Ruthenium and Osmium Complexes of Phosphine-Porphyrin Derivatives as Potential Bimetallic Theranostics: Photophysical Studies

Article abstract of DOI:10.1021/om5011808

A series of (η⁶-p-cymene)ruthenium(II)- and osmium(II) complexes of porphyrin-phosphane derivatives have been synthesized as potential bimetallic theranostic candidates. The photophysical and electrochemical properties were investigated, and th

Full text of DOI:10.1021/om5011808

Article
pubs.acs.org/Organometallics
Ruthenium and Osmium Complexes of Phosphine-Porphyrin
Derivatives as Potential Bimetallic Theranostics: Photophysical
Studies
Pierre D. Harvey,*,†,‡ Semra Tasan,‡ Claude P. Gros,*,‡ Charles H. Devillers,‡ Philippe Richard,‡
Pierre Le Gendre,‡ and Ewen Bodio*,‡
†Dep
́
artement de Chimie, Universite
́
de Sherbrooke, Sherbrooke, Queb
́
ec, Canada J1K 2R1
‡ICMUB (UMR CNRS 6302), Universite
́
de Bourgogne, 21000 Dijon, France
S
* Supporting Information
ABSTRACT: A series of (η6-p-cymene)ruthenium(II)- and osmium(II) complexes
of porphyrin-phosphane derivatives have been synthesized as potential bimetallic
theranostic candidates. The photophysical and electrochemical properties were
investigated, and these species desirably exhibit no or almost no photoinduced
intramolecular atom, energy, and electron transfer between the dye and the metallic
fragment. These favorable features are mostly associated with the presence of their
long chain (i.e., ∼ 1 nm) separating the two functional units. Interestingly, a decrease
in emission intensity and lifetimes (up to 35-fold) has been observed, which was
ascribed to a small heavy atom effect. This effect is possible as a chain folding driven
by an intramolecular H-bond (N−H···Cl−M).
molecules. Arene-ruthenium derivatives can react with N- and
INTRODUCTION
■
S-donors enabling them to bind to both nucleotides and
proteins.5 Since 2005, more and more studies focus on the
processes involving protein targets (e.g., ubiquitin or cathepsin
B)6 or even small peptides such as gluthathione, which is
known as a detoxification agent of metal-based drugs
contributing to resistance development.7 Recently, one of us
investigated some bimetallic versions of this ruthenium
organometallic synthon along with a titanocene center (Chart
1).6b However, although they are convenient for their marked
increased cytotoxic activities, this series suffers, as previous
arene-ruthenium derivatives, from the lack of a label to track
them in vitro and/or in vivo.
Concurrently, porphyrins and their metallo-derivatives have
been the subject of intense research in the field of
photodynamic therapy8 and optical imaging, making them
obvious candidates as theranostic agents.9 It is also well-known
that the use of a heavy atom such as gold(III) inside the
porphyrin rings and derivatives demonstrate a good ability to
act as anticancer agents.10 This also holds true for palladium(II)
(here via photocytotoxicity; photodynamic therapy)11 and
palladium(III).12 Based on these previous investigations, it now
appears as a normal and convenient extension to design
multifunctional theranostic agents, here combining both the
imaging and photodynamic properties of porphyrins, specifi-
cally palladium(II) porphyrins, and the cancer cytotoxicity of
The design of trackable therapeutic agents and more generally
of theranostics is the subject of intense current interest.1
Indeed, the combination of an imaging probe with a therapeutic
moiety allows for a large scope of applications from the
personalized medicine to the understanding of drug mecha-
nisms. Recently, the use of organometallics in theranostic
designs, although a relatively newer topic, was reviewed.2 One
of the popular promising organometallic complexes (and
motifs) used in cancer therapy is the now well-known
RAPTA-C: [Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-7-
phosphatricyclo[3.3.1.1]-decane; Chart 1), along with its
Chart 1. Structures of [Ru(η6-p-cymene)Cl2(pta)] (Left) and
[(η5-Cp)Ti((η5-C5H4-(CH2)4-PPh2-[Ru(η6-p-cymene)Cl2)]
(Right)
osmium analogue and their corresponding functionalized
derivatives.3 RAPTA-C and its analogues display poor IC50
in vitro on cancer cells. However, they have been reported to
exhibit very promising antimetastatic properties in vivo.3c,o
Their mechanism is yet to be clearly established.4 Conversely,
for the quite strongly bonded phosphine and arene ligands, the
chlorido ligands are believed to rapidly interchange with water
Received: December 5, 2014
© XXXX American Chemical Society
A
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Article
the complexes related to the well-known arene-ruthenium
derivatives. This trait would result in the conception of an
“optical bi-theranostic” (two modalities for therapy and one for
optical imaging). One of the key issues is that although the
bricks of construction appear ideal for their own function,
intramolecular interactions between the two moieties pro-
foundly altering their activities are always possible and must be
addressed prior to design and testing. In the case of
fluorescence/phosphorescence imaging and photodynamic
therapy, such interactions between the two fragments are
primarily due to photoinduced energy, electron, and atom
transfers from one unit to the other. It is this preliminary issue
we would like to address.
We now report the preparation, the photophysical and
electrochemical properties of a series of (η6-p-cymene)-
ruthenium(II) and osmium(II) complexes of porphyrin-
phosphane derivatives (employed as dyes) as potential
bimetallic theranostics (Chart 2). In order to preclude or
significantly reduce intermetallic complex interactions, a long
spacing chain between the moieties is used. The choice of a
thiourea unit within the spacer is justified by the facile synthesis
and its high stability in vivo. These targets exhibit desirably no
or almost no photoinduced intramolecular atom, energy, and
electron transfer between the dye and the metallic fragment.
This sought behavior is mainly due to the presence of a long
chain. However, a quenching (up to 35-fold) can be noted and
is due to a small heavy atom effect. This effect is rendered
possible because of a chain folding driven by an intramolecular
H-bond (N−H···Cl−M).
EXPERIMENTAL SECTION
■
Chemicals and Reagents. Solvents were dried and distilled under
argon before use. All the analysis were performed at the Plateforme
̀ ́ ́
d’Analyses Chimiques et de Synthese Moleculaire de l’Universite de
Bourgogne. Synthesis of compound 1, 2, 6−8 was done as previously
reported (see Supporting Information (SI) for details).13
[(η6-p-Cymene)(palladium(II) 5-(4-(N-(2-(diphenylphosphino)-
ethyl)thiocarbamido)-aminophenyl)-10,15,20-triphenylporphyrin)-
OsCl2] (3). The reaction was carried out under an argon atmosphere.
Porphyrin phosphine derivative 2 (99 mg, 0.10 mmol, 1.0 equiv) and
[OsCl2(η6-p-cymene)]2 (39 mg, 0.05 mmol, 0.5 equiv) were dissolved
in dichloromethane (3 mL). The resulting mixture was stirred for 3 h
at room temperature. The completion of the reaction was monitored
by 31P NMR (202.5 MHz, 300 K). The solvent was removed under
reduced pressure. The osmium complex 3 was isolated as a bright red
powder (136 mg, 98%). UV−vis (THF): λmax (nm) (ε, 103 M−1 cm−1)
Chart 2. Structures of the Investigated Bimetallic
Compounds 1−5 along with Model Compounds 6−8
416 (249), 524 (26), 554 (3). IR: ν (cm−1) 297 (νOs−Cl), 795 (νCS),
̅
1
1352 (νC−N), 1508 (νN−C−N), 3049 (νN−H). H NMR (500.13 MHz,
3
DMSO-d6): δ (ppm) 0.79 (d, 6H, J = 6.9 Hz, CH(CH3)2), 1.89 (s,
3H,CH3), 2.17 (hept, 1H, J = 6.9 Hz, CH(CH3)2), 3.02 (m, 2H,
3
3
NH−CH2), 3.44 (m, 2H, CH2−PPh2), 5.44 (d, 2H, J = 5.9 Hz, p-
3
cymene-Os), 5.56 (d, 2H, J = 5.9 Hz, p-cymene-Os), 7.46−7.58 (m,
6H, o- and p-PPh2), 7.63−7.89 (m, 16H, m-PPh2 + NH + C6H4NH +
3
HAr), 8.05 (d, 2H, J = 8.4 Hz, C6H4NH), 8.14−8.17 (m, 7H, NH +
HAr), 8.77−8.87 (m, 8H, Hβ). 13C{1H} NMR (125.8 MHz, CDCl3): δ
(ppm) 180.1, 141.0, 140.9, 140.8, 140.6, 136.0, 134.1, 133.7, 133.1,
132.0, 131.5, 131.3, 131.0, 130.4, 130.4, 130.3, 128.8, 128.4, 128.1,
128.0, 127.0, 121.8, 127.7, 121.6, 120.9, 97.3, 86.5, 81.5, 78.1, 54.9,
29.2, 21.3, 16.8, 16.3. 31P{1H} NMR (202.5 MHz, DMSO-d6): δ
(ppm)
− 21.1. HR-MS (MALDI-TOF): m/z calcd for
C69H57Cl2N6OsPPdS − HCl − Cl+•: 1329.2677 [M − HCl − Cl]+•.
Found: 1329.2627. HR-MS (ESI): m/z calcd for C69H57Cl2N6OsPPdS
− HCl − Cl+•: 1329.26768 [M − HCl − C]+•. Found: 1329.26037.
[(5-(4-(N-(2-(Diphenylphosphino)ethyl)thiocarbamido)-
aminophenyl)-10,15,20-triphenyl-porphyrin)-RuCl2] (4). The reac-
tion was carried out inside a glovebox. Porphyrin phosphine derivative
1 (90 mg, 0.10 mmol, 1.0 equiv) and [RuCl2(η6-p-cymene)]2 (31 mg,
0.05 mmol, 0.5 equiv) were dissolved in dichloromethane (5 mL). The
resulting mixture was stirred for 16 h at room temperature. The
completion of the reaction was monitored by 31P NMR (202.5 MHz,
300 K). The solvent was removed under reduced pressure. The
ruthenium complex 4 was isolated as a bright purple powder (121 mg
> 99%). UV−vis (THF): λmax (nm) (ε, 103 M−1 cm−1) 418 (318), 515
(19), 550 (10), 592 (6), 649 (4). IR: ν (cm−1) 289 (νRu−Cl), 798
̅
(νCS), 1349 (νC−N), 1537 (νN−C−N), 3310 (νN−H). 1H NMR (300.13
MHz, DMSO-d6): δ (ppm) − 2.88 (br s, 2H, NHPorph), 0.76 (d, 6H, 3J
= 6.9 Hz, CH(CH3)2), 1.79 (s, 3H, CH3), 2.26−2.37 (m, 1H,
CH(CH3)2), 2.87−3.04 (m, 2H, NH−CH2‑), 3.33−3.55 (m, 2H,
CH2−PPh2), 5.26 (d, 2H, 3J = 6.2 Hz, p-cymene-Ru, 5.44 (d, 2H, 3J =
6.2 Hz, p-cymene-Ru), 7.52−8.07 (m, 23H, PPh2 + 2NH + C6H4 +
HAr), 8.09−8.24 (m, 8H, C6H4NH + HAr), 8.81−8.92 (m, 8H, Hβ).
13C{1H} NMR (75.5 MHz, DMSO-d6): δ (ppm) 141.2, 134.9, 134.5,
134.2, 133.2, 132.0, 131.4, 131.2, 130.8, 130.4, 128.7, 128.5, 128.1,
126.9, 126.0, 123.7, 121.0, 120.0, 89.6, 86.0, 85.3, 54.9, 21.0, 17.0, 16.7.
31P{1H} NMR (121.5 MHz, DMSO-d6): δ (ppm) 19.9 ppm. HR-MS
(MALDI-TOF): m/z calcd for C69H59Cl2N6PRuS − HCl − Cl+•:
1135.3237 [M − HCl − Cl]+•. Found: 1135.3237. HR-MS (ESI): m/z
B
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Article
calcd for C69H59Cl2N6PRuS − HCl − Cl+•: 1135.3237 [M − HCl −
Cl]+•. Found: 1135.3255.
or less. This absorbance was adjusted to be the same as much as
possible for the standard and the sample for a measurement. Each
absorbance value was measured five times for better accuracy in the
measurements of the quantum yields. The equation Φs = Φr(Fr/Fs)(Is/
Ir)(ns/nr)2 was used to calculate the relative quantum yield of each of
the sample, where Φr is the absolute quantum yield of the reference, n
[(η6-p-Cymene)(palladium(II) 5-(4-(N-(2-(diphenylphosphino)-
ethyl)thiocarbamido)amino phenyl)-10,15,20-triphenylporphyrin)-
RuCl2] (5). The reaction was carried out under an argon atmosphere.
Porphyrin phosphine derivative 2 (97 mg, 0.10 mmol, 1.0 equiv) and
[RuCl2(η6-p-cymene)]2 (30 mg, 0.05 mmol, 0.5 equiv) were dissolved
in distilled dichloromethane (3.5 mL). The resulting mixture was
stirred for 3 h at room temperature. The completion of the reaction
was monitored by 31P NMR (202.5 MHz, 300 K). The solvent was
removed under reduced pressure. The ruthenium complex 5 was
isolated as a bright red powder (125 mg, 99%). UV−vis (THF): λmax
is the refractive index of the solvent, F is the absorptance (F = 1−10−A
,
where A is the absorbance) at the excitation wavelength, and I is the
integrated area under the corrected emission curve. The subscripts s
and r refer to the sample and reference, respectively. A solution of
meso-tetraphenylporphyrin (H2TPP) in 2-MeTHF (ΦF = 0.11)14 was
used as the external reference. The emission lifetimes in the 1 to 10 ns
range were measured on a TimeMaster model TM-3/2003 apparatus
from PTI. The source was a nitrogen laser with high-resolution dye
laser (fwhm ∼ 1400 ps), and the excited lifetimes were obtained from
deconvolution or distribution lifetimes analysis.
(nm) (ε, 103 M−1 cm−1) 416 (249), 523 (26), 554 (3). IR: ν (cm−1)
̅
293 (νRu−Cl), 796 (νCS), 1352 (νC−N), 1508 (νN−C−N), 3049 (νN−H).
1H NMR (500.13 MHz, DMSO-d6): δ (ppm) 0.74 (d, 6H, 3J = 6.9 Hz,
CH(CH3)2), 1.77 (s, 3H, CH3), 2.31 (hept, 1H, 3J = 6.9 Hz,
CH(CH33)2), 2.90 (m, 2H, NH−CH2), 3.40 (m, 2H, CH2−Ph), 5.22
Calculations. Density functional theory (DFT) calculations were
3
performed with Gaussian 0915 at the Universite
́
de Sherbrooke with the
Mammouth supercomputer supported by Le Reseau Quebecois De
(d, 2H, J = 6.2 Hz, p-cymene-Ru), 5.40 (d, 2H, J = 6.2 Hz, p-
cymene-Ru), 7.51−7.59 (m, 6H, o- and p-PPh2), 7.64−7.93 (m, 16H,
m-PPh2 + NH + C6H4NH + HAr), 8.04 (d, 2H, 3J = 8.4 Hz, C6H4NH),
8.10−8.17 (m, 7H, NH + HAr), 8.77−8.87 (m, 8H, Hβ). 13C{1H}
NMR (125.8 MHz, DMSO-d6): δ (ppm) 180.0, 140.9, 140.8, 140.7,
140.6, 139.0, 136.0, 134.1, 133.7, 133.1, 132.5, 132.2, 131.4, 131.3,
131.1, 131.0, 130.4, 130.3, 128.8, 128.5, 128.1, 128.0, 127.0, 121.8,
121.6, 121.5, 121.0, 106.3, 93.9, 89.8, 86.3, 85.5, 54.8, 29.4, 21.4, 20.9,
16.9. 31P{1H} NMR (202.5 MHz, DMSO-d6): δ (ppm) 19.9. HR-MS
(MALDI-TOF): m/z calcd for C69H57Cl2N6PPdRuS − 2Cl+•:
1240.2136 [M − 2Cl]+•. Found: 1240.2148. HR-MS (ESI): m/z
calcd for C69H57Cl2N6PPdRuS − HCl − Cl+•: 1239.21284 [M − HCl
− Cl]+•. Found: 1239.21031.
́
́
́
Calculs Hautes Performances. The DFT geometry optimizations16 were
carried out using the B3LYP method. A 6-31g* basis set was used for
C, H, N, P, and Cl atoms.17 VDZ (valence double ζ) with SBKJC
effective core potentials were used for all Pd and Ru atoms.17 A THF
solvent field was applied to all calculations. A frequency calculation
was performed on the optimized geometries in order to verify the
nature of the stationary point. The frequency calculations showed no
imaginary frequencies indicating that the stationary points found are
true minima.
X-ray Analysis. Intensity data for compound 8 were collected on a
Nonius Kappa APEX II at 115 K. Using Olex2,18 the structure was
solved with the ShelXS19 structure solution program using Direct
Methods and refined with the XL19 refinement package using Least
Squares minimization. All non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were included in
their calculated positions and refined with a riding model. Crystallo-
graphic data are reported in the SI (Table S26).
Instrumentation. 1H (300.13, 500.13, or 600.13 MHz), 13C (75.5,
125.8, or 150.9 MHz), 31P (121.5, 202.5, or 242.9 MHz) NMR spectra
were recorded on a Bruker 300 Bruker Avance III, a Bruker 500
Avance III, or on a Bruker 600 Avance II spectrometer. Chemical shifts
are quoted in parts per million (δ) relative to TMS (1H and 13C),
using the residual protonated solvent (1H) or the deuterated solvent
(13C) as an internal standard. Alternatively, 85% H3PO4 (31P) was
used as external standard. Coupling constants are reported in Hertz
and represent proton−proton coupling. Mass spectra were obtained by
MALDI-TOF with a Bruker DALTONICS Ultraflex II spectrometer.
High-resolution mass measurements were carried out using a Bruker
DALTONICS Ultraflex II spectrometer (HR-MS MALDI-TOF) or
Bruker microTOF-Q ESI-MS and LTQ Orbitrap XL (Thermo) mass
spectrometers and low-resolution mass measurements were carried out
using an amazon SL (Bruker) mass spectrometer. Far infrared spectra
were recorded with IR FT Bruker Vertex 70v spectrophotometer.
Absorption spectra were recorded on a VARIAN CARY 50
spectrometer.
Electrochemistry. Tetra-n-butylammoniumhexafluorophosphate
(TBAPF6) was synthesized by mixing stoichiometric amounts of
tetra-n-butylammonium hydroxide (Alfa-Aesar, 40% w/w aq soln) and
hexafluorophosphate acid (Alfa-Aesar, ca. 60% w/w aq soln). After
filtration, the salt was recrystallized three times in ethanol and dried at
80 °C during at least 2 days. All electrochemical manipulations were
performed using Schlenk techniques in an atmosphere of dry oxygen-
free argon at room temperature (T = 20 3 °C). The supporting
electrolyte was degassed under vacuum before use and then dissolved
to a concentration of 0.1 mol/L. Voltammetric analyses were carried
out in a standard three electrode cell, with an Autolab PGSTAT 302 N
potentiostat, connected to an interfaced computer that employed
Electrochemistry Nova software. The reference electrode was a
saturated calomel electrode (SCE) separated from the analyzed
solution by a sintered glass disk filled with the background solution.
The auxiliary electrode was a platinum wire separated from the
analyzed solution by a sintered glass disk filled with the background
solution. For all voltammetric measurements, the working electrode
was a platinum disk electrode (Ø = 2 mm). In these conditions, when
operating in CH2Cl2 (0.1 M TBAPF6), the formal potential for the
Fc+/Fc couple was found to be +0.44 V vs SCE.
Absorption, Emission, and Excitation Spectra. All samples were
prepared in 2-methyl-tetrahydrofuran, 2MeTHF, which was distilled
over CaH2 under nitrogen. The absorption spectra were recorded at
298 and 77 K using a Varian Cary 300 spectrophotometer and a HP-
8453 diode array spectrophotometer, respectively, at the Universite
Sherbrooke, or on a JASCO V630 Bio spectrometer at the Universite
́
de
de
́
Bourgogne at 298 K. Molar absorptivity determination was verified by
linear least-squares fit of values obtained from at least three
independent solutions at varying concentrations with absorbance
ranging from 0.01 to 2.6. Steady-state emission and excitation spectra
were recorded at 298 and 77 K in a 1.0 cm capped quartz cell and a 5.0
mm (i.d.) NMR tube inserted into quartz EPR Dewar filled with liquid
N2, respectively. Emission spectra were obtained by exciting at the
lowest energy absorption maxima using a Horiba Jobin Yvon
Fluorolog spectrofluorometer equipped with double monochromators.
Fluorescence Quantum Yield and Lifetimes. The measurements of
the emission quantum yields were performed in 2-MeTHF at 298 K.
Three different measurements (i.e., different solutions) were prepared
for each photophysical datum (quantum yields and lifetimes). For
measurements at 298 K, samples were prepared under inert
atmosphere (in a glovebox, PO2 < 10 ppm). The sample and the
standard concentrations were adjusted to obtain an absorbance of 0.05
RESULTS AND DISCUSSION
■
We previously described the synthesis of new porphyrinophos-
phine-gold derivatives (Chart 3). Some of these compounds
then reported as potential theranostics gave interesting results
both in term of photophysical properties (in vitro imaging
experiments were easily performed) and cytotoxic activity.13a
This series is now expanded by synthesizing the corresponding
arene-ruthenium and arene-osmium derivatives (Chart 2). First,
the porphyrin-phosphine ligands 1 and 2 (Scheme 1) were
prepared. In order to preclude or significantly reduce
C
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Article
Chart 3. Structures of the Gold Complexes
intermetallic complex interactions, a long spacing chain
between the moieties is employed.
These ligands were efficiently synthesized in only four steps
involving: (i) mononitration of the tetraphenylporphyrin
(TPP), (ii) reduction of the nitro group by mercaptoethanol,
(iii) reaction with thiophosgene to obtain the corresponding
isothiocyanate compounds, and finally, (iv) coupling with 2-
aminoethyldiphenylphosphine. For the Pd-metalated porphyr-
in-phosphine, an additional complexion step was used between
the nitration and the reduction ones. The ruthenium and
osmium derivatives were easily obtained by reacting the
corresponding phosphine derivatives using 0.5 equiv of
dichlorido(p-cymene)metal dimer in dichloromethane for 3.5
h at room temperature. The three complexes were obtained
quantitatively by simple evaporation of the solvent under
reduced pressure. The metalation reaction was monitored by
UV−vis spectroscopy and 31P NMR spectrometry, and these
Figure 1. ORTEP view of complex 8. Selected bonds (Å) and angles
(deg): Ru−Ct1 1.702(7), Ru−Cl1 2.4139(16), Ru−Cl2 2.427(2),
Ru−P 2.3621(17), Ct1−Ru−Cl1 125.66(25), Ct1−Ru−Cl2
124.89(24), Ct1−Ru−P 131.94(22), Cl1−Ru−Cl2 88.71(7), Cl1−
Ru−P 86.08(6), Cl2−Ru−P 85.60(7).
evidenced when DMSO-d6 was used as the solvent for the
1H NMR spectra. Indeed, a mono-DMSO adduct was observed
in the spectra. This exchange was studied for the Ru(II)-
complexes by variable temperature NMR experiment (see SI
for details). Indeed, all complexes were found in their mono-
DMSO adduct form at ∼90 °C. The lability of the chlorido
ligands is well-known in the literature, and some researchers
have reported that this exchange could also occur with water
molecules. In anticancer studies, the corresponding aqua
complex has been hypothesized as being the active form of
the complex. Nevertheless, the kinetics of this exchange is very
dependent on the complex. In this work, this exchange is very
slow at room temperature. For instance, 40 days were needed
for the completion of the monosubstitution with DMSO.
Moreover, we previously investigated the stability of the model
compound 8 in a mixture containing cell culture medium at 37
1
complexes were fully characterized by H and 13C NMR, IR,
and HRMS mass spectrometry. The molecular ions of the free
base porphyrins 1 and 4 and metal complexes 2, 3, 5 were
observed as the most intense peak in the mass spectra for all
cases. The data agree well with the expected molecular formula.
For example, the HR-MS MALDI-TOF mass spectrum of 5
exhibits the parent-ion peak at m/z = 1240.2148 (calcd for
C69H57N6PPdRuS, [M − 2Cl]+• m/z 1240.2136) (SI).
Notably, the chlorido ligands turned out to be exchangeable
in solution. Interestingly, this phenomenon was clearly
Scheme 1. Synthesis of 3−5
D
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Figure 2. Absorption (black), emission (red), and excitation (blue)
spectra of 1 and 4 in 2-MeTHF at 298 and 77 K. The instrumental
limit of the excitation spectra is 600 nm.
°C, and no change was observed up to 10 days.13b Noteworthy,
a UV−visible study combined with mass spectrometry of 3 and
5 dissolved in a DMSO/water mixture (1/99 v/v) for 3 days at
37 °C was performed, and no degradation of the complexes was
observed (see SI for details).
Figure 3. Absorption (black), emission (red), and excitation (blue)
spectra of 2, 3, and 5 in 2-MeTHF at 298 and 77 K (F = fluorescence;
P = phosphorescence). The excitation spectra are limited to 600 nm.
Crystallography. Compound 8 was synthesized as a model
for the ruthenium(II) moiety for further investigation in
photophysics and electrochemistry. We previously described
the synthesis of this complex,13b but its X-ray structure was
never reported. A suitable monocrystal for X-ray diffraction was
obtained by slow diffusion of pentane in a solution of 8 in
dichloromethane. This structure clearly confirmed the identi-
fication of the complex and highlights the characteristic “piano
stool” conformation of arene−ruthenium complexes (Figure 1).
Spectroscopic and Photophysical Studies. The absorp-
tion spectra of the free base-containing porphyrins, [Fb], 1 and
4 in 2-MeTHF exhibit the expected intense Soret band (S0 →
S2) at ∼418 nm and the Q-bands (S0 → S1) at ∼515, 550, 592,
and 648 nm at 298 K (Figure 2; Table 1).20 For the
palladium(II) porphyrin-containing ligand and complexes,
[Pdporph], 2, 3, and 5, the Soret and Q-bands are noted as
anticipated at ∼416 nm and ∼523 and 554 nm, respectively,
(298 K; Figure 3; Table 1). The excitation spectra superpose
well the absorption, meaning that the emission arises from the
dye and not an impurity.
a
Table 2. Stokes Shifts at 298 and 77 K
Stokes shift Δ (cm−1
)
λ0−0(abs)/
λ0−0(em)
λ0−0(abs)/
λ0−0(em)
dye
298 K
77 K
[Fb]
1
648/651
648/652
70 (F)
95 (F)
641/644
640/645
75 (F)
4
[Pdporph]
2
120 (F)
554/601
554/700
554/603
554/701
554/602
554/700
140 (F)
3760 (P)
145 (F)
3790 (P)
145 (F)
3765 (P)
554/601
554/685
554/602
554/686
554/603
554/686
140 (F)
3450 (P)
145 (F)
3340 (P)
145 (F)
3470 (P)
3
5
a
The uncertainties on λ are 2 nm. F = fluorescence; P =
phosphorescence.
All four dyes are luminescent. The [Fb], 1, and 4 species
exhibit the typical signature generally observed for a
fluorescence of a free base porphyrin (at 652 and 719 nm,
plus a shoulder at ∼780 nm). This assignment is supported by
Table 1. UV−vis Absorption Data in 2-MeTHF at 298 K.
λmax, nm (ε, × 103 M−1·cm−1
)
dye
Soret band
Q bands
[Fb]
1
418 (414.4)
418 (318.4)
514 (18.6)
515 (18.6)
549 (9.3)
550 (9.9)
592 (5.3)
592 (5.5)
648 (4.2)
648 (4.4)
4
[Pdporph]
2
3
5
416 (303.0)
416 (249.2)
416 (248.9)
523 (27.5)
524 (26.4)
523 (26.8)
554 (2.4)
554 (2.5)
554 (2.6)
E
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a
Table 3. Fluorescence Lifetimes, τF, in 2-MeTHF
dye
298 K
77 K
λexc (nm)
λF (nm)
τF (ns)
ΦF (%)
λF (nm)
τem (ns)
[Fb]
1
4
510
510
651 / 718
652 / 719
14.5 0.2
10.4 0.2
12.0
4.4
644
645
10.8 0.2
9.5 0.2
b
λexc (nm)
λP (nm)
τP (μs)
Φem (%)
λP (nm)
τP (μs)
[Pdporph]
2
3
5
510
510
510
700 / 774
701 / 773
700 / 773
101.0 1.5
28.5 0.5
8.9 0.5
6.9
0.8
0.2
685
686
686
1335 20
1350 20
1160 20
a
b
The fluorescence lifetimes, τF, for 2, 3, and 5 are < 150 ps (detection limit). The quantum yields include the sum of both the fluorescence and
phosphorescence.
Figure 4. Comparison of the absorption spectrum of 8 (as potential
acceptor) with the emission spectrum of 5 (as potential energy donor)
in 2-MeTHF at 298 K in order to qualitatively demonstrate that the J-
integral is nil.
the small Stoke shifts (Table 2, Δ; difference between the 0−0
peaks measured in the absorption and emission spectra) here
ranging from 70 to 120 cm−1, and the common size for the
fluorescence lifetime (τF) ordinarily ranging from 10 to 15 ns
(Table 3).20 Conversely, the [Pdporph]-containing species 2, 3
and 5, exhibit both a weak fluorescence (two bands in the 600−
670 nm window) and a strong phosphorescence particularly
pronounced at 77 K (two peaks in the 680−850 nm window),
again based on the same metrics used for 1 and 4.20,21 Indeed,
the τF and Δ are, respectively, <150 ps (detection limit) and
145 cm−1 for the fluorescence and are in the μs time scale and
∼3600 190 cm−1 for the phosphorescence.
Figure 5. Computer modeling of complexes 3 and 5 (note that it also
applies for 4). Top: unfolded. Bottom: folded conformation due to the
presence of an intramolecular H-bond). The dark turquoise, green,
and light turquoise atoms are the palladium(II), chloride, and metal
(Ru or Os), respectively.
For the purpose of this work, the relative intensity is a key
issue. The ligands exhibit reasonable emission quantum yields,
ΦF (12% for 1) and ΦP (∼7% for 2). However, a decrease is
noted in both ΦF (from 12 to 4.4%; factor of ∼2.7) and τF
(from 14.5 to 10.4 ns; decrease of 28%) when a metal center,
[M] (here [M] = [Ru(η6-p-cymene)Cl2] = [Ru]) going from 1
to 4. The decrease in τF is fully consistent with the loose bolt
effect.22 As the mass of the side arm substituent increases, kic
(nonradiative rate constant for internal conversion) also
increase. Moreover, the presence of the [Ru] pendant group
should promote the heavy atom effect, which in turn should
increase kisc (nonradiative rate constant for intersystem
crossing).22 Notably, both effects impact on these photo-
physical parameters in the same direction. However, both τF
and ΦF should vary proportionally because 1/τF = kF + kic + kisc
and 1/ΦF = kF/(kF + kic + kisc), where kF is the radiative rate
constant for fluorescence (the photoreactions excluded from
these expressions), but this is not the case. The decrease in ΦF
by 2.7 fold going from 1 to 4 is rather curious, and one may
conclude that there are some specific interactions occurring.
These trends (i.e., first, decreases in the photophysical metrics
when [M] is coordinated onto the ligand, and second,
disproportion in the decreases of ΦP and τP) are also noted
for 3 ([M] = [Os(η6-p-cymene)Cl2] = [Os]) and 5 ([M] =
[Ru(η6-p-cymene)Cl2] = [Ru]). The interpretation of the data
is a little more complicated in the series 2 versus 3 versus 5.
Indeed, the heavy atom effect should be more pronounced for 3
([Os]) than for 5 ([Ru]), and yet both τP and Φem are smaller
for 5 than for 3. To explain these observations, energy, atom,
and electron transfers are now considered. For the S1 and T1
energy transfer processes (i.e., [Fb]* and [Pdporph]*→ [Ru]
and [Os]), the model complex 8 were investigated (Chart 2).
Two mechanisms are possible: Forster (occurring via
̈
F
DOI: 10.1021/om5011808
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Article
(assuming that the [Pdporph] chromophore can act as an
energy donor) shows a clear lack of spectral overlap (Figure 4).
Because of the very strong spectral similarity of the other
chromophores, the same conclusions apply, and the assumption
that S1 and T1 energy transfer processes from [Fb]* and
[Pdporph]*to [Ru] and [Os] are most unlikely.
For probing the possibility that an atom transfer occurs in
the excited states of 3−5, computer modeling was performed.
The weakest and unhindered bond in the [M] fragment is
unquestionably the M−Cl one, and consequently one should
investigate any short distance Cl...atom interactions since
proximity is the key factor that would favor (or not) this
excited state deactivation process. The lowest energy
conformation is the completely unfolded geometry (Figure 5,
top). Any Cl···atom separations with various atoms in the
[Pdporph] chromophore (i.e., Pd, meso-C, and para-C of the
phenyl group, for examples) well exceed the sum of their
corresponding van der Waals radii (3.35 Å for Cl···C; 3.38 Å for
Cl···Pd). In this conformation, atom transfer is simply
impossible.
A second conformation with a local minimum was noticed
during the computer modeling and exhibit a folded geometry
driven by the presence of an intramolecular H-bond between
the M-Cl unit and H−N group (the calculated Cl···H distance
is ∼2.47 Å; which is under the sum of the van der Waals radii,
2.95 Å, and under the sum of the covalent radii, 1.34 Å) (Figure
5, bottom). Despite this geometry, the Cl···atom separations
between the Cl ligand and any key atom of the dye are still
unreasonably too long for any transfer between the two units.
Moreover, no photodegradation of the complexes was observed
during prolonged exposure to light (in this work all analysis was
performed at 510 nm). This means that, experimentally, the
photoinduced atom transfer simply did not occur. However, the
observation of a folded conformation with a local minimum
brings interesting information about a slight shortening of the
Pd···M distance when going from unfolded to folded geometry
from 16.7 to 12.7 Å.
Figure 6. Modified Latimer diagram for a one-electron transfer for
complexes 4 and 5 using the model species 6, 7, and 8. The excited
state energies are those of the 0−0 peaks observed in the fluorescence
and phosphorescence spectra of 4 and 5 at 77 K (where there is no or
almost no contribution from hot bands rendering the evaluation of the
pure electronic transition more accurate). The oxidation and reduction
potentials are those from Table 4, and the approximated driving forces
for a one-electron transfer are noted in blue.
Coulombic interactions)23 and Dexter (occurring via double
electron exchange).24
The rate of the Forster energy transfer (kForster) can be
̈
̈
described by eq 1 where ΦF°(D) and τF°(D) are, respectively,
the fluorescence quantum yield and lifetime of the donor in the
absence of an acceptor, κ is an orientation factor associated with
the relative alignment of the transition dipole moments of the
donor and acceptor, r is the center-to-center donor−acceptor
distance, n is the medium refractive index, (∫ FD(λ)εA(λ)λ4dλ)/
(∫ FD(λ)dλ) (also called J-integral) is the normalized spectral
overlap between the donor emission and the acceptor
absorption (FD = donor fluorescence intensity, εA = acceptor
absorptivity, λ = wavelength), and Na is Avogadro’s number.
The last possible process to consider is the electron transfer.
In order to address the situation, one must evaluate the driving
force for both photoinduced oxidative and reductive electron
transfer of the [Fb] and the [Pdporph] chromophores.
Modified Latimer diagrams are constructed below after
describing the electrochemistry of three model compounds
6−8.
F (λ)ε (λ)λ4dλ
ΦF◦(D)κ2
⎛
⎜
⎞
⎟
⎠
∫
9000(ln 10)
D
A
kET
=
τF◦(D)r2 128π5n4N
⎝
F (λ)dλ
∫
a
D
(1)
Electrochemistry. The cyclic voltammogram of 6, 7, and 8
(model compounds) were studied in CH2Cl2 0.1 M TBAPF6.
This solvent has been chosen because it solubilizes the studied
compounds and offers a wide potential window. The model
compounds 6 and 7 were selected because they were readily
available as they were used as chemical intermediates during the
synthesis of the target complexes 3, 4, and 5. Although the
remotely placed thiourea function from the central redox center
(i.e., porphyrin ring) is not identical to the NO2 group, both
The rate of a Dexter electron exchange (kDexter) is given by
kET(Dexter) = KJ exp(−2r/L) where K is a pre-exponential
factor that describes the degree of orbital interaction, L is the
sum of the Van de Waals radii of the donor and acceptor, and J
is the same spectral overlap between the donor emission and
the acceptor absorption above.
As a typical example, the comparison of the absorption
spectrum of the acceptor, here modeled by complex 8, with that
of the fluorescence and phosphorescence of complex 5
Table 4. Potential Values of 6, 7, 8 and Ferrocene in CH2Cl2 0.1 M TBAPF6 in V vs SCE
products
3rd reduction
2nd reduction
1st reduction
1st oxidation
2nd oxidation
a
a
a
b
b
6
−1.800
∼ −1.275
−1.300
∼ −1.030
−1.165
−1.165
1.045 (90)
1.360 (90)
a
a
b
b
7
8
1.150 (85)
1.565 (85)
a
a
a
b
−1.780
∼ −0.825
1.160 (85)
b
ferrocene
0.440 (85)
a
b
Epc, irreversible system. E1/2, reversible system, ΔEp values (ΔEp = Epa − Epc) are given in brackets (in mV).
G
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Article
exhibit electron-withdrawing properties thought to be the
resonance structures of the thiourea (HN−CS ↔ HN+C−
S−). It is reasonably assumed that the redox properties of the
central porphyrin macrocycle would be relatively unaltered by
this difference.
In the positive potential range, 6 and 7 exhibit two
monoelectronic reversible oxidations leading, respectively, to
the cation radical and the dication (the cyclic voltammograms
are placed in the SI).25 As expected, the palladium complex 7 is
harder to oxidize than the free base 6 due to its electron-
withdrawing effect on the porphyrin macrocycle. The
ruthenium complex 8 exhibits only one reversible monoelec-
tronic oxidation at 1.16 V versus SCE, which corresponds to
the Ru(II) → Ru(III) electron transfer. A similar oxidation
potential (1.14 V vs. SCE) was previously reported for the very
similar [Ru(η6-p-cymene)Cl2(PPh3)] complex.26
In the negative potential range, the free base porphyrin 6 is
irreversibly reduced in three steps. The first one likely
corresponds to the first porphyrin reduction because the gap
between its first oxidation and reduction, ΔE(ox1 − red1) =
2.21 V, matches well with those found for common porphyrins
(2.15 0.15 V).25 The second reduction might correspond to
the reduction of the nitro group,27 although it is difficult to
assign precisely the third reduction. The redox behavior of the
palladium complex 7 is simpler with a first reversible
monoelectronic reduction of the porphyrin core occurring at
−1.165 V. The second reversible redox system is observed at
−1.30 V, a potential similar to the one observed for the second
reduction of the free base6 (−1.275 V) and corresponds thus
probably to the reduction of the nitro group. The cyclic
voltammogram of the ruthenium complex 8 exhibits very broad
and ill-defined reduction peaks. Nonetheless, modified Latimer
diagrams are constructed, and the driving forces for a reductive
or oxidative one-electron process are indicated in blue (Figure
6).
computer modeling, at first glance, the quenching from a
photoinduced electron transfer, if any, appears to be bound to
be slow or very slow. This conclusion is supported by the
absence of a strong quenching of the dye fluorescence. Indeed,
by estimating its rate, ket, using ket = (1/τF) − (1/τF°) where τF
and τF° are the fluorescence lifetimes of the donor (here [Fb])
in the presence (4) and absence (1) of an electron acceptor,
one finds ket ∼2.7 × 107 at 298 and ∼1.3 × 107 s−1 at 77 K
(data from Table 3). Although the decrease in ket upon cooling
(i.e., rendering the medium more rigid) is consistent with the
expected increase in reorganization energy, the size of these
presumed ket’s is the same as what we find for kic.22
Consequently all of the arguments above, specifically neglecting
the reorganization energy, long separation between the dye and
[M], and very small estimated ket’s, indicate that this process
can certainly be neglected. Because of the very short τF values
for [Pdporph] (< 150 ps), it is not possible to address this
issue for this specific chromophore.
More importantly, because these modified Latimer diagrams
unambiguously indicate that the photoinduced electron transfer
is not thermodynamically favorable in the triplet state, the
question is what then quenches the phosphorescence of the
[Pdporph] unit when [Ru] and [Os] are coordinated onto
ligand 2. Moreover, although a decrease in τP is noted at 298 K
going from ligand 2 to the complexes 3 and 5, why is this
decrease not observed at 77 K? At this point, only
circumstantial evidence can be provided.
Computer modeling permitted to detect the presence of a
folded conformation at higher energy (vide infra). This means
upon Brownian motions both geometries are accessible, and
consequently, the photophysical parameters represent a
weighted mixture associated with each conformation. Upon
cooling the solution by pouring N2(l) inside the Dewar, the
sample experiences a decrease in the available thermal energy
(kT; from 2.48 down to 0.64 kJ/mol), and so, only the
unfolded geometry is favored in all cases and are frozen in the
glassy matrix. The quasi-identical τP data for ligand 2 and
complex 5 (Table 3) confirms this hypothesis (i.e., the metal
atom is far away from the [Pdporph] chromophore). Upon
warming the solution back to 298 K, the τP data return to their
initial state, so the process is reversible. More importantly, no
quenching of the emission spectra are noted when [M] =
AuCl,20 meaning absence of the heavy atom effect. The
presence of an H-bond driven folding is easily demonstrated by
the absence of intramolecular H-bond with the thiourea center
in the corresponding gold(I) complex presented in Chart 3 (as
the P−Au−Cl angle is ∼180° with no possibility of N−H···Cl
interactions).
The four probed possible processes from these diagrams are
the following:
[Fb]* + [Ru] → [Fb]+ + [Ru]−
(reaction 1)
[Fb]* + [Ru] → [Fb]− + [Ru]+
(reaction 2)
[Pdporph]* + [Ru] → [Pdporph]+ + [Ru]−
(reaction 3)
and
[Pdporph]* + [Ru] → [Pdporh]− + [Ru]+
(reaction 4)
The oxidation of Ru(II) into Ru(III) occurs at +1.16 V vs
SCE. The driving forces for the photoinduced reduction of
[Fb]*(S1) + 1-e− into [Fb]−, [Pdporph]*(S1) + 1-e− into
[Pdporph]−, and [Pdporph]*(T1) + 1-e− into [Pdporph]− are
simply not large enough to render these processes thermody-
namically favorable. Similarly, model complex 8 can be reduced
to 8− at −0.83 V vs SCE. The modified Latimer diagrams
indicate that only the photoinduced oxidation of [Fb]*(S1)
into [Fb]+ + 1-e−, [Pdporph]*(S1) into [Pdporph]+ + 1-e−
can be favorable with a very low energy release of ∼0.04 (∼3.9)
and ∼0.11 V (i.e., ∼11 kJ/mol). By neglecting the
reorganization energy for the transition from a neutral species
to a zwitterionic charge separated state, and considering the
long separation between the two units (dye and [M]) based on
CONCLUSION
■
Although ligands 1 and 2 exhibit reasonable emission intensity
for imaging purposes, the anchoring of [M] reduces the
emission intensity and lifetimes, especially for 3 and 5.
Although it was clearly established that the dye−[M]
interactions do not involve any of the three classic quenching
processes (energy, atom, or electron transfer), it became
evident that the presence of a heavy atom near the
chromophore can actually induce this effect. The proximity of
the two fragments is achieved by the folding of the flexible
chain, toward an uphill energy conformations stabilized by an
H-bond (N−H···Cl−M). This work permitted the discovery of
a new feature to consider when designing bimetallic
H
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Organometallics
Article
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theranostics. It may be preferable to use rigid spacers separating
the dye from the metallic center.
ASSOCIATED CONTENT
* Supporting Information
■
S
HRMS (MALDI/TOF) mass spectra of compound 1−5
(Figures S1−S9), 1H, 31P, and 13C NMR spectra of compounds
(Figures S10−S21), cyclic voltammograms of compounds 6−8
(Figures S22−S24), synthesis of porphyrin 1, 2, 6, and 7 and
compound 8 (S25), UV−visible stability study of 3 and 5
(Figures S26−S27), crystal data and structure refinement for 8
(Table S28). This material is available free of charge via the
Internet at http://pubs.acs.org.
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(b) Groessl, M.; Reisner, E.; Hartinger, C. G.; Eichinger, R.;
Semenova, O.; Timerbaev, A. R.; Jakupec, M. A.; Arion, V. B.;
Keppler, B. K. J. Med. Chem. 2007, 50, 2185−2193.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: pierre.harvey@USherbrooke.ca. Tel.: 819-821-7092.
Fax: 819-821-8017.
■
(5) (a) Hartinger, C. G.; Hann, S.; Koellensperger, G.; Sulyok, M.;
Groessl, M.; Timerbaev, A. R.; Rudnev, A. V.; Stingeder, G.; Keppler,
B. K. Int. J. Clin. Pharmacol. Ther. 2005, 43, 583−585. (b) Timerbaev,
A. R.; Hartinger, C. G.; Aleksenko, S. S.; Keppler, B. K. Chem. Rev.
2006, 106, 2224−2248. (c) Schluga, P.; Hartinger, C. G.; Egger, A.;
Reisner, E.; Galanski, M.; Jakupec, M. A.; Keppler, B. K. Dalton Trans.
2006, 1796−1802. (d) Casini, A.; Mastrobuoni, G.; Terenghi, M.;
Gabbiani, C.; Monzani, E.; Moneti, G.; Casella, L.; Messori, L. J. Biol.
Inorg. Chem. 2007, 12, 1107−1117. (e) Scolaro, C.; Chaplin, A. B.;
Hartinger, C. G.; Bergamo, A.; Cocchietto, M.; Keppler, B. K.; Sava,
G.; Dyson, P. J. Dalton Trans. 2007, 5065−5072.
*E-mail: claude.gros@u-bourgogne.fr. Tel.: 33 (0)3 80 39 61
12.
*E-mail: ewen.bodio@u-bourgogne.fr. Tel.: 33 (0)3 80 39 60
76.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Centre National de la Recherche Scientifique (ICMUB, UMR
CNRS 6302) is gratefully thanked for financial support.
■
(6) (a) Adhireksan, Z.; Davey, G. E.; Campomanes, P.; Groessl, M.;
Clavel, C. M.; Yu, H.; Nazarov, A. A.; Yeo, C. H. F.; Ang, W. H.;
Support was provided by the CNRS, the Universite
and the Conseil Regional de Bourgogne through the 3MIM
integrated project (Marquage de Molecules par les Metaux pour
l’Imagerie Medicale). S.T. thanks the French Ministry of
́
de Bourgogne
Droge, P.; Rothlisberger, U.; Dyson, P. J.; Davey, C. A. Nat. Commun.
̈
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2014, 5, 3462. (b) Pelletier, F.; Comte, V.; Massard, A.; Wenzel, M.;
Toulot, S.; Richard, P.; Picquet, M.; Le, G. P.; Zava, O.; Edafe, F.;
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(c) Hartinger, C. G.; Casini, A.; Duhot, C.; Tsybin, Y. O.; Messori, L.;
Dyson, P. J. J. Inorg. Biochem. 2008, 102, 2136−2141.
́
́
́
Research for PhD scholarship. P.D.H. thanks the Agence
Nationale de la Recherche (ANR) and the Sciences and
Engineering Research Council of Canada (NSERC) for
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financial support. Fanny Picquet and Marie Jose Penouilh are
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