Stabilisation of the iminooxo tautomer of 1-methylcytosine in PtII complexes: Role of the ancillary ligands

Article abstract of DOI:10.1016/j.ica.2008.04.030

Reaction of cis-[L₂Pt(μ-OH)]₂(NO₃)₂ (L = PPh₃) with 1-methylthymine (1-MeTy), in DMF, leads to the formation of the mononuclear neutral adduct cis-L₂Pt{1-MeTy(-H)}(ONO₂) (1) whos

Full text of DOI:10.1016/j.ica.2008.04.030

Inorganica Chimica Acta 362 (2009) 725–732
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Stabilisation of the iminooxo tautomer of 1-methylcytosine in PtII complexes:
Role of the ancillary ligands
Diego Montagner a, Ennio Zangrando b, Bruno Longato a,
*
a Dipartimento di Scienze Chimiche, Università di Padova, Via Marzolo 1, 35131 Padova, Italy
b Dipartimento di Scienze Chimiche, Università di Trieste, Via Giorgieri 1, 34127 Trieste, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of cis-[L2Pt(l-OH)]2(NO3)2 (L = PPh3) with 1-methylthymine (1-MeTy), in DMF, leads to the for-
Received 28 February 2008
Accepted 16 April 2008
Available online 22 April 2008
mation of the mononuclear neutral adduct cis-L2Pt{1-MeTy(–H)}(ONO2) (1) whose structure in the solid
state has been obtained by single crystal X-ray diffraction. The deprotonated nucleobase is bounded at
the N(3) site, with the pyrimidinic ring almost perpendicular (78.0(1)°) to the metal coordination plane.
The fourth ligand is a monodentate nitrate group. Addition of 1 equiv. of 1-methylcytosine (1-MeCy)
causes the immediate replacement of the nitrato ligand to form the cationic complex cis-[L2Pt{1-
MeTy(–H)}(1-MeCy,N3)]NO3 (2) in which both the nucleobases are N(3)-platinated. In CD2Cl2 at ꢀ40 °C
2 exists as a mixture of two conformers (2:1 molar ratio) arising from the different orientation of the
nucleobases with respect to the metal coordination plane.
In solution of DMSO, DMF or chlorinated solvents, 2 slowly converts into the isomer cis-[L2Pt{1-MeTy
(–H)}(1-MeCy,N4)]NO3 (3), containing the tautomeric form of the cytosine stabilised through the coordi-
nation at the N(4) atom, as a mixture of conformers whose relative abundance is dependent on the sol-
vent and the temperature.
Dedication to Bernhard Lippert.
Keywords:
Platinum complexes
1-Methylthymine
1-Methylcytosine tautomers
X-ray structures
In contrast, the analogous complex of 2 containing the phosphine PMe3, cis-[(PMe3)2Pt{1-MeTy(–H)}(1-
MeCy,N3)]NO3 (4), also isolated as pure compound, in DMSO solution slowly rearranges leading to the
elimination of the neutral 1-MeTy, with the formation of the dinuclear cytosinate complex cis-
[(PMe3)2Pt{1-MeCy(–H),N3N4}]2(NO3)2, previously characterised by us.
Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction
in the precursor cis-L2Pt{1-MeTy(–H)}(ONO2) (L = PPh3, 1) charac-
terised by X-ray single crystal analysis. The isolated complex cis-
Much is known on the binding modes of the model nucleobase
N(3)-substituted 1-methylcytosine (1-MeCy) to a metal centre, as
neutral and as N(4)-deprotonated (1-MeCy(–H)) ligand [1]. The
usual site of metallation of the neutral base is the N(3)-endocyclic
atom. However, the cases in which the iminooxo tautomer of the
cytosine is stabilised through the coordination at the exocyclic
N(4) have been also described [2] (Scheme 1).
In this paper we present an example of platinum(II) complex in
which the initially N(3)-bonded cytosine (mode a) rearranges into
its more stable tautomeric derivative (mode b). Such isomerisation,
which requires the shift of one of NH2 protons to the N(3) site of
the cytosine ligand, occurs selectively in the cationic complex cis-
[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy)]+ (2), containing the deproto-
nated 1-methylthymine (1-MeTy) and the neutral cytosine ligands,
both coordinated at the N(3)-atom. The mixed complex 2 was pre-
pared by the replacement of the nitrate group by a cytosine ligand
[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy,N4)]NO3 (3), was characterised
by multinuclear and 2D-NMR spectroscopy.
In order to evaluate the role of the PPh3 ligands in the stabilisa-
tion of the cytosine in its tautomeric form, we have prepared the
complex cis-[L2Pt{1-MeTy(–H)}(1-MeCy)]+ (L = PM3, 4), containing
the less hindered and more basic trimethyl phosphine. 4 in DMSO
slowly rearranges leading to the elimination of the neutral 1-MeTy
and the formation of the dinuclear cytosinate complex cis-
[(PMe3)2Pt{1-MeCy(–H),N3N4}]2(NO3)2, previously characterised
[3]. The formal migration of the metal from the N3 to N4 site of
the cytosine molecule in Pt(II) complex was previously observed
in the related species cis-[(dppf)Pt{1-MeTy(–H)}(1-MeCy,N3)]BF4,
where dppf is 1,10-bis(diphenylphosphino)ferrocene [4].
2. Experimental
2.1. Synthesis and materials
cis-[L2Pt(
l-OH)]2(NO3)2 (L = PPh3[5], PMe3[2]) and 1-MeCy [6]
* Corresponding author. Tel.: +39 049 8275197; fax: +39 049 8275161.
E-mail address: bruno.longato@unipd.it (B. Longato).
were prepared as previously reported. 1-MeTy and all the solvents
0020-1693/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2008.04.030

726
D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
a white solid that was recovered by filtration, washed with Et2O
a
b
H
M
and dried under vacuum. (71.8 mg, yield 66%). Elem. Anal. Calc.
for C47H44N6O6P2Pt (1045.92): C, 53.97; H, 4.25; N, 8.03. Found:
C, 52.86; H, 4.14; N, 7.97%. 1H NMR in CD2Cl2 at 25 °C (d): 7.65–
7.16 cm (30H, PPh3); 8.61 s (1H, N4H), 8.38 s (1H, N4H), 6.36 s
NH2
N(4)
M
H
(3)N
N
3
3
(1H, H6), 6.78 d (1H, H6, JHH 6 Hz), 6.08 d (1H, H5, JHH 6 Hz),
2.86 s (3H, NCH3), 2.93 s (3H, NCH3) 1.50 s (3H, CH3); 1H NMR in
CD2Cl2 at ꢀ40 °C (d): 7.92–6.36 cm (30H, PPh3); more abundant
conformer, 8.60 s (1H, N4H), 8.32 s (1H, N4H), 6.39 s (1H, H6),
N
N
O
O
CH3
CH3
3
3
6.78 d (1H, H6, JHH 6 Hz), 6.20 d (1H, H5, JHH 6 Hz), 2.99 s (3H,
NCH3), 2.91 s (3H, NCH3), 1.34 s (3H, CH3); less abundant con-
former, 8.71 s (1H, N4H), 8.31 s (1H, N4H), 6.39 s (1H, H6), 6.80
Scheme 1.
3
3
d (1H, H6, JHH 6 Hz), 6.14 d (1H, H5, JHH 6 Hz), 3.15 s (3H,
NCH3), 2.84 s (3H, NCH3), 1.55 s (3H, CH3). 1H NMR in DMSO-d6
at 25 °C (d): 7.55–7.23 cm (31H, PPh3 and H6); 8.50 s (1H, N4H),
(CH2Cl2, DMF, DMSO-d6, CDCl3, CD2Cl2, CD3CN, Et2O) were Aldrich
products.
3
8.25 s (1H, N4H), 6.78 s (1H, H6), 5.59 d (1H, H5, JHH 6 Hz), 2.89
s (3H, NCH3), 2.80 s (3H, NCH3), 1.40 s (3H, CH3). The 31P{1H}
NMR data are collected in Table 2.
2.1.1. Synthesis of cis-(PPh3)2Pt{1-MeTy(–H)}(ONO2) (1)
To
a
solution of cis-[(PPh3)2Pt(
l
-OH)]2(NO3)2 (72.6 mg,
4.5 ꢁ 10ꢀ2 mmol)
in
CH2Cl2
(5 mL) 1-MeTy (12.7 mg,
9.0 ꢁ 10ꢀ2 mmol) was added, and the suspension stirred at room
temperature for ca. 24 h. The resulting mixture was filtered to
eliminate trace amounts of a solid. Addition of Et2O (35 mL) to
the filtrate afforded a white solid which was isolated and dried un-
der vacuum. The yield of 1 was 64 mg (77%). Purification of the so-
lid from CHCl3, by vapour diffusion of Et2O at room temperature,
afforded crystals having the composition cis-(PPh3)2Pt{1-MeTy
(–H)}(NO3) ꢂ 3H2O. Elem. Anal. Calc. for C42H43N3O8P2Pt (974.8):
C, 51.75; H, 4.45; N, 4.31. Found: C, 51.58; H, 4.26; N, 4.20%. 1H
NMR in CDCl3 (d): 7.78–6.91 cm (30H, PPh3); 6.32 s (1H, H(6)),
2.95 s (3H, NCH3), 1.65 s (3H, CH3); 1H NMR in DMSO-d6 (d)
7.72–7.09 cm (30H, PPh3), 6.88 s (1H, H(6)), 2.96 s, (3H, NCH3),
1.49 s (3H, CH3). The 31P{1H} NMR data are collected in Table 1.
2.1.3. Synthesis of cis-[(PPh3)2Pt{1-MeTy(–H)} (1-MeCy,N4)]NO3 (3)
Twenty-one milligrams of 1 (2.28 ꢁ 10ꢀ5 mol) were dissolved in
3 mL of DMF and then 1-MeCy (2.9 mg, 2.32 ꢁ 10ꢀ5 mol) was
added. After 0.5 h a solution was obtained which was subsequently
stirred for one week at room temperature. Addition of Et2O affor-
ded a white solid that was recovered by filtration, washed with
Et2O and dried under vacuum. The yield of 3 was 15.7 mg, 65%.
Elem. Anal. Calc. for C47H44N6O6P2Pt (1045.92): C, 53.97; H, 4.25;
N, 8.03. Found: C, 52.86; H, 4.14; N, 7.97%. 1H NMR in DMSO-d6:
7.60–7.26 (30H, PPh3); more abundant conformer: 10.69 s (1H,
3
N3H), 6.95 d (1H, H6, JHH 7.0 Hz), 6.83 s (1H, H6), 6.11 s (1H,
3
N4H), 5.43 d (1H, H5, JHH 7.0 Hz), 3.11 (s, 3H, NCH3), 2.49 (s, 3H,
NCH3), 1.42 (s, 3H, CCH3); less abundant conformer: 10.96 s (1H,
3
N3H), 6.92 d (1H, H6, JHH 7.0 Hz), 6.86 s (1H, H6), 6.20 s (1H,
2.1.2. Synthesis of cis-[(PPh3)2Pt{1-MeTy(–H)} (1-MeCy,N3)]NO3 (2)
To a solution of 1 (95.9 mg, 0.10 mmol) in 5 mL of CH2Cl2 was
added 1-MeCy (12.6 mg, 0.10 mmol) which dissolved in a few min-
utes, under stirring at room temperature. Addition of Et2O afforded
3
N4H), 5.61 d (1H, H5, JHH 7.0 Hz), 3.23 (s, 3H, NCH3), 2.71 (s, 3H,
NCH3), 1.49 (s, 3H, CCH3). 1H NMR in CD2Cl2: 10.99 s (1H, N3H),
3
7.65–7.18 (30H, PPh3), 6.71 d (1H, H6, JHH 7.0 Hz), 5.87 s (1H,
3
N4H), 5.39 d (1H, H5, JHH 7.0 Hz), 3.18 (s, 3H, NCH3), 6.40 s (1H,
H6), 3.00 (s, 3H, NCH3), 1.53 (s, 3H, CCH3). The 31P{1H} NMR data
are collected in Table 2.
Table 1
31P{1H}NMR data of complex 1 in various solvents (d in ppm and J in Hz) at 25 °C
2.1.4. Synthesis of cis-[(PMe3)2Pt{1-MeTy(–H)}(1-MeCy,N3)]NO3 (4)
Solvent
PA (1JPPt
)
PB (1JPPt
)
2JPP
A mixture of cis-[(PMe3)2Pt(l-OH)]2(NO3)2 (146 mg, 0.17 mmol)
CH2Cl2
CDCl3
DMF
7.41 (3294)
7.66 (3290)
8.57 (3257)
9.30 (3309)
7.62 (4174)
4.85 (4230)
5.07 (4240)
5.55 (4320)
5.72 (4287)
3.73 (3050)
21.9
21.9
22.2
22.3
21.9
and 1-MeTy (47.6 mg, 0.34 mmol) in DMF (5 mL) was stirred at
room temperature for 48 h, during which most of the solid dis-
solved. Addition of 1-MeCy (42.5 mg, 0.34 mmol) to the resulting
mixture caused the immediate precipitation of a solid, which was
collected by filtration and purified by dissolution in CH2Cl2/DMSO
DMSO-d6
CH3CNa
a
Fresh solution.
Table 2
31P{1H} NMR data of 2 and 3 in different solvents and temperatures (d in ppm and J in Hz). In square brackets the relative abundance of the conformers
Compound
Solvent (temp., K)
PA(1JPPt
)
PB(1JPPt
)
2JPP
2
2
CD2Cl2 (298)
CD2Cl2 (233)
0.98 br s (ca. 3443)
1.82 d (3432)
0.08 d (3434)
0.40 br s (ca. 3478)
1.29 br s (ca. 3430)
10.01 d (3524)
9.65 da
10.51 d (ca.3449)
10.03 d (ca.3449)
9.48 da
ꢀ1.88 d (3630)
ꢀ1.87 d (3596)
ꢀ1.83 d (3596)
ꢀ2.38 d (3597)
ꢀ2.03 d (3637)
3.67 d (3194)
2.87 da
3.51 d (ca.3163)
3.25 d (ca.3163)
4.55 da
20.0
19.7 [35%]
19.5 [65%]
19.9
2
2
3
DMSO-d6 (298)
DMF (298)
CD2Cl2 (298)
20.2
20.9 [94%]
20.8 [6%]
20.5 [69%]
21.0 [27%]
20.2 [4%]
21.0 [93%]
20.4 [7%]
20.9 [74%]
20.6 [26%]
3
CD2Cl2 (183)
3
3
DMF (298)
10.79 d (3476)
3.55 d (3195)
9.96 da
4.11 da
DMSO-d6 (298)
10.31 d (3529)
9.38 d (3595)
2.87 d (3202)
3.54 d (3240)
a
1JPPt not detected.

D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
727
(10:1 vol/vol) and precipitated with Et2O. The white solid, collected
by filtration, washed with Et2O and dried under vacuum was 43 mg
(yield 19%). The elemental analysis and NMR data are consistent
with the composition cis-[(PMe3)2Pt{1-MeTy(–H)}(1-MeCy,N3)]-
NO3 ꢂ DMSO ꢂ H2O. Elem. Anal. Calc. for C17H32N6O6P2Pt ꢂ DM-
SO ꢂ H2O (769.6): C, 29.57; H, 5.50; N, 10.89. Found: C, 29.31; H,
5.64; N, 10.87%. 1H NMR in DMSO-d6: 8.38 s (1H), 8.03 s (1H),
3
3
7.76 d (1H, JHH 7.2 Hz), 7.37 s (1H), 5.78 d (1H, JHH 7.2 Hz), 3.18
2
s (3H), 3.10 s (3H), 1.71 s (3H), 1.43 d (9H, PMe3, JHP 10 Hz).
31P{1H} in DMSO-d6, d (ppm): two AX multiplets at ꢀ28.3 (1JPPt
3424 Hz), ꢀ29.3 (1JPPt 3185 Hz) with JPP = 25.4 Hz (relative abun-
2
dance 65%) and ꢀ28.4 (1JPPt 3424 Hz), ꢀ29.4 (1JPPt 3185 Hz) with
2JPP = 25.4 Hz (relative abundance 35%).
2.2. NMR measurements
NMR spectra were obtained in solution of various solvents at
300 K, in 5-mm sample tubes, with: a Bruker Avance 300 MHz
for 1H and 31P (operating at 300.13 and 121.5 MHz, respectively);
with a Bruker 400 AMX-WB spectrometer for 15N (operating at
40.6 MHz); with a Bruker Avance DMX 600 (5 mm TXI probe with
gradients) using gradients during the mixing time period (0.45 s)
for the NOESY experiment. The 31P NMR spectra in CH2Cl2, DMF
and CH3CN were obtained using a capillary containing D2O for lock
signal.
Fig. 1. Molecular structure of complex 1, cis-(PPh3)2Pt{1-MeTy(–H)}(ONO2) (label-
ling scheme of phenyl C atoms not indicated for sake of clarity). Coordination bond
lengths (Å) and angles (°): Pt–N(3) 2.050(6), Pt–O(1) 2.117(4), Pt–P(1) 2.227(2), Pt–
P(2) 2.270(2), N(3)–Pt–O(1) 87.14(19), N(3)–Pt–P(1) 91.39(16), O(1)–Pt–P(1)
174.60(13), N(3)–Pt–P(2) 170.32(15), O(1)–Pt–P(2) 83.28(13), P(1)–Pt–P(2)
98.28(7).
The 1H chemical shifts were referenced to the residual impurity
of the solvent. The external references were H3PO4 (85 w/w in D2O)
for 31P, and CH3NO2 (in CDCl3 at 50% w/w) for 15N. Inverse detected
spectra were obtained through heteronuclear multiple bond corre-
lation (HMBC) experiments, using parameters similar to those pre-
viously reported [7].
ifests a slight tetrahedral distortion with atom donors displaced by
ca. 0.06 Å. The nucleobase is bound to the metal through the
deprotonated N(3) donor (Pt–N(3) 2.050(6) Å), which represents
the preferentially binding site for this pyrimidine base, while the
Pt–ONO2 bond distance is 2.117(4) Å, with Pt–O–N bond angle of
120.2(4)°.
As far as Pt–P bond lengths, it is worth noting the shorter value
measured for the phosphine trans to the nitrate, (2.227(2) Å) with
respect to that trans to the nucleobase of 2.270(2) Å. The N(3)–Pt–
O(1) angle, 87.14(19)°, is narrower in comparison to the P(1)–Pt–
P(2) one, 98.28(7)°, likely induced by steric requirements.
The Pt–N(3) and Pt–P(2) bond distances, trans to each other, of
length 2.050(6) and 2.270(2) Å, respectively, are comparable with-
in their e.s.d.’s with the values of 2.072(5) and 2.268(2) Å found in
the chlorine derivative, cis-[(PPh3)2Pt{1-MeTy(–H)}Cl] [11], but the
former distance is significantly shorter with respect to the values
of 2.12(1) and 2.097(9) Å measured in the less accurate monocat-
ionic species cis-[(PMe3)2Pt-{1-MeTy(–H)}(CH3CN)]+ and cis-[(PMe3)2
Pt-{1-MeTy(–H)}{CH3C(NH)NH2}]+, [12] respectively, where the
base is trans to PMe3.
The coordination bond angles C(2)–N(3)–Pt and C(4)–N(3)–Pt
(116.3(6)° and 119.4(5)°, respectively) in 1 are only slightly differ-
ent since the base presents a pseudo twofold axis. This feature con-
trasts with the unsymmetrical connection observed for cytosine
and guanine bases where the exocyclic N donor angles differ in
the range 7–12° [13].
2.3. X-ray structure determination
Diffraction data for compound 1 were collected at room tem-
perature on a Nonius DIP-1030H system with Mo K
a radiation
(k = 0.71073 Å). Cell refinement, indexing and scaling of the data
set were carried out using programs DENZO [8] and SCALEPACK [8].
The structure was solved by direct method and subsequent Fourier
analyses [9] and refined by the full-matrix least-squares method
based on F2 with all observed reflections [9]. A residual in the
DF
map was interpreted as lattice water oxygen at half occupancy
(hydrogen atoms not located). All the calculations were performed
using the WINGX System, Ver 1.70.01 [10].
Crystal data of 1 ꢂ 0.5(H2O): C42H38N3O5.50P2Pt, M = 929.78,
monoclinic, space group P21/c, a = 12.184(3), b = 13.796(3),
c = 24.926(4)
Å,
b = 93.27(2)°,
(Mo
) = 3.477 mmꢀ1
V = 4183.0(15) Å3,
Z = 4,
Dcalc = 1.476 g/cm3,
l
K
a
,
F(000) = 1852,
h
range = 2.20–26.02°. Final R1 = 0.0390, wR2 = 0.0903, S = 0.834 for
484 parameters and 53637 reflections, 7948 unique [Rint = 0.0759],
of which 4214 with I > 2r(I), max positive and negative peaks in DF
map 0.669, ꢀ0.577 e Åꢀ3
.
The thymine base is oriented almost normal to the coordination
mean plane forming a dihedral angle of 78.0(1)°, while the nitro
group is more bent, and the mean plane figures out a dihedral an-
gle of 64.6(2)°. The phenyl ring C(11) is oriented in such a way to
3. Results and discussion
3.1. Characterisation of cis-(PPh3)2Pt{1-MeTy(–H)}(ONO2) (1)
The reaction of cis-[(PPh3)2Pt( -OH)]2(NO3)2 with 1-MeTy, car-
ried out in different solvents (CH2Cl2, DMF, CH3CN), affords the
neutral complex cis-(PPh3)2Pt{1-MeTy(–H)}(ONO2) (1) as the only
product that can be isolated.
The X-ray structural determination of 1, reported in Fig. 1,
shows the Pt ion in a square planar coordination geometry
achieved through the phosphorous atoms, the nitrogen donor of
the thymine and the nitrate oxygen. The coordination plane man-
favour an intramolecular
p–p interaction with the model nucleo-
base (see Fig. 1, centroid-to-centroid distance 3.677(5) Å, the dihe-
dral angle formed by the rings 28.0°), and also indicated by the
eclipsed conformation for the torsion angle C(11)–P(1)–Pt–N(3)
l
(1.5°). Another intramolecular weaker
p–p interaction is mani-
fested by phenyl rings C(17) and C(29) that form an angle of 2.7°
and their centroids are 3.795(5) Å far apart. The present structure
confirms an arrangement of the ligands analogous to that found
in the monocationic derivatives cis-[(PPh3)2Pt(1-MeCy)(ONO2)]-
NO3 and cis-[(PPh3)2Pt(9-MeGu)(ONO2)]NO3 [13].

728
D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
The unit cell of 1 shows a void accessible to solvent of 309.0 Å3
+
+
CH3
N
(ca. 7.4% of the volume). We also obtained another crystal form of
cis-(PPh3)2Pt{1-MeTy(–H)}(ONO2), monoclinic, space group P21/c,
unit cell a = 11.899(2), b = 21.878(3), c = 15.985(3) Å, b = 90.63(2)°
and containing 4.5 water molecules of crystallisation. These crystal
data are slightly less accurate and reveal a complex conformation
almost superimposable to that of 1; thus their report is worthless.
The 1H NMR spectra of 1 in various solvents (see Section 2) ex-
hibit a single set of resonances of the nucleobase protons indicative
of the presence of a single species in solution. Similarly, the 31P
NMR spectra are characterised by a single AB pattern in which
O
H2N
L
L
(3)N
O
N
O
N
CH3
Pt
Pt
NH2
CH3
O
L
N(3)
L
N
O
O
CH3
1
N
N
the values of chemical shift and JPPt are clearly dependent on
the solvent, as shown in Table 1. The doublet at higher field exhib-
its the larger value of 1JPPt coupling (in the range 4230–4320 Hz) in
chlorinated solvents, DMSO-d6 and DMF but the opposite holds in
CH3CN.
H3C
H3C
hh
ht
1
L = PPh
The resonance with the higher value of JPPt is attributable to
3
the phosphine trans to the nitrate ligand or to a solvent molecule.
Similar trends on the 31P NMR parameters were noticed for re-
Scheme 2.
lated complexes formed in the reactions of cis-[(PMe3)2Pt(l-
OH)]2X2 (Xꢀ = ClO4, NO3) [12] and cis-[(dppf)Pt(
l-OH)]2X2
the N(3) atom. Due to the different orientations of the nucleobases
with respect to the metal coordination plane (Scheme 2), two con-
formers are expected for complex 2. In the Scheme, the ht con-
former is such to exhibit the methyl group, bound to the N1
atom in 1-MeCy and 1-MeTy, oriented in opposite directions.
The presence of two conformers in solutions of 2 was clearly
evidenced in the 1H and 31P NMR spectra. As shown in Fig. 2a, at
room temperature, the 31P NMR spectrum of a freshly prepared
solution of 2 in CD2Cl2 is characterised by two resonances having
the same relative intensities: a very broad singlet at d 0.98 ppm
(dppf = 1,10-bis(diphenylphosphino)ferrocene; Xꢀ = BF4) [4] with
1-MeTy. In those cases the complexes cis-[(PMe3)2Pt{1-MeTy
(–H)}(CH3CN)]ClO4 and cis-[(dppf)Pt{1-MeTy(–H)}(DMF)]BF4 were
structurally characterised. In the present case, attempts to isolate
similar solvento complexes led invariably to 1.
3.2. Characterisation of cis-[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy,N3)]NO3
(2)
1
(flanked by 195Pt satellites, JPPt ca. 3445 Hz) and a sharp doublet
The addition of 1 equiv. of 1-MeCy to a DMF solution of 1 af-
fords immediately the mixed complex cis-[(PPh3)2Pt{1-MeTy
(–H)}(1-MeCy,N3)]NO3 (2) resulting in the fast replacement of the
nitrato ligand by the added nucleobase. The reaction occurs quan-
titatively in DMF and CH2Cl2 whereas in DMSO an equilibrium be-
tween the species 1 and 2 is observed. The spectroscopic analysis
of the isolated product is consistent with the presence of the
deprotonated 1-MeTy and the neutral 1-MeCy, both platinated at
2
at d ꢀ2.04 (1JPPt = 3631 Hz, JPP = 20.0 Hz). Lowering the tempera-
ture at ꢀ40 °C, two AB multiplets, having relative intensities of
ca 2:1, whose parameters are collected in Table 2, are detectable
(Fig. 2b and c).
Similarly, in the 1H NMR spectrum at room temperature, each
nucleobase shows a single set of resonances. The assignments of
the cytosine NH2 protons were obtained through inverse detected
Fig. 2. 31P{1H} NMR spectra of cis-[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy,N3)]NO3 (2) in CD2Cl2 (ca. 0.1 M): (a) fresh solution, at 25 °C; (b,c) at ꢀ40 °C; (d) after 8 days, at 25 °C.

D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
729
1H, 15N heteronuclear multiple bond coherence experiments
(HMBC). In CD2Cl2, the two NH resonances at 8.61 and
+
CH3
N
+
CH3
N
d
O
8.38 ppm correlate with the same 15N resonance at d = ꢀ270.5
(1JNH = 69 and 89 Hz, respectively). The pertinent spectrum is re-
ported in Fig. 1S of the Supplementary material. At low tempera-
ture (ꢀ40 °C) each nucleobase resonance appears doubled with a
relative intensities of the signals of ca. 2:1 (see Section 2), in agree-
ment with the presence of two head-to-tail and head-to-head con-
formers. The dynamic process leading to the broadening of one of
the phosphine resonance, observed at room temperature (Fig. 2a),
was not investigated in details.
O
(3)N
N
H
H
L
N(4)
L
N(4)
H
H
Pt
Pt
O
O
L
N(3)
N
L
N
N
O
CH3
O
CH3
In solution of chlorinated solvents, DMF or DMSO complex 2 is
only moderately stable. In a few days at room temperature it con-
verts in large extent into the isomer cis-[(PPh3)2Pt{1-MeTy(–H)}(1-
MeCy,N4)]NO3, 3, in which the cytosine is coordinated to the metal
through the N4 atom. The migration of the metal from the N(3) to
N(4) site of the cytosine is evidenced in the 31P NMR spectra by the
appearance of a sharp AB system at lower field, as shown in Fig. 2d
for a solution of 2 in CD2Cl2. After 8 days the residual concentration
of 2 is about 6% in CD2Cl2 as well as in DMF.
H3C
H3C
ht, anti
ht, syn
+
+
H
O
N
H
N
H
N
L
N
O
CH3
L
N
CH3
L
N
Pt
3.3. Characterisation of cis-[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy,N4)]NO3
(3)
Pt
O
H
O
L
N
N
N
O
CH3
O
CH3
Complex 3 was isolated as a pure compound from a solution of
DMF by slow diffusion of Et2O but we were unable to obtain suit-
able crystals for X-ray structure analysis. Its characterisation,
therefore, stems from NMR studies in solution. The presence of
the cytosine in its iminooxo tautomeric form, platinated at the exo-
cyclic N(4) atom, has been established by inverse detection of 1H
and 15N nuclei through HMBC experiments.
N
H3C
H3C
hh, syn
hh, anti
L = PPh
3
The 1H NMR spectrum of 3 in CD2Cl2 exhibits two NH reso-
nances, at d 10.99 and 5.87 ppm, having the same relative intensi-
ties, that correlate with two different nitrogen atoms at d = ꢀ229.6
(1JNH = 89 Hz) and ꢀ252.1 (1JNH = 78 Hz), attributable to the N3 and
N4, respectively (Fig. 3). This latter signal appears further split due
to the coupling with one of the 31P nuclei (2JNP = 118 Hz).
Scheme 3.
A simple inspection of the molecular models, allowing an
orthogonal arrangement of the two nucleobases with respect to
the Pt coordination plane, [2c] leads to draw eight possible con-
formers for complex 3, four of them shown in Scheme 3.
In the head-to-tail conformation the hydrogen on the N4 atom
(of cytosine) and the N1–CH3 group (thymine) lie on the same side
of the P2Pt plane, whereas in the head-to-head arrangement they
are on the opposite sides. Moreover, owing to the double bond
character of the C4–N4 bond, the hydrogen atom bound at the
N3 position can be near (syn) or far (anti) with respect to the metal.
Fig. 2d and 5a indicates that in CD2Cl2 3 is present as a mixture
of two conformers, one of which is largely predominant (ca. 20:1),
both characterised by AB patterns (see Table 2). The major reso-
nances, at d 10.01 and 3.67 ppm, exhibit well resolved 195Pt satel-
lites. It is worth to note that the migration of the metal from the N3
to the N4 site of the cytosine determines a remarkable shift at low-
er field of both the PPh3 resonances and significant changes of the
1JPPt values.
The cis–trans isomerism about the N4@C4 double bond was
investigated through NOESY experiments that allow the evaluation
of the relative distances between the protons [14]. In our case the
cross peak between H5 and N4H is considerably more intensive
than the N3H–N4H cross peak, and it appears in the contour plot
at a relatively larger intensity level (as shown in Fig. 4).
These results allow us to say that the conformer having a trans
arrangement of H3 and H4 around the cytosine N4@C4 double
bond is the predominant species, although we cannot discriminate
between the ht,syn and the hh,syn conformers.
The number of conformers depends on the solvent and the tem-
perature. Fig. 5a and b shows the 31P NMR spectra of 3 in CD2Cl2 at
25 and ꢀ90 °C, respectively. Each doublet of the main system AB
observed at room temperature, appears to be replaced by a couple
Fig. 3. 15N,1H HMBC spectrum of cis-[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy,N4)]NO3 (3)
in CD2Cl2 (evolution time 5.5 ms).

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D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
Fig. 4. NOESY spectrum of 3 in CD2Cl2.
Fig. 5. 31P{1H} NMR spectra (central part) of 3: (a) in CD2Cl2 at 25 °C; (b) in CD2Cl2 at ꢀ90 °C; (c) in DMSO-d6, at 25 °C.
of signals having a relative intensity of 2.5:1 (Table 2) at low tem-
perature. Moreover, in addition to a third relatively broad AB sys-
tem (at d 9.48 and 4.55 ppm), others very weak doublets are
detectable in Fig. 5b. The 31P NMR spectral changes with tempera-
ture find a correspondence on the 1H NMR spectra (see Section 2).
As expected, two set of signals (relative intensities 2.5:1) for each
nucleobase were observed at ꢀ90 °C. These are likely to arise from
a slow rotation of the cytosine ligand around the Pt–N4 bond, at
low temperature.
In agreement with the observations carried out in related cyto-
sine complexes [2c], the relative stability of the conformers de-
pends on the nature of the solvent. As shown in Fig. 5c and Table
2, significant changes on the relative intensities of the NMR signal
occur when 3 is dissolved (or prepared) in DMSO or DMF.

D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
731
3.4. Role of the phosphine on the stabilisation of the cytosine in its
iminooxo tautomeric form
weeks at room temperature about 50% of cis-½ðPMe3Þ2
2þ
Ptf1-MeCyð—HÞgꢃ2 appears to have converted into the thermo-
dynamically stable trinuclear derivative cis-½ðPMe3Þ2Ptf1-MeCy
ð—HÞgꢃ33þ, shown in Fig. 6c as a sharp AB system at lower field.
The same figure indicates that a small amount of the complex 4
is still present in the reaction mixture, along with other unknown
species, not observed initially, responsible of the new singlets at d
ꢀ31.50 and ꢀ31.61 ppm.
The presence of the PPh3 ligands in 3 appears to be important
for the stabilisation of the cytosine ligand in its iminooxo form.
Preliminary results obtained with the analogous complex of 2 con-
taining the phosphine PMe3, cis-[(PMe3)2Pt{1-MeTy(–H)}(1-Me-
Cy,N3)]NO3 (4), in DMSO solution undergoes
a
different
rearrangement that implies an interligand proton exchange, with
elimination of the neutral 1-MeTy molecule. The final product is
a mixture of polynuclear cyclic species cis-[(PMe3)2Pt{1-MeCy
(–H)}]n(NO3)n (n = 2, 3), previously characterised by us [3], contain-
ing the N4-deprotonated cytosine bridging the metal centres
through the N3 and N4 atoms.
The nature of the intermediate(s) leading to cis-½ðPMe3Þ2Pt
2þ
f1-MeCyð—HÞgꢃ2
remains undefined. The presence of an imi-
nooxo species, analogue of 3, seems to be ruled out, since the only
detectable resonance in the low field region of the 1H NMR spec-
trum was that of free 1-MeTy (at d 11.18). A better insight in this
system is strongly limited by the low solubility of 4 in chlorinated
solvents or DMF.
Compound 4, formed in quantitative yield (by NMR) by reacting
stoichiometric amounts of cis-[(PMe3)2Pt(l-OH)]2(NO3)2 and 1-
MeTy in DMF, followed by addition of 1 equiv. of 1-MeCy, is scar-
cely soluble in DMF and CH2Cl2. In DMSO-d6, a fresh solution of 4
contains a mixture of two conformers (relative abundance 3:1),
as indicated by the presence of two sets of signals in the 31P
(Fig. 6a) and 1H NMR spectra (see Section 2). The binding of the
cytosine at the N(3) site is documented by the presence of the
NH2 resonances in the range d 7.9–7.7 in the 1H NMR.
As shown in Fig. 6b, after 20 h at room temperature, two new
sets of sharp multiplets (d = ꢀ25.9 to ꢀ26.7 ppm and ꢀ31.0 to
ꢀ31.9 ppm) develop along with a very broad system, partially
overlapped with the signals of 4. The AB pattern at higher field
is attributable to cis-[(PMe3)2Pt{1-MeCy(–H),N3N4}]2(NO3)2, the
4. Conclusion
In this paper we have presented the characterisation of a rare
example of cytosine complex in which the tautomeric form of
the nucleobase is stabilised through the metal coordination at
the exocyclic nitrogen. The precursor of this species is the isomer
cis-[(PPh3)2Pt{1-MeTy(–H)}(1-MeCy,N3)]+, formed by the facile
substitution of the nitrato ligand in the thyminato complex cis-
(PPh3)2Pt{1-MeTy(–H)}(ONO2). The formal migration of the metal
from the N3 to N4 site of the cytosine molecule, likely due to steric
effects of ancillary ligands, was previously observed in the related
phosphine complex cis-[(dppf)Pt{1-MeTy(–H)}(1-MeCy,N3)]BF4
(dppf = 1,10-bis(diphenylphosphino)ferrocene) [4]. In that case,
however, the isomer cis-[(dppf)Pt{1-MeTy(–H)}(1-MeCy,N4)]+ was
stable only in solution.
dinuclear species formed when cis-[(PMe3)2Pt(l-OH)]2(NO3)2 re-
acts with 1-MeCy [3]. The formation of this N4-deprotonated cyto-
sine complex was confirmed by the appearance of the signals of the
neutral 1-MeTy in the corresponding 1H NMR spectrum. In several
Fig. 6. 31P{1H} NMR spectra (central part) of cis-[(PMe3)2Pt{1-MeTy(–H)}(1-MeCy,N3)]NO3 (4) in DMSO-d6, at 25 °C: (a) fresh solution; (b) after 20 h (at room temperature);
(c) after 2 months (at room temperature).

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D. Montagner et al. / Inorganica Chimica Acta 362 (2009) 725–732
[2] (a) B. Lippert, H. Schöllhorn, U. Thewalt, J. Am. Chem. Soc. 108 (1986) 6616;
Finally, the peculiar properties of the PPh3 ligands in the stabil-
(b) F. Pichierri, D. Holthenrich, E. Zangrando, B. Lippert, L. Randaccio, J. Biol.
Inorg. Chem. 1 (1996) 439;
(c) J. Müller, E. Zangrando, N. Pahlke, E. Freisinger, L. Randaccio, B. Lippert,
Chem. Eur. J. 4 (1998) 397.
isation of the cytosine ligand in its iminooxo form stems on the
comparison with the reactivity of 4, the PMe3 analogue of 2. In this
case a proton exchange from the cytosine to the thyminate ligand
occurs, leading to the elimination of the thymine molecule, to the
[3] (a) G. Trovò, G. Bandoli, U. Casellato, B. Corain, M. Nicolini, B. Longato, Inorg.
Chem. 29 (1990) 4616;
stabilisation of the cytosinate anion into the cyclic species
(b) L. Schenetti, G. Bandoli, A. Dolmella, G. Trovò, B. Longato, Inorg. Chem. 33
(1994) 3169.
[4] G. Bandoli, G. Trovò, A. Dolmella, B. Longato, Inorg. Chem. 31 (1992) 45.
[5] B. Longato, D. Montagner, G. Bandoli, E. Zangrando, Inorg. Chem. 45 (2006)
1805.
2þ
cis-½ðPMe3Þ2Ptf1-MeCyð—HÞgꢃ
and to the trinuclear analogue
cis-½ðPMe3Þ Ptf1-MeCyð—HÞgꢃ2
.
3þ
2
3
[6] T.J. Kistenmacher, M. Rossi, J.P. Caradonna, L.G. Marzilli, Adv. Mol. Relax.
Interact. Process. 15 (1979) 119.
Appendix A. Supplementary material
[7] L. Schenetti, A. Mucci, B. Longato, J. Chem. Soc., Dalton Trans. (1996) 299.
[8] Z. Otwinowski, W. Minor, Processing of X-ray diffraction data collected in
oscillation mode, in: C.W. Carter Jr., R.M. Sweet (Eds.), Methods in
Enzymology, vol. 276, Academic Press, New York, 1997, p. 307.
[9] G.M. Sheldrick, SHELX97 Programs for Crystal Structure Analysis (Release 97-2),
University of Göttingen, Germany, 1998.
CCDC 678476 contains the supplementary crystallographic data
for 1. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.ica.2008.
04.030.
[10] L.J. Farrugia, J. Appl. Crystallogr. 32 (1999) 837.
[11] (a) L. De Napoli, R. Iacovino, A. Messere, D. Montesarchio, G. Piccialli, A.
Romanelli, F. Ruffo, M. Saviano, J. Chem. Soc., Dalton Trans. (1999) 1945;
(b) A. Romanelli, R. Iacovino, G. Piccialli, F. Ruffo, L. De Napoli, C. Pedone, B. Di
Blasio, A. Messere, Organometallics 24 (2005) 3401.
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