Novel symmetrically p-benzyl-substituted 4,5-diaryl-imidazole N-heterocyclic carbene-silver(I) acetate complexes - Synthesis and biological evaluation

Article abstract of DOI:10.1016/j.jorganchem.2012.07.006

Symmetrically substituted N-heterocyclic carbene (NHC) precursors 1a-e and 3a-e were synthesised by reacting 4,5-bisaryl-1H-imidazole with 2 equivalents of 4-benzyl bromide, 4-methylbenzyl bromide, 4-methoxybenzyl chloride, 4-methoxycarbonylbenzyl bromide

Full text of DOI:10.1016/j.jorganchem.2012.07.006

Journal of Organometallic Chemistry 717 (2012) 123e134
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Novel symmetrically p-benzyl-substituted 4,5-diaryl-imidazole N-heterocyclic
carbene-silver(I) acetate complexes e Synthesis and biological evaluation
Frauke Hackenberg, Grainne Lally, Helge Müller-Bunz, Francesca Paradisi, Daniela Quaglia,
*
Wojciech Streciwilk, Matthias Tacke
Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and Chemical Biology (CSCB), UCD School of Chemistry and Chemical Biology,
University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Symmetrically substituted N-heterocyclic carbene (NHC) precursors 1aee and 3aee were synthesised by
reacting 4,5-bisaryl-1H-imidazole with 2 equivalents of 4-benzyl bromide, 4-methylbenzyl bromide, 4-
methoxybenzyl chloride, 4-methoxycarbonylbenzyl bromide or 4-cyanobenzyl bromide to give the
1,3-bis(p-benzyl substituted)-4,5-bisaryl-imidazolium halides. The NHC-silver(I) acetate complexes (1,3-
bisbenzyl-4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2a), (1,3-bis(4-methylbenzyl)-4,5-
bisphenyl-imidazole-2-ylidene) silver(I) acetate (2b), (1,3-bis(4-methoxybenzyl)-4,5-bisphenyl-imid-
azole-2-ylidene) silver(I) acetate (2c), (1,3-bis(4-methoxycarbonylbenzyl)-4,5-bisphenyl-imidazole-2-
ylidene) silver(I) acetate (2d), (1,3-bis(4-cyanobenzyl)-4,5-bisphenyl-imidazole-2-ylidene) silver(I)
acetate (2e), (1,3-bisbenzyl-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4a), (1,3-
bis(4-methylbenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4b), (1,3-bis(4-
methoxybenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4c), (1,3-bis(4-
methoxycarbonylbenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4d) and
(1,3-bis(4-cyanobenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4e) were
yielded by reacting these NHC precursors with silver(I) acetate. The silver(I) acetate complexes 2d, 2e
and 4c were characterised by single crystal X-ray diffraction. Qualitative antibacterial studies against the
Gram-negative bacteria Escherichia coli and the Gram-positive bacteria Staphylococcus aureus, using the
KirbyeBauer disc diffusion method were carried out on the ten NHC-silver(I) acetate complexes 2aee
and 4aee. Also the IC50 values of these ten complexes were determined by an MTT-based assay
against the human renal cancer cell line Caki-1 and the human breast cancer cell line MCF-7. The
Received 17 May 2012
Received in revised form
28 June 2012
Accepted 5 July 2012
Keywords:
Anticancer drugs
Antibacterial drugs
Silver(I) acetate
NHC
Caki-1
MCF-7
complexes 2aee and 4aee revealed the following IC50 values in
m
M against Caki-1: 14 (ꢀ1), 3.6 (ꢀ1.0),
4.2 (ꢀ0.5), 33 (ꢀ2), 59 (ꢀ4), 21 (ꢀ1), 21 (ꢀ2), 21 (ꢀ1), 34 (ꢀ2), 46 (ꢀ2) and against MCF-7: 5.8 (ꢀ0.6), 3.5
(ꢀ0.4), 5.4 (ꢀ0.3), 28 (ꢀ1), 25 (ꢀ2), 11 (ꢀ2), 5.0 (ꢀ0.3), 6.5 (ꢀ0.4), 17 (ꢀ1), 13 (ꢀ1); respectively.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
accompanying cystic fibrosis (CF) and chronic lung infections were
developed [4e7]. Youngs et al. have reported NHC-silver complexes
For many years silver complexes have been reported to exhibit
antibacterial as well as anticancer activity in vitro. Silver complexes
of coumarin derivatives and silver carboxylate dimers possess
anticancer activity against human carcinoma cells as reported by
Egan [1] and Zhu [2], respectively. McKeage has shown phosphine
complexes of silver to be active anticancer agents, even against
cisplatin-resistant cell lines [3]. By combining the bioactive prop-
erties of silver with N-heterocyclic carbene ligands, new antibiotic
complexes for the possible treatment of pulmonary infections
derived from 4,5-dichloro-1H-imidazole, which show anticancer
activity against the human cancer cell lines OVCAR-3 (ovarian),
MB157 (breast), and HeLa (cervical) [5]. Furthermore led the
synthesis and antimicrobial evaluation of NHC silver complexes
derived from 1-benzyl-3-tert-butylimidazole by Ghosh et al. to
another important contribution [8]. Additionally a larger number of
known compounds were evaluated as potential antibiotics by
Roland and Jolivalt [9]. Recently, Gust et al. reported the anticancer
activity of 4,5-diaryl-imidazole derived NHC silver complexes
against MCF-7, MDA-MB-231 (breast) and HT-29 (colon) cancer cell
lines [10].
As previously reported by us, novel benzyl-substituted N-
heterocyclic carbene-silver [11e17] and carbeneegold complexes
* Corresponding author.
E-mail address: matthias.tacke@ucd.ie (M. Tacke).
0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2012.07.006

124
F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
[18,19] exhibited good activity against the cancer cell line Caki-1
(renal) and antibacterial activity against the strains Escherichia
coli and Staphylococcus aureus.
Within this paper we present a new series of symmetrically p-
benzyl-substituted N-heterocyclic carbene-silver acetate complexes
derived from 4,5-bisphenyl-imidazole and 4,5-bisanisyl-imidazole,
their synthesis, cytotoxicity and antibacterial studies.
assuming equivalent Friedel pairs (4c) dataset was collected. An
analytical absorption correction based on the shape of the crystal was
performed [20]. The structures were solved by direct methods using
SHELXS-97 [21] and refined by full matrix least-squares on F2 for all
data using SHELXL-97 [21]. Hydrogen atoms were added atcalculated
positions and refined using a riding model. Their isotropic thermal
displacement parameters were fixed to 1.2 (1.5 for methyl groups)
times the equivalent ones of the parent atom. Anisotropic thermal
displacement parameters were used for all non-hydrogen atoms. A
suitable crystal of 2d and 2e was grown in a saturated solution of
chloroform with slow infusion of pentane, while 4c was grown in
a saturated solution of dichloromethane with slow infusion of
pentane. Further details about the data collection are listed in Table 1.
2. Experimental part
2.1. General
All reactions were carried out under aerobic conditions. All reac-
tions involving silver(I) acetate were carried out under exclusion of
light. 4,5-Bisphenyl-1H-imidazole, benzyl bromide, 4-methylbenzyl
bromide, 4-methoxybenzyl chloride, methyl 4-(bromomethyl)
benzoate, 4-cyanobenzyl bromide, formamide, 4,4-p-methoxy-
benzoin, silver(I)acetate and K2CO3 were procured commercially
from SigmaeAldrich Chemical Company and were used without
further purification. IR Spectra were recorded on a PerkineElmer
Paragon 1000 FT-IR spectrometer employing a KBr disc. NMR
Spectra were measured either on a Varian 300 MHz or 400 MHz
spectrometer. All chemical shifts are reported in ppm and referenced
to TMS. ESI MS was performed on a quadrupole tandem mass spec-
trometer (Quattro Micro, Micromass/Water’s Corp., USA), using
solutions in 100% MeOH. MS spectra were obtained in the ESþ
(electron spray positive ionisation) mode for all compounds. CHN
Analysis was carried out in an Exeter Analytical CE-440 elemental
analyzer. Crystal Data was collected using an Agilent Technologies
(former Oxford Diffraction) SuperNova diffractometer fitted with an
2.2. Synthesis
2.2.1. 1,3-Bis-benzyl-4,5-bisphenyl-imidazolium bromide (1a)
1,3-Bisbenzyl-4,5-bisphenyl-imidazolium bromide was syn-
thesised according to literature [13] to give a yield of 66.2%. The
formation of the product was confirmed by NMR.
2.2.2. 1,3-Bis-(4-methylbenzyl)-4,5-bisphenyl-imidazolium
bromide (1b)
4,5-Bisphenyl-1H-imidazole (1 g, 4.54 mmol), equivalents of 4-
methylbenzyl bromide (1.680 g, 9.08 mmol) and 1.5 equivalents of
K2CO3 (942 mg, 6.82 mmol) were dissolved in acetonitrile and stirred
for 2 d at room temperature. After filtering off the precipitate and
removing the solvent under reduced pressure the obtained sticky
white solid was washed with pentane (2 ꢁ 20 mL) and diethyl ether
(2 ꢁ 20 mL) to yield a white powder (2.051 g, 4.03 mmol, 88.7% yield).
Atlas detector. 2d, and 2e were measured with Mo-K
a
(0.71073 Å), 4c
1H NMR (
d ppm, CDCl3, 300 MHz): 11.17 (s, 1H, NCHN),
with Cu-K (1.54184 Å) at 100 K. A three-fold redundant (2d),
complete assuming inequivalent Friedel pairs (2e) and complete
a
7.48e7.30 (m, 6H, CHphenyl þ CHmethylbenzyl), 7.14e6.87 (m, 12H,
CHphenyl þ CHmethylbenzyl), 5.44 (s, 4H, CH2), 2.29 (s, 6H, CH3).
Table 1
Crystal data and structure refinement for 2d, 2e and 4c.
2d
2e
4c
Empirical formula
Formula weight [g/mol]
C
35H32AgN2O6
C33H26AgN4O2
617.44
C70.75H71.5N4O12Cl1.5Ag2
1438.74
802.86
Crystal system
Space group
Triclinic
P-1 (#2)
Monoclinic
C2/c (#15)
Triclinic
P-1 (#2)
Unit cell dimensions [Å]
a
b
c
a
8.8250(3)
29.4955(9)
8.2592(2)
24.1508(7)
13.4580(4)
16.9528(5)
14.9450(4)
15.2246(4)
116.877(3)ꢂ
101.163(2)ꢂ
97.006(2)ꢂ
1706.08(9)
2
1.563
17.1298(5)
107.092(3)ꢂ
112.693(3)ꢂ
96.891(2)ꢂ
b
104.100(3)ꢂ
g
Volume [Å3]
5706.1(3)
8
1.437
0.743
3323.5(2)
2
1.438
5.808
Z
Density [mg/m3] (calc.)
Absorption coefficient [mmꢃ1
F(000)
]
0.875
816
2512
1479
Crystal size [mm3]
0.3211 ꢁ 0.2116 ꢁ 0.1567
3.30e26.42ꢂ.
ꢃ10 ꢄ h ꢄ 11
ꢃ18 ꢄ k ꢄ 18
ꢃ19 ꢄ l ꢄ 19
48,384
0.2206 ꢁ 0.1980 ꢁ 0.1272
3.42e29.71ꢂ.
ꢃ37 ꢄ h ꢄ 37
ꢃ11 ꢄ k ꢄ 11
ꢃ33 ꢄ l ꢄ 32
31,477
0.2785 ꢁ 0.1791 ꢁ 0.1199
3.01e76.47ꢂ.
ꢃ16 ꢄ h ꢄ 16
ꢃ21 ꢄ k ꢄ 21
ꢃ21 ꢄ l ꢄ 21
35,819
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to qmax
Max. and min transmission
Data/restraints/parameters
Goodness-of-fit in F2
6973 [R(int) ¼ 0.0586]
7085 [R(int) ¼ 0.0279]
13,796 [R(int) ¼ 0.0286]
99.5%
99.2%
98.8%
0.904 and 0.830
6973/0/436
1.047
0.896 and 0.849
7085/0/362
1.053
0.630 and 0.440
13,796/34/868
1.028
Final R indices (I > 2
s
(I))
R1 ¼ 0.0285
wR2 ¼ 0.0647
R1 ¼ 0.0346
wR2 ¼ 0.0685
0.623 and ꢃ0.764 e Åꢃ3
R1 ¼ 0.0266
wR2 ¼ 0.0643
R1 ¼ 0.0325
wR2 ¼ 0.0681
0.418 and ꢃ0.554 e Åꢃ3
R1 ¼ 0.0291
wR2 ¼ 0.0730
R1 ¼ 0.0319
wR2 ¼ 0.0749
0.602 and ꢃ0.863 e Åꢃ3
R Indices (all data)
Largest diff. peak and hole

F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
125
13C NMR (
d
ppm, CDCl3, 100 MHz) 138.91 (NCHN), 132.01,
stirred for 3 d at room temperature. After filtering off the precipi-
tate and removing the solvent under reduced pressure the obtained
sticky white solid was washed with pentane (2 ꢁ 20 mL) and
diethyl ether (2 ꢁ 20 mL) to yield a white powder (1.956 g,
3.68 mmol, 81.0% yield).
130.77, 130.39, 130.29, 129.70, 129.04, 128.50, 124.78
(Cbenzyl þ Cphenyl þ Cimidazole), 51.13 (CH2), 21.14 (CH3).
IR absorptions (KBr, cmꢃ1): 3416 (m), 2992 (m), 1560 (s), 1516
(s), 1448 (s), 1212 (s), 1023 (s), 802 (s).
MS (m/z, QMS-MS/MS): 429.55 [Mþ ꢃ Br].
1H NMR (
d
ppm, CDCl3, 400 MHz): 11.65 (s, 1H, NCHN), 7.52 (d,
J ¼ 8.0 Hz, 4H, CHphenyl þ CHcyanobenzyl), 7.44 (d, J ¼ 7.5 Hz, 2H,
CHphenyl CHcyanobenzyl), 7.35 (t, 7.6 Hz, 4H, CHphenyl
Micro Analysis Calculated for C31H29BrN2 (509.50): Calcd.: C,
73.08%; H, 5.74%; N, 5.50%; Found: C, 72.98%; H, 5.72%; N, 5.19%.
Melting point: 220e226 ꢂC.
þ
J
¼
þ CHcyanobenzyl), 7.30 (d, J ¼ 8.0 Hz, 4H, CHphenyl þ CHcyanobenzyl), 7.07
(d, J ¼ 7.4 Hz, 3H, CHphenyl þ CHcyanobenzyl), 5.64 (s, 4H, CH2).
2.2.3. 1,3-Bis-(4-methoxybenzyl)-4,5-bisphenyl-imidazolium
chloride (1c)
13C NMR (
d ppm, 101 MHz): 138.26 (NCHN), 137.75, 132.79,
132.27, 130.94, 130.52, 129.43, 129.38, 124.03, 117.86, 113.17
(Ccyanobenzyl þ Cphenyl þ Cimidazole), 50.93 (CH2).
4,5-Bisphenyl-1H-imidazole (1 g, 4.54 mmol), equivalents of 4-
methoxybenzyl chloride (1.23 mL, 9.08 mmol) and 1.5 equivalents
of K2CO3 (942 mg, 6.82 mmol) were dissolved in acetonitrile and
refluxed for 5 d. After filtering off the precipitate and removing the
solvent under reduced pressure the obtained sticky white solid was
washed with pentane (2 ꢁ 20 mL) and diethyl ether (2 ꢁ 20 mL) to
yield a white powder (0.977 g, 1.97 mmol, 43.3% yield).
IR absorptions (KBr, cmꢃ1): 3408 (m), 2960 (s), 2226 (s),1557 (s),
1446 (s), 1216 (s), 1022 (s), 840 (s), 817 (s).
MS (m/z, QMS-MS/MS): 451.50 [Mþ ꢃ Br].
Micro Analysis Calculated for C31H23BrN4 (531.45): Calcd.: C,
70.06%; H, 4.36%; N, 10.54%; Found: C, 69.57%; H, 4.05%; N, 10.33%.
Melting point: 290e293 ꢂC.
1H NMR (
J ¼ 8.4 Hz, 4H, CHphenyl þ CHmethoxybenzyl), 7.37 (d, J ¼ 7.2 Hz, 2H,
CHphenyl CHmethoxybenzyl), 7.32 (t, 7.6 Hz, 4H, CHphenyl
d ppm, d6-DMSO, 400 MHz): 9.63 (s, 1H, NCHN), 7.87 (d,
2.2.6. (1,3-Bisbenzyl-4,5-bisphenyl-imidazole-2-ylidene) silver(I)
acetate (2a)
1,3-Bisbenzyl-4,5-bisphenyl-imidazolium silver(I) acetate was
synthesised according to literature [13] to give a yield of 70.7%. The
formation of the product was confirmed by NMR.
þ
J
¼
þ CHmethoxybenzyl), 7.28e7.21 (m, 8 H, CHphenyl þ CHmethoxybenzyl), 5.53
(s, 4H, CH2), 3.83 (s, 6H, CH3).
13C NMR (
d ppm, CDCl3,100 MHz) 159.93 (NCHN),138.06,131.79,
130.76, 130.38, 130.26, 129.07, 125.51, 124.94, 114.31 (Cbenzyl
þ Cphenyl þ Cimidazole), 55.25 (CH2), 50.90 (OCH3).
IR absorptions (KBr, cmꢃ1): 3438 (m), 2930 (m), 1613 (s), 1514
(s), 1453 (s), 1251 (s), 1179 (s), 1030 (s), 817 (s).
2.2.7. (1,3-Bis-(4-methylbenzyl)-4,5-bisphenyl-imidazole-2-
ylidene) silver(I) acetate (2b)
1,3-Bis-(4-methylbenzyl)-4,5-bisphenyl-imidazolium bromide
(1b) (500 mg, 0.98 mmol) and 2.2 equivalents of silver(I) acetate
(360 mg, 2.16 mmol) were dissolved in 30 mL of dichloromethane
and stirred in darkness at room temperature for 3 d. After filtering
off the AgBr by-product, the solvent was reduced to 3 mL and by
adding drop wise 10 mL of pentane a white powder precipitated.
The solvent was decanted and the white precipitate was washed
with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL) to yield
a white powder (370.6 mg, 0.62 mmol, 63.4% yield).
MS (m/z, QMS-MS/MS): 461.52 [Mþ ꢃ Cl].
Micro Analysis Calculated for C31H29ClN2O2 (497.03): Calcd.: C,
74.91%; H, 5.88%; N, 5.64%; Found: C, 74.63%; H, 5.82%; N, 5.45%.
Melting point: 194e196 ꢂC.
2.2.4. 1,3-Bis-(4-methoxycarbonylbenzyl)-4,5-bisphenyl-
imidazolium bromide (1d)
4,5-Bisphenyl-1H-imidazole (1.000 g, 4.54 mmol), equivalents
of 4-methoxycarbonyl-benzyl bromide (2.080 g, 9.08 mmol) and
1.5 equivalents of K2CO3 (942 mg, 6.82 mmol) were dissolved in
acetonitrile and stirred for 2 d at room temperature. After filtering
off the precipitate and removing the solvent under reduced pres-
sure the obtained sticky white solid was washed with pentane
(2 ꢁ 20 mL) and diethyl ether (2 ꢁ 20 mL) to yield a white powder
(1.958 g, 3.28 mmol, 72.2% yield).
1H NMR (
d
ppm, CDCl3, 400 MHz) 7.26 (dt, J ¼ 19.0, 7.1 Hz, 8H,
CHphenyl þ CHmethylbenzyl), 7.01 (dd, J ¼ 7.2, 4.6 Hz, 8H, CHphenyl
þ CHmethylbenzyl), 6.87 (d, J ¼ 7.7 Hz, 2H, CHphenyl þ CHmethylbenzyl),
5.27 (s, 4H, CH2), 2.28 (s, 6H, CH3), 2.08 (s, 3H, CH3actetate).
13C NMR NMR (
d ppm, CDCl3, 101 MHz) 178.64 (NCN), 156.23
(C]O), 137.69, 133.21, 132.49, 130.65, 129.29, 129.05, 128.52, 127.85,
127.39 (Cmethylbenzyl þ Cphenyl þ Cimidazole), 53.38 (CH2), 22.82
(CH3actetate), 21.08 (CH3).
1H NMR (
d ppm, DMSO, 400 MHz) 9.63 (s, 1H, NCHN), 7.87 (d,
J ¼ 8.0 Hz, 4H, CHphenyl þ CHmethoxycarbonylbenzyl), 7.37 (d, J ¼ 7.0 Hz,
IR absorptions (KBr, cmꢃ1): 3440 (m), 3050 (s), 2922 (m), 1568
(s), 1515 (s), 1442 (s), 1402 (s), 801 (s).
2H, CHphenyl þ CHmethoxycarbonylbenzyl), 7.32 (t, J ¼ 7.2 Hz, 4H, CHphenyl
þ
CHmethoxycarbonylbenzyl),
7.28e7.21
(m,
4H,
CHphenyl
MS (m/z, QMS-MS/MS): 491.48 [Mþ ꢃ C8H9(methylbenzyl)].
Micro Analysis Calculated for C33H32AgN2O2 (596.49): Calcd.: C,
66.45%; H, 5.41%; N, 4.70%; Found: C, 66.17%; H, 5.21%; N, 4.38%.
Melting point: 180e182 ꢂC.
þ CHmethoxycarbonylbenzyl), 5.53 (s, 4H, CH2), 3.83 (s, 6H, CH3).
13C NMR (
d
ppm, DMSO,101 MHz) 166.17 (C]O),139.65 (NCHN),
137.58, 132.38, 131.17, 130.63, 129.90, 129.22, 128.50, 125.20
(Cmethoxycarbonylbenzyl þ Cphenyl þ Cimidazole), 52.73 (OCH3), 50.71
(CH2).
2.2.8. (1,3-Bis-(4-methoxybenzyl)-4,5-bisphenyl-imidazole-2-
ylidene) silver(I) acetate (2c)
IR absorptions (KBr, cmꢃ1): 3398 (m), 2998 (m), 1720 (s), 1561
(s), 1431 (s), 1286 (s), 1187 (s), 1108 (s), 754 (s).
MS (m/z, QMS-MS/MS): 517.48 [Mþ ꢃ Br].
1,3-Bis-(4-methoxybenzyl)-4,5-bisphenyl-imidazolium
chlo-
ride (1c) (150 mg, 0.30 mmol) and 2 equivalents of silver(I) acetate
(315 mg, 0.60 mmol) were dissolved in 30 mL of dichloromethane
and stirred in darkness at room temperature for 7 d. After filtering
off the AgBr by-product, the solvent was reduced to 3 mL and by
adding drop wise 10 mL of pentane a white powder precipitated.
The solvent was decanted and the white precipitate was washed
with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL) to yield
a white powder (154.0 mg, 0.25 mmol, 81.7% yield).
Micro Analysis Calculated for C33H29BrN2O4 (597.50): Calcd.: C,
66.34%; H, 4.89%; N, 4.69%; Found: C, 66.21%; H, 4.83%; N, 4.49%.
Melting point: 238e240 ꢂC.
2.2.5. 1,3-Bis-(4-cyanobenzyl)-4,5-bisphenyl-imidazolium bromide
(1e)
4,5-Bisphenyl-1H-imidazole (1.000 g, 4.54 mmol), equivalents
of 4-cyanobenzyl bromide (1.78 g, 9.08 mmol) and 1.5 equivalents
of K2CO3 (942 mg, 6.82 mmol) were dissolved in acetonitrile and
1H NMR (
J ¼ 8.3 Hz, 4H, CHphenyl þ CHmethoxybenzyl), 6.91 (d, J ¼ 8.3 Hz, 4H,
d ppm, CDCl3, 400 MHz) 7.36e7.18 (m, 6H), 7.01 (d,

126
F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
CHphenyl
þ
CHmethoxybenzyl), 6.73 (d,
J
¼
8.3 Hz, 4H,
IR absorptions (KBr, cmꢃ1): 3427 (s), 3057 (s), 2228 (s), 1608 (s),
1580 (s), 1504 (s), 1445 (s), 1403 (s), 815 (s), 701 (s).
MS (m/z, QMS-MS/MS): 559.36 [Mþ ꢃ COOCH3].
CHphenyl þ CHmethoxybenzyl), 5.25 (s, 4H, CH2), 3.76 (s, 6H, OCH3), 2.10
(s, 3H, CH3acetate).
13C NMR (
d
ppm, CDCl3, 101 MHz) 178.61 (NCN), 159.26 (C]O),
Micro Analysis Calculated for C33H26AgN4O2 (618.45): Calcd.: C,
64.09%; H, 4.24%; N, 9.06%; Found: C, 64.28%; H, 4.11%; N, 9.05%.
Melting point: 206e209 ꢂC.
132.43, 130.67, 129.08, 128.97, 128.54, 128.24, 127.89, 113.97, 113.45
(Cmethoxycarbonylbenzyl þ Cphenyl þ Cimidazole), 55.22 (CH2), 53.16
(OCH3), 22.91 (CH3acetate).
IR absorptions (KBr, cmꢃ1): 3414 (m), 2992e2929 (w), 1611 (s),
1579 (s), 1514 (s), 1445 (s), 1251 (s), 1177 (s), 1023 (s), 701 (s).
MS (m/z, QMS-MS/MS): 569.45 [Mþ ꢃ COOCH3].
2.2.11. 4,5-Bis-(4-methoxyphenyl)-1H-imidazole (3)
4,5-Bis(4-methoxyphenyl)-1H-imidazole
was
synthesised
according to literature [22] to give a yield of 38.5%. The formation of
the product was confirmed by NMR.
Micro Analysis Calculated for C33H32AgN2O4 (628.49): Calcd.: C,
63.06%; H, 5.13%; N, 4.46%; Found: C, 62.99%; H, 4.92%; N, 4.37%.
Melting point: 144e146 ꢂC.
2.2.12. 1,3-Bis-benzyl-4,5-bis-(4-methoxyphenyl)-imidazolium
bromide (3a)
2.2.9. (1,3-Bis-(4-methoxycarbonylbenzyl)-4,5-bisphenyl-
imidazole-2-ylidene) silver(I) acetate (2d)
4,5-Bis-(4-methoxyphenyl)-1H-imidazole (280 mg, 1.00 mmol),
equivalents of benzyl bromide (0.24 mL, 2.00 mmol) and 1.50
equivalents of K2CO3 (207 mg, 1.5 mmol) were dissolved in aceto-
nitrile and stirred for 2 d at room temperature. After filtering off the
precipitate and removing the solvent under reduced pressure the
obtained sticky white solid was washed with pentane (2 ꢁ 20 mL)
and diethyl ether (2 ꢁ 20 mL) to yield a white powder (396 mg,
0.731 mmol, 73.1% yield).
1,3-Bis-(4-methoxycarbonylbenzyl)-4,5-bisphenyl-imidazo-
lium bromide (1d) (500 mg, 0.84 mmol) and 2 equivalents of sil-
ver(I) acetate (279 mg, 1.68 mmol) were dissolved in 30 mL of
dichloromethane and stirred in darkness at room temperature for
2 d. After filtering off the AgBr by-product, the solvent was
reduced to 3 mL and by adding drop wise 10 mL of pentane a white
powder precipitated. The solvent was decanted and the white
precipitate was washed with pentane (2 ꢁ 10 mL) and diethyl
ether (3 ꢁ 10 mL) to yield a white powder (400 mg, 0.58 mmol,
69.1% yield).
1H NMR (
6H, CHanisyl
d
ppm, DMSO, 400 MHz): 11.11 (s, 1H, NCHN), 7.29 (m,
CHbenzyl), 7.15 (dd, 6.6, 2.9 Hz, 4H,
þ
J
¼
CHanisyl þ CHbenzyl), 6.99 (m, 4H, CHanisyl þ CHbenzyl), 6.84 (m, 4H,
CHanisyl þ CHbenzyl), 5.47 (s, 4H, CH2), 3.80 (s, 6H, OCH3).
1H NMR (
d
ppm, CDCl3, 400 MHz): 7.83 (d, J ¼ 8.2 Hz, 4H,
13C NMR (
d ppm, DMSO, 101 MHz): 160.96 (NCN), 137.02, 133.51,
CHphenyl þ CHmethoxycarbonylbenzyl), 7.09 (d, J ¼ 8.1 Hz, 4H, CHphenyl
132.16, 131.97, 129.08, 128.92, 128.46, 116.64, 114.52
(Canisyl þ Cbenzyl), 55.34 (CH2), 51.21 (CH3)
þ
þ
CHmethoxycarbonylbenzyl),
CHmethoxycarbonylbenzyl), 6.82 (d,
CHmethoxycarbonylbenzyl), 6.72 (d,
7.01e6.89
(m,
6H,
8.2 Hz, 4H,
8.2 Hz, 4H,
CHphenyl
J
¼
IR absorptions (KBr, cmꢃ1): 3425 (m), 2949 (s), 2835 (w), 1611
(s), 1506 (s), 1450 (s), 1296 (m), 1254 (s), 1160 (s), 1024 (s), 840 (m),
704 (s).
CHphenyl
þ
J
¼
CHphenyl þ CHmethoxycarbonylbenzyl), 5.34 (s, 4H, CH2), 3.87 (s, 6H,
OCH3), 2.09 (s, 3H, CH3actetate).
MS (m/z, QMS-MS/MS): 461.46 [Mþ ꢃ Brꢃ].
13C NMR (
d
ppm, CDCl3, 101 MHz): 178.90 (NCN), 166.56 (C]
Omethoxycarbonylbenzyl), 160.18 (C]O), 141.16, 132.54, 131.82, 130.00,
129.89, 129.86, 127.20, 119.38, 114.14
Micro Analysis Calculated for C31H29BrN2O2 (541.48): Calcd.: C,
68.76%; H, 5.40%; N, 5.17%; Found: C 67.35%; H, 5.39%; N, 5.00%.
Melting point: 192e194 ꢂC.
(Cphenyl þ Cmethoxycarbonylbenzyl þ Cimidazole), 55.23 (CH2), 52.17
(OCH3methoxycarbonylbenzyl), 22.70 (CH3acetate).
IR absorptions (KBr, cmꢃ1): 3421 (m), 3054 (m), 1724 (s), 1611
(s), 1565 (s), 1435 (s), 1281 (s), 1108 (s), 1018 (s), 751 (s), 701 (s).
MS (m/z, QMS-MS/MS): 517.50 [Mþ ꢃ AgOAc].
2.2.13. 1,3-Bis-(4-methylbenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazolium bromide (3b)
4,5-Bis-(4-methoxyphenyl)-1H-imidazole
(280
mg,
1.00 mmol), equivalents of 4-methylbenzyl bromide (371 mg,
2.00 mmol) and 1.5 equivalents of K2CO3 (207 mg, 1.50 mmol)
were dissolved in acetonitrile and stirred for 2 d at room
temperature. After filtering off the precipitate and removing the
solvent under reduced pressure the obtained sticky white solid
was washed with pentane (2 ꢁ 20 mL) and diethyl ether
(2 ꢁ 20 mL) to yield a white powder (175 mg, 0.31 mmol, 30.7%
yield).
Micro Analysis Calculated for C35H32AgN2O6 (684.51): Calcd.: C,
61.41%; H, 4.71%; N, 4.09%; Found: C, 61.56%; H, 4.60%; N, 3.94%.
Melting point: 204e206 ꢂC.
2.2.10. (1,3-Bis-(4-cyanobenzyl)-4,5-bisphenyl-imidazole-2-
ylidene) silver(I) acetate (2e)
1,3-Bis-(4-cyanobenzyl)-4,5-bisphenyl-imidazolium bromide
(1e) (100 mg, 0.19 mmol) and 2 equivalents of silver(I) acetate
(66 mg, 0.40 mmol) were dissolved in 30 mL of dichloromethane
and stirred in darkness at room temperature for 2 d. After filtering
off the AgBr by-product, the solvent was reduced to 3 mL and by
adding drop wise 10 mL of pentane a white powder precipitated.
The solvent was decanted and the white precipitate was washed
with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL) to yield
a white powder (95.5 mg, 0.15 mmol, 81.3% yield).
1H NMR (
J ¼ 8.3 Hz, 4H, CHanisyl þ CHmethylbenzyl), 7.20 (d, J ¼ 7.6 Hz, 4H,
CHanisyl CHmethylbenzyl), 7.12 (d, 7.6 Hz, 4H, CHanisyl
d ppm, CDCl3, 300 MHz): 11.43 (s, 1H, NCHN), 7.92 (dd,
þ
J
¼
þ CHmethylbenzyl), 6.93 (dd, J ¼ 8.2 Hz, 4H, CHanisyl þ CHmethylbenzyl), 5.58
(s, 4H, CH2), 3.90 (s, 6H, OCH3), 2.33 (s, 6H, CH3acetate).
13C NMR (
d
ppm, CDCl3, 101 MHz): 166.30 (NCHN), 141.02,
137.99, 137.66, 132.29, 130.73, 130.47, 130.29, 129.90, 128.40, 121.32
(Canisyl Cmethylbenzyl), 52.27 (CH2), 50.87 (OCH3), 21.39
1H NMR (
d
ppm, CDCl3, 400 MHz): 7.53 (d, J ¼ 8.0 Hz, 4H,
þ
(CH3methylbenzyl).
CHphenyl þ CHcyanobenzyl), 7.39e7.30 (m, 2H, CHphenyl þ CHcyanobenzyl),
7.30e7.23 (m, 4H, CHphenyl þ CHcyanobenzyl), 7.09 (d, J ¼ 7.9 Hz, 4H,
CHphenyl þ CHcyanobenzyl), 7.03e6.94 (m, 4H, CHphenyl þ CHcyanobenzyl),
5.41 (s, 4H, CH2), 2.07 (s, 3H, CH3acetate).
IR absorptions (KBr, cmꢃ1): 3431 (m), 2956 (w), 2835 (w), 1580
(w), 1575 (s), 1505 (s), 1440 (m), 1253 (s), 1178 (s), 1025 (s), 831 (m),
706 (m).
MS (m/z, QMS-MS/MS): 489.55 [Mþ ꢃ Brꢃ].
Micro Analysis Calculated for C33H33BrN2O2 (569.53): Calcd.: C,
69.59%; H, 5.84%; N, 4.92%; Found: C, 69.90%; H, 5.30%; N, 4.62%.
Melting point: 238e240 ꢂC.
13C NMR (
d ppm, CDCl3, 100 MHz): 206.90 (NCN), 156.54 (C]O),
140.76 (CN), 132.88, 132.55, 130.38, 129.75, 128.93, 128.16, 126.89,
118.18, 112.31 (Cphenyl þ Cimidazole þ Ccyanobenzyl), 53.32 (CH2), 22.91
(CH3acetate).

F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
127
2.2.14. 1,3-Bis-(4-methoxybenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazolium chloride (3c)
1H NMR (
J ¼ 7.9 Hz, 4H, CHanisyl þ CHcyanobenzyl), 7.33 (d, J ¼ 7.9 Hz, 4H,
CHanisyl CHcyanobenzyl), 6.97 (d, 8.8 Hz, 4H, CHanisyl
d ppm, DMSO, 400 MHz): 11.54 (s, 1H, NCHN), 7.55 (d,
4,5-Bis-(4-methoxyphenyl)-1H-imidazole (280 mg, 1.00 mmol),
equivalents of 4-methoxybenzyl chloride (0.24 mL, 2.00 mmol) and
1.5 equivalents of K2CO3 (207 mg, 1.50 mmol) were dissolved in
acetonitrile and refluxed for 5 d. After filtering off the precipitate
and removing the solvent under reduced pressure the obtained
sticky white solid was washed with pentane (2 ꢁ 20 mL) and
diethyl ether (2 ꢁ 20 mL) to yield a white powder (245 mg,
0.44 mmol, 43.9% yield).
þ
J
¼
þ CHcyanobenzyl), 6.84(d, J¼ 8.8 Hz, 4H, CHanisyl þ CHcyanobenzyl), 5.60(s,
4H, CH2), 3.80 (s, 6H, OCH3).
13C NMR (
d ppm, DMSO, 101 MHz): 161.20 (NCHN), 138.22,
137.82, 132.72, 132.07, 131.98, 129.30, 117.97, 115.96, 114.71, 112.90
(Canisyl þ Ccyanobenzyl þ Cimidazole), 55.38 (CH2), 50.81 (CH3anisyl).
IR absorptions (KBr, cmꢃ1): 3420 (m), 3006 (m), 2838 (w), 2229
(s), 1638 (w), 1609 (s), 1558 (m), 1508 (s), 1455 (m), 1416 (m), 1296
(m), 1254 (s), 1178 (s), 1022 (s), 826 (s), 665 (m).
1H NMR (
4H, CHanisyl
d
ppm, CDCl3, 300 MHz): 11.48 (s, 1H, NCHN), 7.11 (m,
CHmethoxybenzyl), 6.99 (m, 4H,
þ
MS (m/z, QMS-MS/MS): 511.48 [Mþ ꢃ Brꢃ].
CHanisyl þ CHmethoxybenzyl), 6.85 (m, 4H, CHanisyl þ CHmethoxybenzyl),
6.78 (m, 4H, CHanisyl þ CHmethoxybenzyl), 5.38 (s, 4H, CH2), 3.81 (s, 6H,
OCH3), 3.76 (s, 6H, OCH3).
Micro Analysis Calculated for C33H27BrN4O2 (591.50): Calcd.: C,
67.01%; H, 4.60%; N, 9.47%; Found: C, 66.89%; H, 4.55%; N, 9.42%.
Melting point: 238e240 ꢂC.
13C NMR (
d ppm, CDCl3, 101 MHz): 160.88 (NCHN), 159.89,
137.52, 132.16, 131.58, 130.22, 125.79, 116.95, 114.50, 114.31
(Canisyl þ Cmethoxybenzyl), 55.34 (CH3anisyl), 55.26 (CH3methoxybenzyl),
50.69 (CH2).
2.2.17. (1,3-Bis-benzyl-4,5-bis-(4-methoxyphenyl)-imidazole-2-
ylidene) silver(I) acetate (4a)
1,3-Bis-benzyl-4,5-bis-(4-methoxyphenyl)-imidazolium
bromide (3a) (100 mg, 0.18 mmol) and 2.1 equivalents of silver(I)
acetate (63 mg, 0.38 mmol) were dissolved in 30 mL of dichloro-
methane and stirred in darkness at room temperature for 2 d. After
filtering off the AgBr by-product, the solvent was reduced to 3 mL
and by adding drop wise 10 mL of pentane a white powder
precipitated. The solvent was decanted and the white precipitate
was washed with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL)
to yield a white powder (60 mg, 0.52 mmol, 51.7% yield).
IR absorptions (KBr, cmꢃ1): 3422 (w), 2930 (m), 2838 (w), 1612
(s),1515 (s),1457 (m),1294 (m),1252 (s),1178 (s),1026 (m), 839 (m).
MS (m/z, QMS-MS/MS): 521.52 [Mþ ꢃ Brꢃ].
Micro Analysis Calculated for C33H33ClN2O4 (557.08): Calcd.: C,
71.15%; H, 5.97%; N, 5.03%; Found: C, 70.74%; H, 5.89%; N, 5.12%.
Melting point: 106e108 ꢂC.
2.2.15. 1,3-Bis-(4-methoxycarbonylbenzyl)-4,5-bis-(4-
methoxyphenyl)-imidazolium bromide (3d)
1H NMR
(d
ppm, CDCl3, 300 MHz): 7.23 (m, 6H,
CHanisyl þ CHbenzyl), 7.01(m, 4H, CHanisyl þ CHbenzyl), 6.90 (m, 4H,
CHanisyl þ CHbenzyl), 6.74 (m, 4H, CHanisyl þ CHbenzyl), 5.29 (s, 4H,
CH2), 3.76 (s, 3H, CH3acetate).
4,5-Bis-(4-methoxyphenyl)-1H-imidazole (280 mg, 1.00 mmol),
equivalents of 4-methoxycarbonylbenzyl bromide (458 mg,
2.00 mmol) and 1.5 equivalents of K2CO3 (207 mg, 1.50 mmol) were
dissolved in acetonitrile and stirred for 3 d at room temperature.
After filtering off the precipitate and removing the solvent under
reduced pressure the obtained sticky white solid was washed with
pentane (2 ꢁ 20 mL) and diethyl ether (2 ꢁ 20 mL) to yield a white
powder (250 mg, 0.38 mmol, 38.0% yield).
13C NMR (
d ppm, CDCl3, 101 MHz): 170.34 (NCN), 159.99 (C]O),
136.40, 132.33, 131.94, 128.90, 128.64, 127.93, 127.33, 119.92, 114.37,
113.98, 55.20 (CH2), 53.55 (OCH3), 22.92 (CH3acetate).
IR absorptions (KBr, cmꢃ1): 3445 (w), 3004 (m), 2953 (w), 1722
(s), 1613 (m), 1559 (m), 1508 (m), 1434 (m), 1281 (s), 1183 (s), 1108
(s), 1018 (m), 821 (m), 754 (m).
1H NMR (
d ppm, DMSO, 400 MHz): 11.37 (s, 1H, NCHN), 7.94 (d,
MS (m/z, QMS-MS/MS): 461.46 [Mþ ꢃ AgOCOCH3].
Micro Analysis Calculated for C33H32AgN2O4 (628.49): Calcd.: C,
63.06%; H, 5.13%; N, 4.46%; Found: C, 63.06%; H, 4.92%; N, 4.36%.
Melting point: 118e122 ꢂC.
J ¼ 8.1 Hz, 4H, CHanisyl þ CHmethoxycarbonylbenzyl), 7.22 (d, J ¼ 8.1 Hz,
4H, CHanisyl þ CHmethoxycarbonylbenzyl), 6.96 (d, J ¼ 8.6 Hz, 4H,
CHanisyl
þ
CHmethoxycarbonylbenzyl), 6.82 (d,
J
¼
8.6 Hz, 4H,
CHanisyl þ CHmethoxycarbonylbenzyl), 5.57 (s, 4H, CH2), 3.90 (s, 6H,
OCH3), 3.79 (s, 6H, OCH3).
2.2.18. (1,3-Bis-(4-methylbenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazole-2-ylidene) silver(I) acetate (4b)
13C NMR (
d ppm, DMSO, 101 MHz): 166.29 (C]O), 161.08
(NCHN), 138.12, 137.47, 132.13, 132.05, 130.64, 130.27, 128.33, 116.23,
114.61 (Canisyl þ Cmethoxycarbonylbenzyl þ Cimidazole), 55.34 (CH2), 52.25
(CH3methoxycarbonylbenzyl), 50.91 (CH3anisyl).
1,3-Bis-(4-methylbenzyl)-4,5-bis-(4-methoxyphenyl)-imidazo-
lium bromide (3b) (100 mg, 0.18 mmol) and 2 equivalents of sil-
ver(I) acetate (63 mg, 0.38 mmol) were dissolved in 30 mL of
dichloromethane and stirred in darkness at room temperature for
2 d. After filtering off the AgBr by-product, the solvent was reduced
to 3 mL and by adding drop wise 10 mL of pentane a white powder
precipitated. The solvent was decanted and the white precipitate
was washed with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL)
to yield a white powder (78 mg, 0.11 mmol, 67.8% yield).
IR absorptions (KBr, cmꢃ1): 3427 (w), 2953 (w), 1721 (s), 1612
(m), 1556 (m), 1507 (m), 1434 (s), 1284 (s), 1180 (s), 1108 (s), 1022
(m), 838 (m), 757 (m), 672 (m).
MS (m/z, QMS-MS/MS): 577.51 [Mþ ꢃ Brꢃ].
Micro Analysis Calculated for C35H33BrN2O6 (657.55): Calcd.: C,
63.93%; H, 5.06%; N, 4.26%; Found: C, 63.52%; H, 4.86%; N, 4.18%.
Melting point: 202e203 ꢂC.
1H NMR (
CHanisyl
d
ppm CDCl3, 400 MHz): 7.91 (d, J ¼ 8.0 Hz, 4H,
þ
CHmethylbenzyl), 7.17e6.94 (m, 8H, CHanisyl
2.2.16. 1,3-Bis-(4-cyanobenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazolium bromide (3e)
þ
CHmethylbenzyl), 6.85 (d,
þ CHmethylbenzyl), 5.37 (s, 4H, CH2), 3.91 (s, 6H, OCH3anisyl), 2.29 (s,
J
¼
7.9 Hz, 4H, CHanisyl
4,5-Bis-(4-methoxyphenyl)-1H-imidazole (280 mg, 1.00 mmol),
2 equivalents of 4-cyanobenzyl bromide (391 mg, 2.00 mmol) and
1.50 equivalents of K2CO3 (207 mg, 1.5 mmol) were dissolved in
acetonitrile and stirred for 2 d at room temperature. After filtering
off the precipitate and removing the solvent under reduced pres-
sure the obtained sticky white solid was washed with pentane
(2 ꢁ 20 mL) and diethyl ether (2 ꢁ 20 mL) to yield a white powder
(286 mg, 0.48 mmol, 48.3% yield).
6H, CH3methylbenzyl), 2.06 (s, 3H, CH3acetate).
13C NMR (
d ppm, CDCl3, 101 MHz): 178.94 (NCN), 166.56 (C]O),
141.14, 139.45, 132.75, 130.35, 129.99, 129.87, 129.40, 127.21, 124.32
(Canisyl þ Cmethylbenzyl þ Cimidazole), 53.30 (CH2), 52.16 (OCH3), 22.73
(CH3acetate), 21.27 (CH3methylbenzyl).
IR absorptions (KBr, cmꢃ1): 3416 (m), 2950 (m), 1724 (s), 1612
(m), 1574 (s), 1435 (m), 1404 (w), 1280 (s), 1182 (m), 1110 (s), 1018
(m), 822 (w), 753 (m), 669 (m).

128
F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
MS (m/z, QMS-MS/MS): 489.55 [Mþ ꢃ AgOCOCH3].
silver(I) acetate (61 mg, 0.36 mmol) were dissolved in 30 mL of
dichloromethane and stirred in darkness at room temperature for
2 d. After filtering off the AgBr by-product, the solvent was reduced
to 3 mL and by adding drop wise 10 mL of pentane a white powder
precipitated. The solvent was decanted and the white precipitate
was washed with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL)
to yield a white powder (104 mg, 0.16 mmol, 90.4% yield).
Micro Analysis Calculated for C35H36AgN2O4 (656.54): Calcd.: C,
64.03%; H, 5.53%; N, 4.27%; Found: C, 63.65%; H, 5.03%; N, 3.90%.
Melting point: 155e156 ꢂC.
2.2.19. (1,3-Bis-(4-methoxybenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazole-2-ylidene) silver(I) acetate (4c)
1,3-Bis-(4-methoxybenzyl)-4,5-bis-(4-methoxyphenyl)-imida-
zolium chloride (3c) (100 mg, 0.18 mmol) and 2.1 equivalents of
silver(I) acetate (63 mg, 0.38 mmol) were dissolved in 30 mL of
dichloromethane and stirred in darkness at room temperature for
7 d. After filtering off the AgBr by-product, the solvent was reduced
to 3 mL and by adding drop wise 10 mL of pentane a white powder
precipitated. The solvent was decanted and the white precipitate
was washed with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL)
to yield a white powder (70 mg, 0.10 mmol, 56.7% yield).
1H NMR (
CHanisyl CHcyanobenzyl), 7.11 (d,
d
ppm, CDCl3, 300 MHz): 7.54 (d, J ¼ 8.2 Hz, 4H,
þ
J
¼
8.2 Hz, 4H, CHanisyl
þ CHcyanobenzyl), 6.89 (d, J ¼ 8.2 Hz, 4H, CHanisyl þ CHcyanobenzyl), 6.77
(d, J ¼ 8.2 Hz, 4H, CHanisyl þ CHcyanobenzyl), 5.37 (s, 4H, CH2), 3.77 (s,
3H, OCH3), 2.07 (s, 3H, CH3acetate).
13C NMR (
d ppm, CDCl3, 101 MHz): 179.16 (NCN), 160.40 (C]O),
141.05 (CN), 132.60, 132.55, 131.74, 130.78, 128.12, 118.95, 118.24,
114.33, 112.23 (Canisyl þ Ccyanobenzyl þ Cimidazole), 55.28 (CH2), 53.19
(CH3anisyl), 22.75 (CH3acetate).
1H NMR (
CHanisyl
d
ppm, CDCl3, 300 MHz): 6.93 (t, J ¼ 8.5 Hz, 8H,
IR absorptions (KBr, cmꢃ1): 3415 (w), 2964 (w), 2927 (w), 2228
(s), 1662 (w), 1609 (m), 1574 (m), 1506 (s), 1402 (m), 1253 (s), 1177
(s), 1025 (m), 834 (m).
þ
CHmethoxybenzyl), 6.86e6.62 (m, 8H, CHanisyl
þ CHmethoxybenzyl), 5.21 (s, 4H, CH2), 3.77 (d, J ¼ 1.5 Hz, 12H,
CH3anisyl þ CH3methoxybenzyl), 2.10 (s, 3H, CH3acetate).
MS (m/z, QMS-MS/MS): 511.45 [Mþ ꢃ AgOCOCH3].
Micro Analysis Calculated for C35H30AgN4O4 (678.51): Calcd.: C,
61.96%; H, 4.46%; N, 8.26%; Found: C, 62.23%; H, 4.19%; N, 8.16%.
Melting point: 149e152 ꢂC.
13C NMR (
d ppm, CDCl3, 101 MHz): 178.85 (NCN), 159.95 (C]O),
133.51, 133.02, 132.00, 128.93, 128.50, 128.38, 127.76, 127.24, 120.11,
113.97 (Canisyl þ Cmethoxybenzyl þ Cimidazole), 55.24 (CH2), 55.21
(OCH3anisyl), 53.04 (OCH3methoxybenzyl), 22.95 (CH3acetate).
IR absorptions (KBr, cmꢃ1): 3417 (w), 2954 (w), 2929 (w), 1611
(m), 1580 (m), 1513 (s), 1439 (m), 1403 (w), 1291 (m), 1252 (s), 1176
(s), 1027 (s), 835 (m).
2.3. Antibacterial studies
The silver(I) acetate complexes were screened in preliminary
in vitro antibacterial tests against two bacterial strains. The test
organisms included Staphylococcus aureus (S. aureus) (NCTC 7447)
as a Gram-positive bacteria and Escherichia coli (E. coli) as Gram-
negative bacteria.
MS (m/z, QMS-MS/MS): 521.52 [Mþ ꢃ AgOCOCH3].
Micro Analysis Calculated for C35H36AgN2O6 (688.54): Calcd.: C,
61.05%; H, 5.27%; N, 4.07%; Found: C, 62.00%; H, 5.26%; N, 4.01%.
Melting point: 119e122 ꢂC.
To assess the biological activity of compounds 2aee and 4aee,
the qualitative KirbyeBauer disk-diffusion method was applied
[23]. All bacteria were individually cultured from a single colony in
sterile LB medium [24] overnight at 37 ꢂC in an orbital shaker
incubator. All the work carried out was performed under sterile
conditions.
For each strain, 70 mL of culture were spread evenly on agar-LB
medium. Four 5 mm diameter Whatman paper discs were placed
evenly separated on each plate. Two stock solutions (9:1 DMSO/
2.2.20. (1,3-Bis-(4-methoxycarbonylbenzyl)-4,5-bis-(4-
methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4d)
1,3-Bis-(4-methoxycarbonylbenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazolium bromide (3d) (100 mg, 0.15 mmol) and 2 equivalents of
silver(I) acetate (53 mg, 0.32 mmol) were dissolved in 30 mL of
dichloromethane and stirred in darkness at room temperature for
2 d. After filtering off the AgBr by-product, the solvent was reduced
to 3 mL and by adding drop wise 10 mL of pentane a white powder
precipitated. The solvent was decanted and the white precipitate
was washed with pentane (2 ꢁ 10 mL) and diethyl ether (3 ꢁ 10 mL)
to yield a white powder (60 mg, 0.08 mmol, 53.0% yield).
H2O) of every compound were prepared at 2.2
able to test the effect of different concentrations. Each plate was
then tested with 5 L and 7 L of 2.2 M solution and 5 L and 10
for the 4.4 M solution. The plates were covered and placed in an
mM and 4.4 mM to be
m
m
m
m
mL
1H NMR (
d
ppm, CDCl3, 300 MHz): 7.92 (d, J ¼ 8.2 Hz, 4H,
m
CHanisyl þ CHmethoxycarbonylbenzyl), 7.06 (d, J ¼ 8.3 Hz, 4H, CHanisyl
incubator at 37 ꢂC for 24 h. The plates were then removed and the
area of clearance, which is defined as the distance between the
edge of the filter paper disc and the beginning of the bacterial
growth, was measured for each sample in mm.
þ
þ
CHmethoxycarbonylbenzyl), 6.87 (d,
J
¼
8.7 Hz, 4H, CHanisyl
8.7 Hz, 4H,
CHmethoxycarbonylbenzyl), 6.73 (d,
J
¼
CHanisyl þ CHmethoxycarbonylbenzyl), 5.36 (s, 4H, CH2), 3.91 (s, 6H, OCH3),
3.75 (s, 6H, OCH3), 2.06 (s, 3H, CH3acetate).
13C NMR (
d
ppm, CDCl3, 101 MHz): 178.90 (NCN), 166.56
2.4. Cytotoxicity studies
(C¼Omethoxycarbonylbenzyl), 160.18 (C]O), 141.16, 132.54, 131.82,
130.00, 129.89, 129.86, 127.20, 119.38, 114.14 (Canisyl
þ Cmethoxycarbonylbenzyl þ Cimidazole), 55.23 (CH2), 53.34 (OCH3anisyl),
52.17 (OCH3methoxycarbonylbenzyl), 22.70 (CH3acetate).
Preliminary in vitro cell tests were performed on the human
cancerous renal cell line Caki-1 and the human cancerous breast
cell line MCF-7 in order to compare the cytotoxicity of the
compounds presented in this paper. These cell lines were chosen
based on their regular and long-lasting growth behaviour. The cells
were obtained from the ATCC (American Tissue Cell Culture
Collection) and maintained in Dulbecco’s Modified Eagle Medium
containing 10% (v/v) FCS (fetal calf serum), 1% (v/v) penicillin
IR absorptions (KBr, cmꢃ1): 3434 (w), 2951 (m),1723 (s),1587 (m),
1506 (m),1434 (s),1280 (s),1253 (s),1179 (s),1109 (s),1024 (s), 837 (s).
MS (m/z, QMS-MS/MS): 577.51 [Mþ ꢃ AgOCOCH3].
Micro Analysis Calculated for C37H36AgN2O8 (744.56): Calcd.: C,
59.69%; H, 4.87%; N, 3.76%; Found: C, 58.95%; H, 4.53%; N, 3.53%.
Melting point: 145e146 ꢂC.
streptomycin and 1% (v/v)
well plates containing 200
5000-cells/200
L of medium and were incubated at 37 ꢂC for 24 h
L-glutamine. Cells were seeded in 96-
mL microtitre wells at a density of
2.2.21. (1,3-Bis-(4-cyanobenzyl)-4,5-bis-(4-methoxyphenyl)-
imidazole-2-ylidene) silver(I) acetate (4e)
1,3-Bis-(4-cyanobenzyl)-4,5-bis-(4-methoxyphenyl)-imidazo-
lium bromide (3e) (100 mg, 0.17 mmol) and 2.1 equivalents of
m
to allow for exponential growth. Then the compounds used for the
testing were dissolved in the minimal amount of DMSO (dime-
thylsulfoxide) possible and diluted with medium to obtain stock

F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
129
solutions of 5 ꢁ 10ꢃ4 M in concentration and less than 0.7% of
DMSO. The cells were then treated with varying concentrations of
the compounds and incubated for 48 h at 37 ꢂC. Then, the solutions
were removed from the wells and the cells were washed with PBS
(phosphate buffer solution) and fresh medium was added to the
wells. Following a recovery period of 24 h incubation at 37 ꢂC,
bisphenyl-1H-imidazolium bromide (1e) were synthesised by
stirring (1) with 2 equivalents of 4-methylbenzyl bromide, 4-
methoxybenzyl chloride, 4-methoxycarbonylbenzyl bromide
and 4-cyanobenzyl bromide with 1.5 equivalents of K2CO3 in
acetonitrile for 2e5 d at room temperature to yield the N-
heterocyclic carbene ligand precursors in 88.7, 43.3, 72.2 and
81.0%, respectively. The 4,5-bis-(4-methoxyphenyl)-imidazole
containing precursors 1,3-bis-benzyl-4,5-bis(4-methoxyphenyl)-
1H-imidazolium bromide (3a), 1,3-bis-(4-methylbenzyl)-4,5-
bis(4-methoxyphenyl)-1H-imidazolium bromide (3b), 1,3-bis-(4-
individual wells were treated with 200 mL of a solution of MTT (3-
(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) in
medium. The solution consisted of 22 mg of MTT in 40 mL of
medium. The cells were incubated for 3 h at 37 ꢂC. The medium was
then removed and the purple formazan crystals were dissolved in
methoxybenzyl)-4,5-bis(4-methoxyphenyl)-1H-imidazolium
chlo-
200
m
L DMSO per well. For all tests cells with low passage numbers
ride (3c), 1,3-bis-(4-methoxycarbonyl-benzyl)-4,5-bis(4-methoxy-
phenyl)-1H-imidazolium bromide (3d) and 1,3-bis-(4-cyanobenzyl)-
4,5-bis(4-methoxyphenyl)-1H-imidazolium bromide (3e) followed
the same reaction route to give the respective yields of 35.3, 98.6, 38.0,
38.0 and 50.1%.
were used. A Wallac Victor (Multilabel HTS Counter) Plate Reader
was used to measure absorbance at 540 nm. Cell viability was
expressed as a percentage of the absorbance recorded for control
wells. The values used for the dose response curves represent the
values obtained from four consistent MTT-based assays for each
compound tested.
The silver(I) acetate complex 2a was synthesised according to
[13] to give a yield of 70.7%. In the absence of light, the silver(I)
acetate complexes (1,3-bis(4-methylbenzyl)-4,5-bisphenyl-imid-
azole-2-ylidene) silver(I) acetate (2b), (1,3-bis(4-methoxybenzyl)-
4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2c), (1,3-
bis(4-methoxycarbonylbenzyl)-4,5-bisphenyl-imidazole-2-ylidene)
silver(I) acetate (2d) and (1,3-bis(4-cyanobenzyl)-4,5-bisphenyl-
imidazole-2-ylidene) silver(I) acetate (2e) were prepared by stir-
ring the respective precursor with 2 equivalents of silver(I) acetate
in dichloromethane at room temperature for 3e7 d. The silver
complexes were obtained in 81.0, 63.4, 81.7, 69.1 and 81.3% yield
respectively. The synthesis of the symmetric 4,5-bis(4-
methoxyphenyl)-imidazole silver(I) acetate complexes were
carried out under the same conditions to give the silver(I) acetate
complexes (1,3-bisbenzyl-4,5-bis(4-methoxyphenyl)-imidazole-2-
ylidene) silver(I) acetate (4a), (1,3-bis(4-methylbenzyl)-4,5-bis(4-
methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4b), (1,3-
bis(methoxybenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-
ylidene) silver(I) acetate (4c), (1,3-bis(methoxycarbonylbenzyl)-
3. Results and discussion
In Scheme
1 the synthetic routes for the symmetric
substituted N-heterocyclic carbene ligand precursors as well as
their corresponding silver(I) acetate complexes are given. The
initial precursor 4,5-bisphenyl-1H-imidazole (1) was purchased
from Sigma Aldrich and used without further purification,
whereas the precursor 4,5-bis-(methoxyphenyl)-1H-imidazole
(3) was prepared by stirring 2-bis-(4-methoxyphenyl)ethane-1,2-
dione with formamide according to literature [22]. 1,3-Bis-
benzyl-4,5-bisphenyl-1H-imidazolium
prepared according to literature [13] with a yield of 66.2% while
1,3-bis-(4-methylbenzyl)-4,5-bisphenyl-1H-imidazolium bromide
(1b),
bromide
(1a)
was
1,3-bis-(4-methoxybenzyl)-4,5-bisphenyl-1H-imidazolium
chloride (1c), 1,3-bis-(4-methoxycarbonyl-benzyl)-4,5-bisphenyl-
1H-imidazolium bromide (1d) and 1,3-bis-(4-cyanobenzyl)-4,5-
Scheme 1. General reaction scheme for the synthesis of symmetric substituted NHC precursors 1aee, 3aee and their corresponding NHC-silver(I) acetate complexes 2aee and
4aee.

130
F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate
(4d) and (1,3-bis(4-cyanobenzyl)-4,5-bis(4-methoxyphenyl)-imid-
azole-2-ylidene) silver(I) acetate (4e) in 51.7, 67.8, 56.7, 53.0 and
90.4% yields.
The symmetric substituted N-heterocyclic carbene ligand
precursors as well as the silver(I) acetate complexes were fully
characterized by spectral (1H NMR, 13C NMR, IR, mass), elemental
analysis studies and melting point determination.
C14
C23
C13
C15
O3
C32
C22
C24
C19
C33
C30
C12
C11
C16
C21
C17
C18
C31
O4
C29
C28
C20
C26
C9
C1
N1
Furthermore the solid state structure of the silver(I) acetate
complexes 2d, 2e and 4c was determined by single crystal X-ray
diffraction.
N2
Ag
C27
C25
C6
C2
C10
C5
C3
Due to the positive charge of the molecule, the 1H NMR spectra
of all NHC precursors 1aee and 3aee show a characteristic
C4
O6
C34
C7
downfield shift in the range
d
¼ 9.63e11.65 ppm for the NCHN
O1
C8
O2
O5
proton [25e27]. In addition, their identities have also been
confirmed by a base peak for the [Mþ ꢃ Br] fragments in their
positive mode ESI mass spectra. A successful formation of the
complexes 2aee and 4aee is indicated by the absence of a down-
field NCHN signal and presence of new signals at 3.76e2.06 ppm for
the acetate protons in all the 1H NMR spectra. The 13C NMR reso-
nances of the carbene carbon atoms in complexes 2aee and 4aee
C35
Fig. 1. X-ray diffraction structure of 2d; thermal ellipsoids are drawn on the 50%
probability level.
occur in the range
d 206.90e170.34 ppm respectively. These
agree very well with previously reported examples of this
compound class [12e17] and show that the silver is strongly
bonded to the carbene. The bond length of the silver(I) atom to the
acetate oxygen is in all three structures relatively short with
AgeO(5) ¼ 2.1013(16) Å (2d) and AgeO(1) ¼ 2.1164(13) Å (2e)
compared to the ones our group previously reported, but still within
range of the corresponding ones in similar molecules (see for
example Refs. [26,27]). This short distance suggests a predominantly
covalent character of the AgeO bond. In the NHC silver(I) acetate
complex 4c (Figs. 3 and 4), one of the two silver atoms (Ag(2))
coordinates to two acetate groups. One can see an almost linear
bond angle of 173.89(7)ꢂ at the two coordinate silver atom
C(9)eAg(1)eO(5). The C(44)eAg(2)eO(11) bond angle is with
167.77(7) bent a bit more, and the displacement of Ag(2) from the
line C(44)eO(11) is towards O(6) (Fig. 4). This, together with the
Ag(I)eO(6) distance of 2.6279(16) Å, suggests a weak bond between
the two atoms.
signals are shifted downfield compared to the corresponding
precursors of 1aee and 3aee carbene carbons resonance at the
range 166.30e138.26 ppm respectively which further demon-
strates the formation of expected NHC-silver(I) acetate complexes.
Also the appearance of the 13C NMR resonances for the carbonyl
and methyl carbons of the acetate group of complexes 2aee and
4aee in the range 166.56e156.23 and 22.95e22.70 ppm respec-
tively show the formation of the NHC-silver(I) acetate complexes
[4,6]. Furthermore, positive mode ESI mass spectra of all ten NHC-
silver(I) acetate complexes (2aee, 4aee) are dominated by
[Mþ ꢃ O2CCH3] fragment peaks arising from the loss of one acetate
ligand. The melting points of the NHC precursors 1aee range
between 220 and 293 ꢂC with the only exception for the chloride
containing precursor 1c, which melting point occurs at a lower
temperature (192e194 ꢂC). The same pattern is observed in the
melting points of 3aee where the bromide containing precursors
exhibit much higher melting points (192e240 ꢂC) than the corre-
spondent chloride containing precursor 3c (106e108 ꢂC). The
formation of the silver acetate complexes has a significant influence
on the thermal stability of the compounds and leads to lower
melting points of 144e209 ꢂC for 2aee and 118e156 ꢂC for 4aee.
Overall the thermal stability of the 4,5-bisphenyl-imidazole
compounds is higher than their correspondent 4,5-bis(4-
methoxyphenyl) substituted imidazole analogues.
N4
C21
C20
C22
C31
C27
C28
C23
C18
C19
C26
C24
C29
3.1. Structural discussion
C15
C16
C30
C25
C17
C14
C11
The crystals of 2d and 2e (Figs. 1 and 2) were formed in a satu-
rated solution of chloroform with slow infusion of pentane, while
the crystal of 4c was grown in a saturated solution of dichloro-
methane with slow infusion of pentane. 2d crystallized in the
triclinic space group P-1, 2e in the monoclinic space group C2/c
(#15) and 4c in the triclinic space group P-1 (#2); all in absence of
any solvent molecules. The crystal data and refinements are found
in Table 1, whereas selected bond lengths and bond angles are
compiled in Table 2. The X-ray structures show that the imidazole
ring is planar and the bond lengths and angles in the five
membered imidazole ring (NCNCC) are in good agreement with
those in similar compounds reported earlier by our group [12e17].
The crystal structure of 2d and 2e showa nearlylinear bond angle
of 178.76(7)ꢂ and 174.69(5)ꢂ respectively at the two-coordinated
silver atom. The bond distances of the silver atom to the carbene
of AgeC(10) ¼ 2.060(2) Å (2d) and AgeC(9) ¼ 2.0588(17) Å (2e)
N3
C10
C8
C13
C12
C5
C9
N2
Ag
C6
C1
O1
C32
C33
C4
O2
C2
C3
C7
N1
Fig. 2. X-ray diffraction structure of 2e; thermal ellipsoids are drawn on the 50%
probability level.

F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
131
Table 2
Selected bond lengths [Å] and angles [ꢂ] for 2d, 2e and 4c.
2d
Bond length [Å]
2e
Bond length [Å]
4c
Bond length [Å]
AgeC(10)
AgeO(5)
2.060(2)
2.1013(16)
1.350(3)
1.398(3)
1.348(3)
1.396(3)
1.359(3)
AgeC(9)
AgeO(1)
2.0588(17)
2.1164(13)
1.350(2)
1.392(2)
1.351(2)
1.397(2)
1.361(2)
Ag(I)eC(9)
Ag(I)eO(5)
N(1)eC(9)
2.087(2)
2.1582(14)
1.350(3)
1.348(3)
1.399(3)
1.360(3)
1.393(3)
2.1197(16)
2.073(2)
2.6279(16)
N(1)eC(10)
N(1)eC(11)
C(10)eN(2)
C(18)eN(2)
C(11)eC(18)
N(2)eC(9)
N(2)eC(10)
C(9)eN(3)
C(17)eN(3)
C(10)eC(17)
C(9)eN(2)
N(1)eC(10)
C(10)eC(18)
C(18)eN(2)
Ag(2)eO(11)
Ag(2)eC(44)
O(6)eAg(2)
2d
Bond angle [ꢂ]
178.76(7)
2e
Bond angle [ꢂ]
174.69(5)
4c
Bond angle [ꢂ]
173.89(7)
104.90(17)
126.78(14)
127.84(14)
105.95(18)
106.49(18)
111.34(17)
104.32(6)
84.95(6)
108.72(13)
109.57(13)
124.3(2)
119.7(2)
116.0(2)
C(10)eAgeO(5)
N(2)eC(10)eN(1)
N(2)eC(10)eAg
N(1)eC(10)eAg
C(18)eC(11)eN(1)
C(11)eC(18)eN(2)
C(10)eN(2)eC(18)
C(9)eAgeO(1)
N(2)eC(9)eN(3)
N(2)eC(9)eAg
N(3)eC(9)eAg
C(17)eC(10)eN(2)
C(10)eC(17)eN(3)
C(9)eN(3)eC(17)
C(9)eAg(1)eO(5)
N(2)eC(9)eN(1)
N(2)eC(9)eAg(1)
N(1)eC(9)eAg(1)
C(18)eC(10)eN(1)
C(10)eC(18)eN(2)
C(9)eN(2)eC(18)
C(44)eAg(2)eO(6)
O(11)eAg(2)eO(6)
C(34)eO(5)eAg(1)
C(34)eO(6)eAg(2)
O(6)eC(34)eO(5)
O(6)eC(34)eC(35)
O(5)eC(34)eC(35)
C(69)eO(11)eAg(2)
O(12)eC(69)eO(11)
O(12)eC(69)eC(70)
O(11)eC(69)eC(70)
104.73(17)
125.82(15)
129.43(15)
106.31(18)
105.99(18)
111.67(17)
104.39(14)
128.09(12)
127.21(12)
106.44(14)
105.76(14)
111.75(13)
C(34)eO(5)eAg
111.11(13)
C(32)eO(1)eAg
107.66(12)
O(6)eC(34)eO(5)
O(6)eC(34)eC(35)
O(5)eC(34)eC(35)
124.3(2)
120.5(2)
115.27(19)
O(2)eC(32)eO(1)
O(2)eC(32)eC(33)
O(1)eC(32)eC(33)
123.60(18)
119.80(17)
116.61(17)
119.64(14)
125.7(2)
119.3(2)
115.01(19)
3.2. Biological evaluation
3.2.1. Antibacterial testing
bisbenzyl-4,5-bisphenyl imidazole-2-ylidene) silver(I) acetate 2a,
that would exhibit greater antimicrobial properties than this leading
compound against E. coli and S. aureus bacteria strains.
Using the KirbyeBauer disk diffusion method, the antibacterial
activity of the NHC-silver acetate complexes was tested and sum-
marised in Figs. 5e8. The metal salt (silver(I) acetate) used to
prepare the complexes and the solvent (DMSO) used to prepare the
stock solutions played no role in growth inhibition on the same
bacteria as previously reported [28,29]. An area of clearance of 0 mm
was considered as no activity, areas of 1e3 mm as low, 4e7 mm as
medium, and areas of clearance ꢅ8 mm as high activity. The primary
aim was to synthesise a derivative of the target molecule (1,3-
Almost no antibacterial activity against E. coli was found for the
compounds 4be4d, and against S. aureus nearly no activity was
found for 2e and 4d. Medium activity against E. coli was found only
for two bisphenyl-imidazole silver complexes (2d, 6 mm; 2e,
O5
O3
O11
O12
C25
C33
C23
C22
C21
O6
2.628(7)
O2A
Ag1
C15A
O4
Ag2
C30
C17A
C31
C24
C19
C16A
C11
C14A
C20
C10
C32
C29
C18
C13A
C28
C27
N2
C12A
C26
N1
C8
C9
C6
O6
C5
Ag1
C4
C1
C34
C2
C3
C7
O5
C35
O1
Fig. 4. Interaction between two adjacent molecules via a short Ag/O contact; thermal
ellipsoids are drawn on the 50% probability level, aryl groups are represented by their
ipso carbons only.
Fig. 3. X-ray diffraction structure of 4c; thermal ellipsoids are drawn on the 50%
probability level, disorder neglected.

132
F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
Fig. 5. Area of clearance on Escherichia coli (Gram ꢃve) by 2aee.
Fig. 8. Area of clearance on Staphylococcus aureus (Gram þve) by 4aee.
respectively. All compounds were well soluble in DMSO and stable
in the biological medium over the period of the testing time.
As well as for the antibacterial studies (see above), all IC50 cell
test results were compared to our previously reported complex 2a,
which has shown to have an IC50 value against the human renal
cancer cell line Caki-1 of 14 (ꢀ1)
mM [13]. Unfortunately all 4,5-bis-
(methoxyphenyl)-imidazole silver acetates 4aee exhibited lower
cytotoxic activity against this cell line with 21 (ꢀ1), 21 (ꢀ2), 21
(ꢀ1), 34 (ꢀ2) and 46 (ꢀ2)
mM, respectively. In contrast to this the
4,5-bisphenyl-imidazole silver acetates 2bee have shown partial
improvement in cytotoxic activity against Caki-1. Compounds 2b
and 2c both show a 3e4 fold increase in biological activity and
exhibit therefore IC50 values of 3.6 (ꢀ1) and 4.2 (ꢀ0.5)
2e show like their analogues 4d and 4e a significant lower activity
M. The strong decrease in
mM. 2d and
with IC50 values of 33 (ꢀ2) and 59(ꢀ4)
m
activity in these complexes might be due to the introduction of the
more hydrophilic 4-cyanobenzyl (2d and 4d) and 4-
methoxycarbonylbenzyl (2e and 4e) groups in position 1 and 3 of
the imidazole. The overall tendency seems to be that the 4,5-
bisphenyl substitution is superior to its 4,5-bisanisyl counterpart
with respect to cytotoxicity.
The log dose response curves for complexes 2aee and 4aee
against the cancer cell line MCF-7 are shown in Figs. 11 and 12,
respectively.
Fig. 6. Area of clearance on Escherichia coli (Gram ꢃve) by 4aee.
7 mm), whereas more complexes were active in this range against
S. aureus (2a, 7 mm; 2b, 5 mm, 2d, 4 mm and 4c, 5 mm).
Only compounds 2c and 4a, showed slightly higher activity
against S. aureus compared to 2a.
3.3. Cytotoxicity studies
1.2
1.0
0.8
0.6
The log dose response curves for complexes 2aee and 4aee
against the cancer cell line Caki-1 are shown in Figs. 9 and 10,
2a, IC50 = 14 (+/- 1) 10-6
M
2b, IC50 = 3.6 (+/- 1.0) 10-6
2c, IC50 = 4.2 (+/- 0.5) 10-6
M
M
0.4
0.2
0.0
2d, IC50 = 33 (+/- 2) 10-6
2e, IC50 = 59 (+/- 4) 10-6
M
M
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
Log10 drug concentration
Fig. 9. Cytotoxicity curves from typical MTT assays showing the effect of compounds
2aee on the viability of Caki-1 cells.
Fig. 7. Area of clearance on Staphylococcus aureus (Gram þve) by 2aee.

F. Hackenberg et al. / Journal of Organometallic Chemistry 717 (2012) 123e134
133
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.2
1.0
0.8
4a, IC50 = 21 (+/- 1) 10-6
4b, IC50 = 21 (+/- 2) 10-6
4c, IC50 = 21 (+/- 1) 10-6
4d, IC50 = 34 (+/- 2) 10-6
M
4a, IC50 = 11 (+/- 2) 10-6
M
0.6
0.4
0.2
0.0
M
M
M
M
M
4b, IC50 = 5.0 (+/- 0.3) 10-6
4c, IC50 = 6.5 (+/- 0.4) 10-6
M
M
4d, IC50 = 17 (+/- 1) 10-6
4e, IC50 = 13 (+/- 1) 10-6
M
4e, IC50 = 46 (+/- 2) 10-6
M
-6
-6
2a, IC = 14 (+/- 1) 10
50
2a, IC = 5.8 (+/- 0.6) 10
50
M
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
Log10 drug concentration
Log10 drug concentration
Fig. 10. Cytotoxicity curves from typical MTT assays showing the effect of compounds
4aee on the viability of Caki-1 cells.
Fig. 12. Cytotoxicity curves from typical MTT assays showing the effect of compounds
4aee on the viability of MCF-7 cells.
4. Conclusion and outlook
In comparison to the cell test results against the human renal
cancer cell line Caki-1 (see above), not only 4,5-bisphenyl-imid-
azole silver acetates 2b and 2c exhibited comparable or better IC50
These newly synthesised N-heterocyclic carbene silver acetate
complexes derived from 4,5-diaryl-imidazole have shown some
promising cytotoxic results against the human cancer cell lines
Caki-1 and MCF-7; the cytotoxicity is already comparable to
platinum-based drugs on these specific cell lines. In addition,
significant antibacterial activity against E. coli and S. aureus were
observed but the level of conventional antibiotics was not reached
yet for the derivatives described. Most promising results were ob-
tained for complexes 2b and 2c against both cancer cell lines as well
as against both bacterial strains.
Further studies on the influence of more hydrophilic and
hydrophobic substitution patterns of the imidazole ring on the
cytotoxicity and antibacterial properties of such complexes are in
progress; in future experiments the mode of action of the NHC-silver
acetate complexes and their toxicity in vivo will be investigated.
values (3.5 (ꢀ0.4) and 5.4 (ꢀ0.3)
mM) against this cell line, but also
the two 4,5-bis(methoxyphenyl)-imidazole silver acetates 4b and
4c have shown a good level of activity with values of 5.0 (ꢀ0.3) and
6.5 (ꢀ0.4)
mM.
Interestingly, the substitution pattern in position 1 and 3 of the
imidazole ring seems to play an overall big role in the cytotoxic
activity of these ten new symmetrical substituted NHC silver
acetate complexes. While all four more hydrophilic substituted
complexes 2d, 2e, 4d and 4e show moderate biological activity
against both human cancer cell lines, good activity is found for 2b
and 2c against Caki-1 and MCF-7 and for 4b and 4c against MCF-7
alone. The difference in activity against Caki-1 comparing
complexes 2b and 2c versus 4b and 4c must be directly related to
the change from a proton in position 4 on the phenyl rings to
a methoxy group instead. The therefore more hydrophilic substi-
tution pattern seems to have a direct impact on either the cellular
uptake or the interaction in the cell itself.
Acknowledgement
This project was funded by the UCD School of Chemistry and
Chemical Biology.
1.2
1.0
0.8
0.6
Appendix A. Supplementary material
CCDC 881255, 881256 and 881257 contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2a, IC50 = 5.8 (+/- 0.6) 10-6
2b, IC50 = 3.5 (+/- 0.4) 10-6
2c, IC50 = 5.4 (+/- 0.3) 10-6
M
M
M
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