Unexpected C-H activation of Ru(II)-dithiomaltol complexes upon oxidation

Article abstract of DOI:10.1021/ic7021962

Thione-substituted derivatives of maltol are of interest in several applications of metal-based drugs. In order to investigate the effect of the oxygenation on such thione chelates, Ru complexes of 3-hydroxy-2-methyl-4- thiopyrone (thiomaltol or Htma) and

Full text of DOI:10.1021/ic7021962

Inorg. Chem. 2008, 47, 2864-2870
Unexpected C-H Activation of Ru(II)-Dithiomaltol Complexes upon
Oxidation
Malin Backlund, Joseph Ziller, and Patrick J. Farmer*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received November 7, 2007
Thione-substituted derivatives of maltol are of interest in several applications of metal-based drugs. In order to
investigate the effect of the oxygenation on such thione chelates, Ru complexes of 3-hydroxy-2-methyl-4-thiopyrone
(thiomaltol or Htma) and 3-hydroxy-2-methyl-4H-thiopyran-4-thione (dithiomaltol or Httma), [Ru(bpy)2(tma)]+, 1, and
[Ru(bpy)2(ttma)]+, 2, were synthesized as diamagnetic PF6- salts. Peroxidation of 2 unexpectedly generated products
of C-H activation at its pendant methyl group; an air-stable aldehyde [Ru(bpy)2(ttma-aldehyde)]+, 4, was the
major product. In addition, an intermediate oxidation product [Ru(bpy)2(ttma-alcohol)](PF6), 3, was characterized.
Both 3 and 4 are also formed by reaction of 2 with outersphere oxidants (e.g., Na2IrCl6) and by bulk electrolysis
under anaerobic conditions. Similar oxidations of the analogous [Ru(bpy)2(ettma)]+, 2′, complex (3-hydroxy-2-ethyl-
4H-thiopyran-4-thione; ethyl dithiomaltol or Hettma) formed the corresponding ketone, [Ru(bpy)2(ettma-ketone)](PF6),
4′, by oxidation at the same position adjacent to the conjugated ring. The structures of the aldehyde 4 and starting
materials 1 and 2 have been confirmed by X-ray crystallography, and all complexes have been characterized by
1
UV–vis, H NMR, and IR spectroscopies. Initial mechanistic investigations are discussed.
Scheme 1. Maltol and Related Ligands
Introduction
Sulfur oxygenation of thiones yields sulfine intermediates
which are susceptible to S-atom extrusion, and the biological
effect of thiones, such as dithiuram, has been proposed to
be contingent on such in ViVo sulfur extrusion.1–6 We have
shown that similar oxygenations of metal-bound thiones such
as Ru(II) and Zn(II) dithiocarbamate complexes yield both
Metal-thione complexes derived from maltol are under
S,S- and S,O-bound sulfine derivatives that can undergo both
current investigation for applications in metal transport,
O- and S-atom extrusion.7,8
cancer therapy, and MMP inhibition, Scheme 1.9–12 We
hypothesized that these thione-metal chelates may also
undergo S-based oxidation and extrusion. To test this
* Author to whom correspondence should be addressed. E-mail:
pfarmer@uci.edu.
(1) Madan, A.; Faiman, M. D. Drug Metab. Dispos. 1994, 22, 324–330.
(2) Cen, D. Z.; Gonzalez, R. I.; Buckmeier, J. A.; Kahlon, R. S.; Tohidian,
N. B.; Meyskens, F. L. Mol. Cancer Ther. 2002, 1, 197–204.
(3) Brar, S. S.; Grigg, C.; Wilson, K. S.; Holder, W. D.; Dreau, D.; Austin,
C.; Foster, M.; Ghio, A. J.; Whorton, A. R.; Stowell, G. W.; Whittal,
L. B.; Whittle, R. R.; White, D. P.; Kennedy, T. P. Mol. Cancer Ther.
2004, 3, 1049–1060.
hypothesis, the peroxygenation of thiomaltol and dithiomaltol
was compared with and without complexation to an inert
[Ru(bpy)2]2+ moiety, Schemes 2 and 3.
While peroxidations of the free ligands directly gave
S-extruded products, similar reactions with Ru-dithiomaltol
complexes yielded products of oxidation of the pendant
(4) Cen, D. Z.; Brayton, D.; Shahandeh, B.; Meyskens, F. L.; Farmer,
P. J. J. Med. Chem. 2004, 47, 6914–6920.
(5) Demaster, E. G.; Redfern, B.; Nagasawa, H. T. Biochem. Pharmacol.
1998, 55, 2007–2015.
(9) Puerta, D. T.; Lewis, S. A.; Cohen, S. M. J. Am. Chem. Soc. 2004,
126, 8388–8389.
(6) Hart, B. W.; Faiman, M. D. Biochem. Pharmacol. 1992, 43, 403–
406.
(10) Puerta, D. T.; Cohen, S. M. Inorg. Chem. 2003, 42, 3423–3430.
(11) Monga, V.; Thompson, K. H.; Yuen, V. G.; Sharma, V.; Patrick, B. O.;
McNeill, J. H.; Orvig, C. Inorg. Chem. 2005, 44, 2678–2688.
(12) Dikanov, S. A.; Liboiron, B. D.; Orvig, C. J. Am. Chem. Soc. 2002,
124, 2969–2978.
(7) Brayton, D.; Tanabe, K.; Khiterer, M.; Kolahi, K.; Ziller, J.; Farmer,
P. J. Inorg. Chem. 2006, 45, 6064–6072.
(8) Ng, S.; Ziller, J. W.; Farmer, J. P. Inorg. Chem. 2004, 43, 8301–
8309.
2864 Inorganic Chemistry, Vol. 47, No. 7, 2008
10.1021/ic7021962 CCC: $40.75  2008 American Chemical Society
Published on Web 02/08/2008

Unexpected C-H ActiWation of Ru(II)-Dithiomaltol Complexes
Scheme 2
Figure 1. ESI-MS studies of the oxidation with oxone of [Ru(bpy)2(ttma-
alcohol)]+, 3 (m/z: 587), to form [Ru(bpy)2(ttma-aldehyde)]+, 4 (m/z: 585).
The top spectrum shows [Ru(bpy)2(ttma-alcohol)]+, and the bottom spectrum
is the reaction after 5 h, showing a formation of complex 4. Inserted in the
box is the predicted isotopic envelope for complex 3.
Scheme 3
Column separation gave yields of ∼50% recovered 2, 12%
3, and 9% species 4. Complex 4 was stable, characterized
as an aldehyde by H NMR, and its structure subsequently
1
confirmed by X-ray crystallography.
Complex 3 is air-sensitive and prone to decomposition but
1
has been characterized by ESI-MS, H NMR, and FT-IR.
The mass spectrum of 3 showed a characteristic [2 + 16]
m/z parent ion, indicative of the addition of a single oxygen
atom. First, it was expected that the intermediate, 3, was
oxygenated at the ring sulfide, for example, a sulfoxide,
which might then convert to the observed C-oxygenated
product via subsequent rearrangement. Therefore, 2D cor-
relation spectroscopy (COSY) NMR spectra of 2 and 3 were
obtained for structural comparisons (Supporting Information,
Figures S2 and S3), and the only substantive difference is a
shift of ca. 0.10 ppm of the proton R to the sulfide. In
addition, the NMR spectrum of 3 does not display splitting
indicative of the expected chirality for a sulfoxide (Support-
ing Information, Figure S7). However, most persuasive was
the FT-IR spectrum of 3, which showed a new peak at 1125
cm-1, more reasonably assigned to a C-O stretch rather than
to a S-O stretch.14
To gain further insight into the identity of 3, several
reactivity studies were carried out. The reaction of 3 with
oxygenating agents (oxone, UHP) forms the aldehyde 4,
Figure 1. Treatment of 3 with typical alkylating agents, acetyl
chloride and MeI, yields stable products, as characterized
by ESI-MS (Scheme 4). This is consistent with the expected
reactivity of an alcohol, but not that of a sulfoxide,
Supporting Information, Figure S4.
methyl or ethyl group. This report describes our investiga-
tions into this unusual activity.
Results and Discussion
The synthesis of the maltol-derived ligands (except hptma)
inthisstudyhasbeenpreviouslydescribed.13 Themetal-thione
complexes [Ru(bpy)2(tma)]+, 1, [Ru(bpy)2(ttma)]+, 2, and
[Ru(bpy)2(ettma)]+, 2′, were prepared by reaction of Ru-
(bpy)2Cl2 with the ligand at elevated temperatures. The
resulting complexes were isolated as purple, diamagnetic
-
PF6 salts. Further characterizations are given in the Sup-
porting Information.
Identification of Oxidation Products. Reaction of free
thiomaltol and dithiomaltol with an O-atom transfer agent
such as urea hydrogen peroxide (UHP) induces S extrusion,
in the latter case yielding a novel 3-hydroxy-2-methyl-4H-
thiopyran (Hptma) in fair isolated yield, 31% by NMR
analysis (Scheme 3). Treatment of 1 with O-atom transfer
agents gave only ligand-decomposed products; electrospray
ionization mass spectrometry (ESI-MS) and 1H NMR
analysis suggests these to be solvent-complexed [Ru(bpy)2]2+
species, implying that oxidation leads to ligand-decomposed
species. Treatment of 2 and 2′ with the same agents yields
the aldehyde and ketone derivatives, 4 and 4′, respectively,
as the major isolated products.
Oxidizing Agents. Initially, a series of peroxidation
reagents, such as oxone, m-chloroperbenzoic acid (mCPBA),
and UHP, was found to give similar yields of ca. 15% of 3
and 4 after the reaction of excess reagent with 2 (data not
shown). Other reagents, such as 2,6-dicarboxypyridinium
In a typical experiment, a 4-fold excess of oxone was
added to a solution of 2 in CH3CN at room temperature under
an inert N2 atmosphere and allowed to react overnight.
(13) Brayton, D. F.; Jacobsen, F. E.; Cohen, S. M.; Farmer, P. J. J. Chem.
Soc., Chem. Commun. 2006, 206–208.
(14) Pavia, D. L.; Lampman, G. M.; Kriz, G. S. Introduction to Spectros-
copy; Thompson Learning Inc.: Philadelphia, 2001.
Inorganic Chemistry, Vol. 47, No. 7, 2008 2865

Backlund et al.
Scheme 4
Figure 2. Sequential electronic absorbance spectra of the reaction of
complex 2 with 3 equiv of IBX in CH3CN at room temperature. The reaction
was monitored for 150 min, and a spectrum was taken every 30 min. The
final spectrum is similar to that of the aldehyde, 4.
Table 1. Comparative Yields of 4 Obtained by Oxidation of 2 with
Various Reagents
reagent
UHP
solvent
MeCN
reaction time equiv. per Ru yielda
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
1 h
2 equiv
2 equiv
3 equiv
4 equiv
4 equiv
2%
5%
oxone
IBX
MeCN
MeCN
4%
6%
28%
30%
5%
10%
10%
Na2IrCl6 MeCN w/H2O
Na2IrCl6 MeCN w/NaOH
a Comparative percentage yields were determined by ESI-MS using
[Ru(bpy)2(m-DTC)]+ (complex 1 in ref 8) as an added internal standard
after the reaction was quenched.
chlorochromate (2,6-DCPCC), were also found to yield
similar product yields; however, much larger yields of
complex 4 were obtained from reactions with 2-iodoxyben-
zoic acid (IBX) and Na2Ir(IV)Cl6. Similarly, complex 3 was
obtained under anaerobic conditions, suggesting that the O
atom is obtained from adventitious water.
Figure 3. ESI-MS studies of the reaction of [Ru(bpy)2(ttma)]+, 2, with
Na2IrCl6 in dry MeOH/NaOMe to form apparent methoxy adducts at m/z
601 and 631. Inserted in the box is the predicted isotopic envelope for
complex 2.
A comparative quantification of this reactivity was deter-
mined by using stoichiometric oxidations of 2 with selected
reagents, Table 1. In a typical reaction, a stoichiometric
amount of UHP (0.003 g, 0.035 mmol) was added to an
aerobic solution of 2 (0.013 g, 0.018 mmol) in CH3CN. After
∼24 h, a sample was removed for ESI-MS studies, and a
peak was observed at m/z 585 corresponding to complex 4.
Reported yields in Table 1 are for comparison, as determined
against an added standard, and are less than isolated yields
parameters are given in Table 2. Electrochemically reversible
oxidation couples are observed for complexes 1, 2, and 4,
with ∆Ep equal to ca. 65 mV and ipa/ipc close to unity. In
contrast, the oxidation of complex 3 appears quasi-reversible,
with the ipa/ipc ratio decreasing from unity at slower scan
rates, signifying a loss of the oxidized species by a following
chemical reaction. Also, a small oxidation wave is seen at
ca. 800 mV, close to that of 4, from an apparent product of
the initial oxidation. The similarity of the oxidation potentials
of complexes 1 and 2, with the different tma and ttma
ligands, suggests that the initial oxidation is metal-based.
The positive shift in potential for complex 4 is consistent
with the addition of an electron-withdrawing group on the
ligand and likewise suggests that it would be more stable to
oxidizing or oxygenating reagents.
Analysis of the voltammograms predicts the dominance
of 4 as the bulk oxidation product of 2. The intermediate
product, 3, is oxidized at a potential close to the starting
complex, 2, and thus cannot accumulate during bulk oxida-
tions. After repeated scans, voltammograms of 3 obtained
broad and overlapping oxidation waves, confirming the
existence of mixtures of oxidized products being generated.
1
obtained in larger-scale reactions. For example, H NMR
quantification after chromatography gave a yield of 41% of
4 from the reaction of 2 with 3 equiv of IBX, and only 28%
by ESI-MS, as reported in Table 1. Monitoring the reaction
by UV–vis under the same conditions, Figure 2, shows an
apparent clean conversion from 2 to 4 over 3 h; no buildup
of intermediate species is seen.
In addition, oxidations of 2 with Na2Ir(IV)Cl6 in dry
MeOH/NaOCH3 resulted in products observed by ESI-MS
consistent with the addition of one and two methoxy groups
to complex 2, [2 + 30] and [2+ 60] m/z in Figure 3,
analogous to the addition of sequential water molecules
resulting in complexes 3 and 4. The formation of these
methoxy adducts suggests that the C-H activation occurs
through a cationic intermediate susceptible to solvent attack.
Electrochemical Studies. Cyclic voltammograms of com-
plexes 1–4 in CH3CN are shown in Figure 4, and derived
2866 Inorganic Chemistry, Vol. 47, No. 7, 2008

Unexpected C-H ActiWation of Ru(II)-Dithiomaltol Complexes
Figure 5. Cyclic voltammograms before (top) and after (bottom) anaerobic
electrolysis of complex 2 at +650 mV for 12 h. Conditions: 0.1 M TBAPF6
in anaerobic MeCN, Pt working and counter electrodes, reference Ag/AgCl.
Figure 4. Cyclic voltammograms of complexes 1–4, conditions: 0.1 M
TBAPF6 in anaerobic MeCN, Pt working and counter electrodes, reference
Ag/AgCl.
Table 2. Electrochemical Data for Complexes 1–4a
complex
E1/2 (mV)
∆Ep (mV)
ipa/ipc
1 [Ru(bpy)2(tma)]+
+445
+455
+446
+713
65
62
64
65
0.96
0.97
0.78
0.90
2 [Ru(bpy)2(ttma)]+
3 [Ru(bpy)2(ttma-alcohol)]+
4 [Ru(bpy)2(ttma-aldehyde)]+
a All potentials measured using Ag/AgCl reference electrode, Pt disc
working electrode, and Pt wire counter electrode; scan rate of 100 mV/sec
in MeCN, 0.1 M TBAPF6.
Figure 6. X-band EPR spectrum at 10 K of CH3CN solution of 2 after
reaction with 1 equiv of Na2IrCl6. Conditions: microwave frequency, 9.64
GHz; microwave power, 2.02 mW; modulation amplitude, 4.00 G; time
constant, 164 ms; sweep width, 3300 G; sweep time, 21.0 ms.
Table 3. Structural Data and Comparison of Complexes 1, 2, and 4
to the initial oxidization product of 2, and is consistent with
a Ru(III) d5 S ) ½ system of pseudo-C2V symmetry with
significant broadening due to spin–orbit coupling. Within the
broad absorbance, small rhombic features are observable but
difficult to assign. Cooling the same sample to 10 K allowed
resolution of these features, Figure 6, as an anisotropic
absorbance peaks with g values of 2.204, 2.046, and 1.886.
Similar rhombic signals have been observed for a Ru(III)(L1)-
(L2)2 species in pseudo-C2V coordination environments.15,16
A sample of the bulk electrolysis solution after voltam-
metric analysis in Figure 5 was also analyzed by EPR at 77
K; the resulting spectrum again showed a broad low-intensity
signal with a gavg ) 1.99, with small anisotropic features at
g ) 2.10 and 1.93 (Supporting Information, Figure S6).
Assignment of this spectrum is difficult as the solution
contains a mixture of species, but the rhombic splitting is
distinct from that of oxidized 2 and still readily attributed to
a metal-based rather than organic radical.
complex 1
complex 2
complex 4
cryst syst
space group
color
monoclinic
P21/n
purple
monoclinic
C2/c
purple
triclinic
P1
black
Ru-O (Å)
Ru-S (Å)
∆C-C (Å)
N-Ru-O (deg)
N-Ru-S (deg)
2.080(15)
2.362(6)
0.098
172.9(7)
170.3(5)
2.107(6)
2.320(2)
0.108
172.9(2)
172.0(19)
2.086(2)
2.315(9)
0.108
174.4(10)
171.1(8)
Bulk electrolysis of 2 at 600 mV (normal hydrogen
electrode) was carried out using large-area gold plate working
and counter electrodes. After ∼12 h, the electrolysis mixture
was analyzed by cyclic voltammetry, Figure 5, which
demonstrated the formation of the aldehyde. Square-wave
voltammetric analysis of the resulting solution gave the yield
of 4 as ca. 40%.
ElectronParamagneticResonance(EPR)Characteriza-
tion of Initial Product of Oxidation. As the species 3 and
4 are generated by sequential two-electron oxidations of
complex 2, efforts were made to characterize possible one-
electron oxidized species involved. In addition, complex 2
was reacted with 1 equiv of Ir(IV)Cl6 in a dry box; EPR
analysis of the reaction mixture after 1 h at 77 K shows a
broad structured peak (>1000 G) with a gavg value of 1.95,
well below that expected for a free organic radical (Sup-
porting Information, Figure S6). This signal is attributable
Structural Characterizations. Salts of the cationic com-
plexes 1, 2, and 4 have been characterized by X-ray
diffraction studies (Supporting Information, Figure S5). Slow
vapor diffusion of diethyl ether into CH2Cl2 solutions of
(15) Lever, A. B. P.; Auburn, P. R.; Dodsworth, E. S.; Haga, M. A.; Liu,
W.; Melnik, W.; Nevin, A. J. Am Chem Soc. 1988, 110, 8076–8084.
(16) Haga, M. A.; Dodsworth, E. S.; Lever, A. B. P. Inorg. Chem. 1986,
25, 447–453.
Inorganic Chemistry, Vol. 47, No. 7, 2008 2867

Backlund et al.
Scheme 6
and Hb in Scheme 5). The magnitude of ring current in a
system is measured from the average chemical shift, (δa +
δb)/2, which is δ 7.74 for 2 compared to δ 7.44 for 1.21
This suggests that complex 2 has a greater ring current and
thus more delocalization than 1.
Figure 7. Crystal structure of [Ru(bpy)2(ttma-aldehyde)]+, 4.
Scheme 5
Delocalization in the ttma ligand is likely increased in the
singly oxidized state, as the thiopyrilium resonance structure
would be favored to neutralize the greater charge on a Ru(III)
center. EPR characterization of the initial oxidation product
yielded an anisotropic spectrum at low temperatures, imply-
ing that the unpaired electron has significant metal-based
character.22–25 Thus, it may be the nature of the singly
oxidized intermediate that induces the C-H activation in
the ttma complex, 2, and not the tma complex, 1.
In this system, C-oxidized products are obtained by
reaction of 2 with O-atom transfer agents (oxone, mCPBA,
and UHP) and chemical oxidants (Na2IrCl6 and IBX) and
by electrochemical oxidation. The formation of C-oxidized
products from complex 2 by reaction with Na2IrCl6 or by
bulk electrolysis is consistent with an outersphere single-
electron transfer as the initiating event.
The highest yields of C-H activated products are obtained
in reactions using IBX, a periodinane reagent previously
shown to oxidize carbons adjacent to conjugated systems,
giving aldehyde and ketone products, with regioselectivity
influenced by the conjugation.26–29 IBX is a multifaceted
reagent in that it may act as an electron acceptor, a H-atom
abstractor, and an O-atom donor, all of which may be
involved in its reactivity with 2.
Scheme 6 illustrates one possible mechanism for the initial
transformation of 2 to 3, starting from the singly oxidized
product of 2+. Delocalization of the unpaired electron over
both the Ru and the ttma ligand is possible, but we suggest
cationic complexes 1, 2, and 4 as PF6 salts yielded crystals
suitable for X-ray diffraction studies. Purple crystals of
complexes 1 and 2 are monoclinic, and in space groups P21/n
and C2/c, respectively, while the black crystals of complex
4 are triclinic in the P1 space group, Table 3.
The X-ray diffraction analysis of 4, Figure 7, confirms its
characterization as an aldehyde; the observed C(6)-O(2)
bond length is 1.225 Å, which is appropriate for a
carbon-oxygen double bond.17 The Ru coordination sphere
in all three structures is only slightly distorted from
octahedral, due to constrained bite angles of the maltol-
derived ligands. The Ru-S bond length decreases from
complex 1 to 2, while that of the Ru-O bond lengthens,
perhaps indicative of tighter Ru-S interactions in the latter
complex. Variations in the maltol-ligand C-C bond
lengths were analyzed for the three complexes, as a
measure of delocalization within the complexed ligand.
The observed differences of ca. 0.1 Å indicate significant
bond delocalization, as ∆C-C values for nonaromatic
systems are >0.2 Å.18
Mechanistic Considerations. The C-H oxidations of
complex 2 resemble the comparable oxidations of benzylic
carbons and, by analogy, suggest some aromaticity to the
ttma ring. There is much precedence for aromaticity of the
related thiopyriliums, an oxidized form of the ttma ring
shown in Scheme 5.19,20 Crystallographic data of 2 do
provide evidence of delocalization within the ttma ring.
Delocalization in 1 and 2 can be assessed by NMR, as
measured by the effect of ring current on proton signals (Ha
(21) Jonas, J.; Derbyshire, W.; Gutowsky, H. S. J. Phys. Chem. 1965, 69,
1–5.
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Chem. 1987, 26, 4324–4331.
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Bertotti, M.; Mori, V.; Franco, D. W. Can. J. Chem. 2001, 79, 679–
687.
(25) Kuan, S. L.; Leong, W. K.; Goh, L. Y. Organometallics 2005, 24,
4639–4648.
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123, 3183–3185.
(17) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1977, 99, 4907–4917.
(18) Von Rague Schleyer, P.; Jiao, H. Pure Appl. Chem. 1996, 68, 209–
(27) Nicolaou, K. C.; Montagon, T.; Baran, S.; Zhong, Y. L. J. Am. Chem.
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932.
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145–148.
2868 Inorganic Chemistry, Vol. 47, No. 7, 2008

Unexpected C-H ActiWation of Ru(II)-Dithiomaltol Complexes
on a Schlenk line or in a glovebox. All reactions involving
complexes containing the [Ru(bpy)2]2+ moiety were carried out in
the dark.
that aromaticity in the thiopyrylium cation enables the
activation of the pendant methyl group. The formation of
the alcoholic product requires a second proton-coupled
oxidation, and the facility of IBX in this reaction suggests
that this may take the form of a H-atom abstraction.
Extensive delocalization allows formation of a carbocationic
intermediate that would likely precede the addition of solvent
(water or methanol) at the oxidized carbon. An analogous
pathway would yield the aldehyde upon oxidation of the
alcoholic intermediate.
An alternative is to invoke sequential deprotonations and
oxidations. Potentiometric titrations of complex 2 in dry
MeOH from pH 11.5 to 1.5 gave no indication of protonation
or deprotonation within this range. Oxidations run under
basic conditions, for example, with 4 equiv of NaOH in
MeCN, Table 1, showed only small increases in product
formation. Likewise, reactions with added NaOMe in MeOH
showed relatively modest increases in yield of methoxy
adducts. Thus, we surmise a rate-limiting step may be radical-
dependent.
Physical Measurements. Mass spectra were determined using
a Micromass LCT machine. UV-vis spectra were recorded using
a Perkin-Elmer Lambda 900 machine. 1H NMR spectra were
recorded on Bruker Avance 400 and 500 MHz spectrometers.
Chemical shifts were referenced via the solvent signal. X-band EPR
spectra were recorded on a Burker spectrometer. Experiments were
carried out at liquid nitrogen temperature (77 K) and liquid helium
temperature (10 K). Infrared spectra were recorded on an Impact
410 machine from Nicolet as KBr pellets. Elemental analyses were
performed by Atlantic Microlab, Norcross, GA. All single-crystal
X-ray diffraction structures were solved by the X-ray Crystal-
lography Facility at UCI.
Synthesis of [Ru(bpy)2(tma)](PF6), 1. Ru(bpy)2Cl2 (0.454 g,
0.937 mmol) and Htma (0.266 g, 1.90 mmol) were placed in a
three-neck flask with 5 mL of ethylene glycol. The three-neck flask
was fitted with a condenser, and an inert atmosphere was established
using standard Schlenk techniques. The reaction was brought to
130 °C and stirred under N2 for 45 min. The mixture was then
poured into 200 mL of deionized H2O, and an excess of KPF6 was
added. The purple product was collected on a Buchner funnel under
vacuum filtration. The compound was purified using a basic alumina
column and CH2Cl2/CH3CN as the eluent. The isolated yield was
0.462 g (89%). The compound was crystallized in CH2Cl2/ diethyl
ether, forming purple needle-shaped crystals suitable for X-ray
Conclusions
The R-hydroxyl thione Ru complexes 2 and 2′ undergo
unexpected C-H activation of the methyl and methylene
groups to form aldehyde and ketone products. The ability
of various O-atom transfer agents, outersphere oxidants, and
bulk electrochemical oxidations to form these products
implies that the initiating step is electron transfer; we propose
that C-H activation proceeds due to thiopyrylium-like
aromaticity of the initially oxidized form.
The observed C oxidations are unusual in that the two S
sites on the ttma ligand were unaffected. Similar reactions
of the ligands alone yield the expected S-extruded products;
therefore, the coordination of the ligand to the [Ru(bpy)2]2+
center is crucial for the C-H activation to take place.
However, the question to why C-H activation is more
favorable than S-oxidation in this case remains elusive.
1
diffraction. ESI MS: m/z 555. H NMR (500 MHz, CD3OD): δ
9.52 (d, 1H), 8.73 (d, 1H), 8.63 (d, 1H), 8.58 (d, 2H), 8.44 (d,
1H), 8.09 (t, 2H), 7.96 (t, 1H), 7.86 (d, 1H), 7.80 (t, 1H),
7.74 (d, 1H), 7.71 (d, 1H), 7.67 (t, 1H), 7.61 (t, 1H), 7.40 (d, 1H),
7.32 (t, 1H), 7.15 (t, 1H), 2.27 (s, 3H). Anal. calc for RuN4-
C26O2SH21PF6 ·CH2Cl2: C, 41.28; H, 3.08; N, 7.13. Found: C, 40.75;
H, 3.08; N, 7.55.
Synthesis of [Ru(bpy)2(ttma)](PF6), 2. [Ru(bpy)2(ttma)](PF6)
was synthesized by the same procedure used for 1, starting from
Ru(bpy)2Cl2 (0.350 g, 0.723 mmol) and Httma (0.228 g, 1.45
mmol). The product was obtained as a purple solid. The isolated
yield was 0.295 g (72%). The compound was crystallized in CH2Cl2/
EtO2, forming purple crystals suitable for X-ray diffraction. ESI
1
MS: m/z 571. H NMR (500 MHz, CD3OD): δ 9.54 (d, 1H), 8.65
(d, 1H), 8.61 (d, 1H), 8.58 (d, 2H), 8.45 (d, 1H), 8.08 (t, 2H), 8.05
(d, 1H), 7.97 (t, 1H), 7.90 (d, 1H), 7.79 (t, 1H), 7.71 (d, 1H), 7.64
(t, 1H), 7.64 (d, 1H), 7.58 (t, 1H), 7.32 (t, 1H), 7.15 (t, 1H), 2.06
(s, 3H). Anal. calc for RuN4C26OS2H21PF6: C, 43.64; H, 2.96; N,
7.83. Found: C, 44.32; H, 3.19; N, 7.73.
Experimental Section
Abbreviations. cis-Dichloro-bis-2,2-bipyridineruthenium(II)
(Ru(bpy)2Cl2), dithiomaltol (Httma), ethyl-dithiomaltol (Hettma),
dithiomaltol-aldehyde (Httma-aldehyde), ethyl-dithiomaltol-ketone
(Hettma-ketone), pyronethiomaltol (Hptma), potassium perox-
omonosulfate (oxone), m-chloroperbenzoic acid (mCPBA), 2,6-
dicarboxypyridinium chlorochromate (2,6-DCPCC), urea hydrogen
peroxide (UHP), and 2-iodoxybenzoic acid (IBX).
Materials. cis-Dichlorobis(2,2′-bipyridine) ruthenium(II) dihy-
drate, 99%, was purchased from Strem Chemicals. Basic alumina
was purchased from Fisher Scientific, and all other chemicals were
purchased from Aldrich Chemical Co. Httma and Hettma were
synthesized following published procedures.13 The oxidant 2,6-
DCPCC was generated in situ following a published procedure, by
reacting CrO3 with pyridinium 2,6-dicarboxylic acid in 6 M HCl
for 2 h.30 All common laboratory solvents are of reagent grade
and were dried and degassed using standard techniques. Manipula-
tions requiring anaerobic conditions were carried out under nitrogen
Oxidation of Httma, Isolation of Hptma. Httma (0.15 g, 0.945
mmol) was dissolved in 20 mL of CH3CN and placed in a round-
bottom flask fitted with a N2 inlet adaptor. UHP (0.36 g, 3.80 mmol)
was dissolved in 10 mL of CH3OH and added to the round-bottom
flask. The reaction was stirred under N2 for ∼24 h. The dark green
reaction mixture was then dried in Vacuo and dissolved in CHCl3
followed by an aqueous wash (4 × 100 mL). The CHCl3 layer
was dried over MgSO4 for ∼3 h, followed by evaporation of the
solvent in Vacuo, giving a brown solid. Isolated yield for Hptma:
1
0.024 g (16%). ESI MS: m/z 143 [M]+H. H NMR (500 MHz,
CDCl3): δ 7.74 (d, 1H), 7.17 (d, 1H), 2.41 (s, 3H). Anal. calc for
C6H5O2S·CH3OH: C, 48.26; H, 5.79. Found: C, 48.52; H, 6.18.
Oxidation of 1. Ru(bpy)2(tma) (0.010 g, 0.018 mmol) and 2,6-
DCPCC (0.010 g, 0.034 mmol) were dissolved in CH3CN and added
to a 50 mL round-bottom flask inside a N2 purged dry box. The
reaction was monitored by ESI-MS, and after ∼20 min, a ligand
decomposed peak at m/z 441 ([M]-114) was observed (Supplorting
(30) Tajbakhsh, M.; Hosseinzadeh, R.; Niaki, M. Y. J. Chem. Res. 2002,
10, 508–510.
Inorganic Chemistry, Vol. 47, No. 7, 2008 2869

Backlund et al.
Information, Figure S1). Similar results were observed for the
reaction of 1 with other oxidants.
aldehyde peak was observed by NMR (∼10 ppm) and ESI-MS (m/z
585). A quantitative yield determination from the reaction of
Ru(bpy)2(ttma-aldehyde; 0.010 g, 0.014 mmol) with IBX (0.026
g, 0.093 mmol; 3 equiv of IBX) in 10 mL CH3CN was carried out.
The mixture was purified on basic alumina with CH3CN/MeOH as
Oxidation of 2; isolation of [Ru(bpy)2(ttma-alcohol)](PF6),
3, and [Ru(bpy)2(ttma-aldehyde), 4. Ru(bpy)2(ttma) (0.080 g,
0.112 mmol) and 2,6-DCPCC (0.200 g 0.667 mmol) were dissolved
in CH3CN and added to a 100 mL round-bottom flask fitted with
a nitrogen inlet adaptor. The reaction was carried out in an inert
N2 atmosphere under stirring for 24 h. The solvent was removed
in vacuo, and the products were isolated using an alumina basic
column with CH2Cl2/CH3CN/CH3OH as the eluents. Complexes 3
and 4 were obtained as separate bands off the alumina column.
Further purification was made using a second column with the same
stationary phase and eluent. The isolated yields were 0.010 g (12%)
of 3 and 0.0075 g (9.2%) of 4.
Compound 4 was crystallized in CH2Cl2/EtO2, forming black
single crystals suitable for X-ray diffraction. ESI MS: m/z 585. UV/
vis (nm): 380, 497, 718. 1H NMR (400 MHz, CD3OD): δ 9.96 (s,
1H), 9.22 (d, 1H), 8.61 (m, 4H), 8.49 (d, 1H), 8.14 (d, 1H), 8.12
(d, 1H), 8.12 (d, 1H), 8.02 (t, 1H), 7.92 (d, 1H), 7.87 (d, 1H), 7.86
(t, 1H), 7.71 (t, 1H), 7.64 (m, 2H), 7.38 (t, 1H), 7.21 (t, 1H). Anal.
calc for RuN4C26O2S2H19PF6 ·C5H12: C, 46.44; H, 3.90; N, 6.99.
Found: C, 46.39; H, 3.44; N, 6.81.
1
eluents. The yield of complex 4 was determined as 41% by H
NMR.
UV/Visible Studies of Oxidation of Complex 2. Standard
solutions of Ru(bpy)2(ttma) (0.084 mM) and IBX (1.12 mM) in
CH3CN were prepared separately in a 50 mL volumetric flask and
a 100 mL volumetric flask, respectively. Complex 2 (2 mL) was
placed in a capped UV/vis cell followed by the addition of IBX (3
equiv, 1 mL). The reaction was monitored every 30 min for 150
min. The spectrum shows a direct conversion from the starting
material to the aldehyde, 4.
Oxidation of 2 with Ir(IV). Ru(bpy)2(ttma) (0.005 g, 0.007
mmol) was treated with sodium hexachloridoiridate(IV) (0.006 g,
0.014 mmol) in CH3CN with ca. 2% water by volume. The reaction
was left overnight, and ESI-MS (m/z: 585) and 1H NMR confirmed
the formation of the aldehyde. In a separate experiment, complex
2 was reacted with 4 equiv of Na2IrCl6 (18 umol 2, 70 umol
Na2IrCl6) in 5 mL of CH3CN and ca. 4 equiv of NaOH (0.5 mL
0.1 M NaOH). A similar experiment was run in methanol with 10-
fold excess NaOMe (7 umol 2, 28 umol Na2IrCl6, 4 mg NaOMe,
in 2 mL of CH3CN); after 1 h, ESI-MS showed the formation of
the ether complex, in 12% yield, and 10% diether, Figure 3. When
4 equiv of NaaIrCl6 was used, the observed yields increased to 20%
and 15%, respectively.
Reaction of 3 and 3′ with Oxidants. Oxidation of [Ru(bpy)2(ttma-
alcohol)](PF6) was carried out in a 25 mL round-bottom flask using
a 4-fold excess of oxone as the O-atom transfer agent. The reaction
was carried out on the NMR scale with CD3CN as the solvent and
was followed by 1H NMR and ESI-MS. Formation of [Ru(bpy)2(ttma-
aldehyde)](PF6), 4, was seen after 1 h. The reaction was monitored
for 24 h, and complete formation of 4 was observed. [Ru(bpy)2(ttma-
alcohol)](PF6), 3′, was reacted with oxone as well, and formation
of [Ru(bpy)2(ettma-ketone)]+, 4′, was detected by ESI-MS over-
night.
Alkylation Reactions of 3. [Ru(bpy)2(ttma-alcohol)](PF6) was
treated with excess acetic anhydride in refluxing CH3CN. After 1 h,
formation of [Ru(bpy)2(ttma-acetate)]+ was observed by ESI-MS
as m/z 629. The reaction was left refluxing overnight, and
[Ru(bpy)2(ttma-acetate)]+ was the most abundent peak in the
spectra. In addition, traces of [Ru(bpy)2(ttma-aldehyde)]+, 4, were
seen as m/z 585.
Attempts to crystallize 3 were made using slow vapor diffusion
in CH2Cl2/Et2O, but no single crystal could be isolated. Likewise,
elemental analysis was problematic. ES/MS: m/z 587. UV/vis (nm):
1
355, 532. FT-IR (cm-1): ν(CdC) 850, ν(C-O) 1100. H NMR
(400 MHz, CD3CN): δ 9.44 (d, 1H), 8.58 (d, 1H), 8.40 (m, 3H),
8.28 (d, 1H), 8.00 (m, 3H), 7.90 (m, 2H), 7.72 (t, 1H), 7.64 (m,
2H), 7.53 (m, 2H), 7.24 (t, 1H), 7.07 (t, 1H).
Synthesis of [Ru(bpy)2(ettma)](PF6), 2′. Samples of [Ru-
(bpy)2(ettma)](PF6) were synthesized by the same procedure used
for 1, starting from Ru(bpy)2Cl2 (0.625 g, 1.29 mmol) and Hettma
(0.220 g, 1.29 mmol). The product was obtained as a purple solid.
The isolated yield was 0.590 g (63%). ESI MS: m/z 585. UV/vis
1
(nm): 357, 539. H NMR (500 MHz, CD3OD): δ 9.48 (d, 1H),
8.61 (d, 1H), 8.54 (d, 1H), 8.52 (d, 2H), 8.42 (d, 1H), 8.01 (m,
3H), 7.94 (d, 1H), 7.91 (d, 1H), 7.75 (t, 1H), 7.65 (d, 1H), 7.59
(m, 2H), 7.52 (t, 1H), 7.28 (t, 1H), 7.11 (t, 1H), 2.62 (q, 1H), 2.47
(q, 1H), 0.87 (t, 3H). Anal. calc for RuN4C27OS2H23PF6: C, 44.44;
H, 3.18; N, 7.68. Found: C, 44.37; H, 3.14; N, 7.52.
Oxidation of 2′; Isolation of [Ru(bpy)2(ettma-alcohol)](PF6),
3′, and [Ru(bpy)2(ettma-ketone)](PF6), 4′. [Ru(bpy)2(ettma-alco-
hol)](PF6) was synthesized using the same procedure used for 2,
starting with [Ru(bpy)2(ettma)]+ (0.200 g, 0.274 mmol) and 2,6-
DCPCC (0.164 g, 0.548 mmol). The complexes were separated on
an alumina basic column. Complex 3′ was isolated as a purple salt
A small amount (∼2 mg) of [Ru(bpy)2(ttma-alcohol)](PF6) was
treated with excess MeI in methanol and stirred at room temperature
under N2. The reaction was monitored by ESI-MS, and after ∼24
h, an m/z 601 peak was oberserved, corresponding to the conversion
of an alcohol to a methyl ether.
1
(7.8% yield). ESI MS: m/z 601. UV/vis (nm): 357, 538. H NMR
(500 MHz, CD3OD): δ 9.47 (d, 1H), 8.60 (m, 4H), 8.44 (d, 1H),
8.03 (m, 4H), 7.95 (t, 1H), 7.77 (m 2H), 7.62 (m, 2H), 7.53 (t,
1H), 7.30 (t, 1H), 7.14 (t, 1H), 1.35 (q, 2H), 0.83 (t, 3H). Complex
4′ was isolated as a purple salt, and the isolated yield was 0.011 g
Acknowledgment. We thank Michael Goldfeld for his
assistance with the EPR measurements and Prof. Andy
Borovik for the use of his instrument. This research was
supported by the American Cancer Society Research Scholar
Grant (PJF RSG-03-251-01).
1
(4%). ESI MS: m/z 599. UV/vis (nm): 374, 510, 684. H NMR
(500 MHz, CD3OD): δ 9.28 (d, 1H), 8.62 (d, 2H), 8.60 (d, 1H),
8.55 (d, 1H), 8.50 (d, 1H), 8.13 (m, 2H), 8.08 (d, 1H), 8.02 (m,
2H), 7.87 (d, 1H), 7.85 (d, 1H), 7.69 (m, 2H), 7.62 (t, 1H), 7.37 (t,
1H), 7.22 (t, 1H), 1.98 (s, 3H). FT-IR (cm-1): 1622 (CdO). Anal.
calc for RuN4C27O2S2H21PF6 ·H2O: C, 42.58; H, 3.04; N, 7.36.
Found: C, 42.80; H, 3.05; N, 7.16.
Oxidation of 2 with IBX. Ru(bpy)2(ttma) (0.01 g, 0.011 mmol)
and IBX (0.01 g 0.042 mmol) were dissolved in CD3CN and added
to a 50 mL round-bottom flask fitted with a nitrogen inlet adaptor.
The reaction was carried out in an inert N2 atmosphere under stirring
and was monitored by 1H NMR and ESI-MS. After 2 h, the
Supporting Information Available: ESI-MS analysis of oxida-
tion and alkylation reactions, EPR spectra of bulk electrolysis, and
further characterizations of complexes 1–4 including electronic
1
spectra, IR absorbance spectra, H NMR and 2D COSY NMR
spectra, and crystal structures of complexes 1 and 2.
IC7021962
2870 Inorganic Chemistry, Vol. 47, No. 7, 2008