.6 (Ar–H); 140.8 (NCH2C6H4–CN).
2.6.5. Bromo[1-(2,3,4,5,6-pentamethylbenzyl)-3(4-cyanobenzyl)benzimidazole-2-yli-
dene] silver(I), 2e
Compound 2e was synthesized as described above from 1-(2,3,4,5,6-pentamethylben-
zyl)-3-(4-cyanobenzyl)benzimidazolium bromide (2 mmol) and Ag2O (1 mmol). The reac-
tion produced 2e (0.38 g, 65%) as a solid. M.p.: 148–149 ꢀC. IR (cmꢁ1): v(CN), 1389;

1974
S. D. DÜŞÜNCELI ET AL.
1
v(CꢄN): 2225. H NMR (400 MHz, CDCl3), d (ppm): 2.14 (s, 6H, NCH2C6(CH3)-2,3,4,5,6);
2.22 (s, 6H, NCH2C6(CH3)-2,3,4,5,6); 2.26 (s, 3H, NCH2C6(CH3)-2,3,4,5,6); 5.43 and 5.57 (s,
4H, NCH2C6H4 –CN and NCH2C6(CH3)-2,3,4,5,6); 7.18–7.53 (m, 8H, Ar–H). 13C NMR
(100 MHz, CDCl3), d (ppm): 16.1, 16.2, and 16.5 (NCH2C6(CH3)-2,3,4,5,6); 46.7 and 52.6
(NCH2C6H4–CN and NCH2C6(CH3)-2,3,4,5,6); 110.6, 111.4, 117.1, 123.5, 123.8, 125.0,
126.6, 131.8, 132.5, 133.5, 133.6, and 136.7 (Ar–H); 139.3 (NCH2C6H4–CN).
3. Results and discussion
Aromatic nitrogen containing heterocyclic compounds (N-heterocycles) are one of the
most important classes of nitrogen-donor ligands utilized in the synthesis of biologically
active silver(I) complexes [32]. These compounds represent structural moieties of many
natural products and biologically important molecules, as well as pharmacologically
used agents [33]. Different N-heterocycles such as imidazole and its substituted deriva-
tives [34, 35], tetrazole [36], pyridine and its derivatives [37, 38], quinolines [39], diazines
and benzodiazines [40, 41], bipyridines [42], terpyridines [43], and phenanthrolines [44,
45] have been used for the synthesis of mono- and polynuclear silver(I) complexes,
which have shown remarkable activity against a broad panel of bacterial and fungal
strains which can lead to many infections. Studies on benzimidazole (bim) and its deriv-
atives had been conducted for more than 100 years until researchers found that 5,6-
dimethylbenzimidazole is part of vitamin B12 in 1955. This fact made scientists realize
that benzimidazole-based compounds are both safe and effective at inhibiting the
growth of bacteria. It was demonstrated that benzimidazoles can be used in the clinic
as antibacterial drugs. According to research results, the antibacterial mechanism of ben-
zimidazoles is due to their structural similarity to purine. It is well known that purine
plays an important role in the biosynthesis of nucleic acids and proteins in the bacterial
cell wall. As competitive inhibitors, benzimidazoles can replace purine, thereby blocking
the biosynthesis of key components, killing or inhibiting the growth of bacteria [46].
Silver and its compounds have been widely used as antimicrobial agents. In order to
develop more effective antimicrobial agents, a large number of silver(I) complexes with
oxygen, nitrogen, and sulfur donor ligands have been investigated [47–50]. Among the
complexes studied, silver(I) complexes of imidazole and carbenes have been found to
be the most effective agents [51]. Since the first reports of biological importance of
NHC-silver(I) compounds by Youngs et al., researchers have delved into designing an
effective prescription for cancer as well as bacterial infections utilizing silver, owing to
the employment of silver in medicine since antique times and its low toxicity [52–55].
To investigate further silver(I) complexes of benzimidazole-2-ylidene ligands, we report
here the synthesis and spectroscopic characterization of five benzimidazolium salts as
NHC precursor and their silver(I) complexes and the antimicrobial activity of complexes.
3.1. Synthesis of benzimidazolium salts and silver(I) NHC complexes
The synthetic route for novel nonsymmetrical p-chlorobenzyl or cyanobenzyl-substi-
tuted N-heterocyclic carbenes as ligand precursors (1a–e) and their corresponding
silver(I) complexes (2a–e) depicted in the present work is outlined in Scheme 1.

JOURNAL OF COORDINATION CHEMISTRY
1975
Figure 1. An inversion-symmetric dimer in the structure of 2a. Symmetry transformation used to
generate equivalent atoms is ꢁx, ꢁy þ 1, ꢁz þ 2.
A series of new benzimidazolium salts and their silver(I) complexes were prepared
and characterized. 1,3-Disubstituted benzimidazolium salts, which can act as potential
NHC synthons, were synthesized following the successive N-alkylation of N-substituted
benzimidazoles. Benzimidazole was treated with an appropriate alkyl halide in the
presence of a strong base, KOH or NaH, to afford N-alkylbenzimidazole derivatives in
almost quantitative yields [56]. Consequently, equimolar amounts of N-alkylbenzimida-
zole compounds and 4-chlorobenzyl chloride or 4-cyanobenzyl bromide were heated
in DMF for 8 h to yield the desired chloride or bromide salts 1a–e, which were purified
by repeated precipitation using ethanol/diethyl ether mixture. The complexes were
prepared in good yields following the in-situ deprotonation method by treating benzi-
midazolium salts with silver(I) oxide in the dark (scheme 1). Silver complexes were
readily soluble in polar organic solvents such as DMSO, dimethylformamide and aceto-
nitrile and insoluble in methanol and nonpolar solvents such as diethyl ether and n-
hexane. All the compounds were characterized using various spectroscopic methods.
1
The H NMR spectra of precursors 1a–e show a characteristic downfield shift in the
range d ¼ 10.17–12.17 ppm for the NCHN proton, attributable to the positive charge of
the molecule [20, 57]. Also, benzimidazole and aromatic ring proton resonance peaks
appeared in the region 6.8–7.9 ppm with appropriate peak coupling constants.
Further, the spectra also evidenced peaks in the range 2.26–6.24 ppm attributed to ali-
phatic proton resonances such as benzylic, methyl or methoxy. In the 13C NMR

1976
S. D. DÜŞÜNCELI ET AL.
Figure 2. An inversion-symmetric dimer in the structure of 2e. Symmetry transformation used to
generate equivalent atoms is ꢁx þ 2, ꢁy þ 2, ꢁz þ 1.
spectra, a distinct carbon resonance peak was observed at 140.9–144.0 ppm, which is
ascribed to the resonance of C2 carbon. Similarly, benzimidazole, aromatic ring, and
cyano carbon resonances were observed in the region 112–163 ppm, while the ali-
phatic region evidenced a set of peaks in the range 17–56 ppm, which were assigned
to the resonance of aliphatic carbon nuclei. The most downfield proton resonance
1
peak of the salts was absent in the region 10–13 ppm in the H NMR spectra of the
complexes, confirming the deprotonation of C2 proton followed by successful forma-
tion of the desired silver complexes. In all the silver complexes, the resonances for Ag-
carbene were not observed, which has also been mentioned in the literature and
given as a reason for the fluxional behavior of the NHCs complexes [58–60]. Apart
from these two major differences in the NMR spectra of the complexes, no significant
dissimilarities were observed between the resonances of protons or carbons compared
to the spectra of the salts.
In the IR spectra of benzimidazolium salts (1a–e), stretching vibrational bands of
m(C–N) was observed at 1560–1672 cmꢁ1 and stretching vibrational bands of m(CꢄN)
was observed at 2227 and 2223 cmꢁ1 for 1d and 1e, respectively. In the IR spectra of
silver complexes (2a–e), stretching vibrational bands of m(C–N) was observed at

JOURNAL OF COORDINATION CHEMISTRY
1977
Table 2. Selected geometric parameters for 2a and 2e.
Parameters
2a
Parameters
2e
Bond lengths (Å)
Ag1─Cl1
2.3646(19)
3.099(2)
2.080(7)
1.354(9)
1.394(9)
1.356(10)
1.394(9)
Ag1─Br1
Ag1─Br1ii
Ag1─C1
N1─C1
2.4976(6)
3.0289(6)
2.115(4)
1.357(5)
1.388(5)
1.360(5)
1.385(5)
Ag1─Cl1i
Ag1─C1
N1─C1
N1─C2
N1─C2
N2─C1
N2─C1
N2─C7
N2─C7
Bond angles (ꢀ)
Cl1─Ag1─C1
Cl1i─Ag1─C1
Cl1─Ag1─Cl1i
Ag1─Cl1─Ag1i
Ag1─C1─N1
Ag1─C1─N2
N1─C1─N2
C1─N1─C2
C1─N2─C7
169.4(2)
106.6(2)
84.03(6)
95.97(6)
126.8(6)
128.1(5)
105.1(6)
111.6(6)
111.0(6)
Br1─Ag1─C1
Br1ii─Ag1─C1
Br1─Ag1─Br1ii
Ag1─Br1─Ag1ii
Ag1─C1─N1
Ag1─C1─N2
N1─C1─N2
166.37(11)
102.59(10)
90.473(18)
89.528(17)
127.7(3)
126.6(3)
104.8(3)
C1─N1─C2
111.6(3)
111.4(3)
C1─N2─C7
i
ii
Symmetry codes: ꢁx, ꢁy þ 1, ꢁz þ 2, ꢁx þ 2, ꢁy þ 2, ꢁz þ 1.
1386–1393 cmꢁ1 and stretching vibrational bands of m(CꢄN) was observed at 2235
and 2225 cmꢁ1 for 2d and 2e, respectively. Crude complexes were recrystallized from
dichloromethane and diethyl ether mixture through repeated precipitation to afford
light sensitive off-white solids in good yields. No degradation was observed when the
complexes were kept away from light in solution. So obtained silver complexes were
readily soluble in polar organic solvents such as DMSO, chloroform, dichloromethane
and insoluble in methanol and nonpolar solvents such as diethyl ether and n-hexane.
The molecular structures of 2a and 2e with the atom-numbering scheme are shown
in Figures 1 and 2, respectively, while selected bond lengths and angles are listed in
Table 2.
X-ray diffraction studies reveal the formation of neutral monomeric complexes of
the type (NHC)AgX (X ¼ Cl for 2a and Br for 2e). The complexes show an almost linear
arrangement around the Ag(I) centers with a bonding angle of 169.4(2)ꢀ for 2a and
166.37(11)ꢀ for 2e. X-ray analysis also shows that the 2a and 2e molecules appear to
associate via weak intermolecular AgꢅꢅꢅX1 interactions to form a quasi-dimeric struc-
ture. These f(NHC)AgXg2-type associations demonstrate an Ag2X2 quadrangular
arrangement, which is strictly planar because of the inversion center at the mid-point
i
ii
of the AgꢅꢅꢅAgi/ii line [symmetry codes: ꢁx, ꢁy þ 1, ꢁz þ 2, ꢁx þ 2, ꢁy þ 2, ꢁz þ 1],
and lead to markedly different Ag-X distances. While the length of the direct silver-hal-
ide bond is 2.3646(19) Å in 2a and 2.4976(6) Å in 2e, this additional interaction is sub-
stantially longer at 3.099(2) Å in 2a and 3.0289(6) Å in 2e. The AgꢅꢅꢅAgi/ii distances
[4.0890(14) Å for 2a and 3.9100(7) Å for 2e] are beyond the sum of van der Waals radii
of 3.44 Å [61] for two silver atoms, precluding any significant argentophilic interaction
between the metal ions. The bond angles of C1-Ag1-X1i/ii, Ag1-X1-Ag1i/ii, and X1-Ag1-
X1i/ii are 106.6(2)ꢀ, 95.97(6)ꢀ, and 84.03(6)ꢀ for 2a, and 102.59(10)ꢀ, 89.528(17)ꢀ, and
90.473(18)ꢀ for 2e, respectively. The Ag1-C1 distance is 2.080(7) Å in 2a and 2.115(4) Å
in 2e, and the internal ring angle N1─C1─N2 at the carbene center is 105.1(6)ꢀ in 2a
and 104.8(3)ꢀ in 2e. All the aforementioned data are similar to those of some known
NHC-silver-halide complexes [62–67].

1978
S. D. DÜŞÜNCELI ET AL.
Figure 3. Part of the crystal structure of 2a showing the p … p intermolecular interactions.
Hydrogens have been omitted for clarity.
No intramolecular interactions are observed in the molecular structure of both com-
pounds. However, weak p … p stacking interactions are mainly responsible for the sta-
bilization of the crystal structures. In 2a, two molecules are linked to each other via
p … p stacking interactions in which the five- and six-membered rings of the benzimi-
dazole moieties in the molecules at (x, y, z) and (1 ꢁ x, 2 ꢁ y, 2 ꢁ z) are mutually paral-
lel with a distance of 3.668(5) Å between the ring centroids (Figure 3). In the case of
2e, the pentamethylbenzene ring in the molecule at (x, y, z) stacks above its sym-
metry-related partner at (2 ꢁ x, 1 ꢁ y, 1 ꢁ z) with a distance of 3.867(3) Å between the
ring centroids (Figure 4).
3.2. Antibacterial activities
The antibacterial activities of 2a–2e were evaluated against a panel of Gram-positive
(Staphylococcus aureus, Enterococcus faelacis, and Staphylococcus aureus MRSA), Gram-
negative (Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and
Acinetobacter baumannii), fungal (Candida glabrata and Candida albicans) strains at dif-
ferent concentrations. The complexes were found to be effective, and the results of
the antibacterial studies of NHC-silver(I) complexes against the bacterial strains are
summarized in Table 3.

JOURNAL OF COORDINATION CHEMISTRY
1979
Figure 4. Part of the crystal structure of 2e showing the p … p intermolecular interactions.
Hydrogens have been omitted for clarity.
The complexes displayed improved antibacterial efficacy against Staphylococcus aur-
eus and Enterococcus faecalis strain, comparable with that of the standard drug ampi-
cillin (MIC ¼ 1.56 mg/mL). All complexes were found to display significant activity
against Staphylococcus aureus and Enterococcus faecalis as gram-positive bacteria with
MICs ranging from 12.5 to 100 mg/mL. Complexes 2b and 2e gave the best values
with MICs 12.5 mg/mL for Staphylococcus aureus and 25 mg/mL for Enterococcus faecalis
(Table 3).
The complexes displayed improved antibacterial efficacy against Pseudomonas aeru-
ginosa, Escherichia coli, and Klebsiella pneumoniae strain as gram-negative bacteria,
comparable with that of the standard drug ampicillin (MIC ¼ 3.12 mg/mL) and cipro-
floxacin (MIC ¼ 1.56 mg/mL) for Escherichia coli, amikacin (MIC ¼ 1.56 mg/mL) for
Pseudomonas aeruginosa and ampicillin, amikacin, ciprofloxacin (MIC ¼ 1.56 mg/mL) for
Klebsiella pneumoniae. All compounds did not show good antibacterial activity against
Pseudomonas aeruginosa (MIC ¼ 100–400 mg/mL). All of the complexes showed signifi-
cant activity against Escherichia coli (MIC ¼ 50–100 mg/mL). Complexes 2b and 2e
gave the best values with MIC ¼ 50 mg/mL for Escherichia coli. In contrast, all of the
complexes showed much higher activities against Klebsiella pneumoniae than against
Escherichia coli and Pseudomonas aeruginosa (Table 3).
The complexes displayed improved antibacterial efficacy against Candida glabrata
and Candida albicans as fungal strains, comparable with that of the standard drug flu-
canazole (MIC ¼ 6.25 mg/mL for Candida albicans; MIC ¼ 3.12 mg/mL for Candida glab-
rata). All of the complexes showed same activity against Candida glabrata and
Candida albicans (MIC ¼ 50–100 mg/mL). Complexes 2b and 2e gave the best values
with MICs 50 mg/mL for fungal strains (Table 3).

1980
S. D. DÜŞÜNCELI ET AL.

JOURNAL OF COORDINATION CHEMISTRY
1981
Table 4. Global reactivity descriptors of the molecules.
2a
2b
2c
2d
2e
Ionization Potential (IP)
Electron Affinity (EA)
Electronegativity (v)
Chemical Potential (m)
Global Softness (S)
5.480
2.615
4.047
5.380
2.481
3.930
5.381
2.495
3.938
5.350
2.918
4.134
5.300
2.889
4.094
ꢁ4.047
ꢁ3.930
ꢁ3.938
ꢁ4.134
ꢁ4.094
0.349
0.345
0.346
0.411
0.415
Global Hardness (g)
Electrophilicity Index (x)
1.432
5.716
1.449
5.328
1.443
5.366
1.216
7.024
1.205
6.956
The complexes displayed improved antibacterial efficacy against Acinetobacter bau-
mannii (gram-negative) and Staphylococcus aureus MRSA (gram-positive) strain as
nosocomial agents, comparable with that of the standard drug amikacin (MIC ¼
3.12 mg/mL), and tigecycline (MIC ¼ 1.56 mg/mL) for Acinetobacter baumannii, vanko-
mycin (MIC ¼ 3.12 mg/mL) for Staphylococcus aureus MRSA. All compounds showed no
good antibacterial activity against Acinetobacter baumannii strain (MIC ¼ 100–400 mg/
mL). In contrast, all of the complexes showed significant activity against
Staphylococcus aureus MRSA (MIC ¼ 50–200 mg/mL). Complexes 2b and 2e gave the
best values with MICs 50 mg/mL for Staphylococcus aureus MRSA (Table 3).
Among these complexes, 2b and 2e exhibited the best activities among the whole set
of silver-NHCs tested against all bacteria strains. Similar results were obtained with a benzi-
midazole-based neutral silver-NHC complex with benzodioxanyl and benzyl/4-methylben-
zyl substituents as reported by Akkoc¸ et al. [68]. Similarly, Karatas¸ et al. reported [69] similar
bis-NHC coordinated silver(I) complexes which displayed good antibacterial activity (MIC in
the range 50–200 MIC lg/mL against E. coli). These values are comparable to other related
results in the literature; in some cases, the complexes have shown better results [68–70],
indicating that these new Ag-NHC complexes are quite potent.
3.3. Computational details
Characterized silver complexes geometrically optimized by the ORCA program package
with the RI-BP86 and a TZVP basis set and also tightscf and grid4 options, calculated
Cartesian coordinates of the molecules are given in Tables S1–S5 (Supplementary
material). The positions and energies of the frontier orbitals of the molecules are
important for the evaluation of reactivity [71, 72]. The atoms that frontier orbitals were
situated are the regions where the electron exchange and activity of the molecules
were actualized. The HOMO orbitals of all molecules in the study are on chlorine and
the reactions that the synthesized molecules act as electron provider take place on
chlorine. On the other hand, the LUMO orbitals of the molecules 2a, 2b, and 2c are
on the benzimidazole ring while the LUMO orbitals of the 2d and 2e molecules are
on the benzyl ring and the activity that the molecules perform as the electron
acceptor could be expected on these regions. The energies and illustrations of some
important frontier orbitals of all molecules are given in Table S6
(Supplementary material).
The global reactivity descriptors obtained DFT-based calculation methods providing
useful information for structure/property evaluations of organic and inorganic mole-
cules [73, 74]. HOMO and LUMO energies are utilized for calculating the ionization

1982
S. D. DÜŞÜNCELI ET AL.
Table 5. Wavelength (in nm), oscillator strength (fosc), main orbital contributions of the most
important singlet excitations of 2e calculated with TDDFT/BP86.
State
4
knm
fosc
Main transitions
428.1
0.067
HOMO ! LUMO þ 1 (64.1%)
Br (bonded Ag) ! bim
Br (bonded Ag) ! bim
Br (bonded Ag) ! bim
Br (bonded Ag) ! bim
Ag-Br ! benzyl
benzyl-CN ! bim
benzyl ! benzyl-CN
bim ! bim
HOMO-1 ! LUMO þ 1 (32.6%)
HOMO ! LUMO þ 6 (57.9%)
HOMO-1 ! LUMO þ 6 (38.4%)
HOMO-3 ! LUMO þ 4 (63.3%)
HOMO-8 ! LUMO þ 1 (73.8%)
HOMO-9 ! LUMO (24.1%)
26
300.3
0.030
31
32
38
279.3
277.9
264.6
0.011
0.016
0.021
HOMO-6 ! LUMO þ 1 (22.8%)
HOMO-9 ! LUMO þ 1 (11.5%)
HOMO-8 ! LUMO þ 2 (11.1%)
HOMO-5 ! LUMO þ 1 (42.4%)
HOMO-6 ! LUMO þ 1 (10.7%)
HOMO-6 ! LUMO þ 1 (24.1%)
HOMO-9 ! LUMO (17.9%)
benzyl ! bim
benzyl-CN
40
41
263.6
262.2
0.092
0.053
bim ! bim
bim ! bim
bim ! bim
benzyl ! benzyl-CN
bim ! bim
HOMO-5 ! LUMO þ 1 (16.6%)
HOMO-8 ! LUMO þ 2 (15.2%)
benzyl-CN ! benzyl
potential, electron affinity, and electronegativity of the molecules (Table 4). In this
study, the highest electron affinity and electronegativity were calculated for 2d while
the highest ionization potential was concluded in 2a. Global softness and chemical
hardness are also used as indicator of the reactivity of molecules [75]. Since low hard-
ness and high softness indicates the high reactivity, it is clear that the most active
molecule is 2e and the most stable molecule is 2b. The electrophilicity index is
defined as the electrophilic force of a molecular system against a nucleophile.
According to the calculations in this study, 2d is the most electrophilic molecule while
the most nucleophilic molecule is 2b.
Electronic transitions of the optimized molecules were performed by ORCA package
program with the TDDFT approach [76, 77]. The permitted transitions with oscillator
strength greater than 0.01 and orbital interactions with the contribution greater than
10% were evaluated and given in Table 5 and Tables S7–S10 (Supplementary material).
The highest oscillator strength of the 2a–c molecules, which were synthesized as
chloride salts, were calculated for HOMO!LUMO transitions in the Soret region at
411.1 nm, 406.9 nm, and 408.4 nm, respectively. The other considerable electronic tran-
sitions for these molecules were the ILCT transitions corresponds to the conjugation
on the benzimidazole ring and were calculated at 271.7 nm, 272.7 nm, and 272.8 nm,
respectively. In 2d and 2e, which were synthesized as bromide salts, the oscillator
strength of electronic transitions connected with the benzimidazole conjugation are
higher than that of 2a–c. The electronic transition with the highest oscillator strength
of 2e was calculated as state 40 at 263.6 nm. When the Soret region of 2e was eval-
uated, the state 4 mostly corresponds to Br(bonded Ag) ! bim electronic transitions.
Molecular docking methods provide important theoretical insights into the activity
of synthesized molecules [78–80]. Since the known benzimidazole-derivative molecules
generally show antibacterial activity by inhibition of topoisomerase II, the molecules
were analyzed by using both 1JIJ and 1KZN crystal structures in docking processes of
this study [81]. The energetically favorable docked poses obtained from the rigid
molecular docking of 2a for 1JIJ and 1KZN targets are given in Figure 5. The most
preferable interaction of 2a with 8.35 kcal/mol binding energy in 1JIJ was arisen in the

JOURNAL OF COORDINATION CHEMISTRY
1983
Figure 5. The best docking poses of 2a and 2d with 1JIJ and 1KZN.
region composed Tyr36, Cys37, Gly38, Ala39, Asp40, Thr42, Gly49, His50, Pro53, Leu70,
Thr75, Tyr170, Gln174, Asp177, Val191, Gly192, Gly193, Asp195, Gln196 amino acids.
The significant interactions of 2a are the alkylic interactions between chlorine
(bonded-Ag) and Cys237 and also between chlorines (bonded-benzyls) and Tyr36/
Pro53 with 5.27 Å and 4.23 Å bond lengths, respectively. The preferable dock of 2a
with 7.8 kcal/mol binding energy in 1KZN was arisen in the region composed Val43,
Asn46, Ala47, Glu50, Val71, Gln72, Asp73, Ile78, Ile90, Met91, Val120, Leu130, Thr165,
Val167 amino acids. Alkylic interactions between chlorine (bonded-Ag) and Ile78, Ile90,
Val120 and also chlorine (bonded-benzyl) and Met91, Val120, Leu130, Val167 are
important interactions of 2a in 1KZN. The binding energies of 2b, 2c, 2d, and 2e with
1JIJ were 8.57 kcal/mol, 8.21 kcal/mol, 8.67 kcal/mol, 9.28 kcal/mol, respectively, while
the binding energies with 1KZN were achieved at 6.6 kcal/mol, 9.57 kcal/mol,
11.75 kcal/mol, 13.07 kcal/mol, respectively. The interaction regions of 2b, 2c, 2d, and
2e with 1JIJ and 1KZN are given in Figure S29 (Supplementary material).
4. Conclusion
Five novel symmetrically substituted and nonsymmetrically substituted N-heterocyclic
carbene precursors (1a–e) and their silver complexes (2a–e) were synthesized and
characterized by 1H NMR, 13C NMR and IR spectroscopies and analyzed with DFT/
TDDFT and molecular docking methods. The structures of 2a and 2e were confirmed
by X-ray crystallography. All the complexes have shown high antimicrobial activity
against gram(þ)/(ꢁ) bacteria and fungi strains. More studies are now in progress
including a larger collection of bacteria of different species in order to determine if
the antimicrobial activity is species dependent and its possible application in different
fields. New biologically active Pt or Au NHC complexes have been prepared with an
aim to develop robust cancer chemotherapeutic agents. Furthermore, we will be test-
ing properties of both transmetallation reaction and catalysis of silver complexes that
described this work.

1984
S. D. DÜŞÜNCELI ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
_
€ €
This work was financially supported by the Inonu University Research Fund (FYL-2018-1056). We
also acknowledge the Crystallography Laboratory Unit, Ondokuz Mayis University, for the X-ray
data collection, which was supported by the University Research Fund (Project No:
PYO.FEN.1906.19.001).
References
[1] A.J. Arduengo, R.L. Harlow, M. Kline. J. Am. Chem. Soc., 113, 361 (1991).
[2] A.J. Arduengo, M. Tamm, M.J.C. Calabrese. J. Am. Chem. Soc., 116, 3625 (1994).
[3] A.J. Arduengo, III, S.F. Gamper, M. Tamm, J.C. Calabrese, F. Davidson, H.A. Craig. J. Am.
Chem. Soc., 117, 572 (1995).
€
[4] W.A. Herrmann, C. Kocher. Angew. Chem. Int. Ed. Engl., 36, 2162 (1997).
€
€
[5] W.A. Herrmann, K. Ofele, M. Elison, F.E. Kuhn, P.W. Roesky. J. Organomet. Chem, 480, c7
(1994).
[6] N. Kuhn, T. Kratz, G. Henkel. J. Chem. Soc. Chem. Commun., 23, 1778 (1993).
[7] G. Gasser, I. Ott, N. Metzler-Nolte. J. Med. Chem., 54, 3 (2011).
[8] D. Bourissou, O. Guerret, F. Gabbai, G. Bertrand. Chem. Rev., 100, 39 (2000).
[9] S.P. Nolan. N-Heterocyclic Carbenes: Effective Tools for Organometallic Synthesis, Wiley-VHC,
Weinheim, Germany (2014).
[10] K.M. Hindi, A.J. Ditto, M.J. Panzner, D.A. Medvetz, D.S. Han, C.E. Hovis, J.K. Hilliard, J.B.
Taylor, Y.H. Yun, C.L. Cannon, W.J. Youngs. Biomaterials, 30, 3771 (2009).
€
_
€
_ €
€
€
€ €
ꢁ
[11] U. Kızrak, O. C¸iftc¸i, I. Ozdemir, N. Gurbuz, S.D. Dus¸unceli, M. Kaloglu, L. Mansour, F.
Zaghrouba, N. Hamdi, I. Ozdemir. J. Organomet. Chem., 882, 26 (2019).
[12] S. S¸ahin-Bolukbas¸ı, N. S¸ahin, M.N. Tahir, C. Arıcı, E. C¸evik, N. Gurbuz, I. Ozdemir, B.S.
Cummings. Inorg. Chim. Acta, 486, 711 (2019).
_
€
€ €
€ €
[13] M.A. Iqbal, M.I. Umar, R.A. Haque, M.B. Khadeer Ahamed, M.Z.B. Asmawi, A.M.S.A. Majid. J.
Inorg. Biochem., 146, 1 (2015).
[14] D.A. Medvetz, K.M. Hindi, M.J. Panzner, A.J. Ditto, Y.H. Yun, W.J. Youngs. Met. Based
Drugs, 2008, 384010 (2008).
[15] S.A. Patil, S.A. Patil, R. Patil, R.S. Keri, S. Budagumpi, G.R. Balakrishna, M. Tacke. Future
Med. Chem., 7, 1305 (2015).
[16] L. Boubakri, K. Dridi, A.S. Al-Ayed, I. Ozdemir, S. Yasar, N. Hamdi. J. Coord. Chem., 72, 2080
(2019).
[17] S. Budagumpi, R.A. Haque, S. Endud, G.U. Rehman, A.W. Salman. Eur. J. Inorg. Chem.,
2013, 4367 (2013).
€
_
€
_
€
€
€ €
[18] E.O. Karaca, O. C¸iftc¸i, I. Ozdemir, G. Yakalı, M. Aygun, N. Gurbuz, I. Ozdemir. Appl.
Organomet. Chem., 33, e4851 (2019).
[19] R.E. Andrew, C.M. Storey, A.B. Chaplin. Dalton Trans., 45, 8937 (2016).
[20] A.J. Arduengo, III, H.V.R. Dias, J.C. Calabrese, F. Davidson. Organometallics, 12, 3405
(1993).
ꢂ
[21] O. Guerret, S. Sole, H. Gornitzka, M. Teichert, G. Trinquier, G. Bertrand. J. Am. Chem. Soc.,
119, 6668 (1997).
[22] H.M.J. Wang, I.J.B. Lin. Organometallics, 17, 972 (1998).
[23] A.A.D. Tulloch, A.A. Danopoulos, S. Winston, S. Kleinhenz, G. Eastham. J. Chem. Soc.
Dalton Trans., 4499 (2000).
[24] S. Medici, M. Peana, V.M. Nurchi, M.A. Zoroddu. J. Med. Chem., 62, 5923 (2019).

JOURNAL OF COORDINATION CHEMISTRY
1985
[25] F. Neese. Coord. Chem. Rev., 253, 526 (2009).
[26] F. Neese. WIREs Comput. Mol. Sci., 2, 73 (2012).
[27] Accelrys Software Inc, Discovery Studio Modeling Environment, Release 4.0, Accelrys
Software Inc., San Diego (2013).
[28] X-AREA Version 1.18 and X-RED32 Version 1.04, Stoe & Cie, Darmstadt, Germany (2002).
[29] L. Palatinus, G. Chapuis. J. Appl. Crystallogr., 40, 786 (2007).
[30] G.M. Sheldrick. Acta Crystallogr. A Found Adv., 71, 3 (2015).
[31] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann. J. Appl.
Crystallogr., 42, 339 (2009).
[32] S. Medici, M. Peana, G. Crisponi, V.M. Nurchi, J.I. Lachowicz, M. Remelli, M.A. Zoroddu.
Coord. Chem. Rev., 327-328, 349 (2016).
[33] J.A. Joule, M. Keith. Heterocyclic Chemistry, Blackwell Science, Oxford (2000).
[34] P. Kleyi, R.S. Walmsley, M.A. Fernandes, N. Torto, Z.R. Tshentu. Polyhedron, 41, 25 (2012).
[35] M. McCann, R. Curran, M. Ben-Shoshan, V. McKee, M. Devereux, K. Kavanagh, A. Kellett.
Polyhedron, 56, 180 (2013).
[36] K. Nomiya, R. Noguchi, M. Oda. Inorg. Chim. Acta, 298, 24 (2000).
[37] S.H. Alisir, B. Sarıboga, Y. Topcu, S.-Y. Yang. J. Inorg. Organomet. Polym., 23, 1061 (2013).
[38] S.H. Alisir, S. Demir, B. Sariboga, O. Buyukgungor. J. Coord. Chem., 68, 155 (2015).
€
[39] A.A.A. Massoud, V. Langer, Y.M. Gohar, M.A.M. Abu-Youssef, J. Janis, G. Lindberg, K.
€
€
Hansson, L. Ohrstrom. Inorg. Chem., 52, 4046 (2013).
ꢃ
[40] N.D. Savic, B.. Glisic, H. Wadepohl, A. Pavic, L. Senerovic, J. Nikodinovic-Runic, M.I. Djuran.
Med. Chem. Commun., 7, 282 (2016).
ꢃ
[41] B.. Glisic, L. Senerovic, P. Comba, H. Wadepohl, A. Veselinovic, D.R. Milivojevic, M.I. Djuran,
J. Nikodinovic-Runic. J. Inorg. Biochem., 155, 115 (2016).
[42] S. Aslam, A.A. Isab, M.A. Alotaibi, M. Saleem, M. Monim-Ul-Mehboob, S. Ahmad, I.
Georgieva, N. Trendafilova. Polyhedron, 115, 212 (2016).
ꢂ
[43] M.A. Fik, A. Gorczynski, M. Kubicki, Z. Hnatejko, A. Fedoruk-Wyszomirska, E. Wyszko, M.
Giel-Pietraszuk, V. Patroniak. Eur. J. Med. Chem., 86, 456 (2014).
[44] L. Thornton, V. Dixit, L.O.N. Assad, T.P. Ribeiro, D.D. Queiroz, A. Kellett, A. Casey, J.
Colleran, M.D. Pereira, G. Rochford, M. McCann, D. O’Shea, R. Dempsey, S. McClean, A.F.-
A. Kia, M. Walsh, B. Creaven, O. Howe, M. Devereux. J. Inorg. Biochem., 159, 120 (2016).
ꢃ
[45] N.D. Savic, S. Vojnovic, B.. Glisic, A. Crochet, A. Pavic, G.V. Janjic, M. Pekmezovic, I.M.
Opsenica, K.M. Fromm, J. Nikodinovic-Runic, M.I. Djuran. Eur. J. Med. Chem., 156, 760
(2018).
[46] D. Song, S. Ma. ChemMedChem, 11, 646 (2016).
[47] R. Curran, J. Lenehan, M. McCann, K. Kavanagh, M. Devereux, D.A. Egan, G. Clifford, K.
Keane, B.S. Creaven, V. Mckee. Inorg. Chem. Commun., 10, 1149 (2007).
[48] K. Nomiya, H. Yokoyama. J. Chem. Soc. Dalton Trans., 12, 2483 (2002).
[49] B. Coyle, M. McCann, K. Kavanagh, M. Devereux, V. McKee, N. Kayal, D. Egan, C. Deegan,
G.J. Finn. J. Inorg. Biochem., 98, 1361 (2004).
[50] K. Nomiya, Y. Kondoh, K. Onoue, N.C. Kasuga, H. Nagano, M. Oda, T. Sudoh, S. Sakuma. J.
Inorg. Biochem., 58, 255 (1995).
[51] A.K. Nebioglu, M.J. Panzner, C.A. Tessier, C.L. Cannon, W.J. Youngs. Coord. Chem. Rev.,
251, 884 (2007).
[52] S. Abuskhuna, J. Briody, M. McCann, M. Devereux, K. Kavanagh, J.B. Fontecha, V. McKee.
Polyhedron, 23, 1249 (2004).
[53] H.L. Zhu, Q. Chen, W.L. Peng, S.J. Qi, A.L. Xu, X.M. Chen. Chin. J. Chem., 19, 263 (2001).
_ _
ꢁ
€ €
€
€
[54] O.Z. Yes¸ilel, G. Kas¸tas¸, C. Darcan, I. Ilker, H. Pas¸aoglu, O. Buyukgungor. Inorg. Chim. Acta,
363, 1849 (2010).
[55] S. Ahmad, A. Yousaf, M.N. Tahir, A.A. Isab, M. Monim-Ul-Mehboob, W. Linert, M. Saleem. J.
Struct. Chem., 56, 1653 (2015).
_ €
[56] S. Demir, F. Cos¸kun, I. Ozdemir. J. Organomet. Chem., 755, 134 (2014).
[57] J.C. Garrison, C.A. Tessier, W.J. Youngs. J. Organomet. Chem., 690, 6008 (2005).
[58] A. Bondi. J. Phys. Chem., 68, 441 (1964).

1986
S. D. DÜŞÜNCELI ET AL.
ꢂ
[59] E.A. Doud, M.S. Inkpen, G. Lovat, E. Montes, D.W. Paley, M.L. Steigerwald, H. Vazquez, L.
Venkataraman, X. Roy. J. Am. Chem. Soc., 140, 8944 (2018).
€
[60] J. Mormul, M. Steimann, C. Maichle-Mossmer, U. Nagel. Eur. J. Inorg. Chem., 2013, 3421
(2013).
[61] Q.-X. Liu, Z.-X. Zhao, X.-J. Zhao, Q. Wei, A.-H. Chen, H.-L. Li, X.-G. Wang. CrystEngComm,
17, 1358 (2015).
[62] F. Guarra, N. Busto, A. Guerri, L. Marchetti, T. Marzo, B. Garcia, T. Biver, C. Gabbiani. J.
Inorg. Biochem., 205, 110998 (2020).
[63] R. Kishore, S.K. Das. J. Mol. Struct., 1053, 38 (2013).
[64] L. Ray, V. Katiyar, S. Barman, M.J. Raihan, H. Nanavati, M.M. Shaikh, P. Ghosh. J.
Organomet. Chem., 692, 4259 (2007).
[65] D.J. Nielsen, K.J. Cavell, B.W. Skelton, A.H. White. Inorg. Chim. Acta, 352, 143 (2003).
[66] J. Pytkowicz, S. Roland, P. Mangeney. J. Organomet. Chem., 631, 157 (2001).
[67] H.M. Lee, P.L. Chiu, C.H. Hu, C.L. Lai, Y.C. Chou. J. Organomet. Chem., 690, 403 (2005).
_ €
€
€
[68] Y. Sarı, S. Akkoc¸, Y. Gok, V. Sifniotis, I. Ozdemir, S. Gunal, V. Kayser. J. Enzyme Inhib. Med.
Chem., 31, 1527 (2016).
_
€
€
[69] M.O. Karatas¸, B. Olgundeniz, S. Gunal, I. Ozdemir, B. Alıcı, E. C¸etinkaya. Bioorg. Med.
Chem., 24, 643 (2016).
_ €
_ €
ꢁ
ꢁ
€
[70] N. Kaloglu, M. Kaloglu, I. Ozdemir, S. Gunal, I. Ozdemir. J. Chin. Chem. Soc., 64, 420 (2017).
[71] E. Fujita, J.T. Muckerman. Inorg. Chem., 43, 7636 (2004).
ꢂ
ꢂ
~
ꢂ
[72] S.B. Jimenez-Pulido, N.A. Illan-Cabeza, F. Hueso-Urena, C.R. Maldonado, P. Sanchez-
ꢂ
ꢂ
ꢂ
ꢂ
Sanchez, M. Paz Fernandez-Liencres, M. Fernandez-Gomez, M.N. Moreno-Carretero. Dalton
Trans., 45, 15142 (2016).
[73] R.K. Roy, S. Krishnamurti, P. Geerlings, S. Pal. J. Phys. Chem. A, 102, 3746 (1998).
€
_ €
€
€ €
[74] E. Ustun, S.D. Dus¸unceli, I. Ozdemir. Struct. Chem., 30, 769 (2019).
[75] K.K. Hazarika, N.C. Baruah, R.C. Deka. Struct. Chem., 20, 1079 (2009).
[76] F. Weigend, R. Ahlrichs. Phys. Chem. Chem. Phys., 7, 3297 (2005).
[77] F. Neese. J. Biol. Inorg. Chem., 11, 702 (2006).
[78] L.G. Ferreira, R.N. Dos Santos, G. Oliva, A.D. Andricopulo. Molecules, 20, 13384 (2015).
[79] W.H. Mahmoud, G.G. Mohamed, O.Y. El-Sayed. Appl. Organomet. Chem., 32, c4051 (2018).
[80] M. Berry, B. Fielding, J. Gamieldien. Practical Considerations in Virtual Screening and
Molecular Docking, Elsevier Inc., Waltham, USA (2015).
[81] M. Alamgir, S.C. Black, N. Kumar (Eds.). Bioactive Heterocycles III, Topics in Heterocyclic
Chemistry, Springer-Verlag, Berlin, Heidelberg, Vol. 9, p. 87 (2007).