Modulation of ligand fluorescence by the Pt(II)/Pt(IV) redox couple

Article abstract of DOI:10.1016/j.ica.2011.12.034

The dangling carboxylic acid moiety of the known platinum(II) complex, [Pt(edma)Cl₂] (edma = ethylenediaminemonoacetic acid), was functionalized via amide coupling chemistry with benzyl amine and dansyl ethylenediamine to afford the derivatives [Pt(edBz)Cl₂] (1) and [Pt(edDs)Cl₂] (2). Subsequent oxidation of these platinum(II) complexes with iodobenzene dichloride in DMF yielded the respective platinum(IV) analogs, [Pt(edBz)Cl₄] (3) and [Pt(edDs)Cl₄] (4). All four platinum complexes were characterized by multinuclear NMR spectroscopy, IR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis. In addition, compounds 1 and 3 were structurally characterized by X-ray crystallography. The photophysical properties of the compounds bearing the fluorescent dansyl moiety, 2 and 4, were evaluated. The emission quantum yields of 2 and 4 in DMF are 27% and 1.6%, respectively. This large difference in emission efficiency indicates that the platinum(IV) center in 4 is more effective at quenching the dansyl-based fluorescence than the platinum(II) center in 2. Time-dependent density functional theory calculations indicate that 4 has several low-lying singlet excited states that energetically lie below the primary radiation-accessible excited state of the dansyl fluorophore. These low-energy excited states may offer non-radiative decay pathways that lower the overall emission quantum yield. Treatment of 4 with biologically relevant reducing agents in pH 7.4 phosphate-buffered saline induces a 6.3-fold increase in emission intensity. These results demonstrate that 4 and future derivatives thereof may be useful for imaging the reduction of platinum(IV) complexes in living systems, chemistry of importance for evolving platinum-based anticancer drug strategies.

Full text of DOI:10.1016/j.ica.2011.12.034

Inorganica Chimica Acta 389 (2012) 77–84
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Modulation of ligand fluorescence by the Pt(II)/Pt(IV) redox couple
⇑
Justin J. Wilson, Stephen J. Lippard
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 3 January 2012
The dangling carboxylic acid moiety of the known platinum(II) complex, [Pt(edma)Cl2] (edma = ethylen-
ediaminemonoacetic acid), was functionalized via amide coupling chemistry with benzyl amine and dan-
syl ethylenediamine to afford the derivatives [Pt(edBz)Cl2] (1) and [Pt(edDs)Cl2] (2). Subsequent
oxidation of these platinum(II) complexes with iodobenzene dichloride in DMF yielded the respective
platinum(IV) analogs, [Pt(edBz)Cl4] (3) and [Pt(edDs)Cl4] (4). All four platinum complexes were charac-
terized by multinuclear NMR spectroscopy, IR spectroscopy, electrospray ionization mass spectrometry,
and elemental analysis. In addition, compounds 1 and 3 were structurally characterized by X-ray crystal-
lography. The photophysical properties of the compounds bearing the fluorescent dansyl moiety, 2 and 4,
were evaluated. The emission quantum yields of 2 and 4 in DMF are 27% and 1.6%, respectively. This large
difference in emission efficiency indicates that the platinum(IV) center in 4 is more effective at quenching
the dansyl-based fluorescence than the platinum(II) center in 2. Time-dependent density functional the-
ory calculations indicate that 4 has several low-lying singlet excited states that energetically lie below
the primary radiation-accessible excited state of the dansyl fluorophore. These low-energy excited states
may offer non-radiative decay pathways that lower the overall emission quantum yield. Treatment of 4
with biologically relevant reducing agents in pH 7.4 phosphate-buffered saline induces a 6.3-fold increase
in emission intensity. These results demonstrate that 4 and future derivatives thereof may be useful for
imaging the reduction of platinum(IV) complexes in living systems, chemistry of importance for evolving
platinum-based anticancer drug strategies.
Dedicated to Professor Jon Zubieta on the
occasion of his 65th birthday.
Keywords:
Platinum(IV) anticancer agents
Fluorescence
Dansyl
Cisplatin
DFT calculations
X-ray structures
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
where such reduction occurs in living systems. X-ray fluorescence
and absorption spectroscopy [9–11] has been used to address these
Platinum-based drugs are effective agents for a number of dif-
ferent cancers [1,2]. Dose-limiting toxic side effects and acquired
resistance, however, limit the broader applicability of this class
of compounds. The search for new platinum anticancer agents with
fewer such drawbacks is an active area of research [3,4]. Among
the new classes of platinum compounds explored, octahedral plat-
inum complexes in the +4 oxidation state show considerable
promise. Platinum(IV) anticancer complexes have several advanta-
ges over first- and second-generation square-planar platinum(II)
analogs [5–7]. The additional two ligand-binding sites enable syn-
thetic modification and fine tuning of the pharmacokinetic param-
eters. Compared to platinum(II) complexes, however, the
mechanism of action of platinum(IV) complexes is less well under-
stood. In most cases, these complexes are best reduced first by two
electrons to form square-planar platinum(II) complexes in a pro-
cess that facilitates binding to proteins, DNA, or other cellular tar-
gets [8]. Nevertheless, questions remain about this reductive
activation step. It is not clear how quickly, by what means, and
questions. These methodologies, however, are not applicable to
live cells and generally require synchrotron radiation.
Optical fluorescence microscopy for imaging analytes and pro-
cesses in living systems is well established [12]. This method has
been used to study the cellular localization and uptake of plati-
num–fluorophore conjugates, which were designed as models for
related platinum anticancer drugs [13–15]. Although fluorescence
microscopy, unlike X-ray techniques, cannot directly provide infor-
mation about the oxidation state of metal ions, it is possible to ap-
ply ligand systems in which the fluorescence intensity is
modulated depending on the oxidation state of the coordinated
metal [16,17]. Such a system involving the Pt(IV)/Pt(II) redox cou-
ple has recently been described [18], in which analogous plati-
num(II) and platinum(IV) complexes were coordinated to
fluorescent coumarin ligands by means of an aniline functional
group on the dye. The authors reported a 7-fold greater emission
intensity for the platinum(II) compared to the platinum(IV) com-
plex in DMF solution. Furthermore, confocal fluorescence micro-
scopic imaging analyses revealed strong localization of the
complexes in the cytosol and lysosomes. The free coumarin ligands
exhibited cellular localization similar to that of the complexes,
⇑
Corresponding author.
E-mail address: lippard@mit.edu (S.J. Lippard).
0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.12.034

78
J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
thus raising the possibility that the coumarin ligands are displaced
from platinum in the cell. Similar systems with strongly coordi-
nated bidentate ligands may be able to provide information about
platinum(IV) reduction in live cells.
electrode. Samples were prepared as 2 mM solutions in DMF with
0.1 M (Bu4N)(PF6) as the supporting electrolyte. Peak potentials are
reported at a scan rate of 100 mV/s. The ferrocene/ferrocenium re-
dox couple was 0.54–0.55 V versus Ag/AgCl using the setup de-
scribed here. Optical absorption spectra were recorded with a
Cary 1E spectrophotometer. Emission spectra were obtained with
a Photon Technology International QM-4/2003 fluorimeter. Quan-
tum yields for fluorescence were measured using quinine sulfate
In the present article we describe our work to design a plati-
num–fluorophore conjugate that can be used to monitor plati-
num(IV) reduction in living systems by an emissive turn-on
response. We present the synthesis and characterization of the
dansyl fluorophore-bearing platinum(II) and platinum(IV) com-
plexes, 2 and 4, as well as non-fluorescent analogs 1 and 3
(Scheme 1). Photophysical studies of 2 and 4 indicate the plati-
num(IV) complex to have a significantly lower emission quantum
yield than the platinum(II) complex; upon reduction of 4, a 6.3-fold
emission turn-on response is observed in aqueous buffer. Addition-
ally, computational studies are reported that rationalize the in-
creased fluorescence quenching of 4.
in 0.1 M H2SO4 (U = 0.58) as the reference [22] over a range of at
least five different absorbance values. For measuring these values
in phosphate buffered saline (PBS), the samples were diluted from
DMF solutions to give aqueous solutions containing less than or
equal to 1% DMF. For all photophysical measurements, the sample
temperature was maintained at 25.0 0.5 °C using a circulating
water bath.
2.3. Synthesis of [Pt(edBz)Cl2] (1)
2. Experimental
A solution of CDI (0.230 g, 1.42 mmol) in 10 mL of DMF was
added to a solution of [Pt(edma)Cl2] (0.535 g, 1.39 mmol) in
10 mL of DMF. The resulting mixture was heated at 60 °C for
10 min, and then sparged with N2 for 5 min. Benzylamine
(0.152 g, 1.42 mmol) in 15 mL of DMF was added dropwise to the
solution containing the activated platinum complex. After stirring
for 12 h, the solution was concentrated to 10 mL under reduced
pressure and elevated temperature (60 °C) and then filtered
through Celite. The addition of 10 mL of water afforded the desired
compound as a pale yellow solid, which was isolated by filtration
and washed sequentially with 5 mL of water, 2 ꢁ 5 mL of ethanol,
and 2 ꢁ 5 mL of diethyl ether before being dried in vacuo. Yield:
0.268 g (40%). M.p. 298–300 °C (dec). 1H NMR (400 MHz, DMF-
d7): d 8.60 (t, 1H), 7.35–7.26 (m, 5H), 6.15 (br s, 1H), 5.48 (br s,
2H), 4.43 (d, 2H), 4.27 (d, 1H), 3.71 (dd, 1H), 3.12–3.07 (br m,
1H), 2.82–2.72 (br m, 2H), 2.57–2.55 (br m, 1H). 13C{1H} NMR
(100 MHz, DMF-d7): d 168.2, 139.4, 128.6, 127.7, 127.2, 57.8,
55.1, 47.3, 42.8. 195Pt{1H} NMR (86 MHz, DMF-d7): d ꢀ2339. IR
(KBr, cmꢀ1): 3335 m, 3274 s, 3202 m, 2940 w, 1654 vs, 1576 m,
1545 s, 1455 w, 1436 m, 1425 m, 1392 vw, 1279 w, 1243 m,
1168 w, 1116 w, 1091 w, 1041 w, 967 w, 758 m, 702 s, 611 w,
572 w, 525 w. ESI-MS (negative-ion mode): m/z 509.4 [M+Cl]ꢀ,
944.6 [2M–H]ꢀ, 980.9 [2M+Cl]ꢀ. Anal. Calc. for C11H17Cl2N3OPt: C,
27.92; H, 3.62; N, 8.88. Found: C, 28.30; H, 3.65; N, 8.85%.
2.1. General considerations
All reactions were carried out under normal atmospheric condi-
tions. Solvents were used as received without additional drying or
purification. The compounds, [Pt(edma)Cl2] (edma = ethylenedi-
aminemonoacetic acid) [19], dansyl ethylenediamine (Ds-en)
[20], and iodobenzene dichloride [21], were synthesized as previ-
ously described. Benzylamine and carbonyldiimidazole (CDI) were
purchased from Sigma–Aldrich and used as received.
2.2. Physical measurements
NMR spectra were recorded on a Bruker DPX-400 spectrometer
in the MIT Department of Chemistry Instrumentation Facility at
20 °C. 1H and 13C{1H} NMR spectra were referenced internally to
residual solvent peaks, and chemical shifts are expressed relative
to tetramethylsilane, SiMe4 (d = 0 ppm). 195Pt{1H} NMR spectra
were referenced externally to K2PtCl4 in D2O (d = ꢀ1628 ppm).
NMR spectra of all compounds are shown in the Supplementary
data (Figs. S1–S22). Fourier transform infrared (FTIR) spectra were
recorded with a ThermoNicolet Avatar 360 spectrometer running
the OMNIC software. Samples were prepared as KBr disks. Cyclic
voltammograms were obtained at room temperature using a Vers-
aSTAT3 potentiostat from Princeton Applied Research accompa-
nied by the V3 Studio software. A three-electrode system was
used, comprising a glassy carbon working electrode, a Pt wire aux-
iliary electrode, and a Ag/AgCl (aqueous saturated NaCl) reference
2.4. Synthesis of [Pt(edDs)Cl2] (2)
A solution of CDI (0.206 g, 1.27 mmol) in 20 mL of DMF was
added to a solution of [Pt(edma)Cl2] (0.469 g, 1.21 mmol) in
Scheme 1. Structures of compounds 1–4.

J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
79
16 mL of DMF, and the resulting mixture was stirred at 60 °C for
10 min. The solution was sparged with N2 for 5 min, and then
Ds-en (0.372 g, 1.27 mmol) in 20 mL of DMF was added dropwise.
After stirring at r.t. for 12 h, the mixture was concentrated to 10 mL
under vacuum and increased temperature (60 °C), and then filtered
through Celite. Water (10 mL) was added to the filtrate to precipi-
tate the desired compound. The pale yellow solid was isolated by
filtration, and washed sequentially with water, ethanol, and
diethyl ether. Yield: 0.471 g (59%). M.p. 258–262 °C (dec). 1H
NMR (400 MHz, DMF-d7): d 8.55 (d, 1H), 8.39 (d, 1H), 8.28 (t,
1H), 8.20 (d, 1H), 7.97 (br t, 1H), 7.68 (t, 1H), 7.62 (t, 1H), 7.30
(d, 1H), 6.03 (br s, 1H), 5.44 (br s, 2H), 4.12 (d, 1H), 3.49–3.45
(m, 1H), 3.29–3.26 (m, 2H), 3.01–2.96 (m, 3H), 2.88 (s, 6H), 2.69
(br m, 2H), 2.44 (br m, 1H). 13C{1H} NMR (100 MHz, DMF-d7): d
168.4, 152.2, 136.6, 130.01, 129.99, 129.8, 128.9, 128.2, 123.9,
119.7, 115.6, 57.7, 55.1, 47.3, 45.2, 42.5, 39.6. 195Pt{1H} NMR
(86 MHz, DMF-d7): d ꢀ2345. IR (KBr, cmꢀ1): 3351 m, 3270 m,
3192 m, 3141 m, 2946 w, 1659 vs, 1571 w, 1547 w, 1318 s, 1144
s, 1095 w, 788 s, 629 w, 576 w. ESI-MS (negative-ion mode): m/z
657.8 [M–H]ꢀ. Anal. Calc. for C18H27Cl2N5O3PtS: C, 32.78; H, 4.13;
N, 10.62. Found: C, 32.92; H, 4.12; N, 10.77%.
1316 s, 1254 w, 1234 w, 1158 s, 1141 vs, 1085 m, 1063 m, 1041
m, 960 m, 942 m, 910 w, 839 w, 814 m, 788 s, 681 w, 627 s, 574
s, 554 w, 499 w. ESI-MS (negative-ion mode): m/z 728.5 [M–H]ꢀ,
1458.6 [2M–H]ꢀ. Anal. Calc. for C18H27Cl4N5O3PtS: C, 29.60; H,
3.73; N, 9.59. Found: C, 29.55; H, 3.71; N, 9.36%.
2.7. Theoretical calculations
Density functional theory (DFT) calculations were performed
with the GAUSSIAN 03 (Rev.D01) software package [23]. All calcula-
tions were carried out using the B3LYP functional [24,25]. The
LANL2DZ basis set and effective core potential [26] was used for
the Pt atom and the 6-31++G(d,p) basis set [27] was used for all
other atoms. Geometries of 2 and 4 were optimized in the gas
phase and established as local minima by frequency calculations,
which revealed no imaginary values. The conductor-like polariz-
able continuum model (CPCM) [28] was applied for subsequent
molecular orbital and time-dependent DFT (TDDFT) calculations
to simulate solvation of the compounds in water. The TDDFT calcu-
lations were used to determine the natures, energies, and oscillator
strengths of the 50 lowest energy singlet excited states. Relevant
Kohn–Sham molecular orbitals, the XYZ-coordinates of optimized
2.5. Synthesis of [Pt(edBz)Cl4] (3)
structures, and
a summary the lowest energy (<4.09 eV,
>303 nm) singlet excited states are provided in the Supplementary
data (Figs. S23 and S24, Tables S1–S4).
[Pt(edBz)Cl2] (0.120 g, 0.250 mmol) was dissolved in 10 mL of
DMF with gentle heating at 60 °C. To this solution, iodobenzene
dichloride (0.072 g, 0.26 mmol) in 1 mL of DMF was added drop-
wise. The solution changed color immediately from pale yellow
to bright yellow. After stirring 3 h at r.t., a 25 mL portion of diethyl
ether was added, and the resulting bright yellow solid was col-
lected by filtration. It was further washed with diethyl ether and
then dried in vacuo. Yield: 0.086 g (63%). M.p. 188–198 °C (dec).
1H NMR (400 MHz, DMF-d7): d 8.90 (t, 1H), 7.92 (br s, unresolved
195Pt satellites, 1H), 7.68 (br s, unresolved 195Pt satellites, 1H),
2.8. X-ray crystallographic studies
Single crystals of 1ꢂDMF and 3ꢂDMF were grown by vapor diffu-
sion of diethyl ether into DMF solutions. The single crystals were
mounted in Paratone oil on a cryoloop and frozen under a 100 K
KRYO-FLEX nitrogen cold stream. Data were collected on a Bruker
APEX CCD X-ray diffractometer with graphite-monochromated
MoKa radiation (k = 0.71073 Å) controlled by the APEX2 software
2
7.39–7.27 (m, 5H), 7.10 (br s, JPtH = 56 Hz, 1H), 4.51–4.43 (m,
package [29]. Absorption corrections were applied using SADABS
[30]. The structures were solved using direct methods and refined
on F2 with the SHELXTL-97 software package [31,32]. Structures were
checked for higher symmetry using PLATON [33]. All non-hydrogen
atoms were located and refined anisotropically. Hydrogen atoms
were placed in idealized locations and given isotropic thermal
parameters equivalent to either 1.5 (terminal CH3 or NH3 hydrogen
atoms) or 1.2 times the thermal parameter of the atom to which
they were attached. The highest residual electron density peaks
and holes after complete refinement were located less than
1.33 Å from the platinum atom in the structures of both 1 and 3.
Crystallographic data collection and refinement parameters are
shown in Table 1.
3H), 3.93–3.83 (m, 1H), 3.36–3.20 (br m, 3H), 2.88 (br m, 1H).
13C{1H} NMR (100 MHz, DMF-d7): d 166.7, 139.2, 128.7, 127.8,
127.4, 59.2, 54.5, 47.8, 43.2. 195Pt{1H} NMR (86 MHz, DMF-d7): d
ꢀ382. IR (KBr, cmꢀ1): 3224 m, 3075 m, 3027 m, 2961 w, 1656 vs,
1571 m, 1496 vw, 1453 w, 1409 w, 1329 w, 1298 w, 1266 w,
1203 vw, 1131 vw, 1098 w, 1048 w, 750 m, 701 m, 662 w,
613 w, 595 w, 575 w. ESI-MS (negative-ion mode): m/z 542.5
[M–H]ꢀ, 1086.6 [2M–H]ꢀ. Anal. Calc. for C11H17Cl4N3OPt: C,
24.28; H, 3.15; N, 7.72. Found: C, 24.66; H, 3.36; N, 7.43%.
2.6. Synthesis of [Pt(edDs)Cl4] (4)
A solution of iodobenzene dichloride (0.107 g, 0.390 mmol) in
2 mL of DMF was added dropwise to a solution of [Pt(edDs)Cl2]
(0.250 g, 0.379 mmol) in 16 mL of DMF. The color of the solution
changed immediately from pale yellow to pale orange. After stir-
ring 12 h at r.t., 80 mL of diethyl ether was added to form a sticky
residue on the flask bottom. The diethyl ether and DMF were dec-
anted, and 30 mL of water was added to the residue. The resulting
solid was collected by filtration. It was suspended sequentially in
water, methanol, and diethyl ether before being dried in vacuo.
Yield: 0.103 g (33%). M.p. 245–254 °C (dec). 1H NMR (400 MHz,
DMF-d7): d 8.57–8.53 (m, 2H), 8.41 (d, 1H), 8.23 (d, 1H), 8.01 (t,
1H), 7.90 (br s, 1H), 7.71–7.61 (m, 3H), 7.32 (d, 1H), 6.92 (br s,
2JPtH = 58 Hz, 1H), 4.35–4.30 (m, 1H), 3.74–3.68 (m, 1H), 3.37–
3.29 (m, 3H), 3.16–3.05 (m, 5H), 2.89 (s, 6H). 13C{1H} NMR
(100 MHz, DMF-d7): d 166.7, 152.0, 136.6, 130.0, 129.9, 129.8,
128.9, 128.2, 123.9, 119.8, 115.6, 58.9, 54.3, 47.7, 45.2, 42.3, 40.0.
195Pt{1H} NMR (86 MHz, DMF-d7): d ꢀ386. IR (KBr, cmꢀ1): 3346
s, 3307 m, 3185 m, 3075 m, 2956 w, 2872 w, 2790 w, 1688 vs,
1613 w, 1573 m, 1543 m, 1480 w, 1450 m, 1431 m, 1412 m,
3. Results and discussion
3.1. Synthesis and characterization
The platinum(II) complexes, 1 and 2, were prepared by an
amide coupling reaction between [Pt(edma)Cl2] and benzylamine
or Ds-en, respectively (Scheme 2). This amide coupling reaction
can be used to tether other desired amines to the core platinum(II)
moiety. It is analogous to the amide coupling chemistry that has
been employed to conjugate chemical moieties to the platinum(IV)
complex, c,c,t-[Pt(NH3)2Cl2(O2CC2H4CO2H)2], a derivative of cis-
platin [34,35]. Similar platinum(II) and platinum(IV) complexes
bearing ethylenediamine-N,N0-diester ligands have been reported
previously [36]. In these cases, however, the esterified ligands were
prepared prior to metallation. For a series of platinum(II) peptide
conjugates that were synthesized on a solid-phase support, it
was necessary to protect the platinum-chelating unit during the

80
J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
Table 1
in either water or acetic acid gave rise to a mixture of at least three
different platinum(IV) compounds, as revealed by 195Pt NMR spec-
troscopy. Alternative hypervalent iodine reagents, PhI(OAc)2,
PhI(OH)(OTs), and 2,6-dimethyliodosylbenzene, failed to oxidize
1 and 2 under similar conditions.
X-ray crystallographic data collection and refinement parameters.
1ꢂDMF
14H24Cl2N4O2Pt
3ꢂDMF
C14H24Cl4N4O2Pt
617.26
Formula
Formula weight
C
546.36
Space group
Unit cell dimensions
P21/c
P21/c
Characterization of the platinum complexes was carried out by
conventional spectroscopic methods. The starting material for 1
and 2, [Pt(edma)Cl2], has a strong absorption in its IR spectrum
at 1720 cmꢀ1, which is assigned to the C@O stretching frequency
of the carboxylic acid. In 1 and 2, this absorption is replaced by
lower energy C@O vibrations at 1654 and 1659 cmꢀ1, respectively,
consistent with the disappearance of the free carboxylic acid and
formation of an amide bond. In the IR spectra of 3 and 4, these
absorptions occur at 1656 and 1688 cmꢀ1, respectively. The pres-
ence of the dansyl fluorophore in 2 and 4 was verified by the pres-
ence of S@O stretching frequencies from the sulfone moiety. The
asymmetric and symmetric S@O stretches of 2 occur at 1318 and
a (Å)
b (Å)
c (Å)
b (°)
V (Å3)
Z
13.7730(9)
12.6440(8)
11.2843(7)
102.6200(10)
1917.6(2)
4
14.4637(8)
11.2251(6)
13.3621(8)
109.8980(10)
2039.9(2)
4
qcalc. (g cmꢀ3
T (°C)
)
1.892
2.010
ꢀ173(2)
ꢀ173(2)
l
(MoK
a )
) (mmꢀ1
7.608
7.418
h range (°)
1.52ꢀ29.61
41701
5382
210
99.8
2.49
3.95
1.074
1.123, ꢀ0.447
1.50ꢀ25.05
31699
3604
228
99.8
3.42
6.98
1.086
2.011, ꢀ0.894
Total number of data
Number of unique data
Number of parameters
Completeness to h (%)
1144 cmꢀ1, and those of 4 are at 1316 and 1141 cmꢀ1
.
The 1H and 13C NMR spectra of 1–4 are consistent with the pro-
posed structures. Peak assignments were made using 2D COSY and
1H, 13C-HSQC NMR techniques as detailed in the Supplementary
data (Figs. S1–S22). The aliphatic regions of the 1H NMR spectra
are characterized by complex splitting patterns due diastereotopic
protons on and near the ethylenediamine backbone. Upon forma-
tion of the platinum(IV) complexes, resonances due to the coordi-
nated NH and NH2 groups shift downfield, consistent with
oxidation of the platinum center (Fig. 1). Additionally, the NH res-
onances of the coordinated secondary amine in the platinum(IV)
complexes display satellites arising from coupling to the 195Pt nu-
a
R1 (%)
b
wR2 (%)
GOFc
Maximum, minimum peaks, e Åꢀ3
a
b
c
R1
wR2 = {
GOF = {
=
R
||Fo| ꢀ |Fc||/
R|Fo|.
[w(Fo ꢀ Fc2)2]/
R .
[w(Fo2)2]}1/2
2
R
2
R
[w(Fo ꢀ Fc2)2]/(n ꢀ p)}1/2 where n is the number of data and p is the
number of refined parameters.
synthesis of the peptide fragment [37,38]. The advantage of per-
forming the coupling reaction directly on the coordinated ligand,
as demonstrated here, is that it eliminates the need for protecting
groups during organic or peptide synthesis. We envision that this
synthetic approach will be general and provide access to a range
of interesting functionalized platinum(II) complexes.
Clean oxidation of 1 and 2 to their Pt(IV) derivatives was accom-
plished with the hypervalent iodine reagent, iodobenzene dichlo-
ride (Scheme 3). By multinuclear NMR spectroscopy, we
determined that only the tetrachloroplatinum(IV) complexes 3
and 4 were formed. The use of hydrogen peroxide as the oxidant
2
cleus (I = 1/2, 33%), with JPtH = 56 and 58 Hz for 3 and 4, respec-
tively. Platinum(IV) complexes give rise to well-resolved Pt
satellites, unlike those of platinum(II) [39]. The 13C NMR spectra
display all anticipated resonances. The 195Pt NMR spectra of 1
and 2 reveal resonances at ꢀ2339 and ꢀ2345 ppm, respectively.
These values are typical for platinum(II) in an N2Cl2 coordination
environment [40,41], and the similarity between them indicates
that the peripheral substituents on the amide do not significantly
affect shielding at the platinum nucleus. The 195Pt chemical shifts
Scheme 2. Syntheses of 1 and 2.
Scheme 3. Syntheses of 3 and 4.

J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
81
Fig. 3. ORTEP diagram of 3. Ellipsoids are drawn at the 50% probability level.
Fig. 1. Aromatic region of the 1H NMR spectra of 1 (top) and 3 (bottom) obtained at
20 °C and 400 MHz in DMF-d7. The asterisk marks the signal due to the solvent.
Table 2
Interatomic distances (Å) and angles (°) for 1.a
Bonds
Angles
of 3 and 4 are ꢀ382 and ꢀ386 ppm. These large downfield shifts
relative to those of 1 and 2 are consistent with oxidation to plati-
num(IV). As with 1 and 2, their close proximity indicates that the
electronic environments of the platinum centers are substantially
the same.
Pt(1)–N(1)
Pt(1)–N(2)
Pt(1)–Cl(1)
Pt(1)–Cl(2)
2.024(2)
N(1)–Pt(1)–N(2)
N(1)–Pt(1)–Cl(1)
N(1)–Pt(1)–Cl(2)
N(2)–Pt(1)–Cl(1)
84.14(7)
90.87(5)
174.38(5)
174.97(6)
2.0425(18)
2.3142(5)
2.3246(6)
a
Numbers in parentheses are estimated standard deviations in the last signifi-
Single crystals of 1ꢂDMF and 3ꢂDMF were grown by diffusion of
diethyl ether into DMF solutions of the complexes, and X-ray dif-
fraction analyses revealed their structures, which are depicted in
Figs. 2 and 3. Relevant bond distances and angles for 1 are given
in Table 2. The square-planar geometry and bond lengths are typ-
ical of Pt(II) complexes. A molecule of DMF is in the crystal lattice
of 1 and forms a hydrogen bonding interaction with the NH group
of the amide linkage, with ODMFꢂꢂꢂNamide = 2.83 Å. Also present in
the lattice are short intermolecular Pt–Pt interactions (Fig. 2, right),
marked by a Pt–Pt distance of 3.30 Å. The X-ray crystal structure of
the analogous compound, [Pt(en)Cl2] (en = ethylenediamine), has
been determined for two distinct polymorphs [42,43]. A careful
crystal packing analysis of these polymorphs revealed close Pt–Pt
intermolecular interactions, similar to those observed for 1. In
the orthorhombic form [42], the Pt–Pt separation is 3.38 Å,
whereas the Pt–Pt separation in the triclinic polymorph [43] is
3.42 Å. These Pt–Pt interactions are supported by hydrogen bonds
between the chloride ligands and coordinated amine protons of the
neighboring molecules. The reason for the slightly shorter Pt–Pt
distance in 1 compared to [Pt(en)Cl2] is not immediately obvious.
The structure of 3 is shown in Fig. 3, and relevant bond
distances and angles are reported in Table 3. As observed in the
crystal structure of 1, a molecule of DMF is present and forms a
hydrogen bond with the proton of the amide group
cant figures. Atoms are labeled as indicated in Fig. 2.
octahedral, as expected for a platinum(IV) complex. The Pt–Cl bond
distances are close to 2.3 Å at both the axial and the equatorial
sites.
3.2. Electrochemistry
The cyclic voltammograms of the two platinum(IV) complexes,
3 and 4, were recorded in DMF with 0.1 M Bu4N(PF6) as the sup-
porting electrolyte (Fig. 4). The cathodic peak potentials measured
at a scan rate of 100 mV/s for 3 and 4 are at approximately ꢀ0.3 V
versus Ag/AgCl. For the analogous compound, cis-[Pt(NH3)2Cl4], the
measured peak potential under identical conditions is ꢀ0.45 V
[44]. This result indicates that 3 and 4 are easier to reduce than
cis-[Pt(NH3)2Cl4], despite similar N2Cl4 coordination sphere. The
presence of electron-withdrawing amide groups in 3 and 4 may
produce this positive shift in the peak potential and facilitate their
reduction.
3.3. Photophysical properties
The absorption and emission properties of the fluorescent
(ODMFꢂꢂꢂNamide = 2.81 Å). The coordination geometry of
3
is
compounds 2, 4, and Ds-en were measured in both DMF and
Fig. 2. ORTEP diagrams of 1. The intermolecular Pt–Pt interaction is shown at the right. Ellipsoids are drawn at 50% probability levels.

82
J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
Table 3
Selected interatomic distances (Å) and angles (°) for 3.a
Bonds
Angles
Pt(1)–N(1)
Pt(1)–N(2)
Pt(1)–Cl(1)
Pt(1)–Cl(2)
Pt(1)–Cl(3)
Pt(1)–Cl(4)
2.017(4)
2.109(6)
2.3041(15)
2.3216(14)
2.3065(14)
2.3189(14)
N(1)–Pt(1)–N(2)
N(1)–Pt(1)–Cl(1)
N(1)–Pt(1)–Cl(2)
N(1)–Pt(1)–Cl(3)
N(1)–Pt(1)–Cl(4)
N(2)–Pt(1)–Cl(1)
83.30(18)
91.12(12)
177.20(12)
88.69(13)
87.86(13)
173.63(15)
N(2)–Pt(1)–Cl(2)
N(2)–Pt(1)–Cl(3)
N(2)–Pt(1)–Cl(4)
Cl(1)–Pt(1)–Cl(2)
Cl(1)–Pt(1)–Cl(3)
Cl(1)–Pt(1)–Cl(4)
94.22(14)
91.87(14)
85.70(14)
91.43(5)
91.06(6)
91.05(5)
Cl(3)–Pt(1)–Cl(2)
Cl(4)–Pt(1)–Cl(2)
Cl(3)–Pt(1)–Cl(4)
90.09(5)
93.27(5)
175.99(5)
a
Numbers in parentheses are estimated standard deviations in the last significant figures. Atoms are labeled as indicated in Fig. 3.
platinum center and its oxidation state, as well as the solvent. In
DMF, the platinum(II) center of 2 slightly quenches the emission,
with the quantum yield dropping to 27% from the 40% value mea-
sured for free Ds-en. The relatively high quantum yield of 27% is in
contrast to prior results from our laboratory in which the presence
of a platinum(II) center lowered the quantum yield of a dansylated
ligand by a factor of 15 [45]. In the previous system, however, the
dansyl fluorophore was positioned much more closely to the plat-
inum(II) center. Quenching of dansyl fluorescence by platinum(II)
through the heavy-atom effect thus depends on the spatial separa-
tion between the two moieties [46]. The higher quantum yield of 2
most likely derives from the long distance of the dansyl fluoro-
phore from the platinum(II) center. The emission quantum yield
of the platinum(IV) complex, 4, in DMF is only 1.6%, significantly
less than that of 2. This result indicates 4 to be a good candidate
for displaying the desired fluorescence turn-on response upon
reduction to Pt(II).
In moving from DMF to PBS, significant fluorescence quenching
occurs for all three compounds. The quantum yields of Ds-en and 2
drop to values of 3.2% and 3.3%, respectively. This result is expected
because the emission of the dansyl fluorophore depends strongly
on solvent polarity [47]. Importantly, the increased quenching ef-
fect of the platinum(IV) compound, 4, carries over to the aqueous
environment where the 0.27% quantum yield for emission is still
much lower than that of 2. In water, 4 will therefore elicit a fluores-
cence turn-on response when reduced to platinum(II), as described
below.
Fig. 4. Cyclic voltammograms of 3 (bottom) and 4 (top) measured at a scan rate of
100 mV/s in DMF with 0.1 M (Bu4N)(PF6) as the supporting electrolyte. The
potential is reported vs. Ag/AgCl.
3.4. DFT calculations
Table 4
Time-dependent DFT (TDDFT) calculations were performed to
gain an understanding of the origin of the decreased emission of
4 relative to that of 2. The frontier molecular orbital diagrams of
2 and 4 are shown in Fig. 5. The HOMO for both complexes is a dan-
Photophysical properties of 2 and 4 in DMF and buffered aqueous solution.a
Compound Absorption in
Absorption in
Emission
in DMF
kem (nm),
U
Emission
in PBS kem
(nm),
DMF kmax (nm),
PBS kmax (nm),
e
ꢁ 103
e
ꢁ 103
U
(Mꢀ1 cmꢀ1
)
(Mꢀ1 cmꢀ1
)
syl-based
p
orbital. The LUMOs of 2 and 4 are different, however. In
orbital.
the case of 2, the LUMO, like the HOMO, is a dansyl-based
p
2
339, 4.8(2)
333, 5.19(8)
339, 4.7(1)
328, 4.6(1)
325, 5.1(1)
328, 4.6(1)
520,
0.27(1)
520,
0.016(1)
520,
560,
0.033(2)
560,
0.0027(9)
555,
In 4, the octahedral coordination geometry shifts the energies of
the dxy and dz2 metal orbitals to an energy that lies between those
of the dansyl-based occupied and unoccupied orbitals, resulting in
a LUMO that is metal-based. To understand how these molecular
orbitals affect the photophysical properties of the complexes, the
50 lowest energy singlet excited states were computed for both 2
and 4 (Tables S3 and S4, Supplementary data). Both compounds
are computed to have an identical, dansyl-based excited state in
the visible region (3.32 eV, 373 nm) with a large oscillator strength
(f = 0.1741), corresponding to the HOMO–LUMO transition for 2
and the HOMO–LUMO+2 transition for 4 (Fig. 5). This excited state
transition is the only one that is strongly allowed following irradi-
ation with visible light (k > 310 nm, f > 0.01), and it is therefore
responsible for emission as it relaxes to the ground state. If lower
energy excited states are available, however, relaxation can occur
non-radiatively through them. In 2 only two excited states, both li-
gand field (d–d) in character, are lower in energy than the allowed
HOMO–LUMO transition. Compound 4, on the other hand, has 15
4
Ds-en
0.40(2)
0.032(3)
a
Numbers in parentheses are the standard deviations in the last significant fig-
ures derived from at least three independent measurements.
phosphate-buffered saline (PBS) at pH 7.4. The results are summa-
rized in Table 4. In DMF, the absorption and emission maxima of
the three compounds are nearly identical. This result is expected
because the optical properties of both compounds are dominated
by relatively intense
p–
p⁄ transitions of the dansyl fluorophore.
In moving from DMF to water, the absorption maxima of the three
compounds are blue-shifted by 10 nm, and the emission maxima
are red-shifted by approximately 40 nm. As seen in Table 4, the
emission quantum yields depend on both the presence of the

J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
83
Fig. 5. Frontier Kohn–Sham molecular orbital diagram for 2 (left) and 4 (right).
excited states that are lower in energy than its allowed HOMO–
LUMO+2 transition. Of these 15, the first and second lowest energy
excited states can be described as
(dansyl) ? r⁄ (platinum)
p
charge-separated states. As shown on the right side of Fig. 5 by
the black downward arrows, these excited states provide plausible
non-radiative decay pathways that can be rationalized based on
molecular orbital energies alone. These competing non-radiative
pathways lower the overall quantum yield for emission of 4, rela-
tive to that of 2.
3.5. Response to reducing agents
Fig. 6 displays the emission turn-on response induced by treat-
ment of 4 with a 10-fold excess of glutathione in PBS at pH 7.4.
Substitution of other biological reducing agents, cysteine and
ascorbic acid, for glutathione afforded nearly identical results.
The magnitude and speed of the turn-on response is the same for
the three reducing agents. Within a minute after addition of the
reducing agents, the turn-on response is complete, with no further
increase in emission for up to 15 min. The kinetic behavior of this
turn-on response is consistent with the ability of ascorbic acid to
rapidly reduce a similar compound, [Pt(en)Cl4] [48].
Fig. 6. Emission spectra of 4 before (black line) and after addition of 10-fold excess
of glutathione (red dashes) in pH 7.4 phosphate-buffered saline. The small peak at
680 nm arises from scattered excitation light (kex = 340 nm).
The turn-on response upon reduction affords a 6.3-fold increase
in integrated emission intensity. Control experiments were carried
out in which 4 was treated with the non-reducing amino acid gly-
cine, and the platinum(II) complex, 2, was similarly treated with
glycine as well as the three biological reducing agents. The emis-
sion of 2 did not change upon introduction of any of the four com-
pounds, as anticipated. When 4 was treated with glycine, a 1.2-fold
increase in emission was observed after several scans and minutes.
In an additional control experiment, 4 alone in buffer showed a
similar emission increase after several scans in the fluorimeter.
This small but noticeable emission increase most likely arises from
photoreduction of 4 in the fluorimeter. Such photoreduction of
the metal center is consistent with the proposed fluorescence

84
J.J. Wilson, S.J. Lippard / Inorganica Chimica Acta 389 (2012) 77–84
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4. Summary and conclusions
Dansyl-bearing fluorescent platinum(II) and platinum(IV) com-
plexes have been synthesized together with non-fluorescent ana-
logs. The non-fluorescent analogs have been crystallographically
characterized. The synthetic methodology employed for the syn-
theses of 1 and 2 has sufficient generality to facilitate the prepara-
tion of platinum(II) complexes bearing a variety of peripheral
functional groups. The simple amide-coupling chemistry employed
should aid in the development of novel platinum(II) complexes for
anticancer screening. The results of our photophysical studies
demonstrate selective fluorescence quenching in the platinum(IV),
compound 4, compared to the platinum(II), 2, state. TDDFT calcu-
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tal-based d orbitals energetically positioned between the HOMO
and LUMO of the dansyl fluorophore. Addition of reducing agents
to 4 triggers a 6.3-fold emission turn-on response in aqueous buf-
fer. Compound 4 therefore has the potential to serve as a mecha-
nistic probe to monitor the reduction platinum(IV) complexes in
biology. In theory, such a turn-on response should enable both spa-
tial and temporal resolution of the platinum(IV) reduction event by
fluorescence microscopy. Unfortunately, the practical applicability
of this complex in living cells is limited by its low quantum yield in
water and the rapid rate of reduction. As a first generation plati-
num(IV) redox sensor, however, compound 4 provides a proof of
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This work was supported by Grant CA034992 from the National
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