Rhodium(Cp*) compounds with flavone-derived ligand systems: Synthesis and characterization

Article abstract of DOI:10.1002/zaac.201300145

Organometallic rhodium complexes have been reported to exhibit promising anticancer activity and some examples have been investigated more extensively over the last years. Based on recent successes of cytotoxic rhodium compounds, this work describes the synthesis and characterization of organorhodium(III) complexes with 3-hydroxyflavones as bidentate ligands and η⁵- coordinated pentamethylcyclopentadienyl (Cp*). The organorhodium compounds were synthesized and characterized by means of NMR spectroscopy and single crystals of the compounds were characterized by X-ray diffraction analysis. Interestingly, the rhodium complexes were isolated with methanol or triflate coordinated to the central rhodium atom, yielding positively-charged and neutral complexes, respectively. However, none of the complexes prepared were sufficiently soluble in aqueous media to allow testing their cytotoxicity. Copyright

Full text of DOI:10.1002/zaac.201300145

ARTICLE
DOI: 10.1002/zaac.201300145
Rhodium(Cp*) Compounds with Flavone-derived Ligand Systems: Synthesis
and Characterization
Martina B. Schwarz,[a,b] Andrea Kurzwernhart,[a,b] Alexander Roller,[a]
Wolfgang Kandioller,*[a,b] Bernhard K. Keppler,[a,b] and Christian G. Hartinger*[a,b,c]
Keywords: Cancer chemotherapy; Rhodium complexes; Flavonols; NMR spectroscopy; X-ray diffraction analysis
Abstract. Organometallic rhodium complexes have been reported to thesized and characterized by means of NMR spectroscopy and single
exhibit promising anticancer activity and some examples have been
investigated more extensively over the last years. Based on recent suc-
cesses of cytotoxic rhodium compounds, this work describes the syn-
crystals of the compounds were characterized by X-ray diffraction
analysis. Interestingly, the rhodium complexes were isolated with
methanol or triflate coordinated to the central rhodium atom, yielding
thesis and characterization of organorhodium(III) complexes with 3- positively-charged and neutral complexes, respectively. However, none
hydroxyflavones as bidentate ligands and η5-coordinated pentameth-
of the complexes prepared were sufficiently soluble in aqueous media
ylcyclopentadienyl (Cp*). The organorhodium compounds were syn- to allow testing their cytotoxicity.
cisplatin. The lack of interest, especially in RhIII compounds,
Introduction
has been mostly attributed to the kinetic inertness of the metal
compared to PtII, high general toxicity, and low solubility.
More recently, the biological effects of rhodium compounds
have been more thoroughly investigated, especially after the
discovery of the antitumor properties of dirhodium(II) tetra-
carboxylate complexes.[2] However, recent data also suggest
significant tumor-inhibiting potential of RhIII compounds, such
as mer,cis-[RhCl3(DMSO)2(NH3)] with cytotoxicity towards
human ovarian and colon carcinoma cells[3] and the in vivo
active mer-[RhCl3(NH3)3].[2b] Outstanding cytotoxicity
towards MCF-7 and HT-29 cells with IC50 values in the nano-
molar range was reported for RhIII tris(chelates) such as
[Rh{(CH3)2NCS2)2(dppz)]+ (dppz = dipyrido[3,2-a:2Ј,3,3Ј-
c]phenazine) and OC-6-23-[Rh(2-S-py)2(dpq)]+ (2-S-py = pyr-
idine-2-thiolate, dpq = dipyrido[3,2-f:2Ј,3Ј-h]quinoxaline, see
Scheme 1). For the latter quinone derivative, dose-dependent
ROS (reactive oxygen species) levels in Jurkat leukemia
cells support the assumption of an oxidative stress-related
apoptosis mechanism.[4] Other examples comprise mer-
[RhCl3(DMSO)(pp)] with bidentate polypyridyl (pp) ligands
such as 2,2Ј-bipyridyl (bpy), 1,10-phenanthroline (phen), or di-
pyrido[3,2-f:2Ј,3Ј-h]quinoxaline (dpq) with a considerable an-
titumor effect in vitro and in vivo dependent on the ligand
size, as the polypyridyl ligand system is known to be cytotoxic
itself.[2b,5] Bis(bipyridyl)rhodium(III) complexes of the type
cis-[RhCl2(dppz)(phen)]Cl (Scheme 1) were reported by Mor-
rison and co-workers as potential photoactivatable drugs with
cytotoxicity in human lung carcinoma and nasopharyngeal car-
cinoma cells after irradiation at 311 nm. Irradiation induced
covalent binding of the compounds to nucleobase nitrogen
atoms, followed by a rapid photo-induced hydrolysis to the
dicationic aqua species.[6]
Cancer is still one of the most common diseases leading
to death in economically developed countries. Therefore, the
development of potent chemotherapeutics is urgently required.
The platinum complexes cisplatin, carboplatin and oxaliplatin
are the only transition metal compounds that are currently used
for cancer treatment and are among the most widely applied
chemotherapeutics. Platinum complexes are characterized by
several drawbacks comprising low selectivity, adverse effects
and acquired as well as intrinsic resistance of tumors. There-
fore, complexes featuring other central metal atoms than plati-
num have increasingly attracted the interest of researchers
within the last years, with ruthenium and osmium complexes
being among the most promising drug candidates. Two RuIII
compounds, namely NAMI-A and KP1019, passed clinical
phase I trials and are currently in phase I/IIa trials.[1] Much
fewer investigations have been reported on the biological ef-
fects of the neighboring group 9 transition metal rhodium, even
though the antitumor properties of the rhodium(III) complex
RhCl3·3H2O were reported some years before the discovery of
* Dr. W. Kandioller
Fax: +43-1-4277-52680
E-Mail: wolfgang.kandioller@univie.ac.at
* Prof. Dr. C. G. Hartinger
E-Mail: c.hartinger@auckland.ac.nz
[a] University of Vienna
Institute of Inorganic Chemistry
Waehringer Str. 42
1090 Vienna, Austria
[b] University of Vienna
Research Platform “Translational Cancer Therapy Research”
Waehringer Str. 42
1090 Vienna, Austria
[c] The University of Auckland
School of Chemical Sciences
Private Bag 92019
Auckland 1142, New Zealand
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© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Z. Anorg. Allg. Chem. 2013, 639, (8-9), 1648–1654

Rhodium(Cp*) Compounds with Flavone-derived Ligand Systems
Scheme 1. Structures of the RhIII complexes cis-[RhCl2(dppz)(phen)]+, [([9]aneS3)RhCl(bipy)]2+, [(η5-C5Me5)RhCl(phen)]+ (η5-C5Me5 = Cp*)
and OC-6-23-[Rh(2-S-py)2(dpq)]+.
With the rise of bioorganometallic chemistry,[7] organome- been used for centuries for the treatment of human diseases.[14]
tallic rhodium complexes were also studied on their tumor-
inhibiting properties. Compounds featuring the RhIII(Cp*)
structural moiety (Cp* = η5-pentamethylcyclopentadienyl) at-
tached to pp ligands (Scheme 1) show remarkable in vitro anti-
cancer activity in human breast and colon cancer cells with
IC50 values in the low μM range. Good correlation between
their cytotoxicity and the size of the ligand was observed. The
mode of action might be related to intercalation of the conju-
gate aromatic systems in DNA.[8] Similar activity was ob-
served for related [([9]aneS3)RhCl(pp)]Cl2 ([9]aneS3 = 1,4,9-
trithiacyclononane-κ3S, see Scheme 1) derivatives in MCF-7
and HT-29 cells. In dependence of the pp ligand, DNA damage
by intercalation and/or cleavage and an immediate mito-
chondrial response were observed, both leading to
apoptosis.[2b,9] In an attempt to exploit deficiencies in DNA
mismatch repair, Barton and co-workers reported rhodium
metalloinsertors that bind to DNA mismatches with high affin-
ity and specificity in vitro. For this purpose, they used diimine
complexes, which were found to exhibit cell-selective cytoto-
xicity.[10]
To equip metal fragments with bioactive ligands has become
a promising drug development strategy in recent years.[11] This
approach allows introducing additional features to classic
metallodrugs. Flavonoids with anti-inflammatory, anti-allergic,
antifungal, antiviral, antibacterial, antimicrobial, antidiarrheal,
estrogenic, antioxidant, vascular, and anticancer activities[12]
are such an interesting class of ligands. As natural products,
they are present in fruits, nuts, vegetables, seeds, flowers,
stems, tea, wine, and honey, where they are responsible for
many different functions. For example, flavonoids are assumed
to protect from UV-B radiation in leaves as well as act as fun-
gal pathogens. Additionally, they are known to play a crucial
role in the energy transfer, photosensitization, respiration, pho-
tosynthesis and several other processes in plants.[13] Because
3-Hydroxyflavones are of particular interest in coordination
chemistry because of their ability to act as chelating ligands
with their ortho-configured O,O-donor system consisting of a
keto and a hydroxy functional group. Several complexes using
3-hydroxyflavones were reported with metals like RuII,[15]
FeIII,[16] AlIII,[17] ZnII,[18] PbII,[19] MgII, and CuII[20] and
studied with regard to their physical, chemical and biological
properties.[21]
Recently, we reported RuII(η6-arene) complexes bearing 3-
hydroxyflavone ligands, which exhibit high in vitro anticancer
activities and feature the ability to bind to DNA and inhibit
human topoisomerase IIα.[22] Herein, we have extended
this strategy to organorhodium complexes by attaching
3-hydroxyflavone-derived ligands to RhIII(Cp*) moieties.
Results and Discussion
The 3-hydroxyflavone ligands 3a–e were obtained accord-
ing to an established procedure in a two-step synthesis
(Scheme 1).[23] In an aldol condensation 2-hydroxyacetophe-
none (1) was converted with the respective benzaldehyde de-
rivative under alkaline conditions and at room temperature to
yield the intermediate 2-hydroxychalcones 2. In order to iso-
late the solid 2-hydroxychalcones, the solution was acidified
with acetic acid, whereby light yellow solids precipitated. The
precipitate was filtered and used for the second step without
further purification. In a second step the intermediates were
suspended in ethanol and oxidized by hydrogen peroxide under
alkaline conditions in an Algar-Flynn-Oyamada reaction. The
3-hydroxyflavones 3 were obtained after acidification with hy-
drochloric acid and filtration in moderate to good yields (30–
of their biological properties flavonoid-containing drugs have 75%).
Z. Anorg. Allg. Chem. 2013, 1648–1654
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W. Kandioller, C. G. Hartinger et al.
ARTICLE
at around 94 ppm. Compared to the spectra of the ligands, the
signals assigned to C4, C4a, and C3 are shifted by 10–15 ppm
to higher field. The five carbon atoms of the cyclopentadienyl
ring show a doublet around 94 ppm, which was assigned to a
1J(Rh,C) coupling of the aromatic Cp* carbon atoms and the
central 103Rh metal atom [1J(Rh,C) = 8 Hz; Figure 1]. The ob-
served frequency of 8 Hz is in good agreement with literature
data.[25] In the 13C{1H} NMR spectrum of 4b coupling be-
tween the Ph-carbon atoms with the para fluorine atom can be
observed as doublets at δ = 162 ppm [1J(C,F) = 249 Hz, C4’],
130 ppm [3J(C,F) = 9 Hz, C2’ and C6’] and 115.6 ppm
[2J(C,F) = 22 Hz, C3’ and C5’].
Scheme 2. Synthesis of the 3-hydroxyflavone ligands and the respec-
tive RhIII(Cp*) complexes.
1H, 13C{1H}, and 2D NMR spectroscopy as well as elemen-
tal analysis were used to characterize the obtained compounds.
The peaks of the hydroxyl protons are typically detected in the
range of 8.20–9.90 ppm. 2D NMR spectroscopy was employed
to assign signals of the protons H5, H6, H7, and H8. In the
spectrum of ligand 4b, the protons H2’/H6’ and H3’/H5’ show
a quadruplet and a multiplet instead of a doublet because of
additional couplings with the fluoro substituent in para posi-
tion [4J(F,H) = 6 Hz, H2’/H6’]. In the 13C{1H} NMR spectra,
Figure 1. 13C{1H} NMR spectrum of 4c. The inset shows the
1J(Rh–C) coupling.
Suitable crystals of 4a–e for X-ray diffraction analysis were
the signals of the C=O groups are found around 173 ppm. An grown by slow diffusion of diethyl ether into methanol solu-
interesting feature is the coupling of C4’, C2’/C6’, and C3’/ tions of the complexes at 4 °C (Figure 2). The organorhodium
C5’ with the fluoro substituent which gave doublets rather than compounds adopt the pseudo-octahedral “piano-stool” config-
3
singlets for these carbon atoms [1J(C4’,F) = 249 Hz, J(C2’/ uration, with the facially coordinated aromatic pentamethylcy-
2
C6’,F) = 9 Hz, J(C3’/C5’,F) = 22 Hz].
clopentadienyl rest acting as the seat and the three remaining
The deprotonated cyclopentadienyl donates six electrons to coordination sites represent the legs. These half sandwich com-
the central metal atom and pentamethylcyclopentadienyl com- plexes with different coordinated mono- or bidentate ligands
plexes are additionally stabilized by the five methyl groups next to the arene are chiral molecules and normally the two
with their electron-donating effect. Bis[dichlorido(η5-penta- enantiomers are obtained in a racemic form during the synthe-
methylcyclopentadienyl)rhodium(III)] was synthesized by sus- sis. In the case of 4a–e, the two stereoisomers co-crystallized
pending the violet crystals of RhCl3·H2O in methanol and re- in a ratio of 1:1 in the unit cell. Complex 4a crystallized in
¯
fluxing the mixture for 24 h after addition of pentamethylcy- the triclinic space group P1, whereas 4b–e form monoclinic
clopentadiene. The red solid product was obtained in high pu- crystals in the space groups P21/c (4b, 4c, and 4d) and P21/n
rity and 75% yield by filtration without further purification.[24] (4d) (Table 1).
[Rh(Cp*)Cl2]2 was suspended in methanol with a slight excess
The coordination of the organorhodium fragment to the an-
of the flavonoid 3a–e, sodium methoxide, and silver trifluoro- ionic ligand yielded a non-planar five-membered ring, with
methanesulfonate and refluxed for about 18 h. Filtration, ex- different Rh–O bond lengths of the O,O-chelates to the central
traction with dichloromethane and recrystallization from meth- metal atom. Only small torsion angles of the substituted phenyl
anol/diethyl ether by diffusion at 4 °C gave compounds 4a–e rings of the flavone were found (Table 2) and due to the re-
with trifluoromethanesulfonate either in the first coordination sulting nearly planar ligands, π-stacking of the aromatic flav-
1
sphere or as a counterion. In order to assign all signals in H ones was observed (Figure 3). In the case of 4a and 4e, MeOH
and 13C{1H} NMR, 1H,1H-COSY, HMBC, and HSQC 2D was found coordinated to the central RhIII atom with
NMR experiments were conducted. The 13C{1H} NMR spectra Rh–O(MeOH) bond lengths of 2.1884(12) Å (4a) and
show a singlet for the CH3 groups of the cyclopentadienyl li- 2.177(3) Å (4e) and triflate acts as the counterion to the posi-
1
gand at about 9 ppm (in H NMR a singlet at ca. 1.8 ppm was tively charged complexes. In the case of 4b, 4c, and 4d, κ-O
found) and the five cyclopentadiene ring carbon atoms appear coordination of the counterion triflate was demonstrated by X-
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Z. Anorg. Allg. Chem. 2013, 1648–1654

Rhodium(Cp*) Compounds with Flavone-derived Ligand Systems
Figure 2. X-ray structures of 4a–e drawn at 50% probability level.
Table 1. Crystallographic data and details of data collection for 4a–e.
4a
4b
4c
4d
4e
Empirical formula
C28.50H32F3O7.50RhS C26H23F4O6RhS
C26H23ClF3O6RhS
658.86
C26H23BrF3O6RhS
703.32
C30H34F3O10RhS
746.54
Formula weight /g·mol–1
686.51
642.41
Temperature /K
100(2)
100(2)
100(2)
100(2)
100(2)
Wavelength /Å
0.71073
0.71073
0.71073
0.71073
0.71073
Crystal size /mm
Crystal system
Space group
0.15ϫ0.15ϫ0.15
triclinic
P1
0.13ϫ0.10ϫ0.01
monoclinic
P21/c
0.15ϫ0.12ϫ0.12
monoclinic
P21/c
0.40ϫ0.13ϫ0.03
monoclinic
P21/c
0.20ϫ0.20ϫ0.20
monoclinic
P21/n
¯
a /Å
b /Å
c /Å
α /°
8.3638(4)
12.7551(7)
13.4080(7)
82.061(3)
88.640(3)
89.160(3)
1416.18(13)
2
8.3551(3)
20.4778(8)
14.7587(5)
90
96.201(2)
90
2510.35(16)
4
1.700
8.3505(4)
20.8885(12)
14.7677(8)
90
98.438(2)
90
2548.0(2)
4
1.718
8.3895(4)
21.2582(11)
14.8896(7)
90
99.497(3)
90
2619.1(2)
4
1.784
10.5719(6)
23.8335(15)
12.3925(7)
90
91.066(4)
90
3121.9(3)
4
1.588
β /°
γ /°
Volume /Å3
Z
Calculated density /mg·m–3
1.610
Absorption coefficient /mm–1 0.744
0.834
0.920
2.319
0.688
F(000)
702
1296
1328
1400
1528
θ Range for data collection /° 2.85–30.15
2.43–30.11
–11 Յ h Յ 11
–28 Յ k Յ 28
–20 Յ l Յ 20
46924 / 7373
7373 / 0 / 348
0.0895
2.40–30.11
–11 Յ h Յ 11
–29 Յ k Յ 29
–20 Յ l Յ 20
92704 / 7472
7472 / 0 / 348
0.0456
2.37–26.00
–8 Յ h Յ 10
–26 Յ k Յ 26
–18 Յ l Յ 18
63337 / 5149
5149 / 0 / 348
0.1307
2.11–26.00
–13 Յ h Յ 13
–29 Յ k Յ 29
–15 Յ l Յ 15
90008 / 6162
6162 / 1 / 412
0.1558
Index ranges
–11 Յ h Յ 11
–18 Յ k Յ 17
–18 Յ l Յ 18
Reflections collected / unique 39315 / 8301
Data / restraints / parameters
R(int)
8301 / 1 / 373
0.0899
1.015
Goodness-of-fit on F2 a)
0.989
0.998
1.057
1.027
b)
Final R indices [I Ͼ 2σ(I)]
R1
wR2
0.0359
0.0900
0.0408
0.0768
0.0220
0.0551
0.0437
0.0930
0.0484
0.1094
a) GOF = {Σ[w(Fo – Fc ) ] /(n – p)}1/2, where n is the number of reflections and p is the total number of parameters refined. b) R1 = Σ||Fo| –
2
2 2
|Fc||/Σ|Fo|. wR2 = {Σ[w(Fo – Fc ) ]/Σ[w(Fo ) ]}1/2
.
2
2 2
2 2
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W. Kandioller, C. G. Hartinger et al.
Table 2. Key bond lengths /Å and angles /° of 4a–e (the numbering scheme is equivalent to that used for NMR signal assignment).
ARTICLE
Bond length, angles
4a
4b
4c
4d
4e
Rh–O(C=O···)
Rh–O(C–O···)
Rh–O(MeOH/triflate)
Rh–Cp*(centroid)
O1–C2–C1’–C6’
2.1268(14)
2.0511(14)
2.1884(12)
1.740
2.116(2)
2.0616(19)
2.2208(18)
1.731
2.1200(10)
2.0678(10)
2.2176(10)
1.733
2.129(3)
2.082(3)
2.225(3)
1.743
2.128(3)
2.066(3)
2.177(3)
1.743
2.8(2)
1.7(4)
–1.51(17)
2.8(6)
–1.2(5)
ray diffraction analysis resulting in overall neutral complexes. opment of new anticancer drugs is essential. The combination
The Rh–O(triflate) distances were found at 2.2208(18) Å (4b), of biologically active ligand systems, such as flavonoid ligands
2.2176(10) Å (4c), and 2.225(3) Å (4d) and were significantly with metal fragments, has been shown to be a promising strat-
longer than Rh–O(MeOH) bonds. However, this does not in- egy to obtain compounds with new properties. Flavonoids, a
fluence the two remaining Rh–O bonds between the central class of secondary metabolites of plants, show properties,
metal atom and the flavone ligand, which are in the same range which make them interesting for the use as chelating ligands
for all investigated compounds. The phenolic Rh–O1 bond is in the design of novel chemotherapeutics as they exhibit them-
significantly shorter than the interaction of the 4-keto group to selves anticancer activity. Herein, the synthesis and characteri-
the central metal atom (Rh–O2) for 4a–e, which is in good zation of RhIII(Cp*) complexes with a series of substituted 3-
agreement with data of structurally-related RuII(η6-p-cymene) hydroxyflavone ligands was presented. The 3-hydroxyflavones
complexes bearing 3-hydroxyflavones as chelating ligands.[22] were synthesized in an aldol condensation and subsequent
The neutral triflate complexes 4b–d feature short contacts be- Algar-Flynn-Oyamada reaction to yield the desired product in
tween the triflate oxygen atoms and the Cp*-methyl groups of moderate to good yields. The Rh(Cp*) complexes were ob-
an adjacent molecule, whereas the charged methanol coordi- tained by reaction of the ligands with bis[dichlorido(η5-penta-
nated compounds 4a and 4e with triflate as the counterion in- methylcyclopentadiene)rhodium(III)] under alkaline conditions
teract via fluorides of the anion.
and were characterized by standard analytical methods. All of
the compounds were characterized by X-ray diffraction analy-
sis showing the expected pseudo octahedral piano-stool config-
uration. According to the HSAB theory, rhodium is a harder
acid compared to FeII or RuII with a high charge density while
oxygen is considered a hard base. Therefore, the coordination
of the O,O-chelating 3-hydroxyflavones to the central metal
atom resulted in stable complexes. Unfortunately, the
(η5-Cp*)rhodium(III) complexes exhibit only very limited sol-
ubility in aqueous solution. Therefore, anticancer activity as-
says were not feasible and modifications of the ligands to pro-
vide higher hydrophilicity are required.
Experimental Section
Materials and Methods: 2-Hydroxyacetophenone (Fluka, Acros
Organics), p-toluolaldehyde (Acros Organics), 4-fluorobenzaldehyde
(Fluka), 4-chlorobenzaldehyde (Fluka), 3,4,5-trimethoxybenzaldehyde
(Aldrich), 4-bromobenzaldehyde (Fluka), rhodium(III)chloride (Ald-
rich), 1,2,3,4,5-pentamethylcyclopentadiene (Alrich), and sodium
methoxide (Aldrich) were purchased and used without further purifica-
tion.
Figure 3. π-Stacking interactions in the X-ray structure of 4c.
Solubility is an important parameter in drug development
and to translate a component to clinical studies, especially if
considering intravenous administration. Drug candidates for
cancer treatment need to be soluble in buffers at physiological
pH, in which they can be used for both in vitro testing in
cancer cells and at a later stage for being administered to the
patients. Unfortunately, the synthesized rhodium compounds
Melting points were determined with a Büchi Melting Point B-540
apparatus. Elemental analyses were done by the Microanalytical Labo-
ratory of the University of Vienna with a Perkin-Elmer 2400 CHN
showed insufficient solubility in aqueous media and therefore Elemental Analyser. NMR spectra were recorded with a Bruker FT-
NMR spectrometer Avance IIITM 500 MHz at 25 °C. 1H NMR spectra
no in vitro anticancer activity assays could be conducted.
measurements were performed at 500.10 MHz and 13C{1H} NMR
spectra at 125.75 MHz in [D6]DMSO (for ligands) and CD3OD or
CDCl3 (for complexes). The 2D NMR spectra were measured applying
a gradient-enhanced mode. The 3-hydroxyflavones and bis[dichlori-
do(η5-pentamethylcyclopentadienyl)rhodium(III)] were synthesized
Conclusions
As cancer is one of the most common causes of death and
many types of tumor are still insufficiently treatable, the devel- according to literature procedures.[22, 24]
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Rhodium(Cp*) Compounds with Flavone-derived Ligand Systems
For X-ray diffraction analysis single crystals of the respective complex
ral procedure, using bis[dichlorido(η5-pentamethylcyclopentadienyl)-
were selected for measurement with a Bruker X8 APEX II CCD dif- rhodium(III)] (50 mg, 0.081 mmol), 3-hydroxy-2-(4-fluorophenyl)-
fractometer at 100 K. Single crystals were positioned at 35 mm from 4H-chromen-4-one (46 mg, 0.18 mmol), silver trifluoromethanesulfon-
the detector and 1319 frames for 5 s exposure time over 1° scan width ate (102 mg, 0.395 mmol), and sodium methoxide (11 mg,
were measured for 4a, 988 frames for 50 s over 1° scan for 4b, 1684 0.198 mmol). Yield: 46 mg (41%), red crystals; melting point: 147–
3
frames for 30 s over 1° scan for 4c, 1471 frames for 10 s over 1° scan 149 °C. 1H NMR (500.10 MHz, CD3OD): δ = 8.70–8.73 [dd, J(H,H)
4
3
for 4d, at 40 mm from the detector and 2147 frames for 20 s over 1° = 9 Hz, J(H,F) = 4 Hz, 2 H, H2’/H6’], 8.21 [d, J(H,H) = 8.0 Hz, 1
scan for 4e.
H, H5], 7.72–7.78 (m, 2 H, H6/H8), 7.46 [dd, 3J(H,H) = 7 Hz, 3J(H,H)
= 7 Hz, 1 H, H7], 7.26 [dd, 3J(H,H) = 9 Hz, 3J(H,F) = 9 Hz, 2 H,
H3’H5’], 1.79 (s, 15 H, Cp*) ppm. 13C{1H } NMR (125.75 MHz,
[D6]DMSO): δ = 182.0 (C4), 162.1 [d, J (C,F) = 249 Hz, C4’], 153.5
(C3), 146.0 (C4a), 133.2 (C6), 129.1 (C2), 128.8 [d, J(C,F) = 8 Hz,
C2’/C6’], 124.5 (C5), 123.9 (C7), 119.6 (C8a), 118.3 (C8), 115.4 [d,
2J(C,F) = 22 Hz, C3’/C5’], 98.8 [d, 1J(Rh–C) = 8 Hz, Cp*], 8.6
(Cp*–CH3) ppm.
Crystallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallographic
Data Centre, CCDC, 12 Union Road, Cambridge CB21EZ, UK.
Copies of the data can be obtained free of charge on quoting the
depository numbers CCDC-927588 (4b), -927587 (4a), -927586 (4c),
-927585 (4d) -927584 (4e) (Fax: +44-1223-336-033; E-Mail:
deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk).
1
3
[3-(Oxo-κO)-2-(4-chlorophenyl)-chromen-4-onato-κO](η5-penta-
methylcyclopentadienyl) (trifluoromethanesulfonato-κO)-
rhodium(III) (4c): The reaction was performed according to the gene-
ral procedure, using bis[dichlorido(η5-pentamethylcyclopentadienyl)-
rhodium(III)] (200 mg, 0.324 mmol), 3-hydroxy-2-(4-chlorophenyl)-
4H-chromen-4-one (252 mg, 0.719 mmol), silver trifluoromethanesul-
fonate (406 mg, 1.582 mmol), and sodium methoxide (43 mg,
0.791 mmol). Yield: 154 mg (36%), red crystals, melting point: 142–
144 °C. Elemental analysis for C26H23ClF3O6RhS: calcd. C 47.40, H
3.52, S 4.87, O 14.57%; found: C 47.14, H 3.45, S 4.82, O 14.69%.
The following numbering scheme was used for NMR signal assign-
ment:
3
1H NMR (500.10 MHz, CD3OD): δ = 8.70 [d, J(H,H) = 9 Hz, 2 H,
3
H2’/H6’], 8.26 [d, J(H,H) = 9 Hz, 1 H, H5], 7.79–7.83 (m, 2 H, H6/
3
H8), 7.55–7.58 (m, 2 H, H3’/H5’), 7.52 [t, J(H,H) = 8 Hz, 1 H, H7],
1.82 (s, 15 H, Cp*) ppm. 13C{1H } NMR (125.75 MHz, CD3OD): δ
= 184.5 (C4), 155.6 (C4a), 155.0 (C3), 150.0 (C4’), 136.9 (C1’), 135.2
(C6), 132.1 (C2), 130.0 (C3’/C5’), 129.8 (C2’/6’), 126.3 (C7), 125.0
(C5), 121.2 (C8a), 119.4 (C8), 94.2 [d, 1J(Rh–C) = 8 Hz, Cp*], 8.9
(Cp*–CH3) ppm.
General Procedure for the Synthesis of (η5-Pentamethylcyclopen-
tadienyl)rhodium(III) Complexes 4a–e: Bis[dichlorido(η5-penta-
methylcyclopentadienyl)rhodium(III)] (0.45 equiv.) was suspended in
methanol (25 mL) and added to a solution of flavonoid (1 equiv.), acti-
vated by addition of sodium methoxide (1.1 equiv.), and silver
trifluoromethanesulfonate (2.2 equiv.). The reaction mixture was re-
fluxed for 18 h in an argon atmosphere. The formed silver chloride
was filtered off and the solvent was removed under reduced pressure.
The product was dissolved in dichloromethane, filtered, and concen-
trated. The pure product was crystallized by slow diffusion from meth-
anol/diethyl ether.
[3-(Oxo-κO)-2-(4-bromophenyl)-chromen-4-onato-κO](η5-penta-
methylcyclopentadienyl)(trifluoromethanesulfonato-κO)-
rhodium(III) (4d): The reaction was performed according to the gene-
ral procedure, using bis[dichlorido(η5-pentamethylcyclopentadienyl)-
rhodium(III)] (50 mg, 0.081 mmol), 3-hydroxy-2-(4-bromophenyl)-
4H-chromen-4-one (57 mg, 0.18 mmol), silver trifluoromethanesulfon-
ate (102 mg, 0.395 mmol), and sodium methoxide (11 mg,
0.198 mmol). Yield: 47 mg (42%), red needles, melting point: 211–
213 °C. Elemental analysis for C26H23BrF3O6RhS: calcd. C 44.40, H
3.30, S 4.59, O 13.65%; found: C 44.37, H 3.36, S 4.21, O 13.70%.
{[3-(Oxo-κO)-2-(4-methylphenyl)-chromen-4-onato-κO](η5-penta-
methylcyclopentadienyl)(methanol-κO)rhodium(III)}trifluoro-
methanesulfonate (4a): The reaction was performed according to the
general procedure, using bis[dichlorido(η5-pentamethylcyclopen-
tadienyl)rhodium(III)] (50 mg, 0.081 mmol), hydroxy-2-(4-meth-
ylphenyl)-4H-chromen-4-one (45 mg, 0.18 mmol), silver trifluorome-
thanesulfonate (102 mg, 0.395 mmol), and sodium methoxide (11 mg,
0.198 mmol). Yield: 80 mg (74%), red crystals; melting point: 176–
178 °C. Elemental analysis for C28H30F3O7RhS: calcd. C 50.16, H
4.51, S 4.78%; found: C 50.05, H 4.33, S 4.79%. 1H NMR
3
1H NMR (500.10 MHz, CD3OD): δ = 8.63 [d, J(H,H) = 9 Hz, 2 H,
3
H2’/H6’], 8.26 [d, J(H,H) = 9 Hz, 1 H, H5], 7.79–7.84 (m, 2 H, H6/
H8), 7.71–7.74 (m, 2 H, H3’/H5’), 7.54–7.50 (m, 1 H, H7), 1.81 (s,
15 H, Cp*) ppm. 13C{1H} NMR (125.75 MHz, CD3OD): δ = 184.4
(C4), 155.6 (C4a), 155.1 (C3), 150.1 (C4’), 135.1 (C6), 132.8 (C3’/
C5’), 132.4 (C1’), 130.2 (C2’/C6’), 126.3 (C7), 125.2 (C2), 125.0
(C5), 121.2 (C8a), 119.4 (C8), 94.3 [d, 1J(Rh–C) = 8 Hz, Cp*], 8.9
(Cp*–CH3) ppm.
3
(500.10 MHz, CD3OD): δ = 8.59 [d, J(H,H) = 8 Hz, 2 H, H2’/H6’],
3
8.24 [d, J(H,H) = 9 Hz, 1 H, H5], 7.77–7.81 (m, 2 H, H6/H8), 7.49–
3
{[3-(Oxo-κO)-2-(3,4,5-trimethoxyphenyl)-chromen-4-onato-κO]
(η5-pentamethylcyclopentadienyl) (methanol-κO)rhodium(III)}-
trifluoromethanesulfonate (4e): The reaction was performed accord-
ing to the general procedure, using bis[dichlorido(η5-pentamethylcy-
clopentadienyl)rhodium(III)] (70 mg, 0.113 mmol), 3-hydroxy-2-
(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (83 mg, 0.252 mmol),
silver trifluoromethanesulfonate (142 mg, 0.554 mmol), and sodium
methoxide (15 mg, 0.277 mmol). Yield: 51 mg (30%), red needles;
melting point: 166–168 °C. 1H NMR (500.10 MHz, CD3OD): δ = 8.25
[dd, 4J(H,H) = 1 Hz, 3J(H,H) = 8 Hz, 1 H, H5], 8.13 (s, 2 H, H2’/
7.52 (m, 1 H, H7), 7.38 [d, J(H,H) = 8 Hz, 2 H, H3’/H5’], 2.44 (s, 3
H, 4’CH3), 1.81 (s, 15 H, Cp*) ppm. 13C{1H } NMR (125.75 MHz,
CD3OD): δ = 183.7 (C4), 155.3 (C4a), 154.5 (C3), 151.9 (C4’), 142.0
(C1’), 134.6 (C6), 130.6 (C2), 130.3 (C3’/C5’), 128.8 (C2’/C6’), 126.2
1
(C7), 124.8 (C5), 121.3 (C8a), 119.2 (C8), 94.1 [d, J(Rh–C) = 8 Hz,
Cp*], 21.6 (4’-CH3), 8.9 (Cp*–CH3) ppm.
[3-(Oxo-κO)-2-(4-fluorophenyl)-chromen-4-onato-κO](η5-penta-
methylcyclopentadienyl) (trifluoromethanesulfonato-κO)-
rhodium(III) (4b): The reaction was performed according to the gene-
Z. Anorg. Allg. Chem. 2013, 1648–1654
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.zaac.wiley-vch.de
1653

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ARTICLE
H6’), 7.86–7.77 (m, 2 H, H6/H8), 7.51 [ddd, 3J(H,H) = 8 Hz, J(H,H)
3
4
= 7 Hz, J(H,H) = 1 Hz, 1 H, H7], 3.99 (s, 6 H, 3’/5’–CH3), 3.88 (s,
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151.1 (C3), 141.3 (C1’), 134.8 (C6), 128.8 (C2), 126.3 (C7), 124.9
1
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Acknowledgements
We thank Prof. Vladimir Arion for the refinement of the X-ray diffrac-
tion data, and the Johanna Mahlke neé. Obermann Foundation, the
Hochschuljubiläumsstiftung Vienna, the Genesis Oncology Trust,
COST D39, CM1105, and CM0902 for financial support.
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Received: March 8, 2013
Published Online: May 24, 2013
1654
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© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Z. Anorg. Allg. Chem. 2013, 1648–1654