Stabilization of the N-1-substituted cytosinate iminooxo form in dinuclear palladium complexes

Article abstract of DOI:10.1016/j.poly.2009.01.043

The synthesis, as well as chemical and structural characterization, of 1-(p-toluenesulfonyl)cytosine (1) and its dinuclear complexes of the composition Pd₂(1-TosC^--N3,N4)₄ (3) and Pd₂(1-TosC^--N3,N4)

Full text of DOI:10.1016/j.poly.2009.01.043

Polyhedron 28 (2009) 1057–1064
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Stabilization of the N-1-substituted cytosinate iminooxo form in dinuclear
palladium complexes
a
a
b
c
b,
*
ˇ
´
´
´
Aleksandar Višnjevac , Marija Luic , Renata Kobetic , Dubravka Gembarovski , Biserka Zinic
a
ˇ
´
Division of Physical Chemistry, Ruder Boškovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
b
-
ˇ
Division of Organic Chemistry and Biochemistry, Ruder Boškovi´c Institute, Bijenicka 54, 10000 Zagreb, Croatia
c GlaxoSmithKline, Research Centre Zagreb, Prilaz baruna Filipovi´ca 29, 10000 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis, as well as chemical and structural characterization, of 1-(p-toluenesulfonyl)cytosine (1)
and its dinuclear complexes of the composition Pd2(1-TosCÀ–N3,N4)4 (3) and Pd2(1-TosCÀ–
N3,N4)2DMSO2Cl2 (4) by means of ESI-MS, IR, 1H NMR and X-ray single crystal analysis are described.
Ligand 1 exists in the preferred aminooxo tautomeric form, while both dinuclear complexes reveal the
presence of the iminooxo form of the ligand, where 1-TosCÀ stands for the anion of the cytosine deriva-
tive of 1, bridging two palladium atoms. Complex 3 has a paddlewheel structure with two square-planar
coordination spheres, consisting of four N atoms each, mutually parallel and perpendicular to the inter-
palladium vector. Complex 4 is characterized by two mutually parallel square-planar coordination
spheres consisting of two nitrogens, sulfur from the solvent molecule and a chloride. A feasible chemical
route for the formation of 3 and 4 via the kinetically favoured mononuclear complex Pd(1-TosC–N3)2Cl2
(2) is proposed, based on the IR, 1H NMR, mass spectrometry, elemental analysis and X-ray structure
analysis data.
Received 29 November 2008
Accepted 13 January 2009
Available online 14 February 2009
Keywords:
Dinuclear palladium complexes
N-1-substituted cytosine
Iminooxo form
X-ray diffraction
Mass spectrometry
NMR spectroscopy
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
been characterized by X-ray crystallography ([6] and the refer-
ences therein, [9]).
The relative stability of tautomers of nucleobases is of the high-
est importance for the structure and function of nucleic acids.
Cytosine is a very important nucleobase with respect to the DNA
structure; in its protonated form (C+), it is involved in the forma-
tion of C Á C+ DNA duplexes [1,2] and C Á G Á C+ triplexes [3]. The
iminooxo tautomer of cytosine is a mutagenic base analogue capa-
ble of pairing with adenine [4]. Although three tautomers (Fig. 1)
are possible for N-1-substituted cytosine, the aminooxo tautomer
I has been found to be dominant in the solid state, in aqueous
and DMSO solutions, as well as in nucleic acids. Its abundance ex-
ceeds the iminooxo tautomer II by a factor of 104–105, while the
existence of the iminohydroxo tautomer III seems to be uncertain
[5].
As a part of our program directed toward the synthesis and
characterization of biologically active nucleobase derivatives, we
have recently described the synthesis and in vitro antitumor activ-
ity assays of a series of novel N-1-sulfonyluracil and N-1-sulfonyl-
cytosine derivatives [10,11]. We hereby report on the preparation
and structural characterization of two novel dinuclear Pd(II) com-
plexes of 1-(p-toluenesulfonyl)cytosine (1), containing exclusively
the iminooxo form of the ligand anion (1-TosCÀ).
2. Experimental
2.1. General remarks
It has been shown in a number of cases that reactions of metal
ions with N-1-substituted cytosine, containing a large excess of the
preferred tautomer I, spontaneously lead to the formation of N3,N4
or N4,N4 mononuclear PdL2 complexes containing exclusively the
iminooxo form of the cytosine base [6,7]. There are, however,
few examples of the coexistence of two forms, aminooxo and imi-
nooxo, within the same structure [8]. In addition, very few metal
complexes containing the iminooxo form of the cytosine base have
Infrared spectra were recorded on a Perkin–Elmer 297 spectro-
photometer with the samples prepared as KBr pellets. 1H and 13C
NMR spectra were recorded in DMSO–d6 on Bruker AV 300 and
600 MHz spectrometers using TMS or DMSO–d6 as the internal
standard. Elemental analyses were done on a Perkin–Elmer 2400
Series II CHNS analyzer. The polycrystalline samples were mounted
inside a thin-walled glass capillary (internal diameter 0.3 mm) and
measured on an Oxford Diffraction Xcalibur Nova R diffractometer
with a microfocusing Cu tube. Conductance measurements were
carried out at room temperature using a CD 7A Tacussel conduc-
tance bridge for 10À3 mol dmÀ3 solutions in DMSO.
* Corresponding author. Tel.: +385 1 4561066; fax: +385 1 4680195.
ˇ
E-mail address: bzinic@irb.hr (B. Zinic´).
0277-5387/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2009.01.043

1058
A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
NH
N
NH2
NH
N
HN
HO
N
R
O
N
R
O
N
R
II
III
I
Fig. 1. Tautomers of N-1-substituted cytosine.
2.2. ESI-MS
Mass spectral data were acquired on a LCQ Deca ion trap mass
spectrometer from ThermoFinnigan (San Jose, CA, USA) equipped
with an electrospray ionization (ESI) interface operated in the po-
sitive and negative ion modes, mass range 150–2000. Stock sam-
ples were prepared in CH3OH or DMSO, further diluted to a
concentration of about 0.05 mg/mL in CH3CN, CH3OH or water,
and directly injected. Infusion into the mass spectrometer was per-
formed by the built-in syringe pump at a flow rate of 5
l
L/min.
Fig. 2. Packing diagram of 1.
Nitrogen was used as the auxiliary and sheath gas. Helium was
used as the collision gas in the ion trap. The sheath gas flow was
set at 85 and the auxiliary gas flow at 30 (arbitrary units). The
spray voltage was set at 4.5 kV, while the capillary temperature
was 250 °C and the capillary voltage 17 V. Full mass spectra were
acquired over the mass range m/z 150–2000. Additional solvent
cluster studies were performed by varying the capillary voltage
(10 V) and temperature (250 °C). For MS/MS investigations, charac-
teristic molecular ions were isolated in the ion trap and collision-
ally activated with different collision energies (CE) to find the
optimal CE for a distinct fragmentation. Product ions in the MS/
MS spectra were chosen to perform further MS3 and MS4 experi-
ments, relevant to the confirmation of investigated compounds.
Ph-b), 7.46 (d, 2H, Jc,b = 8.1 Hz, Ph-c), 5.98 (d, 1H, J5,6 = 7.8 Hz, H-
5), 2.42 (s, 3H, CH3); 13C NMR (DMSO–d6) d/ppm: 166.27 (s, C-4),
151.22 (s, C-2), 145.61 (s, Ph-d), 139.73 (d, C-6), 134.47 (s, Ph-a),
129.80 (d, Ph-c), 129.02 (d, Ph-b), 97.50 (d, C-5), 21.20 (q, CH3);
MS (EI) exact mass calculated for C11H11N3O3S: m/e 265.051565
([M]+), found: 265.040053.
2.3.2. Preparation of the complex Pd(1-TosC–N3)2Cl2 (2)
To a solution of 1-(p-toluenesulfonyl)cytosine (1) (0.1061 g,
0.4 mmol) in methanol (9 mL), K2PdCl4 (0.0653 g, 0.2 mmol) was
added. The reaction mixture was stirred and refluxed for 2 h. The
red suspension was cooled to room temperature and a pale yellow
solid product was filtered off, washed with methanol and dried
over vacuo to give 102 mg (76%) of a pale yellow powder 2: IR
2.3. Synthesis
(KBr)
m
max/cmÀ1: 3406 (s), 3313 (s), 3288 (s), 3247 (m), 3207
2.3.1. Preparation of ligand 1
(m), 3107 (m), 3067 (m), 1686 (s), 1650 (s, br), 1613 (s), 1609
(s), 1514 (s), 1503 (s), 1380 (s), 1363 (s), 1276 (s), 1252 (m),
1191 (s), 1171 (s), 1145 (m), 1122 (m), 1107 (m), 1084 (s), 1045
(s), 1017 (m), 974 (m), 815 (m), 792 (s), 766 (s), 706 (s), 695 (s),
673 (s), 613 (s), 590 (s), 552 (s), 541 (s), 480 (m), 361 (m). Anal.
Calc. for C22H22Cl2N6O6PdS2 xH2O (Mr = 725.91): C, 36.40; H,
3.33; N, 11.58; S, 8.83. Found: C, 36.05; H, 2.93; N, 11.55; S, 8.54%.
Synthesis of the ligand 1-(p-toluenesulfonyl)cytosine (1) was
performed according to the procedure reported by Kašnar-Šamprec
et al. [11]. 1-(p-Toluenesulfonyl)cytosine (1) had been synthesized
previously by the reaction of silylated cytosine and p-toluenesulfo-
nyl chloride in acetonitrile, according to Scheme 1. The phenyl-
proton (Ph) assignments were confirmed by carbon-proton con-
nectivity in 1H/13C heteronuclear correlation spectra (HETCOR).
Additionally, in the NOESY spectrum of 1, the assignment of Ph-c
protons was proved by their interaction with methyl-protons. IR
2.3.3. Complex 2 in DMSO-d6 solution
The first set of signals (marked o in Fig. 4): 1H NMR (DMSO–d6) d/
ppm: 8.10 (d, 1H, J6,5 = 8.0 Hz, H-6), 7.88 (d, 2H, J = 8.7 Hz, NH2),
7.84 (d, 2H, Jb,c = 8.1 Hz, Ph-b), 7.44 (d, 2H, Jc,b = 8.0 Hz, Ph-c),
5.94 (d, 1H, J5,6 = 7.9 Hz, H-5), 2.41 (s, 3H, Ph–CH3); 13C NMR
(DMSO–d6) d/ppm: 165.90 (s, C-4), 150.87 (s, C-2), 145.28 (s, Ph-
d), 139.41 (d, C-6), 134.19 (s, Ph-a,), 129.51 (d, Ph-c), 128.72 (d,
Ph-b), 97.25 (d, C-5), 21.11 (q, Ph–CH3).
(KBr) m
max/cmÀ1: 3369 (m), 3100 (m), 3074(m), 1703 (m), 1673
(s), 1524 (s), 1489 (m), 1376 (m), 1353 (m), 1285 (m), 1236 (w),
1184 (m), 1173 (s), 1138 (w), 1116 (m), 1088 (m), 1023 (w), 967
(m), 806 (w), 765 (m), 707 (m), 689 (m), 657 (w), 602 (w), 585
(w), 555 (m), 542 (m); 1H NMR (DMSO–d6) d/ppm: 8.14 (d, 1H,
J6,5 = 7.8 Hz, H-6), 7.95 (brs, 2H, NH2), 7.87 (d, 2H, Jb,c = 8.1 Hz,
NH2
4
NH2
N(SiMe3)2
5
6
N3
2
N
3 eq BSA
1
1.2 eq TsCl
45', 80 oC
N
O
N
CH3CN
80 oC
O
N
H
S
Me3SiO
N
O
O
a
b
BSA = N,O-bis(trimethylsilyl)acetamide
TsCl = p-toluenesulfonyl chloride
cytosine
d
CH3
1
c
Scheme 1. Synthesis of 1-(p-toluenesulfonyl)cytosine (1).

A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
1059
L2PdCl2_mg-ml-stock u DMSO_ACN_ms #384-419 RT: 8.67-9.57 AV: 34 NL: 4.32E7
14022008-L2 Pd Cl 2_direct inj_01 #349-446 RT: 8.02-10.88 AV: 98 NL: 2.56E7
T: + c ESIFull ms [50.00-2000.00]
T: + c ESI Full ms [100.00-2000.00]
750.73
266.04
100
95
100
95
a
b
90
85
80
75
70
65
60
55
90
85
80
75
70
65
60
55
50
45
1005.76
50
266.01
45
40
35
30
25
20
15
10
5
0
1270.77
1308.76
40
672.91
738.90
530.86
937.66
35
30
25
20
15
10
5
672.91
530.89
485.87
381.22
397.09
303.94
1077.56
552.82
369.02
776.79
1115.64
1151.57
937.69
924.59
1348.42
568.57
850.75
303.94
568.66
1115.64
497.47
154.86
371.95
200.25
417.69
636.96
850.65
1009.83
728.04
0
200 300 400 500 600 700 800 900 1000 1100 1200 1300
m/z
200
300
400
500
600
m/z
700
800
900
1000 1100
L2PdCl2_mg-ml-stock u DMSO_H2O_ms #436-466 RT: 9.30-10.09 AV: 30 NL: 9.27E6
T: + c ESI Full ms [100.00-2000.00]
266.04
L2PdCl2_mg-ml-stock u DMSO_MeOH_ms #486-528 RT: 10.75-11.91 AV: 43 NL: 6.70E7
T: + c ESIFull ms [100.00-2000.00]
100
95
1005.78
750.72
100
c
d
95
90
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
85
80
75
70
65
740.86
60
55
50
45
1270.84
672.92
266.04
40
634.99
35
30
25
20
15
10
5
0
1041.71
483.91
1324.60
530.83
937.72
530.89
937.67
673.00
568.72
780.77
854.78
1137.53
1220.56
369.89
154.90
200.30
200.26
303.89
480.97
1007.60
1113.63
1342.94
303.96
552.82
926.58
412.88
1291.31
157.10
417.62
832.57
1218.63
100 200 300 400 500 600 700 800 900 1000 1100 1200 1300
m/z
100 200 300 400 500 600 700 800 900 1000 1100 1200 1300
m/z
Fig. 3. ESI-MS spectra of the yellow solid PdL2Cl2 (2): (a) dissolved in CH3OH; (b) dissolved in DMSO and diluted with CH3CN; (c) dissolved in DMSO and diluted with water
and (d) dissolved in DMSO and diluted with CH3OH.
The second set of signals (marked x in Fig. 4): 1H NMR (DMSO–d6)
d/ppm: 9.34, 9.25, 9.21, 8.89 (4 x brs, 2H, NH), 8.22 (m, 1H, H-6),
7.94 (m, 2H, Ph-b), 7.50 (m, 2H, Ph-c), 6.07 (m, 1H, H-5), 2.43 (s,
3H, Ph–CH3); 13C NMR (DMSO–d6) d/ppm: 163.82 (s, C-4), 148.99
(s, C-2), 146.39 (s, Ph-d), 139.46 (d, C-6), 132.64 (s, Ph-a), 129.92
and 129.77 (d, Ph-c), 129.23 and 129.20 (d, Ph-b), 97.20 (d, C-5),
21.22 (q, Ph–CH3).
954 (w), 808 (w), 757 (w), 723 (m), 680 (m), 651 (w), 607 (vw),
560 (s), 546 (m), 491 (m), 426 (m), 370 (br, m), 360 (m, sh), 249
(m); 1H NMR (DMSO–d6) d/ppm: 7.85 (d, 2H, Jb,c = 8.3 Hz, Ph-b),
7.52 (d, 1H, J6,5 = 8.0 Hz, H-6), 7.45 (d, 2H, Jc,b = 8.2 Hz, Ph-c), 7.26
(brs, 1H, NH-4), 5.92 (d, 1H, J5,6 = 8.0 Hz, H-5), 2.93 (s, 3H
(CH3)2SO–Pd), 2.54 (s, 3H (CH3)2SO–Pd), 2.42 (s, 3H, Ph–CH3).
2.4. X-ray structural analysis
2.3.4. Preparation of complexes 3 and 4
Slow evaporation of the DMF solution of solid material 2 at
room temperature gave, after 10 days, orange needles of complex
3, whereas a 60-day-long crystallization from the DMSO solution
of solid material 2 at room temperature gave crystals of complex
Crystal data, data collection and refinement parameters for
compounds 1, 3 and 4 are summarized in Table 1. Data collections
were performed on an Enraf Nonius CAD4 diffractometer using
graphite monochromated Cu Ka radiation (k = 1.54179 Å). Data
4. Single crystals of
3
and
4
were characterized by X-ray
reduction and cell refinement were carried out using the proce-
dures incorporated into the WINGX package [12]. Intensities were
measured at room temperature. All structures were solved using
direct methods with SIR2002 [13] and refined using the full matrix
least-squares refinement based on F2 with SHELXL [14]. Molecular
illustrations were prepared using ORTEP-III [15]. All non-hydrogen
crystallography.
Complex Pd2(1-TosCÀ–N3,N4)2DMSO2Cl2 (4): IR (KBr)
m
max/cmÀ1
:
3407 (w), 3247 (w), 3103 (w), 3012 (w), 2919 (w), 1670 (s), 1648
(s), 1569 (s), 1475 (m), 1396 (m), 1354 (m), 1282 (s), 1236 (m),
1188 (s), 1172 (s), 1148 (s), 1128 (s), 1087 (s), 1043 (s), 1025 (s),

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A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
Fig. 4. (DMSO–d6) 1H NMR spectra of ligand 1 (bottom), complex PdL2Cl2 (2) at room temperature (middle) and complex Pd2(1-TosCÀ–N3,N4)2DMSO2Cl2 (4) (top).
atoms in the structures were refined anisotropically; hydrogen
atoms were included in their geometrically calculated positions
(except for some hydrogen atoms included in hydrogen bonding)
and refined according to the riding model. In the structure of 3,
the substantial residual electron density due to the unresolvable
disorder of solvent molecules was reduced by the SQUEEZE [16] rou-
tine incorporated into PLATON [17].
Kašnar-Šamprec et al. [11]. Silylation of cytosine was accomplished
with N,O-bis(trimethylsilyl)acetamide in acetonitrile at 80 °C. Con-
densation of silylated cytosine with p-toluenesulfonyl chloride in
acetonitrile gave ligand 1 in 80% yield after recrystallization from
methanol (Scheme 1).
In our previous report, we have shown that N-1-sulfonyluracil
derivatives can adopt chiral conformations, possessing M and P
helicities in the crystalline state [18]. A partial and a total sponta-
neous resolution upon crystallization was observed for 1-(p-tolu-
enesulfonyl)uracil and 1-(1-naphthylsulfonyl)uracil, respectively,
while the structurally closely related 1-(p-toluenesulfonyl)thy-
mine crystallized as a racemic compound. Unlike its uracil counter-
part, 1-tosylcytosine (ligand 1) does not exhibit à la Pasteur
separation of conformational enantiomers upon crystallization,
3. Results and discussion
3.1. Synthesis and crystal structure of ligand 1
The synthesis of the ligand 1-(p-toluenesulfonyl)cytosine (1),
(1-TosC), was performed according to the procedure reported by
Table 1
Crystallographic data for compounds 1, 3 and 4.
Compound
1
3 (squeezed)
4
Formula
C11H11N3O3S
265.00
colorless plate
0.25 Â 0.20 Â 0.07
monoclinic
P21/c
13.166 (2)
5.660 (3)
15.95 (1)
96.02 (5)
1182 (1)
4
C44H36N12O12Pd2S4
1269.92
yellow needle
0.3 Â 0.07 Â 0.07
orthorhombic
Pnab
17.372(3)
17.882(2)
21.570(5)
90.
C30H44Cl2N6O10Pd2S6
1124.77
yellow plate
0.2 Â 0.15 Â 0.05
monoclinic
C2/n
42.122(8)
12.5940(9)
16.6390(7)
97.12(4)
Formula weight (g molÀ1
Crystal color and habit
)
Crystal dimensions (mm)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
b (°)
V (Å3)
6701(2)
4
1.295
5.969
8759(2)
8
1.706
10.915
Z
qcalc (g cmÀ1
)
1.491
2.503
l
(Cu K
a
) (mmÀ1
)
Absorption correction
none
w
-scan
w-scan
F(000)
552
2560
4544
h max. (°)
76.46
76.07
76.4
No. of reflections collected
3126
6976
9308
No. of reflections observed [I > 2
r(I)]
1966
1607
6889
Parameters
120
337
515
R1
wR2
qmax
0.0444
0.1234
0.71, À0.58
0.0777
0.2320
1.13, À1.80
0.0915
0.2717
2.62, À2.32
,
qmin (e ÅÀ3
)

A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
1061
and crystallizes in the centrosymmetric space group P21/a. How-
ever, it exhibits analogous conformational chirality in the solid
state with respect to the S–N bond. This is due to the enhanced
hydrogen bonding potential of the cytosine, where the presence
of a double hydrogen bond donor (amino nitrogen N4) instead of
a single H bond donor (endocyclic N3–H) in the case of the uracil
derivative, enables the formation of centrosymmetric dimers and
tetramers, and finally leads to a centrosymmetric crystal arrange-
ment. The crystal structure of the ligand 1 is characterized by
hydrogen-bonded centrosymmetric dimers of the graph set motif
R22 (8) [19], formed by hydrogen bonds N4–H4bÁÁÁN3i, and centro-
symmetric tetramers of the graph set motif R44 including hydrogen
bonds N4–H4bÁÁÁN3i and N4–H4aÁÁÁO2ii (Fig. 2). Thus, these two
hydrogen-bonded centrosymmetric rings share the common edge
made by the hydrogen bond N4–H4BÁÁÁN3i and form an infinite
double layer along the crystallographic a-axis.
tion metal complexes [20,21]. The mass spectrum reflects the com-
position of the species present in the solution. Franska studied
cytosine platinum(II) complexes by ESI-MS in DMSO and observed
the formation of cationic complexes with Pt(II). Singly charged
[cytosine + PtCl + 2DMSO]+ ions were detected at a low cone volt-
age [22].
Our MS studies (ESI-MS and HRMS) confirmed the molecular
formula of complex 2. The spectra were taken at a low cone voltage
(10 V). Molecular ions containing palladium gave rise to a number
of peaks showing the characteristic natural isotope percent distri-
bution of the compounds containing one or two palladium atoms.
Masses of the complexes reported in this paper are those contain-
ing the most abundant stable isotope of each element in the com-
plex. Since the examined solid, complex 2, had a low solubility in
CH3OH or CH3CN, these being the common solvents used for ESI-
MS studies, it was dissolved in DMSO and then diluted with
CH3OH, water or CH3CN in our experiments (Fig. 3). The obtained
spectra were compared with the theoretical spectra, matching
completely the molecular peak percent distribution caused by
the Pd isotopes.
3.2. Synthesis and characterization of complexes 2, 3 and 4
3.2.1. Synthesis
1-(p-Toluenesulfonyl)cytosine (1) and K2PdCl4 in a 2:1 molar
ratio were refluxed for 2 h in methanol and, upon cooling to room
temperature, the pale yellow solid 2 was obtained. Solid 2 is solu-
ble in polar coordinative solvents like DMF and DMSO, and insolu-
ble in most other organic solvents and in water. The same solid
product 2 was obtained using DMF instead of methanol, as proved
by the X-ray powder diffraction method (data not shown). Slow
evaporation of a DMF solution of solid material 2 over 10 days at
room temperature gave orange needles of complex 3, whereas a
60 day crystallization of the DMSO solution at room temperature
gave crystals of complex 4 (Scheme 2). The structures of complexes
3 and 4 were confirmed by X-ray structural analysis.
The presence of the complex PdL2Cl2 (2) was confirmed by
detection of the ions from CH3OH solutions: at m/z 635.00 assigned
as the [PdL(L–H)]+ ion and at m/z 672.91 assigned as [PdL2Cl]+, or
DMSO solutions: at m/z 730.78 assigned as the [(PdL2Cl2)Na]+ ion
and at m/z 748.75 assigned as the [(PdL2Cl2)K]+ ion, in the ES+
mode. The mononuclear complex PdL2Cl2 exchanged chloride
quickly with another ligand forming a PdL3Cl type complex. The
presence of that complex was confirmed after detection of the ions
from CH3OH solution: at m/z 937.75 assigned as the (PdL3Cl)+ ion.
Dissolving complex 2 in DMSO and further diluting with water,
methanol or acetonitrile showed clearly that the species present
in the solutions depend strongly on the added solvent properties.
The formation and stability of the formed species were monitored
by ESI-MS and LC–MS. Interaction between complex 2 and DMSO
was detected as a new species eluted at a retention time of 48.67
minutes with m/z 1086 and assigned as [Pd2L3(DMSO)]+.
The molecular formula of the pale yellow solid 2 (PdL2Cl2,
where L = 1-(p-toluenesulfonyl)cytosine) (1) was confirmed by ele-
mental analysis and ESI-MS spectrometry.
3.2.2. ESI-MS studies
Since ESI-MS is the softest desorption/ionization method, it is
ideally suited to investigate the coordination behaviour of transi-
It was also found that when complex PdL2Cl2 was dissolved in
DMSO, new dinuclear Pd(II) complexes 4 containing two DMSO
molecules in the structure were detected (complex 4 at m/z
NH2
K2PdCl4
N
Pd(1-TosC-N3)2Cl2 (2)
CH3OH ,
Δ
O
N
R
DMSO, 60 days, rt
1
R
R
N
DMF, 10 days, rt
R
N
N
O
O
O
O
S
N
Pd
Pd
N
Pd
Cl
N
HN
Cl
HN
HN
NH
NH
O
Pd
N
NH
S
O
N
R
N
N
4
O
O
N
R
N
R
R = Tos =
O
S
CH3
a
3
d
O
c
b
Scheme 2. Synthesis of complexes: Pd(1-TosC–N3)2Cl2 (2), Pd2(1-TosCÀ–N3,N4)4 (3) and Pd2(1-TosCÀ–N3,N4)2DMSO2Cl2 (4).

1062
A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
992.59 assigned as the [Pd2(L–H)2(DMSO)2Cl2Na]+ ion or at m/z
1009.46 assigned as the [Pd2(L–H)2(DMSO)2Cl2K]+ ion, and its frag-
ments). Complex 3 or its fragments were detected by MS at m/z
1268.77 assigned as the [Pd2(L–H)4]+ ion or at m/z 1290.80 as-
signed as the [Pd2(L–H)4]Na+ ion or at m/z 1308.76 assigned as
the [Pd2(L–H)4]K+. A detailed MS study of the complex PdL2Cl2 will
be described elsewhere.
due to the high symmetry of the complex and large upfield shifts
for the H-6 (d 7.60 ppm, doublet J6,5 = 8 Hz) and the NH-4 (d
7.26 ppm, broad singlet) protons.
3.2.4. Infrared spectra
The infrared spectra with tentative band assignments (m )
/cmÀ1
for cytosine, according to the literature [23], some characteristic
changes in ligand 1 and the bands in the spectra of complexes 2
and 4 are shown in Table 2. The strong to weak bands, observed be-
3.2.3. Solution studies
Compound 2 is generally insoluble in common organic solvents,
except DMF and DMSO. The molar conductivity value in DMSO
proves that complex 2 is a non-electrolyte. This finding indicates
that both the chloride anions and the organic ligands are located
in the internal coordination sphere of the Pd(II) complex. Despite
the fact that most palladium complexes (PdL2Cl2) exhibit a fast ex-
change of axial ligands with solvent molecules, 2 is stable in
DMSO–d6 for several days at room temperature.
tween 3407 and 3100 cmÀ1, are associated with
m
(N–H). Ligand 1
(keto-amino tautomer) shows characteristic
m
as(NH2) and s(NH2)
m
vibrations at 3369 and 3100 cmÀ1 for the C4 amino group, while
the ketoimino form of the ligand anion in 4 shows the N–H stretch-
ing of the imine group at 3407, 3247 and 3103 cmÀ1, which is also
indicated by the 1H NMR spectrum.
Solid PdL2Cl2 (2) shows six bands between 3406 and 3107 cmÀ1
,
supporting the existence of two rotamers [24]. The band assigned
to
(C(2)@O), which appears around 1703 cmÀ1 in the free ligand
spectrum, is appreciably shifted to lower frequencies. This modifi-
cation and changes in the zone between 1700 and 1400 cmÀ1
involving the stretching of (C@O, C@C, C@N, ring, C–N, etc.), are
With respect to the 1H NMR spectrum of ligand 1, the spectrum
(DMSO–d6) of complex 2 exhibits two pairs of signals for each pro-
ton in a 2:1 ratio (Fig. 4). The first set of resonances of 2 (marked o
in Fig. 4) displays two sets of doublets in the aromatic region, cor-
responding to the H-6 and H-5 protons (d 8.10 and 5.94 ppm) and
phenyl Ph-b and Ph-c protons (d 7.84 and 7.44 ppm). Two amino
protons at N-4, readily exchangeable with deuterium by addition
of D2O, appear as a broadened doublet at d 7.88 ppm. These data
are in accord with the keto-amino form of the ligand in the com-
plex Pd(1-TosC–N3)2Cl2 (2). On the other hand, all the protons of
the second set of resonances in the DMSO solution of 2 (marked
x in Fig. 4) were shifted upfield. Signals of the H-6 and H-5 (d
8.22 and 6.07 ppm) and Ph-b and Ph-c protons (d 7.94 and
7.50 ppm) show significant additional splitting of the H-5, H-6
and Ph doublets and the broadened singlets at d 9.34, 9.25, 9.21
and 8.89 ppm are assigned to NH protons. The latter observations
may be explained by the existence of two possible rotamers in 2,
which is also evident from the infrared spectra.
m
,
m
related to the new charge distribution in the ring of the complexes.
For the palladium complex PdL2Cl2 (2), three bands at 280, 306 and
360 cmÀ1, and for complex 4 one split band within 360–370 cmÀ1
are attributed to the m(Pd–Cl) vibrations, while the bands within
the 426–480 cmÀ1 range are assignable to the
vibrations [25].
m(Pd–N) stretching
3.2.5. Crystal structure of 3
The molecular structure of
3 includes two Pd atoms,
2.6210(15) Å apart, with the interatomic Pd1–Pd2 vector along
the twofold symmetry axis parallel to the crystallographic b-axis.
The relatively short interpalladium distance is probably caused
by steric hindrance of the bulky ligands. The coordination spheres
of both Pd atoms inside the binuclear metal complex are virtually
identical. They both consist of two exocyclic imino N4 [Pd1–N4,
1.970(9) Å; Pd2–N4, 2.039(12) Å] and two endocyclic N3 [Pd1–
N3, 2.067(10) Å; Pd2–N3, 2.090(9) Å] atoms. The coordination
spheres of the two palladium atoms are inseparable since they in-
volve four ligand molecules, each of which binds to one Pd atom
through its endocyclic N3 and to the other one through the exocy-
clic N4; hence each of the four ligand molecules bridges two palla-
dium atoms via its N–C–N moiety. The asymmetric unit contains
two ligand molecules (A and B), as well as two Pd atoms with
half-site occupancy. The asymmetric unit is then repeated by a
twofold symmetry axis operation to give a paddlewheel binuclear
structure where the adjacent ligand molecules are head-to-tail ori-
ented with respect to the twofold axis, i.e. with respect to the inter-
palladium vector (Fig. 5).
The complete geometries of both coordination spheres of com-
plex 3 are given in Table 3. The atom numbering in the ligand mol-
ecule B is composed of a prefix ‘‘2” and the second digit,
corresponds to the numbering scheme defined for the ligand mol-
ecule A. Thus, for example, N3 of the ligand molecule A corre-
sponds to N23 of the ligand molecule B. It is evident that the Pd–
N3 (endocyclic nitrogen) contacts are somewhat longer than the
Pd–N4 (exocyclic imino-nitrogen) ones. The four nitrogens forming
the first coordination sphere around Pd1 (N23, N23i, N4 and N4i)
are in an almost perfect square-planar arrangement. The maximum
deviation from the least square plane defined by Pd1 and the four
nitrogen atoms is only 0.0891(11) Å, whereas the least square
plane defined only by these four nitrogen atoms reveals a maxi-
mum deviation of 0.025(11) Å.
The 1H NMR spectrum of the dipalladium complex Pd2
(1-TosCÀ–N3,N4)2DMSO2Cl2 (4) is considerably different and
shows only one signal for each H5, H6, Ph-b, Ph-c and NH-4 proton,
Table 2
IR frequencies for cytosine (Cy), ligand 1 and complexes 2 and 4.
m
(cmÀ1
)
Cy
1
2
4
N–H
3387
3174
3369
3100
3406
3313
3288
3247
3207
3107
1686
1650
1613
1609
1514
1503
1380
1363
1191
1171
1191
1171
1145
974
3407
3247
3103
C@O
C@C
C@N
1664
1640
1617
1537
1504
1466
–
1703
1673
1524
1489
1670
1648
1569
1475
NH2 ring
SO2
1376
1353
1184
1173
1184
1173
1138
967
1396
1354
1188
1172
1025
S–N
–
–
1018
490–426
m(Pd–N)
–
478
453
417
m(Pd–Cl)
–
–
361
305
370
360
Similarly, the Pd2 coordination sphere least square plane
including palladium reveals a maximum deviation of 0.0878(9) Å,
excluding Pd2, 0.013(11) Å. In addition, remarkable planarity is re-
280

A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
1063
Table 4
Bond distances (Å) inside the cytosine ring in 1, 3 and 4.
1
3A
3B
4A
4B
N1–C2
C2–N3
N3–C4
C4–N4
C4–C5
C5–C6
C6–N1
1.432(3)
1.339(3)
1.340(2)
1.312(3)
1.436(3)
1.317(3)
1.396(3)
1.382(16)
1.389(16)
1.421(14)
1.308(15)
1.440(15)
1.351(17)
1.369(17)
1.504(16)
1.380(16)
1.443(14)
1.279(15)
1.461(17)
1.290(15)
1.381(15)
1.417(12)
1.334(12)
1.386(10)
1.307(12)
1.429(11)
1.329(14)
1.393(13)
1.407(11)
1.380(12)
1.374(11)
1.291(12)
1.452(12)
1.308(14)
1.396(11)
negative charge at the endocyclic N3 atoms compensates the posi-
tive charge of the Pd atom in the complex structure.
3.2.6. Crystal structure of 4
Molecular structure of 4 is given in Fig. 6 as an ORTEP drawing.
Complex 4 is a dinuclear bridging molecule where two palladium
atoms, being 2.9358(10) Å apart, are each coordinated by one exo-
cyclic imino-nitrogen N4 and one endocyclic nitrogen N3. The
coordination spheres are each completed by one DMSO molecule
(through its sulfur atom) and one chlorine atom. Two ligand mol-
ecules bridge two Pd atoms in such a manner that each ligand com-
plexes one Pd atom with its exocyclic imino-nitrogen N4 and the
other one with its endocyclic N3. The positive charge of the Pd
atoms (+2) is compensated by one chlorine and one deprotonated
endocyclic nitrogen, bearing a negative charge, as a consequence of
the iminooxo form stabilization upon Pd complexation (vide supra).
The geometry of the cytosine ring is given in Table 4. A compar-
ison with the analogous values observed in the ligand structure re-
veals an increase of the single bond character of the N3–C4 bond,
similarly to the case of complex 3. In both cases, stabilization of
the iminooxo form took place upon the coordination of Pd(II).
The two bridging rings involve both palladium atoms, as well as
N3, C4 and N4 of both ligand molecules, and the corresponding
planes form an interplanar angle of 89.9(2)°. The molecule contains
two DMSO molecules coordinated to the Pd atoms through their
sulfur atoms. A search of the current version of CSD (2007 release)
shows that the abundance of O-bonded and S-bonded Pd–DMSO
adducts is almost equal. Details of the coordination sphere geom-
etries are given in Table 5. The maximum deviation from the coor-
dination sphere least square plane, defined by Pd1, S3, Cl1, N3 and
Fig. 5. ORTEP drawing of complex 3 with a partial atom numbering scheme and 30%
ellipsoid probability. Hydrogen atoms are omitted for clarity.
vealed by the two planes defined by N3, C4, N4, Pd1, N4i, C4i, N3i
and Pd2 [max. deviation of the least square plane, 0.038(10) Å] and
N23, C24, N24, Pd1, N24i, C24i, N23i and Pd2 [max. deviation of the
least square plane, 0.061(9) Å]. These two planes intersect at the
Pd1–Pd2 vector, forming an interplanar angle of 89.3(3)°. This class
of ligands reveals a conformational chirality along the N–S bond, as
previously described by us [17]. Although 3 crystallizes in the cen-
trosymmetric space group Pnab, discrete complex molecules do not
contain an intramolecular inversion centre, and all the ligand mol-
ecules present inside the single complex molecule are of the same
chirality. However, the crystal structure contains complex mole-
cules of both chiralities, related by the extramolecular inversion
centers.
The cytosine ring geometries for ligand 1 as well as for com-
plexes 3 and 4 are given in Table 4. In both symmetrically indepen-
dent ligand molecules 3A and 3B, the bond distances inside the
cytosine rings reveal remarkable alterations compared to the anal-
ogous values in the structure of ligand 1. This is due to the stabil-
ization of the iminooxo form of the ligand anion upon Pd
coordination. While the length of the N3–C4 bond in ligand 1
clearly reflects its double bond character, this bond is significantly
longer in both coordinated ligand molecules in complex 3, suggest-
ing an increase of its single bond character. This implies that the
Table 3
Coordination sphere geometries in 3 (i; 1/2 À x, y, Àz).
Bond lengths (Å)
Pd1–N23
Pd1–N23i
Pd1–N4
2.067(10)
2.067(10)
1.970(9)
1.970(9)
Pd2–N3
2.090(9)
2.090(9)
2.039(12)
2.039(12)
Pd2–N3i
Pd2–N24
Pd2–N24i
Pd1–N4i
Bond angles (°)
N23–Pd1–N23i
N23–Pd1–N4
N23–Pd1–N4i
N23i–Pd1–N4
N23i–Pd1–N4i
N4–Pd1–N4i
172.4(4)
90.9(4)
88.8(4)
88.8(4)
90.9(4)
175.0(4)
N3–Pd2–N3i
173.3(4)
86.3(4)
93.4(4)
93.4(4)
86.3(4)
174.5(4)
N3–Pd2–N24
N3–Pd2–N24i
N3i–Pd2–N24
N3i–Pd2–N24i
N24–Pd2–N24i
Fig. 6. ORTEP drawing of 4. Ellipsoids are given on a 30% probability scale. The atom
numbering is provided partially and hydrogens are omitted for clarity, except for
those included in hydrogen bonding. The solvent molecule connected by the
hydrogen bond N24–HÁÁÁO9 is included.

1064
A. Višnjevac et al. / Polyhedron 28 (2009) 1057–1064
Table 5
Grants No. 098-0982914-2935, 098-1191344-2943 and 098-
0982904-2927.
Geometry of the coordination spheres around Pd1 and Pd2 in 4.
Pd1
Pd2
References
Bond lengths (Å)
Pd–S
Pd–Cl
Pd–N3 (N23)
Pd–N4 (N24)
2.263(3)
2.292(3)
2.029(7)
2.028(8)
2.252(3)
2.299(2)
2.034(7)
2.020(7)
[1] K.A. Hartman, A. Rich, J. Am. Chem. Soc. 87 (1965) 2033.
[2] R.B. Inman, J. Mol. Biol. 9 (1964) 624.
[3] P. Rajagopal, J. Feigon, Nature 339 (1989) 637.
[4] L.C. Sowers, G.V. Fazakerley, R. Eritja, B.E. Kaplan, M.F. Goodman, Proc. Natl.
Acad. Sci. USA 83 (1986) 5434.
Angles (°)
[5] (a) B. Lippert, H. Schöllhorn, U. Thewalt, J. Am. Chem. Soc. 108 (1986) 6616;
(b) W. Saenger, in: Principles of Nucleic Acid Structure, Springer Verlag, New
York, 1982;
(c) M. Monshi, K. Al-Farhan, S. Al-Resayes, G. Ghaith, A.A. Hasanein,
Spectrochim. Acta, Part A 53 (1997) 2669.
[6] D. Montagner, E. Zangrando, B. Longato, Inorg. Chim. Acta (2008), doi:10.1016/
j.ica.2008.04.030.
S–Pd–Cl
91.10(10)
89.7(2)
173.8(2)
176.1(2)
90.7(2)
90.29(10)
89.1(2)
172.5(2)
178.5(2)
90.3(2)
S–Pd–N3 (N23)
S–Pd–N4 (N24)
Cl–Pd–N3 (N23)
Cl–Pd–N4 (N24)
N3 (N23)–Pd–N4 (N24)
88.1(3)
90.2(3)
[7] (a) F. Zamora, M. Kunsman, M. Sabat, B. Lippert, Inorg. Chem. 36 (1997) 1583;
(b) A.H. Velders, B. van der Geest, H. Kooijman, A.L. Spek, J.G. Haasnoot, J.
Reedijk, Eur. J. Inorg. Chem. (2001) 369;
(c) L.Y. Kuo, M.G. Kanatzidis, M. Sabat, A.L. Tipton, T.J. Marks, J. Am. Chem. Soc.
113 (1991) 9027.
[8] P.J.S. Miguel, P. Lax, M. Willermann, B. Lippert, Inorg. Chim. Acta 357 (2004)
4552.
N24, is 0.0722(6) Å, whereas in the case of the one defined by Pd2,
S4, Cl2, N4 and N23, it is 0.076(7) Å.
The crystal structure is characterized by discrete complex mol-
ecules, each of which is connected to two DMSO molecules (in
addition to those included in the coordination around Pd), via the
imino-nitrogens N4 and N24 and the oxygen atoms of the neigh-
bouring non-coordinated solvent molecules [N4–HÁÁÁO10,
2.965(12) Å, 166°; N24–HÁÁÁO9, 3.074(15) Å, 146°] (Fig. 6).
[9] J. Müller, E. Zangrando, N. Pahlke, E. Freisinger, L. Randaccio, B. Lippert, Chem.
Eur. J. 4 (1998) 397.
ˇ
[10] (a) Lj. Glavaš-Obrovac, I. Karner, B. Zinic´, K. Pavelic´, Anticancer Res. 21 (2001)
1979;
ˇ
ˇ
(b) B. Zinic´, M. Zinic´, I. Krizmanic´, EP
0 877 022 B1, Synthesis of the
Sulfonylpyrimidine Derivatives with Anticancer Activity, 2003.;
(c) F. Supek, M. Kralj, M. Marjanovic´, L. Šuman, T. Šmuc, I. Krizmanic´, B. Zinic´,
Invest. New Drugs 26 (2008) 97.
ˇ
4. Conclusions
´
[11] J. Kašnar-Šamprec, Lj. Glavaš-Obrovac, M. Pavlak, I. Mihaljevic, V. Mrljak, N.
ˇ
Štambuk, P. Konjevoda, B. Zinic´, Croat. Chem. Acta 78 (2005) 261.
[12] L.J. Faruggia, J. Appl. Cryst. 32 (1999) 837.
[13] M.C. Burla, M. Camalli, B. Carrozzini, G.L. Cascarano, C. Giaccovazzo, G. Polidori,
Complexation of Pd(II) with 1-(p-toluenesulfonyl)cytosine li-
gand (1) leads initially to the formation of a kinetically favoured
mononuclear complex 2, regardless of the solvent used. This, ini-
tially formed complex undergoes rearrangements in aprotic polar
solvents, resulting in the formation of two different dinuclear
bridging species (3 from DMF and 4 from DMSO), where the ligand
anion (1-TosCÀ) exists in a rare iminooxo form and is coordinated
to Pd(II) through both its exocyclic (N4) and endocyclic nitrogen
atom (N3).
R. Spagna, SIR2002, Version 1.0,
A Program for Automatic Solution and
Refinement of Crystal Structures, University of Bari, Bari, Italy, 2002.
[14] G.M. Sheldrick, SHELX97: Program for the Refinement of Crystal Structures,
Universität Göttingen, Germany, 1997.
[15] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565.
[16] P. van der Sluis, A.L. Spek, Acta Crystallogr., Sect. A 46 (1990) 194.
[17] A.L. Spek, PLATON
– A Multipurpose Crystallographic Tool, Version 40607,
University of Utrecht, Utrecht, The Netherlands, 1998–2007.
ˇ
ˇ
ˇ
´
´
ˇ
´
[18] A. Višnjevac, M. Zinic, M. Luic, D. Ziher, T. Kajfez Novak, B. Zinic, Tetrahedron
63 (2007) 86.
[19] J. Bernstein, R.E. Davies, L. Shimani, N.-L. Chang, Angew. Chem. 107 (1995)
1689.
Supplementary data
[20] J.H. Gross, Mass Spectrometry, Springer, Berlin, 2004.
ˇ
[21] L.C. Gatlin, F. Turecek, in: R.B. Cole (Ed.), Electrospray Ionization Mass
Spectrometry: Fundamentals, Instrumentation, and Applications, Wiley, New
York, 1997, p. 527.
CCDC 695234, 695235 and 695236 contains the supplementary
crystallographic data for compounds 1, 3 and 4, respectively. These
data can be obtained free of charge via http://www.ccdc.cam.ac.uk/
conts/retrieving.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.
[22] M. Franska, Intern. J. Mass Spectrometry 261 (2007) 86.
[23] (a) M. Tsuboi, S. Takahasha, I. Harada, in: J. Duchesene (Ed.), Physicochemical
Properties of Nucleic Acids, vol. 2, Academic Press, London, 1973, p. 91;
(b) H. Susi, J.S. Ard, J.M. Purcell, Spectrochim. Acta 29A (1973) 725;
(c) E.D. Radchenko, G.G. Sheina, N.A. Smorygo, Y.P. Blagoi, J. Mol. Struct. 116
(1984) 387;
(d) Y. Nishimura, T. Tsuboi, Chem. Phys. 98 (1985) 71.
[24] E. Nir, I. Huenig, K. Kleinermanns, M.S. de Vries, Phys. Chem. Chem. Phys. 5
(2003) 4780.
Acknowledgments
ˇ
ˇ
[25] (a) L. Szucova, Z. Travnicek, M. Zatloukal, I. Popa, Bioorg. Med. Chem. 14
(2006) 479;
ˇ ´
We thank Dr. sc. Ljerka Tušek-Bozic for conductometric mea-
(b) I.A. Efimenko, A.P. Kurbakova, Transition Met. Chem. 19 (1994) 539;
(c) P.-C. Kong, F.D. Rochon, Can. J. Chem. 59 (1981) 3293.
surements. We appreciate the financial support of the Ministry of
Science, Education and Sports of the Republic of Croatia through