Tetrameric 1:1 and monomeric 1:3 complexes of silver(I) halides with tri(p-tolyl)-phosphine: A structural and biological study

Article abstract of DOI:10.1016/j.ica.2007.07.034

Silver(I) halides react with tri(p-tolyl)phosphine (tptp, C₂₁H₂₁P) in MeOH/MeCN solutions in 1:1 or 1:3 molar ratios to give complexes of formulae {[AgCl(tptp)]₄} (1) or [AgX(tptp)₃] (X = Cl (2), Br (3), I (4)),

Full text of DOI:10.1016/j.ica.2007.07.034

Available online at www.sciencedirect.com
Inorganica Chimica Acta 362 (2009) 1003–1010
www.elsevier.com/locate/ica
Tetrameric 1:1 and monomeric 1:3 complexes of silver(I) halides
with tri(p-tolyl)-phosphine: A structural and biological study
a
a,
a,
a
Sotiris Zartilas , Sotiris K. Hadjikakou *, Nick Hadjiliadis *, Nikolaos Kourkoumelis ,
a
b
c
c
d
Loukas Kyros , Maciej Kubicki , Martin Baril , Ian S. Butler , Spyros Karkabounas ,
e
Jan Balzarini
a
Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
b
Department of Chemistry, A. Mickiewicz, University, ul. Grunwaldzka 6, 60-780 Poznan, Poland
Department of Chemistry, McGill University, 801 Sherbrooke, Montreal Quebec, Canada H2A 2K6
c
d
Department of Experimental Physiology, Medical School, University of Ioannina 45110 Ioannina, Greece
Katholieke Universiteit Leuven, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium
e
Received 8 March 2007; received in revised form 13 July 2007; accepted 25 July 2007
Available online 9 August 2007
Dedicated to Bernhard Lippert.
Abstract
Silver(I) halides react with tri(p-tolyl)phosphine (tptp, C21H21P) in MeOH/MeCN solutions in 1:1 or 1:3 molar ratios to give
complexes of formulae {[AgCl(tptp)]4} (1) or [AgX(tptp)3] (X = Cl (2), Br (3), I (4)), respectively. The complexes were characterized
1
by elemental analyses, and FT-IR far-IR, FT-Raman, TG and H, 13C, 31P NMR spectroscopic techniques. Crystal structures of com-
plexes 2–4 were determined by X-ray diffraction at room temperature (rt). The crystal structure of 1 and 4 was also determined at 100(1)
and 140(2) K (lt), respectively. In complex 1 four l3-Cl ions are bonded with four Ag(I) ions forming a cubane while the coordination
sphere of silver(I) ions is completed by one P atom from a terminal tri(p-tolyl)phosphine ligand. In complexes 2–3 one terminal halogen
and three P atoms from phosphine ligands form a tetrahedral arrangement around the metal ion. Complexes 1–4 were tested for in vitro
cytostatic activity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, ben-
zo[a]pyrene) carcinogenesis and against murine leukemia (L1210) and human T-lymphocyte (Molt4/C8 and CEM) cells. The silver(I)
complexes 1–4 show strong activity.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: Bioinorganic chemistry; Silver(I) complexes; Tri(p-tolyl)phosphine; Crystal structures; Cytostatic activity
1. Introduction
mers [1]. Especially, the biomedical applications and uses
of silver(I) complexes are related to their antibacterial
action [2], which appears to involve interaction with
DNA [3]. Also, it has been shown that Ag(I) ions extermi-
nate almost instantaneously the microbes by stopping the
thoroughfare of breathing of cells [4]. Recently, Ag(I)
thioamide complexes have been studied for their antitumor
activity [5]. The mechanism of anti-tumor action of Ag(I)
compounds is still unknown. It is well known, however,
that many drugs, which inhibit the growth of tumor cells
act either by interfering with the bases and/or nucleotides
of the double helix of DNA or with the metalloenzymes
The ability of silver(I) complexes to adopt geometries
with variable nuclearities and structural diversity makes
the study of silver(I) chemistry very attractive [1]. Such sil-
ver(I) complexes exhibit a wide range of applications in
medicine, in analytical chemistry or in industry of poly-
*
Corresponding authors. Tel.: +30 26510 98374 (S.K. Hadjikakou), tel.:
+30 26510 98420; fax: +30 26510 98786 (N. Hadjiliadis).
E-mail addresses: shadjika@uoi.gr (S.K. Hadjikakou), nhadjil@uoi.gr
(N. Hadjiliadis).
0020-1693/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2007.07.034

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S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
that are necessary for the rapid growth of malignant cells
[6].
(293(2) K), for comparison but the results were exactly
the same with the ones already published [8e].
The ligand tri(p-tolyl)phosphine was chosen for the prep-
aration of new Ag(I) complexes expected to posses biological
activity. The known phosphine complexes of metal with
applications in medicine is auronofin (tri-ethyl-phosphine-
gold(I) thioglucose (Et3PAuTg)) and its second generation
drug Ridaura TM (tri-ethyl-phosphine (2,3,4,6-tetra-acetyl-
glycopyrasonato-S-)gold(I) (Et3PauSATg)), an extensively
gold(I) anti-arthritic drug in use, which contain phosphine
[2a]. This complex was found to be highly cytostatic to
tumour cells and active against i.p. P388 leukaemia
[7a,7b,7c,7d,7e]. Sadler et.al. [7f], have studied the effect of
auranofin complexes in the growth of Pseudomonas putida.
This paper, reports the synthesis and structural character-
ization of four new silver complexes with tri(p-tolyl)phos-
phine of formulae {[AgCl(tptp)]4} (1); [AgCl(tptp)3] (2);
[AgBr(tptp)3] (3) and [AgI(tptp)3] (4). Complexes 1–4 were
tested for in vitro cytostatic activity against sarcoma cancer
cells (mesenchymal tissue) from the Wistar rat, polycyclic
aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogen-
esis and against murine leukemia (L1210) and human T-lym-
phocyte (Molt4/C8 and CEM) cells.
2.2. Thermal analysis
Thermal analysis in flowing nitrogen shows that com-
plex 1 decomposes with one step at 233–315 ꢁC; with
66.8% endothermic mass loss, which is attributed to the
loss of four ligand molecules. Also the same feature is
observed in thermographs of complexes 3 and 4, which
decomposed at 188–362 ꢁC with 81.3% mass loss of three
ligand molecules in case of 3 and at 200–367 ꢁC with
80.2% mass loss in case of 4.
The thermograph of complex 2, however, shows a two-
step decomposition, one with mass loss of 54.6%, which is
assigned to the loss of two ligand molecules at 200–320 ꢁC
and a second with mass loss of 26.5% of its weight, corre-
sponding to the mass of the third ligand.
2.3. Spectroscopy
2.3.1. Vibrational spectroscopy
The infrared spectra of complexes 1–4; show distinct
vibrational bands at 1097 cmꢂ1 in 1, 1095 cmꢂ1 2,
1095 cmꢂ1 3 and 1092 cmꢂ1 in 4; which were tentatively
assigned to the symmetric vibrations of the m(C–P) bond
[9a] and at 512, 502 cmꢂ1 1; 515, 507 cmꢂ1 2; 515,
507 cmꢂ1 3 and 510, 499 cmꢂ1 4 [9a,9b]; to the anti-sym-
metric vibrations. The corresponding m(C–P) bands of the
free tri-p-tolylphosphine ligand are found at 1089 cmꢂ1
for the symmetric vibration and at 516 cmꢂ1, 505 cmꢂ1
for the anti-symmetric. The slight shifts towards higher fre-
quencies of the symmetric vibrations of the m(C–P) in the
spectra of complexes 1–4 as compared to the corresponding
bands of the free ligand, can be explained either by the shift
of p-electron density from the benzene ring to the unfilled
d-orbitals of the ligand donor atom (phosphorus) or by
the back donation of electron density from the filled d-orbi-
tals of the metal to the vacant d-orbitals of the ligand
through d–d, bonding. Both these tendencies strengthen
the P–C bond and hence instead of a decrease, a slight
increase in v(P–C) is noticed [9a].
2. Results and discussion
2.1. General aspects
The synthesis of complexes 1–4 was carried out in
CH3OH/CH3CN (1:1) [8] according to the reactions shown
below:
CH3OH
AgCl þ ðtptpÞ
f½AgClðtptpÞꢁ4g
ð1Þ
ð2Þ
ð3Þ
ƒƒƒƒƒ!
CH3CN=50 ꢀC
CH3OH
AgCl þ 3ðtptpÞ
AgX þ 3ðtptpÞ
½AgClðtptpÞ3ꢁ
ƒƒƒƒƒƒƒƒ!
CH3CN=80 ꢀC ðrefluxÞ
CH3OH
½AgXðtptpÞ ꢁ
ƒƒƒƒƒ!
3
CH3CN=50 ꢀC
X ¼ Br; I
Metal conductance (Km) values of the complexes in
CH3CN solutions are 1–14 (cmꢂ1 molꢂ1 Xꢂ1) showing that
the complexes are not conducting in solution. The geome-
try around silver(I) ions in all complexes is tetrahedral.
Complex 1 adopts a tetramer cubane configuration, which
consist of Ag–P bridged by l3-Cl atoms, while complexes
2–4 have a monomer tetrahedral structure with the general
formula AgP3X (X = Cl, Br, I). The formulae of complexes
1–4 were first deduced by elemental analyses and spectro-
scopic data. Crystals of the complexes are stable in air
but were kept in darkness. Complexes 1–4 were soluble in
CH3Cl, DMSO, CH3CN and CH3OH.
The crystal structure of complex 4 at 293(2) has been
also reported elsewhere [8e] but we repeat its structure
determination here at 140(2) K in order to investigate the
influence of low temperature in crystal packing. This crys-
tal structure was also re-determined at room temperature
The bands at 186 and 136 cmꢂ1 in case of complex 1; at
172 cmꢂ1 in 2; at 135 cmꢂ1 in 3 and at 125 cmꢂ1 in 4 were
assigned to the vibrations of the Ag–X bonds, respectively
(X = Cl, Br, I) [9c]. The presence of two vibrations for the
Ag–Cl bonds in case of complex 1 is due to the unequal
Ag–Cl bond distances for the l3-Cl bridging atoms in con-
H
H
3
3
2
2
H
H
5
4
1
H
P
H
H
3
Scheme 1.

S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
1005
Fig. 3. Molecular diagram of the crystal structure of complex 3.
Fig. 1. Molecular diagram of the crystal structure of complex 1.
Fig. 4. Molecular diagram of the crystal structure of complex 4.
2.3.2. NMR spectroscopy
1
Fig. 2. Molecular diagram of the crystal structure of complex 2.
The H NMR spectrum of the free ligand tptp (Scheme
1) in CDCl3 solution shows a resonance signal at 2.36 ppm
for the H(C5) protons of the methyl groups and at 7.14
ppm and at 7.27 ppm for the aromatic H(C2) and H(C3)
protons of the ligand, respectively. These last two signals
are shifted at 7.06 ppm in complex 1; at 7.03 ppm in 2; at
7.07 ppm in 3 and 4 indicating coordination of the ligand
to the metal ion.
trast to the terminal chloride ions of the complexes 2–4 (see
crystal structures).
The Raman spectra show vibrational bands at 490 cmꢂ1
for complex 1 and at 502 and 511 cmꢂ1 for 2, which were
assigned as the vibrations of the Ag–P bonds [10a,10b].
The presence of two bands for the Ag–P bond stretching
vibrations in case of complex 2 indicate two unequal Ag–
P bonds in the complex, in accordance with the findings
from TGA-DTA analysis described previously for this
complex.
The 13C NMR spectra of the free ligand shows a peak at
139.24 ppm that is assigned to C1. This peak undergoes the
most significant shifts of all and appears at 140.51 ppm in
1; at 139.55 ppm in 2; at 139.70 ppm in 3 and at

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S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
Table 1
˚
Selected bond lengths (A) and angles (ꢁ) for the compounds 1–4 with e.s.d.’s in parentheses
1 at 293 K
2 at 293 K
3 at 293 K
4 at 293 K
4 at 140 K
Ag1–Cl1
Ag1–Cl2
Ag1–Cl3
Ag2–Cl1
Ag2–Cl2
Ag2–Cl4
Ag3–Cl2
Ag3–Cl3
Ag3–Cl4
Ag4–Cl1
Ag4–Cl3
Ag3–Cl4
Ag1–P1
Ag2–P2
Ag3–P3
Ag4–P4
2.566(8)
2.622(9)
2.735(7)
2.807(8)
2.697(9)
2.526(6)
2.640(8)
2.583(9)
2.780(8)
2.704(6)
2.709(9)
2.780(8)
2.384(8)
2.394(8)
2.394(5)
2.403(10)
Ag1–Cl1
Ag1–P1
Ag1–P2
Ag1–P3
Cl1–Ag1–P1 108.88(5)
Cl1–Ag1–P2 104.17(5)
Cl1–Ag1–P3
P1–Ag1–P2
P1–Ag1–P3
P2–Ag1–P3
2.6186(17) Ag1–Br1
2.5566(12) Ag1–P1
2.5347(11) Ag1–P2
2.5609(11) Ag1–P3
2.7050(6)
Ag1–I1
2.8655(9)
Ag1–I1
2.8736(6)
2.5208(15)
2.5453(15)
2.5444(13)
101.55(4)
112.12(4)
98.57(3)
2.5545(10) Ag1–P1
2.5367(10) Ag1–P2
2.5624(10) Ag1–P3
2.5294(17) Ag1–P1
2.558(2) Ag1–P2
2.5529(17) Ag1–P3
102.37(5)
111.54(5)
99.44(5)
Br1–Ag1–P1 109.39(3)
Br1–Ag1–P2 103.66(3)
I1–Ag1–P1
I1–Ag1–P2
I1–Ag1–P3
P1–Ag1–P2 117.81(6)
P1–Ag1–P3 111.94(6)
P2–Ag1–P3 111.77(6)
I1–Ag1–P1
I1–Ag1–P2
I1–Ag1–P3
P1–Ag1–P2 118.13(5)
P1–Ag1–P3 111.87(5)
P2–Ag1–P3 112.31(5)
99.54(5)
115.89(4)
108.40(4)
118.22(4)
Br1–Ag1–P3
P1–Ag1–P2
P1–Ag1–P3
P2–Ag1–P3
99.95(3)
115.92(4)
108.06(3)
118.25(3)
Cl1–Ag1–Cl2 100.4(3)
Cl1–Ag1–Cl3 94.4(2)
Cl2–Ag1–Cl3 101.3(2)
Cl1–Ag2–Cl2
Cl1–Ag2–Cl4
Cl2–Ag2–Cl4
92.8(3)
92.0(2)
98.5(2)
Cl2–Ag3–Cl3 105.0(2)
Cl2–Ag3–Cl4
Cl3–Ag3–Cl4
Cl1–Ag4–Cl3
Cl1–Ag4–Cl4
93.8(2)
98.3(3)
92.0(2)
93.3(2)
Cl3–Ag4–Cl4 100.3(3)
The 31P NMR spectrum of complex 1 shows one signal
at 4.31 ppm while the spectra of complexes 3 and 4 show
two resonance signals at 1.08 and at 27.05 ppm in case of
3 and at ꢂ4.34 and at 27.11 ppm in case of 4. The presence
of one resonance signal in the case of cubane like complex 1
indicate that the four phosphine ligands are equivalent in
solution. In the case of complexes 3 and 4 with a tetrahe-
dral geometry, however, the two signals observed, suggest
that a ligand exchange equilibrium is established in solu-
tion of these complexes [9d], most probably because of
the high steric effect of the bulky phosphine ligand.
Table 2
Cytostatic activity of complexes 1–4 as 50% inhibitory concentration
(IC50) values against sarcoma cancer cells (mesenchymal tissue) from the
Wistar rat. water molecules
Complex
IC50 (lM)
24 h
48 hrs
72 h
1
2
3
4
0.825
0.650
0.750
0.850
0.750
0.750
0.640
0.800
0.750
0.750
0.750
0.750
Table 3
2.3.3. Crystal and molecular structures of {[AgCl(tptp)]4}
(1), [AgCl(tptp)3] (2), [AgBr(tptp)3] (3) and
[AgI(tptp)3] (4)
Inhibitory effects of complexes 1–4 as 50% inhibitory concentration (IC50
on the proliferation of murine leukemia cells (L1210/0) and human
T-lymphocyte cells (Molt4/C8, CEM/0)
)
Ortep diagrams of complexes 1–4 are shown in Figs. 1–4,
while selected bond lengths and angles are given in Table 1.
Complex 1 (Fig. 1) consists of four Ag(I) ions bridged by
l3-chloride ions, forming a cube like core. Thus, each Ag(I)
ion is bonded with a tri-p-tolylphosphine (tptp) ligand
through the phosphorus atom and three l3-Cl atoms form-
ing a distorted tetrahedral arrangement around each metal
center. The Ag–Cl bond length varies between 2.526 and
*
Complex
IC50 (lM)
L1210/0
Molt4/C8
CEM/0
1
2
3
4
28 26
P100
1.8 0.0
13
3
2.5 18
P100
2.3 0.1
>100
2.1 0.1
2.7 0.2
4.6 3.1
2.7 0.5
˚
2.807 A and are in agreement to those found in the cubane
139.80 ppm in 4. Despite the fact that these shifts are not
that large most probably due to a back donation effect
[9a], they are nonetheless indicative of the coordination
with the metal ion.
like complex [(Ph3P)4Ag4Cl4] (Ph3P = triphenylphosphine)
[11a] where Ag–Cl bond distances vary from 2.5316(25) to
2.7604(27) A and in the dimeric complex [Ag(C36H30P2)Cl]2
˚
[11b] where the two Ag–Cl bond distances are at 2.5472 and

S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
1007
˚
2.7909 A, respectively. The Ag–P bond lengths in complex
zo[a]pyrene) carcinogenesis. Table 2 presents the antiprolif-
erative effects of complexes after treatment with variable
concentration, at 24, 48 and 72 h exposure time, as 50%
inhibitory concentration (IC50) values. The corresponding
(IC50) value found for cis-platin, against sarcoma cancer
cells (mesenchymal tissue) from the Wistar rats, is 4–
5 lM [13a],while complexes 1–4 show a pronounced cyto-
static activity against the tumor cell lines studied (see Table
2). The cytostatic activity of complexes 1–4, was smaller
than the corresponding ones found for organotin(IV)-thio-
amide complexes tested from our group with best results
obtained with {[(C6H5)3Sn]2(mna) Æ [(CH3)2CO]} (H2mna =
2-mercapto-nicotinic acid) (IC50 = 0.005 lM) [13a,13b],
followed by [(C6H5)2Sn(cmbzt)2] (Hcmbzt = 5-chloro-2-
mercapto-benzothiazole) (IC50 = 0.3–0.5 lM) [13c,13d]
and [(C6H5)3Sn(PMT)] (PMTH = 2-mercapto-pyrimidine)
((IC50 = 0.1 lM) [13c,13d].
˚
1 vary from 2.384 to 2.403 A and are also in agreement to
those found in complex [(Ph3P)4Ag4Cl4] [11a] (2.3755(27)–
2.3878(26) A). They are shorter, however, than the corre-
sponding Ag–P bond distances found in the dimer
[Ag(C36H30P2)Cl]2 (2.467(2)–2.472(2) A) [11b] and signifi-
cantly shorter than the Ag–P bond lengths found in the
monomeric complexes 2, 3 and 4 (2.53–2.56 A) (Table 1)
indicating a dependence on the geometry of the complex.
A weak metal-metal interaction was found between Ag1–
˚
˚
˚
˚
Ag3 and Ag3–Ag4 (3.280 and 3.435 A, respectively) in com-
plex 1, which are shorter than the sum of their van der
Waals radii (3.44 A) indicating a d –d interaction [8a].
10 10
˚
All the remaining Agꢃ ꢃ ꢃAg distances are longer than two-
fold the value of van der Waals radii; Ag1ꢃ ꢃ ꢃAg2 = 3.548,
Ag1ꢃ ꢃ ꢃAg4 = 3.631, Ag2ꢃ ꢃ ꢃAg3 = 3.537 and Ag2ꢃ ꢃ ꢃAg4
˚
= 3.652 A, respectively.
Complexes 1–4 were also tested against murine leukemia
(L1210) and human T-lymphocyte (Molt4/C8 and CEM)
cells (Table 3). The values obtained show strong cytostatic
activitywiththebromide3andiodide4tetrahedralcomplexes
to be the strongest. Complex 3, also show stronger cytostatic
activity against murine leukemia (L1210) and human T-lym-
phocyte (Molt4/C8 and CEM)cells thanthe silver(I)–thioam-
ide complexes {[Ag6(l2-Br)6(l2-StpmH2)4(l3-StpmH2)2]n}
and {[Ag4(l2-StpmH2)6](NO3)4}n (StpmH2 = 2-mercapto-
3,4,5,6-tetrahydro-pyrimidine) tested previously [5].
Complexes 2–4 (Figs. 2–4) are monomeric Ag(I) com-
plexes with tetrahedral geometries around the metal ion
formed by three P atoms from the tptp ligands and a halo-
gen ion (X = Cl, Br, I). The Ag–P bond lengths vary from
2.53 to 2.56 A and are in agreement with those found in
the [Ag(Ph3P)3Cl] [11c,11d] complex (average Ag–P =
˚
˚
˚
2.55 A), in [(Ph3P)AgBr] [11d] (average Ag–P = 2.54 A),
˚
in [(Ph3P)3AgI] [11d] (average Ag–P = 2.63(1) A), [(Ph3P)3-
AgI] [12a] (average Ag–P = 2.5913 A) and [(Ph3P)3AgI]
[12b] (average Ag–P = 2.60 A) and in [(tptp)3AgI] [8e]
(Ag–P = 2.55 A). No significant changes were observed
˚
˚
All complexes were also tested for anti-HIV-1 and -
HIV-2 activities, but were found inactive.
˚
between the structures of complex 4 solved at 140 or
293 K, indicating that the temperature has no effect on
the complex conformation.
2.5. Computational study
2.4. Biological tests
The stability in the structure of 1 caused by cyclical delo-
calization of d as well as (d-p)p-type orbitals electron den-
sity, instead of the usual p orbitals on metal–ligand rings (d
orbital aromaticity) [14], was calculated by mean of
nucleus-independent chemical shifts (NICS) method. The
Complexes 1–4 were tested for in vitro cytostatic activity
against sarcoma cancer cells (mesenchymal tissue) from the
Wistar rat, polycyclic aromatic hydrocarbons (PAH, ben-
Fig. 5. Geometrical parameters for the core structures of compounds 1 and {[Ag6(l3-Hmna)4(l3-mna)2]2ꢂ Æ [(Et3NH)+]2 Æ (DMSO)2 Æ (H2O)} (5).

1008
S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
use of NICS method in 3D structures has been recently,
evaluated extensively [14e,14d] showing the successful esti-
mation of aromaticity. In this work the NICS values have
been calculated for complex 1 at: (i) special positions
located at the centre of the plane determined by the three
nearest Ag atoms (NICS-3Ag) where Agꢃ ꢃ ꢃAg contacts
are shorter than the sum of van der Waals radii (Fig. 5a)
(ꢂ2.4 ppm) and at (ii) the cage centres (NICS(0.0))
(ꢂ0.2 ppm). For comparison we extended our calculation
on the {[Ag6(l3-Hmna)4(l3-mna)2]2ꢂ Æ [(Et3NH)+]2 Æ (DM-
SO)2 Æ (H2O)} (5) complex [15] (NICS-3Ag = ꢂ5.5 ppm
and NICS(0.0) = 0.2, respectively (Fig. 5b)) and on ben-
zene (NICS(0.0) = ꢂ6.9 ppm) and the recently calculated
{[Ag4Cl4(l3-StpmH2)4]n} aggregate [14f], (NICS =
ꢂ9.7 ppm), at the same level of theory. The core of com-
plex 1 exhibits pseudo-tetrahedral (Td) symmetry while
the cores of complex 5 and C6H6 adopt D3d and D6h sym-
metry, respectively. These results show aromaticity in the
special position at the centre of the plane established by
the three nearest Ag atoms in cases of 1 and 5. However,
the aromaticity calculated in complex 1 is significantly
lower than the corresponding found in the nano-tube
shaped {[Ag4Cl4(l3-StpmH2)4]n} aggregate [14f] where the
NICS data of ꢂ9.7 ppm at the cage barycentre confirmed
a strong aromatic character. Shielding influence reached
its minimum value of ꢂ13.1 ppm at NICS(1.7) [14f].
the chlorides of 1 and 2 complexes stronger cytostatic activ-
ity is found for complex 2 with tetrahedral geometry than
that of 1 with the cubane structure. This may be explained
by the aromaticity calculated at special positions located
at the centre of the plane determined by the three nearest
Ag atoms (NICS-3Ag) in case of complex 1, which may give
extra stability to this structure. Finally none of the com-
plexes show anti HIV activity.
4. Experimental
4.1. Materials and instruments
All solvents used were of reagent grade. Silver(I) chlo-
ride and Silver(I) bromide were prepared by mixing aque-
ous solutions of AgNO3 with the appropriate amount of
NaCl and NaBr (Merck or Aldrich), respectively. The pre-
cipitations were filtered off and dried on a filtering paper in
darkness. Silver(I) iodide (Fluka AG, Buchs SG) was of
analytical reagent. Tri-p-tolyl-phosphine (Fluka) was used
with no further purification. Elemental Analyses for C,
H, N, were carried out with a Carlo Erba EA model
1108 elemental analyzer. Melting points were measured in
open tubes with a Stuart Scientific apparatus and are
uncorrected. IR spectra in the region of 4000–370 cmꢂ1
were obtained from KBr discs, while far-IR spectra in the
region 400–30 cmꢂ1 were obtained from polyethylene discs,
with a Perkin–Elmer Spectrum GX FT-IR spectrophotom-
3. Conclusions
1
eter. The H and 13C NMR spectra were recorded on a
Four new Ag(I) complexes were synthesized by reacting
silver halogenides and tri-p-tolyl-phosphine. The geometry
is found to depend on the stoichiometry of the reaction.
Thus, the 1:1 ligand to metal ratio leads to the formation
of the cubane {[AgCl(tptp)]4} (1), while the 1:3 ratio results
in the formation of the tetrahedral complexes, [AgX(tptp)3]
(X = Cl (2), Br (3), I (4)). The formation of the cubane like
complex 1 may be explained by the aromaticity calculated
at special positions located at the centre of the plane deter-
mined by the three nearest Ag atoms (NICS-3Ag), which
may give extra stability to this structure. This may also
explain the weak Agꢃ ꢃ ꢃAg (d10–d10) interaction found
Bruker AC250 MHFT NMR instrument in CDCl3 solu-
tions. Chemical Shifts are given in ppm referenced to inter-
nal TMS. The 31P NMR spectra were recorded in CD3CN
solutions.
4.2. Synthesis and crystallization of {[(AgC(tptp)]4} (1),
[AgCl(tptp)3] (2), [AgBr(tptp)3] (3) and
[AgI(tptp)3] (4)
A 20 ml of CH3OH/CH3CN (1:1) solution of tri-p-tolyl-
phosphine (tptp) (0.153 g 0.5 mmol) with 0.5 mmol silver(I)
salt (AgCl, 0.073 g, or AgBr, 0.095 g or AgI, 0.117 g) was
stirred for 15 min at 50 ꢁC. In case of complex 2 the
20 ml CH3OH/CH3CN (1:1) solution of tri-p-tolyl-phos-
phine (tptp) (0.153 g 0.5 mmol) and AgCl (0.0036 g
0.17 mmol) was stirred under reflux until clearness. The
resultant suspensions were filtered off and the filtrates were
kept in darkness at room temperature. After few days col-
orless crystals of complexes were obtained; suitable for X-
ray crystallographic.
˚
between Ag1–Ag3 and Ag3–Ag4 (3.276 and 3.444 A,
respectively), which are shorter than the sum of their van
˚
der Waals radii (3.44 A).The IC50 values of complexes 1–
4, against sarcoma cancer cells, vary from 0.650 to
0.850 lM with the corresponding value for cisplatin to be
4–5 lM [13a], but weaker than that of organotin(IV)–thio-
amide complexes [13a,13b,13c,13d]. Complexes 1–4 also
show strong cytostatic activity against murine leukemia
(L1210) and human T-lymphocyte (Molt4/C8 and CEM)
cells (Table 3). This activity is higher than that of the
corresponding silver(I)–thioamide complexes {[Ag6(l2-
Br)6(l2-StpmH2)4(l3-StpmH2)2]n} and {[Ag4(l2-StpmH2)6]-
(NO3)4}n (StpmH2 = 2-mercapto-3,4,5,6-tetrahydro-pyrimi-
dine) [5]. Iodine 4 and bromine 3 silver(I) complexes with
tetrahedral geometry show significantly stronger cytostatic
activity than the corresponding chlorides, while between
1: Yield: 0.020 g; m.p: 235–244 ꢁC; (C84H84P4Ag4Cl4)
(1789.4); Anal. Calc.: C, 56.34; H, 4.72. Found: C, 56.64;
H, 5.18%. MID-IR (cmꢂ1) (KBr): 3030w, 2189w, (1925–
1908)w, 1596m, 1497s, 1397s, 1310m, 1188vs, 1097vs,
806vs, 708s, 643s, 629vs, 610s, 512vs, 424m, 375m. FAR-
IR (cmꢂ1) (pe): 186w, 136w, 113w. UV–is (kmax nm, loge),
(CHCl3), (C = 1 · 10ꢂ5 M): kmax ¼ 250, loge = 4.851,
1
kmax ¼ 242, loge = 4.854, UV–is (kmax nm, loge), (MeOH).
2

S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
1009
Table 4
Crystal data and the structure refinement details for the complexes 1–4
1; 293 K
2; 293 K
3; 293 K
4; 293 K
4; 140 K
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
C84H84Ag4Cl4P4
1790.68
100(1)
triclinic
P1
12.752(2)
13.014(2)
15.094(2)
80.491(13)
66.165(16)
61.602(17)
2014.4(5)
1
C63H63AgClP3
1056.36
293(2)
orthorhombic
Pna21
20.5161(9)
26.3246(12)
10.6442(7)
90
90
90
5748.7(5)
4
1.221
C63H63AgBrP3
1100.82
293(2)
orthorhombic
Pna21
20.487(4)
26.186(5)
10.674(2)
90
C63H63AgIP3
1146.81
293(2)
C63H63AgIP3
1146.81
140(2)
triclinic
triclinic
ꢀ
ꢀ
P1
P1
˚
a (A)
11.038(2)
11.548(2)
23.227(5)
99.29(3)
92.12(3)
106.19(3)
2795.4(11)
2
11.0058(5)
11.4509(5)
22.9459(8)
99.461(3)
91.648(3)
106.350(4)
2728.5(2)
2
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
90
90
3
˚
V (A )
5726.3(19)
4
1.277
Z
qcalcd (g cmꢂ3
)
1.476
1.21
0.0793, 0.1972
1.362
1.0
0.0546, 0.1691
1.396
1.1
0.0687, 0.1867
l (mmꢂ1
R, wR2 [I > 2r(I)]
)
0.5
1.2
0.0483, 0.1282
0.0463, 0.1094
1
(C = 1 · 10ꢂ5 M): kmax = 250, loge = 4.804. H NMR (d
ppm), (CDCl3): 2.34(s), 7.31(d), 7.1(d), 13C NMR (d
ppm) (CDCl3): 21.88, 77.51, 134.2, 130, 140.5. Conductiv-
(CDCl3): 21.42, 77.0, 134, 129.5, 139.7. Conductivity
(Km) in CH3CN = 11 cmꢂ1 molꢂ1 Xꢂ1
.
ity (Km) in CH3CN = 1 cmꢂ1 molꢂ1 Xꢂ1
.
4.3. Cytostatic, antiviral activity assays and computational
details
2: Yield: 0.084.g; m.p: 175–177 ꢁC (C63H63P3AgCl)
(1055.4) Anal. Calc.: C, 71.70; H, 5.97. Found: C, 71.70;
H, 5.96%. MID-IR (cmꢂ1) (KBr): 3013m, 1916m, 1595m,
1498s, 1396m, 1308m, 1189s, 1090s, 847w, 710m, 640w,
623m, 604w, FAR-IR (cmꢂ1) (pe): 172w, 151m, UV–is
These have been described in detail elsewhere [5,13,14f].
4.4. X-ray structure determination
(kmax nm, loge), (CHCl3), (C = 2 · 10ꢂ5 M): kmax ¼ 251,
1
loge = 4.745, kmax ¼ 243, loge = 4.747, UV–is (kmax nm,
Intensity data for the colourless crystals of 1–4 were col-
lected by the x scan technique in the h_2h range of range 2–
60 for 1 at 100 K and 0.00 + 0.35 for 2–4 at 293 K and at
140 K temperature for 4 on a KUMA KM4CCD four-cir-
cle diffractometer [16a] with CCD detector, using graphite-
2
loge),
(MeOH),
(C = 2 · 10ꢂ5
M):
kmax = 254,
loge = 4.532, 1H NMR (d ppm), (CDCl3): 2.2–2.33(s),
7.3(d), 7.1(d), 13C NMR (d ppm) (CDCl3): 21.37, 77, 134,
129.5, 139.5. Conductivity (Km) in CH3CN =
14 cmꢂ1 molꢂ1 Xꢂ1
.
monochromated MoKa (k = 0.71073 A) at 293(2) K. Cell
˚
3: Yield: 0.073 g; m.p: 178–186 ꢁC; (C63H63P3AgBr)
(1099.8) Anal. Calc.: C, 68.74; H, 5.76. Found: C, 68.85;
H, 6.12%. MID-IR (cmꢂ1) (KBr): 3020m, 1910m, 1803w,
1597s, 1498s, 1396s, 1377w, 1309s, 1189s, 1095s, 851–
840w, 806vs, 708vs, 642vs, 628vs, 609vs, 517–508vs,
427m, 410m. FAR-IR (cmꢂ1) (pe): 135w. UV–is (kmax nm,
loge), (CHCl3), (C = 2 · 10ꢂ5 M): kmax1 = 253, loge =
4.677 kmax2 = 242, loge = 4.674, UV–is (kmax nm, loge),
parameters were determined by a least-squares fit [16b].
All data were corrected for Lorentz-polarization effects
and absorption [16b,16c].
The structure was solved with direct methods with SHEL-
XS97 [16d] and refined by full-matrix least-squares proce-
dures on F2 with SHELXL97 [16e]. All non-hydrogen atoms
were refined anisotropically, hydrogen atoms were located
at calculated positions and refined as a ‘riding model’ with
isotropic thermal parameters fixed at 1.2 times the Ueq’s of
appropriate carrier atom. Significant crystal data are given
in Table 4.
1
(MeOH) (C = 2 · 10ꢂ5 M): kmax = 253, loge = 4.404, H
NMR (d ppm), (CDCl3): 2.34(s), 7.31(d), 7.1(d), 13C
NMR (d ppm) (CDCl3): 21.40, 77, 133.74, 129.5, 147.5.
Conductivity (Km) in CH3CN = 7 cmꢂ1 molꢂ1 Xꢂ1
.
4: Yield: 0.081 g; m.p: 158–163 ꢁC; (C63H63P3AgI)
(1146.8); Anal. Calc.: C, 65.92; H, 5.53. Found: C, 65.9;
H, 5.78%. MID-IR (cmꢂ1) (KBr): 3021w, 1910w, 1597m,
1497s, 1189s, 1121w, 1092vs, 1035w, 803vs, 706s, 642m,
628s, 608s, 508w, 430m, 418w, FAR-IR (cmꢂ1) (pe):
5. Supplementary material
CCDC 622155, 622156, 622157, 622158, and 622159
contain the supplementary crystallographic data for 1, 2,
3, 4 and 4 at 140 K. These data can be obtained free of
151s,
125m,
UV–is
(kmaxnm,
loge),
(CHCl3),
charge
via
http://www.ccdc.cam.ac.uk/conts/retriev-
(C = 2 · 10ꢂ5 M): kmax1 = 253, loge = 4.611, kmax2 = 240,
loge = 4.656, UV–is (kmax nm, loge) (MeOH),
ing.html, or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.
ac.uk.
(C = 2 · 10ꢂ5 M): kmax = 258, loge = 4.566, H NMR (d
1
ppm), (CDCl3): 2.33(s), 7.3(d), 7.1(d), 13C NMR (d ppm)

1010
S. Zartilas et al. / Inorganica Chimica Acta 362 (2009) 1003–1010
(c) S. Attar, N.W. Alcock, G.A. Bowmaker, J.S. Frye, W.H. Bearden,
Acknowledgement
J.H. Nelson, Inorg. Chem. 30 (1991) 4166;
(d) E.L. Muetterties, C.W. Alegranti, J. Am. Chem. Soc. 94 (1972)
6386.
This work was carried out in partial fulfillment of the
requirements for an M.Sc. thesis of Mr S.Z. within the
graduate program in Bioinorganic Chemistry.
[10] (a) I. Krossing, L. van Wullen, Chem. Eur. J. 8 (2002) 700;
(b) G.A. Bowmaker, Effendy, J.V. Hanna, P.C. Healy, B.W. Skelton,
A.H. White, J. Chem. Soc., Dalton Trans. (1993) 1387.
[11] (a) B-K. Teo, J.C. Calabrese, Inorg. Chem. 15 (1976) 2467;
(b) A. Cassel, Acta Cryst. B35 (1979) 174;
References
(c) A. Cassel, Acta Cryst. B37 (1981) 229;
(d) L.M. Engelhardt, P.C. Healy, V.A. Patrick, A.H. White, Aust. J.
Chem. 40 (1987) 1873.
[1] (a) P.G. Blower, J.R. Dilworth, Coord. Chem Rev. 76 (1987) 121;
(b) E.S. Raper, Coord. Chem. 61 (1985) 115;
(c) E.S. Raper, Coord. Chem. Rev. 129 (1994) 91;
(d) E.S. Raper, Coord. Chem. Rev. 153 (1996) 199.
[2] (a) Martidale, The Extra Pharmacopoeia, 28th ed., The Pharmaceu-
tical Press, London, 1982;
(b) M. Wruble, J. Am. Pharm. Assoc. Sci. Ed. 32 (1943) 80.
[3] H.S. Rosenkranz, S. Rosenkranz, Antimicrob. Agents Chemother. 2
(1972) 373.
[4] E.E. Tredget, H.A. Shankowsky, A. Groenveld, R. Burrell, Burn
Care Rehabil. 19 (1998) 531.
[5] P.C. Zachariadis, S.K. Hadjikakou, N. Hadjiliadis, A. Michaelides, S.
Skoulika, J. Balzarini, E. De Clercq, Eur. J. Inorg Chem. (2004) 1420.
[6] (a) J.J. Roberts, J.M. Pascoe, Nature 235 (1972) 282;
(b) D.R. Williams, Educ. Chem. 11 (1974) 124.
[7] (a) J. Vicente, M.T. Chicote, C. Rubio, Chem. Ber. 129 (1996) 327;
(b) J. Vicente, M.T. Chicote, M.C. Lagunas, Inorg. Chem. 32 (1993)
3748;
[12] (a) D.E. Hibbs, M.B. Hursthouse, K.M. Abdul-Malik, M.A. Beckett,
P.W. Jones, Acta Cryst. C52 (1996) 884;
(b) M. Camali, F. Caruso, Inorg. Chim. Acta 127 (1987) 209.
[13] (a) M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, M.
Schurmann, K. Jurkschat, J. Binolis, S. Karkabounas, K. Charalab-
¨
opoulos, Bioinorg. Chem. Appl. 1 (2003) 227;
(b) M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, M.
Schurmann, K. Jurkschat, A. Michaelides, S. Skoulika, T. Bakas, J.
¨
Binolis, S. Karkabounas, K. Haralampopoulos, J. Inorg. Biochem. 96
(2003) 425;
(c) M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, M.
Kubicki, S. Skoulika, T. Bakas, M. Baril, I.S. Butler, Inorg. Chem.
46 (2007) 1187;
(d) M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, E.R.
Milaeva, J.A. Gracheva, V.-Y. Tyurin, N. Kourkoumelis, K.C.
Christoforidis, A.K. Metsios, S. Karkabounas, K. Charalabopoulos,
Eur. J. Med. Chem., in press, doi:10.1016/j.ejmech.2007.03.028.
[14] (a) P.v.R. Schleyer, C. Maerker, A. Dransfeld, H. Jiao, N.J.R.v.E.
Hommes, J. Am. Chem. Soc. 118 (1996) 6317;
(c) O. Steigelmann, P. Bissinger, H. Schmidbaur, Angew. Chem. Int.
Ed. 29 (1990) 1399;
O. Steigelmann, P. Bissinger, H. Schmidbaur, Angew. Chem. 102
(1990) 1473;
(d) B.P. Esposito, R. Najjar, Coord. Chem. Rev 232 (2002) 137;
(e) M.J. McKeage, L. Maharaj, S.J. Berners-Price, Coord. Chem.
Rev. 232 (2002) 127;
(f) M.D. Rhodes, P.J. Sadler, M.D. Scawen, S. Silver, J. Inorg.
Biochem. 46 (1992) 129.
(b) C. Corminboeuf, C.S. Wannere, D. Roy, R.B. King, P.v.R.
Schleyer, Inorg. Chem. 45 (2006) 214;
(c) C.A. Tsipis, Coord. Chem. Rev. 249 (2005) 2740;
(d) J. Li, C.-W. Liu, J.-X. Lu, J. Cluster Sci. 7 (1996) 469;
(e) Z. Chen, R.B. King, Chem. Rev. 105 (2005) 3613;
(f) S. Zartilas, N. Kourkoumelis, S.K. Hadjikakou, N. Hadjiliadis, P.
Zachariadis, M. Kubicki, A.-Y. Denisov, I.S. Butler, Eur. J. Inorg.
Chem. (2007) 1219.
[8] (a) K. Nomiya, S. Takahashi, R. Noguchi, J. Chem. Soc., Dalton
Trans. (2000) 2091;
(b) K. Nomiya, R. Noguchi, T. Shigeta, Y. Kondoh, K. Tsuda, K.
Ohsawa, N.C. Kasuga, M. Oda, Bull. Chem. Soc. Jpn. 73 (2000) 1143;
(c) P. Aslanidis, P.J. Cox, S. Divanidis, P. Karagiannidis, Inorg.
Chim. Acta 357 (2004) 2677;
(d) P.J. Cox, P. Aslanidis, P. Karagiannidis, S.K. Hadjikakou, Inorg.
Chim. Acta 310 (2000) 268;
[15] P.C. Zachariadis, S.K. Hadjikakou, N. Hadjiliadis, A. Michae-
lides, S. Skoulika, Y. Ming, Y. Xiaolin, Inorg. Chim. Acta 343
(2003) 361.
[16] (a) KUMA KM-4CCD user manual, KUMA Diffraction, Wroclaw,
Poland, 1999;
(b) CRYSALIS, Program for Reduction of the Data from KUMA CCD
Diffractometer, KUMA Diffraction, Wroclaw, Poland, 1999;
(c) R.H. Blessing, J. Appl. Crystallogr. 22 (1989) 396;
(d) G.M. Sheldrick, Acta Cryst. A 46 (1990) 467;
(e) G.M. Sheldrick, SHELXL-97, Program for the Refinement of Crystal
Structures, University of Go¨ttingen, Go¨ttingen, Germany, 1997.
(e) R. Meijboom, Acta Cryst. E63 (2007) m78.
[9] (a) R.N. Dash, D.V. Ramana Rao, Z. Anorg. Allg. Chem. 393 (1972)
309;
(b) W. McFarlane, P.D. Akrivos, P. Aslanidis, P. Karagiannidis, C.
Hatzisymeon, M. Newman, S. Kokkou, Inorg. Chim. Acta 281 (1998)
121;