Synthesis, characterization, and reactivity of trans-[PtCl(R′R″SO)(A)2]NO3 (R′R″SO = ME2SO, MeBzSO, MePhSO; A = NH3, py, pic). Crystal structure of trans-[PtCl(Me2SO)(py)2]+

Article abstract of DOI:10.1021/ic000107n

Trans complexes such as trans-[PtCl₂(NH₃)₂] have historically been considered therapeutically inactive. The use of planar ligands such as pyridine greatly enhances the cytotoxicity of the trans geometry. The complexes trans-[PtCl(R′R″SO)(A)₂]NO₃ (R′R″SO = substituted sulfoxides such as dimethyl (Me₂SO), methyl benzyl (MeBzSO), and methyl phenyl sulfoxide (MePhSO) and A = NH₃, pyridine (py) and 4-methylpyridine or picoline (pic)) were prepared for comparison of the chemical reactivity between ammine and pyridine ligands. The X-ray crystal structure determination for trans-[PtCl(Me₂SO)(py)₂]NO₃ confirmed the geometry with S-bound Me₂SO. The crystals are orthorhombic, space group P2₁2₁2₁, with cell dimensions a = 7.888(2) A, b = 14.740(3) A, c = 15.626(5) A, and Z = 4. The geometry around the platinum atom is square planar with l(Pt-Cl) = 2.304(4) A, l(Pt-S) = 2.218(5) A and l(Pt-N) = 2.03(1) and 2.02(1) A. Bond angles are normal with Cl-Pt-S = 177.9(2)°, Cl-Pt-N₁ = 88.0(4)°, Cl-Pt-N₂ = 89.3(5)°, S-Pt-N₁ = 93.8(4)°, S-Pt-N₂ = 88.9(4)°, and N₁-Pt-N₂ = 177.2(6)°. The intensity data were collected with Mo Kα radiation with a λ = 0.710 69 A. Refinement was by full-matrix least-squares methods to a final R value of 3.80%. Unlike trans-[PtCl₂(NH₃)₂], trans-[PtCl₂(A)₂] (A = py or pic) complexes do not react with Me₂SO. The solvolytic products of cis-[PtCl₂(A)₂] (A = py or pic) were characterized. Studies of displacement of the sulfoxide by chloride were performed using HPLC. The sulfoxide was displaced faster for the pyridine complex relative to the ammine complex. Chemical studies comparing the reactivity of trans-[PtCl(R′R″SO)(amine)₂]NO₃ with a model nucleotide, guanosine 5′-monophosphate (GMP), showed that the reaction gave two principal products: the species [Pt(R′R″SO)(amine)₂(N7-GMP)], which reacts with a second equivalent of GMP, forming [Pt(amine)₂(N7- GMP)₂]. The reaction pathways were different, however, for the pyridine complexes in comparison to the NH₃ species, with sulfoxide displacement again being significantly faster for the pyridine case.

Full text of DOI:10.1021/ic000107n

Inorg. Chem. 2001, 40, 1745-1750
1745
Synthesis, Characterization, and Reactivity of trans-[PtCl(R′R′′SO)(A)2]NO3 (R′R′′SO )
Me2SO, MeBzSO, MePhSO; A ) NH3, py, pic). Crystal Structure of
trans-[PtCl(Me2SO)(py)2]+
Ana P. S. Fontes,† A° ke Oskarsson,‡ Karin Lo1vqvist,‡ and Nicholas Farrell*,§
Department of Chemistry, Universidade Federal de Juiz de Fora, Juiz de Fora, MG 36036-330, Brazil,
Inorganic Chemistry 1, Chemical Center, University of Lund, P.O. Box 124, S-22100 Lund, Sweden,
and Department of Chemistry, Virginia Commonwealth University, 1001 W. Main Street,
Richmond, Virginia 23284-2006
ReceiVed February 2, 2000
Trans complexes such as trans-[PtCl2(NH3)2] have historically been considered therapeutically inactive. The use
of planar ligands such as pyridine greatly enhances the cytotoxicity of the trans geometry. The complexes trans-
[PtCl(R′R′′SO)(A)2]NO3 (R′R′′SO ) substituted sulfoxides such as dimethyl (Me2SO), methyl benzyl (MeBzSO),
and methyl phenyl sulfoxide (MePhSO) and A ) NH3, pyridine (py) and 4-methylpyridine or picoline (pic))
were prepared for comparison of the chemical reactivity between ammine and pyridine ligands. The X-ray crystal
structure determination for trans-[PtCl(Me2SO)(py)2]NO3 confirmed the geometry with S-bound Me2SO. The
crystals are orthorhombic, space group P212121, with cell dimensions a ) 7.888(2) Å, b ) 14.740(3) Å, c )
15.626(5) Å, and Z ) 4. The geometry around the platinum atom is square planar with l(Pt-Cl) ) 2.304(4) Å,
l(Pt-S) ) 2.218(5) Å, and l(Pt-N) ) 2.03(1) and 2.02(1) Å. Bond angles are normal with Cl-Pt-S ) 177.9-
(2)°, Cl-Pt-N1 ) 88.0(4)°, Cl-Pt-N2 ) 89.3(5)°, S-Pt-N1 ) 93.8(4)°, S-Pt-N2 ) 88.9(4)°, and N1-Pt-
N2 ) 177.2(6)°. The intensity data were collected with Mo KR radiation with λ ) 0.710 69 Å. Refinement was
by full-matrix least-squares methods to a final R value of 3.80%. Unlike trans-[PtCl2(NH3)2], trans-[PtCl2(A)2]
(A ) py or pic) complexes do not react with Me2SO. The solvolytic products of cis-[PtCl2(A)2] (A ) py or pic)
were characterized. Studies of displacement of the sulfoxide by chloride were performed using HPLC. The sulfoxide
was displaced faster for the pyridine complex relative to the ammine complex. Chemical studies comparing the
reactivity of trans-[PtCl(R′R′′SO)(amine)2]NO3 with a model nucleotide, guanosine 5′-monophosphate (GMP),
showed that the reaction gave two principal products: the species [Pt(R′R′′SO)(amine)2(N7-GMP)], which reacts
with a second equivalent of GMP, forming [Pt(amine)2(N7-GMP)2]. The reaction pathways were different, however,
for the pyridine complexes in comparison to the NH3 species, with sulfoxide displacement again being significantly
faster for the pyridine case.
Introduction
This paper compares the effect of NH3 and pyridine groups on
the chemistry and reactivity of the sulfoxide ligands in trans-
Trans-planaramine platinum (TPA) complexes of general
formula trans-[PtCl2((L)(L′)] (L ) L′ ) pyridine, thiazole, or
L ) quinoline, L′ ) NH3 or substituted sulfoxide R′R′′SO)
display greatly enhanced cytotoxicity in comparison to the
geometric isomer of cisplatin, trans-[PtCl2(NH3)2] (trans-DDP).
A significant feature of these new transplatinum complexes is
their activity in both murine and human tumor cells resistant to
cisplatin.1-3 To explain these findings, we have begun to explore
the chemistry and DNA binding of this potentially important
new class of platinum antitumor agents.4-6 An important
structural feature of these newer trans complexes is the presence
of a sterically demanding ligand such as pyridine or quinoline.
[PtCl(R′R′′SO)(amine)2]NO3 and reports studies on their reac-
tion with a model mononucleotide, guanosine 5′-monophosphate
(GMP). The use of sulfoxide as ligands gave cationic complexes
that are more water soluble than the starting material trans-
[PtCl2(A)2]. The literature reports antitumor active cationic
complexes having some characteristics similar to those described
in this paper, [PtCl(R′R′′SO)(damch)]+ and cis-[PtCl(NH3)2-
(py)]+.7,8 For platinum complexes, the lability of sulfoxide as
leaving group depends on the structure of the sulfoxide, with
Me2SO having a lability similar to chloride.9,10 Further, the
mechanism of action of the series cis-[PtCl(R′R′′SO)(diamine)]+
most likely involves displacement of sulfoxide by DNA to give
† Universidade Federal de Juiz de Fora.
(7) Farrell, N.; Kiley, D.; Schmidt, W.; Hacker, M. Inorg. Chem. 1990,
29, 397.
(8) Hollis, L. S.; Amundsen, A. R.; Stern, E. W. J. Med. Chem. 1989,
32, 128.
(9) Farrell, N. Chemical and Biological Activity of Metal Complexes
Containing Dimethylsulfoxide. In Platinum, Gold and Other Metal
Chemotherapeutic Agents, Lippard, S. J., Ed.; ACS Symposium Series;
American Chemical Society: Washington, D.C., 1983; Vol. 209, p
279.
(10) Romeo, R.; Cusumano, M. Inorg. Chim. Acta 1981, 49, 167.
(11) Lempers, E. L.M.; Bloemink, M.; Reedijk, J. Inorg. Chem. 1991, 30,
201.
‡ University of Lund.
§ Virginia Commonwealth University.
(1) Farrell, N. P.; Ha, T. T. B.; Souchard, J.-P.; Wimmer, F. L.; Cros, S.;
Johnson, N. P. J. Med. Chem. 1989, 32, 2240.
(2) van Beusichem, M.; Farrell, N. Inorg. Chem. 1992, 31, 634.
(3) Farrell, N.; Kelland, L. R.; Roberts, J. D.; van Beusichem, M. Cancer
Res. 1992, 52, 5065.
(4) Farrell, N. Metal Ions Biol. Sys. 1996, 32, 603.
(5) Bierbach, U.; Farrell, N. Inorg. Chem. 1997, 36, 3657.
(6) Bierbach, U.; Qu, Y.; Hambley, T. W.; Peroutka, J.; Nguyen, H.;
Doedee, M.; Farrell, N. Inorg. Chem. 1999, 38, 3535.
10.1021/ic000107n CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/09/2001

1746 Inorganic Chemistry, Vol. 40, No. 8, 2001
Fontes et al.
bifunctional adducts.7,11 It was therefore of interest to examine
the interactions of the trans complexes with GMP, and the initial
results are reported in this paper.
for C18H20ClN3O4SPt: C, 35.73; H, 3.31; N, 6.95. Found: C, 35.93;
H, 3.11; N, 6.70.
trans-[PtCl(Me2SO)(pic)2]NO3, VI. The same general reaction
conditions were used as above. Yield: 68%. Anal. Calcd for C14H20-
ClN3O4SPt: C, 30.19; H, 3.59; N, 7.55. Found: C, 30.51; H, 3.94; N,
7.53.
Experimental Section
Starting Materials and Methods. The complexes trans-[PtCl2(A)2]
where A ) NH312 and py13 were prepared by literature methods. trans-
[PtCl2(pic)2] was prepared by the same procedure used for the pyridine
complex.13 Standard sulfoxides were purchased from Aldrich and used
without further purification. Guanosine 5′-monophosphate sodium salt
(GMP) was from Aldrich. IR spectra were obtained as KBr disks on
Nicolet FT6000 series and Perkin-Elmer 1430 spectrophotometers.
NMR spectra were run on Bruker 250- and 270-MHz spectrometers.
195Pt NMR spectra were run in D2O with reference to a 0.1 M Na2-
PtCl6 solution in D2O as external reference on a Bruker 250 MHz
spectrometer. Samples were run by using a pulse width of 15 µs.
Usually a sweep width of 30 kHz was used, and 5000-10000 scans
were adequate. All shifts are positive to lower shielding. Elemental
analyses were by Robertson Laboratories, Madison, NJ.
Synthesis of Complexes. trans-[PtCl(R′R′′SO)(NH3)2]NO3. The
Me2SO complex, complex I, has been described previously.14,15 The
complexes were prepared in basically the same manner with slight
modifications in workup and crystallization. The preparation is
exemplified for the Me2SO case. To a suspension of trans-[PtCl2(NH3)2]
(1.0 g, 3.3 mmol) in 30 mL of MeOH was added AgNO3 (0.57 g, 3.3
mmol) and Me2SO (1.3 mL, 1.43 g, 18 mmol). The reaction mixture
was stirred at 80 °C overnight. The insoluble AgCl precipitate was
filtered off and the filtrate evaporated to dryness. Ethanol and ether
were added until the solution became cloudy. Upon cooling, the white
solid was filtered off and recrystallized from MeOH/ether. The product
was dried in a vacuum with heat. Yield: 85%. Anal. Calcd for C2H12-
ClN3O4SPt: C, 5.93; H, 2.97; N, 10.38. Found: C, 5.92; H, 3.02; N,
10.43.
trans-[PtCl(MeBzSO)(NH3)2]NO3, II. The same general reaction
conditions were used but with stoichiometric equivalents of MeBzSO.
Upon evaporation, an oil was obtained, 2 mL of MeOH was added to
dissolve the oil, and the product then precipitated out with ether. Upon
cooling, the white solid was filtered off and recrystallized from MeOH/
ether. Yield: 69%. Anal. Calcd for C8H16ClN3O4SPt: C, 19.98; H,
3.33; N, 8.74. Found: C, 19.93; H, 3.41; N, 8.86.
trans-[PtCl(MePhSO)(NH3)2]NO3, III. The same general reaction
conditions were used, and in this case the oil obtained upon evaporation
was stirred overnight with ether, which resulted in precipitation of a
white solid, which was filtered off and recrystallized from MeOH/ether.
Yield: 70%. Anal. Calcd for C7H14ClN3O4SPt: C, 18.01; H, 3.00; N,
9.00. Found: C, 18.72; H, 2.82; N, 8.93.
trans-[PtCl(Me2SO)(py)2]NO3, IV. To a suspension of trans-[PtCl2-
(py)2] (1.0 g, 2.4 mmol) in 30 mL of MeOH was added AgNO3 (0.4 g,
2.4 mmol) and Me2SO (2 mL, 2.2 g, 28 mmol). The reaction mixture
was stirred at 80 °C overnight. The insoluble AgCl precipitate was
filtered off, and the filtrate was evaporated down. To the oil was added
2 mL of MeOH, then a white solid precipitated out after stirring for
about 10 min. Ether was then added to intensify the precipitation. After
cooling overnight, the white solid was filtered off and recrystallized
from hot MeOH/ether. The product was dried in a vacuum with heat.
Yield: 66%. Anal. Calcd for C12H16ClN3O4SPt: C, 27.25; H, 3.03; N,
7.95. Found: C, 26.71; H, 2.95; N, 7.56.
trans-[PtCl(MeBzSO)(py)2]NO3, V. The same general conditions
were used as for the previous complex but with 2 equiv of sulfoxide
ligand. Upon evaporation to an oil, acetone was added to dissolve the
excess MeBzSO, and the product was precipitated out with ether. Upon
cooling, the white solid was filtered off, recrystallized from MeOH/
ether, and washed with acetone to remove any remaining free ligand.
The product was dried in a vacuum with heat. Yield: 45%. Anal. Calcd
trans-[PtCl(MeBzSO)(pic)2]NO3, VII. The same general conditions
were used as above but again with 2 equiv of sulfoxide ligand. Upon
evaporation to an oil, the product was precipitated out with ether. After
cooling overnight, the white solid was filtered off, recrystallized from
hot MeOH/ether, and washed with acetone to remove the excess free
ligand. The product was dried in a vacuum with heat. Yield: 53%.
Anal. Calcd for C19H22ClN3O4SPt: C, 37.94; H, 3.79; N, 6.64. Found:
C, 38.08; H, 3.73; N, 6.63.
Displacement Studies. High-pressure liquid chromatography (HPLC)
separations were performed on an ISCO equipment consisting of pump
model 2350, absorbance detector model V4, and gradient programmer
model 2360. The column was a SPHERISORB ODS-2 5 µm, 250 mm
× 4.6 mm C18 from ISCO. The water was double-distilled and
deionized. All the solvents used were HPLC pure, filtered over a
micropore filter (0.2 µm), and degassed in a sonificator (Branson 3200).
The wavelength used for the analyses was 245 nm, where the maximum
absorption for free MeBzSO occurs. The complexes were dissolved in
0.7 mL of water and 0.3 mL of MeOH, and a 50-fold excess of NaCl
was added. A 15 µL portion of this solution was injected in the column
every 10 min. The system of solvents consisted of 50% water and 50%
MeOH, in the isocratic mode. The integration of the area under the
curve (AUC) of the peak of interest was used to measure the free
MeBzSO concentration. A pseudo-first-order kinetics approach was
used to calculate the rate constants through plotting ln(AUCf-AUCt)
versus time. The slope corresponded to the pseudo-first-order rate
constant, k′.
Reactions Followed by NMR Spectroscopy. The solvolysis of cis-
and trans-[PtCl2(amine)2] in Me2SO was followed by 195Pt and 1H NMR
spectroscopy using 0.025 M solutions in both cases. For the reactions
of trans-[PtCl(R′R′′SO)(amine)2]NO3 with GMP the following con-
centrations were used: 10 mM of the complexes and either 10 or 20
mM GMP in 1 mL of D2O. The reactions were performed in an NMR
tube, and spectra were recorded at regular time intervals.
Acid-Base Titrations. Solutions of 0.1 and 1 M of NaOD and DCl
were used to reach the desired pH. The pH values (uncorrected for
deuterium isotope effects) were measured in a Fisher Scientific
instrument, model Accumet 925, having an ultrathin pH electrode from
Aldrich as reference electrode (Hg/Hg2Cl2).
Crystal Structure Determination. Colorless crystals of trans-[PtCl-
(DMSO)(py)2]NO3 suitable for structure analysis were grown by slow
evaporation of saturated methanolic solutions at room temperature. The
crystal was mounted on a glass fiber, and all measurements were made
on an Enraf-Nonius CAD-4 diffractometer with graphite monochro-
mated Mo KR radiation. Cell constants and an orientation matrix for
data collection, obtained from a least-squares refinement using the
setting angles of 22 carefully centered reflections in the range 12.89 <
2θ < 38.88, corresponded to an orthorhombic cell. A total of 1854
reflections were collected. The intensities of two representative reflec-
tions which were measured after every 60 min of X-ray exposure time
remained constant throughout data collection, indicating crystal and
electronic stability (no decay correction was applied). The data were
corrected for Lorentz and polarization effects. Crystal data are given
on Table 3. The structure was solved by direct methods. The non-
hydrogen atoms were refined either anisotropically or isotropically.
Neutral atom scattering factors were taken from Cromer and Waber.16
17
Anomalous dispersion effects were included in Fcalc
;
the values for
∆f′and ∆f′′ were those of Cromer.18 All calculations were performed
using the TEXSAN19 crystallographic software package of Molecular
Structure Corporation.
(12) Kauffman, G. B.; Cowan, D. O. Inorg. Synth. 1963, 7, 239.
(13) Kauffman, G. B. Inorg. Synth. 1963, 7, 249.
(14) Delafontaine, J.-M.; Khodadad, P.; Toffoli, P.; Rodier, N. Acta
Crystallogr. C 1985, 41, 702.
(15) Sundquist, W. I.; Ahmed, K. J.; Hollis, L. S.; Lippard, S. J. Inorg.
Chem. 1987, 26, 1524.
(16) Cromer, D. T.; Waber, J. T. International Tables for X-ray Crystal-
lography; The Kynoch Press: Birmingham, England; 1974; Vol. IV,
Table 2.2 A.
(17) Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17, 781.

Cationic Transplatinum Complexes
Inorganic Chemistry, Vol. 40, No. 8, 2001 1747
Table 1. NMR Spectroscopy Data for
trans-[PtCl(R′R′′SO)(A)2]NO3
δ(1H)a
complex
R′R′′SO
3.6 (28.2)
A
δ(195Pt)
I
II
-3123
-3143
3.54 (28.6), 4.98(dd),
7.56(m), 7.66(m)
3.86 (27.7), 7.78(m),
8.22(m)
III
-3159
-2902
IV
V
VI
VII
3.28 (27.7)
7.7(t), 8.15(t), 8.9(d)
3.16, 7.57(m)
3.25 (30.3)
7.57(m), 8.06(t), 8.5(m) -2891
2.52, 7.52(d), 8.67(d)
2.47, 7.38(d), 8.28(d)
-2909
-2890
3.12, 7.57(m)
a See Experimental Section for details. All values in ppm, 1H rel. to
TMS, 195Pt rel. to Na2 PtCl6. Singlets except where indicated, d )
doublet, dd ) double doublet, m ) multiplet. Numbers in parentheses
3
refer to J(Pt-H) (Hz) and are given only when observed clearly.
Table 2. Crystallographic Data for trans-[PtCl(Me2SO)(py)2]NO3
formula
PtClN3SO4C12H16
528.88
fw
Figure 1. Structures of sulfoxides and their complexes trans-[PtCl-
(R′R′′SO)(A)2]+ used in this study.
cryst dimens
0.250 × 0.162 × 0.075 mm
orthorhombic P212121
7.888(2) Å
space group
a
b
4.740(3) Å
reactions. The characterizing data are given in Table 1. The
chemical shifts of the sulfoxide protons for all the complexes
indicated an S-bonded sulfoxide.7 For the ammine complexes
the signal corresponding to the S-Me protons is shifted 0.90-
0.98 ppm to lower field compared to the free ligand. In the
case of the aromatic amine complexes this shift is smaller, 0.5-
0.6 ppm, which is probably due to the ring current effect.20 The
phenyl protons of the sulfoxide are shifted to lower field as
well; for complex II these signals occur as two multiplets at
7.66 and 7.56 ppm compared to 7.46 and 7.38 ppm for free
MeBzSO. The 1H NMR spectrum for complex II also shows a
doublet of doublets at 4.98 ppm due to the diasteriomeric
methylenic protons of MeBzSO. In the case of complexes V
and VII these signals overlap with the solvent and were not
observed. The 195Pt chemical shifts confirm that the sulfoxide
is bound through the sulfur. The 195Pt NMR chemical shifts for
all the complexes depend mainly on the nature of the amine.
Compared to the pyridine complexes, the signals for the ammine
complexes occur upfield since the NH3 is a better donor with
no back-bonding capacity; for instance, the signal for trans-
[PtCl2(NH3)2] occurs at -2243 ppm and for trans-[PtCl2(py)2]
at -1946 ppm. In the 195Pt NMR spectrum for trans-[PtCl-
(Me2SO)(NH3)2]NO3, it is possible to observe the coupling
between the platinum and the nitrogen atoms, 1J(195Pt-14N) )
203 Hz.21,22 The IR spectra of the ammine complexes show a
strong ν(SO) around 1130 cm-1. For the aromatic amines this
band occurs around 1140 cm-1. No attempt was made to
c
15.626(5) Å
1817(1) Å3
4
V
Z
Dcalc
1.933 g/cm3
Enraf-Nonius CAD-4
Mo KR (λ ) 0.710 69 Å)
80.78 cm-1
23 °C
diffractometer
radiation
µ(Mo KR)
temperature
tot. no. of reflns
R, %
1854
3.8
3.9
Rw, %
Table 3. Selected Bond Distances (Å) and Angles (deg) for
trans-[PtCl(Me2SO)(py)2]+
Bond Lengths
Pt-Cl 2.304(4) Pt-S 2.218(5) Pt-N1 2.03(1) Pt-N2 2.02(1)
S-O1 1.46(1) S-C11 1.80(2) S-C12 1.81(2)
Bond Angles
Cl-Pt-S
177.9(2)
88.0(4)
89.3(50
93.8(4)
88.9(4)
177.2(6)
111.8(8)
120(2)
Cl-N1-C5
Pt-N2-C6
Pt-N2-C10
C6-N2-C10
N1-C1-C2
Pt-S-O1
Pt-S-C12
O1-S-C11
O1-S-C12
Pt-N1-C5
118(1)
129(1)
119(1)
120(1)
126(2)
115.1(7)
111.6(9)
107(1)
108(1)
120(1)
Cl-Pt-N1
Cl-Pt-N2
S-Pt-N1
S-Pt-N2
N1-Pt-N2
Pt-S-C11
N1-C5-C4
N2-C6-C7
C11-S-C12
25(2)
103(1)
Results and Discussion
Figure 1 shows the structures of the sulfoxides and the
complexes prepared. The general method used for preparation
of the complexes consisted of the reaction of trans-[PtCl2(A)2]
(A ) NH3, py, or pic) with AgNO3 in the presence of the
appropriate sulfoxide as follows:
distinguish ν(PtS) and ν(PtCl), which appear around 320 cm-1
,
as the bands due to vibrations of the sulfoxide occur in this
region as well.23
trans-[PtCl2(A)2] + AgNO3 + R′R′′SO f
trans-[PtCl(R′R′′SO)(A)2]NO3 + AgCl
(18) Cromer, D. T.; Waber, J. T. International Tables for X-ray Crystal-
lography; The Kynoch Press: Birmingham, England; 1974; Vol. IV,
Table 2.3.1.
(19) TEXSAN-TEXRAY Structure Analysis Package, Molecular Structure
Corporation: Woodlands, TX, 1985.
(20) Odani, A.; Shimata, R.; Masuda, H.; Yamauchi, O. Inorg. Chem. 1991,
30, 2133.
(21) Boreham, C. J.; Broomhead, J. A.; Fairlie, D. P. Aust. J. Chem. 1981,
34, 659.
(22) Qu, Y.; Valsecchi, M.; del Greco, L.; Spinelli, S.; Farrell, N. Magnet.
Reson. Chem. 1993, 31, 920.
The facile preparation of trans-[PtCl(Me2SO)(NH3)2]Cl by
simply dissolving trans-DDP in Me2SO has been reported.14,15
Interestingly, this approach did not work for the pyridine
derivatives (see also below), and more forcing conditions using
chloride abstraction with AgNO3 were necessary. AgNO3 was
used to prepare the ammine complexes for consistency and to
avoid the presence of excess chloride in the substitution
(23) de Almeida, S. G.; Hubbard, J. L.; Farrell, N. Inorg. Chim. Acta 1992,
193, 149.

1748 Inorganic Chemistry, Vol. 40, No. 8, 2001
Fontes et al.
1
Table 4. 195Pt and H NMR Spectroscopy Data for Solvolysis of
a
cis-[PtCl2(A)2] (A ) py and pic) in Me2SO-d6
δ(195Pt)
δ(1H)
species
cis-PtCl2(A)2
free picoline
cis-[PtCl2(Me2SO)(A)2]
A ) py A ) pic H (ortho) H (meta) -CH3
-1954 -1961
-2851 -2862
8.56(d)
8.42(d)
8.72(d)
8.50(d)
7.30(d) 2.34(s)
7.21(d) 2.31(s)
7.38(d) 2.40(s)
7.47(d) 2.43(s)
trans-[PtCl2(Me2SO)(A)2] -3014 -3023
a See Experimental Section for details. 1H NMR data only for A )
1
pic; d ) doublet; s ) singlet. All values in ppm, H rel. to TMS.
complexes, cis- and trans-[PtCl2(pyr)2] in Me2SO. Such inves-
tigations have been carried out previously for cis- and trans-
[PtCl2(NH3)2], and both react readily with Me2SO to give
initially the corresponding [PtCl(Me2SO)(NH3)2]+.27 The trans
isomer reacts more rapidly than cis-[PtCl2(NH3)2], and the
substitution of the first chloride by Me2SO in trans-[PtCl2-
(NH3)2] is very favored. The solvolysis reactions of cis- and
trans-[PtCl2(amine)2] in Me2SO were followed by 195Pt NMR
Figure 2. Molecular structure of trans-[PtCl(Me2SO)(py)2]+ in the
crystal.
Description of the Structure of trans-[PtCl(Me2SO)(py)2]-
NO3. To further confirm the structures and to examine structural
effects on the reactivity of the Me2SO ligand, a single-crystal
structure determination was performed on trans-[PtCl(Me2SO)-
(py)2]NO3. The crystal data are given in Table 2 and important
distances and angles in Table 3. The structure of the complex
is shown in Figure 2, confirming that the sulfoxide is bound to
the platinum through the sulfur. The complex displays the
expected square-planar configuration about the platinum with
N-Pt-S and N-Pt-Cl angles close to 90°. The angle N1-
Pt-S, 93.8°, is a little large; however it can be related to other
platinum complexes having sulfoxide as ligands.23 The geometry
around the sulfur is normal. The Pt-S bond length of 2.218 Å
is close to those found in the trans-[PtCl(Me2SO)(NH3)2]+,
2.197 Å14 and 2.204 Å,15 determinations. The bond distances
and angles in the pyridine rings are about the same as found in
trans-[PtCl2(py)2].24 The dihedral angles between the pyridine
molecules and the coordination plane are 91.6° and 92.9° to
minimize the steric hindrance. The Pt-S bond length is slightly
longer and the Pt-Cl bond at 2.304 Å is slightly shorter than
those found in similar compounds with the same trans influence
such as trans-[PtCl(Me2SO)(NH3)2]+ and cis-[PtCl2(Me2SO)-
(py)].14,25 Indeed, all the crystallographically determined bond
distances and bond angles for both pyridine and NH3 species
are very close to each other, suggesting that any differences in
reactivity are not the result of ground-state effects.
1
spectroscopy for both pyridine and picoline and by H NMR
spectroscopy for the picoline derivative. Unlike trans-[PtCl2-
(NH3)2], the pyridine complexes simply do not react with Me2-
SO. Even up to 24 h after mixing only the signal corresponding
to the original complexes was observed. Hoover and Zipp
studied the reaction of trans-[PtCl2(py)2] with Me2SO in
methanol using conductimetry.28 They reported the displacement
of the chloride giving trans-[Pt(Me2SO)2(py)2]2+ as the pur-
ported final product. We did not observe any reaction between
the trans complex and Me2SO. Likewise, no reaction was
observed in Me2SO for trans-[PtI2(py)2].29
The cis compounds [PtCl2(py)2] react very rapidly with Me2-
SO, and a signal due to the first product was observed after 1
h. The solvolysis products were characterized as an equilibrium
mixture of cis- and trans-[PtCl2(Me2SO)(amine)] by their 195Pt
1
and H NMR spectra and comparison with literature data (See
Table 4 and Supporting Information Figures S1 and S2).31-33
The 195Pt NMR chemical shifts for cis- and trans-[PtCl2(Me2-
SO)(pyridine)] were -2862 and -3023 ppm, respectively.
Marzilli et al.30 reported chemical shifts for cis- and trans-
[PtCl2(Me2SO)(A)] at -2856 and -3018 ppm (A ) py) and at
-2859 and -3020 ppm (A ) pic), similar to those found for
cis- and trans-[PtCl2(Me2SO)(quin)] chemical shifts at -2871
and -3016 ppm, respectively.2 The following scheme represents
the solvolysis reaction:
Solvolysis of [PtCl2(A)2] in Me2SO. The synthesis of trans-
[PtCl(R′R′′SO)(amine)2]+ complexes required more forcing
conditions for pyridine than for NH3 and provided evidence of
differences in reactivity between ammine (NH3) and aromatic
amines. Indeed, we were unable to prepare pyridine complexes
with sterically demanding sulfoxides such as MePhSO, and even
the synthesis and recrystallization of trans-[PtCl(Me2SO)(pic)2]+
was unpredictable in our hands: on several occasions trans-
[PtCl2(pic)2] precipitated from solution upon workup after the
initial metathesis reaction. A reasonable explanation for this
observation is that a small amount of Cl- produced from
solvolysis of the initially formed trans-[PtCl(Me2SO)(pic)2]+
could displace Me2SO, giving back the starting material. This
effect is reminiscent of the disproportionation in concentrated
solutions of trans-[PtCl(H2O)(NH3)2]+ to trans-[PtCl2(NH3)2]
The results on solvolysis may be compared with the reaction
of cis-[PtCl2(Me2SO)2] with pyridines and other heterocycle
donors, which has been extensively studied. The final products
are always cis/trans-[PtCl2(amine)(Me2SO)], through initial
formation of the cationic species cis-[PtCl(Me2SO)2(amine)]+.
The relative proportions of the cis and trans final products is
dependent on the nature of the amine as well as solvent
medium.30,32 Ha et al. also used the reaction of cis-[PtI2(py)2]
and the diaqua cation trans-[Pt(H2O)2(NH3)2]2+ 26
.
To determine whether steric or electronic factors contributed
to the diminished reactivity of complexes containing pyridine
ligands, we investigated the solvolytic reactions of the starting
(24) Colamarino, P.; Orioli, P. L. J. Chem. Soc., Dalton Trans. 1975, 1656.
(25) Belsky, V. K.; Konovalov, V. E.; Kukushkin, V. Y. Acta Crystallogr.
1991, C47, 292.
(26) Appleton, T. G.; Bailey, A. J.; Barnham, K. J.; Hall, J. R. Inorg. Chem.
1992, 31, 3077.
(27) Kerrison, J. S.; Sadler, P. J. J. Chem. Soc., Chem. Commun. 1977,
861.
(28) Hoover, T.; Zipp, A. P. Inorg. Chim. Acta 1982, 63, 9.
(29) Ha, T. B.; Wimmer, F. L.; Souchard, J. P.; Johnson, N. P. J. Chem.
Soc., Dalton Trans. 1990, 1251.

Cationic Transplatinum Complexes
Inorganic Chemistry, Vol. 40, No. 8, 2001 1749
with Me2SO to obtain trans-[PtI2(Me2SO)(py)].29 The isomer-
ization was explained by postulating the initial displacement
of one iodide by Me2SO forming cis-[PtI(Me2SO)(py)2]+, with
further reaction of the displaced iodide giving the final product
trans-[PtI2(Me2SO)(py)] plus free pyridine. The solvolysis of
the chloride complexes above does not appear to follow this
mechanism, but direct initial formation of cis-[PtCl2(Me2SO)-
(py)] is implied for two main reasons. First, the 195Pt chemical
shift for cis-[PtCl2(Me2SO)(amine)] agrees with the literature
data. For chloride leaving groups, the proposed intermediate
cis-[PtCl(Me2SO)(amine)2]+ (δ(Pt) ) -2957 and -2964 ppm
for amine ) pyridine and picoline respectively30) was never
observed in our reactions. In contrast, free picoline was detected
by 1H NMR spectroscopy at times when only the cis-[PtCl2(Me2-
SO)(A)] species was present in solution (spectrum run after 1
h, see Figure S1), indicating that Me2SO is displacing the amine.
Further possible intermediates may be proposed such as cis-
[PtCl(Me2SO)2(py)]+ formed from cis-[PtCl2(Me2SO)(py)], but
these were never detected. If formed, the likelihood is that such
a species would be consumed very rapidly due to the mutual
cis labilization of two Me2SO groups.33,34 These solvolysis
reactions attest to an important difference in reactivity between
ammine and pyridine complexes.
Displacement Reactions of trans-[PtCl(MeBzSO)-
(amine)2]+. To compare the effects of pyridine and ammine
ligands in substitution reactions, the rate of displacement of the
sulfoxide in trans-[PtCl(MeBzSO)(A)2]NO3 (A ) NH3, py, or
pic) with excess NaCl was measured. The displacement of the
sulfoxide was followed by the appearance of the free sulfoxide
HPLC peak. Those experiments were done only for the MeBzSO
complexes because their reaction times are more convenient
since they react faster than the Me2SO complexes and the
appearance of the free sulfoxide peak in the HPLC of the
reaction mixture is easily monitored. The following scheme
represents the reaction:
Table 5. Pseudo-First-Order Rate Constants for the Reaction of
Displacement of Sulfoxide by Cl- for
trans-[PtCl(MeBzSO)(A)2]NO3
A
temperature (°C)
k′ (s-1) × 105
NH3
25
37
25
37
37
1.57
2.20
pyridine
45.60
64.25
98.18
4-picoline
Table 6. 1H NMR Data for the Reactions of
trans-[PtCl(R′R′′SO)(NH3)2]NO3 and 2 equiv of GMP
δ
speciesa
free 5′-GMP
[Pt(Me2SO)(NH3)2(GMP)]
[Pt(MeBzSO)(NH3)2(GMP)]
[Pt(NH3)2(GMP)2]
H8
H1′
SCH3
8.17
8.96
8.94
8.90
5.91(d)
6.05(d)
6.04(d)
6.02(d)
3.71, 3.68
3.58
a All the complexes are trans. Charges omitted for clarity. See
Experimental Section for details. 1H NMR data only for A ) pic.
1
Singlets except where indicated; d ) doublet. All values in ppm, H
rel. to TMS.
(diam)] + MeBzSO at 37 °C were 0.049 × 10-5 s-1 for diam
) R,R-1,2-diaminocyclohexane (dach) and 0.196 × 10-5 s-1
for diam ) 1,1-diaminomethylcyclohexane (damch).7 Thus, the
sulfoxide is displaced faster for all the trans compounds,
presumably explained by the presence of the trans chloride.7
The high values of the rate constants may also explain the
difficulties in synthesis noted above.
Reactions with Guanosine 5′-Monophosphate (GMP). To
further investigate differences in reactivity between ammine and
pyridine complexes, the reactions of trans-[PtCl(R′R′′SO)(A)2]-
NO3 (R′R′′SO ) Me2SO, MeBzSO and A ) NH3 and py) and
1 or 2 equiv of GMP were performed in an NMR tube at 310
K. Interestingly, the patterns were the same, and only the
reactions with 2 equiv of the mononucleotide were examined
in detail. No buffer was used to avoid complexation with the
platinum.35 The pH was between 7.0 and 6.5 during the entire
reaction time. The complex trans-[PtCl(Me2SO)(NH3)2]+ has
been shown to react faster with DNA and produce more
bifunctional adducts (as measured by interstrand cross-linking)
than the dichloride.15,36 For both amines, the reaction pathway
was consistent with that previously observed for cis-[PtCl-
(R′R′′SO)(diamine)]+.7,11 Initial formation of trans-[Pt(R′R-
′′SO)(GMP)(amine)2]+ (1) appears to be followed by competing
reactions of sulfoxide displacement by the displaced chloride
or by a further molecule of GMP, giving trans-[PtCl(GMP)-
(amine)2] (2) and trans-[Pt(GMP)2(amine)2] (3), respectively.
The monosubstituted species may then react further by slow
displacement of the chloride.37-39 Because of the difficulty in
analyzing these competing reactions, the results of these
experiments are discussed only briefly below. Table 6 sum-
trans-[PtCl(MeBzSO)(A)2]+ + Cl- f
trans-[PtCl2(A)2] + MeBzSO
The HPLC peak of the complex decreased in intensity with time
with parallel increase in intensity of free ligand as it is displaced
by chloride. The other reaction product, trans-[PtCl2(amine)2],
precipitates from solution and was characterized by IR spectra
compared to an authentic sample. The reactions were performed
at 298 and 310 K. Since Cl- was used in excess in all the
reactions and the ion concentration remained essentially con-
stant, in general no noncoordinating anions such as ClO4- were
added. Analysis of appearance of free sulfoxide versus time gave
first-order plots. The pseudo-first-order rate constants are given
in Table 5. The data show that the sulfoxide is more rapidly
displaced for the aromatic amines than for the ammine
complexes. There is a 1- to 2-order magnitude increase in rate
constant for the pyridine complexes over that of NH3 and a
further distinct increase in rate in moving from pyridine to the
4-substituted picoline. The pseudo-first-order rate constants
found for the reaction [PtCl(MeBzSO)(diam)]+ + Cl- f [PtCl2-
1
marizes the pertinent H and 195Pt NMR data.
Reaction of trans-[PtCl(R′R′′SO)(NH3)2]NO3 with GMP
(R′R′′SO ) Me2SO, MeBzSO). The reactions were very similar
for both sulfoxide complexes. Loss of some sulfoxide ligand is
(35) Appleton, T. G.; Berry, R.D.; Davis, C.A.; Hall, J. R.; Kimlin, H. A.
Inorg. Chem. 1984, 23, 3514.
(36) Soares Fontes, A. P.; Zou, Y.; Farrell, N. J. Inorg. Biochem. 1994,
55, 79.
(37) Marcelis, A. T. M.; van Kralingen, C. G.; Reedijk, J. J. Inorg. Biochem.
1980, 13, 213.
(38) Chu, G. Y. H.; Mansy, S.; Duncan, R. E.; Tobias, R. S. J. Am. Chem.
Soc. 1978, 100, 593.
(30) Marzilli, L. G.; Hayden, Y.; Reily, M. D. Inorg. Chem. 1986, 25,
974.
(31) Kong, P.; Iyamuremye, D.; Rochon, F. D. Can. J. Chem. 1976, 54,
3224.
(32) Annibale, G.; Bonivento, M.; Cattalini, L.; Tobe, M. L. J. Chem. Soc.,
Dalton Trans. 1992, 3433.
(33) Lanza, S.; Minniti, D.; Romeo, R.; Tobe, M. L. Inorg. Chem. 1983,
22, 2006.
(34) Farrell, N. J. Chem. Soc., Chem. Commun. 1982, 331.
(39) Arvanitis, G. M.; Gibson, D.; Emge, T. J.; Berman, H. M. Acta
Crystallogr. 1994, C50, 1217.

1750 Inorganic Chemistry, Vol. 40, No. 8, 2001
Fontes et al.
Figure 4. 1H NMR spectrum showing the H1′ of 5′-GMP region for
the reaction of trans-[PtCl(Me2SO)(py)2]NO3 and 2 equiv of GMP after
9 h. The four species are described in the text.
ing the observed differences in chemical shift for ammine and
pyridine complexes.40 The identity of the final product was also
confirmed by comparison with an authentic sample of trans-
[Pt(GMP)2(pic)2] prepared from trans-[Pt(NO3)2(pic)2] and
GMP.41
The rapid loss of Me2SO is further testimony to the steric
demands of the pyridine ligand in comparison to NH3; in this
case three planar ligands, two pyridine and one purine, will
create steric crowding around the Pt square plane, which is
relieved by loss of the S-bound ligand.
Conclusions. This work was aimed at an understanding of
the role of the pyridine ligands in the activation of the trans
platinum geometry. Consistently, the sulfoxide ligand in the
pyridine complexes is displaced more readily than the corre-
sponding ammine species. Steric effects are likely to explain
this difference, as is also the case for the dramatic differences
in solvolysis observed for the [PtCl2(py)2] isomers. The inability
to observe substitution reactions of the trans isomer by Me2SO
may be a result of steric effects caused by the presence of two
pyridine ligands and a slower rate of chloride displacement in
the presence of planar ligands.4,6 The reduced kinetic reactivity
of the trans-[PtCl2(py)2] may thus be manifested in a more
suitable pharmacokinetic profile, leading to the observed
enhancement of biological activity in comparison to trans-[PtCl2-
(NH3)2].1-4 The steric effects of the 2-picoline ligand have also
been used to produce the compound cis-[PtCl2(NH3)(2-pic)],
ZDO473, currently in Phase II clinical trials, whose reactivity
toward biomolecules is less than that of cisplatin.42 The chemical
differences are sufficient to impart a profile of biological activity
to ZDO473 complementary to that of the clinically used drug.43
These findings suggest that these approaches may also lead to
the development of clinically relevant trans platinum com-
pounds.
Figure 3. 1H NMR spectra versus time for the reaction of trans-[PtCl-
(Me2SO)(NH3)2]NO3 and 2 equiv of GMP at 310 K, pH ) 7.
observed immediately, and the intensity of the free sulfoxide
ligand increased as the reaction proceeded. Loss of bound
sulfoxide did not correlate with disappearance of free GMP,
and even after 40 h there was still free GMP and species having
bound sulfoxide in solution, Figure 3. Nevertheless, the 195Pt
NMR spectrum after 40 h reaction showed only one signal at
-2467 ppm assigned to the major product trans-[Pt(NH3)2-
(GMP)2], in agreement with the literature value of -2469 ppm.40
Two signals corresponding to the Me2SO methyl protons are
observed for the purported initial species trans-[Pt(Me2SO)-
(GMP)(NH3)2]+ due to inequivalence upon GMP binding to Pt.
For the corresponding MeBzSO complex, the 1H NMR spectrum
also shows two multiplets at 7.71 and 7.57 ppm corresponding
to the aromatic protons of the ligand.
Reaction of trans-[PtCl(R′R′′SO)(py)2]NO3 with GMP. The
analysis of these reactions is more complicated due to overlap
of the pyridine signals with the H8 signals of the various species
produced and (where used) the phenyl protons of MeBzSO.
Therefore, only the picoline/Me2SO complex with the simplest
NMR spectrum was examined. The complexity of the reaction
is most clearly seen in the case of trans-[PtCl(Me2SO)(pic)]+,
where the H1′ region shows four doublets after approximately
1 h of reaction, indicating the presence of the species (1, 2, 3)
listed above along with unreacted GMP, Figure 4. Nevertheless,
the increased rate of reaction of the pyridine complexes was
inferred by the production of 100% of free sulfoxide after
approximately 9 h with no peaks present corresponding to either
starting material or trans-[Pt(Me2SO)(GMP)(pic)2]+. Again, the
appearance of free sulfoxide did not correlate with disappearance
of GMP, and indeed unreacted GMP was observed throughout
the reactions (followed up to 40 h). After 9 h the main species
is most likely to be the 1:2 adduct, trans-[Pt(pic)2(GMP)2], since
the 195Pt NMR spectrum showed only one peak at -2331 ppm,
which is analogous to that of trans-[Pt(NH3)2(GMP)2] consider-
Acknowledgment. This work is supported by grants from
NIH and NSF. We thank Fulbright, CAPES (Brazil) and CNPq
(Brazil) for a fellowship to A.P.S.F. K.L. and Å.O. acknowledge
the support of The Swedish Natural Science Research Council.
Supporting Information Available: Two figures (1H and 195Pt
NMR spectra) on the time course of the solvolysis of cis-[PtCl2(4-
pic)2] in Me2SO. Complete tables of crystallographic data, positional
parameters, thermal displacement parameters, intramolecular bond
lengths and bond angles, torsion angles, and selected contacts for trans-
[PtCl(Me2SO)(py)2]NO3. This material is available free of charge via
the Internet at http://pubs.acs.org.
(40) Bancroft, D. P.; Lepre, C. A.; Lippard, S. J. J. Am. Chem. Soc. 1990,
112, 6860.
(41) Mathieson, M. T.; Champoux, J.; Soares Fontes, A. P.; Doedee, M.
J.; Farrell, N. Ligand Effects in Platinum Antitumor Complexes. 208th
American Chemical Society Meeting, Washington D.C., August, 1994.
(42) Holford, J.; Raynaud, F.; Murrer, B. A.; Grimaldi, K.; Hartley, J. A.;
Abrams, M.; Kelland, L. R. Anti-Cancer Drug Des. 1998, 13, 1.
(43) Holford J.; Sharp S. Y.; Murrer B. A.; Abrams, M.; Kelland L. R. Br.
J. Cancer 1998, 77, 366.
IC000107N