Synthesis, characterization, and photophysical properties of three platinum(II) complexes bearing fluorescent analogues of the Di-2-pyridylmethane ligand

Article abstract of DOI:10.1021/ic100411p

Three new ligands of the general formula [RNHCH(py)₂] (py = pyridine; R = tosyl, Ts-dpm; R = dansyl, Ds-dpm; R = 7-nitro-1,2,3- benzoxadiazole, NBD-dpm) have been synthesized and characterized. Reactions of these ligands with cis-[Pt(DMSO)₂Cl₂] (DMSO = dimethyl sulfoxide) in methanol affords [Pt(Ts-dpm)Cl₂] (1), [Pt(Ds-dpm)Cl₂] (2), and [Pt(NBD-dpm)Cl₂] (3). The crystal structures of these complexes reveal bidentate coordination of the ligands to the Pt center with nonplanar chelate rings. Because of inequivalent substituents on the methine carbon atom of the ligands, distinct exo and endo isomers exist in the three complexes. X-ray analyses indicate that 1 crystallizes in the endo conformation, 2 in the exo conformation, and 3 as a mixture of the two conformers. The ¹H NMR and ¹⁹⁵Pt NMR spectra of the complexes display two sets of independent signals corresponding to the chemically inequivalent exo and endo conformers. The exo conformer was determined by 2D NMR spectroscopy to be thermodynamically favored for all three complexes. Density functional theory (DFT), time-dependent DFT, and atoms in molecules calculations were carried out for both conformers of 3 to investigate differences in their electronic structures and to explore intramolecular interactions. In the presence of dioxygen, 1 thermally decomposes at 60 C to form several unidentified products. Compound 2 is thermally stable even in the presence of dioxygen and water but upon light exposure decomposes to form a new platinum(II) species with a ¹⁹⁵Pt NMR shift of-2177 ppm. Compound 3 reacts both thermally and photochemically in the presence of dioxygen and trace amounts of water to form both 4-amino-7-nitro-2,1,3-benzoxadiazole and [Pt(dpk)Cl₂] (dpk = di-2-pyridyl ketone). Oxidation of 1 and 3 with H₂O₂ in acetic acid affords a mixture of compounds, two of which contain dpm ligands bound in a tridentate manner to platinum.

Full text of DOI:10.1021/ic100411p

Inorg. Chem. 2010, 49, 5303–5315 5303
DOI: 10.1021/ic100411p
Synthesis, Characterization, and Photophysical Properties of Three Platinum(II)
Complexes Bearing Fluorescent Analogues of the Di-2-pyridylmethane Ligand
Justin J. Wilson, Juliana Fedoce Lopes, and Stephen J. Lippard*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received March 2, 2010
Three new ligands of the general formula [RNHCH(py)2] (py = pyridine; R = tosyl, Ts-dpm; R = dansyl, Ds-dpm; R =
7-nitro-1,2,3-benzoxadiazole, NBD-dpm) have been synthesized and characterized. Reactions of these ligands with
cis-[Pt(DMSO)2Cl2] (DMSO = dimethyl sulfoxide) in methanol affords [Pt(Ts-dpm)Cl2] (1), [Pt(Ds-dpm)Cl2] (2), and
[Pt(NBD-dpm)Cl2] (3). The crystal structures of these complexes reveal bidentate coordination of the ligands to the Pt
center with nonplanar chelate rings. Because of inequivalent substituents on the methine carbon atom of the ligands,
distinct exo and endo isomers exist in the three complexes. X-ray analyses indicate that 1 crystallizes in the endo
1
conformation, 2 in the exo conformation, and 3 as a mixture of the two conformers. The H NMR and 195Pt NMR
spectra of the complexes display two sets of independent signals corresponding to the chemically inequivalent exo and
endo conformers. The exo conformer was determined by 2D NMR spectroscopy to be thermodynamically favored for
all three complexes. Density functional theory (DFT), time-dependent DFT, and atoms in molecules calculations were
carried out for both conformers of 3 to investigate differences in their electronic structures and to explore intramolecular
interactions. In the presence of dioxygen, 1 thermally decomposes at 60 °C to form several unidentified products.
Compound 2 is thermally stable even in the presence of dioxygen and water but upon light exposure decomposes to
form a new platinum(II) species with a 195Pt NMR shift of -2177 ppm. Compound 3 reacts both thermally and
photochemically in the presence of dioxygen and trace amounts of water to form both 4-amino-7-nitro-2,1,
3-benzoxadiazole and [Pt(dpk)Cl2] (dpk = di-2-pyridyl ketone). Oxidation of 1 and 3 with H2O2 in acetic acid affords
a mixture of compounds, two of which contain dpm ligands bound in a tridentate manner to platinum.
Introduction
coordination chemistry.9,10 For example, the structure and
characterization of the platinum blues and related com-
plexes11-13 resulted from interest in the therapeutic potential
of such compounds. More recently, new platinum chemistry
has been developed to access previously unavailable com-
pounds with enhanced toxicity and selectivity for cancer cells.
In designing light-activated platinum complexes, chemists
have demonstrated interesting photoreactivity of plati-
num(IV) azido units.14,15 In our laboratory, we expanded upon
previously known outer-sphere carboxylation reactions of plati-
num(IV) hydroxo complexes16 to devise convenient methods for
Cisplatin, cis-diamminedichloroplatinum(II),1-4 was approved
by the FDA in 1978 for the treatment of testicular and bladder
cancer. It has since proved to be an extremely effective
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which include nephrotoxicity, nausea, and neurotoxicity.5-8
Diminishing these negative side effects has been a driving
force in the search for new, less toxic platinum therapeutics.
Studies of cisplatin and its mechanisms of activity and
toxicity have unveiled new fundamental aspects of platinum
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2010 American Chemical Society
Published on Web 04/27/2010
pubs.acs.org/IC

5304 Inorganic Chemistry, Vol. 49, No. 11, 2010
Wilson et al.
covalently tethering cisplatin to estrogen,17 peptides,18 carbon
nanotubes,19,20 and gold nanoparticles21 in order to increase
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Chart 1
The development of fluorescent cisplatin analogues22 for
use in cellular imaging studies has also provided a new
opportunity to explore fundamental platinum chemistry.
Several platinum complexes containing fluorescent ligands
have been synthesized by us23 and by others.24-30 Apart from
being easily visualized with fluorescence microscopy, some of
these compounds exhibit interesting fundamental properties.
When coumarin analogues were used as ligands for
platinum,29 the fluorescence-quenching capabilities of the
complexes depended on both the oxidation state of the
platinum atom and the nature of the ligand. Platinum
complexes containing fluorescent anthracene derivatives as
ligands28 adopt a novel bidentate mode achieved through
coordination of the nitrogen atom of a pyridine ring and a
carbon-carbon double bond. Intrinsically fluorescent com-
plexes containing bile acid derivatives as ligands have also
been investigated.31,32
In the present study, we have explored three derivatives of
di-2-pyridylmethane (dpm)33-35 modified with either the
nonfluorescent tosyl group (Ts-dpm) or the fluorescent
dansyl (Ds-dpm) or 7-nitro-1,2,3-benzoxadiazole group
(NBD-dpm). Our choice of dpm derivatives was motivated
by two considerations. First, the starting material for pre-
paring these ligands, 2-(di-2-pyridyl)methanamine, is readily
functionalized with number of commercially available fluor-
escent groups.36 As such, it is possible to tune the hydro-
phobicity and photophysical properties by choice of the
fluorophore. The fluorescent properties of the ligands offer
the potential to track the cellular distribution of the platinum
complexes. We were also motivated by reports in the litera-
ture of platinum complexes with similar dpm-based ligands
that exhibit significant cytotoxic properties.37-39 We antici-
pated that the fluorophore-modified ligands described here
would similarly confer cytotoxic properties to platinum. In
this Article, we describe the synthesis and physical characteri-
zation of the platinum complexes 1-3 (Chart 1). In addition
to characterization in the solid state by X-ray crystallography
and in solution by 195Pt and 1H NMR spectroscopy, we have
investigated the photophysical properties of these complexes
and their ligands. The results are analyzed with the aid of
time-dependent density functional theory (TDDFT) calcula-
tions performed for 3. Complexes 1-3 are thermally and
photochemically reactive. The implications of this chemistry
for the development of light- or heat-activated platinum
prodrugs are discussed. Preliminary oxidative reactions of
these complexes have been explored.
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Experimental Section
General Considerations. Di-2-pyridylmethanamine was pre-
pared from commercially available di-2-pyridyl ketone by a
reported method.40 K2PtCl4, purchased from Strem Chemicals,
was used to prepare cis-[Pt(DMSO)2Cl2].41 [Pt(dpk)Cl2]42 and
4-amino-7-nitro-2,1,3-benzoxadiazole (NBD-NH2)43 were also
prepared by literature procedures. Other reagents were used as
received from commercial vendors. Methanol (MeOH) and
acetonitrile (CH3CN) were used without prior degassing or
drying. Tetrahydrofuran (THF) was saturated with argon and
purified by passage over two columns of Al2O3 prior to use.
N-(Di-2-pyridylmethyl)tosylamide (Ts-dpm). To a mixture of
di-2-pyridylmethanamine (0.706 g, 3.80 mmol) and Na2CO3
(1.21 g, 11.4 mmol) in 25 mL of CH3CN was added dropwise a
solution of tosyl chloride (0.703 g, 3.70 mmol) in 5 mL of
CH3CN. The resulting mixture was stirred at room temperature
for 12 h and then filtered. The colorless filtrate was concentrated
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Article
Inorganic Chemistry, Vol. 49, No. 11, 2010 5305
in vacuo to a volume of approximately 10 mL, at which point
Ts-dpm separated from the solution as a white crystalline solid.
This solid was collected by vacuum filtration. An additional
crop was collected by further concentration of the filtrate to
(ppm) 10.15 (1H, d, NH), 9.13 (2H, d), 8.19 (2H, t), 7.87-7.84
(4H, m), 7.60 (2H, t), 7.36 (2H, d), 6.79 (1H, d, py2CHNHR),
2.34 (3H, s, CH3). 195Pt NMR (86 MHz, DMF-d7): δ (ppm)
-2082 (endo), -2198 (exo). ESI-MS: m/z 603.9 [M]-. Anal.
Calcd for 1, C18H17Cl2N3O2SPt: C, 35.71; H, 2.83; N, 6.94.
Found: C, 35.71; H, 2.87; N, 6.96.
1
yield 0.551 g (44%) of Ts-dpm. Mp: 143-144 °C. H NMR
(400 MHz, CDCl3): δ (ppm) 8.41 (2H, d, J = 4.7 Hz), 7.59 (2H,
d, J = 8.0 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.28 (3H, m), 7.08 (4H,
m), 5.68 (1H, d, J = 5.8 Hz), 2.28 (3H, s). 13C NMR (100 MHz,
CDCl3): δ (ppm) 158.1, 148.9, 143.2, 137.1, 137.0, 129.5, 127.4,
122.8, 122.3, 62.1, 21.6. ESI-MS: m/z 340.0 [M þ H]þ, 338.0
[M - H]-. Anal. Calcd for Ts-dpm, C18H17N3O2S: C, 63.70; H,
5.05; N, 12.38. Found: C, 63.71; H, 5.06; N, 12.55.
[Pt(Ds-dpm)Cl2] (2). By following the procedure described for
1 using 1.14 g (2.69 mmol) of cis-[Pt(DMSO)2Cl2] and 1.50 g
(3.58 mmol) of Ds-dpm, 2 was obtained as a yellow solid (1.75 g,
1
95%). H NMR (400 MHz, DMF-d7), exo þ endo: δ (ppm)
10.40 (d, NH, exo), 9.65 (d, NH, endo), 9.14 (d, o-py, endo), 9.08
(d, o-py, exo), 8.62 (d, exo), 8.53 (d, endo), 8.47 (d, exo), 8.36 (d,
exo), 8.20 (d, endo), 8.02-7.98 (m, exo þ endo), 7.75-7.48 (m,
exo þ endo), 7.29 (d, exo), 7.18 (d, endo), 6.82 (d, py2CHNHR,
exo), 6.30 (d, py2CHNHR, endo), 2.85 (s, N(CH3)2, endo), 2.83
(s, N(CH3)2), exo). 195Pt NMR (86 MHz, DMF-d7): δ (ppm)
-2105 (endo), -2199 (exo). ESI-MS: m/z 682.8 [M - H]-. Anal.
Calcd for 2, C23H22Cl2N4O2SPt: C, 40.36; H, 3.24; N, 8.19.
Found: C, 40.40; H, 3.36; N, 8.30.
N-(Di-2-pyridylmethyl)dansylamide (Ds-dpm). To a mixture
of dansyl chloride (3.60 g, 13.4 mmol) and Na2CO3 (7.10 g,
67.0 mmol) in 20 mL of CH3CN was added dropwise di-2-
pyridylmethanamine (2.75 g, 14.8 mmol) in 5 mL of CH3CN.
The resulting mixture was stirred at room temperature for 12 h
and then filtered. The orange filtrate was concentrated to
dryness under vacuum to give a thick oil, which was purified
by silica gel column chromatography, eluting with 9:1 CH2Cl2/
MeOH. After chromatography, the product was initially ob-
tained as a thick yellow-green oil. Upon recrystallization with
1:1 MeOH/Et2O, pure Ds-dpm was obtained as a pale-yellow
crystalline solid (4.20 g, 75%). Mp: 101-104 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 8.34 (1H, dt, J = 8.7 and 0.8 Hz), 8.30
(1H, dt, J = 8.4 and 1.0 Hz), 8.23 (2H, m), 8.12 (1H, dd, J = 7.3
and 1.3 Hz), 7.50 (1H, app t), 7.40 (1H, d, J = 6.5 Hz),
7.34-7.30 (3H, m), 7.11 (2H, d, J = 7.2 Hz), 7.07 (1H, dd,
J = 7.32 and 0.8 Hz), 6.93-6.90 (2H, m), 5.57 (1H, d, J = 6.5
Hz), 2.78 (6H, s). 13C NMR (100 MHz, CDCl3): δ (ppm) 157.8,
151.7, 148.7, 136.6, 134.9, 130.3, 130.0, 129.64, 129.62, 128.3,
123.1, 122.5, 122.0, 119.5, 115.1, 62.5, 45.6. ESI-MS: m/z 419.1
[M þ H]þ, 441.0 [M þ Na]þ, 859.2 [2M þ Na]þ. Anal. Calcd for
Ds-dpm, C23H22N4O2S: C, 66.01; H, 5.30; N, 13.39. Found: C,
65.80; H, 5.16; N, 13.44.
[Pt(NBD-dpm)Cl2] (3). By following the procedure described
for 1 using 0.106 g (0.250 mmol) of cis-[Pt(DMSO)2Cl2] and
0.100 g (0.290 mmol) of NBD-dpm, 3 was obtained as an
orange-brown solid (0.109 g, 71%). 1H NMR (400 MHz,
DMF-d7), endo conformer: δ (ppm) 10.40 (1H, d, NH), 9.31
(2H, d), 8.63 (1H, d), 8.40-8.35 (4H, m), 7.73 (2H, t), 7.17 (1H,
d, py2CHNHR), 7.00 (1H, d); exo conformer: δ (ppm) 10.44
(1H, d, NH), 9.28 (2H, d), 8.77 (1H, d), 8.31 (2H, t), 8.18 (2H, d),
7.70 (2H, t), 7.60 (1H, br, py2CHNHR), 7.13 (1H, d). 195Pt
NMR (86 MHz, DMF-d7): δ (ppm) -2057 (endo), -2196 (exo).
ESI-MS: m/z 612.8 [M]-. Anal. Calcd for 3, C17H12Cl2N6O3Pt: C,
33.24; H, 1.97; N, 13.68. Found: C, 33.28; H, 2.04; N, 13.44.
Oxidation Chemistry of 1. To a suspension of 1 (0.050 g,
0.083 mmol) in 10 mL of glacial acetic acid was added 30% H2O2
(66 μL, 0.58 mmol). The resulting suspension was stirred at
room temperature for 12 h and then filtered to collect 0.029 g of
an off-white solid, which was washed with 10 mL of Et2O. The
1H NMR spectrum of this material freshly dissolved in DMSO-
d6 revealed the presence of a single compound formulated to be
the Cs-symmetric meso-[Pt(κ3-Ts-dpm)Cl2(OH)], a result incon-
sistent with the lack of symmetry observed in the isolated crystal
N-(Di-2-pyridylmethyl)-7-nitro-2,1,3-benzoxadiazole-4-amine
(NBD-dpm). To a mixture of di-2-pyridylmethanamine (0.802 g,
4.33 mmol) and K2CO3 (3.00 g, 22.0 mmol) in 15 mL of THF
was added dropwise a 10 mL THF solution of 4-chloro-7-nitro-
2,1,3-benzoxadiazole (NBD-Cl; 0.900 g, 4.50 mmol). The mix-
ture was stirred at room temperature for 12 h and then filtered.
The dark-brown filtrate was concentrated to dryness in vacuo,
and the resulting residue was partitioned between 50 mL of
CH2Cl2 and 50 mL of 1 M HCl. The organic layer was separated,
and the aqueous layer was further extracted with two 25 mL
portions of CH2Cl2. The organics were combined, washed with
50 mL of saturated NaCl, and dried with MgSO4. Pure NBD-
dpm was obtained after silica gel chromatography (5% MeOH
in CH2Cl2) as a brown solid (0.714 g, 46%). Mp: 188-192 °C
(dec). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.15 (1H, bs), 8.65
(2H, d, J = 4.8 Hz), 8.35 (1H, d, J = 8.6 Hz), 7.65 (2H, t, J = 7.7
Hz), 7.40 (2H, d, J = 7.9 Hz), 7.26 (2H, t, J = 6.1 Hz, overlaps
with residual CHCl3 peak), 6.13 (1H, d, J = 8.6 Hz), 6.02 (1H,
bs). 13C NMR (100 MHz, CDCl3): δ (ppm) 157.1, 149.4, 144.8,
144.1, 142.5, 137.9, 136.5, 124.7, 123.7, 122.0, 100.9, 63.2. ESI-
MS: m/z 349.1 [M þ H]þ, 370.9 [M þ Na]þ, 718.8 [2M þ Na]þ.
Anal. Calcd for NBD-dpm, C17H12N6O3: C, 58.62; H, 3.47; N,
24.13. Found: C, 58.13; H, 3.44; N, 24.02.
1
ox. After several days standing in solution, the 1H NMR
spectrum revealed the presence of at least two different com-
pounds (Figure S1, Supporting Information, SI).
Oxidation Chemistry of 3. To an orange suspension of 3
(0.020 g, 0.043 mmol) in 5 mL of glacial acetic acid was added
30% H2O2 (34 μL, 0.30 mmol). After stirring at room tempera-
ture for 12 h, acetic acid was removed under reduced pressure
from the resulting red suspension. A 10 mL portion of Et2O was
added to the red residue, and the dark-red solid that resulted was
collected by filtration and washed with 20 mL of Et2O. The yield
was 0.022 g. The 1H NMR spectrum of this material indicated
the presence of at least two different compounds (Figure S2, SI).
No attempts were made to isolate and characterize these
compounds.
Thermal and Photochemical Reactions. Photochemical reac-
tions were performed using a 1000 W high-pressure Hg/Xe arc
lamp (Oriel). Compounds 2 and 3 were irradiated in standard
borosilicate NMR tubes. Because of the low absorptivity of 1 in
the visible region, it was irradiated in a quartz NMR tube to
allow better UV light penetration. Thermal reactions were
conducted by placing NMR tubes covered with aluminum foil
in a temperature-controlled oil bath. The temperature was
maintained between 60 and 65 °C. Dioxygen- and water-
free samples were prepared in a nitrogen-filled glovebox with
[Pt(Ts-dpm)Cl2] (1). Ts-dpm (0.270 g, 0.800 mmol) in 10 mL
of MeOH was added to a suspension of cis-[Pt(DMSO)2Cl2]
(0.330 g, 0.780 mmol) in 10 mL of MeOH. After stirring for 12 h
at room temperature, the reaction mixture was filtered to collect
1 as a white solid. The solid was washed sequentially with 10 mL
of MeOH and 10 mL of Et2O before being dried in vacuo to
obtain 0.417 g (88%) of 1. 1H NMR (400 MHz, DMF-d7), endo
conformer: δ (ppm) 9.54 (1H, d, NH), 9.23 (2H, d), 8.13 (2H, t),
7.90 (2H, d), 7.60 (2H, t, overlapped by exo conformer peaks),
7.78 (2H, d), 7.34 (2H, d, overlapped by exo conformer peaks),
6.15 (1H, d, py2CHNHR), 2.39 (3H, s, CH3); exo conformer: δ
˚
dimethylformamide (DMF)-d7 that had been dried over 4 A
molecular sieves for 48 h. NMR tubes were sealed with rubber
septa and electrical tape.
Physical Measurements. NMR measurements were recorded
on a Bruker DPX-400 spectrometer in the MIT Department of

5306 Inorganic Chemistry, Vol. 49, No. 11, 2010
Wilson et al.
Chemistry Instrumentation Facility. 1H and 13C NMR spectra
were referenced internally to residual solvent peaks, and chemi-
cal shifts are expressed relative to tetramethylsilane (SiMe4; δ =
0 ppm). 195Pt NMR spectra were referenced externally using a
standard of K2PtCl4 in D2O (δ = -1628 ppm). Optical absorp-
tion spectra were recorded with a Cary 1E spectrophotometer.
Emission spectra were obtained with a Photon Technology
International QM-4/2003 fluorimeter. Quantum yields for
fluorescence were measured using either fluorescein in 0.1 M
NaOH (Φ = 0.95)44 for NBD-dpm and 3 or quinine sulfate in
0.1 M H2SO4 (Φ = 0.58)45 for Ds-dpm and 2 as references and
by exciting samples at their wavelengths of maximum absor-
bance. Electrospray ionization mass spectrometry (ESI-MS)
measurements were acquired on an Agilent Technologies 1100
series LC-MSD trap.
phase. XYZ coordinates and vibrational frequencies of the opti-
mized solution-phase geometries of the conformers of 3 are
provided in Tables S1 and S2 in the SI.
X-ray Crystallographic Studies. Single crystals were mounted
in paratone oil on a cryoloop and frozen under a 110 or 100 K
KRYO-FLEX nitrogen cold stream. Data were collected on a
Bruker APEX CCD X-ray diffractometer with graphite-mono-
˚
chromated Mo KR radiation (λ = 0.710 73 A) controlled by the
SMART software package.59 Empirical absorption corrections
were applied using SADABS.60 The structures were solved using
direct methods and refined on F2 with the SHELXTL-97 soft-
ware package.61,62 Structures were checked for higher symmetry
using PLATON.63 All non-hydrogen atoms were located and
refined anisotropically. In general, all hydrogen atoms were
placed in idealized locations and given isotropic thermal para-
meters equivalent to either 1.5 (methyl hydrogen atoms) or 1.2
times the thermal parameter of the atom to which they were
attached. For NBD-dpm and 2, the amine and sulfonamide
hydrogen atoms (H3N) were located on the difference Fourier
Theoretical Calculations. DFT calculations were performed
for the two conformers of 3 using the Gaussian 03 (revision D01)
software package.46 Atoms in molecules (AIM) calculations
were carried out with Xaim.47 The geometries were optimized
using the B3LYP48-50 functional and the 6-31þþg(d,p)51,52
basis set for the light atoms (hydrogen, carbon, nitrogen,
oxygen, and chlorine) and the LANL2DZ53 basis set for the
platinum atom. The effective core potential basis set includes
corrections for relativistic effects. Geometry optimizations in
solution were carried out using an implicit solvation model
through the Integral Equation Formalism Polarizable Conti-
nuum Model (IEFPCM)54 for DMF,55 ε = 36.71. The molec-
ular cavity was built up by the Universal Force Field (UFF)
model. For both conformers, frequency calculations were per-
formed to ensure that the geometries are true energy minima.
The simulated UV-vis absorption spectra were calculated with
TDDFT methods using the 100 lowest singlet excited states of the
closed-shell complexes in a DMF solution. The AIM theory56-58
calculations were performed using the wave function generated by
Gaussian 03 calculations of the optimized geometry in the gas
˚
map and refined with constrained H-N bond distances (0.88 A)
and isotropic thermal parameters (1.2 times the thermal para-
meter of the attached nitrogen atom).
X-ray-quality crystals of the ligands Ds-dpm and NBD-dpm
were grown by evaporation from 1:1 MeOH/Et2O and CH2Cl2
solutions, respectively. X-ray-quality crystals of the platinum
complexes 1-3, 1ox, and 3ox were grown by vapor diffusion of
diethyl ether into DMF solutions. Compound 2 crystallized with
a well-ordered molecule of DMF in the asymmetric unit.
Compound 3 crystallized with half a molecule of disordered
diethyl ether in the asymmetric unit, with the central oxygen
atom occupying a crystallographic inversion center. This mole-
cule of diethyl ether was refined anisotropically with the help of
similarity restraints on bond distances (SADI) and anisotropic
thermal parameters (SIMU and DELU). In addition, 3 crystal-
lized as a disordered mixture of the exo and endo conformers.
Restraints to enforce planarity (FLAT) and similarity (SAME,
SIMU, and DELU) were used in the refinement of the dis-
ordered NBD rings. The thermal parameters of C6 and its
disordered component C6A were constrained to be identical
with the use of the EADP command.64 Both 1ox and 3ox afforded
only small, low-quality crystals. Refinement suffered from
several unreasonable thermal ellipsoids. The ellipsoid of the
oxygen atom of the hydroxo ligand in 1ox failed the Hirschfeld
(44) Brannon, J. H.; Magde, D. J. Phys. Chem. 1978, 82, 705–709.
(45) Eastman, J. W. Photochem. Photobiol. 1967, 6, 55–72.
(46) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision
D.01; Gaussian, Inc.: Wallingford, CT, 2004.
rigid-bond test.65 The Pt-O bond distance was around 2.1 A,
˚
˚
which is 0.1 A longer than most Pt-hydroxo bond lengths.
These two results suggest some occupational disorder between a
chloride and an oxygen atom. Unfortunately, this disorder
could not be satisfactorily modeled, even with restraints. The
thermal ellipsoid of C6 in 3ox became nonpositive definite upon
the initial anisotropic refinement and was therefore subse-
quently constrained to equal that of its neighbors. Additionally,
large solvent-accessible voids that contained heavily disordered
electron density were present in both cases, thus affecting the
overall weighting factor of the refinement. Because of these
problems, only the probable atomic connectivity is discussed for
(47) Ortiz, J. C.; Bo, C. Xaim;X Atoms in Molecules Interface, 1.0;
Universitat Rovira i Virgili: Tarragona, Spain, 1998.
(48) Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100.
(49) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(50) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(51) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257–2261.
(59) SMART, Software for the CCD Detector System, version 5.6; Bruker
AXS: Madison, WI, 2000.
(60) Sheldrick, G. M. SADABS: Area-Detector Absorption Correction;
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University of Gottingen: Gottingen, Germany, 1996.
(52) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Jonh Wiley & Sons, Inc.: New York, 1986.
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€
(61) Sheldrick, G. M. SHELXTL-97; University of Gottingen: Gottingen,
Germany, 2000.
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64, 112–122.
ꢁ
(54) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032–3041.
(63) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht
University: Utrecht, The Netherlands, 2008.
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(57) Bader, R. F. W. Atoms in Molecules: A Quantum Theory; Clarendon
Press: Oxford, U.K., 1994.
Sawaya, M. R. Crystal Structure Refinement: A Crystallographer’s Guide
to SHELXL; Oxford University Press Inc.: New York, 2006.
(65) Hirshfeld, F. L. Acta Crystallogr., Sect. A: Found. Crystallogr. 1976,
32, 239–244.
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Article
Inorganic Chemistry, Vol. 49, No. 11, 2010 5307
Table 1. Summary of the X-ray Crystallographic Information and Data Collection Parameters for Ds-dpm, NBD-dpm, and Compounds 1-3
Ds-dpm
NBD-dpm
1
2 DMF
3
3 0.5Et2O
3
formula
fw
space group
C23H22N4O2S
418.51
Pbca
10.4517(9)
15.8232(13)
24.852(2)
C17H12N6O3
348.33
C2/c
13.9662(10)
10.6609(8)
21.2035(15)
C18H17Cl2N3O2PtS
605.40
Cc
11.4122(12)
13.2503(14)
13.7957(19)
C26H29Cl2N5O3PtS
757.59
P1
C19H17Cl2N6O3.50Pt
651.38
P1
˚
a, A
9.3238(12)
10.2881(13)
16.284(2)
74.290(2)
79.220(2)
65.939(2)
1367.8(3)
2
1.839
-273(2)
5.439
1.30-26.51
24 234
5667
350
99.5
2.87
6.22
1.055
1.450, -1.758
8.5263(4)
11.3987(6)
11.9663(6)
86.0360(10)
85.1820(10)
69.5230(10)
1084.67(9)
2
1.994
-263(2)
6.752
1.71-26.37
19 570
4436
435
100.0
2.50
5.16
1.092
1.086, -0.606
˚
b, A
˚
c, A
R, deg
β, deg
γ, deg
101.7580(10)
112.456(2)
3
˚
V, A
Z
F
4109.9(6)
8
1.353
-263(2)
0.186
1.64-26.37
55 468
4194
276
100.0
4.41
9.45
1.033
0.312, -0.378
3090.8(4)
8
1.497
-263(2)
0.108
1.96-28.70
31 855
3998
238
100.0
4.53
10.93
1.024
0.438, -0.318
1927.9(4)
4
2.086
-273(2)
7.683
2.47-28.28
18 845
4712
246
100.0
2.24
4.46
1.006
1.424, -0.767
calcd, g cm-3
T, °C
3
μ(Mo KR), mm-1
Θ range, deg
total no. of data
no. of unique data
no. of param
completeness to Θ (%)
R1a (%)
wR2 b (%)
GOFc
max, min peaks, e A
-3
˚
3
P
P
P
P
P
a R1 = ||Fo| - |Fc||/ |Fo|. b wR2 = { [w(Fo2 - Fc2)2]/ [w(Fo2)2]}1/2. c GOF = { [w(Fo2 - Fc2)2]/(n - p)}1/2 where n is the number of data and p is
the number of refined parameters.
these structures. A summary of the crystallographic data and
refinement information for the ligands and 1-3 is presented in
Table 1 and those for 1ox and 3ox in Table S3 in the SI.
Scheme 1
Results and Discussion
Ligand Synthesis and Characterization. The three
ligands were prepared in moderate to good yields from
di-2-pyridylmethanamine and the corresponding sulfonyl
(Ts-dpm and Ds-dpm) or aryl (NBD-dpm) chloride in the
presence of a carbonate salt as a base to neutralize the
hydrochloric acid byproduct, as shown in Scheme 1. Di-2-
pyridylmethanamine is a convenient starting material for
the synthesis of these new fluorescent ligands. The pri-
mary amine group is readily functionalized by a number
of amine-specific fluorescent labeling reagents,36 while
the two pyridyl arms remain available for metal coordi-
nation. This property is demonstrated here by our use of
dansyl and NBD, both well-known fluorophores. Be-
cause platinum complexes containing similar ligands dis-
play cytotoxic activities similar to that of cisplatin,37-39
we hypothesized that platinum complexes utilizing our
modified dpm ligands would similarly be cytotoxic.
The three ligands were characterized by H and 13C
1
˚
amide or amine. The N N distance is 2.73 A for
NMR spectroscopy and by ESI-MS. Both Ds-dpm and
NBD-dpm were structurally characterized by X-ray dif-
fraction. The NMR spectra of the ligands are consistent
with the structures depicted in Scheme 1.
3 3 3
˚
Ds-dpm and 2.60 A for NBD-dpm. Ds-dpm exhibits no
other noteworthy intra- or intermolecular interactions in
the solid state. In contrast, NBD-dpm engages in a long-
range intermolecular π-stacking interaction along the
crystallographic c axis (Figure S3, SI). This stacking
interaction occurs in a BBABB-type pattern, where the
pyridine ring (A) is flanked on either side by two con-
secutively stacked NBD heterocycles (B). The interplanar
The 13C NMR spectra displayed characteristic reso-
nances for the methine carbon atoms (py2CHNHR) at
62-63 ppm for all three ligands. The proton resonance of
this methine carbon atom appeared as a doublet near
5.6 ppm in the 1H NMR spectra of Ts-dpm and Ds-dpm.
In NBD-dpm, this resonance was a broad singlet at 6 ppm.
The molecular structures of Ds-dpm and NBD-dpm as
determined by X-ray crystallography are shown in Figure 1.
Both structures reveal an intramolecular hydrogen bond
between N2 of the pyridine ring and N3 of the sulfon-
˚
distance between the NBD heterocycles is 3.37 A, and the
spacing between the NBD heterocycle and pyridine ring
˚
is 3.23 A.
Synthesis and Solid-State Characterization of Platinum
Complexes. The platinum complexes 1-3 were prepared

5308 Inorganic Chemistry, Vol. 49, No. 11, 2010
Wilson et al.
Figure 1. Molecular structures of Ds-dpm (left) and NBD-dpm (right). Thermal ellipsoids are drawn at the 50% probability level. Carbon (gray) and
hydrogen (green circles) atoms are not labeled.
Scheme 2
by treatment of a suspension of cis-[Pt(DMSO)2Cl2]
in MeOH with a methanolic solution of the ligand, as
shown in Scheme 2. This general synthetic route for the
preparation of diiminedichloroplatinum(II) compounds
has been used previously.66-70 The platinum complexes
were isolated as analytically pure solids in yields of
greater than 70%. These compounds were characterized
both in the solid state by X-ray diffraction and in solution
by NMR spectroscopy.
ring. In 3, the NBD heterocycle is tilted to one side, thus
destroying a potential mirror plane containing Pt1, C6,
and N3.
Unlike the related diimine ligands 2,20-bipyridine and
1,10-phenanthroline, which form five-membered planar
chelate rings, dpm and the analogues studied here give
rise to six-membered chelate rings that are not planar. As
observed in the structures of 1-3, the chelate rings adopt
a boatlike conformation. Because the bridging methine
carbon atom is bound to two inequivalent substituents in
addition to the pyridine rings, two different conforma-
tional isomers exist. These conformers, exo and endo, are
depicted in Scheme 3.
The molecular structures of 1-3 are shown in Figure 2.
Selected bond distances and angles are displayed in Table 2.
As anticipated, the ligands adopt a bidentate coordina-
tion mode through the nitrogen atoms of the pyridine
rings. The typical square-planar geometry for plati-
num(II) is observed for 1-3 with only minor deviations
from the ideal 90° L-Pt-L bond angles. These values
range from 87.6° to 92.0° in the three complexes. The
Compound 1 crystallizes exclusively as the endo con-
former, 2 as the exo conformer, and 3 as a disordered
mixture of the two. The occupancy factors of the dis-
ordered components of 3 were allowed to refine freely,
and a final value of 66% was obtained for the exo
conformer. The two disordered components of 3 are
shown in Figure 3.
˚
Pt-L bonds have the expected distances of about 2 A for
˚
Pt-Npy and 2.3 A for Pt-Cl. In the solid state, these
compounds are asymmetric. For 1 and 2, the tosyl and
dansyl groups are positioned over a coordinating pyridine
Another noteworthy feature in the structures of 1-3 is
a close Pt-H interaction observed for the hydrogen
atoms of the methine carbon (C6) in the exo conformers
and the hydrogen atom of amine or sulfonamide nitrogen
(N3) of the endo conformers. For 1 and the endo con-
(66) Fanizzi, F. P.; Natile, G.; Lanfranchi, M.; Tiripicchio, A.; Laschi, F.;
Zanello, P. Inorg. Chem. 1996, 35, 3173–3182.
(67) Tu, C.; Wu, X.; Liu, Q.; Wang, X.; Xu, Q.; Guo, Z. Inorg. Chim. Acta
2004, 357, 95–102.
(68) Maheshwari, V.; Bhattacharyya, D.; Fronczek, F. R.; Marzilli, P. A.;
Marzilli, L. G. Inorg. Chem. 2006, 45, 7182–7190.
(69) Pascali, S. A. D.; Migoni, D.; Papadia, P.; Muscella, A.; Marsigliante, S.;
Ciccarese, A.; Fanizzi, F. P. Dalton Trans. 2006, 5077–5087.
(70) Maheshwari, V.; Carlone, M.; Fronczek, F. R.; Marzilli, L. G. Acta
Crystallogr., Sect. B: Struct. Sci. 2007, 63, 603–611.
˚
former of 3, the hydrogen atom of N3 is 2.88 and 2.90 A
from the Pt center, respectively. The corresponding
N-H-Pt angles are 102.4° and 110.9°. Shorter Pt-H
distances are observed in the exo conformers. For 2 and
the exo conformer of 3, the hydrogen atom of C6 is at

Article
Inorganic Chemistry, Vol. 49, No. 11, 2010 5309
a
˚
Table 2. Selected Interatomic Distances (A) and Angles (deg) for 1-3
1
2 DMF
3
3 0.5Et2O
3
Pt1-Cl1
Pt1-Cl2
Pt1-N1
Pt1-N2
2.2980(13)
2.2903(11)
2.032(4)
2.2917(9)
2.2943(9)
2.015(3)
2.018(3)
2.2851(10)
2.3044(9)
2.015(3)
2.020(3)
2.009(3)
N1-Pt1-N2
N1-Pt1-Cl1
N1-Pt1-Cl2
N2-Pt1-Cl1
N2-Pt1-Cl2
Cl1-Pt1-Cl2
87.93(14)
178.33(10)
90.90(10)
90.65(11)
178.73(11)
90.52(4)
87.71(11)
178.70(8)
90.39(8)
91.09(8)
177.41(8)
90.83(3)
87.64(11)
177.48(8)
90.47(8)
89.92(9)
178.11(9)
91.98(4)
a The numbers in parentheses are the estimatedstandard deviations of
the last significant figures. Atoms are labeled as indicated in Figure 2.
Figure 3. Disordered components of 3. Both exo (left) and endo (right)
conformers were observed.
Scheme 3
others.72-74 These studies examined whether such inter-
actions should be considered agostic. Authentic agostic inter-
actions are characterized as covalent 3-center-2-electron
interactions.75 In all of the studies, these particular d8
square-planar interactions were characterized as purely
electrostatic in nature and therefore not agostic. In the cases
of 1-3, the close Pt-H distances are most likely a con-
sequence of the ligand-binding geometry. However, the
NMR data discussed below are consistent with the presence
of weak electrostatic interactions.
Figure 2. Molecular structures of 1-3. Thermal ellipsoids are drawn at
the 50% probability level. Carbon and hydrogen atoms are not labeled.
Solvent molecules of crystallization for 2 and 3 are omitted for clarity.
Disorder in 3 has been omitted as well.
˚
distances of 2.79 and 2.67 A from the platinum atom with
C-H-Pt angles of 95.5° and 97.4°, respectively. The nature
of similar axial M-H interactions in d8 square-planar
complexes has previously been investigated by us71 and by
(72) Yao, W.; Eisenstein, O.; Crabtree, R. H. Inorg. Chim. Acta 1997, 254,
105–111.
(73) Hambley, T. W. Inorg. Chem. 1998, 37, 3767–3774.
(74) Zhang, Y.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A.; Oldfield, E.
Organometallics 2006, 25, 3515–3519.
(71) Sundquist, W. I.; Bancroft, D. P.; Lippard, S. J. J. Am. Chem. Soc.
1990, 112, 1590–1596.
(75) Brookhart, M.; Green, M. L. H.; Parkin, G. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 6908–6914.

5310 Inorganic Chemistry, Vol. 49, No. 11, 2010
Wilson et al.
Table 3. 195Pt and Selected 1H NMR Chemical Shifts for the Conformers of 1-3
δ 195Pt,
ppm
δ 1H,
o-py, ppm
δ 1H,
N-H, ppm
δ 1H,
methine H, ppm
compound
exo-1
endo-1
exo-2
endo-2
exo-3
endo-3
-2198
-2082
-2199
-2105
-2196
-2057
9.13
9.23
9.08
9.14
9.28
9.31
10.15
9.54
10.40
9.65
10.44
10.40
6.79
6.15
6.82
6.30
7.60, broad
7.17
part to hydrogen-bonding interactions with the highly
polar DMF solvent. The methine proton resonances (C6
in Figure 2) were identified based on coupling to the NH
resonances (observed by 1H-1H COSY) and by coupling to
carbon atoms near 65 ppm (observed by 1H-13C HSQC).
These resonances occur between 6.3 and 7.2 ppm in com-
plexes 1-3.
1H-1H NOESY experiments identified the exo con-
former as the major species in solution for all three
compounds. Especially diagnostic is the presence of an
NOE cross-peak between the NH proton and the protons
at the 3 position of the pyridine rings only in the major set
of signals. A similar cross-peak was observed between the
methine proton and the protons at the 3 position of the
pyridine ring in the minor set of signals, corresponding to
the endo conformer. Negative-phase cross-peaks between
analogous protons of the exo and endo conformers were
also observed, indicating that interconversion between
the conformers occurs within the 2 s mixing period of the
experiment.
The methine proton resonances of the exo conformers
1-3 occur about 1 ppm downfield from those in the endo
conformers. This downfield shift is consistent with an
electrostatic interaction between the methine proton and
the Pt center, as observed in the crystal structures and
discussed above. Agostic interactions, on the other hand,
would shift these resonances upfield.75
Figure 4. VT 1H NMR spectra of 3 in DMF-d7. As the temperature is
elevated above 50 °C, the distinct resonances for the exo and endo
conformers coalesce. For full peak assignment of 3 at 20 °C, see Figure
S12 in the SI. VT-NMR spectra for 1 and 2 are provided in Figures S4 and
S5in the SI. The singletat8 ppm markedbyan asteriskisfromthe solvent.
NMR Spectroscopic Characterization of 1-3. The three
platinum complexes are insoluble in nonpolar organic
solvents and water. The compounds are very soluble in
DMSO and DMF. Given the propensity of DMSO to
interact with platinum(II) by ligand substitution
reactions,76-78 DMF-d7 was chosen as the solvent for
1
conducting NMR spectroscopic studies of 1-3. The H
NMR spectra of 1-3 in DMF-d7 at 20 °C displayed two
distinct sets of resonances of unequal intensity corre-
sponding to the inequivalent exo and endo conformers.
At temperatures above 65 °C, the signals coalesce as
interconversion rapidly occurs and the different confor-
mers become indistinguishable on the NMR time scale, as
shown in Figure 4 for 3 [see Figures S4 and S5 in the SI for
variable-temperature NMR (VT-NMR) spectra for 1 and
2]. This process is reversible through several temperature
cycles. However, prolonged exposure of these com-
pounds to elevated temperatures does eventually lead to
decomposition (vide infra).
195Pt NMR spectra for 1-3 were recorded at 20 °C in
DMF-d7. As expected, two distinct resonances are ob-
served for each compound, corresponding to the
two conformers (Figure 5). The observed chemical
shifts (-2057 to -2199 ppm) for these complexes are in
the range expected for platinum(II) with an N2Cl2
coordination environment.79-81 For all three complexes,
the exo conformer resonance occurs upfield from that in the
endo conformer, indicating greater shielding of the Pt
nucleus in the former. In the three complexes, the
chemical shifts of the exo conformers all fall within
3 ppm of -2198 ppm. This similarity is remarkable given
the large, 15 000 ppm window for the 195Pt nucleus. The
chemical shifts of the endo conformers span a wider range.
The shifts are -2082, -2105, and -2057 ppm for 1-3
respectively. This wider range in shifts reflects the fact that
the endo conformations position the different functional
groups of the ligands closer to the Pt center than the exo
conformations.
Proton resonances were assigned using 2D NMR spectro-
scopic techniques (Figures S6-S14, SI). Selected 1H and
195Pt NMR chemical shifts are displayed in Table 3. The
resonances of the protons ortho to the coordinating
nitrogen atoms of the pyridine rings fall between 9.0
and 9.3 ppm for the three complexes in both conforma-
tions. These resonances are 0.6-1.0 ppm downfield from
the corresponding values in the free ligands, consistent
with coordination to the Pt center. In the 1H-13C HSQC
spectra, the amine and sulfonamide protons could be
identified as the only resonances not correlated to a
carbon nucleus. These proton chemical shifts are farthest
downfield, with values ranging from 9.5 to 10.4 ppm. The
large downfield shifts of these protons are attributed in
To assess the thermodynamic stability of the exo con-
former relative to that of the endo conformer, van’t Hoff
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53–60.

Article
Inorganic Chemistry, Vol. 49, No. 11, 2010 5311
Table 5. Electronic Absorption and Emission Data for Ligands and Platinum
Complexes in a DMF Solution
absorption λmax
,
emission λem
nm (Φ)
,
compound
nm (ε ꢀ 10-3, M-1 cm-1
)
3
Ts-dpm
Ds-dpm
NBD-dpm
1
2
3
268 (5.04)
269 (18.7), 340 (4.90)
270 (8.80), 330 (6.30), 468 (22.0)
270 (10.00), 310 (5.10)
266 (16.30), 312 (8.50)
521 (0.30)a
524 (0.32)b
440 (0.019)a
545 (0.003)b
270 (19.0), 388 (13.60),
476 (sh, 25.80), 496 (28.20)
a Referenced to quinine sulfate (Φ = 0.58 in 0.1 M H2SO4).45
b Referenced to fluorescein (Φ = 0.95 in 0.1 M NaOH).44
Figure 5. 195Pt NMR spectra of 1 (bottom), 2 (middle), and 3 (top) in
DMF-d7. Signals are observed for both the exo (major) and endo (minor)
conformers.
Table 4. Thermodynamic Parameters for the Exo to Endo Conversion of 1-3 in a
DMF Solution
4H°,
3
4S°,
4G°(298 K),
compound kcal mol-1
cal K-1 mol-1
kcal mol-1
3
3
3
1
2
3
þ1.38 ( 0.05
þ2.10 ( 0.07
þ1.31 ( 0.05
-2.4 ( 0.2
-3.9 ( 0.2
-2.5 ( 0.1
þ2.09 ( 0.07
þ3.25 ( 0.09
þ2.06 ( 0.06
plots were constructed from VT-NMR experiments
(Figures S15-S17, SI). The values of 4H°, 4S°, and
4G° (at 298 K) for conversion of the exo conformer to
the endo conformer are listed in Table 4. The larger size
of the dansyl group may influence the greater thermo-
dynamic preference for the exo conformer in 2, relative to
1 and 3. In general, these energy differences are quite
small, consistent with the presence of both conformers in
the solid-state structures.
Figure 6. UV-vis absorption spectra for Ts-dpm (;), Ds-dpm (red b),
NBD-dpm (green ꢀ), 1 (blue 9), 2 (maroon ), and 3 (purple O) in DMF
*
at room temperature.
pyridine rings do not induce significant quenching of the
fluorophores.
Photophysical Properties. Relevant photophysical
properties for the ligands and compounds 1-3 in a
DMF solution are summarized in Table 5, and optical
absorption spectra are shown in Figure 6. Emission
spectra of the compounds are provided in Figure 7. A
Upon coordination to platinum(II), the absorption
features of the ligands are altered. The pyridine-localized
1π-π* transitions occur at nearly the same wavelength
but with a 2-fold increase in the extinction coefficients in
the platinum complexes. For 1, a new band at 310 nm is
observed that is not present in the free ligand. For 2, the
band at 340 nm in the free ligand is shifted to higher
energy, appearing at 312 nm. The major bands of NBD-
dpm are red-shifted significantly to 388 and 496 nm when
coordinated to platinum in 3.
1
pyridine-localized π-π* transition appears in all three
ligands around 270 nm. For Ts-dpm, this is the only
spectral feature observed. The band at 340 nm and the
absorptions at 330 and 468 nm of Ds-dpm and NBD-
1
dpm, respectively, can be assigned to π-π* transitions
localized in the naphthalene ring system and fused hetero-
cycle of the two ligands. Ts-dpm is nonemissive. Both Ds-
dpm and NBD-dpm emit in the green region of the visible
spectrum at 521 and 524 nm with quantum yields of
0.30 and 0.32, respectively. These values are similar to
those reported for other compounds conjugated with
dansyl82-84 and NBD.85,86 This result indicates that the
Platinum coordination also affects the emission proper-
ties of the ligands (Figure 7). Like Ts-dpm, 1 is not
emissive. The platinum complexes 2 and 3 exhibit broad,
unstructured emission bands similar to those of the free
ligands. The emission band of 2 is centered at 440 nm,
which is 80 nm (3500 cm-1) higher in energy than the free
ligand. In contrast, the emission band of 3 is centered at
545 nm, 20 nm (740 cm-1) lower in energy than the free
ligand.
The measured quantum yields for fluorescence of 2 and
3 are 0.019 and 0.003, respectively, indicating large
quenching of the ligand fluorescence. This effect most
likely arises from the close proximity of the Pt center to
the fluorophores. Heavy atoms can increase the rates
of spin-forbidden radiation-less transitions in aromatic
(82) Himel, C. M.; Mayer, R. T. Anal. Chem. 1970, 42, 130–132.
(83) Hudson, E. N.; Weber, G. Biochemistry 1973, 12, 4154–4161.
€
(84) Passaniti, P.; Maestri, M.; Ceroni, P.; Bergamini, G.; Vogtle, F.;
Fakhrnabavi, H.; Lukin, O. Photochem. Photobiol. Sci. 2007, 6, 471–479.
(85) Matsushita, Y.; Takahashi, M.; Moriguchi, I. Chem. Pharm. Bull.
1986, 34, 333–339.
(86) Haugland, R. P.; Spence, M. T. Z.; Johnson, I. D.; Basey, A. The
Handbook: A Guide to Fluorescent Probes and Labeling Technologies, 10th
ed.; Molecular Probes: Eugene, OR, 2005.

5312 Inorganic Chemistry, Vol. 49, No. 11, 2010
Wilson et al.
Figure 7. Room temperature normalized emission spectra of (left) Ds-dpm (red b) and 2 (maroon ) and (right) NBD-dpm (green ꢀ) and 3 (blue O) in
*
DMF. Spectra were obtained by exciting compounds at their wavelengths of maximum absorption.
systems, thus lowering the overall quantum yield of
fluorescence.87,88 Fluorescence quenching of a dansyl
fluorophore by platinum(II) occurs in a series of com-
pounds with different-sized linkers between the metal
atom and fluorophore.89 As expected, the fluorescence
was quenched to a larger extent when the dansyl group
was closer to the Pt center. The large quenching effect
observed for 2 and 3 is undesirable for potential cellular
imaging applications. For future ligand design, longer
and more rigid alkyl chains as spatial linkers may be
necessary to position the fluorophores farther away from
the Pt center to avoid quenching by the heavy-atom effect.
DFT Calculations. Compound 3 was chosen for theo-
retical calculations because structural data from X-ray
crystallography could be obtained for both the exo and
endo conformers, both of which occur in the crystal
lattice, and also because of the relatively small size of
the NBD chromophore, which simplifies calculations.
Both conformers were optimized in the gas phase and in
a DMF solution using the X-ray coordinates as the
starting geometry. The solution-optimized structures
were in good agreement with the X-ray results (see Table
S4 and Figure S18 in the SI for a comparison). A common
feature between both conformers in these optimized
structures is the tilting of the NBD heterocycle consistent
with the X-ray structure. Attempts to optimize either
conformer in Cs symmetry led to a structure that was
not a true minimum, as indicated by the presence of
imaginary vibrational frequencies.
from the highest occupied molecular orbital (HOMO;
MO 116) to lowest unoccupied molecular orbital
(LUMO; MO 117) transition in both conformers. The
higher energy band at 330 nm (388 nm, experimental) is
described by a transition from the HOMO to the
LUMOþ1 (MO 118) in the exo conformer and from the
HOMO to the LUMOþ2 (MO 119) in the endo confor-
mer. Lastly, an electronic transition from MO 106 to the
LUMOþ1 is the primary contributor to the band at
219 nm (270 nm, experimental) for both conformers.
The MOs involved in these transitions for both confor-
mers are shown in Figure 8.
As seen in Figure 8, these orbitals predominantly reside
on the NBD heterocycle, and thus the electronic transi-
tions are best described as ligand-to-ligand π-π*. Upon
closer examination of Figure 8, one can also notice
interesting differences in the electronic structures between
the two conformers. Notably, the endo conformer dis-
plays a higher degree of electron delocalization through-
out the entire molecule, whereas the analogous MOs in
the exo conformer are entirely localized on the NBD
heterocycle. This effect is exemplified by MOs 106, 116,
117, 118, and 119 of the endo conformer, which all have
significant Pt d-orbital character and pyridine π-orbital
character. We speculate that this delocalization arises
from conjugation with the p orbital of the overhanging
nitrogen atom. In the exo conformer, only the C-H σ and
σ* orbitals would be available for such an interaction.
However, both of these orbitals are expected to be well
outside of the energy range for interaction with the Pt
orbitals.
The simulated electronic spectra, as calculated by
TDDFT methods, are nearly identical for both confor-
mers. Information regarding all electronically allowed
transitions and their corresponding oscillator strengths
is provided in Table S5 in the SI. Compared to the
experimental spectrum (Figure 6), the simulated spectra
are similar with respect to the number of bands, but all
of the absorbance maxima are consistently shifted by ap-
proximately 50 nm to higher energy. The dominant band
at 445 nm (496 nm, experimental) arises predominantly
Theoretical studies of 3 were also extended to investi-
gate the nature of the axial Pt-H interactions observed in
the two conformers as described above. These interac-
tions were evaluated by using the theory of AIM deve-
loped by Bader.56-58 In the gas-phase-optimized struc-
tures of the two conformers, we sought bond critical
points (BCPs) between the platinum atom and the hydrogen
atom in question. A Pt-H BCP was located for the endo
conformer but not the exo conformer. The BCP describing
the Pt-H interaction of the endo conformer is defined
by an electron density, F(r), of 0.0180 au and a value of
(87) Lower, S. K.; El-Sayed, M. A. Chem. Rev. 1966, 66, 199–241.
(88) Koziar, J. C.; Cowan, D. O. Acc. Chem. Res. 1978, 11, 334–341.
(89) Christoforou, A. M.; Marzilli, P. A.; Marzilli, L. G. Inorg. Chem.
2006, 45, 6771–6781.
2
the Laplacian, r F(r), of 0.0522 au. The magnitude of

Article
Inorganic Chemistry, Vol. 49, No. 11, 2010 5313
Figure 8. MOs that contribute to the main electronic absorption bands for both the exo (left) and the endo (right) conformers. Arrows indicate the
calculated electronic transitions. MO surfaces are shown with a contour value of 0.02 au.
Scheme 4
these values and the positive sign of the Laplacian meet the
criteria for a closed-shell hydrogen-bonding interaction.90
Further investigations of the electron topology of the exo
conformer revealed the presence of a BCP between the
methine proton and a nitrogen atom of the NBD hetero-
cycle (N5, Figure 3). No analogous BCP was located in
the endo conformer. This BCP also meets the criteria
2
for a hydrogen bond with F(r) = 0.0180 au and r F(r) =
0.0617 au. These results show that both protons in question
are involved in electrostatic interactions. Although the
methine proton of the exo conformer does not form a
hydrogen bond with the platinum atom, the downfield shift
1
spectrum or solution color. However, upon irradiation,
the pale-yellow color of a solution of 2 turns dark red over
the course of several days. The conversion is complete
after 80 h, as monitored by 1H NMR spectroscopy
of this resonance, as observed in the H NMR spectrum,
is consistent with the predicted electrostatic interaction with
the nitrogen atom of the NBD heterocycle. A summary
of these BCPs including their coordinates is presented in
Table S6 in the SI.
1
(Figure S19, SI). The H NMR spectrum of the photo-
product displays resonances consistent with the presence
of a dansyl group and two equivalent pyridine rings.
Neither the sulfonamide nor the methine proton was
observed, indicating their absence in this photoproduct.
The 195Pt NMR spectrum displayed a peak at -2177 ppm
(Figure S20, SI). This value is within the range expected
for platinum(II) having an N2Cl2 coordination environ-
ment.79,81 Attempts to crystallize the major photoproduct
of 2 were unsuccessful. Additional attempts to characterize
the compound by ESI-MS were also unsuccessful; no
diagnostic peaks were observed in the MS spectrum in
either positive- or negative-ion mode. Our current working
hypothesis for the identity of this photoproduct is that a
dichloroplatinum complex ligated by a sulfonylimine ana-
logue of Ds-dpm forms, as illustrated in Scheme 4. This
formulation is consistent with the lack of methine and NH
protons in the 1H NMR spectrum.
Thermal and Photochemical Reactivity. Compounds
1-3 are stable for over 4 weeks in a DMF solution when
kept in the dark at room temperature. To assess the
stability of these compounds under elevated temperatures
and exposure to light, controlled thermolytic and photo-
1
lytic reactions were monitored by H and 195Pt NMR
spectroscopy.
At 60 °C in the dark, aerated solutions of 1 in DMF
slowly decompose. Several new resonances appear in the
1H NMR spectrum, and the solution color changes
gradually from almost colorless to pale yellow. The
thermal reaction is slow; after 85 h at 60 °C, only 25%
of the starting compound is consumed. The decomposi-
tion products are numerous and were not conclusively
identified. Irradiation of 1 at room temperature led to no
observable changes in the 1H NMR spectrum.
An aerated solution of 2 in DMF is stable at 60 °C for at
least 60 h, with no noticeable change in the H NMR
1
Thermolysis of 3 at 60 °C for 80 h leads to its complete
conversion to several new compounds, as monitored
by H NMR spectroscopy. Two of the newly formed
1
(90) Koch, U.; Popelier, P. L. A. J. Phys. Chem. 1995, 99, 9747–9754.

5314 Inorganic Chemistry, Vol. 49, No. 11, 2010
Wilson et al.
Scheme 5
reports of heat-activated platinum prodrugs in the litera-
ture. Several ruthenium complexes that exhibit enhanced
cytotoxicity at elevated temperatures have recently been
reported.91
For 1-3, the same thermal and photochemical condi-
tions were applied under dioxygen- and water-free con-
ditions by using samples prepared in a nitrogen-filled
glovebox in septa-sealed NMR tubes. Neither irradiation
with light nor heating at 65 °C for up to 72 h produced
noticeable changes in the 1H NMR spectra. It is therefore
clear that dioxygen and at least trace amounts of water are
necessary to promote the photochemical and thermal
transformations reported here.
Figure 9. Frombottomtotop:1H NMR spectra of3, 3 afterthermolysis
at 60 °C for 80 h, NBD-NH2, and [Pt(dpk)Cl2] in DMF-d7. Resonances
marked with circles are assigned to [Pt(dpk)Cl2], and resonances marked
with crosses are assigned to NBD-NH2. The doublets at 8.8 and 7.3 ppm
and the broad singlet at 7.8 ppm are currently unassigned. The sharp
singlet at 8 ppm in all spectra marked by an asterisk is from the solvent.
Oxidation Chemistry. Compounds 1 and 3 could be
successfully oxidized to their platinum(IV) analogues by a
procedure recently described for the oxidation of
platinum(II) pyridylazido complexes.15 Suspensions of
the complexes in acetic acid were treated with H2O2 to
afford the oxidized products. The anticipated products of
these reactions were platinum(IV) hydroxoacetato spe-
cies, but the observed products were generally more
products were conclusively identified as [Pt(dpk)Cl2] and
NBD-NH2. Figure 9 shows the 1H NMR spectrum of 3,
its thermolysis products, and authentic samples of
[Pt(dpk)Cl2] and NBD-NH2 in DMF-d7. The resonances
marked with circles correspond to [Pt(dpk)Cl2] and the
resonances marked with crosses to NBD-NH2. Further
support for these assignments comes from 195Pt NMR
spectroscopy and ESI-MS. At 40 h into the thermolysis
reaction, a 195Pt NMR spectrum was obtained of the
reaction mixture. In addition to the two signals observed
for the conformational isomers of 3, a new signal at
-1958 ppm appeared (Figure S21, SI). This value
matches the 195Pt chemical shift of [Pt(dpk)Cl2] measured
1
complex. In the case of 1, an initial H NMR spectrum
of the isolated solid indicated the presence of a single
compound. The 1H NMR spectrum was consistent with
Cs symmetry and no sulfonamide proton. Additionally,
coupling to the 195Pt nucleus was observed for protons
ortho to the coordinating nitrogen atoms of the pyridine
rings (JPtH = 27.2 Hz) and, more surprisingly, to the
methine (C6, Figure 2) proton (JPtH = 20.4 Hz). Upon
standing in solution, however, this compound undergoes
chemical transformations to at least two new species over
1
1
independently, thus supporting its assignment in the H
the course of several days, as monitored by H NMR
NMR spectrum. ESI-MS studies of the reaction mixture
revealed a peak at m/z 178.9 in the negative-ion mode.
This value matches that calculated for NBD-NH-, m/z
179.0. The doublets at 8.8 and 7.3 ppm and the broad
peak at 7.8 ppm in the 1H NMR spectrum are not
assigned but most likely correspond to another NBD-
containing compound.
Decomposition of 3 to [Pt(dpk)Cl2] and NBD-NH2
also proceeds photochemically, as depicted in Scheme 5.
Irradiation of 3 at room temperature produces the same
changes in the 1H NMR spectrum as those observed for
the thermal reaction. The photochemical reaction, how-
ever, is much slower. After 85 h of irradiation at room
temperature, only 50% conversion of 3 occurs.
Because [Pt(dpk)Cl2] is nearly as cytotoxic as cisplatin
in several cell lines,38 the ability of 3 to generate this
compound by light exposure or a temperature increase is
of interest for the design of platinum prodrugs. If 3 is
sufficiently less cytotoxic than [Pt(dpk)Cl2], it might
function as an efficient, heat-activatable prodrug.
Although light-activated platinum prodrugs have been
studied and reported,14,15 to our knowledge there are no
spectroscopy (Figure S1, SI). The red material isolated
from the oxidation reaction of 3 was also investigated by
1H NMR spectroscopy. The 1H NMR resonances reveal
the presence of at least two different compounds (Figure
S2, SI).
Attempts to crystallize these oxidized products for
structural characterization afforded small, weakly dif-
fracting crystals from the reactions of both 1 and 3.
Because several issues were encountered with data collec-
tion and refinement (see the Experimental Section), only
the probable connectivity is considered here. The struc-
tures of these oxidized compounds, 1ox and 3ox, are shown
in Figure 10.
The chemical formulas of 1ox and 3ox as postulated
from the crystal structures are rac-[Pt(κ3-Ts-dpm)Cl2-
(OH)] and [Pt(κ3-NBD-dpm)Cl3]. A common feature
between the two structures is the change in the coordina-
tion mode of the dpm ligands from κ2 to κ3 upon oxida-
tion. A third binding atom of the dpm ligands is provided
(91) Renfrew, A. K.; Scopelliti, R.; Dyson, P. J. Inorg. Chem. 2010, 49,
2239–2246.

Article
Inorganic Chemistry, Vol. 49, No. 11, 2010 5315
Figure 10. Ball-and-stick structures of 1ox and 3ox as determined by X-ray crystallography demonstrating likely atomic connectivity. Carbon and
hydrogen atoms are not labeled. The hydrogen atom of O(3) in 1ox was not located and is not shown.
by the deprotonated anionic sulfonamide or amine nitrogen
(N3, Figure 10). In this coordination mode, the methine
proton is only three bonds from the Pt center, thus
oxygen-dependent photo- and thermochemical behavior.
Although the products of these reactions for 1 and 2 have
not been unambiguously characterized, the final products for
such reactions of 3 were identified as [Pt(dpk)Cl2] and NBD-
NH2. Because [Pt(dpk)Cl2] is cytotoxic,38 3 may prove to be
useful as a prodrug.
1
accounting for the Pt-H coupling observed in the H
NMR spectrum described above. It is also noteworthy
that 1ox lacks the pseudo-Cs symmetry that is observed in
1-3 and in the initial oxidation product of 1 as observed
by NMR spectroscopy, thus indicating that the com-
plex isomerizes in solution from the meso isomer (both
chlorides trans to pyridine) to the rac isomer. Also of
interest are the three chloride ions in the coordination
sphere of Pt in 3ox. Given that no additional chloride
source was present in the reaction mixture, the additional
chloride ion of 3ox must have been provided by another
platinum complex. Although the characterization of
these oxidation products is incomplete, these results
demonstrate that the dpm-based ligands can bind in a
tridentate manner.
Acknowledgment. This work was supported by the
National Cancer Institute under Grant CA034992. J.F.L.
is grateful for the CAPES-BRAZIL postdoctoral fellow-
ship (process 4470-08-7). Spectroscopic instrumentation
at the MIT DCIF is maintained with funding from
NIH Grant 1S10RR13886-01. The authors thank Dr. Joel
Rosenthal for assistance with photochemical experiments.
Supporting Information Available: X-ray crystallographic
data in CIF format for compounds Ds-dpm, NBD-dpm, and
1-3, XYZ coordinates of the DMF solution-optimized struc-
tures of the two conformers of 3 (Table S1), vibrational fre-
quencies of the solution-optimized structures of 3 (Table S2),
X-ray crystallographic data and refinement parameters for 1ox
and 3ox (Table S3), structural comparison between the calcu-
lated and experimental geometries of 3 (Table S4), summary of
calculated electronic transitions and oscillator strengths (Table
S5), summary of the BCPs (Table S6), 1H NMR spectra for the
oxidation products of 1 and 3 (Figures S1 and S2), π-stacking
interactions in the crystal lattice of NBD-dpm (Figure S3), VT-
NMR spectra of 1 and 2 (Figures S4 and S5), 2D NMR spectra
for 1-3 (Figures S6-S14), van’t Hoff plots for 1-3 (Figures
S15-S17), comparison of the X-ray structures and solution-
optimized geometries of 3 (Figure S18), 1H NMR spectra of the
photoreaction of 2 (Figure S19), and 195Pt NMR spectra of the
photoreaction of 2 and thermal reaction of 3 (Figures S20 and
S21). This material is available free of charge via the Internet at
http://pubs.acs.org.
Conclusions
We report the synthesis and characterization of three new
ligands and their corresponding platinum complexes. Two of
the ligands are fluorescent. Use of di-2-pyridylmethanamine
asa starting material provides access to fluorescent ligands by
using any fluorescent amine-labeling reagent. These ligands
can bind in either a bidentate or tridentate coordination
mode, a property of relevance to their chemistry with
platinum(IV) and other transition metals that form octa-
hedral complexes. Coordination of platinum to the ligands
induces significant fluorescence quenching. Such quenching is
undesirable for cellular imaging applications. DFT calcula-
tions on 3 revealednoveldifferencesin the MOs of the exo and
endo conformers. The platinum complexes exhibit interesting