H. Zetty Zulikha et al. / Inorganica Chimica Acta 411 (2014) 40–47
41
O
N
2.2. Syntheses
O
N
HO
N
N
N
N
N
N
Ag
O
O
Ag
O
O
2.2.1. Synthesis of 3-(2-cyanobenzyl)-1-methylimidazolium
hexafluorophosphate (2)
O
O
A mixture of 2-bromomethylbenzonitrile (0.91 g, 4.6 mmol)
and 1-methylimidazole (0.38 g, 4.6 mmol) was refluxed in 1,4-
dioxane (30 mL) for 20 h. The resulted solution was cooled using
ice bath to get thick brown oil and the solvent was removed by
decantation. The product was then washed with fresh 1,4-diaoxane
(3 ꢀ 3 mL) and so obtained bromide salt 1 was directly converted
into its hexafluorophosphate counterpart by salt metathesis reac-
tion using KPF6 (0.83 g, 4.5 mmol) in methanol (25 mL). Resultant
mixture was stirred for 3 h and was left to stand overnight. White
precipitate thus formed was filtered, washed with distilled water
(3 ꢀ 5 mL) to remove unreacted KPF6, and air dried. Colourless
blocks were obtained by slow evaporation of the salt solution in
acetonitrile at ambient temperature. Yield: 78.6%; M.P: 150.0–
151.0 °C. 1H NMR (500 MHz, d6-DMSO): d 3.90 (3H, s, N-CH3),
5.69 (2H, s, benzonitrilic-CH2), 7.47 (1H, d, Ar–H, J = 8.0 Hz), 7.64
(1H, t, Ar–H, J = 7.25 Hz), 7.77 (2H, t, Ar–H, J = 6.75 Hz), 7.98 (2H,
d, imidazolium H40 and H50, J = 9.0 Hz), and 9.18 (1H, s, imidazoli-
um H20). 13C{1H}NMR (125 MHz, d6-DMSO): d 35.9 (N-CH3), 50.3
(benzonitrilic-CH2), 111.0 (benzonitrile-ArC), 116.8 (nitrile-CN),
122.7, 124.2 (imidazolium C40 and C50), 129.2, 129.6, 133.59,
134.0 (benzonitrile-ArC), 137.3 (benzonitrile-ArC) and 137.4 (imi-
SCC1
SCC8
N
N
O
O
Ag
O
O
N
O
N
Ag
O
O
N
O
N
SBC1
SCC-benzoate
Chart 1. Ag(I)–NHC complexes as antimicrobial/anticancer agents.
groups working on bioorganometallic chemistry of NHC Ag(I)
complexes. On the other hand, a nitrile-functionalized anticancer
drug candidate SBC1 was evaluated for its potential in vitro and
in vivo against many human derived cancer cell lines, which
showed potent activity [9].
While chemists have employed different strategies in the
design and synthesis of novel Ag and Au–NHC-based anticancer
agents; however, their exact mechanisms of action still remain
relatively less explored [10]. These include the more selective
delivery and activation of metal-based drugs/prodrugs to the in-
fected sites and the discovery of novel non-covalent interactions
with the DNA of infected cell. Recently, we have reported a series
of mono- and bis-carbene Ag(I) complexes of imidazole based
NHC ligands and their proven anticancer potential against different
human cancer lines [11,12]. Interestingly, increased anticancer
potentials of complexes were observed when the central azole is
functionalized. We are emphasizing this comparison between
non-functionalized and functionalized compounds where efforts
have been made to identify their biomolecular target especially
in the cancer infected cell and their mode of action. This article
covers imidazole derived Ag(I)–NHC complexes, their design, syn-
thesis, anticancer potential and their comparison in more detail
than our recent papers.
dazolium C20). FTIR (KBr disc) cmꢁ1: 3152, 3121
(C„N), 1637, 1015 (C@N, imidazole). Anal. Calc. for C12H12N3F6-
m(C–H), 2223
m
m
P1: C, 42.0; H, 3.5; N, 12.2. Found: C, 42.0; H, 2.8; N, 12.1%.
2.2.2. Synthesis of bis-[3-(2-Cyanobenzyl)-1-methylimidazolium
silver(I)] bishexafluorophosphate (5)
A solution of the imidazolium salt 2 (0.4 g, 1.2 mmol) and Ag2O
(0.27 g, 1.2 mmol) in acetonitrile (30 mL) was stirred at room tem-
perature for 12 h in glassware wrapped with aluminium foil to ex-
clude light. A solution with black suspension was obtained. The
black suspension was filtered through a pad of celite and the fil-
trate was evaporated to dryness under reduced pressure to afford
complex 5 as grey solid. This solid was further recrystallized with
acetonitrile and left to dry at ambient temperature. Crystals suit-
able for single crystal X-ray diffraction studies were obtained by
slow diffusion of diethyl ether into the complex solution in aceto-
nitrile at room temperature. Yield: 68.6%; M.P: 236.5–237.2 °C. 1H
NMR (300 MHz, d6-DMSO): d 3.77 (3H, s, N-CH3), 5.53 (2H, s, ben-
zonitrilic-CH2), 7.27 (1H, d, Ar–H, J = 8.8 Hz), 7.50 (2H, t, Ar–H,
J = 6.5 Hz), 7.68 (1H, t, Ar–H, J = 6.8 Hz), and 7.87 (2H, d, imidazoli-
um H40 and H50, J = 9.3 Hz). 13C{1H}NMR (75 MHz, d6-DMSO): d
38.7 (N-CH3), 52.9 (benzonitrilic-CH2), 111.4 (benzonitrile-ArC),
118.2 (nitrile-CN), 123.0, 123.5 (imidazolium C40 and C50), 129.8,
130.0, 134.3, 134.5 (benzonitrile-ArC), 141.1 (benzonitrile-ArC)
2. Experimental
2.1. General considerations
All chemicals and solvents were obtained from commercial
sources and used as received without further purification. Imidaz-
ole, 2-bromomethylbenzonitrile, 1-methylimidazole, potassium
hexafluorophosphate, 5-fluorouracil (standard used in anticancer
activity), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoli-
um bromide for the MTT assay were purchased from Sigma–Al-
drich. Synthesis and spectral characterization of the bromide and
hexafluorophosphate salts 3 and 4, and silver complex 8 have been
reported in our earlier papers [13]. NMR spectra were recorded in
d6-DMSO using Bruker 500 MHz Ascend and Bruker Avance
300 MHz spectrometers. Chemical shifts (d) are described in ppm
from TMS as internal reference. Signals are labeled as singlet (s),
doublet (d), triplet (t) and multiplet (m). The melting points of
the reported compounds were assessed by using a Stuart Scientific
SMP-1 (UK) instrument. Elemental analysis was carried out by Per-
kin-Elmer series II, 2400 microanalyzer. The single crystal X-ray
diffraction data of the compounds were collected using a Bruker
SMART APEX2 CCD area-detector diffractometer. Calculations,
structure refinement, molecular graphics and the material for pub-
lication were performed using the SHELXTL and PLATON software
packages.
and 181.7 (C20–Ag). FTIR (KBr disc) cmꢁ1: 3147, 3115
2269 (C„N), 1666, 1042 (C@N, imidazole). Anal. Calc. for C24H22-
m(C–H),
m
m
Ag2N6F12P2: C, 32.0; H, 2.5; N, 9.3. Found: C, 32.4; H, 1.8; N, 9.5%.
2.2.3. Synthesis of 3-(2-cyanobenzyl)-1-methylimidazolium silver(I)
hexafluorophosphate (6)
This compound was prepared in a manner analogous to that for
5, only with aforementioned salt 2 (0.60 g, 1.8 mmol) was added to
the acetonitrile solution (30 mL) of Ag2O (0.20 g, 0.9 mmol) and the
mixture was stirred for 12 h to yield complex 6 as grey solid. Yield:
75.4%; M.P: 176.4–178.0 °C. 1H NMR (500 MHz, d6-DMSO): d 3.77
(3H, s, N-CH3), 5.53 (2H, s, benzonitrilic-CH2), 7.28 (1H, d, Ar–H,
J = 8.0 Hz), 7.50 (2H, t, Ar–H, J = 7.3 Hz), 7.67 (1H, t, Ar–H,
J = 6.3 Hz), and 7.85 (2H, d, imidazolium H40 and H50, J = 9.0 Hz).
13C{1H}NMR (125 MHz, d6-DMSO): d 38.3 (N-CH3), 52.1 (benzoni-
trilic-CH2), 110.6 (benzonitrile-ArC), 117.2 (nitrile-CN), 122.6,
123.3 (imidazolium C40 and C50), 128.7, 128.9, 133.4, 133.7