Controlling the reactivity of ruthenium(II) arene complexes by tether ring-opening

Article abstract of DOI:10.1021/ic902243q

The closed- and open-tethered Ru^II Carene complexes [Ru ^II(η⁶:η¹-C₆H ₅(C₆H₄)NH₂)(en)]Cl₂ (2) and [Ru^II(η⁶C₆H₅(C ₆H₄)NH₂)Cl(en)]Cl (3), where en is ethylenedlamine, have been synthesized and their X-ray structures determined. Interconversion between 2 and 3, that Is, tethered-arene ring-closure and ring-opening, in different solvents has been investigated. Complex 2 opens in dimethylsulfoxide (DMSO) by solvent-induced dissociation of the NH₂ group of the pendant arm. In methanol, however, equilibrium between 2 and 3 Is reached after 12 h when both species coexist In solution In a ratio of 2:1 (open/closed). In water (pH 7), complete ring closure of 3 to 2 at 298 K occurs in less than 2 h. The tether ring of complex 2 opens at basic pH and closes at neutral pH. Complex 2 opens over time (18 h) in concentrated HCl. The opening-closing process Is fully reversible in the pH range 2-12. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 2 and 3, their UV-vis properties, and their stability compared to their aqua derivatives. Control of tether-ring-opening can contribute toward a strategy for activation and for achieving cytotoxic selectivity of ruthenium arene anticancer drugs.

Full text of DOI:10.1021/ic902243q

3310 Inorg. Chem. 2010, 49, 3310–3319
DOI: 10.1021/ic902243q
Controlling the Reactivity of Ruthenium(II) Arene Complexes
by Tether Ring-Opening
Ana M. Pizarro,† Michael Melchart,‡ Abraha Habtemariam,† Luca Salassa,† Francesca P. A. Fabbiani,‡
Simon Parsons,‡ and Peter J. Sadler*,†
†Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K., and
‡School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, U.K.
Received November 18, 2009
The closed- and open-tethered RuII η6-arene complexes [RuII(η6:η1-C6H5(C6H4)NH2)(en)]Cl2 (2) and [RuII(η6-
C6H5(C6H4)NH2)Cl(en)]Cl (3), where en is ethylenediamine, have been synthesized and their X-ray structures
determined. Interconversion between 2 and 3, that is, tethered-arene ring-closure and ring-opening, in different
solvents has been investigated. Complex 2 opens in dimethylsulfoxide (DMSO) by solvent-induced dissociation of the
NH2 group of the pendant arm. In methanol, however, equilibrium between 2 and 3 is reached after 12 h when both
species coexist in solution in a ratio of 2:1 (open/closed). In water (pH 7), complete ring closure of 3 to 2 at 298 K
occurs in less than 2 h. The tether ring of complex 2 opens at basic pH and closes at neutral pH. Complex 2 opens
over time (18 h) in concentrated HCl. The opening-closing process is fully reversible in the pH range 2-12.
Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes
2 and 3, their UV-vis properties, and their stability compared to their aqua derivatives. Control of tether-ring-opening
can contribute toward a strategy for activation and for achieving cytotoxic selectivity of ruthenium arene anticancer
drugs.
Introduction
Organometallic transition metal complexes with a poten-
tial coordinating atom such as nitrogen, oxygen, and phos-
phorus tethered to a η6-arene ligand have been reported
previously. For example, Scolaro et al. have investigated the
effect of different functionalized arenes in potentially cyto-
toxic Ru-arene complexes on their ability to form hydrogen
bonds, and the relationship to cell uptake, DNA binding, and
cytotoxicity.7 Also, Miyaki et al. have investigated the for-
mation and the stability of several organometallic arene
ruthenium catalysts containing a pendant aliphatic arm with
a chelating heteroatom.8 Furthermore, Melchart et al.
synthesized a series of tethered neutral RuII complexes of
general formula [RuII(η6:η1-arene:N)Cl2], as well as the more
stable derivatives [RuII(η6:η1-arene:N)(oxalate)], and inves-
tigated their stability with regard to arene loss in solution and
suitability as cytotoxic bifunctional ruthenium agents.9,10
In the pursuit of controlled metal-complex activation,
Habtemariam et al. reported chelate ring-opening/closing
Organometallic Ru η6-arene complexes have well-known
applications in catalysis1 and are of increasing medicinal
interest.2-4 Complexes of general formula [RuII(η6-arene)-
(XY)Z], where XY is a chelating ligand and Z a labile
ligand, have shown encouraging potential as anticancer
agents.5 The activation of these complexes through hydro-
lysis of the Ru-Z bond is highly dependent on the degree of
lability of the leaving group, leading to activity in both
catalysis and nucleotide binding.6 Therefore, controlling
the activation of these bonds can provide a strategy for
achieving cytotoxic selectivity and contribute toward the
rational design process.
*To whom correspondence should be addressed. E-mail: p.j.sadler@
warwick.ac.uk.
(1) Noyori, R.; Ohkuma, T.; Sandoval, C. A.; Muniz, K. Asymmetric
Synth. 2007, 321–325.
(2) Melchart, M.; Sadler, P. J. In Bioorganometallics; Jaouen, G., Ed.;
Wiley-VCH: Weinheim, Germany, 2006; pp 39-64.
(3) Peacock, A. F. A.; Sadler, P. J. Chem.—Asian J. 2008, 3, 1890–1899.
(4) Renfrew, A. Chimia 2009, 63, 217–219.
(7) Scolaro, C.; Geldbach, T. J.; Rochat, S.; Dorcier, A.; Gossens, C.;
Bergamo, A.; Cocchietto, M.; Tavernelli, I.; Sava, G.; Rothlisberger, U.;
Dyson, P. J. Organometallics 2006, 25, 756–765.
(5) Habtemariam, A.; Melchart, M.; Fernandez, R.; Parsons, S.; Oswald,
I. D. H.; Parkin, A.; Fabbiani, F. P. A.; Davidson, J. E.; Dawson, A.; Aird,
R. E.; Jodrell, D. I.; Sadler, P. J. J. Med. Chem. 2006, 49, 6858–6868.
(6) Wang, F.; Habtemariam, A.; van der Geer, E. P. L.; Fernandez, R.;
Melchart, M.; Deeth, R. J.; Aird, R.; Guichard, S.; Fabbiani, F. P. A.;
Lozano-Casal, P.; Oswald, I. D. H.; Jodrell, D. I.; Parsons, S.; Sadler, P. J.
Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 18269–18274.
(8) Miyaki, Y.; Onishi, T.; Kurosawa, H. Inorg. Chim. Acta 2000,
300-302, 369–377.
(9) Melchart, M.; Habtemariam, A.; Novakova, O.; Moggach, S. A.;
Fabbiani, F. P. A.; Parsons, S.; Brabec, V.; Sadler, P. J. Inorg. Chem. 2007,
46, 8950–8962.
(10) Melchart, M. Ph.D. Thesis, University of Edinburgh, 2006.
r
pubs.acs.org/IC
Published on Web 03/05/2010
2010 American Chemical Society

Article
Inorganic Chemistry, Vol. 49, No. 7, 2010 3311
for square-planar bis(aminophosphine)platinum(II) and
palladium(II) complexes.11 They were able to control the
dynamics of the chelate formation, which was dependent not
only on the substituents and length of the tether but also on
the pH and chloride concentration of the aqueous solution.
Transition metal complexes with hemilabile chelating
ligands containing mixed funtionalities have been shown to
have potential applications as precursors in catalytic pro-
cesses, small-molecule activation, and molecule-based sen-
sors in recent years.12,13 The hemilability of a chelate can be
described as a (reversible) dynamic process that involves
dissociation and recoordination to the metal center of a
weakly bound donor.
In this work we have studied a Ru-arene complex with a
hemilabile amino-derivatized arene ligand, where the η6-
bound arene is inert to substitution but the amino group
offers two reversible functionalities: (i) binding to the RuII
center to form a tether-ring-closed (inactivated) complex, or
(ii) dissociation of the amine from the RuII center (as a
dangling arm) to afford an open-tether complex with a
pendant free amino group. In the open form the vacant site
on the ruthenium is occupied by either chloride or a solvent
molecule (activated complex). In aqueous solution, the
tether-ring dynamics are pH dependent, giving the potential
to finely tune the activation process to biological conditions,
for example, the acidic environment of the tumor.14
ESI-HR-MS (m/z): calcd for {C12H11Cl2NRu þ Na}þ, 363.9201;
found, 363.9202 (100%).
[Ru(η6-C6H5(C6H4)NH3)Cl3] (1 HCl). Complex 1, [Ru(η6:
3
η1-C6H5(C6H4)NH2)Cl2], (118 mg, 0.35 mmol) was suspended
in concentrated HCl (ca. 12 M, 15 mL) and left stirring at
ambient temperature in the dark for 18 h. Red crystals suitable
for X-ray diffraction were collected by filtration and washed
with 1 M HCl, ethanol and ether. Yield: 98 mg (75%). 1H NMR
(DMSO-d6): δ 7.38 (d, 1H, J = 7.5 Hz), δ 7.16 (t, 1H, J = 7.5
Hz), δ 6.79 (d, 1H, J = 7.5 Hz), δ 6.67 (t, 1H, J = 7.5 Hz), δ 6.22
(d, 2H, J = 6 Hz), δ 6.13 (t, 1H, J = 6 Hz), δ 5.95 (t, 2H, J = 6
Hz), δ 5.42 (bs, 2H). Anal. Calcd for C12H12Cl3NRu: C, 38.16;
H, 3.20; N, 3.71. Found: C, 38.45; H, 3.26; N, 3.76.
[Ru(η6:η1-C6H5(C6H4)NH2)(en)]Cl2 (2). Complex 1, [Ru(η6:
η1-C6H5(C6H4)NH2)Cl2], (119 mg, 0.35 mmol) was suspended
in 95% aqueous methanol (2 mL). Ethylenediamine (28 μL,
0.42 mmol) was added, and the mixture was stirred for 2 h at
ambient temperature. The solvent was removed in vacuo, and
complex 2 was isolated as a yellow powder. Yield: 49%. X-ray
diffraction quality crystals were obtained after reducing the
volume of the reaction mixture to one-quarter on a rotary
evaporator and storing at 277 K for 18 h. Yellow crystals were
obtained from the cold methanol solution affording the structure
of complex 2. 1H NMR (methanol-d4): δ 7.66 (d, 1H, J = 7.5 Hz),
δ 7.56 (t, 1H, J = 7.5 Hz), δ 7.51 (t, 1H, J = 7.5Hz), δ 7.45 (d, 1H,
J = 7.5 Hz), δ 6.23 (t, 2H, J = 6 Hz), δ 5.66 (d, 2H, J = 6 Hz), δ
5.50 (t, 1H, J = 6 Hz), δ 2.67 (m, 2H), δ 2.52 (m, 2H). 13C NMR
(D2O; 1,4-dioxan): δ148.9, 135.7, 130.2, 128.1, 127.1, 126.0, 109.8,
90.8, 77.8, 72.6, 45.0, 44.9. Anal. Calcd for C12H19Cl2N3Ru: C,
41.90; H, 4.77; N, 10.47. Found: C, 40.97; H, 4.80; N, 10.79. ESI-
MS (m/z): {C14H19N3Ru - H}þ, 330.0 (100%).
We have investigated the interconversion of the inactive
closed-ring complex [Ru(η6:η1-C6H5(C6H4)NH2)(en)]Cl2, 2,
and its activated open-tether ruthenium complex, [Ru(η6-
C6H5(C6H4)NH2)Cl(en)]Cl, 3, (as a function of the solvent
and pH), which can offer a vacant site on the metal ion for
substrate binding, with the aim of controlling the binding
availability of such RuII-arene derivatives.
[Ru(η6-C6H5(C6H4)NH2)Cl(en)]Cl (3). Complex 1, [Ru(η6:
η1-C6H5(C6H4)NH2)Cl2], (119 mg, 0.35 mmol) was suspended
in 95% aqueous methanol (2 mL). Ethylenediamine (28 μL,
0.42 mmol) was added, and the mixture was stirred for 2 h at
ambient temperature. The solvent was reduced to approxi-
mately 0.5 mL on a rotary evaporator, and the concentrated
solution was stored at 277 K for 18 h. Yellow crystals of complex
2 were filtered off from the cold methanol solution. A second
batch of orange crystals grew after a few days by slow gas
diffusion of tert-butylmethyl ether into the methanolic filtrate
at 277 K. The crystals obtained were suitable for X-ray ana-
lysis. 1H NMR (methanol-d4): δ 7.42 (d, 1H, J = 7.5 Hz), δ 7.21
(t, 1H, J = 7.5 Hz), δ 6.86 (d, 1H, J = 7.5 Hz), δ 6.81 (t, 1H, J =
7.5 Hz), δ 6.03 (d, 2H, J = 6 Hz), δ 5.99 (t, 1H, J = 6 Hz), δ 5.70
(t, 2H, J = 6 Hz), δ 2.53 (m, 2H), δ 2.39 (m, 2H).
Experimental Section
Materials. The diolefin ethyl-1,4-cyclohexadiene-3-carboxy-
late and [Ru(η6-etb)Cl2]2 (etb = ethyl benzoate) were prepared
as described elsewhere.9,15 2-Aminobiphenyl, ethylenediamine,
tetrahydrofuran (THF), tert-butylmethyl ether, (CD3)2SO (99%),
CD3OD (99.8%) and D2O (99.9%) were purchased from Sigma-
Aldrich. Ethylenediamine was distilled over sodium prior to
use. RuCl3 nH2O was purchased from Precious Metals Online
3
[Ru(η6-C6H5(C6H4)NH2)(DMSO-d6)(en)]Cl2 (4). Complex 2,
[Ru(η6:η1-C6H5(C6H4)NH2)(en)]Cl2, (2.3 mg, 5.7 μmol) was
dissolved in a minimum amount of DMSO-d6 (ca. 100 μL)
and left standing overnight at ambient temperature. Complex 4
precipitated out of solution when 1.5 mL of diethyl ether was
added. The solvent was removed from the brown solid by centri-
fugation, washed with ether, and dried in air. 1H NMR (DMSO-
d6): δ 7.38 (d, 1H, J = 7.5 Hz), δ 7.13 (t, 1H, J = 7.5 Hz), δ 6.79
(t, 1H, J = 7.5 Hz), δ 6.67 (d, 1H, J = 7.5 Hz), δ 6.60 (bs, 2H), δ
6.00 (t, 1H, J = 6 Hz), δ 5.97 (d, 2H, J = 6 Hz), δ 5.67 (t, 2H, J =
6 Hz), δ 5.28 (s, 2H), δ 4.11 (bs, 2H), δ 2.30 (m, 2H), δ 2.23 (m,
2H). 13C NMR (DMSO-d6): δ 146.8, 131.8, 130.2, 130.2, 118.8,
PMO Pty Ltd. and from Alfa Aesar. Hydrochloric acid, 1,4-
dioxane, 1,2-dichloroethane, acetone, diethyl ether, methanol,
and ethanol were supplied by Fisher Scientific. Ethanol was
dried over Mg/I2.
Preparations. [Ru(η6:η1-C6H5(C6H4)NH2)Cl2] (1). [Ru(η6-
etb)Cl2]2 (510 mg, 0.79 mmol) and 2-aminobiphenyl (270 mg,
1.60 mmol) were suspended in 1,2-dichloroethane (50 mL). The
mixture was stirred for 45 min at ambient temperature giving a
red solution. THF (2 mL) was added, and the mixture degassed
with argon for 30 min. The vessel was closed, and the reaction
mixture heated under pressure at 393 K for 18 h. The dark red-
brown, air-stable microcrystalline material was collected by
filtration, washed with acetone and diethyl ether, and dried in
air (488 mg, 90% yield). Anal. Calcd for C12H11Cl2NRu: C,
42.24; H, 3.25; N, 4.11. Found: C, 41.80; H, 3.11; N, 3.96.
117.5, 116.5, 97.8, 86.2, 84.1, 79.9, 44.7. IR (νS-O): 1101 cm-1
.
Methods and Instrumentation
(a). X-ray Crystallography. Diffraction data for compounds
1 HCl, 2, and 3 were collected at 150 K using a Bruker Smart
Apex CCD diffractometer. Absorption corrections for all data
(11) Habtemariam, A.; Watchman, B.; Potter, B. S.; Palmer, R.; Parsons,
S.; Parkin, A.; Sadler, P. J. J. Chem. Soc., Dalton Trans. 2001, 1306–1318.
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3
sets were performed with the multiscan procedure SADABS.16
(13) Bader, A.; Lindner, E. Coord. Chem. Rev. 1991, 108, 27–110.
(14) Griffiths, J. R. Br. J. Cancer 1991, 64, 425–427.
(15) Therrien, B.; Ward, T. R.; Pilkington, M.; Hoffmann, C.; Gilardoni,
F.; Weber, J. Organometallics 1998, 17, 330–337.
(16) Sheldrick, G. M. SADABS 2001-2004; University of Gottingen:
Gottingen, Germany, 2006.

3312 Inorganic Chemistry, Vol. 49, No. 7, 2010
Pizarro et al.
The structure of 1 HCl was solved by direct methods (SIR92),17
appropriate kinetic equation. OriginPro 8 SR2 (OriginLab
Corp., MA, U.S.A.) was used to fit the exponential decay and
to obtain the rate constant.
3
and that of 2 and 3 by Patterson methods (DIRDIF).18 Refine-
ment was against F2 using all data (CRYSTALS19 for 1 HCl
3
and 2 and SHELXL20 for 3). Hydrogen atoms attached to
nitrogen were found in difference maps, and the pattern of
H-bonding in the two structures is consistent with the positions
suggested. In 3, H-atoms on N11 were refined subject to the
restraint that the two NH distances are equal. All non-H atoms
were refined with anisotropic displacement parameters. The
programs ChemCraft,21 Mercury 1.4.1,22 and ORTEP 3223 were
used for analysis of data and production of graphics.
(g). pH Titrations. The pH titrations were followed by NMR
and UV-visible spectroscopy. Experiments were carried out at
298 K. The pH values were adjusted with dilute HClO4 or HNO3
for the acidic titration, and with KOH or NaOH for the basic
titration.
NMR Spectroscopy. The spectra were recorded at pH values
measured at about 298 K directly in the NMR tube, before
and after recording the 1H NMR spectra, using a Corning 145
pH meter equipped with an Aldrich micro combination elec-
trode, calibrated with Aldrich buffer solutions at pH 4, 7,
and 10.
The crystal structures of 1 HCl, 2, and 3 have been deposited
3
in the Cambridge Crystallographic Data Center under the
accession numbers CCDC 752219, 752220, and 752221, respec-
tively.
UV-vis Spectroscopy. An aqueous solution of complex 2
(830 μM) was prepared. pH values of the solution in H2O were
measured at about 298 K, before and after recording the spectra.
UV-vis spectra were recorded on a Varian Cary 300 UV-
visible spectrophotometer using 1 cm path-length quartz cuv-
ettes (volume 0.5 mL). Data were processed with OriginPro 8
SR2 (OriginLab Corp., MA, U.S.A.).
(b). NMR Spectroscopy. 1H NMR spectra were acquired for
samples in 5 mm NMR tubes at 298 K on either a Bruker DMX
500 or a Bruker AVA 600 NMR spectrometer, using TBI [1H,
13C, X] or TXI [1H, 13C, X] probeheads equipped with z-field
gradients. All of the data processing was carried out using
1
TOPSPIN version 2.0 (Bruker U.K. Ltd.). H NMR chemical
shifts were internally referenced to TSP via 1,4-dioxane (δ 3.76)
for aqueous solutions, CHD2OD (δ 3.31) for methanol-d4 or
(CHD2)(CD3)SO for DMSO-d6 (δ 2.50). 1D and 2D spectra
were recorded using standard pulse sequences, which were
modified by Dr. Dusan Uhrin and Mr. Juraj Bella, at the
University of Edinburgh. Water signals were suppressed using
presaturation or Shaka methods.24 All the experiments followed
by NMR were carried out in deuterated solvent at 298 K, with
exception of the experiment in aqueous solution where the
solvent was 90% H2O/10% D2O. Typically, 1 mg of complex
was dissolved in 1 mL of the solvent (ca. 2.5 mM), and 600 μL of
this solution was added to a 5 mm NMR tube.
(h). Computational Details. All calculations were performed
with the Gaussian 03 (G03) program25 employing the Density
Functional Theory (DFT) method. For complexes 2 and 3 the
correlation functionals PBE1PBE26 and B3LYP27,28 were used
with the LanL2DZ basis set29 and effective core potential for the
Ru atom and the 6-31G** basis set30 for all other atoms.
Geometry optimizations of 2 and 3 in the ground state were
performed in the gas phase. Furthermore, geometry optimiza-
tion at the PBE1PBE/LanL2DZ/6-31G** level of 2 plus a Cl-
counterion [2þCl] and 2 plus a H2O molecule [2þH2O] were
obtained to compare the stability of complexes 2, 3, and [5þH]
(coordinated H2O instead of OH-). The nature of all stationary
points was confirmed by normal-mode analysis. The conductor-
like polarizable continuum model method (CPCM)31 with water
as solvent was used to calculate the electronic structure and the
excited states of 2 and 3, [2þCl] and 5 in aqueous solution.
Thirty-two singlet excited states and the corresponding oscilla-
tor strengths were determined with a time dependent DFT (TD-
DFT)32,33 calculation. Only selected electronic transitions are
reported. The electronic distribution and the localization of the
singlet excited states were visualized using electron density
difference maps (EDDMs).34-36 GaussSum 1.0537 was used
for EDDMs calculations and for the electronic spectrum simu-
lation. Results of all calculations are summarized in detail in the
Supporting Information Section.
(c). Elemental Analysis. CHN elemental analyses were per-
formed on a CE-440 Elemental Analyzer by Exeter Analytical
(U.K.) Ltd.
(d). MS. Electrospray ionization mass spectra (ESI-MS)
were obtained on a Micromass Platform II mass spectrometer,
and aqueous solutions were infused directly. The capillary
voltage was 3.5 V, and the cone voltage was varied between
20 and 45 V depending on sensitivity. The source tempera-
ture was 353 K. Mass spectra were recorded with a scan range
of m/z 250-1200 for positive ions. High resolution MS data
were obtained using a Bruker MicroTOF, Bruker MaXis mass
spectrometer.
(e). IR. FT-IR spectra were acquired at ambient temperature
as dimethylsulfoxide (DMSO) solutions (4000-600 cm-1) on a
Perkin-Elmer Paragon 1000 spectrometer.
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Wallingford, CT, 2004.
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(f). Analysis of Tethered-Arene Ring-Opening/Closure in So-
1
lution. In the time-course H NMR experiments, the time of
dissolution of the reactants was taken as t = 0. 1H NMR spectra
were recorded at convenient intervals until no further changes
were observed.
The data of the time-course dynamics of the tethered chelate
in different solvents, based on peak integrals, were fitted to the
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Article
Inorganic Chemistry, Vol. 49, No. 7, 2010 3313
Chart 1. Ruthenium(II) Arene Complexes Studied in This Work
amine protons peaks of the pendant-arm NH2, in the two-
dimensional (2D) [1H,1H] NOESY NMR spectrum. The
closed tether (2) showed NOE correlations between the
NH2 of the tether and the NH2(en) and the CH2(en)
signals. The open tether (4) showed no NOE correlations
for the NH2 of the tether. A cross peak between the NH2
of the tether and the signal of residual water in DMSO-d6,
indicated that these protons exchange chemically with
one another.
Complex 4, [Ru(η6-C6H5(C6H4)NH2)(DMSO-d6)(en)]2þ
,
was isolated by precipitation, characterized by NMR (see
Supporting Information, Figure S1) and IR spectroscopy
but was not further purified. The IR spectrum of complex
4 showed a band at 1101 cm-1 assignable to the S-O
stretching frequency for S-bonded sulphoxide.38 This is
at higher frequency compared to the free ligand (νS-O
=
1050 cm-1), thus confirming unequivocally that the
DMSO is bound through the S.39,40 S-coordination of
DMSO has been reported to predominate in RuII(η6-
arene) species.41-44
Complex 5, [Ru(η6-C6H5(C6H4)NH2)(en)(OH)]þ, was
formed during a basic titration, by adding strong base
(0.1 M NaOH) to an aqueous solution of complex 2 (vide
infra). It was characterized by 1H NMR in aqueous solu-
tion at pH > 9 (see Supporting Information, Figure S2).
1
The H NMR signals of the unbound arene appeared at
7.39-6.98 ppm and those assignable to the bound arene at
5.88-5.70 ppm. The amine proton signals for the en ligand
were at 6.02 and 3.47 ppm, for the NH proton pointing up
toward the arene ligand and down away the arene ligand,
respectively. The CH2(en) proton signals appeared as a
complex signal centered at 2.48 ppm. Characterization
of 5 was further confirmed by UV-vis spectra (experi-
mental and theoretical by DFT calculations), where an in-
tense ligand-centered (2-aminophenyl) transition at about
300 nm appearing at pH>10 confirms the presence of the
open tether (vide infra).
Results
Synthesis and Characterization. The synthesis of the
amino-tethered dichlorido RuII arene complex 1, [Ru(η6:
η1-C6H5(C6H4)NH2)Cl2], was based on a variation of a
published method.9,15 The thermal displacement of ethyl
benzoate in the dimer [Ru(η6-etb)Cl2]2 (etb=ethyl ben-
zoate) by 2-aminobiphenyl in 1,2-dichloroethane under
pressure resulted in the formation of complex 1.
Reaction of 1 with 12 M HCl for 18 h at ambient
temperature afforded X-ray quality crystals of complex
1 HCl. Reaction of [Ru(η6:η1-C6H5(C6H4)NH2)Cl2] (1)
X-ray Crystal Structures and DFT-Optimized Geome-
3
and [Ru(η6-C6H5(C6H4)NH3)Cl3] (1 HCl) with ethylene-
tries. The X-ray crystal structures of [Ru(η6-C6H5-
3
diamine in aqueous methanol at ambient temperature
gave [Ru(η6:η1-C6H5(C6H4)NH2)(en)]Cl2 (2) as a yellow
powder after removal of the solvent. In the case of
(C6H4)NH3)Cl3] (1 HCl), [Ru(η6:η1-C6H5(C6H4)NH2)-
3
(en)]Cl2 (2), and [Ru(η6-C6H5(C6H4)NH2)Cl(en)]Cl (3)
were determined. Their structures and atom numbering
schemes are shown in Figure 1. Crystallographic data and
selected bond lengths and angles are shown in Tables 1
and 2, respectively. The complexes adopt the expected
pseudo-octahedral “three-legged piano-stool” geometry
with the ruthenium η6-bonded to the arene ligand (Ru to
1 HCl, a 30% mol excess of the diamine was required
3
to afford complex 2 in low yield. Isolation of the open-
tether [Ru(η6-C6H5(C6H4)NH2)Cl(en)]Cl (3) from meth-
anolic solutions by standard purification techniques
was unsuccessful on account of its hygroscopic nature.
Only through the growth of crystals could pure com-
plex 3 be isolated, in low yield, and X-ray determina-
tion was crucial in the unequivocal assignment of its
structure.
˚
centroid of bound ring, 1.65-1.67 A), and σ-bonded to
three additional ligands which constitute the three legs of
the stool. For compound 1 HCl, the three ligands are
˚
3
three chlorides (2.41-2.44 A), for compound 2 and 3
two of the three positions are occupied by two nitrogen
1
CHN elemental analysis, H NMR, and IR spectro-
scopy were used to characterize complexes 1-3, including
1 HCl, (Chart 1). X-ray crystallography aided the char-
acterization of complexes 1 HCl, 2, and 3.
3
(38) Nakamoto, K. Infrared and Raman Spectra of Inorganic and Co-
ordination Compounds; John Wiley: New York, 1986.
(39) Bora, T.; Singh, M. M. Trans. Met. Chem. 1978, 3, 27–31.
(40) Alessio, E.; Balducci, G.; Calligaris, M.; Costa, G.; Attia, W. M.;
Mestroni, G. Inorg. Chem. 1991, 30, 609–618.
(41) Chen, H. Ph.D. Thesis, University of Edinburgh, 2003.
(42) Beasley, T. J.; Brost, R. D.; Chu, C. K.; Grundy, S. L.; Stobart, S. R.
Organometallics 1993, 12, 4599–4606.
(43) Chandra, M.; Pandey, D. S.; Puerta, M. C.; Valerga, P. Acta
Crystallogr., Sect. E: Struct. Rep. Online 2002, E58, m28–m29.
(44) Mashima, K.; Kaneko, S.-i.; Tani, K.; Kaneyoshi, H.; Nakamura, A.
J. Organomet. Chem. 1997, 545-546, 345–356.
3
1
The H NMR signals of the η6-bound arene for com-
plexes 1 HCl, 2, 3, 4, and 5 are shifted to high field (by up
3
to ca. 2 ppm) and of the unbound phenyl ring on the
tethered arm for complexes 1 HCl, 3, 4, and 5 (open
tethers) to low field, by up to about 0.3 ppm and by up to
0.8 ppm for complex 2 (closed tether), compared to the
free ligand in the same solvent. Assignment for complexes
2 and 4 in DMSO-d6 was carried out by analysis of the
3

3314 Inorganic Chemistry, Vol. 49, No. 7, 2010
Pizarro et al.
Table 1. Crystallographic Data for [RuII(η6-C6H5(C6H4)NH3)Cl3], 1 HCl, [RuII-
3
(η6:η1-C6H5(C6H4)NH2)(en)]Cl2, 2, and [RuII(η6-C6H5(C6H4)NH2)Cl(en)]Cl, 3
1 HCl
3
2
3
formula
MW
crystal description red block
C12H12Cl3NRu C14H19Cl2N3Ru C14H19Cl2N3Ru
377.66
401.30
yellow block
401.29
orange block
0.24 ꢀ 0.23 ꢀ
0.23
crystal size (mm) 0.61 ꢀ 0.49 ꢀ 0.48 ꢀ 0.23 ꢀ
0.24
0.71073
150
0.20
0.71073
150
˚
λ (A)
T (K)
0.71073
150
crystal system
space group
monoclinic
P21/n
13.1377(4)
6.8928(2)
15.0526(5)
90
110.648(2)
90
1275.54(7)
4
orthorhombic monoclinic
P212121
9.0448(2)
11.0210(3)
15.7360(4)
90
P21/c
˚
a (A)
11.5327(9)
9.2986(7)
14.9108(11)
90
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
90
90
108.770(5)
90
3
˚
vol (A )
Z
1568.61(7)
4
1514.0(2)
4
R [F > 4σ(F)]a
Rw
0.0235
0.0618
1.0634
0.0186
0.0485
0.7529
0.0401
0.1081
1.050
b
GOFc
ΔF max and
min (e A
0.61 and -0.65 0.39 and -0.30 1.286 and -1.335
-3
˚
)
P
P
P
P
2
2 2
2 1/2
] .
aR = ||Fo| - |Fc||/ |Fo|. b Rw = [ w(Fo - Fc ) / wFo
P
c GOF = [ [w(Fo2 - Fc ) ]/(n - p)]1/2, where n = number of reflections
2 2
and p = number of parameters.
˚
Table 2. Selected Bond Lengths (A) and Angles (deg) for Complexes 1 HCl,
2, and 3
3
˚
bond length (A)/
angle (deg)a
1 HCl
3
2
3
Ru1-X
2.4053(5)
2.4367(4)
2.4175(5)
2.1970(18)
2.1798(18)
2.1799(18)
2.1591(18)
2.1707(18)
2.1721(19)
1.466(2)
2.1368(17)
2.1196(17)
2.1481(17)
2.113(2)
2.188(2)
2.197(2)
2.206(2)
2.195(2)
2.185(2)
1.464(2)
1.501(3)
79.85(7)
89.87(6)
86.63(7)
85.15
2.120(4)
2.141(4)
2.4006(12)
2.238(5)
2.200(5)
2.182(5)
2.166(5)
2.162(5)
2.173(5)
1.406(6)
1.483(7)
79.36(15)
85.95(11)
85.77(11)
51.83
Ru1-Y
Ru1-Z
Ru1-C7
Ru1-C8
Figure 1. X-ray structures and atom numbering schemes for com-
Ru1-C9
plexes (A) [RuII(η6-C6H5(C6H4)NH3)Cl3], 1 HCl; (B) [RuII(η6:η1-C6H5-
3
Ru1-C10
Ru1-C11
Ru1-C12
C1-N11
(C6H4)NH2)(en)]Cl2, 2; and (C) [RuII(η6-C6H5(C6H4)NH2)Cl(en)]Cl, 3;
50% probability ellipsoids. The H atoms (except on the nitrogen pendant
from the tether) and counterions are omitted for clarity.
C6-C7
1.489(2)
˚
atoms of the ethylenediamine chelate (2.12-2.14 A). The
third position is occupied by a nitrogen, pendant from the
X-Ru1-Y
X-Ru1-Z
Y-Ru1-Z
dihedral angle
Ru1-centroidb
offset C6c
87.049(16)
87.532(17)
86.288(17)
54.48
1.647
<0.02 (þ)
˚
˚
tethered arene in 2 (2.15 A), and a chloride in 3 (2.40 A).
RuII-Cl and RuII-N bond lengths are in agreement with
values reported previously for arene complexes.45,46
All three complexes crystallized with four molecules
in the unit cell. The biphenyl unit is twisted by 54° and 52°
1.654
0.488 (-)
1.666
0.055 (þ)
a Atom labeling scheme used for purposes of comparison only. The
crystallographic atom labeling schemes for individual complexes are
different and specified in Figure 1. b Measured using Mercury 1.4.1.
c Offset of C6 with respect to the plane formed by bound arene (carbons
C7-C12). (þ) away from ruthenium; (-) toward ruthenium.
in 1 HCl and 3, respectively, and 85° in 2. Adjacent
molecules crystallized with their bound arenes parallel
3
(45) Morris, R. E.; Aird, R. E.; Murdoch, P. d. S.; Chen, H.; Cummings,
J.; Hughes, N. D.; Parsons, S.; Parkin, A.; Boyd, G.; Jodrell, D. I.; Sadler,
P. J. J. Med. Chem. 2001, 44, 3616–3621.
(46) Chen, H.; Parkinson, J. A.; Parsons, S.; Coxall, R. A.; Gould, R. O.;
Sadler, P. J. J. Am. Chem. Soc. 2002, 124, 3064–3082.
to each other. The extended crystal structure of 1 HCl
3
showed intermolecular π-π stacking of the unbound are-
nes with a distance between arene centroids of 3.65 A, and
˚

Article
Inorganic Chemistry, Vol. 49, No. 7, 2010 3315
˚
between parallel planes of 3.35 A (Supporting Informa-
tion, Figure S3). The two rings are offset such that the ring
normal and the vector between the arene centroids form
an angle of 22°. The crystal structure of complex 3 did not
show π-π stacking, despite the fact that the unbound
phenyl rings are parallel. The dihedral angle between the
two quasi-parallel rings is 3.5°. The chloride ligands in
1 HCl are extensively involved in H-bonding with the
3
NH3(tether) hydrogens (N-H Cl distance 2.25-2.53
3 3 3
˚
A). In complex 3, the chlorides (both counterion and
ligand) are involved in H-bonding to the NH2(tether)
hydrogen atoms (N-H Cl distances of 2.55 and
3 3 3
˚
2.61 A) and to the hydrogen atoms on the NH2(ethyl-
enediamine) ligand (N Cl distances in the range
˚
3 3 3
3.10-3.47 A). In complex 2, the chloride counterions
also appear to be involved in H-bonding to the ethylen-
Figure 2. Conversion over time of [RuII(η6:η1-C6H5(C6H4)NH2)(en)]2þ
2 (2.9 mM; black squares) into [RuII(η6-C6H5(C6H4)NH2)(DMSO-d6)-
(en)]2þ, 4 (white squares), over time at 298 K by displacement of the NH2
group in the tether arm of 2 by a molecule of solvent in DMSO-d6. The
solid lines represent computer best fits of a pseudo-first order reaction
,
˚
diamine ligand (N Cl distances 3.17 and 3.26 A) or the
3 3 3
˚
NH2(tether) (N Cl distances 3.24 and 3.25 A).
3 3 3
giving a rate constant of 4.81 ( 0.23 ꢀ 10-5 s-1
.
The DFT optimized structures of 2 and 3 are in
agreement with the X-ray data, although both the func-
tionals employed tend to overestimate bond distances
(B3LYP in particular). When a Cl- counterion is in-
cluded in the geometry optimization of 2, [2þCl], the
computed bond distances have a better agreement with
the experimental ones (Supporting Information, Table
S1). Interestingly, energy comparison between the struc-
ture of closed-tether [2þCl] and open-tether 3 in the gas
phase shows that the latter is about 17 kcal/mol more
stable (Supporting Information, Figure S4). Further-
more, DFT calculations show that the closed-tether 2
(calculated as [2þH2O]) is 5.8 kcal/mol more stable than
its open form coordinating a H2O molecule, [5þH]
(Supporting Information, Table S1).
Solution Studies of the Tethered-Arene Chelate. The
dynamics of the tethered-arene chelate in different sol-
vents were investigated by NMR spectroscopy.
Figure 3. Relative populations in methanol solution of [RuII(η6:η1-
C6H5(C6H4)NH2)(en)]2þ, 2 (2.9 mM; black squares), and [RuII(η6-C6H5-
(C6H4)NH2)Cl(en)]þ, 3 (white squares), over time at 298 K by displace-
ment of the NH2 group in the tether arm of 2 by a chloride ion. The plots
show fits to single-exponential functions giving a half-life of about 5 h.
In (CD3)2SO, complex 2 formed the open-tethered
DMSO adduct complex 4, [Ru(η6-C6H5(C6H4)NH2)-
(DMSO-d6)(en)]2þ, over 18 h. The NH2 on the pendant
arm of the arene ligand dissociated from the ruthenium
and was substituted by a molecule of DMSO. The ESI-
MS fragment observed at 449.33 m/z is assignable to the
species {C16H18D6ClN3ORuS}þ, confirming formation
of cation 4 (Supporting Information, Figure S5). The
conversion of complex 2 into complex 4 in DMSO-d6 was
followed by NMR spectroscopy. The data were obtained
1
ratio 70% to 30%, respectively. The recorded H NMR
spectra showed little change even when the sample was
kept at room temperature for 50 days.
When complex 2 was dissolved in water no change was
1
observed in the H NMR spectrum up to a period of
3 days at pH about 7. When complex 3 was dissolved in
water, however, it was fully converted to complex 2 within
2 h (Figure 4). The conversion of the open-tether complex
3 into closed-tether complex 2 in water was followed
1
by integration of H NMR peaks in spectra recorded at
various time intervals at 298 K and were fitted to pseudo-
first order reaction kinetics (Figure 2). At 298 K, the rate
constant for this reaction is 4.81 ( 0.23 ꢀ 10-5 s-1, and
the half-life is about 4 h (237 min). The spectrum showed
little change when the sample was kept at ambient
temperature for a period of 10 days.
In methanol, complex 2 formed the open-tethered
monocation complex 3 within 12 h. The Ru-N bond
involving the pendant arm NH2 is dissociated, and the
amine is substituted by a chloride ligand (two equivalents
present in solution, as counterions of the ruthenium-
arene dication complex 2). The time-course reaction was
followed by 1H NMR spectroscopy, and the data for the
conversion of 2 into 3 in methanol were fitted to a single-
exponential function (Figure 3). At 298 K, the half-life is
about 5 h. Complexes 3 and 2 exist in equilibrium in a
1
by H NMR spectroscopy. The time-course data were
fitted to first-order kinetics. At 298 K, the rate constant
of this reaction is 4.71 ( 0.11 ꢀ 10-4 s-1 with a half-life of
24 min.
An aliquot of an aged DMSO solution containing the
open-cation [Ru(η6-C6H5(C6H4)NH2)(DMSO)(en)]2þ (4)
was diluted with D2O to a final concentration of 10%
DMSO. Within 2 h complex 4 was totally converted to
the closed form 2 (Supporting Information, Figure S6).
At 298 K, the rate constant for this first order reaction is
5.59 ( 0.10 ꢀ 10-4 s-1 with a half-life of 20 min. When
an aliquot of the aged DMSO solution was diluted into
brine (prepared in D2O) to a final concentration of 10%
DMSO, complex 2 formed over time and equilibrium was
reached after about 4 h (see Supporting Information,

3316 Inorganic Chemistry, Vol. 49, No. 7, 2010
Pizarro et al.
Figure 4. Conversion of [RuII(η6-C6H5(C6H4)NH2)Cl(en)]þ, 3 (2.9 mM;
white circles) into [RuII(η6:η1-C6H5(C6H4)NH2)(en)]2þ, 2 (black circles),
over time at 298 K by displacement of the chloride ligand in 3 by the NH2
group in the tether arm to form 2 in water. The plots represent computer
best fits of a first order reaction giving a rate constant of 4.71 ( 0.11 ꢀ
10-4 s-1
.
Figure S7). At equilibrium, the ratio of the two complexes
2:4 was 87%:13%. The equilibrium constant was 6.7
at 298 K.
Effect of pH. Acid Titration. Complex 2 was dissolved
in H2O/D2O (9:1) (ca. 2.9 mM). 1H NMR peaks of
complex 2 did not shift or vary in intensity throughout
the pH range 7-2, nor over 24 h at pH 2. The tether
chelate opened when complex 2 was reacted in 12 M HCl
for 18 h. The NH2 group of the pendant arm dissociated
from ruthenium and was protonated to give [Ru(η6-
C6H5(C6H4)NH3)Cl(en)]2þ. This assignment was based
Figure 5. pH dependence of the signals corresponding to the η6-bound
arene region of 1H NMR spectra of [RuII(η6:η1-C6H5(C6H4)NH2)-
(en)]Cl2, 2, in H2O/D2O (9:1). Refer to the structure for assignment of
the arene signals. *The broad NMR peaks at 6.6 ppm and 6.0 ppm
correspond to the ethylenediamine NHu protons (protons pointing up
toward the η6-arene) of 2 and 5, respectively.
1
on analysis of the H NMR signals of an aliquot of
the acidic solution diluted with DMSO-d6 (Supporting
Information, Figure S8), and comparison with those of
complex 4 in DMSO-d6.
Base Titration. A new set of 1H NMR peaks appeared
during the titration of 2 with NaOH, over the pH range
6-12 (Figure 5). At pH 9, a complete set of new signals
was observed, and their intensity increased as the solution
approached pH 12. The new signals were attributed to the
formation of an open-tether complex on the basis of the
chemical shift pattern. The species was assigned as com-
plex 5, [Ru(η6-C6H5(C6H4)NH2)(en)(OH)]þ.
The increase in intensity of the resonance peaks of
complex 5 was accompanied by a concurrent decrease in
the intensity of peaks for complex 2, which disappeared
altogether at about pH 12. Incidentally, the diminishing
peaks of 2 also shifted toward higher field as pH 12 was
approached.
Figure 6. Changes in absorbance in the range 200-600 nm upon
increasing pH in an aqueous solution of complex 2 (0.8 mM) at 298 K.
The band at about 300 nm is assignable to complex 5.
The conversion of 2 into 5 was fully reversible, as shown
by NMR spectroscopy. On neutralization of the basic
solution with dilute HNO3, the H NMR signals corre-
sponding to complex 2 reappeared, while those signals
attributed to complex 5 disappeared.
The pH-effect on complex 2was also followed by UV-vis
spectroscopy (Figure 6). Assignment of the UV-vis spec-
trum of 2 was obtained through calculating 32 singlet
transitions with the TD-DFT method (Supporting Infor-
mation, Figures S9-S11). The low-energy band at 340 nm is
metal-centered in character, as well as the more intense band
at about 300 nm. The highest energy band is mainly
composed of transitions with a metal-to-ligand charge-
transfer character, where electron density migrates from
the metal center to the 2-aminophenyl ligand.
The basic titration (pH range 6-12) of the aqueous
solution of 2 showed an increase in the absorbance band
at about 300 nm as the pH was increased. Such behavior is
consistent with the opening of the tethered complex 2 and
the formation of 5. The TD-DFT predicted UV-vis
spectrum of 5 showed, in fact, an intense ligand-centered
(2-aminophenyl) transition at 309 nm (Supporting Infor-
mation, Figures S12 and S13). Similarly, the calculated
UV-vis spectrum of the open-tether complex 3 had an
intense ligand-centered band in the same region (Support-
ing Information, Figures S14 and S15). When the pH was
decreased to pH 8, the bands in the experimental spec-
trum decreased in intensity to those of the initial UV-vis
trace, showing complete reversibility, in agreement with
1

Article
Inorganic Chemistry, Vol. 49, No. 7, 2010 3317
the results obtained by NMR. Further acidification of the
solution to pH 3 did not result in any further change to the
UV-vis spectrum.
been able to correlate this reactivity with the strength of the
Ru-arene bond.7 It has been suggested that a more rigid
tether backbone would decrease the stability of the Ru-
coordinated arene and lead to arene loss by weakening of
the RuII-η6-arene bond.10 Melchart et al. observed an
improvement in the stability of the coordinated arene in
the complex [RuII(η6:η1-C6H5(CH2)2NH2)(oxalate)] (only
ca. 16% decomposed in 24 h) in comparison to its dichlo-
rido analogue [RuII(η6:η1-C6H5(CH2)2NH2)Cl2] (fully de-
composed within 8 h).10 The improvement was attributed
to the stabilizing effect of the bidentate oxalate ligand. In
the present work arene-loss related decomposition was not
observed for 2 in any of the solvents used. The stabilization
gained by the presence of the chelating ethylenediamine
leads to a ruthenium center fixed in a rigid and stable
bicyclical framework and may account for the strong
binding between ruthenium and the arene in 2.
Discussion
As a potential strategy for the controlled activation of RuII
arene anticancer complexes, we have synthesized tethered
complexes which, upon dissociation of a RuII-Ntether bond,
offer a vacant site for biomolecule interaction. Dissociation is
promoted by the strain generated by the 5-membered chelate
ring and is aided by solvent coordination. Tether ring-open-
ing is a potentially useful concept in anticancer drug design.
Synthesis, Stability, and Characterization. The arene
exchange reaction used to obtain complex 1 from the di-
mer [Ru(η6-etb)Cl2]2 appears tobefavored in1,2-dichloro-
ethane at high temperatures in a pressure vessel.10 Almost
quantitative yields were achieved under the above con-
ditions. The mechanism by which pressure influences the
yield is not clear. However, it could assist in overcoming
activation barriers between the tether arene and the
ruthenium center.
X-ray Crystal Structures. The structural constraints
within the closed-tether complex 2 are apparent from the
orientation of the two phenyl rings which are almost
perpendicular to each other with a dihedral or torsion
angleof85°, incomparison with the smallerbiphenyltwists
The neutral dichlorido complex 1, [RuII(η6:η1-C6H5-
(C6H4)NH2)Cl2], appeared to be insoluble in most
common solvents, whereas related complexes, such as
[RuII(η6-p-cymene)Cl2(p-methylaniline)], and [RuII(η6-
benzene)Cl2(p-methylaniline)] are reported to be soluble
in dichloromethane and/or in chloroform.47,48 After pro-
longed sonication, complex 1 appeared to dissolve in
DMSO-d6 but detailed examination of the 1H NMR
spectrum showed a chemical shift pattern consistent with
the open tether [RuII(η6-C6H5(C6H4)NH2)Cl2(DMSO)],
where the NH2(tether) in 1 was displaced by a DMSO
molecule.
of 54° and 52° in 1 HCl and 3, respectively. The replace-
3
ment of the NH2 group of the pendant arm by a phosphino
group does not appear to show structural differences with
regard to the biphenyl twists (69-88°).50-56 However, the
distances between the centroids of the bound arenes and
the ruthenium centers appear to be longer (ranging from
˚
˚
1.684 to 1.791 A) than in 2 (1.654 A). Further evidence for
the strain within the structure of 2 is the observation that
the distance between the central ruthenium atom and the
˚
NH2 group of the pendant arm (2.148 A) is significantly
longer than those of the Ru-N bonds of ethylenediamine
in the same complex (2.120 and 2.137 A). In addition, the
˚
Detailed analysis of NMR signals of the RuII com-
1
plexes showed similar chemical shift patterns for the H
NMR signals of the open- (1 HCl, 3, 4, and 5) and closed-
differences in the distances between Ru-Cipso and Ru-
Cpara for the η6-bound arene (Ru1-C7 and Ru1-C10 in
3
˚
Table 2) are 0.04, 0.09, and 0.07 A for 1 HCl, 2, and 3,
3
(2) tethers in different solvents. The chemical shifts of the
proton resonances of the η6-arene and phenyl ring pro-
tons in the pendant arm turned out to be useful markers to
follow the dynamics of tether ring-opening and closing in
solution.
respectively, suggesting that the tilt in the η6-bound arene
is more pronounced for 2 than for the other open-tethered
complexes 1 HCl and 3. The tilt is toward the ipso carbon
3
only for 2 in this work and not for complexes 1 HCl and 3.
3
This is again attributable to the constraints imposed by
the closure of the tethered arm. A similar tilt has been
reported for the crystal structure of a related analogue
[RuII(η6:η1-C6H5(C6H4)NH2)(oxalate)].10 Conformational
constraints have been reported in aliphatic two-carbon
tethers compared with less strained three- and four-
carbon tethers, which has been related to the difference
in catalytic activity in asymmetric hydrogenation of aro-
matic ketones.57
Strongly coordinating solvents such as acetonitrile or
DMSO are known to be capable of displacing arenes from
RuII complexes such as [Ru(η6-arene)Cl2(L)]. These com-
plexes are often not stable in such solvents and can convert
totally to species such as [RuCl2(solvent)4],49 or lose the
arene upon oligonucleotide coordination as shown for
complexes where the arene is benzene, p-cymene, phenyl-
ethyl alcohol, or N,N-dimethylbenzylamine and L is a
phosphine derivative, such as PTA.7 Arene-loss-related
decomposition has also been documented for tethered
RuII-arene complexes with 5-membered tethered rings,
such as [RuII(η6:η1-C6H5(CH2)2NH2)Cl(phosphine)]þ,7
and [RuII(η6:η1-C6H5(CH2)2NH2)Cl2].9 The phosphine-
containing tethered complex undergoes more arene-loss
than open-tether analogues. DFT calculations have not
The relatively short distance observed for C1-N11 in 3
˚
(1.407 A) compared to 1 HCl (1.466 A) and 2 (1.464 A) is
˚
˚
3
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(56) Aikawa, K.; Kaito, I.; Mikami, K. Chem. Lett. 2007, 36, 1482–1483.
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98–99.
(47) Bates, R. S.; Begley, M. J.; Wright, A. H. Polyhedron 1990, 9, 1113–
1118.
(48) Begley, M. J.; Harrison, S.; Wright, A. H. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1991, C47, 318–320.
(49) Valerga, P.; Puerta, M. C.; Pandey, D. S. J. Organomet. Chem. 2002,
648, 27–32.

3318 Inorganic Chemistry, Vol. 49, No. 7, 2010
Pizarro et al.
consistent with the absence of coordination/protonation
of the NH2(tether), since C-NH2 distances appear to be
shorter when the lone pair of electrons on the nitrogen is
not involved in coordinative or covalent binding.58-60
The presence of an NH2-ended tether in a metal complex,
which is neither coordinated to the metal center nor
protonated is unprecedented, all other examples in the
literature appear to show the metal-free amino-tether
protonated.7,8,61
Solution Chemistry. The driving force for tether-open-
ing is thought to be the relaxation of strain imposed by the
rigid five-membered ring containing an aromatic back-
bone, together with the coordination of a monodentate
ligand. The higher extent of formation of the ring-opened
complex 3in methanol is consistent with the results obtained
by DFT calculations in the gas phase, which showed a
higher stability for 3 compared to [2þCl] (ca. 17 kcal/mol)
(Supporting Information, Figure S4). Mijaki et al. have
reported that complexes of general formula [Ru(η6:η1-
C6H5(CH2)3OH)Cl(PR3)]BF4 (R = Ph or Et) and [Ru(η6:
η1-C6H5(CH2)3OH)(N,N0)](BF4)2 ring-open in the pre-
sence of Cl- to give the open-tether chlorido complexes
in almost quantitative yields. The reason for this facile
ring-opening is the weakness of the metal-oxygen bond.
Amino chelate complexes such as [Ru(η6:η1-C6H5(CH2)n-
NH2)Cl(PPh3)]BF4 (n = 2, 3), however, remained in their
closed state in the presence of chloride ions.8 Melchart
Figure 7. HOMO orbital of complex 3 (PBE1PBE/LanL2DZ/6-31G**,
isovalue 0.02).
phino group contributed to opening the ring by weakening
of the Pt-N bond. In the case of the chelating rings
containing primary amines, ring-opening was induced by
protonation of the amine group.11
ꢀ
et al. observed the same stability vis-a-vis tether-opening
Ring-closure of the tether appears to be highly favored
in aqueous solution (neutral pH) as shown by the short
half-life (24 min) for the conversion of chlorido complex 3
to tethered complex 2 in water and DMSO complex 4 to 2
in DMSO/water (1:9) (20 min, 298 K), which involve
displacement of chloride and DMSO (Figure 4 and
Supporting Information, Figure S5), respectively, by the
tether arm amino group. In the presence of a large excess
of chloride ions, the chelation of the tether was inhibited
by up to 13% (Supporting Information, Figure S6),
which highlights the competition of the Cl- ions with
the NH2(tether) for the vacant site on the ruthenium
center. The DFT calculations showed that the highest
occupied molecular orbital (HOMO) orbital of complex 3
has an overlap between a p orbital of the NH2 group and a
d orbital of the metal center (Figure 7). This interaction
may readily promote the closing of the tether under
aqueous conditions, where Cl- release is facilitated.
At basic pH (9-12) formation of the hydroxido com-
plex 5 was observed as a result of nucleophilic attack by
hydroxide on the ruthenium center in a concerted event
likely assisted by H-bonding. Complete tether-ring-open-
ing interconversion of 2 into 5 occurs at pH 12 (Figure 5).
Such behavior was unexpected as protonation of the NH2
group was believed to be crucial for the Ru-N bond
dissociation (vide supra).
for the two- and three-carbon tethered complexes of for-
mula [Ru(η6:η1-C6H5(CH2)nNH2)Cl2] (n = 2, 3), where
the release of the ring strain in DMSO came about
through dissociation of the η6-arene (more extensive and
faster for the more strained two-carbon tether), but not
through dissociation of the Ru-Ntether bond. Mijaki et al.
also reported the open-tether complex [Ru(η6-C6H5-
(CH2)2N(CH3)2)Cl2(PPh3)], where closure of the chelat-
ing tether was not favorable because of the steric hind-
rance imposed by a tertiary amine.8,62 Scolaro et al.
showed that the complex [Ru(η6-C6H5(CH2)2NH3)Cl2-
(phosphine)]Cl can only be maintained in a tether-open
state by protonation.7 In the case of 2, acid titration (down
to pH 2) and keeping the solution at that pH for 24 h
did not result in ring-opening. This could only be
achieved by the use of a large excess of hydrochloric acid
(12 M) over 18 h, resulting in the formation of [Ru(η6-
C6H5(C6H4)NH3)Cl(en)]2þ. These results suggest that
the opening of the tether under acidic conditions is
thermodynamically favorable but kinetically slow. Hab-
temariam et al. reported the chelate ring-opening dy-
namics of aminophosphine complexes of general for-
mula [M(R1R2N(CH2)nPPh2)2]2þ, (M = PtII or PdII) in
water,11 and were abletocontrol ring-opening and -closure
by factors such as ring size (n = 2 or 3) and substi-
tuents on the coordinating nitrogen atom (R1 and R2 =
H, Me, benzyl, cyclohexyl). The trans effect of the phos-
In addition, there is NMR evidence of a deprotonation
process occurring for 2 at pH values approaching 12.
However, the pKa could not be determined by 1H NMR
spectroscopy on account of the decrease in intensity and
(58) Smith, G.; Wermuth, U. D.; White, J. M. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 2006, C62, o402–o404.
(59) Zhang, S. F.; Sun, Y. Q.; Yang, G. Y. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 2004, C60, m299–m301.
1
complete disappearance of the H NMR signals during
the titration under these basic conditions.
(60) Upreti, S.; Ramanan, A. Inorg. Chim. Acta 2005, 358, 1241–1246.
(61) Habtemariam, A.; Parkinson, J. A.; Margiotta, N.; Hambley, T. W.;
Parsons, S.; Sadler, P. J. J. Chem. Soc., Dalton Trans. 2001, 362–372.
(62) Meyerstein, D. Coord. Chem. Rev. 1999, 185-186, 141–147.
Decreasing the pH from basic to neutral values is likely
to trigger in the first instance protonation of the hydro-
xido ligand in 5. Aqua adducts of ethylenediamine RuII

Article
Inorganic Chemistry, Vol. 49, No. 7, 2010 3319
arene complexes in general have high pKa values (ca. 8).63
Protonation of the hydroxido ligand in 5 could then lead
to tether-closure since Ru-OH2 bonds are normally
reactive,6 whereas Ru-OH bonds are relatively inert.
Consistently, DFT calculations suggest that the energetic
balance between [2þH2O] and [5þH] favors ring closure
(5.8 kcal/mol). The reversibility of the process was fully
confirmed by the UV-vis titration (Figure 6), indicating
high stability of the system making the behavior of the
arene-tether ligand comparable with that of previously
described hemilabile ligands.12
nium arene prodrugs which will allow activation upon tether-
opening only under specific conditions. Most importantly,
the activation/deactivation process is fully reversible and
complex 2 does not undergo arene-loss decomposition in
the solvents used in this work.
Further work will be directed toward the development of
new η6:η1-arene:N hemilabile ligands with finely tuned elec-
tronic and steric properties so that activation of tethered
ruthenium organometallic arene complexes can be controlled
under biologically relevant conditions. Control over the
opening and closure of the tether ring as a function of pH
might provide a Ru-arene complex which is specifically
activated in cancer cells.14
Conclusions
The possible contributions of these systems as catalysts,
or their exploitation in other applications where comp-
lexes containing other metal-hemilabile ligands are being
successfully developed, for example, as small molecule sen-
sors,65 or as a tool in supramolecular chemistry,66 have yet to
be explored.
The versatile coordination properties of an amino-deriva-
tized arene have been investigated in different solvents. We
have shown that constraints of a five-membered ruthenium-
(II) tether ring (enhanced by a rigid aromatic backbone),
formed by an η6-arene ligand and pendant η1-donor atom,
can be tailored to weaken the otherwise strong (nonlabile)
RuII-NH2(tether) bond in [RuII(η6:η1-C6H5(C6H4)NH2)-
(en)]Cl2 (2). This complex is stable as no arene-loss was
observed under highly acidic or basic conditions or in dif-
ferent solvent systems. In methanol, complex 2 can exist as an
equilibrium between open- (activated) (3) and closed- (inacti-
vated) (2) tether forms. In DMSO, 2 can open to form 4. In
addition, 2 opens both in concentrated hydrochloric acid,
and in water at pH 12.
Acknowledgment. This research was supported by the
EC (Marie Curie Intra European Fellowships for A.M.P.
(515560 METCOMDPLINK) and L.S. (220281 PHOTO-
RUACD) within the 6th and 7th European Community
Framework Programmes, respectively), and by Science
City (AWM and ERDF). We thank the EPSRC and The
University of Edinburgh for a studentship for M.M., and
members of EC COST Action D39 for stimulating discus-
sions.
Conveniently, 2 opens to form 3, 4, or 5 without requiring
protonation of the primary amine, -NH2, which remains
available for further interactions, for example C-terminal
labeling of amino acids and peptides,64 or other biological
substrates, and organic polymers.
Supporting Information Available: Computational details
(tables of selected bond lengths and angles, molecular orbitals
and absorption spectra), kinetic, MS and NMR data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
The solution behavior of the closed-tether complex 2
supports the concept that it is possible to synthesize ruthe-
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L. N.; Rheingold, A. L. Inorg. Chem. 2005, 44, 496–501.
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€
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