Synthesis and antimicrobial studies of 1-methyl-2-dimethylaminoethyl- substituted benzimidazolium salts and N-heterocyclic carbene-silver complexes

Article abstract of DOI:10.1080/00958972.2012.654469

The synthesis and antimicrobial studies of 1-methyl-2-dimethylaminoethyl- substituted carbene precursors and silver complexes are reported. The carbene precursors (1a-d) have been prepared from 1-methyl-2-dimethylaminoethyl- substituted benzimidazole and various alkyl halides. The silver-NHC complexes (2a-d) were synthesized from the benzimidazolium salts and Ag₂O in dichloromethane at room temperature. The new compounds were characterized by ¹H NMR, ¹³C NMR, FT-IR, and elemental analyses. The new carbene precursors and Ag-complexes were tested for their invitro antimicrobial activity against a variety of Gram-positive and Gram-negative bacteria, as well as for their antifungal activities against Candida albicans and Candida tropicalis. Copyright

Full text of DOI:10.1080/00958972.2012.654469

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Synthesis and antimicrobial studies
of 1-methyl-2-dimethylaminoethyl-
substituted benzimidazolium salts
and N-heterocyclic carbene–silver
complexes
Beyhan Yığıt a , Yetkın Gök b , İlknur Özdemır b & Selamı Günal c
a Department of Chemistry, Faculty of Science and Arts, Adiyaman
University, 02040 Adiyaman, Turkey
b Department of Chemistry, Faculty of Science and Arts, Inönü
University, 44280 Malatya, Turkey
c Department of Microbiology, Faculty of Medicine, Inönü
University, 44280 Malatya, Turkey
Available online: 20 Jan 2012
To cite this article: Beyhan Yığıt, Yetkın Gök, İlknur Özdemır & Selamı Günal (2012): Synthesis and
antimicrobial studies of 1-methyl-2-dimethylaminoethyl-substituted benzimidazolium salts and N-
heterocyclic carbene–silver complexes, Journal of Coordination Chemistry, 65:3, 371-379
To link to this article: http://dx.doi.org/10.1080/00958972.2012.654469
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Journal of Coordination Chemistry
Vol. 65, No. 3, 10 February 2012, 371–379
Synthesis and antimicrobial studies of 1-methyl-2-dimethylami-
noethyl-substituted benzimidazolium salts and N-heterocyclic
carbene–silver complexes
_
_
_
_
_
˘
¨
¨
BEYHAN YIGIT*y, YETKIN GOKz, ILKNUR OZDEMIRz and
_
¨
SELAMI GUNALx
yDepartment of Chemistry, Faculty of Science and Arts, Adiyaman University,
02040 Adiyaman, Turkey
zDepartment of Chemistry, Faculty of Science and Arts, Inonu University,
¨
¨
44280 Malatya, Turkey
xDepartment of Microbiology, Faculty of Medicine, Inonu University,
¨
¨
44280 Malatya, Turkey
(Received 12 October 2011; in final form 9 December 2011)
The synthesis and antimicrobial studies of 1-methyl-2-dimethylaminoethyl-substituted carbene
precursors and silver complexes are reported. The carbene precursors (1a–d) have been
prepared from 1-methyl-2-dimethylaminoethyl-substituted benzimidazole and various alkyl
halides. The silver–NHC complexes (2a–d) were synthesized from the benzimidazolium salts
and Ag2O in dichloromethane at room temperature. The new compounds were characterized
by 1H NMR, 13C NMR, FT-IR, and elemental analyses. The new carbene precursors and
Ag-complexes were tested for their in vitro antimicrobial activity against a variety of Gram-
positive and Gram-negative bacteria, as well as for their antifungal activities against Candida
albicans and Candida tropicalis.
Keywords: N-heterocyclic carbene; Benzimidazolium salts; Silver; Antimicrobial; Medical
inorganic chemistry
1. Introduction
The coordination chemistry of N-heterocyclic carbenes (NHCs) has developed
significantly since the isolation and first complexation studies of stable NHCs by
Arduengo in the early 1990s [1–3]. NHC complexes exhibit excellent catalytic activity
for many useful organic transformations, notably C–C and C–N cross-coupling
reactions, C–H bond activation, and metathesis [4–19]. Silver NHC complexes have
particular interest because of their wide use as ligand transfer agents to group 8–10
metals, catalysis, nanomaterials, and also biological activity as antimicrobial agents
[20–37]. Ag–NHC complexes are easily prepared by three different procedures:
(i) reaction of azolium salts with silver bases such as Ag2O, Ag2CO3, and AgOAc;
(ii) reaction of free NHC silver salts; and (iii) reaction of azolium salts with silver salts
*Corresponding author. Email: byigit@adiyaman.edu.tr
Journal of Coordination Chemistry
ISSN 0095-8972 print/ISSN 1029-0389 online ꢀ 2012 Taylor & Francis
http://dx.doi.org/10.1080/00958972.2012.654469

372
B. Y|g˘|t et al.
under basic phase transfer conditions [38–40]. Among these approaches, route (i) is
more convenient and most frequently used.
We have previously reported antibacterial and antifungal properties of ruthenium(II)
carbene complexes, azolium salts, and neutral 2-aryl derivatives of benzimidazole,
benzothiazole, and benzoxazole [41, 42]. Herein we report the synthesis and antimi-
crobial activities of 1-methyl-2-dimethylaminoethyl-substituted benzimidazolium salts
(1a–d) and their silver complexes (2a–d).
2. Experimental
2.1. Materials and methods
All preparations of 1,3-dialkylbenzimidazolium salts 1a–d and silver–carbene com-
plexes 2a–d were performed under argon using standard Schlenk techniques and dry
1
solvents. All chemicals were purchased from Aldrich Chemical Co. H and 13C NMR
spectra were taken using a Bruker AC300P FT spectrometer operating at 300.13 MHz
(1H), 75.47 MHz (13C). Chemical shifts (ꢀ) are given in ppm relative to TMS
and coupling constants (J) in Hz. FT-IR spectra were recorded on a Mattson
1000 spectrophotometer as wavenumbers in cmꢀ1. Melting points were measured in
open capillary tubes with an Electrothermal-9200 melting point apparatus and are
_
uncorrected. Elemental analyses were performed by TUBITAK Microlab (Ankara,
Turkey).
Minimal inhibitory concentration for each compound was investigated against
standard bacterial strains: Staphylococcus aureus (ATCC 29213), Enterococcus faecalis
(ATCC 29212), Escherichia coli (ATCC 25922), and Pseudomonas aeruginosa (ATCC
27853). These were obtained from the American Type Culture Collection (Rockville,
MD, USA). The fungal strains Candida albicans and Candida tropicalis were obtained
from the Department of Microbiology, Faculty of Medicine, Ege University (Turkey).
Bacterial strains were subcultured on Muller Hinton Broth (HiMedia Laboratories Pvt.
Ltd, Mumbai, India) and fungal strains were also on RPMI 1640 Broth (Sigma-Aldrich
Chemie GmbH, Taufkirchen, Germany).
2.2. General procedure for the preparation of the 1,3-dialkylbenzimidazolium
salts (1a–d)
Alkyl halides (1 mmol) were added slowly to
a solution of 1-(1-methyl-2-
dimethylaminoethyl)benzimidazole (1 mmol) in DMF (4 mL) at 25ꢁC. The reaction
mixture was stirred at room temperature for 1 h and then heated for 12 h at 60ꢁC.
Diethyl ether (10 mL) was added to obtain a white crystalline solid, which was filtered
off. The solid was washed with diethyl ether (3 ꢂ 10 mL), dried under vacuum, and
recrystallized from EtOH/Et2O (1 : 2) at room temperature.
2.2.1. 1-(1-Methyl-2-dimethylaminoethyl)-3-benzylbenzimidazolium
chloride
(1a).
Yield: 85%, m.p.: 218–219ꢁC, IR ꢁ(NCN): 1562 cmꢀ1. Anal. Calcd for C19H24N3Cl
(%): C, 69.18; H, 7.33; N, 12.74. Found: C, 69.19; H, 7.35; N, 12.72. 1H NMR

N-heterocyclic carbene–silver
373
(ꢀ, CDCl3): 1.13 (d, 3H, JHH ¼ 6.6 Hz, CH(CH3)CH2N(CH3)2), 2.31 (s, 6H, CH(CH3)
CH2N(CH3)2), 3.28 (m, 1H, CH(CH3)CH2N(CH3)2), 4.50, 4.67 (m, 2H, CH
(CH3)CH2N(CH3)2), 5.89 (s, 2H, CH2C6H5), 7.26, 7.80 (m, 9H, Ar–H), 11.45 (s, 1H,
NCHN). 13C {H} NMR (ꢀ, CDCl3): 9.7, 40.3, 49.5, 51.2 (CH(CH3)CH2N(CH3)2), 57.9
(CH2C6H5), 113.1, 113.6, 126.8, 126.9, 128.0, 128.1, 129.0, 129.2, 130.8, 131.6, 133.1
(Ar–C), 144.4 (NCHN).
2.2.2. 1-(1-Methyl-2-dimethylaminoethyl)-3-(2,4,6-trimethylbenzyl)benzimidazolium
chloride (1b). Yield: 91%, m.p.: 208–209ꢁC, IR ꢁ(NCN): 1563 cmꢀ1. Anal. Calcd for
C22H30N3Cl (%): C, 71.04; H, 8.13; N, 11.30. Found: C, 71.07; H, 8.14; N, 11.32.
1H NMR (ꢀ, CDCl3): 1.10 (d, 3H, JHH ¼ 8.7 Hz, CH(CH3)CH2N(CH3)2), 2.31 (s, 6H,
CH(CH3)CH2N(CH3)2), 3.25 (m, 1H, CH(CH3)CH2N(CH3)2), 2.27, 2.31 (s,
9H, CH2C6H2(CH3)3-2,4,6), 4.56, 4.75 (m, 2H, CH(CH3)CH2N(CH3)2), 5.78 (s, 2H,
CH2C6H2(CH3)3-2,4,6), 6.91 (s, 2H, CH2C6H2(CH3)3-2,4,6), 7.25, 7.84 (m, 4H, Ar–H),
10.88 (s, 1H, NCHN). 13C{H} NMR (ꢀ, CDCl3): 9.5, 40.1, 47.0, 49.1
(CH(CH3)CH2N(CH3)2), 20.0, 21.0 (CH2C6H2(CH3)3-2,4,6), 57.9 (CH2C6H2(CH3)3-
2,4,6), 113.1, 113.6, 125.3, 126.8, 126.9, 130.1, 131.1, 131.7, 137.9, 139.6 (Ar–C), 144.3
(NCHN).
2.2.3. 1-(1-Methyl-2-dimethylaminoethyl)-3-(2,3,5,6-tetramethylbenzyl)benzimidazolium
chloride (1c). Yield: 88%, m.p.: 247–248ꢁC, IR ꢁ(NCN): 1558 cmꢀ1. Anal. Calcd for
1
C23H32N3Cl (%): C, 71.57; H, 8.36; N, 10.89. Found: C, 71.56; H, 8.34; N, 10.90. H
NMR (ꢀ, CDCl3): 1.09 (d, 3H, JHH ¼ 6.6 Hz, CH(CH3)CH2N(CH3)2), 2.16 (s, 6H,
CH(CH3)CH2N(CH3)2), 3.44 (m, 1H, CH(CH3)CH2N(CH3)2), 2.16, 2.25 (s, 12H,
CH2C6H(CH3)4-2,3,5,6), 4.47 (m, 2H, CH(CH3)CH2N(CH3)2), 5.78 (s, 2H,
CH2C6H(CH3)4-2,3,5,6), 7.15 (s, 1H, CH2C6H(CH3)4-2,3,5,6), 7.71, 8.22 (m, 4H, Ar–
H), 8.94 (s, 1H, NCHN). 13C {H} NMR (ꢀ, CDCl3): 9.2, 19.0, 46.3, 48.7
(CH(CH3)CH2N(CH3)2), 15.7, 20.6 (CH2C6H2(CH3)3-2,3,5,6), 56.7 (CH2C6H2(CH3)3-
2,3,5,6), 114.3, 114.4, 126.9, 127.2, 129.1, 131.7, 131.9, 133.9, 134.8 (Ar–C),
142.2 (NCHN).
2.2.4. 1-(1-Methyl-2-dimethylaminoethyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimidazo-
lium chloride (1d). Yield: 92%, m.p.: 258–259ꢁC, IR ꢁ(NCN): 1561 cmꢀ1. Anal. Calcd
for C24H34N3Cl (%): C, 72.06; H, 8.57; N, 10.51. Found: C, 72.08; H, 8.53; N, 10.56. 1H
NMR (ꢀ, CDCl3): 1.19 (d, 3H, JHH ¼ 6.6 Hz, CH(CH3)CH2N(CH3)2), 2.02 (s, 6H,
CH(CH3)CH2N(CH3)2), 2.73 (m, 1H, CH(CH3)CH2N(CH3)2), 2.16, 2.26 (s, 15H,
CH2C6(CH3)5-2,3,4,5,6), 4.75, 5.03 (m, 2H, CH(CH3)CH2N(CH3)2), 5.73 (s, 2H,
CH2C6(CH3)5-2,3,4,5,6), 7.28, 8.36 (m, 4H, Ar–H), 9.26 (s, 1H, NCHN). 13C {H} NMR
(ꢀ, CDCl3): 10.3, 17.2, 46.9, 48.3 (CH(CH3)CH2N(CH3)2), 16.9, 17.2, 17.5
(CH2C6(CH3)5-2,3,4,5,6), 58.4 (CH2C6(CH3)5-2,3,4,5,6), 114.4, 114.5, 126.3, 127.2,
127.3, 131.9, 132.2, 133.2, 134.4, 136.7 (Ar–C), 142.5 (NCHN).
2.3. General method for preparation of Ag(I)–NHC complexes (2a–d)
˚
A solution of benzimidazolium salt (1.0 mmol), Ag2O (0.5 mmol), and activated 4 A
molecular sieves in dichloromethane (20 mL) was stirred at room temperature for 24 h

374
B. Y|g˘|t et al.
in the dark. The reaction mixture was filtered through Celite and solvent removed under
reduced pressure. The crude product was recrystallized from dichloromethane/hexane
at room temperature.
2.3.1. Chloro-[1-(1-methyl-2-dimethylaminoethyl)-3-benzylbenzimidazol-2-ylidene]silver
(I) (2a). Yield: 76%, m.p.: 174–175ꢁC, IR ꢁ(CN): 1602 cmꢀ1. Anal. Calcd for
C19H23N3AgCl (%): C, 52.25; H, 5.31; N, 9.62. Found: C, 52.23; H, 5.30; N, 9.65.
1H NMR (ꢀ, d-DMSO): 1.06 (d, 3H, JHH ¼ 6.6 Hz, CH(CH3)CH2N(CH3)2), 2.35 (s, 6H,
CH(CH3)CH2N(CH3)2), 3.21 (heks., JHH ¼ 6.6 Hz, 1H, CH(CH3)CH2N(CH3)2), 4.26,
4.55 (m, 2H, CH(CH3)CH2N(CH3)2), 5.63 (s, 2H, CH2C6H5), 7.23, 7.40 (m, 9H, Ar–H).
13C {H} NMR (ꢀ, d-DMSO): 11.4, 41.0, 52.4, 52.5 (CH(CH3)CH2N(CH3)2), 59.1
(CH2C6H5), 111.6, 112.2, 124.2, 128.1, 129.1, 129.3, 133.5, 134.4, 134.9 (Ar–C).
2.3.2. Chloro-[1-(1-methyl-2-dimethylaminoethyl)-3-(2,4,6-trimethylbenzyl]benzimidazol-
2-ylidene]silver (I) (2b). Yield: 80%, m.p.: 168–169ꢁC, IR ꢁ(NCN): 1611 cmꢀ1. Anal.
Calcd for C22H29N3AgCl (%): C, 55.19; H, 6.10; N, 8.78. Found: C, 55.21; H, 6.11; N,
1
8.80. H NMR (ꢀ, d-DMSO): 0.94 (d, 3H, JHH ¼ 6.9 Hz, CH(CH3)CH2N(CH3)2), 2.30
(s, 6H, CH(CH3)CH2N(CH3)2), 3.18 (heks., 1H, JHH ¼ 6.9 Hz, 1H, CH(CH3)
CH2N(CH3)2), 2.24, 2.36 (s, 9H, CH2C6H2(CH3)3-2,4,6), 4.21, 4.45 (m, 2H,
CH(CH3)CH2N(CH3)2), 5.53 (s, 2H, CH2C6H2(CH3)3-2,4,6), 6.98 (s, 2H,
CH2C6H2(CH3)3-2,4,6), 7.22, 7.41 (m, 4H, Ar–H). 13C {H} NMR (ꢀ, d-DMSO): 11.4,
41.9, 48.1, 52.7 (CH(CH3)CH2N(CH3)2), 20.4, 21.2 (CH2C6H2(CH3)3-2,4,6), 59.1
(CH2C6H2(CH3)3-2,4,6), 111.5, 111.8, 124.0, 124.1, 126.8, 130.1, 130.3, 134.3, 137.5,
139.4 (Ar–C).
2.3.3. Chloro-[1-(1-methyl-2-dimethylaminoethyl)-3-(2,3,5,6-tetramethylbenzyl)-benzimi-
dazol-2-ylidene]silver (I) (2c). Yield: 77%, m.p.: 158–159ꢁC, IR ꢁ(NCN): 1602 cmꢀ1
.
Anal. Calcd for C23H31N3AgCl (%): C, 56.05; H, 6.34; N, 8.53. Found: C, 56.03; H,
6.35; N, 8.49. 1H NMR (ꢀ, d-DMSO): 0.97 (d, 3H, JHH ¼ 6.6 Hz, CH
(CH3)CH2N(CH3)2), 2.29 (s, 6H, CH(CH3)CH2N(CH3)2), 3.16 (heks., 1H,
JHH ¼ 6.9 Hz, CH(CH3)CH2N(CH3)2), 2.15, 2.16 (s, 12H, CH2C6H(CH3)4-2,3,5,6),
4.16, 4.41 (m, 2H, CH(CH3)CH2N(CH3)2), 5.51 (s, 2H, CH2C6H(CH3)4-2,3,5,6), 7.11,
7.75 (m, 5H, Ar–H). 13C {H} NMR (ꢀ, d-DMSO): 11.5, 40.9, 47.8, 52.9
(CH(CH3)CH2N(CH3)2), 16.2, 20.7 (CH2C6H(CH3)4-2,3,5,6), 59.0 (CH2C6H(CH3)4-
2,3,5,6), 111.5, 112.9, 124.0, 124.2, 126.7, 128.8, 131.2, 133.5, 134.1, 135.0, 135.3,
143.8 (Ar–C).
2.3.4. Chloro-[1-(1-methyl-2-dimethylaminoethyl)-3-(2,3,4,5,6-pentamethylbenzyl)-benzi-
midazol-2-ylidene]silver (I) (2d). Yield: 82%, m.p.: 188–189ꢁC, IR ꢁ(NCN): 1604 cmꢀ1
.
Anal. Calcd for C24H33N3AgCl (%): C, 56.87; H, 6.56; N, 8.29. Found: C, 56.85;
H, 6.59; N, 8.30. 1H NMR (ꢀ, d-DMSO): 0.92 (d, 3H, JHH ¼ 6.6 Hz, CH(CH3)
CH2N(CH3)2), 2.00 (s, 6H, CH(CH3)CH2N(CH3)2), 2.97 (heks., 1H, JHH ¼ 6.8 Hz,
CH(CH3)CH2N(CH3)2), 2.18, 2.23 (s, 15H, CH2C6(CH3)5-2,3,4,5,6), 4.32, 4.46
(m, 2H, CH(CH3)CH2N(CH3)2), 5.74 (s, 2H, CH2C6(CH3)5-2,3,4,5,6), 7.42, 8.16

N-heterocyclic carbene–silver
375
(m, 4H, Ar–H). 13C {H} NMR (ꢀ, d-DMSO): 11.3, 40.0, 47.3, 51.9
(CH(CH3)CH2N(CH3)2), 16.6, 17.4 (CH2C6(CH3)5-2,3,4,5,6), 57.6 (CH2C6(CH3)5-
2,3,4,5,6), 112.6, 114.3, 124.4, 126.1, 126.9, 127.1, 131.6, 132.0, 133.4, 134.2, 135.7,
136.7, 141.8 (Ar–C).
2.4. Antimicrobial activity
The antimicrobial activities of the Ag–NHC complexes were determined by using agar
dilution procedure recommended by the Clinical and Laboratory Standards Institute
[43, 44]. Minimal inhibitory concentrations for each compound were investigated
against standard bacterial strains, S. aureus, E. faecalis, E. coli, and P. aeruginosa and
fungal strains, C. albicans and C. tropicalis. Their turbidities matched that of a
McFarland no. 0.5 Turbidity Standard. The stock solution of all compounds was
prepared in DMSO. All dilutions were carried out with distilled water. The
concentrations of the tested compounds were 800, 400, 200, 100, 50, 25, 12.5, and
6.25 mg mLꢀ1. Ampicillin and ciprofloxacin were used as antibacterial standard drugs,
while fluconazole was used as antifungal standard drug whose minimum inhibitory
concentration (MIC) values are provided. A loopful (0.01 mL) of the standardized
inocula of the bacteria and yeasts (106 CFUs mLꢀ1) was spread over the surface of agar
plates. All were inoculated after 16–20 h of incubation for bacteria and 48 h for yeasts.
The lowest concentration of the compounds that prevented visible growth was
considered to be the MIC.
3. Results and discussion
3.1. Synthesis and characterization of benzimidazolium salts (1a–d)
1-Methyl-2-dimethylaminoethyl-substituted benzimidazolium salts 1a–d are conven-
tional NHC precursors. The functionalized benzimidazolium salts 1a–d were synthe-
sized by consecutive alkylation of 1-(1-methyl-2-dimethylaminoethyl)benzimidazole
(scheme 1). The salts (1a–d) were obtained in almost quantitative yield by quarter-
nazition of 1-(1-methyl-2-dimethylaminoethyl)benzimidazole in DMF with a variety of
alkyl halides. The salts are stable to air and moisture both in the solid state and in
solution. The structures of 1a–d were established by spectroscopic data and elemental
1
analyses (see section 2). The H NMR spectra of the benzimidazolium salts further
supported the assigned structures; the resonances for C(2)–H were observed as sharp
singlets at 11.45, 10.88, 8.94, and 9.26 ppm, respectively, for 1a–d. 13C NMR chemical
shifts were consistent with the proposed structures; the imino carbon are typical singlets
in the 1H-decoupled mode at 144.4, 144.3, 142.2, and 142.5 ppm, respectively, for
benzimidazolium chlorides 1a–d. The IR data for benzimidazolium salts 1a–d clearly
indicate the presence of –C¼N– with a ꢁ(C¼N) at 1562, 1563, 1558, and 1561 cmꢀ1
,
respectively, for 1a–d. The NMR and IR values are similar to results of other 1,3-
dialkylbenzimidazolium salts [45, 46].

376
B. Y|g˘|t et al.
N(CH3)2
H3C
N(CH3)2
H3C
N
N
Cl
N
N
Cl
N(CH3)2
H3C
1a
1b
N
N
+
N(CH3)2
Cl
H3C
N(CH3)2
H3C
N
N
N
Cl
Cl
N
1c
Scheme 1. Synthesis of 1-(1-methyl-2-dimethylaminoethyl)-3-alkylbenzimidazolium salts.
1d
3.2. Synthesis and characterization of silver–carbene complexes (2a–d)
The carbene precursor 1-(1-methyl-2-dimethylaminoethyl)-3-alkylbenzimidazolium
salts were prepared from 1-methyl-2-dimethylaminoethylbenzimidazole and various
alkyl halides. Treatment of the benzimidazolium salts with 0.5 equivalent of Ag2O in
CH2Cl2 afforded quantitatively the expected carbenes 2a–d (scheme 2) after 24 h. Ag–
NHCs 2a–d were obtained as white solids in 76–82% yield. The silver–carbene
complexes (2a–d) were soluble in halogenated solvent and insoluble in non-polar
solvents.
1H and 13C NMR spectra are consistent with the proposed formulae. In the 1H NMR
and 13C NMR spectra in d-DMSO, loss of signals for the benzimidazolium proton
(NCHN) at 11.45, 10.88, 8.94, 9.26 ppm and benzimidazolium carbon (NCHN) at
144.4, 144.3, 142.2, 142.5 ppm showed the formation of the expected silver complexes.
In 2a–d, the resonances for carbene carbon were not detected, which has also been
mentioned in the literature and given as a reason for the fluxional behavior of NHC
complexes [18, 47–51]. Silver–NHC complexes exhibit a characteristic ꢁ(C¼N) band at
1602, 1611, 1602, and 1604, respectively, for 2a–d.
3.3. Antimicrobial properties of carbene precursors and silver complexes
The antimicrobial activities reported in terms of MIC values are defined as the lowest
concentration of an antimicrobial that visibly inhibits growth of bacteria after overnight

N-heterocyclic carbene–silver
377
N(CH3)2
H3C
N(CH3)2
H3C
N
N
AgCl
N
N
AgCl
N(CH3)2
H3C
2a
2b
N
Cl
N
R
+
N(CH3)2
H3C
N(CH3)2
Ag2O
H3C
N
N
N
N
AgCl
AgCl
2c
2d
Scheme 2. Synthesis of Ag(I)–NHC complexes.
incubation. Minimal inhibitory concentrations for each compound were investigated
against bacterial strains S. aureus (ATCC 29213), E. faecalis (ATCC 29212), E. coli
(ATCC 25922), P. aeruginosa (ATCC 27853) and fungal strains C. albicans and
C. tropicalis. Antimicrobial activities of the carbene precursors and silver complexes
were determined by using agar dilution procedure and tested with different concen-
trations of the compounds. The MIC of synthesized compounds against Gram-positive,
Gram-negative, and fungi are summarized in table 1. Ampicillin, ciprofloxacin, and
fluconazole were used as standard drugs for comparison.
As shown in table 1, antimicrobial activities against bacteria and fungi in the carbene
precursors (1a–d) were 800–100 mg mLꢀ1 and silver complexes 100–50 mg mLꢀ1
concentrations. The silver complexes (2a–d) exhibit activity on both bacteria and
fungi, but the activities are much poorer than the standards.
Benzimidazolium salt (1a) containing benzyl on the N-atom showed poor antimi-
crobial activity against both bacteria and fungi. However, 1b bearing mesityl methyl
group showed activity against bacteria S. aureus and E. faecalis. The salts (1c) and (1d)
exhibit the same activity against all bacteria. While 1b and 1d showed activity (MIC
100 mg mLꢀ1), 1c showed poor activity against all fungi.
Similar results were observed for the silver complexes; 2b derived from benzimida-
zolium salt (1b) showed better antibacterial activity (MIC 50 mg mLꢀ1) than 2a, 2c,
and 2d. All of the silver–carbene complexes exhibit similar activity against all fungi.

378
B. Y|g˘|t et al.
Table 1. MIC (mg mLꢀ1) carbene precursors and silver–NHCs tested against bacterial and fungus.
Ag–NHC
E. coli
S. aureus
E. faecalis
P. aeruginosa
C. albicans
C. tropicalis
1a
1b
1c
1d
2a
2b
2c
2d
800
800
800
800
50
50
50
50
400
100
200
200
100
50
100
100
3.12
0.39
–
400
100
400
400
50
50
50
100
1.56
0.78
–
800
800
800
800
50
50
50
100
–
400
100
200
100
50
50
50
50
400
100
200
100
50
50
50
50
Ampicillin
Ciprofloxacin
Fluconazole
3.12
1.56
–
–
–
3.12
–
–
3.12
3.12
–
From the data obtained in this work, the position of methyl on the aromatic ring may
play a crucial role in antimicrobial activity.
4. Conclusions
We have synthesized and characterized carbene precursors and their silver complexes.
Antimicrobial activities of the new compounds were investigated for bacteria and fungi.
The silver complexes (2a–d) showed better activity against all bacteria and fungi than
carbene precursors (1a–d). Although the mechanism of antimicrobial activity is not
known, it was found that substituents on nitrogen have an effect on antimicrobial
activity. Detailed investigations focusing on new compound and other biomedical
applications are ongoing.
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