Synthesis, characterisation and cytotoxicity studies of ruthenium arene complexes bearing trichlorogermyl ligands

Article abstract of DOI:10.1016/j.ica.2018.09.019

The synthesis of five half sandwich ruthenium(II) trichlorogermyl complexes of the type [(η⁶-Arene)Ru(PR₃)Cl(GeCl₃)] (PR₃ = Phosphane and phosphite ligands; Arene = p-cymene or C₆H₅-OC

Full text of DOI:10.1016/j.ica.2018.09.019

Accepted Manuscript
Synthesis, Characterisation and Cytotoxicity Studies of Ruthenium Arene Com-
plexes Bearing Trichlorogermyl Ligands
Connor Deacon-Price, Dario Romano, Tina Riedel, Paul J. Dyson, Burgert Blom
PII:
S0020-1693(18)31159-9
https://doi.org/10.1016/j.ica.2018.09.019
ICA 18477
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 July 2018
5 September 2018
6 September 2018
Please cite this article as: C. Deacon-Price, D. Romano, T. Riedel, P.J. Dyson, B. Blom, Synthesis, Characterisation
and Cytotoxicity Studies of Ruthenium Arene Complexes Bearing Trichlorogermyl Ligands, Inorganica Chimica
Acta (2018), doi: https://doi.org/10.1016/j.ica.2018.09.019
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Synthesis, Characterisation and Cytotoxicity Studies of
Ruthenium Arene Complexes Bearing Trichlorogermyl
Ligands
Connor Deacon-Price,[a] Dario Romano,[b] Tina Riedel,[c] Paul J. Dyson,[c] Burgert Blom *[a]
[a]
burgert.blom@maastrichtuniversity.nl
Faculty of Science and Engineering, Maastricht Science Programme (MSP), Maastricht University, P.O. Box 616
6200 MD, Maastricht, the Netherlands
[b]
Aachen Maastricht Institute for Biobased Materials
Faculty of Science and Engineering, Maastricht University, Brightlands Chemelot Campus
Urmonderbaan 22, 6167 RD Geleen, the Netherlands
[c]
Institut des Sciences et Ingénierie Chimiques,
Ecole Polytechnique Fédérale de Lausanne (EPFL),CH•1015 Lausanne, Switzerland
Keywords: bioorganometallic chemistry • ruthenium complexes • cytotoxicity studies • trichlorogermyl ligand • insertion•
group 14 chemistry
Supporting Material is available containing the Cartesian coordinates of the DFT optimised structures.
Abstract: The synthesis of five half sandwich ruthenium(II) trichlorogermyl complexes of the type [(η6-
Arene)Ru(PR3)Cl(GeCl3)] (PR3 = Phosphane and phosphite ligands; Arene = p-cymene or C6H5-
OC2H4OH)
is
reported:
(2),
[(η6-p-cymene)Ru(P(OMe)3)Cl(GeCl3)]
[(η6-p-cymene)Ru(PPh3)Cl(GeCl3)]
(1),
(3),
[(η6-p-
[(η6-p-
cymene)Ru(P(OPh)3)Cl(GeCl3)]
cymene)Ru(pta)Cl(GeCl3)] (pta
=
1,3,5-triaza-7-phosphaadamantane) (4) and [(η6-C6H5-
OC2H4OH)Ru(pta)Cl(GeCl3)] (5). The nature of the 6-arene and phosphane ligand was varied and the
.
complexes have been prepared by facile insertion of GeCl2 (from GeCl2 (dioxane)) into the Ru-Cl
bonds of the respective easily accessible precursor complexes [(η6-Arene)Ru(PR3)Cl2]. The
1

1
complexes were fully spectroscopically characterized by H, 13C{1H} and 31P{1H} NMR spectroscopy,
UV-Vis, ATR-IR, HRMS (ESI) and their thermal behavior elucidated by TGA. Their cytotoxicity to
human ovarian carcinoma (A2780) and non-tumorigenic human embryonic kidney HEK293 cell lines is
also reported, and represents the first cytotoxic investigations of Ru(II) germyl complexes to date. The
first DFT studies (B3LYP; basis set 6- 31+G(d,p) for H, C, O, P, Cl, N, and Ge atoms and DGDZVP for
Ru atom) on trichlorogermyl ruthenium complexes were carried out on complex 2 and 5 in order to
gain insights into the bonding situation between Ru and Ge and are reported.
2

1. Introduction
Cancer is amongst one of the most critical challenges that face society. Approximately 8.2 million
deaths worldwide were caused by the disease in 2012 [1]. Of those treated, approximately half will
receive some form of chemoradiotherapy [2]. Amongst the most common chemotherapeutic agents
are platinum based compounds and half of all cancer patients that undergo chemotherapy will receive
treatment with a platinum based antineoplastic agent [3]. Of particular note is the drug cis-platin, which
has retained its position of prominence since its anticancer properties were discovered almost fifty
years ago. [4,5] Despite being one of the most potent anticancer drugs [6], there are several key
issues that surround the use of cis-platin, and other platinum based antineoplastics in chemotherapy.
These include cancer’s building resistances [7,8], and the vast array of side effects that they cause [9].
It is apparent that alternatives to platinum based antineoplastics are required, specifically involving in
the substitution of platinum for other transition metals [10]. This has led to the development of
ruthenium based antineoplastics [11]. These compounds display a variety of advantages over that of
platinum based chemotherapeutics. These include a mechanism of action that limits toxicity and
maximises specificity [12-20], having ideal ligand exchange rate properties [21-24], and possessing a
highly
customizable
structure
in
terms
of
ligand
design
[25-27].
A promising example of a ruthenium based antineoplastic is RAPTA-C. When given in combination
with other anticancer drugs, RAPTA-C is observed to effect a reduction in tumour growth by 80%, in
very low dosages with the absence of side effects [28]. Such promising results informed our decision
to base new complexes on the structure of RAPTA-C (Chart 1).
Chart 1. Structure of RAPTA-C, a promising anticancer agent.
It has been found that the presence of trichlorostannyl groups in the ligand sphere of Ru(II) arene
complexes can increase the cytotoxicity of ruthenium-arene drugs [29a-b]. Despite these encouraging
results, little further work has been reported in this regard. In particular, substitution of Sn with Ge
might afford complexes that also exhibit enhanced cytotoxic properties, with the advantage of possibly
3

being more selective towards cancer cells. To our knowledge, no previous study has been conducted
on elucidating the cytotoxicity of ruthenium based complexes bearing germanium ligands in the ligand
sphere of Ru(II), and herein we report the first such study. A series of novel trichlorogermyl complexes
of the type [(η6-Arene)Ru(PR3)Cl(GeCl3)] (PR3 = Phosphane and phosphite ligands; Arene = p-cymene
or C6H5-OC2H4OH) have been prepared in a facile way by facile insertion reactions of GeCl2 into the
Ru-Cl bonds of easily accessible precursor complexes [(η6-Arene)Ru(PR3)Cl2] affording the complexes
[(η6-Arene)Ru(PR3)Cl(GeCl3)] (Figure 1) [30]. Both arene and phosphane have been modulated and
their cytotoxicity towards human ovarian carcinoma (A2780) and non-tumorigenic human embryonic
kidney HEK293 cell lines is reported.
Figure 1. All synthesized complexes in this report (1 - 5): 1 – [η6-p-cymene)Ru(P(OMe)3)Cl(GeCl3)]; 2 – [(η6-p-
cymene)Ru(P(OPh)3)Cl(GeCl3)]; 3 – [(η6-p-cymene)Ru(PPh3)Cl(GeCl3)]; 4 – [(η6-p-cymene)Ru(pta)Cl(GeCl3)]; 5 –
[(η6-C6H5-OC2H4OH)Ru(pta)Cl(GeCl3)].
(Where
pta
is
1,3,5-triaza-7-phosphaadamantane,C6H12N3P).
2. Experimental Section
2.1 General Experimental Section
All experiments and manipulations that involved the germanium(II) chloride dioxane complex (1:1)
were performed under anaerobic conditions using a Saffron Scientific Equipment Ltd. DAB01S Glove
Box and/or standard Schlenk techniques with dry nitrogen as an inert atmosphere in dried and
degassed dichloromethane. All other experiments and manipulations were performed in either
dichloromethane, or a mixture of dichloromethane and methanol. Standard workup protocols were
4

utilized to acquire the desired complexes, with specific reactions shown by scheme 2. All reagents
used were purchased from Sigma-Aldrich. [(η6-p-cymene)Ru(P(OMe)3)Cl2] [31] and [(η6-p-
cymene)Ru(P(OPh)3)Cl2] [31] which were synthesized in prior experiments by associated research
groups
within
the
same
laboratory.
NMR spectra were recorded using a Bruker UltraShield 300 and Bruker Avance III HD Spectrometer,
in WG-1000-7 5mm NMR sample tubes. This hardware was run on and the data acquired processed
on Bruker’s TopSpin 3.1 software. 1H and 13C{1H} spectra were calibrated using residual solvent peaks
for reference, when possible. This was done for all solvents: chloroform-d (δH 7.26 ppm; δC 77.2
ppm), dimethyl sulfoxide-d6 (δH 2.50 ppm; δC 39.5 ppm), and deuterium oxide (δH 4.79 ppm). In
cases where complexes were only sparingly soluble filtration was performed to remove any solids,
allowing for an entirely liquid phase sample. Abbreviations: s = singlet; d = doublet; t = triplet, q =
quartet, ABq = AB quartet; sept = septet; m = multiplet; br = broad; v = very. All coupling constants are
quoted in Hz. In the case of broad signals, half height widths (Δv 1/2) are also quoted in Hz. Through
the use of 2-D spectra, including H,H COSY, H,C HSQC, and H,C HMBC, unambiguous signal
assignments can be made. However, it should be noted that not all complexes have had such analysis
techniques implemented. A and B superscripts denote diastereotopic groups, often relating to methyl
1
groups present on η6-p-cymene after a group 4 dihalide insertion has been successfully executed. H
NMR was recorded at 300.1 MHZ, 13C{1H}NMR was recorded at 75.5 MHz, and 31P{1H}NMR was
recorded at 121.5 MHz. All NMR results were recorded between 297 K and 301 K.
Melting points were acquired through slow heating in capillary tubes using the Stuart SMP10 melting
point apparatus. All complex samples undergo decomposition rather than melting, which is denoted as
“+ dec.”. High resolution Electron Ionisation Spray (ESI) mass spectra were recorded using an
Orbitrap LTQ XL of Thermo Scientific mass spectrometer at the Technische Universitaet Berlin. Raw
data was evaluated and processed using the X-calibur computer program. In all cases the isotope
distribution pattern of the signal was checked against theory . All values reported related to the line of
highest intensity. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) was
carried out using Shimadzu’s IRAffinity-1S Fourier Transform Spectrometer coupled with a MIRacle 10
Single Reflection ATR accessory, using Shimadzu’s IRsolution (version 1.60) software to analyse and
process raw data. Specifications are as follows: % Transmission; Apodization - Happ-Genzel; 64
scans per measurement. Abbreviations: w = weak; m = medium; s = strong; v = very; br = broad.
5

Background spectra were recorded before measurements were made, using ethanol to prepare the
sample area.
Ultraviolet–visible spectroscopy (UV-vis) was recorded using Shimadzu’s UV-3600 Plus, UV-vis-NIR
Spectrophotometer coupled with LISR-3100 for diffuse reflectance measurement, with raw data being
analysed and processed using Shimadzu’s UVProbe (version 2.42) software. Scans were run from
750 – 200 nm, with the scan speed set at medium and scan intervals set at 0.5 nm. The solvents used
is dependent on the complex being measured, as solubility between complexes can vary widely.
Thermogravimetric analysis (TGA) was recorded using TA Instrument’s Q500 Thermogravimetric
Analyzer, with raw data being analysed and processed using TA Instrument’s Universal Analysis 2000
(version 4.5A, build 4.5.0.5) software. Measurements were performed between room temperature and
500 °C, as to exceed this temperature may cause damage to the device.
2.2 Density Functional Theory Calculations
DFT calculations were performed to model the complexes 2 and 5. Guassian09 software package was
used. For all the calculations, the level of theory used for all calculations is B3LYP [40] with the basis
set 6- 31+G(d,p) for H, C, O, P, Cl, N, and Ge atoms and DGDZVP for Ru atom. Geometry
optimizations were calculated without any constrains. Energies and Natural Bond Order analyses were
calculated on the optimized structures.
2.3 Cell culture and inhibition of cell growth
The human A2780 ovarian carcinoma and HEK embryonic kidney cells were obtained from the
European Collection of Cell Cultures (Salisbury, U.K.). A2780 and A2780cisR cells were grown
routinely in RPMI-1640 medium, while HEK cells were grown in DMEM medium, with 10% fetal
bovine serum (FBS) and 1 % antibiotics at 37°C and 5% CO2. Cytotoxicity was determined
using
the
MTT
assay
(MTT
=
3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-
tetrazolium·bromide). Cells were seeded in 96-well plates as monolayers with 100 μL of cell
suspension (approximately 5000 cells) per well and pre-incubated for 24 h in medium
supplemented with 10% FBS. Compounds were prepared as DMSO solutions and then
dissolved in the culture medium and serially diluted to the appropriate concentration, to give a
6

final DMSO concentration of 0.5%. 100 μL of the drug solution was added to each well, and
the plates were incubated for another 72 h. Subsequently, MTT (5 mg/mL solution) was added
to the cells and the plates were incubated for a further 2 h. The culture medium was aspirated,
and the purple formazan crystals formed by the mitochondrial dehydrogenase activity of vital
cells were dissolved in DMSO. The optical density, directly proportional to the number of
surviving cells, was quantified at 590 nm using a multiwell plate reader, and the fraction of
surviving cells was calculated from the absorbance of untreated control cells. Evaluation is
based on means from at least two independent experiments, each comprising triplicates per
concentration level.
2.4
Synthesis
of
Complex
1
[(η6-p-cymene)Ru(P(OMe)3)Cl(GeCl3)]:
[Ru(η6-p-cymene)Cl2{P(OMe)3}] (0.149 g, 3.46x10-4 mol) was measured within a glovebox under inert
N2 atmosphere, and was subsequently placed in a Schlenk flask. Germanium(II) chloride dioxane
complex (1:1) (0.094 g 3.83x10-4 mol) was then also added to this Schlenk flask. Dried and degassed
dichloromethane (~50mL) was added to this vessel via syringe, and was agitated by hand. This
elicited a colour change from a transparent red solution, to a transparent orange solution within 30
seconds. The vessel was then sealed, removed from the glovebox, and allowed to stir at room
temperature under a static N2 pressure for a further 1.5 hours. No further colour change occurred
across this time period. The solvent was then removed in vacuo at 40 °C, affording an oily orange
substance. Diethyl ether (30 mL) was added to this material in a round bottomed flask, affording an
orange precipitate and a solution in which the material was sparingly soluble. In order to solubilise,
dichloromethane (10 mL) was added to this solution to produce a 3:1 mixture of diethyl ether:
dichloromethane. This orange supernatant was further concentrated in vacuo to produce an oily
orange substance. Diethyl ether (10 mL) was added to this oily material, producing a red precipitate
and a yellow solution. This yellow solution was decanted off, and the precipitate allowed to air dry.
This
resulted
in
in
the
formation
stable.
of
a
dark
of dark
orange
orange
solid
solid
powder.
(69%).
dec.
Soluble
Melting
chloroform.
Point:
Air
0.138g
132
°C
+
3
1H NMR: (300.1 MHz, CHCl3-d1, 25°C): δ = 5.92 – 5.84 (m, 4H, η6-C6H4), 3.85 (d, J(H,P) = 11.3 Hz,
7

3
3
9H, P(OCH3)3), 2.79 (sept, J(H,H) = 7.0 Hz, 1H, CH(CH3)2), 2.12 (s, 3H, CH3), 1.26 (d, J(H,H) = 5.5
A
3
B
Hz, 3H, CH(CH3)2 ), 1.23 (d, J(H,H) = 5.4 Hz, 3H, CH(CH3)2 ). 13C{1H}NMR: (75.5 MHz, CHCl3-d1,
26°C): δ = 119.4 (d, 2J(C,P) = 3.9 Hz, η6-C6H4), 103.5 (d, 2J(C,P) = 1.6 Hz, η6-C6H4), 95.1 (d, 2J(C,P) =
2
5.8 Hz, η6-C6H4), 93.5 (d, J(C,P) = 2.1 Hz, η6-C6H4), 91.9 (d, 2J(C,P) = 9.2 Hz, η6-C6H4), 89.7 (s, η6-
2
A
C6H4), 54.7 (d, J(C,P) = 7.9 Hz, P(OCH3)3), 30.6 (s, CH(CH3)2), 22.3 (s, CH3), 21.7 (s, CH(CH3)2 ),
B
18.5 (s, CH(CH3)2 ). 31P{1H}NMR: (121.5 MHz, CHCl3-d1, 25°C): δ = 125.3 (s). HRMS (ESI (+)) =
502.93904 (63%), 436.03867 (59%), 395.01191 [M-GeCl3]+ (100%) (calc 395.01169). ATR-FTIR:
μ(cm−1) = 3071 (w), 2951 (m, Alkyl C-H Stretching), 2870 (w), 2849 (w), 2025 (w), 1931 (w), 1896 (w),
1539 (w, Aromatic C=C Bending), 1506 (w), 1464 (m), 1445 (m), 1375 (w), 1260 (w), 1179 (m, P-O-
Me), 1011 (vs, P-O-C), 891 (w), 872 (m), 856 (m, Aromatic C-H Bending), 785 (vs, P-O-C), 737 (vs),
702 (m), 675 (m), 631 (w). TGA: (°C, Weight % decrease): 130 – 193 (18%), 193 – 232 (6%), 260 –
350
(10%).
UV/Vis
λmax
(chloroform):
347.0
nm.
2.5
Synthesis
of
Complex
2
[(η6-p-cymene)Ru(P(OPh)3)Cl(GeCl3)]:
[Ru(η6-p-cymene)Cl2{P(OPh)3}] (0.150 g, 2.43x10-4 mol) was measured within a glovebox under inert
N2 atmosphere, and was subsequently placed in a Schlenk flask. Germanium(II) chloride dioxane
complex (1:1) (0.065 g, 2.68x10-4 mol) was then also added to this Schlenk flask. Dried and degassed
dichloromethane (50 mL) was added to this vessel, which was then agitated, eliciting an immediate
colour change from a transparent dark red solution to a transparent yellow solution. This vessel was
sealed, and stirred outside of the glovebox for a further 10 minutes. The solvent was removed in vacuo
at 40 °C until a canary yellow precipitate was formed. This powder was dried in vacuo for a further 15
minutes in order to remove excess dioxane, affording a yellow solid. Crystals suitable for single crystal
X-ray diffraction analysis were grown from chloroform-d at 7 °C, whilst allowing evaporation to take
place. Soluble in dichloromethane, very sparingly soluble in chloroform. Air stable. 0.101g of canary
yellow
solid
(54%).
Melting
Point:
224
°C
+
dec.
1H NMR: (300.1 MHz, CHCl3-d1, 24°C): δ = 7.32 – 7.19 (m, 15H, P(OPh)3), 5.88 – 5.39 (m, 4H, η6-
3
3
C6H4), 2.64 (sept, J(H,H) = 6.9 Hz, 1H, CH(CH3)2), 2.03 (s, 3H, CH3), 1.19 (d, J(H,H) = 6.9 Hz, 3H,
A
3
B
CH(CH3)2 ), 1.08 (d, J(H,H) = 7.0 Hz, 3H, CH(CH3)2 ). No 13C{1H}NMR is available due to low
solubility. 31P{1H}NMR: (121.5 MHz, CHCl3-d1, 25°C): δ = 116.7 (s). HRMS (ESI (+)) = 670.97637
8

(100%), 622.97609 (4%), 318.18591 (6%), 282.27971 (9%) ATR-FTIR: μ(cm−1) = 3065 (w), 2955 (w),
2922 (m, Alkyl C-H Stretching), 2853 (w), 1587 (m, Aromatic C=C Bending), 1485 (s), 1454 (m), 1393
(w), 1261 (m), 1207 (s), 1186 (vs, P-O-Ar), 1152 (s), 1088 (m), 1053 (m), 1026 (s), 1007 (m). 949 (vs),
908 (vs), 893 (vs), 874 (s, P-O), 802 (s, P-O-C), 775 (vs), 766 (vs), 737 (s), 719 (s), 685 (vs). TGA:
(°C, Weight % decrease): 207 – 250 (16%), 250 – 371 (22%), 371 – 492 (21%). UV/Vis λmax
(dichloromethane): 438.5 nm. Connectivity confirmed by single crystal X-ray diffraction analysis of
single
crystals
(low
quality
data
set.
Omitted
from
discussion).
2.6
Synthesis
of
Complex
3
[(η6-p-cymene)Ru(PPh3)Cl(GeCl3)]:
Dichloro(p-cymene)ruthenium(II) dimer (0.509 g, 8.31x10-4 mol) was measured and added to
triphenylphosphine (3.268 g, 1.25x10-2 mol) in a round bottomed flask. Dichloromethane (50 mL) was
added to this vessel, and the reaction mixture was stirred under reflux (50 °C) for 3 hours. No colour
change occurred across the duration of this reaction, remaining a transparent dark red solution
throughout. The solvent was removed in vacuo at 40 °C to a highly concentrated solution (~8 mL).
Diethyl ether (50 mL) was added to this solution, causing the product to precipitate out of solution, and
the supernatant was subsequently decanted off. This was repeated four more times until the decanted
supernatant was colourless. A dark red crystalline material was obtained, and was allowed to air dry
for 1 hour before proceeding with analysis and further reactions. A yield of 0.748 g (1.32x10-3 mol,
79.2%)
was
recorded.
This product, [Ru(η6-p-cymene)Cl2(PPh3)], (0.300 g, 5.28x10-4 mol) was added to a Schlenk flask
within a glovebox under an inert N2 atmosphere. Germanium(II) chloride dioxane complex (1:1) (0.129
g, 5.55x10-4 mol) was then added to this vessel, which was then sealed and placed on a Schlenk line.
Dried and degassed dichloromethane (20 mL) was added to this vessel This reaction mixture was
allowed to stir for 15 minutes. The solution went from a transparent cabernet red to a transparent
amber solution in approximately 1 minute. This solvent was then concentrated in vacuo at 40 °C to
form a highly concentrated solution (~5 mL), until the point of insipience was reached. This solution
was allowed to rest, before decanting the supernatant off, leaving behind an orange-red semi-
crystalline residue. This material was then dried in vacuo for 15 minutes at room temperature.
Soluble in dichloromethane, sparingly soluble in chloroform and dimethyl sulfoxide. Air stable. 0.238 g
9

of orange-red solid (63%). Melting Point: 124 °C + dec.1H NMR: (300.1 MHz, CHCl3-d1, 25°C): δ =
7.66 – 7.23 (m, 15H, PPh3), 6.10 (d, 3J(H,H) = 6.1 Hz, 1H, η6-C6H4), 5.68 (d, 3J(H,H) = 5.9 Hz, 1H, η6-
C6H4), 5.39 (d, 3J(H,H) = 5.9 Hz, 1H, η6-C6H4), 4.79 – 4.77 (m, 1H, η6-C6H4), 2.70 (sept, 3J(H,H) = 6.9
A
Hz, 1H CH(CH3)2), 1.52 (s, 3H, CH3), 1.21 (d, 3J(H,H) = 6.9 Hz, 3H, CH(CH3)2 ), 1.16 (d, 3J(H,H) = 6.9
B
x
Hz, 3H, CH(CH3)2 ). 13C{1H}NMR: (75.5 MHz, CHCl3-d1, 26°C, ppm): δ = 133.4 (d, J(C,P) = 9.9 Hz,
1
4
C2,6 or C3,5 PPh3), 132.6 (d, J(C,P) = 48.0 Hz, C1 PPh3), 129.6 (d, J(C,P) = 2.5 Hz, C4 PPh3), 127.3
(d, xJ(C,P) = 10.3 Hz, C2,6 or C3,5 PPh3), 98.0 (s, η6-C6H4), 94.2 (d, 2J(C,P) = 3.4 Hz, η6-C6H4), 92.7 (s,
η6-C6H4), 88.0 (s, η6-C6H4), 87.4 (s, η6-C6H4), 87.3 (s, η6-C6H4), 29.3 (s, CH(CH3)2), 21.2 (s,
A
B
CH(CH3)2 ), 20.7 (s, CH(CH3)2 ), 15.9 (s, CH3). 31P{1H}NMR: (121.5 MHz, CHCl3-d1, 26°C): δ = 28.9
(s). 31P{1H}NMR: (121.5 MHz, DMSO-d6, 26°C, ppm): δ = 32.9 (s, exchanged, 30%), 29.3 (s, product,
70%). HRMS (ESI (+)) = 706.99000 (2%), 682.02768 (16%), 668.99667 (100%), 641.00159 (16%),
574.10092 (6%), 533.07416 [M-GeCl3]+ (calc 533.07388) (24%), 279.09349 (6%). ATR-FTIR: μ(cm−1)
= 2988 (m), 2970 (m), 2901 (m, Alkyl C-H Stretching ), 2872 (m), 2361 (m), 2322 (m), 1977 (w), 1558
(w), 1541 (w), 1506 (m, Aromatic C=H Bending), 1487 (w), 1472 (m), 1456 (m), 1433 (s), 1395 (w),
1375 (m), 1339 (w), 1314 (w), 1260 (m), 1182 (w), 1159 (w), 1090 (vs), 1059 (s), 1028 (s), 1001 (m),
972 (w), 924 (w), 901 (w), 860 (m), 845 (w), 799 (s, Aromatic C=C Bending), 746 (vs), 691 (vs), 669
(m, P-C), 631 (s), 617 (w). TGA: (°C, Weight % decrease): 222 – 254 (12%), 254 – 287 (4%), 287 –
373
(19%),
373
–
493
(16%).
UV/Vis
λmax
(dichloromethane):
358.0
nm.
2.7
Synthesis
of
Complex
4
[(η6-p-cymene)Ru(pta)Cl(GeCl3)]:
Germanium(II) chloride dioxane complex (1:1) (0.108 g, 4.67x10-4 mol) was measured in to a Schlenk
flask within a glove box. [Ru(η6-p-cymene)Cl2(pta)] (0.206 g, 4.45x10-4 mol) was then added to this
vessel. Dried and degassed dichloromethane (50 mL) was added to the vessel via syringe, to dissolve
the reagents. This produced a transparent red solution. This reaction mixture was stirred at room
temperature for 1 hour, forming a translucent orange solution. The solvent was removed from the
vessel
in
vacuo
at
40
°C.
This
produced
an
orange
powder.
Soluble in dimethyl sulfoxide, water, and chloroform. Air stable. 0.201 g of orange solid (76%). Melting
Point: 172 °C + dec.1H NMR: (300.1 MHz, H2O-d2, 25°C): δ = 6.33 – 5.65 (m, 4H, η6-C6H4), 4.87 (br s,
3
6H, NCH2N), 4.45 – 4.32 (m, 6H, PCH2N), 2.50 (sept, J(H,H) = 6.8 Hz, 1H, CH(CH3)2), 2.01 (s, 3H,
10

CH3), 1.13 (d, 3J(H,H) = 6.8 Hz, 6H, CH(CH3)2) (These signals correspond to the exchanged product).
13C{1H}NMR: (75.5 MHz, DMSO-d6, 25°C, ppm): δ = 70.7 (s, NCH2N), 66.8 (s, PCH2N), 30.7 (s,
CH(CH3)2), 24.5 (s, CH(CH3)2), 22.2 (d, 3J(C,P) = 36.3 Hz, CH(CH3)2), 18.8 (s, CH3) (Aromatic signals
not visible, due to low signal to noise ratio). 13C{1H}NMR: (75.5 MHz, H2O-d2, 28°C): δ = 116.9 (s, η6-
C6H4), 101.2 (s, η6-C6H4), 94.6 (d, 2J(C,P) = 3.5 Hz, η6-C6H4), 91.4 (d, 2J(C,P) = 2.8 Hz, η6-C6H4), 88.9
(d, 2J(C,P) = 4.9 Hz, η6-C6H4), 88.0 (s, η6-C6H4), 70.9 (d, 3J(C,P) = 5.3 Hz, NCH2N), 66.6 (s, PCH2N),
A
B
30.8 (s, CH(CH3)2), 22.1 (s, CH(CH3 )2), 21.0 (s, CH(CH3 )2), 18.7 (s, CH3) (These signals correspond
to the exchanged product). 31P{1H}NMR: (121.5 MHz, CHCl3-d1, 25°C): δ = -36.0 (v br s, Δv1/2 = 40.5
Hz ). 31P{1H}NMR: (121.5 MHz, H2O-d2, 26°C): δ = -19.1 (s, exchanged, 96%), -28.1 (s, unexchanged
product, 4%). HRMS (ESI (+)) = 577.01601 (100%), 544.00013 (30%), 535.98937 [M-HCl-Cl]+ (calc
535.94184) (41%), 466.03814, (17%), 428.06163 [M-GeCl3]+ (calc 428.05962) (51%), 312.01077
(2%), 229.17127 (6%). ATR-FTIR: μ(cm−1) = 2963 (m, Alkyl C-H Stretching), 2903 (w), 1624 (w,
Aromatic C=C Bending), 1541 (w), 1506 (w), 1449 (w), 1406 (w), 1389 (w), 1304 (w), 1260 (vs), 1219
(w, C-N), 1080 (vs), 1018 (vs), 984 (s), 951 (s), 939 (s), 887 (m), 870 (s, Aromatic C-H Bending), 795
(vs), 772 (vs), 729 (m, P-C), 662 (m), 631 (m), 610 (m). TGA: (°C, Weight % decrease): 85 – 195
(7%), 195 – 275 (11%), 275 -387 (10%), 387 – 489 (17%). UV/Vis λmax (water): 404.0 nm.
2.8
Synthesis
of
Complex
5
[(η6-C6H5-OC2H4OH)Ru(pta)Cl(GeCl3)]:
A slightly altered version of the methods demonstrated Matsinha, et. al., was used to synthesise this
[29d]
complex.
Dichloro(η6-2-phenoxyethanol)ruthenium(II) dimer (0.556 g, 1.02 mmol) was measured
1:1 dichloromethane: methanol solution (50 mL). 1,3,5-triaza-7-
and dissolved in
a
phosphaadamantane (0.328 g, 2.09 mmol) was added to this mixture, and was then stirred at 50 °C
for 30 minutes. The solution started as a brown colour, and became darker brown as the reaction
proceeded. The solvent was then removed in vacuo at 40 °C giving a brick orange precipitate. This
material was dissolved in a hot 1:1 dichloromethane: methanol solution (100 mL) and allowed to stand
for 2 hours. This gave a black precipitate, which was separated from the orange solution via vacuum
filtration. The filtrate was then concentrated in vacuo at 40 °C until the point of insipience was reached.
The red-orange supersaturated solution was then placed at -25 °C for 16 hours. The supernatant was
decanted affording a burnt orange precipitate. This precipitate was washed with diethyl ether (10 mL).
11

This powder dried in vacuo for 2 h, affording the precursor [Ru(η6-2-phenoxyethanol)Cl2(pta)].
[Ru(η6-2-phenoxyethanol)Cl2(pta)] (0.142 g, 3.05x10-4 mol) was then weighed into a Schlenk tube in a
glove with germanium(II) chloride dioxane complex (1:1) (0.074 g, 3.20x10-4 mol). then dissolved in
dichloromethane (20 mL). The reaction was stirred for 18 h at room temperature. The materials are
only sparingly soluble in dichloromethane, resulting in a translucent orange solution. This solution
became slightly lighter in colour after this reaction period, yet remained translucent. The mixture was
then vacuum filtered, yielding an orange precipitate as product which was dried in vacuo.
Soluble in dimethyl sulfoxide, and water. Air stable. 0.097g of orange solid (52%). Melting Point: 174
°C
+
dec.
1H NMR: (300.1 MHz, H2O-d2, 27°C): δ = 6.09 – 5.85 (m, 3H, η6-C6H5), 5.56 (d, 3J(H,H) = 6.4 Hz, 1H,
3
η6-C6H5), 5.19 (t, J(H,H) = 5.4 Hz, 1H, η6-C6H5), 4.88 (s, 6H, NCH2N), 4.83 (s, 1H, OH), 4.39 (s, 6H,
PCH2N), 4.24 (t, 3J(H,H) = 5.2 Hz, 2H, 6-ArOCH2), 3.90 (t, 3J(H,H) = 5.2 Hz, 2H, CH2CH2OH) (These
are the signals of the unexchanged product, other signals visible in the baseline corresponding to the
exchanged product). 13C{1H}NMR: (75.5 MHz, DMSO-d6, 28°C): δ = 159.1 (s, η6-C6H5), 141.5 (d,
3J(C,P) = 3.0 Hz, η6-C6H5), 129.9 (s, η6-C6H5), 120.9 (s, η6-C6H5), 114.9 (s, η6-C6H5), 91.3 (s, η6-C6H5),
71.0 (s, NCH2N), 69.8 (s, PhOCH2), 60.0 (s, CH2CH2OH), 59.5 (s, PCH2N) (signals corresponding to
unexchanged product). 31P{1H}NMR: (121.5 MHz, H2O-d2, 27°C): δ = -16.9 (exchanged, 22%), -23.9
(s, unexchanged, 78%). 31P{1H}NMR: (121.5 MHz, DMSO-d6, 27°C): δ = -22.7 (s). HRMS (ESI (+)) =
467.99483 (11%), 432.01808 [M-GeCl3]+ (calc 432.01816) (100%), 402.00744, (2%), 315.96757 (6%).
ATR-FTIR: μ(cm−1) = 3362 (v br w, OH), 3075 (w), 2961 (w, Alkyl C-H Stretching), 1626 (w), 1524 (vs),
1447 (s), 1410 (m), 1304 (m), 1261 (vs), 1219 (m, C-N), 1144 (w), 1115 (m), 1082 (s), 1053 (m), 1024
(vs), 982 (vs), 947 (s), 939 (vs), 908 (s), 897 (s), 837 (vs, Aromatic C-H Bending), 812 (vs), 770 (vs),
743 (s, P-C), 727 (s), 660 (vs), 608 (m). TGA: (°C, Weight % decrease): 157 – 201 (4%), 201 – 272
(9%), 272 – 431 (19%), 431 – 495 (6%). UV/Vis λmax (dimethyl sulfoxide,): 346.5 nm.
12

3. Results and Discussion
Literature procedures were followed for the synthesis of the pta precursor complexes [(η6-p-
cymene)Ru(pta)Cl2], and [(η6-C6H5-OC2H4OH)Ru(pta)Cl2], with only slight modifications. [29c-e] [(η6-p-
cymene)RuCl2]2 was cleaved with two molar equivalents of P(OMe)3, PPh3 and P(OPh)3 affording the
precursors [(η6-p-cymene)Ru(PR3)Cl2] (PR3 = P(OMe)3, PPh3 and P(OPh)3), also prepared using
standard literature procedures [31]. These easily accessible half sandwich ruthenium(II) dichloride
complexes were subsequently treated with GeCl2(dioxane) in a 1:1 ratio, typically in dichloromethane
affording, by facile GeCl2 insertion into the Ru-Cl bonds of the respective precursor complexes, the
novel trichlorogermyl half-sandwich complexes 1-5 (Scheme 1) selectively [30]. The complexes 1-5
are remarkably stable and can be handled in air without any noticeable decomposition taking place.
This suggests that the trichlorogermyl ligand is stable to hydrolysis on coordination to the Ru centre.
Scheme 1. Top and middle: Cleavage of Ru(II) dimer complexes to produce the known piano-stool precursors.
Bottom: Insertion of GeCl2 into the Ru-Cl bonds of precursors from I and II yielding target complexes 1 – 5.
The trichlorogermyl complexes were isolated with moderate to high yields (54 – 76 %) and ranged in
colour from canary-yellow to orange red.
1H NMR spectroscopy proved an exceptionally useful tool for confirming the insertion of the GeCl2 into
the Ru-Cl bonds of the precursor complexes to afford the Ru-GeCl3 moiety. In particular for the
13

complexes bearing the p-cymene ring (1-3), the insertion of the GeCl2 renders the CH3 groups of the
iPr on the p-cymene ring diastereotopic and two sets of resonance signals are observed for
A
B
CH(CH3 )(CH3 ), with a common cross peak in the two dimensional H,H-COSY spectrum for these
A
B
resonance signals to the methine proton CH(CH3 )(CH3 ). In complex 4 these signals are isochronous
in H2O-d2. A similar picture emerges in the 13C{1H} NMR spectra of complexes 1-4, where again two
A
B
sets of resonance signals are observed for the diastereotopic CH(CH3 )(CH3 ) methyl groups. This is
i
in contrast to the starting materials for complexes 1-4 i.e. [(η6-p-cymene)Ru(PR3)Cl2], where the Pr
groups are not diastereotopic and typically feature one resonance signal for both equivalent
CH(CH3)2. In addition, the presence of a GeCl3 ligand on the Ru(II) centre typically results in six
resonance signals for the coordinated arene ring in the 13C{1H} NMR spectra, due to loss of symmetry
2
in the complexes. In most cases for these resonance signals, a J(C,P) coupling is observed to the
Ru(II) bound phosphane ligand.
The presence of phosphane or phosphite ligands in complexes 1-5 provided a further instructive
spectroscopic handle to track the completion of the reactions and a comparison to their respective
precursor complexes ([(η6-Arene)Ru(PR3)Cl2]), prior to GeCl2 insertion (Table 1).
Table 1. Summary of 31P{1H}NMR data with different solvents (“X” indicates a solvent which was not used for
measurement of a complex. Round brackets indicate the ligand exchange product).
31P{1H}NMR
CHCl3-d1
125.3
116.7
28.9
DMSO-d6
H2O-d2
1
2
3
4
5
X
X
X
X
29.3 (32.9)
X
-36.0
X
X
-28.1 (-19.1)
-23.9 (-16.9)
-22.7
For example: Complex 1 features a singlet resonance signal in the 31P{1H} NMR spectrum ( = 125.3
ppm) which is shifted downfield from its precursor complex [(η6-p-cymene) Ru(P(OMe)3)Cl2)] (=
115.9 ppm) [31]. Similarly, the precursor complex of 2: [(η6-p-cymene)Ru(P(OPh)3)Cl2] ( = 104.2
ppm), [31] has a resonance signal that is upfield shifted from 2. This relates to a downfield chemical
14

shift of 9.4 ppm and 12.5 ppm respectively in 1 and 2 due to the deshielding effect of the GeCl3 ligand.
Similarly, [(η6-p-cymene)Ru(PPh3)Cl2], the precursor to complex 3, features a resonance signal at  =
24.1 ppm [32], whilst 3 is shifted downfield by 5.4 ppm ( = 28.9 ppm). The 31P{1H} NMR spectra of
some complexes (3 – 5, those soluble in these solvents) were also recorded in coordinating H2O-d2
and DMSO-d6 and showed two sets of resonance signals: one high field shifted signal corresponding
the unexchanged species, and a low field shifted signal likely corresponding to a ligand exchange
product. This is likely due to ligand exchange facilitated by the coordinating solvent, affording species
-
of the type [(η6-arene)Ru(PR3)D:(GeCl3)]+Cl- or [(η6-arene)Ru(PR3)D:Cl]+GeCl3 (D: = H2O-d2 or
DMSO-d6) [33,34]. Another possible explanation for the presence of two resonance signals is potential
hydrolysis of the hydrolytically sensitive Ge-Cl bonds in the GeCl3 moiety affording other species,
potentially: [(η6-arene)Ru(PR3)Cl(Ge(OD)3)]. The latter is unlikely and was ruled out by hydrolysis
experiments (see below). Attempts at isolating the exchange species was unsuccessful. Notably,
Complex 4, [(η6-p-cymene)Ru(pta)Cl(GeCl3)], displays a significant increase in the exchange product
ratio, with approximately 96% of the complex forming the exchange product, whilst only 4% of the
unexchanged complex remains (in H2O-d2). In complex 5 the ratio is 78 % unexchanged to 22 %
exchanged, indicating that it is more stable to aquation (ligand exchange). Hydrolytic stability is known
to be an important factor in anticancer agents [37-39].
The species appear to be in equilibrium with each other (exchanged : non-exchanged) as following the
31P NMR spectra over time (several hours) revealed no change in the relative intensities of the
respective species.
The complexes were found to be thermally robust with decomposition temperatures in all cases above
100 °C: (1: 132, 2: 224, 3: 124, 4: 172, 5: 174 ºC). TGA was also conducted on all complexes in order
to further elucidate their thermal behavior with a view of trying to establish their modes of
decomposition thermally. The η6-p-cymene groups can be seen as the 16% loss in complex 2, and the
19% loss in complex 3. Phenyl groups from triphenylphosphane correspond to a 12% loss in complex
3. It is difficult to label any further fragment losses with confidence given the fact that many fragments
share similar molecular weights. Nevertheless these results underline the robust nature of the
complexes, thermally.
15

In order to preclude the presence of any hydrolysis on the GeCl3 ligand in the complexes, solid-state
ATIR spectroscopy was conducted on all complexes. A Ge-OH stretching vibration is expected at
3571 cm-1 [36 a, c] which is not detected in any of the complexes. In fact, for complexes 1-4 the
highest wavenumber stretching vibration is close to ca. 3000 cm-1 clearly indicative of no Ge-OH
present, further providing evidence for the robust nature of the GeCl3 ligand. In complex 5 a stretching
vibration at 3362 cm-1 is observed corresponding to the pendant OH group on the alkyl chain attached
to the aryl ring.
Solution UV-Vis spectroscopy was conducted on all complexes showing some large variations on the
absorption band positions: (1: 347, 2: 438.5, 3: 358, 4: 404, 5: 346.5 nm).
.
Surprisingly, trichlorogermyl ruthenium complexes (complexes of the type LnRu-GeCl3; Ln = Ligand
sphere) have escaped investigations by DFT studies, and we carried out such an analysis for
complexes 2 and 5. The DFT optimized structure for complex 2 can be found in figure 2, while a visual
representation of the frontier orbitals for complex 2 can be found in figure 3. Similar representations for
complex 5 can be found in the supporting information.
Figure 2. Optimized structure for complex 2. (DFT, B3LYP; basis set 6- 31+G(d,p) for H, C, O, P, Cl, Ge atoms
and DGDZVP for Ru atom). (Cyan = Ru, Olive-green = Ge, Green = Cl, Grey = C, Red = O, Orange = P, White =
H).
16

Figure 3. HOMO (left) and LUMO (right) for complex 2. (B3LYP; basis set 6- 31+G(d,p) for H, C, O, P, Cl, Ge
atoms and DGDZVP for Ru atom). Energy of the HOMO is -6.08 eV. Energy of the LUMO is -2.39 eV.
From figure 3 (left) it is possible to visualize that most of the electron density of the HOMO is
delocalized on the arene to the ruthenium and germanium together with a significant localization also
on the chlorine bound to the ruthenium; while the LUMO is mostly located on the germanium-chloride
atoms and the arene centre, with some delocalisation over the coordinated arene ring.
Natural bond analysis (NBO) was calculated to establish the nature of bonds with particular focus on
the ruthenium-germanium atoms and bond. Table 2 summarizes the DFT results of the natural bond
order analysis for complexes 2 and 5.
Table 2. Natural bond order analysis for complexes 2 and 5. (B3LYP; basis set 6- 31+G(d,p) for H, C, O, P, Cl, N,
Ge atoms and DGDZVP for Ru atom).
Atom
Bond
Polariz.
(%)
s-character
(%)
p-character
(%)
d-character
(%)
NBO
Charge
Complex 2
Ru
Ge
47.22
52.78
23.72
76.40
23.26
53.02
0.24
- 0.707
+1.247
23.36
Complex 5
22.51
Ru
Ge
51.67
48.33
24.12
43.77
53.37
0.36
- 0.648
+1.249
55.86
The Wiberg index (WBI) for the Ru-Ge bond calculated for complex 2 is 0.76 while for complex 5 is
0.78, so they are comparable to each other within narrow limits and slightly less than 1. In both
17

complexes the Ge atom features a somewhat positive NBO charge and the Ru-Ge bonds are slightly
polarized in both complexes. Moreover, complex 5 features a higher degree of p-orbital mixing in Ge
(55.86 %) compared to only 23.36 % in complex 2 where the latter has more s-character. This
variation is indeed surprising given the similar nature of the complexes studied, and suggests that the
nature of the other ligands plays a role in the nature of the Ru-Ge bond..
Considering the fact that the LUMO is to a large extent localised, in both complexes on the Ge-Cl
bonds in the GeCl3 ligand (Figure 3), this might imply that there is a potential risk of hydrolysis to form
Germanium hydroxide species, as Ge-Cl bonds are known to be somewhat hydrolytically labile.[35] In
order to probe this potential hydrolytic sensitivity towards the Ge-Cl bonds in the GeCl3 moiety, a
1
simple experiment was conducted whereby a sample of complex 4 was dissolved in water and H
NMR spectra recorded after stirring and removal of the solvent. No evidence of any Ge-OH resonance
1
signals were detected in the H NMR spectra, even at very high concentrations and a high number of
scans, indicating that hydrolysis of the GeCl3 does not occur. Typically, the Ge-OH group is visible in
1H NMR spectra, in metal bound germyl complexes and even Ge(II) hydroxy species that are not
coordinated to transition metals [36].
In vitro cytotoxicity testing of complexes 1-5 were performed on human ovarian carcinoma A2780 and
non-tumorigenic human embryonic kidney HEK293 cell lines (Table 3). Complexes 3 and 5 showed
some activity with IC50 values of 183 ± 5 and 111 ± 1 on A2780 cells, respectively. Comparable
activity was observed for 3 on HEK293 cells. Notably, complex 5 showed some selectivity towards the
cancer cell line A2780 with a twice higher activity on cancer cells compared to non-tumorigenic
HEK293 cells. Complex 2 was insoluble in any solvent (DMF, DMEM or PBS) compatible with
biological medium, therefore, the cytotoxicity test could not be performed for this compound.
Complexes 1 and 4 were non-cytotoxic up the measured concentration of 1000uM. Compared to
cisplatin, complexes 3 and 5 are approximately 100 times less active. The apparent lack of cytotoxicity
1 and 4 and low activity of 3 and 5 is surprising, given the previous promising results with SnCl3 in the
coordination sphere of Ru arene complexes[29a,b]. Obviously, replacing SnCl3 by GeCl3 leads to a
loss in cytotoxic activity, which might be due to the fact that the presence of the GeCl3 ligand leads to
rapid aquation (see above) and hydrolytic instability, which is known to play a role in cytotoxicity [37-
18

39]. It is tempting to speculate that complex 5 features a much higher cytotoxicity compared to
complex 4 which might be due to its higher stability towards aquation (see above). The complete loss
of cytotoxicity in 4 vs 5 despite similar solubility properties potentially underlines the importance of rate
of aquation, and since in 4 this is very rapid, might lead to decrease in cytotoxicity.
Table 3. IC50 values of all complexes and cisplatin in either DMF or DMEM (Dulbecco modified eagle medium)
solvent on A2780 and HEK cells.
Complex
Solvent
DMF
IC50 (A2780)
> 1000
IC50 (HEK)
> 1000
1
2
Insoluble
DMF
N/A
N/A
3
183 ± 5
> 1000
111 ± 1
1.5 ± 0.1
146 ± 32
> 1000
207 ± 22
7 ± 1
4
DMF
5
DMEM
DMEM
cisplatin
4. Conclusions
Facile entry into a range of half sandwich ruthenium(II)-arene complexes bearing trichlorogermyl
groups was enabled through facile insertion reactions of GeCl2 into the Ru-Cl bonds of readily
accessible precursor complexes. The resulting complexes were found to be thermally stable and
stable in air, and shown in some cases to undergo rapid aquation or ligand substitution in coordinating
solvents. The complexes were fully characterised by a range of spectroscopic methods and by DFT
methods, and the first cytotoxic tests of Ru(II) germyl complexes to date were carried out for all 5
complexes on the A2780 and HEK cell lines showing only very weak cytotoxicity. The low cytotoxicity
in this class of compound is at odds with analogous trichlorostannyl complexes, and might be as a
result of enhanced aquation kinetics which are known to decrease cytotoxicity in biological systems
[37-39]. Hence trichlorogermyl ligands in the coordination sphere of Ru(II) are not suitable for
anticancer agents based on Ru(II) arene complexes.
19

5. Acknowledgements
The authors would like to thank the Maastricht Science Programme (MSP) and Maastricht University for financial support
of this research. We would also like to thank Dr. M. Schlangen (TU-Berlin, Germany) for the HRMS data.
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TOC Image
A series of trichlorogermyl complexes of the type [η6-(Arene)Ru(PR3)Cl(GeCl3)], including full spectroscopic characterisation are reported and their
cytotoxicity towards A2780 or HEK293 cell lines are also reported along with DFT studies.
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