Novel benzimidazolium salts and their silver complexes: Synthesis and antibacterial properties

Article abstract of DOI:10.1016/j.inoche.2012.04.033

A series of unsymmetrical N,N-disubstituted benzimidazolium salts were synthesized as N-heterocyclic carbene (NHC) precursors. These compounds were used to synthesize of N-heterocyclic carbene silver(I) complexes. New compounds were characterized by NMR and IR spectroscopies and elemental analyses. The antibacterial activity of all the compounds was tested against Gram (+)/(-) and fungal strains using the agar dilution procedure.

Full text of DOI:10.1016/j.inoche.2012.04.033

Inorganic Chemistry Communications 21 (2012) 142–146
Contents lists available at SciVerse ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Novel benzimidazolium salts and their silver complexes: Synthesis and
antibacterial properties
Selami Günal a, Nazan Kaloğlu b, İlknur Özdemir b, Serpil Demir b, İsmail Özdemir b,
⁎
a
İnönü University, Faculty of Pharmacy, Department of Microbiology, 44280 Malatya, Turkey
b
İnönü University, Faculty Science and Arts, Chemistry Department, 44280 Malatya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of unsymmetrical N,N-disubstituted benzimidazolium salts were synthesized as N-heterocyclic
carbene (NHC) precursors. These compounds were used to synthesize of N-heterocyclic carbene silver(I)
complexes. New compounds were characterized by NMR and IR spectroscopies and elemental analyses.
The antibacterial activity of all the compounds was tested against Gram (+)/(−) and fungal strains using
the agar dilution procedure.
Received 14 March 2012
Accepted 20 April 2012
Available online 27 April 2012
Keywords:
Antibacterial
© 2012 Elsevier B.V. All rights reserved.
Benzimidazolium salts
N-heterocyclic carbene
Silver NHC complexes
Since the first isolation of a stable, free N-heterocyclic carbene
(NHC) by Arduengo in 1991 [1], NHCs had become crucial ligands in
organometallic chemistry and homogeneous catalysis [2–4]. The
NHC–metal complexes are remarkably stable toward heat, air, and
moisture, and many organic reactions using metal–NHC complexes
as catalysts have been investigated, such as olefin metathesis [5,6],
C–C [7,8], and C–N [9] bond formation reactions. Later discoveries
revealed that silver and gold derivatives of NHCs can be used in
medicinal applications. NHC complexes of silver have become
common-place in the organometallic literature. One reason for this
is that NHC silver cpmplexes are easily prepared by a one-pot reac-
tion of an azolium salt with Ag2O, which can be easily derived. Anoth-
er reason for this is that carbene silver complexes can be used as
carbene transfer reagent for synthesis of Ni, Pd, Pt, Cu, Au, Rh, Ir,
and Ru carbene complexes, such a route affords a convenient method
for the preparation of these carbene metal complexes [10,11]. In addi-
tion, a new discovery shows that silver carbene complexes have
shown interesting biological activity as antimicrobial and anticancer
agents [12,13]. The achievement such as their synthetic routes, struc-
tural features and applications of Ag–NHC complexes has been sum-
marized by Youngs and coworkers [14,15] and Lin et al. [16,17],
respectively. The first use of silver NHCs as antimicrobial agents was
reported by Youngs and coworkers in 2004 [12].
evidenced by the use of silver sulfadiazine (Silvadine) in burn wards
worldwide since 1968 [19,20]. High antimicrobial activity and mini-
mal side effects of silver sulfadiazine have made it a very convenient
therapy for treatment of infections in burns over the past four de-
cades [21–24].
In recent years, considerable attention has been given to the synthesis
of benzimidazole derivatives because of their various pharmacological
activities such as antitumour, anti-ulcer, antibacterial, and antifungal
properties [25–32]. Although there are different antibacterial and antifun-
gal drugs used in the treatment of bacterial and fungal infections, some of
them have undesirable side effects [33]. Therefore, many clinically effec-
tive antibacterial and antifungal drugs have become less effective due to
the development of resistance to these drugs. Since benzimidazole com-
pounds have been found to have a broad range of pharmacological activ-
ity, many research groups have been interested in this type of heterocyclic
compound [25–32].
In the light of the general importance of these compounds, we
wish to report the synthesis and characterization of benzimidazolium
salts and their silver complexes. The Ag(I) complexes and the metal-
free ligands were screened for their ability to inhibit the growth of a
number of Gram-positive and Gram-negative and fungi strains.
The reaction of N-butylbenzimidazole with aryl halides to prepare
the benzimidazolium salts was found to be very good yields in DMF at
80 °C for 12 h (Scheme 1) [34].
The salts are air- and moisture-stable both in the solid state and in so-
lution. The 1H NMR spectra of the benzimidazolium salts 1a–1e exhibit
the signal for the NCHN proton in the range of δ 11.10–11.83 ppm.
These values are typical for NCHN protons of benzimidazolium salts
[35,36]. The 13C NMR spectra of 1a–1e exhibit the NCN resonances be-
tween δ 143.5 and 144.0 ppm, which are also typical values previously
Silver has a long standing use as an antimicrobial agent, particu-
larly in modern medicine for the prevention and treatment of bacte-
rial infections associated with severe burn wounds [18]. This is
⁎
Corresponding author.
E-mail address: ismail.ozdemir@inonu.edu.tr (İ. Özdemir).
1387-7003/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2012.04.033

S. Günal et al. / Inorganic Chemistry Communications 21 (2012) 142–146
143
Scheme 1. Synthesis of benzimidazolium salts (1a–1e).
reported for benzimidazolium salts [37,38]. IR data for benzimidazolium
salts clearly indicate the presence of the –C_N–group with a υ(C_N) vi-
bration between 1442 and 1465 cm−1. The NMR and IR values are similar
to those found for other 1,3-dialkylbenzimidazolium salts.
Synthesis of the Ag(I) complexes were conducted in the absence
of light and all complexes were stored in the dark. The reaction of
the benzimidazolium salt with 2 equiv. Ag2O in dichloromethane
resulted in the silver–NHC complex as a crystalline solid (Scheme 2)
[39].
The benzimidazolium salts and silver–NHC complexes were char-
acterized by analytical and spectroscopic techniques [34,39]. The FT-
IR spectroscopy, 1H- and 13C NMR spectroscopy, and elemental anal-
ysis data of the title compound confirm the proposed structure.
The silver complexes are stable in the air and toward the moisture
with good solubility in polar solvents. The successful formation of sil-
ver carbene complexes was indicated by the absence of a peak of
NCHN proton region of δ 11.10–11.83 ppm in their 1H NMR spectra
further suggested full conversion to silver (I) NHC complexes.
Nolan et al. have recently reported the synthesis of a series of
mono-carbene silver halides [R2NHC]-AgCl and have demonstrated
the influence of halide ions and the solvent on the structural formulas
of Ag(I)–NHCs [40]. Similar results have been communicated by Lee
et al. [41]. Ion-pair complexes have been obtained in the reaction of
N,N-dimethylimidazoliumiodide with Ag2O in DCM [42]. Fluxional
behavior between [R2NHC]-AgX and [(R2NHC)2-Ag]+[AgX2]− species
was observed in solution for most of the complexes [43]. Mechanism
of formation of silver N-Heterocyclic carbenes was reported by Peris
and coworkers in 2007 [44]. According to these results, the mono-
meric compound NHC-Ag-X, in which the two ligands adopt a linear
disposition, seems to be the most favorable species in CH2Cl2 solution.
It is well known that silver ions and silver based compounds are
highly toxic to microorganisms [45,46] showing strong biocidal ef-
fects. Therefore as an advancement of our previous studies, we have
now prepared a series of Ag(I) complexes of NHC and investigated
their antimicrobial activity. Antimicrobial activity was observed for
all compounds against the both gram(+)/(−) bacterials and fungal
strains using the agar dilution procedure recommended by the Clini-
cal and Laboratory Standards Institute [47–49]. The solvent used to
prepare the stock solutions (DMSO) played no role in growth inhibi-
tion on the same bacteria strains. The antimicrobial activities of the
NHC precursors (1a–1e) and their corresponding silver complexes
(2a–2e) are summarized in Table 1.
As shown table, antimicrobial activity was observed in silver–NHC
complexes (2a–2e) tested against bacteria and fungi at 100–25 μg/mL
concentrations. NHC precursors (1a–1e) are less active than
corresponding silver complexes against all bacteria strains. Same ac-
tivity was observed for compounds 1b with 1c and 2c with 2e against
all bacteria strains. Compound 2a was found effective in inhibiting the
growth of all bacterial strains with MICs values between 25 and
50 μg/mL. Especially these compounds are more effective against
fungi strains (Table 1). On comparison with the benzimidazolium
salts, the silver complexes have shown enhanced activity. The com-
plexes exhibited enhanced antibacterial activity, which is due to the
synergistic effect that increases the lipophilicity of the complexes. Be-
cause microorganism cell is surrounded by a lipid membrane. Al-
though the cytotoxic effects of silver against Gram-positive and
Gram-negative bacteria have long been established, the mechanisms
of action are not completely understood. Sporadic studies of the cell
toxicity mechanisms of silver suggest that silver ions kill organisms
through a variety of ways.

144
S. Günal et al. / Inorganic Chemistry Communications 21 (2012) 142–146
Scheme 2. Synthesis of silver–NHC complexes (2a–2e).
In conclusion, a series of novel unsymmetrically substituted N-
Acknowledgments
heterocyclic carbene precursors and their silver complexes were syn-
thesized and characterized by 1H NMR, 13C NMR, IR and elemental
analyses. New silver complexes shown high antibacterial activity
compared with the precursors against gram(+)/(−) and fungi
strains. More studies are now in progress including a larger collection
of bacteria of different species in order to determine if the antimicro-
bial activity is species dependent and its possible application in differ-
ent fields. New biological active Pt or Au NHC complexes will be
prepared with an aim to develop robust cancer chemotherapeutic
agents. Furthermore we will test the properties of both transmetallation
reaction and catalysis of silver complexes described in this work.
This work was financially supported by the Technological and Sci-
entific Research Council of Turkey TUBİTAK [TBAG (108T411)] and
İnönü University Research Fund (İ.Ü.B.A.P: 2009/13).
References
[1] A.J. Arduengo, R.L. Harlow, M. Kline, A stable crystalline carbene, J. Am. Chem. Soc.
113 (1991) 361–363.
[2] F.E. Hahn, M.C. Jahnke, Heterocyclic carbenes: synthesis and coordination chemistry,
Angew. Chem. Int. Ed. 47 (2008) 3122–3172.
[3] W.A. Herrmann, N-Heterocyclic carbenes: a new concept in organometallic catalysis,
Angew. Chem. Int. Ed. 41 (2002) 1290–1309.
[4] S. Díez-González, N. Marion, S.P. Nolan, N-Heterocyclic carbenes in late transition
metal catalysis, Chem. Rev. 109 (2009) 3612–3676.
[5] T.M. Trnka, R.H. Grubbs, The development of L2X2Ru=CHR olefin metathesis catalysts:
an organometallic success story, Acc. Chem. Res. 34 (2001) 18–29.
Table 1
Minimal inhibitory concentrations (lg/mL) of compounds.
[6] R.E. Giudici, A.H. Hoveyda, Directed catalytic asymmetric olefin metathesis. Selec-
tivity control by enoate and ynoate groups in Ru-catalyzed asymmetric ring-
opening/cross-metathesis, J. Am. Chem. Soc. 129 (2007) 3824–3825.
[7] E.A.B. Kantchev, C.J. O'Brien, M.G. Organ, Palladium complexes of N-heterocyclic
carbenes as catalysts for cross-coupling reactions—a synthetic chemist's perspec-
tive, Angew. Chem. Int. Ed. 46 (2007) 2768–2813.
[8] S.K. Schneider, P. Roembke, G.R. Julius, H.G. Raubenheimer, W.A. Herrmann,
Pyridin-, quinolin- and acridinylidene palladium carbene complexes as highly
efficient C–C coupling catalysts, Adv. Synth. Catal. 348 (2006) 1862–1873.
[9] L.R. Titcomb, S. Caddick, F.G.N. Cloke, D.J. Wilson, D. McKerrecher, Unexpected
reactivity of two-coordinate palladium–carbene complexes; synthetic and
catalytic implications, Chem. Commun. (2001) 1388–1389.
[10] T.J. Siciliano, M.C. Deblock, K.M. Hindi, S. Durmus, M.J. Panzner, C.A. Tessier,
W.J. Youngs, Synthesis and anticancer properties of gold (I) and silver (I)
N-heterocyclic carbene complexes, J. Organomet. Chem. 696 (2011)
1066–1071.
[11] S. Liu, T. Hsieh, G. Lee, S. Peng, Carbene transfer between transition-metal ions,
Organometallics 17 (1998) 993–995.
Compound E. coli S. aureus E. faecalis P. aerug C. albicans C. tropicalis
1a
1b
1c
1d
1e
2a
200
400
400
400
800
50
200
400
400
400
800
50
200
200
200
200
400
50
200
200
200
200
400
50
100
100
100
200
200
25
100
100
100
200
200
25
2b
2c
2d
2e
100
100
100
100
3.12
1.56
–
100
100
100
100
3.12
0.39
–
100
100
50
100
1.56
0.78
–
50
100
50
100
–
50
50
25
50
50
50
25
50
Amp.a
Cip.a
Fluc.a
–
–
3.12
–
–
–
3.12
3.12
a
Amp.: Ampicillin, Cip.: Ciprofloxacin, Fluc.: Fluconazole.

S. Günal et al. / Inorganic Chemistry Communications 21 (2012) 142–146
145
[12] A. Melaiye, R.S. Simons, A. Milsted, F. Pingitore, C. Wesdemiotis, C.A. Tessier, W.J.
Youngs, Formation of water-soluble pincer silver(I)-carbene complexes: a novel
antimicrobial agent, J. Med. Chem. 47 (2004) 973–977.
[13] W.J. Youngs, A.R. Knapp, P.O. Wagers, C.A. Tessier, Nanoparticle encapsulated
silver carbene complexes and their antimicrobial and anticancer properties: a
perspective, Dalton Trans. 41 (2012) 327–336.
[14] J.C. Garrison, W.J. Youngs, Ag(I) N-heterocyclic carbene complexes: synthesis,
structure, and application, Chem. Rev. 105 (2005) 3978–4008.
[15] A. Kascatan-Nebioglu, M.J. Panzner, C.A. Tessier, C.L. Cannon, W. Youngs, N-heterocyclic
carbene–silver complexes: a new class of antibiotics, J. Coord. Chem. Rev. 251 (2007)
884–895.
190–191 °C, ν(CN) =1449 cm−1. Anal. Calc. for C19H23N2Cl: C, 72.48; H, 7.36; N,
8.90. Found: C, 72.44; H, 7.35; N, 8.87%. Yield 85 (0.267 g). 1-butyl-
%
3-(2,3,4,5,6-pentamethylbenzyl)benzimidazolium chloride (1c):1H NMR (CDCl3):
0.96 (t, J=7.3 Hz, 3H, NCH2CH2CH2CH3), 1.42 (sex., J=7.5 Hz, 2H, NCH2CH2CH2-
CH3), 1.98 (quint., J=7.5 Hz, 2H, NCH2CH2CH2CH3), 2.23, 2.27and 2.28 (s, 15H,
CH2C6(CH3)5-2,3,4,5,6), 4.69 (t, 2H, J=7.3 Hz, NCH2CH2CH2CH3 ) 5.89 (s, 2H,
CH2C6(CH3)5- 2,3,4,5,6), 7.23–7.70 (m, 4H,C6H4), 11.10 (s, 1H, NCHN). 13C{1H}
NMR (CDCl3): 16.9, 17.3, 19.8 (C6(CH3)5-2,3,4,5,6), 13.52, 31.4, 47.5 (NCH2CH2-
CH2CH3, NCH2CH2CH2CH3 and NCH2CH2CH2CH3), 48.4 (NCH2CH2CH2CH3),
58.1(CH2C6(CH3)5-2,3,4,5,6), 111.4, 112.1, 124.1, 124.3, 127.2, 129.7, 129.8,
131.7, 138.4,138.5 (C6H4 and CH2C6(CH3)5-2,3,4,5,6), 143.5 (NCHN). M.p.:
217–218 °C,ν(CN) =1459 cm−1. Anal. Calc. for C23H31N2Cl: C, 74.47; H, 8.42; N,
7.55. Found: C, 74.45; H, 8.39; N: 7.53%. Yield 95 % (0.333 g). 1-butyl-3-(3-
methoxybenzyl)benzimidazolium chloride (1d):1H NMR (CDCl3): 0.97 (t,
J=7.3 Hz, 3H, NCH2CH2CH2CH3), 1.45 (sex., J=7.5 Hz, 2H, NCH2CH2CH2CH3),
2.03 (quint., J=7.5 Hz, 2H, NCH2CH2CH2CH3), 3.70 (s, 3H, CH2C6H4-3-OCH3),
4.61 (t, 2H, J=7.3 Hz, NCH2CH2CH2CH3), 5.85 (s, 2H, CH2C6H4-3-OCH3), 7.24-
7.70 (m, 8H, C6H4 and CH2C6H4-3-OCH3), 11.65 (s, 1H, NCHN). 13C{1H} NMR
(CDCl3): 13.5, 19.8 and 31.3 (NCH2CH2CH2CH3, NCH2CH2CH2CH3 and NCH2CH2-
CH2CH3), 47.5 (NCH2CH2CH2CH3), 51.3 (CH2C6H4-3-OCH3), 55.6 (CH2C6H4-3-
OCH3), 112.9, 113.8, 113.9, 114.8, 120.4, 127.0, 127.1, 130.3, 131.3, 131.4, 134.4,
160.2 (C6H4 and CH2C6H4- 3-OCH3); 143.6 (NCHN). M.p.:191–192 °C, ν(CN)
=1442 cm−1. Anal. Calc. for C19H23N2OCl: C, 68.97; H, 7.01; N, 8.47. Found: C,
68.93; H, 6.97; N, 8.51%. Yield 82 % (0.271 g). 1-butyl-3-(3,4,5-trimethoxybenzyl)
benzimidazolium chloride (1e):1H NMR (CDCl3): 0.97 (t, J=7.3 Hz, 3H, NCH2CH2-
CH2CH3), 1.44 (sex., J=7.5 Hz, 2H, NCH2CH2CH2CH3), 2.04 (quint., J=7.8 Hz, 2H,
NCH2CH2CH2CH3), 3.79 and 3.81 (s, 9H, CH2C6H2-3,4,5-(OCH3)3), 5.29 (t,
J=7.5 Hz, 2H, NCH2CH2CH2CH3 ), 5.85 (s, 2H, CH2C6H2-3,4,5-(OCH3)3), 7.28–
7.75 (m, 6H, C6H4 and CH2C6H2-3,4,5-(OCH3)3), 11.83 (s, 1H, NCHN). 13C{1H}
NMR (CDCl3): 13.4, 19.8, 31.2 (NCH2CH2CH2CH3, NCH2CH2CH2CH3 and NCH2CH2-
CH2CH3), 47.5 (NCH2CH2CH2CH3), 51.6 (CH2C6H2-3,4,5-(OCH3)3), 56.6 and 60.8
(CH2C6H2-3,4,5-(OCH3)3), 106.1, 113.0, 113.8, 127.0, 127.1, 128.5, 131.2, 131.4,
138.5, 153.8 (C6H4 and CH2C6H2-3,4,5-(OCH3)3), 143.6 (NCHN). M.p.:
194–195 °C, ν(CN) =1443 cm−1. Anal. Calc. for C21H27N2O3Cl: C, 64.52; H, 6.96;
N, 7.17. Found C, 64.48; H, 7.01; N, 7.20%. Yield 89 % (0.347
[16] C.S. Vasam, I.J.B. Lin, Preparation and application of N-heterocyclic carbene
complexes of Ag(I), Coord. Chem. Rev. 251 (2007) 642–670.
[17] H.M.J. Wang, I.J.B. Lin, Synthesis of silver(I)−carbene complexes. useful carbene
transfer agents, Organometallics 17 (1998) 972–975.
[18] A. Melaiye, W.J. Youngs, Silver and its application as an antimicrobial agent,
Expert Opin. Ther. Pat. 14 (2005) 125–130.
[19] C.L. Fox, Arch. Surg. 96 (1968) 1840.
[20] C.L. Fox, US Patent 3, 761, 590, May 18, 1970.
[21] H.S. Carr, T.J. Wlodkowski, H.S. Rosenkranz, Silver sulfadiazine: in vitro
antibacterial activity, Antimicrob. Agents Chemother. 4 (1973) 585–587.
[22] A.R.C. Lee, H. Leem, J. Lee, K.C. Park, Reversal of silver sulfadiazine-impaired
wound healing by epidermal growth factor, Biomaterials 26 (2005) 4670–4676.
[23] H.S. Rosenkranz, H.S. Carr, Silver sulfadiazine: effect on the growth and metabolism
of bacteria, Antimicrob. Agents Chemother. 2 (1972) 367–372.
[24] C.L. Fox Jr., S.M. Modak, Mechanism of silver sulfadiazine action on burn wound
infections, Antimicrob. Agents Chemother. 5 (1974) 582–588.
[25] A.K. Singh, J.W. Lown, Design, synthesis and antitumor cytotoxicity of novel bis-
benzimidazoles, Anticancer Drug Des. 15 (2000) 265–275.
[26] S.T. Huang, I.J. Hsei, C. Chen, Synthesis and anticancer evaluation of
bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles, Bioorg. Med.
Chem. 14 (2006) 6106–6119.
[27] S.A. Galal, K.H. Hegab, A.S. Kassab, M.L. Rodriguez, S.M. Kerwin, A.M.A. El-
Khamry, H.I.E. Divani, New transition metal ion complexes with benzimidazole-
5-carboxylic acid hydrazides with antitumor activity, Eur. J. Med. Chem. 44
(2009) 1500–1508.
[35] F.E. Hahn, M.C. Jahnke, T. Pape, Synthesis of pincer-type bis(benzimidazolin-2-
ylidene) palladium complexes and their application in C–C coupling reactions,
Organometallics 26 (2007) 150–154.
[36] S. Demir, İ. Özdemir, B. Çetinkaya, Use of bis(benzimidazolium)–palladium sys-
tem as a convenient catalyst for Heck and Suzuki coupling reactions of aryl bro-
mides and chlorides, Appl. Organomet. Chem. 20 (2006) 254–259.
[37] S. Yasar, İ. Özdemir, B. Cetinkaya, J.-L. Renaud, C. Bruneau, Benzylic
imidazolidinium, 3,4,5,6-tetrahydropyrimidinium and benzimidazolium salts:
applications in ruthenium-catalyzed allylic substitution reactions, Eur. J. Org.
Chem. (2008) 2142–2149.
[38] Y. Gök, N. Gürbüz, İ. Özdemir, B. Çetinkaya, E. Çetinkaya, Benzimidazolin-2-
ylidene‐palladium-catalysed coupling reactions of aryl halides, Appl. Organomet.
Chem. 19 (2005) 870–874.
[28] E. Carlsson, P. Lindberg, S. Unge, Chem. Br. 5 (2002) 42–45.
[29] B. Cetinkaya, E. Cetinkaya, H. Kücükbay, R. Durmaz, Synthesis and antimicrobial
activity of electron rich olefin derived cyclic ureas, Arzneimittelforschung 46
(1996) 1154–1158.
[30] K.F. Ansari, C. Lal, Synthesis and evaluation of some new benzimidazole derivatives
as potential antimicrobial agents, Eur. J. Med. Chem. 44 (2009) 2294–2299.
[31] U. Yılmaz, H. Kücükbay, N. Sireci, M. Akkurt, S. Gunal, R. Durmaz, M.N. Tahir,
Synthesis, microwave-promoted catalytic activity in Suzuki–Miyaura cross-
coupling reactions and antimicrobial properties of novel benzimidazole salts
bearing trimethylsilyl group, Appl. Organomet. Chem. 25 (2011) 366–373.
[32] İ. Özdemir, S. Demir, S. Günal, İ. Özdemir, C. Arıcı, D. Ülkü, Synthesis, characteri-
zation and antimicrobial activity of new silver complexes with N-heterocyclic
carbene ligands, Inorg. Chim. Acta 363 (2010) 3803–3808.
[39] Synthesis of silver–NHC complexes (2a–2e) A solution of benzimidazolium salt
[33] D.A. Williams, T.L. Lemke, O. Foye, Foye's Principles of Medicinal Chemistry, 5th
ed. Lippincott Williams and Wilkins, Philadelphia. USA, 2002.
(1.0 mmol), Ag2O (0.5 mmol) and activated
4
molecular sieves in dic-
hloromethane (30 mL) was stirred room temperature for 8 hours in dark condi-
tion. The reaction mixture was filtered through celite and the solvent removed
under reduced pressure. The crude product was recrystallized from
dichloromethane/hexane at room temperature. (Scheme 2). Chloro[1-(butyl)-3-
(4-methylbenzyl)benzimidazolylidene]silver(I), (2a) 1H NMR (CDCl3): 0.99 (t,
J=7.4 Hz, 3H, NCH2CH2CH2CH3), 1.44 (sex., 2H, J=7.5 Hz, NCH2CH2CH2CH3),
1.93 (quint., 2H, J=7.5 Hz, NCH2CH2CH2CH3), 2.33 (s, 3H, CH2C6H4–4-CH3),
4.44 (t, 2H, J=7.3 Hz, NCH2CH2CH2CH3), 5.61 (s, 2H, CH2C6H4–4-CH3),
7.12–7.39 (m, 8H, C6H4 and CH2C6H4‐4-CH3). 13C{1H} NMR (CDCl3): 13.7,
20.1, 21.1, 32.4 (CH2C6H4–4-CH3, NCH2CH2CH2CH3 and NCH2CH2CH2CH3,
NCH2CH2CH2CH3), 49.50 (NCH2CH2CH2CH3), 53.4 (CH2C6H4–4-CH3), 111.5,
112.2, 124.2, 124.3, 127.2, 129.8, 131.8, 133.7, 133.9, 138.5 (C6H4 and
[34] All reactions carried out under argon in flame-dried glassware using standard
Schlenk techniques. Chemicals were obtained from Sigma Aldrich and Fluka.
Melting points were determined in glass capillaries under air with an
Electrothermal-9200 melting point apparatus. FT-IR spectra were recorded as
KBr pellets in the range 400–4000 cm−1 with a ATI UNICAM 1000 spectrometer.
1H and 13C-NMR spectra were recorded with a Varian AS 400 Merkur spectrom-
eter operating at 400 MHz (1H), 100 MHz (13C) in CDCl3 with tetramethylsilane
as an internal reference. Coupling constants (Jvalues) are given in hertz. NMR
multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet,
quint.
=
quintet, sex
=
sextet and
m
=
multiplet signal. Synthesis of
solution of 1-
benzimidazolium salts (1a–1e) (Scheme 1). To
a
butylbenzimidazole (10 mmol) in DMF (10 ml) was added slowly aryl halides
(10 mmol) at 25 °C and the resulting mixture was stirred at 80 °C for 12 h. Dieth-
ylether (15 ml) was added to obtain a white crystalline solid which was filtered
off. The solid was washed with diethylether (3×15 ml), dried under vacuum.
The crude product was recrystallized from EtOH–Et2O at room temperature. 1-
butyl-3-(4-methylbenzyl)benzimidazolium chloride (1a): 1H NMR (CDCl3): 0.97
(t, J=7.3 Hz, 3H, NCH2CH2CH2CH3), 1.44 (sex., J=7.5 Hz, 2H, NCH2CH2CH2CH3),
2.03 (quint., J=7.5 Hz, 2H, NCH2CH2CH2CH3), 2.89 (s, 3H, CH2C6H4-4-CH3), 4.60
(t, 2H, J=7.3 Hz, NCH2CH2CH2CH3), 5.80 (s, 2H, CH2C6H4-4-CH3), 7.12–7.39 (m,
8H, C6H4 and CH2C6H4-4-CH3), 11.80 (s, 1H, NCHN). 13C{1H} NMR (CDCl3):
13.5, 19.9, 21.2 (NCH2CH2CH2CH3, NCH2CH2CH2CH3 and NCH2CH2CH2CH3), 31.3
(C6H4-4-CH3), 47.6 (NCH2CH2CH2CH3), 51.4 (CH2C6H4-4-CH3), 111.4, 112.1,
124.1, 124.2, 127.2, 129.7, 129.8, 131.7, 138.4, 138.5 (C6H4 and CH2C6H4-4-CH3),
143.5 (NCHN). M.p.: 195–196 °C, ν(CN) =1465 cm−1. Anal. Calc. for C19H23N2Cl:
C, 72.48; H, 7.36; N: 8.90. Found: C, 72.44; H, 7.35; N: 8.87%. Yield 90%
(0.283 g). 1-butyl-3-(2-methylbenzyl)benzimidazolium chloride (1b):1H NMR
(CDCl3): 0.99 (t, J=7.3 Hz, 3H, NCH2CH2CH2CH3), 1.45 (sex., J=7.8 Hz, 2H,
NCH2CH2CH2CH3), 2.06 (quint., J=7.5 Hz, 2H, NCH2CH2CH2CH3), 2.41 (s, 3H,
CH2C6H4-2-CH3), 4.66 (t, 2H, J=7.3 Hz, NCH2CH2CH2CH3), 5.93 (s, 2H,
CH2C6H4-2-CH3), 7.10–7.73 (m, 8H, C6H4 and CH2C6H4-2-CH3); 11.65 (s, 1H,
NCHN). 13C{1H} NMR (CDCl3): 13.5, 19.5, 19.8 (NCH2CH2CH2CH3, NCH2CH2CH2-
CH3 and NCH2CH2CH2CH3), 31.4 (C6H4-2-CH3), 47.6 (NCH2CH2CH2CH3), 50.2
(CH2C6H4-2-CH3), 113.0, 114.0, 126.8, 127.0, 127.1, 128.2, 129.2, 130.7, 131.3,
131.4, 131.6, 136.6 (C6H4 and CH2C6H4-2-CH3), 144.0 (NCHN). M.p.:
CH2C6H4–4-CH3). M.p.: 216–217 °C, ν(CN)=1448 cm−1
. Anal. Calc. for
C19H22N2AgCl: C, 54.11; H, 5.26; N, 6.64. Found C, 54.14; H, 5.20; N, 6.69 %.
Yield 71 % (0.298 g). Chloro[1-(butyl)-3-(2-methylbenzyl)benzimidazolylidene]
silver(I), (2b) 1H NMR (CDCl3): 1.03 (t, J=7.5 Hz, 3H, NCH2CH2CH2CH3), 1.45
(sex., 2H, J=7.5 Hz, NCH2CH2CH2CH3), 1.95 (quint., 2H, J=7.5 Hz,
NCH2CH2CH2CH3), 2.43 (s, 3H, CH2C6H4–2-CH3), 4.48 (t, 2H, J=7.3 Hz,
NCH2CH2CH2CH3), 5.61 (s, 2H, CH2C6H4‐2-CH3), 6.07–7.62 (m, 8H, C6H4 and
CH2C6H4‐2-CH3). 13C{1H} NMR (CDCl3): 13.5, 19.6, 20.2, 32.4 (CH2C6H4–4-
CH3, NCH2CH2CH2CH3, NCH2CH2CH2CH3 and NCH2CH2CH2CH3), 49.7
(NCH2CH2CH2CH3), 51.7 (CH2C6H4–2-CH3), 111.5, 112.2, 113.9, 124.2, 126.4,
126.6, 128.4, 130.9, 132.7, 135.4 (C6H4 and CH2C6H4–2-CH3). M.p.:
210–211 °C, ν(CN)=1460 cm−1. Anal. Calc. for C19H22N2AgCl: C, 54.11; H,
5.26; N, 6.64. Found C, 54.07; H, 5.22; N, 6.61%. Yield 67% (0.281 g). Chloro
[1-(butyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimidazolylidene]silver(I), (2c)
1H NMR (CDCl3): 0.94 (t, J=7.5 Hz, 3H, NCH2CH2CH2CH3), 1.36 (sex., 2H,
J=7.8 Hz, NCH2CH2CH2CH3), 1.85 (quint., 2H, J=7.5 Hz, NCH2CH2CH2CH3),
2.20, 2.30 and 2.35 (s, 15H, CH2C6(CH3)5‐2,3,4,5,6), 4.36 (t, 2H, J=7.3 Hz,
NCH2CH2CH2CH3), 5.48 (s, 2H, CH2C6(CH3)5‐2,3,4,5,6), 7.38–7.50 (m, 4H,
C6H4). 13C{1H} NMR (CDCl3): 13.7, 17.1, 17.2, 17.4, 20.1 and 32.3
(CH2C6(CH3)5)-2,3,4,5,6),
(NCH2CH2CH2CH3,
NCH2CH2CH2CH3
and
NCH2CH2CH2CH3), 47.7 (NCH2CH2CH2CH3), 50.2 (CH2C6(CH3)5)-2,3,4,5,6),
111.4, 111.5, 123.9, 124.2, 126.6, 132.9, 133.7, 134.2, 134.4 and 137.3 (C6H4
and CH2C6(CH3)5)-2,3,4,5,6). M.p.: 234–236 °C, ν(CN)=1401 cm−1
.
Anal.
Calc. for C23H30N2AgCl: C, 57.81; H, 6.33; N, 5.86. Found C, 57.86; H, 6.32; N,

146
S. Günal et al. / Inorganic Chemistry Communications 21 (2012) 142–146
(0.386 g). Chloro[1-(butyl)-3-(3-methoxylbenzyl)
5.81 %. Yield 81
%
[45] R.M. Slawson, M.I. Van Dyke, H. Lee, J.T. Trevors, Plasmid 27 (1992) 72.
[46] G. Zhao, S.E. Stevens, Multiple parameters for the comprehensive evaluation of
the susceptibility of Escherichia coli to the silver ion, Biometals 11 (1998) 27–32.
[47] Antimicrobial activities of theAg(I) complexes and carbene precursors were
determined by using agar dilution procedure recommended by the Clinical and
Laboratory Standards Institute. Minimal inhibitory concentrations for each com-
pound were investigated against standard bacterial strains; Staphylococcus aureus
ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922,
Pseudomonas aeruginosa ATCC 27853 were obtained from American Type Culture
Collection (Rockville, MD.) and the fungal strains Candida albicans and Candida
tropicalis 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).
Their turbidities matched that of a McFarland no. 0.5 turbidity standard. The
stock solution of all compounds were prepared in dimethyl sulfoxide (DMSO).
All of the dilutions were done with distilled water. The concentrations of the test-
ed compounds were 800, 400, 200, 100, 50, and 25 μg/mL. Ampicillin and cipro-
floxacin were used as antibacterial standard drugs, while fluconazole were used
as antifungal standard drugs whose minimum inhibitory concentration (MIC)
values are provided. A loopful (0.01 mL) of the standardised inoculum of the bac-
teria and yeasts (106 CFUs/mL) was spread over the surface of agar plates. All the
inoculated plates were incubated at 35 °C and results were evaluated 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 mini-
mal inhibitory concentration (MIC).
benzimidazolylidene]silver(I), (2d) 1H NMR (CDCl3): 1.01 (t, J=7.6 Hz, 3H,
NCH2CH2CH2CH3), 1.45 (sex., 2H, J=7.5 Hz NCH2CH2CH2CH3), 1.92 (quint.,
2H, J=7.8 Hz, NCH2CH2CH2CH3), 3.78 (s, 3H, CH2C6H4‐3-OCH3), 4.45 (t, 2H,
J=7.3 Hz, NCH2CH2CH2CH3), 5.63 (s, 2H, CH2C6H4–3-OCH3), 6.78–7.42 (m,
8H, C6H4 and CH2C6H4‐3-OCH3). 13C{1H} NMR (CDCl3): 13.5, 20.1 and 32.4
(NCH2CH2CH2CH3,
NCH2CH2CH2CH3
and
NCH2CH2CH2CH3),
49.6
(NCH2CH2CH2CH3), 53.3 (CH2C6H4‐3-OCH3), 55.3 (C6H4‐3-OCH3), 111.5,
112.2, 112.9, 113.6, 113.8, 113.9, 119.3, 124.3, 130.2, 133.8, 136.4 and 160.0
(C6H4 and CH2C6H4‐3-OCH3). M.p.:225–228 °C, ν(CN)=1455 cm−1
.
Anal.
Calc. for C19H22N2OAgCl: C, 52.14; H, 5.07; N, 6.40. Found C, 52.09; H, 5.10; N,
6.37 %. Yield 57 (0.248 g). Chloro[1-(butyl)-3-(3,4,5-trimethoxylbenzyl)
%
benzimidazolylidene]silver(I), (2e) 1H NMR (CDCl3): 0.97 (t, J=7.3 Hz, 3H,
NCH2CH2CH2CH3), 1.42 (sex., J=7.2 Hz, 2H, NCH2CH2CH2CH3), 1.92 (quint.,
J=7.3 Hz, 2H, NCH2CH2CH2CH3), 3.81 and 3.82(s, 9H, CH2C6H2‐3,4,5-(OCH3)
3), 4.45 (t, J=7.2 Hz, 2H, NCH2CH2CH2CH3), 5.55 (s, 2H, CH2C6H2‐3,4,5-
(OCH3)3), 7.28–7.49 (m, 6H, C6H4 and CH2C6H2‐3,4,5-(OCH3)3). 13C{1H}
NMR (CDCl3): 13.7, 20.2 and 32.3 (NCH2CH2CH2CH3, NCH2CH2CH2CH3 and
NCH2CH2CH2CH3), 49.59 (NCH2CH2CH2CH3), 53.5 (CH2C6H2‐3,4,5-(OCH3)3),
56.3 and 60.9 (C6H2‐3,4,5,-(OCH3)3), 104.6, 111.6, 112.0, 124.3, 124.4, 130.6,
133.7, 133.8, 138.2, and 153.7 (C6H4 and CH2C6H2–3,4,5-(OCH3)3). M.p.:
204–205 °C, ν(CN)=1478 cm−1. Anal. Calc. for C21H26N2O3AgCl: C, 50.67; H,
5.26; N, 5.63. Found C, 50.69; H, 5.20; N, 5.65 %. Yield 80 % (0.397 g).
[40] P. de Fre´mont, N.M. Scott, E.D. Stevens, T. Rammnial, O.C. Lightbody, C.L.B.
Macdonald, J.A.C. Clyburne, C.D. Abernethy, S.P. Nolan, Synthesis of well-defined
n-heterocyclic carbene silver(I) complexes, Organometallics 24 (2005) 6301–6309.
[41] P.L. Chiu, C.Y. Chen, C.-C. Lee, M.-H. Hsieh, C.-H. Chuang, H.M. Lee, Structural var-
iations in novel silver(I) complexes with bitopic pyrazole/N-Heterocyclic carbene
ligands, Inorg. Chem. 45 (2006) 2520–2530.
[42] W. Chen, F. Liu, Synthesis and characterization of oligomeric and polymeric silver
imidazol-2-ylidene iodide complexes, J. Organomet. Chem. 673 (2003) 5–12.
[43] I.J.B. Lin, C.S. Vasam, Silver (I) N-heterocyclic carbenes, Comments Inorg. Chem.
25 (2004) 75–129.
[48] Clinical and Laboratory Standards Instıtute, Methods for dilution antimicrobial
susceptibility tests for bacteria that grow aerobically; Approved Standard-
Seventh Edition, CLSI Document M7-A7, Clinical and Laboratory Standards Instı-
tute, Wayne, Pennsylvania USA, 2003.
[49] Clinical and Laboratory Standards Institute, Reference method for broth dilution
antifungal susceptibility testing of yeasts; Approved Standard-Second Edition,
NCCLS document M27-A2, NCCLS, 940 West Valley Road, Suite 1400, Wayne,
Pennsylvania 19087–1898 USA1-56238-469-4, 2002.
[44] J.M. Hayes, M. Viciano, E. Peris, G. Ujaque, A. Lledós, Mechanism of formation of
silver N-Heterocyclic carbenes using silver oxide: a theoretical study, Organome-
tallics 26 (2007) 6170–6183.