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Bis-cyclometalated rhodium- and iridium-complexes with the 4,4′-dichloro-2,2′-bipyridine ligand. Evaluation of their photophysical properties and biological activity
Accepted Manuscript
Research paper
Bis- Cyclometalated Rhodium- and Iridium- Complexes With the 4,4’-Dichloro-2,2’-Bipyridine Ligand. Evaluation of their Photophysical Properties and
Biological Activity
Marion Graf, Yvonne Gothe, Nils Metzler-Nolte, Rafał Czerwieniec, Karlheinz
Sünkel
PII:
DOI:
Reference:
S0020-1693(17)30247-5
http://dx.doi.org/10.1016/j.ica.2017.04.006
ICA 17510
To appear in:
Inorganica Chimica Acta
Received Date:
Accepted Date:
29 March 2017
3 April 2017
Please cite this article as: M. Graf, Y. Gothe, N. Metzler-Nolte, R. Czerwieniec, K. Sünkel, Bis- Cyclometalated
Rhodium- and Iridium- Complexes With the 4,4’-Dichloro-2,2’-Bipyridine Ligand. Evaluation of their
Photophysical Properties and Biological Activity, Inorganica Chimica Acta (2017), doi: http://dx.doi.org/10.1016/
j.ica.2017.04.006
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Bis- Cyclometalated Rhodium- and Iridium- Complexes With the
4,4’-Dichloro-2,2’-Bipyridine Ligand.
Evaluation of their Photophysical Properties and
Biological Activity
Dedicated to Prof. Hans-Christian Böttcher on the Occasion of his 60th Birthday
Marion Grafa, Yvonne Gotheb, Nils Metzler-Nolteb, Rafał Czerwieniecc
Karlheinz Sünkela*
a
Department of Chemistry, Ludwig Maximilian University of Munich, Butenandtstraße 5–13,
81377 Munich, Germany
b
c
Ruhr University of Bochum, Universitätsstraße 150, 44801 Bochum, Germany
Institute of Physical and Theoretical Chemistry University of Regensburg, Universitätsstraße
31, 93053 Regensburg, Germany
ABSTRACT
The synthesis and characterization of new cyclometalated complex salts [M(C^N)2(4,4’Cl2bpy)]PF6 (M = Rh and Ir; C^N = 2-(p-tolyl)pyridinato (1 and 2), 2-phenyl-5-chloropyridinato (3 and 4); 4,4’-Cl2bpy = 4,4’-dichloro-2,2’-bipyridine) is described. Compounds 1
- 4 were obtained by reaction of 4,4’-dichloro-2,2’-bipyridine with the complexes [{M(µCl)(C^N)2}2] (M = Rh, Ir) in refluxing CH2Cl2/MeOH mixtures. The molecular structures of
compounds 1 and 4 were confirmed by X-ray diffraction. The Ir compounds show
phosphorescence in PMMA film and in solution at ambient temperature. Furthermore, all
compounds display significant cytotoxicity against human cancer cell lines with the IC50
values in the 0.4 - 2 µM range.
KEYWORDS: Cyclometalated complexes; Rhodium; Iridium; phosphorescence; cytotoxicity
__________________________________________________________________________
* Corresponding author. Tel.: +49 89218077773; fax: +49 89218077774
E-mail address: suenk@cup.uni-muenchen.de (K. Sünkel)
2
1. Introduction
Bis-cyclometalated Ir(III) complexes play an important role in the development of
modern optoelectronic technologies (e.g. organic light emitting diodes − OLEDs and lightemitting electrochemical cells − LEECs), biological labels, and chemical sensors [1]. It was
found by several groups that as well for LEEC’s [2] as for sensoric applications [3], NLO
materials[4] and bio-medical diagnostic and therapeutic studies [59] the use of water-soluble
complexes of the type [M(C^N)2(N^N)]+ was particularly beneficial. Starting from the longknown compounds with M = Rh [10] and Ir [11], C^N = 2-phenylpyridinato (ppy) and N^N =
2,2’-bipyridine (bpy) or phenanthroline (phen), numerous studies were performed to elucidate
the effects of various substituents on the photophysical and electrochemical properties of the
complexes and how they influence the device performance in different applications [12-14].
Our group described a series of cyclometalated M(III) complexes (M = Rh, Ir) [15], including
complexes containing biomolecules as the ancillary ligands [16].
Recently we found that the complexes [M(ptpy)2 ](ddpmp)]PF6 (M = Rh, Ir; ddmp =
4,7-dichloro-2,9-dimethyl-1,10-phenanthroline)), which contain chloro-substituents on the
pyridine parts of the phenanthroline ligand, showed promising luminescence and cytotoxic
properties [17]. In this paper we describe the synthesis and characterization of four new
cyclometalated complex salts [M(C^N)2(4,4’-Cl2bpy)]PF6 which contain the structurally
related 4,4’-dichloro-2,2’-bipyridine ligand, which was also studied before in a Rh(I) complex
[18] for catalytic properties, a Ru(II) complex [19] as agent against tuberculosis or a Rh(III)
complex [20] for indirect electrochemical cofactor regeneration.
2. Experimental
2.1. General considerations
All manipulations were performed under an atmosphere of dry nitrogen using
conventional Schlenk techniques. 4,4’-dichloro-2,2’-bipyridine (Aldrich), 2-(p-tolyl)pyridine
(Aldrich), 5-chloro-2-phenyl-pyridine (Synchem) were used as received.
[{M(µ-Cl)(C^N)2}2] (M = Rh, Ir) were prepared by adequately modified literature
methods [15b, e]. NMR spectra were usually recorded in CD2Cl2 using a Jeol Eclipse 400
instrument operating at 400 MHz (1H) and 100 MHz (13C) respectively. Chemical shifts are
given in ppm, referenced to the solvent signals at δ = 5.30 (1H) or 53.8 ppm (13C). Mass
spectra were measured using a Jeol Mstation JMS 700 spectrometer. Elemental analyses (C,
H, N) were performed by the Microanalytical Laboratory of the Department of Chemistry,
LMU Munich, using a Heraeus Elementar Vario EL instrument.
3
Dulbecco’s Modified Eagle’s Medium (DMEM), containing 10% fetal calf serum, 1%
penicillin and streptomycin, was used as growth medium. MCF-7 and HT-29 cells were
detached from the wells with trypsin and EDTA, harvested by centrifugation and resuspended
again in the cell culture medium. The assays were carried out on 96 well plates with 6000
(3000) cells per well for MCF-7 (HT-29, respectively). After 24 h of incubation at 37°C and
10% CO2, the cells were treated with the compounds 1 and 2 (with DMSO concentrations of
0.5%) with a final volume of 200 µl per well. For a negative control, one series of cells was
left untreated. The cells were incubated for 48 h followed by adding 50 µl MTT (2.5 mg/ml).
After an incubation time of 2 h, the medium was removed and 200 µl DMSO were added. The
formazan crystals were dissolved and the absorption was measured at 550 nm, using a
reference wavelength of 620 nm. Each test was repeated in quadruplicates in two independent
experiments for each cell line.
2.2. Starting Materials
2.2.1. [{Ir(µ-Cl)(5-Cl-ppy)2}2]
Yield: 440 mg (65.5 %). Anal. Calc. for C44H28Cl6 Ir2N4: C, 43.68; H, 2.33; N, 4.63 Found:
C, 44.04; H, 2.57; N, 4.51 %. MS (FAB+): m/z = 1210.5 [M+H]+, 604.3 [M/2 +]. 1H NMR: δ
9.14 (d, J = 6.3 Hz, 4 H), 7.95 (d, J = 2.3 Hz, 4 H), 7.54 (dd, J =7.9/ 1.2 Hz, 4 H), 6.91 (dd, J
= 6.3/ 2.3 Hz, 4H), 6.89-6.83 (m, 4H), 6.68 (td, J =7.5/ 1.3 Hz, 4 H), 5.95 (dd, J =7.8/ 1.1
Hz, 4H). 13C {1H} NMR (100 MHz, CDCl3): δ 169.7, 151.1, 145.3, 145.1, 142.7, 130.6,
130.1, 124.4, 122.4, 122.0, 119.1.
2.2.2. [{Rh(µ-Cl)(5-Cl-ppy)2}2]
Yield: 45 mg (31.5 %). Anal. Calc. for C44H28Cl6N4Rh2 : C, 51.24; H, 2.74; N, 5.43. Found: C,
51.31; H, 3.06; N, 5.00 %. MS (FAB+): m/z = 1033 [M++2H], 516 [M/2+], 479 [M/2+-Cl]. 1H
NMR: δ 9.09 (m, 4 H), 7.93 (d, J = 2.4 Hz, 4 H), 7.58 (dd, J = 7.8/ 1.4 Hz, 4 H), 6.92 (m,
4H), 6.88 (dt, J = 6.2/ 2.3 Hz, 4H), 6.74 (dt, J = 7.6/ 1.4 Hz, 4H), 5.96 (d, J = 7.2 Hz, 4H). 13C
{1H} NMR: δ 166.68/ 166.66, 166.3 (d, JRhC = 36,6 Hz), 152.9, 145.9, 143.0, 132.4, 130.27/
130.25, 124.50/ 124.49, 123.2, 122.66/122.65, 119.67/ 119.66.
2.3. Synthesis of [Rh(ptpy)2(4,4’Cl2bpy)]PF6 (1)
To a solution of [{Rh(µ-Cl)(ptpy)2}2] (142 mg, 0.15 mmol) in 25 mL of CH2Cl2/
MeOH (1v: 1v) 4,4’-Cl2bpy = 4,4’-dichloro-2,2’-bipyridine (90 mg, 0.4 mmol) was added and
the mixture refluxed with stirring for 2 h. After cooling to room temperature, KPF6 (70 mg,
4
0.4 mmol) was added. The solvent was removed to dryness in vacuo and the residue dissolved
in dichloromethane and chromatographed on alumina with CH2 Cl2/ acetone (9:1) as the
eluent. The solution was evaporated to dryness and the residue was redissolved in 5 ml of
dichloromethane and 1 was crystallized by slow diffusion of n-hexane.
Yield: 142 mg (58.4%). Anal. Calc. for C34H26Cl2 F6N4PRh: C, 50.45; H, 3.24; N, 6.92.
Found: C, 50.78; H, 3.48; N, 6.50 %. MS (FAB+): m/z = 663.4 [M+] complex cation. 1H NMR
(400 MHz, CD2Cl2): δ 8.36 (d, J= 1.9 Hz, 2 H), 7.95 (d, J= 5.8 Hz, 2 H), 7.91 (d, J= 7.8 Hz, 2
H), 7.88- 7.83 (m, 2 H), 7.68 (d, J= 7.9 Hz, 2 H), 7.50 (dd, J= 5.8/ 1.8 Hz, 2 H), 7.46 (d, J=
5.8 Hz, 2 H), 7.07- 7.01 (m, 2H), 6.96 (d, J= 8.4 Hz, 2 H), 6.09 (s, 2H), 2.13 (s, 6 H). 13C
{1H} NMR (400 MHz, CD2Cl2): δ 166.4 (d, JRhC = 32Hz), 165.18/165.17, 154.9, 151.4,
148.8, 148.7, 141.47/141.46, 141.2, 138.8, 133.7, 128.8, 125.3, 125.00, 124.99, 123.39/
123.38, 120.17/120.15, 21.6.
2.4. Synthesis of [Ir(ptpy)2(4,4’-Cl2bpy)]PF6 (2)
To a solution of [{Ir(µ-Cl)(ptpy)2}2] (169 mg, 0.15 mmol) in 25 mL of a mixture of
CH2Cl2/MeOH
(1:1) the ligand 4,4’-Cl2bpy = 4,4’-dichloro-2,2’-bipyridine (90 mg, 0.4
mmol) was added and the mixture refluxed with stirring for 2 h. After cooling to room
temperature KPF6 (70 mg, 0.38 mmol) was added. The solvent was removed in vacuo and the
residue was dissolved in dichloromethane and chromatographed on alumina with
CH2Cl2/acetone (9:1) as the eluent. The solution was evaporated to dryness and the residue
redissolved in 5 ml of dichloromethane. The product was precipitated by slow diffusion of
hexane. Suitable crystals for X-ray diffraction were obtained by slow diffusion of hexane into
a solution of dichloromethane/chloroform at room temperature.
Yield: 142 mg (52.7 %). Anal. Calc. for C34H26Cl2F6IrN4P: C, 45.44; H, 2.92; N, 6.23.
Found: C, 44.91; H, 3.09; N, 5.87 %. MS (FAB+): m/z = 753.3 [M+] complex cation. 1HNMR: δ 8.36 (d, J= 2 Hz, 2 H), 7.90 (m, 4 H), 7.75 (m, 2 H), 7.60 (d, J= 12 Hz, 2 H), 7.44
(m, 4 H), 6.97 (m, 2 H), 6.88 (d, J= 8 Hz, 2 H), 6.05 (s, 2 H), 2.13 (s, 6 H). 13C {1H} NMR: δ
167.6, 166.0, 151.5, 149.0 148.4, 147.8, 141.4, 140.9, 138.3, 132.3, 132.3, 129.1, 125.3,
124.9, 124.0, 123.0, 119.6, 21.5.
2.5. Synthesis of [Rh(5-Cl-ppy)2(4,4’Cl2bpy)]PF6 (3)
5
To a solution of [{Rh(µ-Cl)(5-Cl-ppy)2}2] (155 mg, 0.15 mmol) in 20 mL of a mixture
of CH2Cl2/MeOH (1:1), the ligand 4,4’-Cl2bpy = 4,4’-dichloro-2,2’-bipyridine (68 mg, 0.3
mmol) was added and the mixture was stirred and refluxed for 2 hours. After cooling to room
temperature KPF6 (74 mg, 0.4 mmol) was added. The solvent was removed in vacuo and the
residue was dissolved in dichloromethane and chromatographed on alumina with
CH2Cl2/acetone (9:1) as the eluent. Crystals were obtained by slow diffusion of isohexane
into a solution in dichloromethane/chloroform at room temperature.
Yield: 141.3 mg (55 %). Anal. Calc. for C32H20Cl4F6N4PRh: C, 45.21; H, 2.37; N,
6.59. Found: C, 45.21; H, 2.72; N, 6.43 %. MS (FAB+): m/z = 705.2 [M+] complex cation.
1
H NMR: δ= 8.39 (d, J= 2.0 Hz, 2 H), 7.95 (d, J= 2.2 Hz, 2 H), 7.89 (d, J= 5.7 Hz, 2
H), 7.74 (d, J= 7.3 Hz, 2 H), 7.51 (dd, J= 5.8/ 2.0 Hz, 2 H), 7.46 (d, J= 6.2 Hz, 2 H), 7.16 (t,
J= 7.5 Hz, 2 H), 7.12 (dd, J= 6.2/ 2.2 Hz, 2 H), 7.08-7.02 (m, 2 H), 6.36 (d, J= 7.6 Hz, 2 H).
13
C {1H} NMR : δ= 166.5 (d, JRhC= 32 Hz), 166.03/166.01, 154.8, 151.2, 149.9, 149.0,
147.5, 142.8, 133.1, 131.63/131.61, 129.0, 125.5, 125.4, 124.5, 124.4, 120.82/120.81.
2.6. Synthesis of [Ir(5-Cl-ppy)2(4,4’-Cl2bpy)]PF6 (4)
To a solution of [{Ir(µ-Cl)(5-Cl-ppy)2}2] (181.5 mg, 0.15 mmol) in 20 mL of a
mixture of CH2Cl2/ MeOH (1:1), the ligand 4,4’-Cl2bpy = 4,4’-dichloro-2,2’-bipyridine (68
mg, 0.3 mmol) was added and the mixture was stirred and refluxed for 2 hours. After cooling
to room temperature KPF6 (70 mg, 0.38 mmol) was added. The solvent was removed in vacuo
and the residue was dissolved in dichloromethane and chromatographed on alumina with
CH2Cl2/ acetone (9:1) as the eluent. Suitable crystals for X-ray diffraction were obtained by
slow diffusion of isohexane into a solution in dichloromethane/chloroform at room
temperature.
Yield: 160.5 mg (57 %). Anal. Calc. for C32H20Cl4F6IrN4P: C, 40.91; H, 2.15; N, 5.96.
Found: C, 40.61; H, 2.33; N, 5.69 %. MS (FAB+): m/z = 793.4 [M+] complex cation.
1
H-NMR: δ = 8.41 (d, J= 2.1 Hz, 2 H), 7.94 (d, J = 2.2 Hz, 2 H), 7.86 (d, J = 5.9 Hz, 2
H), 7.70 (dd, J = 7.9/ 1.1 Hz, 2 H), 7.50 (dd, J= 5.9/ 2.1 Hz, 2 H), 7.47 (dd, J= 6.3/ 0.5 Hz, 2
H), 7.15- 7.05 (m, 4 H), 6.99 (td, J= 7.4/ 1.3 Hz, 2 H), 6.33 (dd, J= 7.6/ 0.7 Hz, 2H).
13
C {1H} NMR: δ= 168.8, 156.0, 151.4, 149.5, 149.0, 148.3, 146.9, 142.5, 131.8,
131.6, 129.3, 125.7, 125.5, 124.0, 123.3, 120.3.
6
2.7. X-ray structural determinations
A suitable single crystal of 1 was selected by means of a polarization microscope,
mounted on the tip of a glass fiber, and investigated on a BRUKER D8 Venture
diffractometer using Mo-Kα radiation (λ = 0.71073 Å). The crystal turned out to be a racemic
twin, containing two symmetry-independent molecules in the asymmetric unit. The intensities
were corrected for absorption by the semi-empirical multiscan method (SADABS). The
structure was solved by direct methods (SIR 97) using a HKLF4 file and refined by full-matrix
least-squares calculations on F2 (SHELXL-2014/7) using a HKLF5 file with BASF= 0.268, as
implemented in the software package WINGX. [21] Refinement turned out to be rather
difficult, as the compound co-crystallized with CH2Cl2, MeOH and water, which could be
localized (however, severely disordered) and refined using several restraints. Even then,
analysis by PLATON showed the presence of 4.8% solvent accessible voids. Anisotropic
displacement parameters were refined for all non-hydrogen atoms except the carbon and
oxygen atoms of the disordered solvent molecules.
Crystals of 4 suitable for an X-ray diffraction study were grown from
CH2Cl2/CHCl3/hexane solutions. Data collection, structure solution (SIR 97) and refinement
(SHELXL-2014/7) could be performed without any problems. There were neither co-crystallized
solvents nor any residual solvent accessible voids.
Details of the crystal data, data collection, structure solution, and refinement
parameters are summarized in Table 1.
2.8. Photophysical Measurements.
UV-Vis absorption spectra were recorded with a Varian Cary 300 double beam
spectrometer. Luminescence spectra were measured with a Horiba Jobin Yvon Fluorolog 3
steady-state fluorescence spectrometer. For decay time measurements a PicoQuant LDH-P-C375 pulsed diode laser (λexc = 372 nm, pulse width 100 ps) was applied as the excitation
source. The emission signal was detected with a cooled photomultiplier attached to a FAST
ComTec multichannel scalar card with a time resolution of 250 ps. Photoluminescence
quantum yields were determined with a Hamamatsu C9920-02 system equipped with a
Spectralon integrating sphere. Diluted solutions (c ≈ 10 −5 M−1) in dichloromethane (CH2Cl2)
were degassed by several freeze-pump-thaw cycles (p = 1×10−5 mbar). Polymer films
containing about 0.1 weight% of the Ir complex were obtained by dissolving the emitter and
7
poly(methyl methacrylate) (PMMA) in dichloromethane and spin-coating this solutions onto
quartz glass substrates. PMMA films were measured under continuous flushing with nitrogen.
8
Table 1:Crystal data and structure refinement details for 1 and 3.
Compound
1
4
Empirical formula
C35.75H30.5Cl4.5F6N4OPRh
C32H20Cl4F6IrN4P
Formula weight
939.55
939.49
Temperature [K]
100(2)
173(2)
Crystal system
Monoclinic
Space group
P 21
P 21/n
a [Å]
11.6660(6)
9.4737(3)
b
25.4895(14)
13.8553(4
c
14.1754(8) Å
24.5688(8)
93.879(2).
93.509(3)
4205.5(4)
3218.88(17)
2x2
4
Density (calc., [g/cm ])
1.484
1.939
Absorption coefficient
0.790 mm-1
4.597
F(000)
1886
1816
Crystal size [mm3]
0.08 x 0.04 x 0.03
0.279 x 0.118 x 0.07
Theta range for data collection
2.881 to 26.453°.
4.31 to 26.37°.
Index ranges
-14≤h≤14, 0≤k≤31, 0≤l≤17
-11≤h≤11, -15≤k≤17, -19≤l≤30
Reflections collected
11822
20539
Independent reflections
11822
6559 [R(int) = 0.0426]
Completeness
99.7 %
99.6 %
Max. and min. transmission
0.7454 and 0.693
1 and 0.84257
Data / restraints / parameters
11822 / 17 / 949
6559 / 0 / 433
Goodness-of-fit on F2
1.125
1.086
Final R indices [I>2sigma(I)]
R1 = 0.0540, wR2 = 0.1271
R1 = 0.0529, wR2 = 0.1325
R indices (all data)
R1 = 0.0631, wR2 = 0.1323
R1 = 0.0618, wR2 = 0.1389
Absolute structure parameter
0.05(5)
-
Largest diff. peak and hole [e.Å-3]
1.381 and -0.626
4.992 and -1.278
Unit cell dimensions
ß [°]
3
Volume [Å ]
Z
3
2.9. Computational Methodology.
Molecular geometries and electronic structures of [Rh(ptpy)2(4,4’-Cl2bpy)]PF6 and
[Ir(ptpy)2(4,4’-Cl2bpy)]PF6 were calculated using the density functional theory (DFT) with
the hybrid gradient corrected correlation functional B3LYP [22]. The Ahlrichs split-valence
basis set SVP [23] was applied for atoms C, H, N, and Cl and the quadruple-zeta quality basis
9
set QZVP [24] was used for Rh and Ir atoms. Inner-core electrons of Rh and Ir were
substituted with relativistic effective core potentials. [25] TD-DFT calculations for
[Ir(ptpy)2(4,4’-Cl2bpy)]+ (2) were performed in the optimized ground state geometry using the
same B3LYP functional and basis sets. Ten lowest singlet and triplet excitations were
computed. All computations were carried out using the Gaussian 09 program package.[26]
2.10. Cell culture and cytotoxicity.
Dulbecco’s Modified Eagle’s Medium (DMEM), containing 10% FCS, 1% penicillin and
streptomycin, was used as growth medium. MCF-7 and HT-29 cells were detached from the
wells with trypsin and EDTA, harvested by centrifugation and re-suspended in cell culture
medium. The assays have been carried out on 96 well plates with 6000 cells per well for both
cell lines. After 24 h of incubation at 37°C and 10% CO2, the cells were treated with the
compounds (with DMSO concentrations of 0.5%) with a final volume of 200 µl per well. For
the negative control, one series of cells was left untreated. The cells were incubated for 48 h
followed by adding 50 µl MTT (2.5 mg/ml). After an incubation time of 2 h, the medium was
removed and 200 µl DMSO were added. The formazan crystals were dissolved and the
absorption was measured at 550 nm, using a reference wavelength of 620 nm. Each test was
repeated in triplicates or quadruplicates in at least three independent experiments for each cell
line.
3. Results and discussion
3.1. Synthesis and characterization of compounds
The cyclometalating ligands 2-para-tolyl-pyridine (“Hptpy”) and 5-Chloro-2phenylpyridine (“HClppy”) were used for the synthesis of the chloro-bridged dimers [{M(µCl)(C^N)2}2] (M = Rh, Ir; C^N= ptpy, ClPppy) starting from the corresponding M(I)
complexes [{M(µ-Cl)(coe)2}2] by an oxidative addition reaction as described previously [15b,
e]. Subsequently, the preparation of the cationic mononuclear title complexes was started by
cleavage of these dimeric compounds by the chelating ligand 4,4’-Cl2bpy = 4,4’-dichloro2,2’-bipyridine in a refluxing mixture of dichloromethane/methanol. The primarily formed
chloride salts [M(C^N)2(4,4’-Cl2bpy)]Cl yielded after metatheses with KPF6 the
hexafluorophosphate derivatives 1 – 4 (see Scheme 1). All compounds were obtained as
yellow crystals in good yields and were characterized by elemental analyses, 1H and 13C NMR
10
spectroscopy, mass spectrometry and additionally for 1 and 4 by single crystal X-ray
diffraction studies.
Scheme 1: Synthesis of compounds 1–4
3.2. Crystal and molecular structures of 1 and 4
Figure 2: Molecular Structure of the cation
Figure 1: Molecular Structure of the cation
of compound 4; shown is the Λ isomer
of compound 1; shown is the isomer with
∆ configuration
ORTEP drawings of both compounds can be seen in Figures 1 and 2. Compound 1
crystallized unfortunately as a racemic twin with disordered solvent molecules in approximate
stoichiometry (1)4(CH2Cl2)5(MeOH)2(H2O)2. The unit cell contains two symmetryindependent molecules of 1, one with ∆- configuration and one with Λ configuration on Rh.
11
The nitrogen atoms of the cyclometalating ligands are in a mutual trans- configuration, as
usually observed. The bond parameters (in Å and °) involving the metal atoms are collected in
Table 2. As can be seen there, these parameters are for both independent molecules identical
within the 2σ criterion. The bonds from rhodium to the bpy nitrogen atoms are by ca. 0.1Å
longer than to the nitrogen atoms of the cyclometallating ligands, which is presumably due to
the trans influence of the Rh-C bonds. Very similar parameters were observed in the related
thienyl-pyridine complex [Rh(thpy)2(bpy)]Cl, (comp.”A” in Table 2) [10c]. The planes of the
two pyridine rings of the bpy ligand are slightly twisted (4.4° and 8.0°).
Compound 4 crystallizes with no solvents in the centrosymmetric space group P21/n
with only one independent molecule in the asymmetric unit. Again, the nitrogen atoms of the
cyclometallating ligands are in mutual trans configuration. Bond parameters around the
central iridium atom are collected again in Table 2. Again, the bond lengths from the metal to
the bpy nitrogen atoms are longer than those to the Clppy nitrogen atoms, but somewhat
surprising, they are actually slightly shorter than the corresponding bond lengths of the
rhodium compound. However, similar distances and angles were reported for the related
[Ir(ppy)2(bpy)]PF6 (comp. “B” in Table 2) [2c]. The planes of the two halves of the bipy
ligand are again slightly twisted by 7°, while in B this torsion angle amounts only to 1.4°.
Table 2: Bond geometries around the metal atoms in 1 and 4 and two related complexes.
M-Nbpy
1 (mol. 1) 2.158(11)
2.153(10)
1 (mol. 2) 2.156(10)
2.175(9)
A
2.145(3)
2.138(4)
2.136(6)
4
2.136(6)
2.129
B
2.136
M-NC^N
M-CC^N
(N-M-N)bpy
(N-M-C)C^N (N-M-N’)C^N C-M-Nbpy
2.023(10)
2.061(10)
2.050(10)
2.038(11)
2.055(4)
2.065(4)
2.054(6)
2.021(6)
2.047
2.042
1.998(12)
2.012(10)
2.013(10)
1.988(14)
1.984(4)
1.993(5)
2.031(8)
2.015(7)
2.024
2.004
75.5(4)
80.5(5)
81.6(4)
82.2(5)
81.3(5)
80.7(2)
81.1(2)
79.7(3)
80.1(3)
80.68
80.02
75.0(4)
76.7(1)
76.1(2)
76.20
173.3(4)
172.9(4)
170.7(1)
172.9(3)
172.09
173.8(6)
171.8(5)
171.6(5)
174.0(5)
173.6(2)
173.7(2)
172.8(3)
175.6(3)
171.92
171.90
3.3. Photophysical properties
UV-Vis absorption spectra were studied in dichloromethane (c = 0.05 mM) at room
temperature. Absorption maxima for both Rh and Ir complexes are listed in Table 3 (below).
The respective spectra of [Rh(ptpy)2(4,4’-Cl2bpy)]PF6 (1) and [Ir(ptpy)2(4,4’-Cl2bpy)]PF6 (2)
are shown in Fig. 3. With reference to previous studies on related complexes [1c, 17, 27–31]
the higher-energy intense bands occurring at λabs ≤ 330 (with maximum molar absorption
coefficients ε in the order of 104 M−1cm−1) nm are assigned to spin-allowed ligand-centered π
12
→ π* transitions of the ptpy and 4,4’-Cl2bpy ligands. In the lower energy region, between 330
and 400 nm for [Rh(ptpy)2(4,4’-Cl2bpy)]PF6 (1) and 330 – 450 nm for [Ir(ptpy)2(4,4’Cl2bpy)]PF6 (2), respectively, weaker absorption bands (ε in the order of several thousand
M−1cm−1) are observed. Since such absorptions are not displayed by the free ligands ptpyH
and 4,4’-Cl2bpy, the long-wavelength absorption bands of the Rh and Ir complexes are
assigned to metal-to-ligand charge-transfer (MLCT) transitions involving the occupied dπ
orbitals of the metals (4dπ(Rh) and 5d π(Ir) in [Rh(ptpy)2(4,4’-Cl2bpy)]PF6 (1) and
[Ir(ptpy)2(4,4’-Cl2bpy)]PF6 (2), respectively) and empty π* orbitals of the ptpy and 4,4’Cl2bpy ligands. The significant red-shift of the MLCT absorptions in the Ir complex as
compared to the Rh congener is readily accounted for the higher energy of the occupied d
orbitals of the 5d 6 ion Ir3+ than in the 4d6 ion Rh3+, respectively.
The above assignments are further supported by results of the TD-DFT calculations. In
particular, the frontier orbitals of [Ir(ptpy)2(4,4’-Cl2bpy)]+ (2) drawn in Fig. 3 involve
different regions of the molecule. As analyzed in Table 3, The HOMO is largely composed of
a 5dπ atomic orbital of Ir with significant admixtures of the π (ptpy) character and the LUMO
(π*) is largely centered on the 4,4’-Cl2bpy ligand. Since the lowest energy transitions S0→T1
and S0→S1 result mainly from the HOMO→LUMO excitation, distinct charge-transfer
character (5d π(Ir)→ π*(4,4’-Cl2bpy)) of the lowest excited states is predicted.
Table 3. Percent contributions of Ir, ptpy, and 4,4’-Cl2bpy to selected highest occupied
lowest virtual molecular orbitals of [Ir(ptpy)2(4,4’-Cl2bpy)]+ (2). The Mulliken population
analysis was performed for the ground-state Kohn-Sham orbitals resulting from the
B3LYP/{SVP+QZVP(ECP)} DFT calculations using the Chemissian computer program [32
Orbital
Energy (eV)
Ir (%)
ptpy1 (%)
ptpy2 (%)
4,4’-Cl2bpy (%)
HOMO – 5
-9.018
40
27
27
6
HOMO – 4
-8.920
64
15
15
5
HOMO – 3
-8.874
28
33
33
5
HOMO – 2
-8.661
16
41
41
-
HOMO – 1
-8.468
5
47
47
-
HOMO
-7.942
35
32
32
2
LUMO
-5.439
3
-
-
96
LUMO + 1
-4.616
3
2
2
93
LUMO + 2
-4.347
1
2
2
95
13
LUMO + 3
-4.222
5
47
47
1
LUMO + 4
-4.142
4
46
46
4
LUMO + 5
-3.718
3
47
47
4
Table 4. Vertical transition energies, oscillator strengths, and orbital character of three lowest
energy electronic transitions of [Ir(ptpy)2(4,4’-Cl2bpy)]+ (2) resulting from TD-DFT
computations on the B3LYP/[SVP+QZVP(ECP)] level of theory.
Transition Energy Oscillator
/eV
strength
Main contributions
S0→T1
1.809
0
HOMO→LUMO (96 %)
S0→T2
2.406
0
HOMO-5→LUMO (64 %)
HOMO-3→LUMO (16 %)
HOMO-1→LUMO (16 %)
S0→T3
2.474
0
HOMO-4→LUMO (55 %)
HOMO-2→LUMO (40 %)
S0→S1
1.837
0.0002
HOMO→LUMO (98 %)
S0→S2
2.509
0.0105
HOMO-1→LUMO (98 %)
S0→S3
2.580
0.0006
HOMO-4→LUMO (61 %)
HOMO-2→LUMO (38 %)
Natural transition orbitals [33]
hole
electron
14
Figure 3. UV-Vis absorption and room-temperature luminescence spectra of [M(ptpy)2(4,4’Cl2bpy)]PF6. M = Rh (1): Blue solid line (solvent CH2Cl2). M = Ir (2): Black dashed lines
(solvent CH2Cl2) and dotted line (PMMA matrix).
The iridium complexes [Ir(ptpy)2(4,4’-Cl2bpy)]+ (2) and [Ir(5-Cl-ppy)2(4,4’-Cl2bpy)]+
(4) are luminescent in solution and in organic polymer matrices. (Fig. 3 and Table 5) In
dichloromethane at ambient temperature, they show weak red emission centered at 660 nm (2)
and 643 nm (4) with the quantum yields φPL of 3 and 6 %, respectively. The decay times τ are
60 and 50 ns, respectively. In poly(methyl methacrylate) (PMMA), the emissions with
maxima at λem = 580 nm (2) and 560 nm (4) are significantly blue shifted relative to the liquid
solution. The quantum yields and emission decay times increase by about 10 times to φPL = 32
% and τ = 900 ns for [Ir(ptpy)2(4,4’-Cl2bpy)]+ (2) and φPL = 60 % and τ = 950 ns for, [Ir(5-Clppy)2(4,4’-Cl2bpy)]+ (4), respectively. The relatively small radiative rates calculated
according to
kr = φPL/τ,
being kr = 3.6 × 105 s−1 for 2 and kr = 6.3 × 10 5 s−1 for 4, respectively, point to a spin
forbidden character of the corresponding electronic transitions. Thus, the emitting state is
assigned as the lowest triplet state 3MLCT (5dπ(Ir)→ π*(4,4’-Cl2bpy)). However, the kr
values are still relatively high as for phosphorescence. A corresponding allowedness is results
from strong spin-orbit coupling of the lowest triplet state to the higher 1MLCT singlet states.
(cf. [1c ,34].)
Rigidochromic effects similar to those described above for [Ir(ptpy)2(4,4’-Cl2bpy)]+
(2) and [Ir(5-Cl-ppy)2(4,4’-Cl2bpy)]+ (4), such as the spectral blue shift and increase of φPL
and τ when liquid solution (CH2Cl2) is replaced with a rigid polymer matrix (PMMA), were
already reported for analogous luminescent iridium complexes. [17,29,31,35,36] Thus, the
observed emission enhancement in rigid PMMA matrix as compared to the liquid CH2Cl2
solution can be accounted for different electrostatic interactions of the 3MLCT-excited
molecule with the induced dipole moments in its close surrounding. In solution, the solutesolvent rearrangements lead to significant stabilization of the 3MLCT excited state and, thus,
to a lower emission energy (longer wavelength; λem = 660 nm (for 2) in CH2 Cl2). As a
consequence, vibrational coupling between the emitting 3MLCT state and the ground state
increases leading, according to the energy-gap law [1c ,37], to more effective non-radiative
relaxation manifested by distinctly lower φPL and τem values. On the contrary, in PMMA such
reorganizations are largely suppressed. Thus, non-radiative relaxation of the apparently blue-
15
shifted emission (λem = 580 nm (for 2) in PMMA) becomes less important and the φPL and τem
values remain large.
Table 5. UV-vis absorption and luminescence dataa for complexes 1 – 4 at ambient
temperature.
Complex
1
2
3
4
365 (0.9);
266 (4.1)
-
390 (0.8);
273 (4.6)
660
373 (0.9);
266 (5.5)
-
380 (0.8);
275 (4.6)
643
φPL [%] (CH2Cl2)
-
3
-
6
τem [ns] (CH2Cl2)
-
60
-
50
λem [nm] (PMMA)
-
580
-
560
φPL [%] (PMMA)
-
32
-
60
τem [ns] (PMMA)
-
900
-
950
λabs [nm], ε [104 M−1cm−1]
in parentheses. (CH2Cl2)
λem [nm] (CH2Cl2)
a) λabs = absorption maximum, ε = molar absorption coefficient, λem = emission maximum,
φPL = emission quantum yield, and τem = emission decay time, respectively.
3.5. Biological activity.
Several cyclometalated Ir(III) and Rh(III) complexes not only show strong luminescence, but
also manifest encouraging antiproliferative properties both in vitro and in vivo. For this
reason, the antiproliferative activity of the complexes towards the cancer cell lines MCF-7
(human breast adenocarcinoma) and HT-29 (colon adenocarcinoma) has been evaluated using
the MTT assay. The resulting IC50 values are shown in Table 4.
Table 4 Antiproliferative effects of complexes 1 – 4 in MCF-7 and HT-29 cells. IC50 values
are expressed as means [µM] (± standard deviation) of three independent experiments.
Numbers are reported to two relevant digits in all cases for consistency, thus resulting in
apparently different precision
IC50/µM
Compound
HT-29
MCF-7
[Rh(ptpy)2(Cl2-bpy)]PF6 (1)
0.41 ± 0.21
2.37 ± 0.81
[Ir(ptpy)2(Cl2-bpy)]PF6 (2)
0.55 ± 0.19
1.43 ± 0.21
16
[Rh(Cl-ptpy)2(Cl2-bpy)]PF6 (3)
0.663 ± 0.060
1.68 ± 0.52
[Ir(Cl-ptpy)2(Cl2-bpy)]PF6 (4)
0.609 ± 0.098
2.00 ± 0.52
Cisplatin
4.14 ± 0.31
23.03 ± 0.25
It is found that all complexes exhibit appreciable cytotoxicity against the two cell lines with
IC50 values ranging from 0.4 µM to 2.4 µM. The highest activity was observed for 1, which
exhibits a 10-fold higher activity towards both cell lines than the clinical drug cisplatin.
In a previous work, we have investigated similar cyclometalated complexes, in which the
bipyridine moiety was substituted by a phenanthroline unit.[17] In accordance with these
previously tested compounds, the MCF-7 cells show lower sensitivity to the compound
treatments than the HT-29 cells. The complexes show similar cytotoxic activity compared to
their phenanthroline analogues with the exception of having slightly higher IC50 values for
MCF-7 cells. All in all, all compounds exhibit a strong cytotoxic activity in the high
nanomolar/ low micromolar range with no significant difference in the cytotoxic behavior
between the two metals in this specific ligand system. These initial biological studies illustrate
the high antiproliferative potential of our complexes emphasising the suitability of
cyclometalated iridium and rhodium complexes as new promising anti-cancer agents.
4. Conclusions
The syntheses, photophysical properties, and biological activity of four new biscyclometalated cationic complexes [M(C^N)2(4,4’-Cl2bpy)]PF6 (M = Rh; Ir; C^N = ptpy,
Clppy) are reported. Crystal and molecular structures of the new complexes were confirmed
by X-ray crystal structure determination Iridium complexes 2 and 4 are luminescent in
solution and in polymer matrices at ambient temperature. The emission assigned to a 3MLCT
state strongly depends on the environment. In a rigid polymer matrix (PMMA),
[Ir(ptpy)2(4,4’-Cl2bpy)]+ (2) and [Ir(5-Cl-ppy)2(4,4’-Cl2bpy)]+ (4) show moderately strong
yellow luminescence whereas in solution (CH2Cl2) the emission is significantly red shifted.
The emission quantum yield φPL and decay time τem values are significantly larger in rigid
PMMA than in liquid solution due to different efficiency of non-radiative relaxations to the
ground state. This rigidochromic behavior is accounted for distinctly different stabilization of
17
the 3MLCT-excited state in flexible solution and quasi-solid polymer films. All compounds
exhibit cytotoxic effects towards two cell lines (HT29 and MCF-7).
Acknowledgments
The authors are grateful to the Department of Chemistry of the Ludwig Maximilians
University Munich for support. P. Mayer is acknowledged for collecting the X-ray crystal
data and Ms. Mahboubeh Jamshidi (University Regensburg) is acknowledged for her
assistance with photophysical measurements. The Johnson Matthey plc, Reading, UK, is
gratefully acknowledged for a generous loan of hydrated iridium chloride.
Supplementary material
CCDC-1528482 (1) and –1528483 (4) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
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Highlights
• 4 new bis-cyclometalated Rh and Ir complexes with 4,4‘-Cl2BiPy are described
• Crystal structures of [M(C^N)2(4,4’Cl2BiPy)] (M=Rh,Ir) are reported
• All complexes show antiproliferative activity against certain cancer cells
• The Ir complexes are strong yellow emitters in PMMA matrix