NMR investigation of the spontaneous thermal- and/or photoinduced reduction of trans dihydroxido Pt(IV) derivatives

Article abstract of DOI:10.1021/ic302100x

The initial aim of the present work was the synthesis of the axial disuccinato Pt(IV) derivative of [PtCl₂(cis-1,4-DACH)] (Kiteplatin, 1 in Figure 1) (DACH = diaminocyclohexane), which contains an isomeric form of the diamine ligand present in oxaliplatin (i.e., 1R,2R-DACH). The interest in this compound stems from its activity on several cisplatin and oxaliplatin-resistant cell lines. Oxidation of 1 with hydrogen peroxide affords cis,trans,cis-[PtCl₂(OH)₂(cis-1,4-DACH)] (2) which was treated with succinic anhydride in suitable solvents. To our surprise, in dimethylformamide (DMF) (50-70 C or under light irradiation) or in dimethylsulfoxide (DMSO) (under light irradiation) the formation of the succinato complex cis,trans,cis-[PtCl₂{OC(O)CH₂CH ₂C(O)OH}₂(cis-1,4-DACH)] (3) was accompanied by reduction to 1. It was found that solvolysis of 2 and formation of a μ-oxo dinuclear species (5) is the key step. The dinuclear species can then undergo reduction to a 1:1 mixture of 1 and 2 with concomitant elimination of oxygen (1/2 O ₂ in the form of H₂O₂). The whole process is fostered by heat and/or light, which could favor solvolysis of 2 as well as decomposition of hydrogen peroxide to water and oxygen so preventing the reoxidation of 1 to 2. Because of its peculiar behavior, compound 5 could be exploited also for the development of a technology for water splitting.

Full text of DOI:10.1021/ic302100x

Article
pubs.acs.org/IC
NMR Investigation of the Spontaneous Thermal- and/or
Photoinduced Reduction of trans Dihydroxido Pt(IV) Derivatives
Emanuele Petruzzella,† Nicola Margiotta,*,† Mauro Ravera,‡ and Giovanni Natile*,†
†Dipartimento di Chimica, Universita
̀
degli Studi di Bari “A. Moro”, via E. Orabona 4, 70125 Bari, Italy
‡Dipartimento di Scienze e Innovazione Tecnologica, Universita
15121 Alessandria, Italy
̀
del Piemonte Orientale “Amedeo Avogadro”, viale T. Michel 11,
S
* Supporting Information
ABSTRACT: The initial aim of the present work was the synthesis
of the axial disuccinato Pt(IV) derivative of [PtCl2(cis-1,4-DACH)]
(Kiteplatin, 1 in Figure 1) (DACH = diaminocyclohexane), which
contains an isomeric form of the diamine ligand present in
oxaliplatin (i.e., 1R,2R-DACH). The interest in this compound
stems from its activity on several cisplatin and oxaliplatin-resistant
cell lines. Oxidation of 1 with hydrogen peroxide affords cis,trans,cis-
[PtCl2(OH)2(cis-1,4-DACH)] (2) which was treated with succinic
anhydride in suitable solvents. To our surprise, in dimethylforma-
mide (DMF) (50−70 °C or under light irradiation) or in
dimethylsulfoxide (DMSO) (under light irradiation) the formation
of the succinato complex cis,trans,cis-[PtCl2{OC(O)CH2CH2C(O)-
OH}2(cis-1,4-DACH)] (3) was accompanied by reduction to 1.
It was found that solvolysis of 2 and formation of a μ-oxo dinuclear species (5) is the key step. The dinuclear species can then
undergo reduction to a 1:1 mixture of 1 and 2 with concomitant elimination of oxygen (1/2 O2 in the form of H2O2). The whole
process is fostered by heat and/or light, which could favor solvolysis of 2 as well as decomposition of hydrogen peroxide to water
and oxygen so preventing the reoxidation of 1 to 2. Because of its peculiar behavior, compound 5 could be exploited also for the
development of a technology for water splitting.
were known to possess similar biological properties. Platinum-
(IV) complexes appear to act as prodrugs and are activated in
vivo by reduction to the Pt(II) species.4 Up to now, all platinum
drugs in clinical use are Pt(II) compounds (cisplatin, carboplatin
(cis-diammine-1,1-cyclobutanedicarboxylato-platinum(II)), and
oxaliplatin (R,R-1,2-diaminocyclohexane-oxalato-platinum(II)),
and all of them are administered intravenously because of their
instability in the gastrointestinal tract. Pt(IV) complexes are, in
general, kinetically more inert, and this feature has been exploited
for oral administration.5,6 Moreover, the presence of two additional
ligands in axial positions could be exploited to tuning the
lipophilicity, the rate of reduction, and the overall pharmacokinetic
profile of Pt(IV) substrates.
INTRODUCTION
■
Since the discovery of the antiproliferative activity of cis-
diamminedichloridoplatinum(II) (cisplatin, Figure 1) by
Rosenberg,1−3 also the corresponding platinum(IV) species
The first two Pt(IV) complexes which underwent phase I
clinical trials (tetraplatin (tetrachlorido-R,R-1,2-diaminocyclohexane-
platinum(IV)) and iproplatin (cis-dichlorido-trans-dihydroxido-
bis-isopropylamine-platinum(IV)); Figure 1) showed unfavorable
pharmacokinetic behaviors. Tetraplatin, having a cathodic
potential of −90 mV, was reduced already in the bloodstream
causing systemic toxicity. In contrast, iproplatin, having a
reduction potential of −730 mV, was found to be inactive because
of its notsufficiently fast reduction.7 The rateof reduction depends
Received: September 27, 2012
Published: February 18, 2013
Figure 1. Chemical structures of anticancer platinum complexes.
© 2013 American Chemical Society
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1
300 MHz instrument. H chemical shifts were referenced using the
internal residual protic peak of the solvent (2.50 ppm for DMSO-d6,
8.03 ppm for DMF-d7, 4.8 ppm for D2O).
strongly upon the nature of the axial ligands and is too fast for axial
chlorides, while it is too slow for axial hydroxides. An intermediate
behavior is observed for axial carboxylato ligands.8,9 For instance,
satraplatin (cis-dichlorido-trans-diacetato-cis-ammine,cyclohexyl-
amine-platinum(IV), Figure 1) has a reduction potential of
−250 mV and is under phase III clinical trials.7 Interestingly, the
electrochemical potentials can be satisfactorily predicted by
statistical models based on a combination of surface areas (total
and polar), lowest unoccupied molecular orbital (LUMO)
energies, and dipole moments.10
However, in some instances good results in terms of
cytotoxicity have been reported also for axial hydroxido Pt(IV)
complexes,11 in spite of their highly negative reduction potential.
Moreover, new interest in this class of Pt(IV) compounds arose
from the possibility to obtain complexes activated by visible
light.12
195Pt NMR spectra were referenced to K2PtCl4 (external standard
placed at −1620 ppm with respect to Na2[PtCl6]).27
ESI-MS spectra were recorded on Agilent 1100 Series LC-MSD-
Trap-System VL.
Kiteplatin (1) was prepared according to a literature method.19
Synthesis of cis,trans,cis-[PtCl2(OH)2(cis-1,4-DACH)] (2). Com-
pound 2 was prepared according to an already reported procedure24
with slight modifications. Briefly, a suspension of [PtCl2(cis-1,4-DACH)]
(1) (208.6 mg, 0.55 mmol) in 28 mL of H2O was treated with a solution
of H2O2 in H2O (30% w/w, 2.0 mL). The mixture was stirred at 70 °C for
2 h in the dark. The resulting yellow solution was filtered and then
concentrated under reduced pressure to a minimum volume. Addition
of acetone induced the formation of a pale yellow precipitate that was
isolated by filtration of the mother liquor, washed with ice cold water, and
dried under vacuum. Yield 80% (183 mg, 0.44 mmol).
Pt(IV) complexes with optimal lipophilicity13 have been
prepared by carboxylation of the axial positions. Moreover, by
using axial carboxylato ligands carrying also free carboxylic
groups, further functionalization of the platinum(IV) substrate
can be pursued. The easiest way is to condense the uncoordinated
carboxylic group with an aminic or an alcoholic functionality,
forming the corresponding amide or ester (the reaction can be
favored by the presence of 1,1′-carbonyldiimidazole).7,13 In this
way, biologically active residues can be incorporated in the axial
positions of the Pt(IV) complex to act as targeting moiety or to
induce an additional pharmacological effect at the active site
where reduction to Pt(II) liberates the axial ligands.14,15 In this
context we wish to acknowledge the pioneering work of Lippard,
who prepared estrogen-tethered platinum(IV) derivatives with
the hope that the estrogen, once liberated, could sensitize the cell
to cisplatin.14 Lippard also tethered several units of platinum(IV)
anticancer drugs to soluble, single-walled, carbon nanotubes used
as longboat delivery systems for an effective transport of platinum
drugs across the cell membrane.16
The initial aim of the present work was the synthesis of the
axial disuccinato Pt(IV) derivative of [PtCl2(cis-1,4-DACH)]
(Kiteplatin, 1 in Figure 1) (DACH = diaminocyclohexane),
which contains an isomeric form of the diamine ligand present in
oxaliplatin (i.e., 1R,2R-DACH). The interest in compound 1
stems from its activity on several cisplatin and oxaliplatin-resistant
cell lines.17−22 Pt(IV) derivatives of 123−25 have been extensively
investigated by Khokhar’s group that, among a series of complexes
having general formula cis,trans,cis-[PtIVCl2X2(cis-1,4-DACH)]
(X = CH3(CH2)nCOO, n = 0−8), found that cis,trans,cis-
[PtIVCl2(acetato)2(cis-1,4-DACH)] was the most active in the
murine L1210 leukemia model.24 However, to the best of our
knowledge, no Pt(IV) derivatives of kiteplatin with free carboxylic
functions, suitable for further functionalization, have yet been
prepared. Therefore we planned to prepare the desired com-
pound by reaction of cis,trans,cis-[PtCl2(OH)2(cis-1,4-DACH)]
(2), obtained by oxidation of 1 with hydrogen peroxide, with
succinic anhydride in suitable solvents. To our surprise, the
reaction between 2 and succinic anhydride (performed in the
conditions reported in the literature for the preparation of similar
compounds),13,14,16 leads also to reduction of 2 to the parent
complex 1. This prompted us to investigate, in detail, the
mechanism of this side reaction.
1H NMR. (DMSO-d6) 6.33 (4H, NH2), 2.89 (2H, CHa, see Figure 2
for the numbering of protons), 2.07 (4H, CHbHc), 1.45 (4H, CHbHc)
ppm; (DMF-d7) 6.70 (4H, NH2), 3.25 (2H, CHa), 2.26 (4H, CHbHc),
1.67 (4H, CHbHc) ppm. 195Pt NMR: (DMSO-d6) 964.6 ppm; (DMF-d7)
871.7 ppm. IR: (KBr pellet) 3421, 3210, 1629, 1574, 547, 396, 322,
215 cm−1. ESI-MS: C6H16Cl2N2O2PtNa [2+Na]+ Calcd: 437.01. Found:
m/z 436.9. Anal.: C6H18Cl2N2O3Pt (2·H2O) Calcd: C, 16.67; H, 4.20; N,
6.48%. Found: C, 16.42; H, 4.15; N, 6.29%.
Synthesis of cis,trans,cis-[PtCl2{OC(O)CH2CH2C(O)OH}2(cis-
1,4-DACH)] (3). A suspension of 2 (180.0 mg, 0.44 mmol) in
dimethylsulfoxide (DMSO) (2 mL), maintained at 70 °C, was treated
with succinic anhydride (350.0 mg, 3.53 mmol). The obtained mixture
was kept under magnetic stirring at 70 °C in the dark for 24 h;
meanwhile it became a brown solution. The solution was cooled to room
temperature, filtered, and frozen at −21 °C to be freeze-dried. The
obtained brown oil was treated with diethyl ether and stirred overnight.
Diethyl ether was removed, and the resulting yellow oil was treated
with methanol. The methanol solution was filtered, concentrated to a
minimum volume, and treated with acetone. The obtained solution was
concentrated to a minimum volume. The latter procedure (addition of
acetone and evaporation) was repeated three times. Finally, addition
of diethyl ether induced the precipitation of a sticky pale-yellow solid.
Diethyl ether was removed and the solid was dried under vacuum. The
obtained solid was suspended in diethyl ether, and the suspension was
kept under magnetic stirring for 1 h; then the solid was collected by
filtration of the solvent, washed with diethyl ether, and dried under
vacuum. Yield 70% (191.0 mg, 0.31 mmol).
1H NMR. (DMSO-d6) 12.10 (s, 2H, COOH), 8.13 (m, 4H, NH2),
2.94 (s, 2H, CHa; see Figure 3 for numbering of protons), 2.51 (4H,
CHd), 2.38 (m, 4H, CHe), 1.59 (m, 8H, CHb,c) ppm. 195Pt NMR:
(DMSO-d6) 1217.0 ppm. IR: (KBr pellet) 3434 (s), 1710 (s), 1632 (s),
1374 (m), 1248 (m), 667(m), 340 (m) cm−1. ESI-MS: C14H24Cl2N2-
O8PtNa [3+Na]+ Calcd: 637.05. Found: m/z 636.9. Anal.:
C14H24Cl2N2O8Pt (3) Calcd: C, 27.37; H, 3.94; N, 4.56%. Found: C,
27.44; H, 4.32; N, 4.99%.
Synthesis of cis,trans,cis-[PtCl2(OH)(μ-O)1/2(cis-1,4-DACH)]2
(5). A solution of 2 (106.0 mg, 0.26 mmol) in H2O (3.5 mL) was
treated with dimethylformamide (DMF, 12.0 mL). The resulting yellow
solution was stirred at 50 °C for 30 min in the dark and then allowed to
cool to room temperature; meanwhile, a pale-yellow precipitate formed.
The solid was isolated by filtration of the solvent, washed with diethyl
ether, and dried under vacuum. Yield 50% (51.9 mg).
1H NMR. (DMSO-d6) 6.28 (8H, NH2), 2.87 (4H, CHa), 2.04 (8H,
CHbHc), 1.44 (8H, CHbHc), −0.25 (broad, 2H, OH) ppm; (DMF-d7)
6.42 (8H, NH2), 3.23 (4H, CHa), 2.26 (8H, CHbHc), 1.62 (8H,
CHbHc), −0.26 (broad, 2H, OH) ppm. 195Pt NMR: (DMSO-d6) 970.7
ppm; (DMF-d7) 873.0 ppm. IR: (KBr pellet) 3426, 3213, 1631, 1575,
544, 395, 321, 210 cm−1. ESI-MS: C12H30Cl4N4O3Pt2 [5-H]− Calcd:
808.03. Found: m/z 808. Anal.: C12H30Cl4N4O3Pt2 (5) Calcd: C, 17.79,
H, 3.73, N, 6.91%. Found: C, 17.84, H, 3.96, N, 6.70%.
EXPERIMENTAL SECTION
Materials and Methods. Commercial reagent grade chemicals and
■
1
solvents were used as received without further purification. H NMR
Synthesis of [PtCl4(cis-1,4-DACH)] (6). Compound 6 was
and [1H-195Pt] HSQC spectra were recorded on a Bruker Avance DPX
prepared according to a procedure reported in the literature23 with a
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Figure 2. 1H NMR (top) and [1H-195Pt] HSQC 2D (bottom) spectra of 2 in DMSO-d6, the asterisks indicate residual solvent peaks (the resonance at
2.50 ppm showing coupling of residual methyl protons of DMSO-d6 with 13C, JH,13C = 137.4 Hz). The sketch of compound 2 is also reported with the
numbering of protons.
Figure 3. 1H NMR spectrum of 3 in DMSO-d6, the asterisks indicate residual solvent peaks (the resonance at 2.50 ppm showing coupling of residual
methyl protons of DMSO-d6 with 13C, JH,13C = 137.4 Hz). # indicate residual traces of acetone and diethylehter used in the synthesis of compound 3.
The sketch of compound 3 and the numbering of protons are also reported.
slight modification. Briefly, a solution of 2 (124.0 mg, 0.30 mmol) in
H2O (25 mL) was treated with concentrated HCl (12.4 mL). The
mixture was stirred for 2 days, then the solution was evaporated
to dryness under reduced pressure. The resulting solid was washed
with ice-cold water and dried under vacuum. Yield 65% (87.0 mg,
0.19 mmol).
Table 1. Summary of the Experimental Conditions Used to
Investigate the Reduction of Complexes 2 and 5
a
reduction
reduction
solvent
temperature
70 °C
50 °C
room temperature dark
room temperature artificial light
dark
light
of 2
of 5
DMF
DMF
DMF
DMF
dark
dark
yes
yes
no
1H NMR. (DMSO-d6) 6.78 (4H, NH2), 2.83 (2H, CHa), 2.07 (4H,
CHbHc), 1.52 (4H, CHbHc) ppm. Anal.: C6H14Cl4N2Pt (6) Calcd: C,
15.98, H, 3.13, N, 6.21%. Found: C, 15.88, H, 3.22, N, 6.13%.
NMR Investigation of the Reduction of cis,trans,cis-
[PtCl2(OH)2(cis-1,4-DACH)] (2) and cis,trans,cis-[PtCl2(OH)-
(μ-O)1/2(cis-1,4-DACH)]2 (5). General Procedure. Three milligrams
of 2 (0.007 mmol) or 5 (0.004 mmol) were dissolved in 750 μL of
solvent (DMF-d7 or DMSO-d6) and transferred into an NMR tube. The
samples were kept in different light and temperature conditions (Table 1)
and monitored by 1H NMR.
yes
no
yes
no
yes
yes
no
DMSO 70 °C
DMSO room temperature dark
no
DMSO room temperature artificial light
yes
yes
a
The behavior of complexes 2 and 5 was investigated also in water in
the same experimental conditions, no reduction was observed.
Electrochemical Measurements. An Autolab PGSTAT12 electro-
chemical analyzer (Eco Chemie, Utrecht, The Netherlands), interfaced
to a personal computer running GPES 4.9 electrochemical software, was
used for the electrochemical measurements. A standard three-electrode
cell was designed to allow the tip of the reference electrode (Ag/AgCl,
saturated KCl) to closely approach the working electrode (a glassy
carbon, GC, disk, diameter 0.1 cm, sealed in epoxy resin). The GC working
electrode was polished with alumina followed by diamond paste, then
rinsed with distilled water and dried. This process yielded an almost
completely reproducible surface for all experiments. All measurements
were carried out under nitrogen in DMSO, containing 0.1 M [NBu4][PF6]
as supporting electrolyte, or aqueous 0.05 M phosphate buffer (PB,
pH 7.4), containing 5 mM NaCl. The complex concentration was
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Scheme 1. Different Products of the Carboxylation Reaction Performed in DMSO or DMF
5.0 ×10−4 M. The temperature of the solution was kept constant (25 1°C)
The same is true for other literature reports on the same
compound.23−25
by circulation of a thermostatted water/ethanol mixture through
a jacketed cell. The cell was protected from light by wrapping in an
aluminum foil. Positive-feedback iR compensation was applied
routinely. All peak potentials were measured at 0.2 V s−1 scan rate
and reported vs Ag/AgCl,KClsat.. In the case of experiments performed
in DMSO, the stability of the reference electrode was verified
frequently by measuring the potential of the reversible ferrocene
(0/1+) couple, added as an internal standard, fixed at E°′ = +0.45 V vs
SCE (i.e., +0.495 V vs Ag/AgCl,KClsat.).27
The second step was the carboxylation of the dihydroxido
platinum(IV) complex by reaction with succinic anhydride. In
accord with already reported procedures,7,13,14 the carboxylation
reaction was carried out in DMSO (Scheme 1). The obtained
dicarboxylato derivative, cis,trans,cis-[PtCl2{OC(O)CH2CH2C-
(O)OH}2(cis-1,4-DACH)] (3), was characterized by elemental
analysis, NMR, IR, and ESI-MS. The 1H NMR of compound 3
in DMSO-d6 is reported in Figure 3. The singlet falling at
12.10 ppm is assigned to the proton of the free (uncomplexed)
carboxylic groups. The singlets with Pt satellites falling at 8.13
(2JPt−H = 62.9 Hz) and 2.94 (3JPt−H = 82.6 Hz) ppm are assigned
to the aminic and to the methynic protons of coordinated cis-1,4-
DACH, respectively. The multiplet centered at 2.38 ppm belongs
to methylenic protons of monocoordinated succinato ligands.
In particular, this signal is assigned to the methylenes which are
bound to the uncoordinated carboxylic groups (protons e in
Figure 3). The signal of the other methylenic protons (d in
Figure 3) overlaps with the residual solvent signal and was
assigned with the help of a [1H-13C] HSQC 2D experiment
(data not shown). Finally, the multiplet falling at 1.59 ppm and
integrating for eight protons was assigned to the four CH2 groups
of coordinated DACH.
RESULTS
■
Synthesis of the Pt Complexes. The synthesis of the
platinum(IV) complex cis,trans,cis-[PtCl2(OH)2(cis-1,4-DACH)]
(2) was carried out by treating the corresponding Pt(II) precursor
[PtCl2(cis-1,4-DACH)] (Kiteplatin, 1),18,19 with H2O2 (30% w/w
water solution) according to an already reported procedure.23
The reaction time, however, was reduced from 1 day to 2 h. Com-
pound 2 has been characterized by elemental analysis, NMR, IR,
and ESI-MS.
1
The 1D H NMR and 2D [1H-195Pt] HSQC spectra of 2 in
DMSO-d6 are reported in Figure 2. The singlets with Pt satellites
falling at 6.33 (2JPt−H= 68.6 Hz) and 2.89 (3JPt−H= 94.8 Hz) ppm
and having cross peaks with the platinum resonance at 964.6 ppm,
are assigned to the aminic and to the methynic protons of
coordinated cis-1,4-DACH (Ha), respectively. Two multiplets
centered at 2.07 and 1.45 ppm, each one integrating for 4 protons,
are assigned to the methylenic protons Hb and Hc, respectively.
The Pt resonance (964.6 ppm) is in the range typical for a Pt(IV)
atom in a N2Cl2O2 coordination environment.26,28 A similar
spectrum is obtained using DMF-d7 as solvent (Supporting
Information, Figure S1). In the latter case the 195Pt chemical shift
falls at 871.7 ppm.
The 195Pt NMR of 3 in DMSO-d6 is reported in Supporting
Information, Figure S2 and exhibits a broad singlet falling at
1217.0 ppm. The 195Pt chemical shift is in good agreement with
that already reported for similar Pt(IV) dicarboxylato derivatives.14,23
Carboxylation Performed in DMF, an Unexpected
Result. The carboxylation reaction described in the previous
paragraph was also carried out in DMF, a solvent that has already
been used for the carboxylation of analogous compounds.7,13,14
By using this latter solvent, we obtained not only the
dicarboxylated Pt(IV) derivative 3, but also the reduced Pt(II)
species Kiteplatin (1; Scheme 1) as evidenced by the 1H NMR
spectrum recorded on the crude reaction product. In particular,
We have been unable to detect the signals of the axial
hydroxido ligands, probably because of rapid exchange with the
residual water present in our solvents (DMSO-d6 and DMF-d7).
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Table 2. Cathodic Ep values of 0.5 mM Solutions of Complexes 2, 3, and 6 Measured at 0.2 V s−1 Scan Rate by Using Cyclic
Voltammetry in DMSO, Containing 0.1 M [NBu4][PF6] as Supporting Electrolyte, and in Water, Containing 0.5 mM Phosphate
a
Buffer and 5 mM NaCl
b
complex
cis-[PtCl4(cis-1,4-DACH)] (6)
Ep,c in DMSO (V)
Ep,c in H2O (V)
b
−0.547
−1.22
−1.86
−1.25
−0.055
b
ctc-[PtCl2(OH)2(cis-1,4-DACH)] (2)
ctc-[PtCl2{OC(O)CH2CH2C(O)OH}2(cis-1,4-DACH)] (3)
ctc-[PtCl2(OH)(μ-O)1/2(cis-1,4-DACH)]2 (5)
cis-[PtCl4(NH3)2]
−0.967
b
−1.42
−0.975
−0.204
−0.815
−0.892
c
c
ctc-[PtCl2(OH)2(NH3)2]
c
ctc-[PtCl2{OC(O)CH2CH2C(O)OH}2(NH3)2]
a
b
c
Working electrode: glassy carbon; E vs. Ag/AgCl,KClsat.. This work. From ref 9.
a signal at 4.9 ppm with broad Pt satellites was unambiguously
assigned to the NH2 protons of coordinated cis-1,4-DACH in the
Pt(II) precursor complex 1 (data not shown).
ligands upon reduction of the octahedral Pt(IV) complex to the
square-planar Pt(II) species. The trend of Ep,c values is in accord
with that observed for other Pt(IV) complexes. In particular, the
trans-dichlorido complex 6 has the highest Ep,c value, the trans-
dihydroxido derivative 2 has the second highest value, and the
trans-disuccinato derivative 3 has the less favorable reduction
potential. There are several reports indicating that reduction is
most easy for axial chlorido complexes, is intermediate for acetato,
and is least favorable for hydroxido species,5,29 with reduction
rates generally correlating with reduction potentials.30 However,
on passing from acetato to succinato, the Ep,c decreases and
becomes the most negative. Therefore, the data reported in
Table 2 for the cis-1,4-DACH complexes parallel those reported
for the cisplatin derivatives cis,trans,cis-[PtCl2X2(NH3)2] (X = Cl,
OH, or succinato)9 (also reported in Table 2).
We monitored the reaction course by NMR spectroscopy
using DMF-d7 as solvent and similar experimental conditions
1
(70 °C in the dark). The H NMR spectrum revealed the
presence of the signals of the reduced product 1 already after 24 h
reaction time.
To exclude the involvement of the anhydride in the reduction
process, the dihydroxido complex 2 was dissolved in DMF and
kept in the dark at 70 °C for one day. The spectrum in DMSO-d6
of the residue obtained by evaporation to dryness of the above
solution shows unambiguously the presence of signals belonging
to 1 (data not shown).
In contrast with what has been observed in DMF, the
carboxylation reaction performed in analogous conditions (dark,
70 °C) but using DMSO as solvent, does not yield the reduction
product 1.
In pure organic solvent (DMSO) all peak potentials are shifted
to lower values with respect to those obtained in water, but the
trend is maintained (Ep,c 3 < 2 < 6).
Investigation of the Mechanism Underlying the
Reduction Reaction. A series of experiments was performed
to investigate the influence of light, temperature, and solvent
on the reduction of complex 2 to complex 1 in the absence of
an added reducing agent. Table 1 summarizes the obtained
results. Analogous reactions were performed on cis,trans,cis-
[PtCl2(OH)2(R,R-1,2-DACH)] which contains the isomeric
form of DACH present in oxaliplatin; no reduction was observed.
Therefore the reduction appears to be a characteristic feature of
the derivatives containing cis-1,4-DACH, and this also explains
why no reduction has been observed by other groups who have
carried out the synthesis of axial disuccinato Pt(IV) complexes
starting from the dihydroxido Pt(IV) derivatives of cisplatin,
oxaliplatin, and [PtCl2(en)] (en = ethylendiamine).7,13
The influence of the axial ligands was investigated by
performing analogous reactions starting from [PtCl4(cis-1,4-
DACH)] (6). Under the same experimental conditions used in
the case of 2 and summarized in Table 1, no reduction of 6 to 1
was observed. This finding appears to be in contrast with the
electrochemical data reported in the literature, showing that
Pt(IV) complexes having two axial chlorido ligands have more
positive reduction potentials than those having axial hydroxido
ligands and therefore should be more prone to undergo reduction.
Reduction Potentials. We measured the reduction
potentials Ep,c of the Pt(IV) complexes with cis-1,4-DACH
investigated in this work (namely: trans-dihydroxido, 2; trans-
disuccinato, 3; and trans-dichlorido, 6) by cyclic voltammetry
(CV), and the results are reported in Table 2. In phosphate buffer,
all complexes showed the usual Pt(IV)-electrochemical behavior,
with a chemically irreversible 2e− reduction (E2C mechanism).
The irreversibility is due to the detachment of the two axial
Since we observed the reduction by the solvent only starting
from complex 2 and not from complex 6, this means that factors
other than reduction potential must be at play.
Monitoring of the Reduction Reaction by NMR in DMF-
d7. To gain more information about the reduction reaction, the
progress of the reaction of 2 in DMF-d7 (performed at 50 °C in
the dark) was monitored by 1H NMR spectroscopy (Figure 4).
The spectrum of the initial yellow solution (Figure 4a) showed
only the peaks of the starting substrate (marked with ▲ in
Figure 4). After 4 h the solution turned to dark yellow and the
1H NMR spectrum (Figure 4b) showed additional signals.
Two broad pseudotriplets falling at 7.43 and 6.95 ppm (⧫) are
assigned to a Pt(IV) species having unequivalent NH2 protons,
possibly because of the presence of different ligands in the axial
positions; formation of a cis,trans,cis-[PtCl2(OH)(solvent)(cis-
1,4-DACH)]+ species (4a in Scheme 2), by solvolysis of one
axial hydroxido ligand, could be the answer.31 Our attempts to
isolate this intermediate species have been so far unsuccessful,
but evidence in favor of the hypothesized Pt(IV) complex with
unsymmetrical axial ligands came from the [1H-195Pt]-HSQC 2D
spectrum (Figure 5) showing a correlation between the aminic
signals falling at 7.43 and 6.95 ppm and a Pt atom having a 195Pt
chemical shift of 925.5 ppm. These two cross-peaks indicate that
the two aminic signals belong to the same compound. The same
spectrum shows also equivalence of the two methylenic protons
of 1,4-DACH indicating that they have the same cis ligands
(chlorides). Furthermore, the 195Pt chemical shift is in agreement
with a PtIV cation in a N2Cl2O2 coordination environment and the
electrospray ionization mass spectrometry (ESI-MS) spectrum,
recorded on the NMR sample, shows a peak at m/z = 476
corresponding to [PtCl2(OD)(DMF-d7)(cis-1,4-DACH)]+.
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Figure 4. 1H NMR monitoring of the reduction of 2 in DMF-d7 performed at 50 °C in the dark after (a) 0 h; (b) 4 h; (c) 12 h;(d) 1 day; (e) 5 days.
The residual methyl protons of DMF-d7 show satellites due to coupling with 13C, JH,13C ca. 140 Hz and × indicates a minor impurity in the sample.
Scheme 2. Oxidation and Reduction Processes for Complexes
Bearing cis-1,4-DACH Ligand
Figure 5. [1H-195Pt]-HSQC 2D spectrum of a mixture of 2 and 4a in DMF-d7.
species present in solution was the reduced complex 1 (Figure 4e);
the absence of the H2O2 signal is in accord with its complete
Another signal, in the region of the aminic protons (6.42 ppm,
# in Figure 4b), indicates the presence of another platinum
complex. This species has been shown to be the dinuclear
complex 5 that has also been synthesized independently (see
following discussion). After 12 h, a signal at 4.90 ppm, which
belongs to the aminic protons of the platinum(II) species 1 (● in
Figure 4c), and a broad signal at 10.4 ppm, belonging to H2O2, are
well evident.32 By this time the aminic signals of the solvato
species 4a (⧫ in Figure 4b) have disappeared completely. After
1 day, the solution turned light brown and the signals of complex
1 (●) increased in intensity (Figure 4d). After 5 days, the only
disproportionation into O2 and H2O fostered by the high
temperature and the long waiting time. This experiment
demonstrates that (i) the reduction of 2 takes place in DMF in
the dark already at 50 °C; (ii) the reduction mechanism involves
intermediate species.
To investigate the role of the temperature in the reduction
process, we performed the reaction in the dark at room temperature
in DMF-d7: no reduction was observed. Probably, under these
experimental conditions, H2O2 is not subtracted to the equilibrium
or, alternatively, the formation of the intermediate species is not
favored.
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Figure 6. 1H NMR spectra of 2 in DMSO-d6 exposed to the artificial light at room temperature at zero time (a) and after 3 h (b), 8 h (c), and 4.5 days
(d). The solvent peak at 2.50 ppm shows satellites due to coupling of residual methyl protons of DMSO-d6 with 13C, JH,13C = 137.4 Hz.
Next we investigated the influence of light. The DMF-d7
solution of 2 was kept at room temperature in artificial light.
A reduction of the starting complex 2, with a trend analogous
to that observed in the reaction performed at 50 °C in the dark,
was observed (Supporting Information, Figure S3). The forma-
tion of H2O2 in the reduction process32 was proven by addition
of ethylgallate which acts as a H2O2 scavenger; a decrease in
the intensity of the signal at 10.4 ppm, assigned to H2O2, was
observed (Supporting Information, Figure S3).
Another cross peak at 2.84/482 ppm can be assigned to the
methynic protons of the DACH ligand in the same complex;
their equivalence indicates that solvolysis does not involve the cis
chlorides. Moreover, the 195Pt chemical shift, which is at lower
field with respect to that found for the solvato species containing
DMF (complex 4a, 925.5 ppm), can be taken as an indication
that in 4b the solvent molecule is S-coordinated to the metal.
Finally, the ESI-MS spectrum recorded on the NMR sample
showed the presence of a peak at m/z = 481 corresponding to
[PtCl2(OD)(DMSO-d6)(cis-1,4-DACH)]+. The formation of
the reduced species was proven by the presence of a signal at
4.9 ppm which is characteristic of the aminic protons of 1 (● in
Figure 6b). After 8 h, the solution became dark brown, and the
signals of the starting Pt(IV) complex (2) almost disappeared. In
DMSO, a good coordinating solvent, complex 1 also underwent a
solvation process as evidenced by the presence of signals at
5.3 and 4.9 ppm, the latter overlapping with the aminic protons of
1 (Δ and ○ in Figure 6c) assigned to the non equivalent aminic
protons of the Pt(II) solvato species cis-[PtCl(DMSO)(cis-1,4-
DACH)]+. A proof in support of the latter assignment came
from the [1H-195Pt] HSQC 2D spectrum showing cross peaks in
the region 5.3/−3100 and 4.9/−3100 ppm (1H/195Pt; data not
shown). The observed value of the 195Pt chemical shift is
comparable to literature data reported for cis-[PtCl(DMSO)(cis-
1,4-DACH)]+ species.33,34
Monitoring of the Reduction Reaction by NMR in
DMSO-d6. We wanted to see if light could induce reduction of
complex 2 in DMSO-d6 solution. The reaction was monitored by
1H NMR spectroscopy for 4 days, and the results are shown in
Figure 6. Starting from a pale yellow solution of 2 in DMSO-d6
(▲ in Figure 6a), after 3 h exposure to the sunlight the solution
1
turned dark yellow and the H NMR spectrum (Figure 6b)
showed the appearance of a resonance at 10.4 ppm, assigned to
H2O2, and a resonance at 6.28 ppm (#), assigned to the aminic
protons of the dinuclear Pt(IV) species 5, which is slightly upfield
with respect to the signal of the aminic protons in 2 (Δδ = 0.05
ppm) (see following discussion). Another signal at 6.59 ppm (⧫)
can be assigned to two of the four aminic protons of the solvato
species cis,trans,cis-[PtCl2(OH)(DMSO)(cis-1,4-DACH)]+
(4b). Although this latter species could not be isolated, it was
possible to confirm its formation by [1H-195Pt]-HSQC 2D and
ESI-MS spectrometry. The [1H-195Pt] HSQC 2D spectrum
(Figure 7) showed two (1H-195Pt) cross peaks falling at 6.59/482
and 6.35/482 ppm that can be assigned to the aminic protons
of a DACH Pt(IV)-complex with unsymmetrical axial ligands.
As already observed in DMF-d7 (Supporting Information,
Figure S3), also the reduction of 2 in DMSO-d6, carried on at room
temperature and in the presence of artificial light, is accompanied
by the release of H2O235 (experiment with ethylgallate, Supporting
Information, Figure S4). Therefore, in both solvents the reduction
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Figure 7. [1H-195Pt] HSQC spectrum of 4b in DMSO-d6.
Figure 8. 1H NMR (top) and [1H-195Pt] HSQC 2D (bottom) spectra of 5 in DMSO-d6, the asterisks indicate residual solvent peaks. The solvent peak at
2.50 ppm shows satellites due to coupling of residual methyl protons of DMSO-d6 with 13C, JH,13C = 137.4 Hz.
takes place through a similar mechanism and leads to the same final
products.
assigned to the methylenic protons Hb and Hc of DACH,
respectively. Finally, the broad signal at −0.25 ppm can be
assigned to an hydroxido ligand in axial position. The 1H NMR
spectrum of compound 5, taken in DMF-d7, is reported in
Supporting Information, Figure S5.
Synthesis and Reduction of 5 Performed in DMF and
DMSO. The second intermediate observed in the reduction of
complex 2 in DMF (dinuclear complex 5) was isolated while
attempting to isolate the solvato-species 4a. 2 was dissolved in
the minimum amount of water and treated with DMF. After
a while, the temperature was lowered from 50 °C to room
temperature causing the precipitation of a compound which
proved to be a dinuclear complex (5) as evidenced by elemental
analysis, ESI-MS, and NMR spectroscopy.
The [1H-195Pt]-NMR HSQC spectrum of 5 in DMSO-d6 is
also reported in Figure 8. It shows two cross peaks correlating the
aminic and methynic protons of DACH with a Pt atom falling at
970.7 ppm. The 195Pt chemical shift is in the range typical for a
Cl2N2O2 coordination environment.
A DMF-d7 solution of 5, kept in the dark at room temperature,
did not show signs of reduction. However, if the sample was
warmed to 50 °C, in the dark, reduction to 1 took place
(Supporting Information, Figure S6). Analogous reduction
took place at room temperature if the sample of 5 in DMF-
d7 was exposed to the sun light (Supporting Information,
Figure S7).
The ESI-MS spectrum of compound 5 exhibits a peak at m/z
808.5 which corresponds to a dinuclear Pt(IV) species having
formula C12H29Cl4O3N4Pt2. The 1H NMR spectrum (Figure 8)
in DMSO-d6 shows two singlets with Pt satellites at 6.29 (2JPt−H
=
65.0 Hz) and 2.89 ppm (3JPt−H = 83.3 Hz) assigned to the
aminic protons and to the methynic protons of DACH (Ha), res-
pectively. Two multiplets centered at 2.09 and 1.44 ppm can be
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Also a DMSO-d6 solution of 5, kept at room temperature in
the dark, was stable. In contrast, if it was exposed to artificial light
reduction took place (Supporting Information, Figure S8).
Our interpretation of the experimental data is that the inter-
mediate dinuclear complex 5 is a key intermediate for the reduction
of Pt(IV) to Pt(II), and this takes place with the concomitant
formation of H2O2.
Unlike complex 2, complex 5, dissolved in DMSO-d6 and
kept at 70 °C in the dark, undergoes reduction to complex 1
(Supporting Information, Figure S9), confirming that complex 5
is the key species in the redox process. Moreover, in both solvents
5 did not appear to undergo solvolysis with formation of solvato-
species (4a,b) indicating that, most probably, the solvato-species
precedes rather than follows the formation of 5. Furthermore,
the solvato-species (4a and 4b) appear to be crucial for the
formation of 5. While in DMF the formation of 4a is both light
and heat-driven; in contrast, in DMSO the formation of 4b is
only light-driven.
The observation that in DMSO (70 °C, dark) the starting
complex 2 is not reduced but 5 is, could mean that complex 5 has
an Ep,c higher than that of 2 and hence is more easily reduced.
We measured the reduction potential Ep,c of complex 5 by
cyclic voltammetry and found that the dimetallic complex 5
behaves exactly as its congener 2, albeit a very small cathodic shift
in the value of Ep,c is observed (Ep,c = −1.25 and −1.22 V for 5
and 2 in DMSO, respectively; Table 2). At equimolar
concentration, 5 shows, as expected, a peak current ip,c twice as
much as that of 2 (5 contains two Pt units per molecule), and
the situation does not change when maintained in solution for
prolonged time. When the CV of 5 was performed in pure
water, or when water was added to the DMSO solution, the
reduction peak shifted to −0.975 V, a value very similar to that of
2 (−0.967 V; Table 2).
The mechanism by which Meyer’s blue dimer oxidizes water to
oxygen has not yet been fully clarified. A possibility is an initial
four electron oxidation from RuIII-O-RuIII to RuV-O-RuV
followed by water oxidation (via a μ-oxo-μ-peroxo intermediate)
and regeneration of the blue dimer.
Also Pt(IV) complexes can undergo photoreductive elimi-
nation. Unlike the Pt(IV) compound trans,cis,cis-[Pt(OH)2-
(MeNH2)2(bpy)]2+, which does not undergo photoreduction
to a Pt(II) species in D2O,44 the related complexes mer-
[PtCl3(MeNH2)(bpy)]+ and trans,cis,cis-[PtCl2(MeNH2)2-
(bpy)]2+ undergo reductive elimination of Cl2 or hypochlorous
acid (HOCl) upon irradiation. These results are in line with the
more negative reduction potential of the trans-dihydroxido
Pt(IV) species with respect to the trans-dichlorido derivatives.
In the light of the above observation, the formation of a
dimeric μ-oxo compound such as 5 could be crucial for reduction
of a Pt(IV) trans-dihydroxido complex with release of hydrogen
peroxide. On this basis we propose for the spontaneous reduction
of our compound 2 the mechanism summarized in Scheme 2. A
key intermediate, which appears to be involved in the reductive-
elimination step, is the μ-oxo dinuclear complex 5, which has been
isolated and fully characterized. Its formation probably requires
the preliminary solvation of 2 (displacement of an axial hydroxido
ligand by a solvent molecule with formation of 4). The solvation
step, which is only the first step in the overall process leading to
reduction with simultaneous elimination of hydrogen peroxide,
depends upon the solvent used. It is both light- and heat-driven in
DMF while it is only light-driven in DMSO.
The solvato species 4 would then react with 2 forming the
dinuclear Pt(IV) complex with an oxo bridge 5. Complex 5
would spontaneously undergo reduction to a 1:1 mixture of 1
and 2 with simultaneous elimination of oxygen (1/2 O2 in the
form of H2O2). Our current hypothesis is that a water molecule
could give a nucleophilic attack on an axial hydroxido ligand which
leaves a lone-pair of electrons on platinum. This would lead, in one
step, to the formation of hydrogen peroxide, compound 2, and
compound 1. This would correspond to an “inner-sphere” redox
mechanism fostered by the presence of the dinuclear μ-oxo
species. Thereasonwhy such a mechanism would occur inthe case
of 5, but not in the case of 2, could be the simultaneous formation
of 1 equiv of 1 and 1 equiv of 2 in the case of 5 as opposed to the
formation of only 1 equiv of 1 in the case of 2.
DISCUSSION
■
Various examples of reductive elimination of H2O2 from metal
complexes have been reported in the literature. For instance:
thermal elimination of hydrogen peroxide from dihydroxytellur-
anes,36 photoelimination of H2O2 from PbIV(OH)62− with forma-
37
tion of PbII(OH)42−
,
and photoelimination of H2O2 from
Tp*CuII(μ−OH)2CuIITp* and formation of CuITp* (Tp* =
hydrotris(3,5-dimethyl-1-pyrazolyl)borate).38
A recent paper from Milstein and co-workers39,40 has reported
an artificial catalyst for the sunlight-induced splitting of water
into O2 and H2 with important fallout in the field of renewable
energy. The catalyst, the mononuclear ruthenium complex cis-
[Ru(OH)2(PNN)(CO)] (PNN stands for the tridentate ligand
2-(di-tert-butylphosphino-methyl)-6-diethylaminomethyl)-pyri-
dine), is capable of leading to the stoichiometric liberation of
O2 and H2 in consecutive thermal- and light-driven steps. In
particular, the cis-dihydroxido Ru complex was proposed, after
irradiation, to liberate H2O2 in a reductive elimination step. H2O2
would then catalytically disproportionate into O2 and H2O, a
process which is well-known to be catalyzed by metal complexes.
However, only indirect evidence for the formation of H2O2 was
given. In a theoretical investigation, Fang and co-workers41
proposed a mechanism for the direct formation of O2 (without
intermediate formation of H2O2) involving the formation of a
dimeric aggregate of the cis-dihydroxido Ru complex.
According to the mechanism outlined in Scheme 2, starting
from pure 5, the first redox process would lead to 1 equiv of 1 and
1 equiv of 2. Therefore, performing the reaction in DMSO in the
dark at high temperature (conditions in which pure 2 does not
undergo reduction to 1), one should expect to end up with an
equimolar mixture of 1 and 2. However, this is not the case and
complete reduction of 5 to 1 is observed. Our explanation of this
apparently contradictory result is that 1 can catalyze the
solvolysis of 2 to 4 and hence the formation of new 5 which
can then undergo reduction. The process would go on until the
reduction of 2 to 1 is complete. The platinum(II) catalyzed
ligand substitution to a Pt(IV) complex is a long known
process.45−47 To check this hypothesis, we added a catalytic
amount of 1 to a solution of 2 in DMSO kept in the dark at 70 °C.
Compound 2, which was stable before the addition of 1, started
to undergo reduction which ended up with the complete
conversion of 2 to 1, fully confirming our hypothesis.
Another important historical catalyst, capable to oxidize water
to O2, is the μ-oxo blue dimer discovered by Meyer.42,43 Similarly
to complex 5, Meyer’s blue dimer is a μ-oxo species, cis-[(bpy)2-
(H2O)RuIIIORuIII(OH2)(bpy)2]4+ (bpy = 2,2′-bipyridine).
CONCLUSION
In this work we have reported an improved procedure for
the synthesis of the cis,trans,cis-[PtCl2(OH)2(cis-1,4-DACH)]
■
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complex (2) and its conversion to the disuccinato complex
cis,trans,cis-[PtCl2{OC(O)CH2CH2C(O)OH}2(cis-1,4-DACH)]
(3). The presence of two uncoordinated carboxylic groups in the
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The serendipitous discovery of a reduction process involving
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form of H2O2) from a trans dihydroxido Pt(IV) complex.
The reduction observed in the present investigation has no
precedents in the literature concerning the carboxylation of axial
trans dihydroxido Pt(IV) complexes derived from clinically used
cisplatin or oxaliplatin. Therefore it could be ascribed (but this
needs to be proved) to the presence of the cis-1,4-DACH ligand.
We believe that complex 5, with its peculiar behavior, could
be further exploited for the development of a technology for
water splitting. Moreover, the results of this investigation
could serve also as guidelines in planning the carboxylation and
other reactions involving complexes of type 2. Finally this work
highlights the role of the solvent in possible side reactions.
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ASSOCIATED CONTENT
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■
S
* Supporting Information
Figures S1−S9: 1H NMR spectra recorded on compounds 2 and
5, under different experimental conditions, with the intent of
unravel their reduction mechanism. This material is available free
of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*Fax: +39-080-5442230 (N.M), +39-080-5442230 (G.N.). E-
mail: nicola.margiotta@uniba.it (N.M), giovanni.natile@uniba.it
(G.N.).
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful to Mr. Giovanni Dipinto (University of
Bari, Italy) for the ESI-MS analyses. The University of Bari
■
̀
(Italy), the Italian Ministero dell’Universita e della Ricerca
(MiUR, FIRB Accordi di Programma 2011 − Rete Integrata per
la Nano Medicina, RINAME), the European Union (COST
Action CM1105, Functional metal complexes that bind to
biomolecules), and the Inter-University Consortium for
Research on the Chemistry of Metal Ions in Biological Systems
(C.I.R.C.M.S.B.) are acknowledged for support.
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