Cyclometalated iridium(III) complexes with deoxyribose substituents

Article abstract of DOI:10.1002/chem.201301776

Fundamental study of enzymatic nucleoside transport suffers for lack of optical probes that can be tracked noninvasively. Nucleoside transporters are integral membrane glycoproteins that mediate the salvage of nucleosides and their passage across cell mem

Full text of DOI:10.1002/chem.201301776

DOI: 10.1002/chem.201301776
Cyclometalated IridiumACTHNUTRGNEUG(N III) Complexes with Deoxyribose Substituents
Ayan Maity,[a] Jung-Suk Choi,[b] Thomas S. Teets,[c] Nihal Deligonul,[a]
Anthony J. Berdis,*[b] and Thomas G. Gray*[a]
Abstract: Fundamental study of enzy-
matic nucleoside transport suffers for
lack of optical probes that can be
es. Reported here are nucleoside ana-
logues in which emissive, cyclometalat-
plexes show visible luminescence at
room temperature and 77 K with mi-
crosecond-length triplet lifetimes. A
ed iridium
N
tracked
noninvasively.
Nucleoside
to C-1 of deoxyribose in place of can-
onical nucleobases. The resulting com-
representative complex is crystallo-
graphically characterized. Transport
and luminescence are demonstrated in
cultured human carcinoma (KB3-1)
cells.
transporters are integral membrane
glycoproteins that mediate the salvage
of nucleosides and their passage across
cell membranes. The substrate recogni-
tion site is the deoxyribose sugar, often
with little distinction among nucleobas-
Keywords: click chemistry · fluo-
rescent probes · iridium · metala-
tion · nucleobases
Introduction
receptor ERa.[39] Sugars have been conjugated to iridium
complexes indirectly through tethers that end in amino-oxy
moieties.[40] These functional groups undergo bioconjugation
reactions with the carbonyl groups of reducing sugars. The
resulting complexes enter HeLa cells, and perinuclear stain-
ing occurs. Internalization is rapid for the glucose conjugate
and less so for those of galactose, lactose, or maltose.
Iridium
ACHTUNGTRENNUNG
nescence tagging. Cyclometalated complexes of iridiumAHCTUNGTRENNUNG
are rugged, coordinatively saturated organometallics that
withstand the inhospitable settings of living cells.[1–11] These
complexes are high-yielding phosphorescence lumophores
that emit visible light across a range of wavelengths. Triplet
luminescence arises from either a metal-to-ligand charge-
Nucleoside transporters are integral membrane glycopro-
teins.[41] These proteins regulate cellular proliferation, neuro-
transmission, and cardiovascular activity by mediating the
passage of natural and synthetic nucleosides both in and out
of mammalian cells. They are imperfectly understood, de-
spite being essential to cell survival and proliferation. In
cells actively dividing, de novo nucleoside synthesis predom-
inates. In other cells, nucleosides are recycled, and nucleo-
side transporters enable salvaging. There are two broad
classes of transporters: equilibrative nucleoside transporters
(ENT) and concentrative nucleoside transporters (CNT).
The equilibrative transporters move nucleosides into or out
of the cell, along a concentration gradient. Concentrative
nucleoside transporters ferry nucleosides inwards, against
the gradient. For most CNTs, nucleoside transport is cou-
pled to Na+ transport, and these proteins are sodium–nu-
cleoside symporters. Another isoform, designated CNT3,
utilizes Na+ and/or H+ to facilitate nucleoside transport.[42]
Many chemotherapeutic drugs are nucleoside ana-
logues,[43–51] and their effectiveness depends on nucleoside
transporters for cellular uptake. Mechanistic understanding
of these glycoproteins is sparse, mainly because of limited
structural information on such dynamic biomolecules. To
date, there is a single report of a crystal structure of a CNT
from the bacterium Vibrio cholera.[52] Although more struc-
tures are likely to emerge, there is a clear need for probes
that accurately report on the activity of transporters in cells
and live animals.
transfer (MLCT) state or
a
ligand-centered excited
state.[12–21] Emission wavelengths are subject to rational
tuning.[22–27] The complexesꢀ excited-state properties make
them light-emitting beacons; their ground-state attributes
suggest them for experiments in cells.[28–34]
Cyclometalated iridiumACTHNUTRGENU(GN III) complexes accommodate the
standard techniques of bioconjugation. Reports of their at-
tachment to biologically relevant molecules are legion.[35]
Complexes have been tethered to biotin for binding and
crosslinking streptavidin.[36,37] Iridium
ACTHNUTRGNEUNG(III) complexes have
also been attached to steroids, such as estradiol.[38] Lo and
co-workers report that emission of two distinct iridium com-
plexes tethered to estradiol intensifies upon binding to the
[a] A. Maity, Dr. N. Deligonul, Prof. Dr. T. G. Gray
Department of Chemistry, Case Western Reserve University
10900 Euclid Avenue, Cleveland Ohio 44106 (USA)
E-mail: tgray@case.edu
[b] Dr. J.-S. Choi, Prof. Dr. A. J. Berdis
Department of Chemistry, Cleveland State University
2121 Euclid Avenue, Cleveland, Ohio 44115 (USA)
E-mail: a.berdis@csuohio.edu
[c] Dr. T. S. Teets
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, Massachusetts 02139 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301776.
15924
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15924 – 15932

FULL PAPER
This work reports optical markers for the facilitated diffu-
sion of nucleosides. Nucleoside transporters recognize the
sugar moiety; the nucleobase is secondary. We describe
tion by silica gel column chromatography. Ligand 7 recurs in
all complexes in this work.[54–56]
Metallonucleosides were prepared by the treatment of 7
iridium
G
with known, chloro-bridged iridiumACTHNGUTERNNU(G III) dimers. An example
sugars through b-glycoside linkages. These non-natural nu-
cleosides assemble in copper-catalyzed [3+2] cycloaddition
reactions of azides with terminal alkyne precursors. Metala-
appears in Scheme 2. Ambient workup and precipitation
yielded the products as analytically pure solids in isolated
yields ranging from 62–79%. Scheme 3 enumerates the non-
nucleoside ligands.
tion follows in thermal reactions with iridium
Instead of a nucleobase, the deoxyribose sugar supports cy-
clometalated iridium(III) at the 1’-position. The new probes
(III) dimers.[53]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
are visible-light emitters. Their syntheses and optical proper-
ties are disclosed, along with crystallographic findings, cellu-
lar experiments, and density-functional theory calculations
of a representative complex.
Results and Discussion
Synthesis: Synthesis of a chelating deoxyribose ligand pro-
ceeded as in Scheme 1. Concentrated hydrochloric acid
(1.5 equiv) was treated with 2-deoxy-d-ribose in methanol.
Scheme 2. Synthesis of a typical iridiumACTHNUTRGNEU(GN III) metallonucleoside.
Scheme 3. Cyclometalating ligands.
Vapor diffusion of pentane into a chloroform solution af-
forded diffraction-quality single crystals of [Ir(ppy)2(7)]-
(PF6). A thermal ellipsoid depiction appears in Figure 1. Iri-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ꢀ
dium carbon bond lengths are 2.017(4) and 2.019(7) ꢂ; the
nucleoside pyridyl and triazolyl nitrogen donors exert simi-
ꢀ
lar trans influences. Iridium pyridyl nitrogen bond lengths
are 2.047(5) and 2.048(6) ꢂ for the 2-phenylpyridine ligands,
ꢀ
and 2.163(5) ꢂ for the nucleoside. The Ir Ntriazolyl distance is
2.141(4) ꢂ, also reflecting a trans disposition to carbon.
Counterion and intraACTHUNTGRNENUGliACHUTNTGERNNUGgand metrics, including those of the
sugar, are unexceptional.
New complexes were characterized by absorption and lu-
minescence spectroscopies. Absorption features appear in
the visible region from about 250–435 nm, with more intense
bands in the ultraviolet. The weaker, longer-wavelength fea-
tures have been ascribed to spin-allowed and spin-forbidden
metal-to-ligand charge transfer (MLCT) transitions,[57] and
the more intense bands of shorter wavelength to ligand
Scheme 1. Synthesis of nucleoside 7.
The methyl-protected product 2 was treated with para-toluo-
yl chloride in pyridine to protect the 3’- and 5’-hydroxyls.
Compound 3 was converted to chloro-Hoffer sugar 4 with
an HCl solution in glacial acetic acid generated by adding
acetyl chloride to an aqueous solution of acetic acid. The
chloro sugar dissolved in N,N-dimethylformamide was treat-
ed with sodium azide to yield the two anomers, a and b, of
protected azido sugar 5. The resulting diastereomeric mix-
ture was separated by silica gel column chromatography.
Deprotection with sodium methoxide in dry methanol af-
forded azidodeoxyribose 6. Copper-catalyzed [3+2] cyclo-
addition with 2-ethynylpyridine produced 7 after purifica-
!
p* p transitions. Such absorption features are common-
place among C^N chelated complexes of iridium
N
Luminescence: The new complexes emit in fluid solution
and in low-temperature glasses. Normalized emission spec-
tra at 77 K appear in Figure 2; emission maxima and life-
times are gathered in Table 1. The cyclometalating ligands
modulate the luminescence; emission colors span the visible
Chem. Eur. J. 2013, 19, 15924 – 15932
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15925

A. J. Berdis, T. G. Gray et al.
Taken together, the spectra indicate emitting states of con-
siderable ligand character, with origins that range from
3MLCT to ligand-centered.
Calculations: The complex [IrACHTUNGTRNEUNG
(btp)2(7)]+ was selected for
density-functional theory calculations because of its long-
wavelength emission, which minimizes interference from
cellular autofluorescence. A frontier Kohn–Sham orbital
energy level diagram is shown in Figure 3a with selected or-
bital depictions in Figure 3b. The highest-occupied Kohn–
Figure 1. Thermal ellipsoid representation (50% probability) of the
cation of [Ir(ppy)2(7)](PF6) (8) along c. Hydrogen atoms and counterion
are omitted for clarity. A partial atom labeling scheme is indicated. Se-
A
ACHTUNGTRENNUNG
ꢀ
ꢀ
lected interatomic distances [ꢂ]: Ir1 C34, 2.017(4); Ir1 C23, 2.019(7);
ꢀ
ꢀ
ꢀ
ꢀ
Ir1 N6, 2.047(5); Ir1 N5, 2.048(6); Ir1 N1, 2.141(4); Ir1 N4, 2.163(5).
Selected angles [8]: N1-Ir1-N4, 76.7(3); C23-Ir1-N5, 80.2(3).
Figure 2. Normalized emission spectra (77 K) of new complexes in
2-methyltetrahydrofuran glass.
Figure 3. a) Frontier Kohn–Sham orbital energy level diagram of
[IrACHTNUTGRNEUNG
(btp)2(7)]+. Continuum water solvation is included. b) Plots of selected
orbitals (isodensity level is 0.03 a.u.). A color depiction of this Figure ap-
pears as the Supporting Information.
Table 1. Emission wavelengths (lem), lifetimes (t), and quantum yields
ꢀ
(fem) of iridium
N
tetrahydrofuran.
Sham orbital (HOMO) is delocalized over iridium (20%)
and the cyclometalating btp ligands (79%); percentages are
of electron density as calculated by a Mulliken population
analysis.[59] The lowest unoccupied Kohn–Sham orbital
(LUMO) concentrates (91%) on the pyridyl–triazolyl arm.
Because the LUMO resides on the ancillary (pyridyl–tria-
zolyl) ligand, the red-shifted absorption profile is attributa-
ble to high-energy, occupied btp p orbitals.
Sample
295 K
t [ms]
77 K
lem [nm]
[a]
lem [nm]
fem
t [ms]
[Ir
[Ir
[Ir
[Ir
N
475
475
520
592
565
1.5
1.6
6.8
7.2
1.2
0.15
0.13
0.026
0.044
0.064
475
475
500
582
542
4.4
5.8
62
13
4.6
[Ir(pq)2(7)]+
[a]ꢁ10%; absorbance of solutions was ꢂ0.1.
spectrum. Vibronic structure is pronounced. Their microsec-
ond-scale emission lifetimes indicate phosphorescence.
Cellular uptake of 8: Transport of compound 8 into KB3-
1 cells was evaluated using fluorescence microscopy analysis.
15926
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15924 – 15932

Cyclometalated IridiumACTHUNTGRNEUNG(III) Complexes
FULL PAPER
In these experiments, human epidermal carcinoma cells,
KB3-1, were treated with a fixed concentration (50 mm) of 8,
and images of treated cells were taken at variable time
points using an excitation wavelength of 315 nm and an
emission wavelength of 510 nm. To provide higher quality
images, cells were also stained with Hoechst 33342 to stain
their nuclei, which appeared blue (excitation wavelength of
340 nm and an emission wavelength of 480 nm). Images pro-
vided in Figure 4a show an increase in green fluorescence
signal that, in some cases, appears to co-localize with the
nuclei. In addition, the increase in green fluorescence signal
that reflects intracellular accumulation of 8 in KB3-1 cells
occurs in a time-dependent manner, reaching a maximal
amount in 24 h.
the fluorescent analogue. This nucleoside acts as a substrate
for all nucleoside transporters, including hENT and hCNT
family members,[60–65] and should thus function as a broad-
spectrum inhibitor for the uptake of 8. Cells were treated
with DMSO (vehicle) or 2’-deoxyadenosine (10 or 200 mm)
for 24 h prior to treatment with 10 or 50 mm of compound 8.
Data provided in Figure 5 show that the inclusion of 10 mm
2’-deoxyadenosine exerts little effect on the uptake of either
low (10 mm) or high (50 mm) concentrations of 8. In contrast,
pretreatment with 200 mm 2’-deoxyadenosine attenuates the
phosphorescence signal caused by the uptake of 8. The abili-
ty of high concentrations of 2’-deoxyadenosine to block
uptake suggests that the transport of 8 is catalyzed by one
or more hENT family members. This suggestion is based on
the fact that hENT family members have weaker affinity for
natural nucleosides, such as 2-deoxyadenosine, compared to
hCNTs.[66,67]
The dose-dependency of the uptake of 8 was similarly
evaluated. In these experiments, KB3-1 cells were treated
The accumulation of
KB3-1 cells was also quantified
using plate-reader assay.
8 in
a
KB3-1 cells were seeded onto
12-well plates at a density of
200000 cells per well. After
overnight incubation to allow
cell attachment, the cells were
treated with variable concentra-
tions of 8 for an additional
48 h. After 48 h, the medium
containing 8 was removed, and
the cells were washed twice
with 200 mL of phosphate-buf-
fered saline (PBS). Each wash-
ing step was performed for
10 min at 378C. All washes
were collected and analyzed as
described in the Experimental
Figure 4. a) Time-dependent accumulation of 8 into human epidermal carcinoma cell lines, KB3-1. Images of
cells treated with 50 mm of 8 were taken 4, 8, 12, and 24 h post-treatment. b) Dose-dependent accumulation of
8 into KB3-1 cells. Cells were incubated with 10 and 50 mm of 8 for 24 h. Compound 8 shows green fluores-
cence whereas the nuclei are stained with Hoechst 33342 (blue). Scale bars (100 mm) are provided for refer-
ence.
with variable concentrations of
compound 8 for a fixed time in-
terval (24 h). Representative
data in Figure 4b show that
KB3-1 cells treated with 50 mm
8 show more intense phosphor-
escence than cells treated with
10 mm 8. As before, the higher
emission intensity reflects intra-
cellular accumulation of 8 that
occurs in
manner.
a
dose-dependent
We next evaluated if the
uptake of 8 occurs by passive
diffusion or by the activity of
one or more nucleoside trans-
porters. This was accomplished
by quantifying the ability of the
natural nucleoside, 2’-deoxyade-
Figure 5. The uptake of 8 is dependent on nucleoside transporter activity. KB3-1 cells were treated with varia-
ble concentration of 8 (10 and 50 mm) in the absence and presence of increasing concentrations of 2’-deoxyade-
nosine. Cell images were taken after 24 h of exposure to 8. Compound 8 shows green fluorescence whereas
nosine, to block the uptake of nuclei are stained with Hoechst 33342 (blue). Scale bars (100 mm) are provided for reference.
Chem. Eur. J. 2013, 19, 15924 – 15932
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15927

A. J. Berdis, T. G. Gray et al.
Section to measure the concentration of unbound 8. The
cells were then treated with 0.25% trypsin and harvested by
centrifugation. The supernatant was removed, and the cells
were again washed with 1 mL of PBS at 378C to remove un-
bound and bound nucleoside. After this last wash step, the
cells were lysed using 0.1% Triton X-100 in 1ꢃPBS. The
amount of 8 present in the lysate was then measured using
a fluorescent plate reader (lex =340 nm/lem =480 nm). The
data provided in Figure 6 show a dependency on the fluores-
cence signal as a function of the concentration of 8, thus val-
idating that 8 accumulates inside KB3-1 cells.
Experimental Section
Materials and methods: Experimental procedures involving air- or mois-
ture-sensitive substances were performed under argon using either
Schlenk line techniques or in a nitrogen-filled MBraun drybox. Anhy-
drous solvents were used directly from an MBraun solvent purification
system or were purchased from Sigma–Aldrich. 1H NMR experiments
were performed on a Varian-400 FT NMR spectrometer operating at
1
399.7 MHz. H chemical shifts are reported in parts per million (d), mea-
sured from tetramethylsilane (0 ppm) and are referenced to residual sol-
vent in CDCl3 (7.26 ppm), [D6]acetone (2.05 ppm) or CD2Cl2 (5.32 ppm)
for 1H NMR. 13C{1H} NMR spectra were recorded on a Varian INOVA
AS-600 spectrometer operating at 150.0 Hz. 13C NMR chemical shifts are
reported in parts per million (d), measured from tetramethylsilane
(0 ppm) and are referenced to solvent residuals in CDCl3 (77.00 ppm) or
CD2Cl2 (54.00 ppm). The configuration of the nucleoside was confirmed
by 1H NMR NOE difference spectroscopy on a Varian INOVA AS-600
instrument. High-resolution electrospray ionization mass spectrometry
(Hi-Res ESI-MS) experiments were performed on an IonSpec HiRes
ESI-FTICRMS at the University of Cincinnati Mass Spectrometry facili-
ty. Solvents were degassed by bubbling argon for 20 min prior to use for
UV/Vis and luminescence measurements. UV/Vis and luminescence data
were recorded using a Cary 5G UV/Vis/NIR spectrometer and a Cary
Eclipse spectrometer, respectively. Thin layer chromatography (TLC)
was carried out using Whatman silica gel UV254 plates. Column chroma-
tography was performed using Fisher Scientific silica gel, sizes 32–63. El-
emental analyses were carried out by Robertson Microlit Laboratories,
Ledgewood, NJ.
Chemicals from commercial sources were used as received. 2-Deoxy-d-
ribose, pyridine, p-toluoyl chloride, acetyl chloride, 2-ethoxyethanol, and
sodium methoxide (NaOMe) were purchased from Acros Organics.
Sodium azide (NaN3), N,N-diisopropylethylamine (DIPEA) and cop-
per(I) iodide (CuI) were purchased from Sigma–Aldrich. IridiumACHTUNGTRENNUNG(III)
chloride (IrCl3·3H2O) and ammonium hexafluorophosphate (NH4PF6)
were purchased from Strem Chemicals.
Figure 6. Quantifying the cellular accumulation of compound 8 in KB3-
1 cells. Cells were treated with variable concentrations of 8 for 48 h and
the fluorescence intensities of lysed cells were measured with a fluores-
cence plate reader. Data points for lysed KB3-1 cells are provided as cir-
cles and data points for the collected supernatants are provided as
squares. These experiments represent an average of three or four inde-
pendent experiments performed on different days. The error bars repre-
sent standard deviations.
Hofferꢀs
a-chlorosugar
(1-a-chloro-3,5-di-(O-p-toluoyl)-2-deoxy-d-
ribose) was synthesized with a slight modification of the first step of an
established procedure[68] in which an equivalent amount of concentrated
hydrochloric acid was used in place of dissolving hydrogen chloride gas
in methanol. Cyclometalated IrIII m-chloro-bridged dimers, (C^N)2Ir
ACHTUNGTRENNUNG
Conclusion
Cl)2IrACHTUNGERTN(UNNG C^N)2 (abbreviated as [{IrACHTUTGNRENNUG(C^N)2ACTHUNGTRENNUNG
the method reported by Nonoyama;[69] IrCl3·3H2O was refluxed with 2–
2.5 equiv cyclometalating ligand in a 3:1 mixture of 2-ethoxyethanol and
Described herein is a synthetic strategy with which deoxyri-
bose sugars are linked to chelating pyridyl-triazoles. An effi-
cient method has been developed that attaches these sugar-
water. Synthesis and characterization of [{Ir
(m-Cl)}2],[71] [{Ir (m-Cl)}2],[72] [{Ir(pq) (m-Cl)}2],[73] and [{Ir
(bzq)2A 2A
Cl)}2][74] were reported previously.
1-b-Azido-3,5-di-(O-p-toluoyl)-2-deoxy-d-ribose (5b): NaN3 (0.390 g,
5.99 mmol) was added to mixture of a-chlorosugar (1.50 g,
A
R
ACHTUNGTRENNUNG
A
R
G
N
U
CHTUNGTRENNUNG
bearing ligands to cyclometalated iridiumACTHNUTRGNE(NUG III). The resulting
assemblies are luminescent. Choice of the cyclometalating
C^N ligand controls emission colors, and lumophores of
many hues can be prepared.
a
4
3.85 mmol) in dry DMF (50 mL), stirred at RT for 30 min. The mixture
was vigorously stirred at RT for 2 h in an inert atmosphere as the reac-
tion was tracked by TLC. After completion of the reaction, EtOAc
(100 mL) was added to the mixture to form a uniform organic layer. The
organic layer was washed with water (2ꢃ100 mL) followed by brine
(150 mL) and dried (over anhydrous Na2SO4). Evaporation under re-
duced pressure afforded the crude product mixture (1.4 g, 92%, b/a
ꢃ1:1), which was resolved by chromatography using diethyl ether/hex-
anes (1:9 v/v) mixture. Compound 5b was eluted as the first fraction.
Yield: 0.823 g (54%); Rf =b: 0.55 (diethyl ether/hexanes=30:70);
1H NMR (400 MHz, CDCl3): d=7.97 (d, 2H, J=8.1 Hz), 7.89 (d, 2H, J=
8.2 Hz), 7.24–7.21 (m, 4H), 5.70 (t, 1H, J=5.2 Hz), 5.56 (td, 1H, J=5.5,
2.4 Hz), 4.59–4.50 (m, 3H), 2.42–2.39 ppm (m, 8H); HRMS: calcd for
C21H21N3NaO5 [M+Na]+: 418.1379; found: 418.1376.
Membrane-bound enzymes translocate nucleosides from
extracellular space into the cytosol in the first step of nu-
cleoside metabolism. Most nucleoside transport enzymes
support sweeping variations in the nucleobase. The pendant
(deoxy)sugar is the recognition site of nucleoside substrates.
Chemical tags that monitor nucleoside transport are few,
and studies of transport in vivo are hindered. The conjugates
herein join an emissive complex to a deoxyribose sugar.
They are potential photoactive surrogates of natural nucleo-
sides; their biodisposition can be tracked optically. These
studies are in progress.
1-a-Azido-3,5-di-(O-p-toluoyl)-2-deoxy-d-ribose (5a): Collected as the
second fraction from the column. Yield: 0.7 g (46%); Rf =a: 0.48 (diethyl
ether/hexanes=30:70); 1H NMR (400 MHz, CDCl3): d=7.96 (d, 2H, J=
8.3 Hz), 7.91 (d, 2H, J=8.2 Hz), 7.27–7.23 (m, 4H), 5.71 (d, 1H, J=
5.6 Hz), 5.51–5.48 (m, 1H), 4.72 (q, 1H, J=3.8 Hz), 4.63–4.50 (m, 2H),
15928
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15924 – 15932

Cyclometalated IridiumACTHUNTGRNEUNG(III) Complexes
FULL PAPER
2.58–2.52 (m, 1H), 2.42 (s, 3H), 2.41 (s, 3H), 2.25–2.21 ppm (m, 1H);
8.19 (t, 1H, J=7.8 Hz), 8.14 (d, 2H, J=8.3 Hz), 7.95–7.85 (m, 4H), 7.78–
7.69 (m, 3H), 7.55 (t, 1H, J=5.6 Hz), 7.13–7.05 (m, 2H), 6.86 (d, 1H, J=
7.4 Hz), 6.78 (d, 1H, J=7.5 Hz), 6.46 (q, 1H, J=8.8 Hz), 6.17–6.14 (m,
2H), 4.63–4.48 (m, 1H), 4.07–4.08 (m, 1H), 3.76–3.62 (m, 2H), 2.64–2.53
(m, 2H), 2.08 (s, 3H), 2.05 ppm (s, 3H); 13C NMR (150 MHz, CD2Cl2):
d=168.56, 167.97, 150.83, 150.03, 149.92, 149.85, 149.19, 148.89, 146.81,
141.91, 141.84, 141.48, 140.69, 140.03, 138.51, 138.45, 133.19, 132.75,
127.03, 125.21, 124.82, 124.36, 124.29, 123.85, 123.67, 123.52, 123.39,
123.10, 119.79, 91.76, 89.10, 70.78, 61.92, 42.78, 22.05 ppm (2 CH3-C);
UV/Vis (acetonitrile): lmax (e)=249 (15000), 267 (sh, 14000), 378 nm
(3000 mꢀ1 cmꢀ1); emission (acetonitrile): lex (Int.)=480 (160), 508 nm
(147); HRMS: calcd for C36H34IrN6O3 [MꢀPF6]+: 791.2316; found:
791.2320; elemental analysis calcd for C36H34F6IrN6O3P: C 46.20, H 3.66,
N 8.98; found: C 46.51, H 3.85, N 9.21.
HRMS: calcd for C21H21N3NaO5 [M+Na]+: 418.1379; found: 418.1366.
1-b-Azido-2-deoxy-d-ribose (6): Dry MeOH (50 mL) followed by sodium
methoxide (0.410 g, 7.58 mmol) were added to a dry round-bottom flask
loaded with 5b (0.950 g, 2.4 mmol). The reaction mixture was stirred
under inert atmosphere at RT for 24 h and monitored by TLC. After this
time, the solvent was removed under vacuum. The residue was loaded on
a silica gel column, and the desired product 6 was isolated when eluted
with 5% MeOH in diethyl ether. Yield: 0.310 g (81%); Rf =0.60 (metha-
nol/diethyl ether=5:95); 1H NMR (400 MHz, CDCl3): d=5.55 (t, 1H,
J=4.0 Hz), 4.39 (d, 1H, J=4.8 Hz), 3.95–3.92 (m, 1H), 3.75–3.66 (m,
2H), 2.15–2.11 ppm (m, 2H); HRMS: calcd for C5H9N3NaO3 [M+Na]+:
182.0542; found: 182.0545.
1-(1’-b-2’-Deoxy-d-ribofuranosyl)-4-(5-(2-pyridinyl))-1,2,3-triazole
(7):
[Ir
in dry acetonitrile (20 mL). To this was added a 10 mL THF solution of
compound (0.025 g, 0.096 mmol) followed by NH4PF6 (0.016 g,
ACTHUNGTREN(GNUN bzq)2(7)]PF6: [{IrAHCTUNRTGENGN(NU bzq)2ACHTNUGTERN(NUGN m-Cl)}2] (0.045 g, 0.038 mmol) was suspended
Compound 6 (0.540 g, 3.39 mmol) was dissolved in a mixture of THF
(10 mL) and toluene (40 mL). 2-Ethynylpyridine (0.54 mL, 5.35 mmol),
DIPEA (2.7 mL, 15.5 mmol), and CuI (0.646 g, 3.39 mmol) were added
to the reaction mixture. The solution was heated to reflux. The reaction
was complete after 24 h, as monitored by TLC. The solvent was removed
by rotary evaporation. The crude reaction mixture was loaded on a silica
gel column packed with 1:1 v/v diethyl ether/hexanes. The desired prod-
uct 7 was isolated when the eluant polarity was increased to 1:9 v/v
MeOH/diethyl ether. Yield: 0.665 g (75%); Rf =0.20 (methanol/diethyl
ether=5:95); 1H NMR (400 MHz, CDCl3): d=8.49 (d, 1H, J=4.0 Hz),
8.46 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.77 (td, 1H. J=6.0, 1.6 Hz), 7.24–
7.21 (m, 1H), 6.42 (tapp, characteristic peak for b-anomer, 1H, J=6.7 Hz),
4.77 (d, 1H, J=4.8 Hz), 4.13 (d, 1H, J=3.9 Hz), 3.88–3.72 (m, 2H), 2.89–
2.83 (m, 1H), 2.63–2.57 ppm (m, 1H); 13C NMR (150 MHz, CDCl3): d=
149.72, 149.23, 148.03, 137.24, 123.14, 121.53, 120.43, 88.96, 88.39, 71.69,
62.61, 41.67 ppm; HRMS: calcd for C12H14N4NaO3 [M+Na]+: 285.0964;
found: 285.0974; elemental analysis calcd for C12H14N4O3: C 54.96, H
5.38, N 21.36; found: C 55.12, H 5.42, N 21.34.
7
0.096 mmol). The reaction mixture was purged with argon, heated to
458C, and left to stir for 12 h. The reaction was complete after this time
period as indicated by TLC. The solvent was removed under reduced
pressure to render a dark-orange residue. The crude reaction mixture
was washed with THF, water, and ice-chilled methanol, followed by di-
ethyl ether and pentane. The product was vacuum dried to give analyti-
cally pure compound. Yield: 0.058 g (79%); 1H NMR (400 MHz,
CD2Cl2): d=9.48 (d, 1H, J=13.7 Hz), 8.31–8.29 (m, 3H), 8.06 (ddd, 1H,
J=8.9, 5.3, 1.2 Hz), 7.91–7.85 (m, 4H), 7.78 (t, 1H, J=6.5 Hz), 7.72–7.68
(m, 2H), 7.51 (d, 1H, J=7.6 Hz), 7.47–7.37 (m, 3H), 7.18–7.12 (m, 2H),
7.10 (td, 1H, J=7.2, 1.4 Hz), 6.40–6.24 (m, 3H), 4.79–4.62 (m, 1H), 3.98–
3.94 (m, 1H), 3.85–3.82 (m, 2H), 2.70–2.36 ppm (m, 2H). 13C NMR
(150 MHz, CD2Cl2): d=158.10, 157.52, 151.21, 150.41, 149.44, 149.06,
148.37, 148.13, 146.42, 143.19, 141.57, 141.32, 140.15, 137.70, 134.86,
134.56, 130.50, 130.39, 130.29, 129.83, 129.74, 129.41, 127.79, 126.92,
124.88, 124.44, 124.10, 123.85, 122.95, 122.74, 122.37, 121.30, 120.80, 91.60,
88.92, 69.79, 61.11, 42.43 ppm; UV/Vis (acetonitrile): lmax (e)=242
(14000), 315 nm (8000 mꢀ1 cmꢀ1); emission (acetonitrile): lex (Int.)=516
(176), 540 nm (sh, 150); HRMS: calcd for C38H30IrN6O3 [MꢀPF6]+:
811.2003; found: 811.2004; elemental analysis calcd for C38H30F6IrN6O3P:
C 47.75, H 3.16, N 8.79; found: C 47.86, H 3.36, N 9.11.
[Ir
pended in acetonitrile (20 mL). To this was added a 10 mL THF solution
of compound (0.024 g, 0.092 mmol) followed by NH4PF6 (0.012 g,
ACHTUNGTRENNUNG(ppy)2(7)]PF6 (8): [{IrACHTUNRTEGGN(NNU ppy)2ACHTGUNTREN(NUNG m-Cl)}2] (0.040 g, 0.037 mmol) was sus-
7
0.076 mmol). After being purged with argon, the reaction mixture was
heated to 458C and left to stir for 12 h. The reaction was complete after
this time period as indicated by TLC. The solvent was removed under re-
duced pressure to render a dark-orange residue. The crude reaction mix-
ture was washed with THF, water, and ice-cold acetone followed by di-
ethyl ether and pentane. The product was vacuum-dried to give analyti-
cally pure compound. Yield: 0.053 g (75%); 1H NMR (400 MHz,
CD2Cl2): d=9.23 (d, 1H, J=3.2 Hz), 8.25 (dd, 1H, J=5.0, 4.2 Hz), 8.01
(t, 1H, J=7.8 Hz), 7.95–7.92 (m, 2H), 7.83 (d, 1H, J=5.4 Hz), 7.81–7.76
(m, 2H), 7.72–7.68 (m, 3H), 7.50 (dd, 1H, J=6.3, 5.3 Hz), 7.29 (t, 1H,
J=7.3 Hz), 7.10–6.96 (m, 4H), 6.92 (t, 1H, J=7.1 Hz), 6.86 (t, 1H, J=
7.6 Hz), 6.50–6.41 (m, 1H), 6.31–6.28 (m, 2H), 4.73–4.62 (m, 1H), 4.12–
4.08 (m, 1H), 3.96–3.80 (m, 2H), 2.76–2.53 ppm (m, 2H); 13C NMR
(150 MHz, CD2Cl2): d=168.59, 167.95, 150.83, 150.04, 149.94, 149.82,
149.22, 149.07, 146.68, 144.56, 140.18, 138.71, 138.64, 132.50, 132.07,
131.12, 130.43, 127.13, 125.32, 124.92, 124.46, 124.36, 124.13, 124.00,
123.79, 123.69, 123.31, 122.86, 120.19, 91.88, 89.11, 70.97, 62.04,
42.82 ppm; UV/Vis (acetonitrile): lmax (e)=249 (27000), 380 nm
(4000 mꢀ1 cmꢀ1); emission (acetonitrile): lex (Int.)=478 (190), 506 nm
(178); HRMS: calcd for C34H30IrN6O3 [MꢀPF6]+: 763.2003; found:
763.2004; elemental analysis calcd for C34H30F6IrN6O3P: C 44.98, H 3.33,
N 9.26; found: C 45.21, H 3.52, N 9.35.
[IrCATHNUGTRNE(NNGU btp)2(7)]PF6: [{IrACHTUNRTGEN(GUNN btp)2ACHTNUGTNER(NUGN m-Cl)}2] (0.050 g, 0.038 mmol) was suspended
in dry acetonitrile (25 mL). To this was added a solution of compound 7
(0.026 g, 0.098 mmol) in 10 mL dry THF, followed by NH4PF6 (0.014 g,
0.086 mmol). After being purged with argon, the reaction mixture was
sealed and heated to 458C. The reaction was complete after 12 h as indi-
cated by TLC. The solvent was removed under reduced pressure to
render a brick-red residue. The crude reaction mixture was washed with
THF, water and ice-cold methanol, followed by diethyl ether and pen-
tane. The remaining product was dried under vacuum to give analytically
pure compound. Yield: 0.061 g (78%); 1H NMR (400 MHz,
[D6]acetone): d=9.48 (d, 1H, J=9.0 Hz), 8.47 (d, 1H, J=5.6 Hz), 8.27
(d, 1H, J=6.3 Hz), 8.07–7.98 (m, 2H), 7.94–7.80 (m, 3H), 7.65–7.30 (m,
5H), 7.20 (dd, 2H, J=8.9, 6.3 Hz), 7.10 (t, 2H, J=6.4 Hz), 6.89 (dd, 2H,
J=7.6, 6.1 Hz), 6.45–6.40 (m, 1H), 6.19–6.09 (m, 2H), 4.70–4.39 (m, 1H),
4.21–3.92 (m, 1H), 3.76–3.52 (m, 2H), 2.74–2.52 ppm (m, 2H); UV/Vis
(acetonitrile): lmax (e)=283 (31000), 325 (20000), 435 nm (7500 mꢀ1 cmꢀ1);
emission (acetonitrile): lex (Int.)=593 (180), 637 nm (126); HRMS: calcd
for C38H30IrN6O3S2 [MꢀPF6]+: 875.1445; found: 875.1437; elemental anal-
ysis calcd for C38H30F6IrN6O3PS2: C 44.75, H 2.96, N 8.24; found: C 44.88,
H 3.19, N 8.27.
[IrACHTUNGTRENNUNG(tpy)2(7)]PF6: [{IrACHTUNGTRENNUNG(tpy)2ACHTNUGTNER(NUGN m-Cl)}2] (0.046 g, 0.041 mmol) was suspended
[Ir(pq)2(7)]PF6: [{Ir(pq)2ACTHNUTRGNEUNG(m-Cl)}2] (0.040 g, 0.031 mmol) was suspended in
in dry acetonitrile (25 mL). To this was added a solution of compound 7
(0.026 g, 0.099 mmol) dissolved in 10 mL dry THF, followed by NH4PF6
(0.014 g, 0.086 mmol). After being purged with argon, the reaction mix-
ture was sealed and heated to 458C. The reaction was complete after
12 h as indicated by TLC. The solvent was removed under reduced pres-
sure to render a dark-orange residue. The crude reaction mixture was
washed with THF, water and ice-cold acetone, followed by diethyl ether
and pentane. The remaining product was dried under vacuum to give an-
alytically pure compound. Yield: 0.047 g (62%); 1H NMR (400 MHz,
[D6]acetone): d=9.43 (d, 1H, J=5.9 Hz), 8.40 (dd, 1H, J=5.3, 3.2 Hz),
dry acetonitrile (20 mL). To this was added a solution of 7 in 10 mL dry
THF, followed by NH4PF6 (0.013 g, 0.078 mmol). After being purged with
argon, the reaction mixture was heated to 458C and left to stir for 16 h.
The reaction was complete after this time period as indicated by TLC.
The solvent was removed under reduced pressure to render a dark-
orange residue. The crude reaction mixture was washed with THF, water
and ice-cold acetone followed by diethyl ether and pentane. The product
was vacuum-dried to give analytically pure compound. Yield: 0.048 g
(76%); 1H NMR (400 MHz, CD2Cl2): d=8.90 (m, 1H), 8.28–8.13 (m,
Chem. Eur. J. 2013, 19, 15924 – 15932
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15929

A. J. Berdis, T. G. Gray et al.
4H), 8.08–8.05 (m, 2H), 7.95 (q, 1H, J=5.8 Hz), 7.77–7.69 (m, 4H), 7.60
(q, 1H, J=9.1 Hz), 7.39–7.11 (m, 7H), 6.93 (q, 1H, J=8.2 Hz), 6.86 (q,
1H, J=7.4 Hz), 6.79–6.75 (m, 1H), 6.69 (d, 1H, J=7.6 Hz), 6.52 (dd, 1H,
J=8.5, 6.7 Hz), 6.30–6.26 (m, 1H), 4.60–4.27 (m, 1H), 3.96–3.95 (m, 1H),
3.71–3.63 (m, 2H), 2.57–2.22 ppm (m, 2H); 13C NMR (150 MHz,
CD2Cl2); d=171.10, 170.21, 151.59, 149.67, 148.51, 148.31, 148.08, 147.21,
146.88, 146.41, 140.43, 140.19, 139.85, 135.77, 134.94, 131.99, 131.76,
131.09, 130.59, 129.67, 129.32, 128.30, 128.03, 127.51, 127.37, 127.08,
126.97, 126.64, 126.03, 125.79, 125.25, 123.68, 123.57, 123.26, 123.05,
117.88, 117.80, 91.31, 89.11, 69.81, 61.48, 41.99 ppm; UV/Vis (acetoni-
trile): lmax (e)=234 (8200), 264 (7600), 332 nm (4000 mꢀ1 cmꢀ1); emission
(acetonitrile): lex (Int.)=567 nm (245); HRMS: calcd for C42H34IrN6O3
[MꢀPF6]+: 863.2322; found: 863.2328; elemental analysis calcd for
C42H34F6IrN6O3P: C 50.05, H 3.40, N 8.34; found: C 50.15, H 3.77, N 8.60.
ochromatic MoKa radiation with the omega scan technique. The unit cells
were determined using SMART[78] and SAINT+.[79] Data collection for
all crystals was conducted at 100 K (ꢀ1738C). All structures were solved
by direct methods and refined by full matrix least squares against F2 with
all reflections using SHELXTL.[80] Refinement of extinction coefficients
was found to be insignificant. All non-hydrogen atoms were refined ani-
sotropically. Hydrogen atoms were placed in standard calculated posi-
tions and were refined with an isotropic displacement parameter 1.2-
times that of the adjacent carbon or oxygen.
Computations: Spin-restricted density-functional theory calculations
were executed with Gaussian09 (rev.A.02).[81] Geometries were fully op-
timized. Calculations employed the exchange and correlation functionals
of Perdew, Burke, and Ernzerhof,[82] and the TZVP basis set. For iridium,
the Stuttgart–Dresden (SDD) effective core potential and basis set were
used; scalar relativistic effects are included implicitly. Harmonic frequen-
cy calculations returned all real vibrational frequencies. The calculations,
including geometry optimizations, impose continuum solvation in water,
using the integral equation formalism of Tomasiꢀs polarizable continuum
model.[83–86] Population analyses were performed with the AOMix-CDA
software of Gorelsky.[87, 88]
Luminescence measurements: Steady-state luminescence spectra were re-
corded at room temperature on a Cary Eclipse fluorescence spectropho-
tometer or on an automated Photon Technology International (PTI)
QM-4 fluorimeter equipped with a 150 W Xe arc lamp and a Hamamatsu
R928 photomultiplier tube. Excitation light was excluded with suitable
glass filters. Sample solutions were added to a quartz ESR tube equipped
with
a Teflon valve, freeze-pump-thaw degassed (four cycles, 1ꢃ
10ꢀ5 Torr), and sealed. Low temperature emission spectra were recorded
in rigid solvent glass at 77 K by immersion of the sealed ESR tubes into
a liquid nitrogen-filled dewar. Time-resolved phosphorescence lifetime
data were recorded on a nanosecond laser system described previously.[75]
Acknowledgements
Emission quantum yields (23ꢁ28C) were measured[76] in deoxygenated
This research was supported by NSF grant CBET 1066107. We thank
Professor D. G. Nocera (Harvard University) for access to instrumenta-
tion. T.S.T. acknowledges the Fannie and John Hertz Foundation for
a graduate research fellowship. N.D. thanks the Republic of Turkey for
a fellowship.
2-methyltetrahydrofuran by referencing sample luminescence intensities
to those of optically dilute standards of 9,10-diphenylanthracene (fem
=
0.9) in cyclohexane.[77] Quantum yields, f, were computed by using Equa-
tion (1):
ꢀ
ꢁ
Arh2sDs
Ash2rDr
ꢀs ¼ ꢀr
ð1Þ
[1] Y. Yang, Q. Zhao, W. Feng, F. Li, Chem. Rev. 2013, 113, 192–270.
[2] F. L. Thorp-Greenwood, Organometallics 2012, 31, 5686–5692.
[3] M. Patra, G. Gasser, ChemBioChem 2012, 13, 1232–1252.
[4] E. Baggaley, J. A. Weinstein, J. A. G. Williams, Coord. Chem. Rev.
2012, 256, 1762–1785.
where r and s indicate reference and sample, respectively, A is the ab-
sorbance at wavelength lexc, h is the refractive index of the solvent, and
D is the integrated area beneath the absorption spectrum.
[5] F. L. Thorp-Greenwood, R. G. Balasingham, M. P. Coogan, J. Orga-
nomet. Chem. 2012, 714, 12–21.
[6] K. K.-W. Lo, A. W.-T. Choi, W. H.-T. Law, Dalton Trans. 2012, 41,
6021–6047.
[7] K. K.-W. Lo, S. P.-Y. Li, K. Y. Zhang, New J. Chem. 2011, 35, 265–
287.
[8] Q. Zhao, C. Huang, F. Li, Chem. Soc. Rev. 2011, 40, 2508–2524.
[9] K. K.-W. Lo, K. Y. Zhang, S. P.-Y. Li, Pure Appl. Chem. 2011, 83,
823–840.
Cell culture procedures: KB3-1 cells were cultured at 378C in humidified
air with 5% CO2 and maintained in Dulbeccoꢀs modified Eagleꢀs
medium (Mediatech, VA) supplemented with 10% fetal bovine serum
(USA Scientific), 100 UmLꢀ1 penicillin (Invitrogen, NY), 100 mgmLꢀ1
streptomycin and 250 mL gentamicin. The doubling time for these cells is
approximately 24 h. In cell-based experiments, a fixed amount of com-
pound 8 was dissolved in 100% DMSO to obtain a final stock concentra-
tion of 100 mm. Serial dilutions of compound 8 (10–0.01 mm) were then
made from this stock solution using 100% DMSO as the co-solvent.
[10] K. L. Haas, K. J. Franz, Chem. Rev. 2009, 109, 4921–4960.
[11] A. Ruggi, D. N. Reinhoudt, A. H. Velders, in Bioinorganic Medicinal
Chemistry (Ed.: E. Alessio), Wiley, New York 2011, pp. 383–406.
[12] S. Sprouse, K. A. King, P. J. Spellane, R. J. Watts, J. Am. Chem. Soc.
1984, 106, 6647–6653.
[13] K. A. King, P. J. Spellane, R. J. Watts, J. Am. Chem. Soc. 1985, 107,
1431–1432.
[14] Y. Ohsawa, S. Sprouse, K. A. King, M. K. DeArmond, K. W. Hanck,
R. J. Watts, J. Phys. Chem. 1987, 91, 1047–1054.
[15] K. Ichimura, T. Kobayashi, K. A. King, R. J. Watts, J. Phys. Chem.
1987, 91, 6104–6106.
[16] F. O. Garces, K. A. King, R. J. Watts, Inorg. Chem. 1988, 27, 3464–
3471.
[17] F. O. Garces, R. J. Watts, Inorg. Chem. 1990, 29, 582–584.
[18] K. Dedeian, P. I. Djurovich, F. O. Garces, G. Carlson, R. J. Watts,
Inorg. Chem. 1991, 30, 1685–1687.
[19] A. P. Wilde, K. A. King, R. J. Watts, J. Phys. Chem. 1991, 95, 629–
634.
[20] C. Ulbricht, B. Beyer, C. Friebe, A. Winter, U. S. Schubert, Adv.
Mater. 2009, 21, 4418–4441.
Visualizing the cellular uptake of compound 8 by microscopy: The cellu-
lar uptake of compound 8 was visualized by microscope imaging of KB3-
1 cells. Cells were plated on 35 mm glass bottom microwell dishes and
pre-incubated in the absence or presence of variable concentrations of 2’-
deoxyadenosine. After 24 h, cells were treated with variable concentra-
tions of compound 8 (0–200 mm) for time periods varying from 4 to 48 h.
Cells were then washed twice with 1ꢃPBS, fixed with 4% paraformalde-
hyde, and washed twice with 1ꢃPBS. Images were obtained using
a Nikon (TE 2000-S) microscope with UV lamp. Positive controls were
obtained measuring cellular uptake of Hoechst 33342 at a final concen-
tration of 5 mgmLꢀ1. For the detection of compound 8, an excitation
wavelength (lex) of 365 nm and an emission wavelength (lem) of 477 nm
were used.
Studies for the quantification of compound 8 were performed by seeding
cells onto 12-well plates at a density of 200000 cells per well. After 24 h,
cells were treated with variable concentrations of compound
8 (0–
200 mm) for 24–48 h. Cells were treated with 0.25% trypsin and harvested
by centrifugation. The supernatant was removed and then washed with
PBS. Cells were lysed with 0.1% Triton X-100 in 1ꢃPBS and then ob-
served using a fluorescent plate reader (lex =340 nm/lem =480 nm).
[21] H. Yersin, W. J. Finkenzeller, in Highly Efficient OLEDs with Phos-
phorescent Materials (Ed.: H. Yersin), Wiley-VCH, Weinheim 2008,
pp. 1–97.
X-ray single crystal structure analysis: Single crystal X-ray data were col-
lected on a Bruker AXS SMART APEX CCD diffractometer using mon-
15930
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15924 – 15932

Cyclometalated IridiumACTHUNTGRNEUNG(III) Complexes
FULL PAPER
[22] F. Neve, A. Crispini, S. Campagna, S. Serroni, Inorg. Chem. 1999,
38, 2250–2258.
Beyer, C. Ulbricht, D. Escudero, C. Friebe, A. Winter, L. Gonzꢇlez,
U. S. Schubert, Organometallics 2009, 28, 5478–5488; d) E. Orselli,
R. Q. Albuquerque, P. M. Fransen, R. Frçhlich, H. M. Janssen, L.
De Cola, J. Mater. Chem. 2008, 18, 4579–4590.
[23] A. B. Tamayo, S. Garon, T. Sajoto, P. I. Djurovich, I. M. Tsyba, R.
Bau, M. E. Thompson, Inorg. Chem. 2005, 44, 8723–8732.
[24] S. Stagni, S. Colella, A. Palazzi, G. Valenti, S. Zacchini, F. Paolucci,
M. Marcaccio, R. Q. Albuquerque, L. De Cola, Inorg. Chem. 2008,
47, 10509–10521.
[55] J. M. Fernꢇndez-Hernꢇndez, J. I. Beltrꢇn, V. Lemaur, M.-D. Gꢇlvez-
Lꢈpez, C.-H. Chien, F. Polo, E. Orselli, R. Frçhlich, J. Cornil, L.
De Cola, Inorg. Chem. 2013, 52, 1812–1824.
[25] A. F. Rausch, M. E. Thompson, H. Yersin, J. Phys. Chem. A 2009,
113, 5927–5932.
[56] K. N. Swanick, S. Ladouceur, E. Zysman-Colman, Z. Ding, Chem.
Commun. 2012, 48, 3179–3181.
[26] N. M. Shavaleev, F. Monti, R. D. Costa, R. Scopelliti, H. J. Bolink,
E. Ortꢄ, G. Accorsi, N. Armaroli, E. Baranoff, M. Grꢅtzel, M. K. Na-
zeeruddin, Inorg. Chem. 2012, 51, 2263–2271.
[57] A. B. Tamayo, B. D. Alleyne, P. I. Djurovich, S. Lamansky, I. Tsyba,
N. N. Ho, R. Bau, M. E. Thompson, J. Am. Chem. Soc. 2003, 125,
7377–7387.
[27] N. M. Shavaleev, F. Monti, R. Scopelliti, A. Baschieri, L. Sambri, N.
Armaroli, M. Grꢅtzel, M. K. Nazeeruddin, Organometallics 2013, 32,
460–467.
[28] C. Li, M. Yu, Y. Sun, Y. Wu, C. Huang, F. Li, J. Am. Chem. Soc.
2011, 133, 11231–11239.
[29] D.-L. Ma, W.-L. Wong, W.-H. Chung, F.-Y. Chan, P.-K. So, T.-S. Lai,
Z.-Y. Zhou, Y.-C. Leung, K. Y. Wong, Angew. Chem. 2008, 120,
3795–3799; Angew. Chem. Int. Ed. 2008, 47, 3735–3739.
[30] X. Wang, J. Jia, Z. Huang, M. Zhou, H. Fei, Chem. Eur. J. 2011, 17,
8028–8032.
[31] Y. You, Y. Han, Y.-M. Lee, S. Y. Park, W. Nam, S. J. Lippard, J. Am.
Chem. Soc. 2011, 133, 11488–11491.
[32] Y. You, S. Lee, T. Kim, K. Ohkubo, W.-S. Chae, S. Fukuzumi, G.-J.
Jhon, W. Nam, S. J. Lippard, J. Am. Chem. Soc. 2011, 133, 18328–
18342.
[33] P.-K. Lee, W. H.-T. Law, H.-W. Liu, K. K.-W. Lo, Inorg. Chem. 2011,
50, 8570–8579.
[34] P. Steunenberg, A. Ruggi, N. S. van den Berg, T. Buckle, J. Kuil,
F. W. B. van Leeuwen, A. H. Velders, Inorg. Chem. 2012, 51, 2105–
2114.
[58] Y. You, W. Nam, Chem. Soc. Rev. 2012, 41, 7061–7084.
[59] R. S. Mulliken, J. Chem. Phys. 1955, 23, 1833–1840.
[60] L. Dagnino, L. L. Bennett, Jr., A. R. P. Paterson, J. Biol. Chem.
1991, 266, 6312–6317.
[61] M. M. Gutierrez, K. M. Giacomini, Biochim. Biophys. Acta 1993,
1149, 202–208.
[62] M. E. Schaner, J. Wang, L. Zhang, S.-F. Su, K. M. Gerstin, K. M.
Giacomini, J. Pharmacol. Exp. Ther. 1999, 289, 1487–1491.
[63] K. M. King, V. L. Damaraju, M. F. Vickers, S. Y. Yao, T. Lang, T. E.
Tackaberry, D. A. Mowles, A. M. Ng, J. D. Young, C. E. Cass, Mol.
Pharmacol. 2006, 69, 346–353.
[64] A. N. Elwi, V. L. Damaraju, M. L. Kuzma, D. A. Mowles, S. A. Bald-
win, J. D. Young, M. B. Sawyer, C. E. Cass, Am. J. Physiol. Renal
Physiol. 2009, 296, F1439–1451.
[65] H. Li, G. A. Smolen, L. F. Beers, L. Xia, W. Gerald, J. Wang, D. A.
Haber, S. B. Lee, PLoS One 2008, 3, e2353.
[66] D. A. Griffith, S. M. Jarvis, Biochim. Biophys. Acta 1996, 1286, 153–
181.
[67] M. Podgorska, K. Kocbuch, T. Pawelczyk, Acta Biochim. Pol. 2005,
52, 749–758.
[35] Q. Zhao, M. Yu, L. Shi, S. Liu, C. Li, M. Shi, Z. Zhou, C. Huang, F.
Li, Organometallics 2010, 29, 1085–1091.
[68] V. Rolland, M. Kotera, J. Lhomme, Synth. Commun. 1997, 27, 3505–
3511.
[36] K. K.-W. Lo, J. S.-W. Chan, L.-H. Lui, C.-K. Chung, Organometallics
2004, 23, 3108–3116.
[69] M. Nonoyama, Bull. Chem. Soc. Jpn. 1974, 47, 767–768.
[70] E. Baranoff, B. F. E. Curchod, J. Frey, R. Scopelliti, F. Kessler, I.
Tavernelli, U. Rothlisberger, M. Graetzel, Md. K. Nazeeruddin,
Inorg. Chem. 2012, 51, 215–224.
[71] I. Shin, S. Yoon, J. I. Kim, J. Lee, T. H. Kim, H. Kim, Electrochim.
Acta 2011, 56, 6219–6223.
[72] T. Peng, Y. Yang, Y. Liu, D. Ma, Z. Houc, Y. Wang, Chem.
Commun. 2011, 47, 3150–3152.
[73] M. Schmittel, S. Qinghai, Chem. Commun. 2012, 48, 2707–2709.
[74] S. Lamansky, P. Djurovich, D. Murphy, F. Abdel-Razzaq, H. Lee, C.
Adachi, P. E. Burrows, S. R. Forrest, M. E. Thompson, J. Am. Chem.
Soc. 2001, 123, 4304–4312.
[75] E. J. McLaurin, A. B. Greytak, M. G. Bawendi, D. G. Nocera, J. Am.
Chem. Soc. 2009, 131, 12994–13001.
[76] J. N. Demas, G. A. Crosby, J. Phys. Chem. 1971, 75, 991–1024.
[77] S. Hamai, F. Hirayama, J. Phys. Chem. 1983, 87, 83–89.
[78] Bruker Advanced X-ray Solutions, SMART for WNT/2000 (Version
5.628), Bruker AXS, Inc., Madison, WI, 1997–2002.
[79] Bruker Advanced X-ray Solutions, SAINT, Version 6.45, Bruker
AXS, Inc., Madison, WI, 1997–2003.
[80] Bruker Advanced X-ray Solutions, SHELXTL, Version 6.10, Bruker
AXS, Inc., Madison, WI, 2000.
[37] K. K-W. Lo, J. S.-Y. Lau, Inorg. Chem. 2007, 46, 700–709.
[38] K. K-W. Lo, K. Y. Zhang, S.-K. Leung, M.-C. Tang, Angew. Chem.
2008, 120, 2245–2248; Angew. Chem. Int. Ed. 2008, 47, 2213–2216.
[39] K. K.-W. Lo, K. Y. Zhang, C.-K. Chung, K. Y. Kwok, Chem. Eur. J.
2007, 13, 7110–7120.
[40] H.-W. Liu, K. Y. Zhang, W. H.-T. Law, K. K.-W. Lo, Organometallics
2010, 29, 3474–3476.
[41] J.-S. Choi, A. J. Berdis, Future Med. Chem. 2012, 4, 1461–1478.
[42] K. M. Smith, M. D. Slugoski, S. K. Loewen, A. M. Ng, S. Y. Yao,
X. Z. Chen, E. Karpinski, C. E. Cass, S. A. Baldwin, J. D. Young, J.
Biol. Chem. 2005, 280, 25436–25449.
[43] A. J. Berdis, Biochemistry 2008, 47, 8253–8260.
[44] W. Plunkett, V. Gandhi, Hematol. Cell Ther. 1996, 38 Suppl 2, S67–
74.
[45] V. Gandhi, W. Plunkett, Clin. Pharmacokinet. 2002, 41, 93–103.
[46] W. B. Parker, J. A. Secrist 3rd, W. R. Waud, Curr. Opin. Investig.
Drugs 2004, 5, 592–596.
[47] V. Gandhi, W. Plunkett, Curr. Opin. Oncol. 2006, 18, 584–590.
[48] D. S. Gesto, N. M. F. S. A. Cerqueira, P. A. Fernandes, M. J. Ramos,
Curr. Med. Chem. 2012, 19, 1076–1087.
[49] P. W. Marks, Expert Rev. Anticancer Ther. 2012, 12, 299–305.
[50] C. A. Koczor, R. A. Torres, W. Lewis, Expert Opin. Drug Metab.
Toxicol. 2012, 8, 665–676.
[51] T. Robak, P. Robak, Curr. Pharm. Des. 2012, 18, 3373–3388.
[52] Z. L. Johnson, C.-G. Cheong, S.-Y. Lee, Nature 2012, 483, 489–493.
[53] For an alternative metalation, see: A. Maity, B. L. Anderson, N. De-
ligonul, T. G. Gray, Chem. Sci. 2013, 4, 1175–1181.
[81] Gaussian09 (RevisionA.02), M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A.
[54] For examples of cyclometalated iridiumACTHNUTRGNE(UNG III) complexes bearing one
chelating triazole or triazolate ligand, see: a) S. Liu, P. Mꢆller, M. K.
Takase, T. M. Swager, Inorg. Chem. 2011, 50, 7598–7609; b) S. Za-
narini, M. Felici, G. Valenti, M. Marcaccio, L. Prodi, S. Bonacchi, P.
Contreras-Carballada, R. M. Williams, M. C. Feiters, R. J. M. Nolte,
L. De Cola, F. Paolucci, Chem. Eur. J. 2011, 17, 4640–4647; c) B.
Chem. Eur. J. 2013, 19, 15924 – 15932
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15931

A. J. Berdis, T. G. Gray et al.
Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, ꢉ.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox,
Gaussian, Inc., Wallingford CT, 2009.
[86] B. Mennucci, E. Cancꢊs, J. Tomasi, J. Phys. Chem. B 1997, 101,
10506–10517.
[87] S. I. Gorelsky, AOMix: Program for Molecular Orbital Analysis,
York University, Toronto, 1997: http://www.sg-chem.net.
[88] S. I. Gorelsky, A. B. P. Lever, J. Organomet. Chem. 2001, 635, 187–
196.
[82] J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 1996, 77,
3865–3868.
[83] S. Miertus, E. Scrocco, J. Tomasi, Chem. Phys. 1981, 55, 117–129.
[84] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999–
3093.
[85] E. Cancꢊs, B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 107, 3032–
3041.
Received: May 8, 2013
Published online: October 8, 2013
15932
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15924 – 15932