Diastereoselective Synthesis and Two-Step Photocleavage of Ruthenium Polypyridyl Complexes Bearing a Bis(thioether) Ligand

Article abstract of DOI:10.1021/acs.inorgchem.9b01669

Thioethers are good ligands for photoactivatable ruthenium(II) polypyridyl complexes, as they form thermally stable complexes that are prone to ligand photosubstitution. Here, we introduce a novel symmetric chelating bis(thioether) ligand scaffold, based on 1,3-bis(methylthio)-2-propanol (4) and report the synthesis and stereochemical characterization of the series of novel ruthenium(II) polypyridyl complexes [Ru(bpy)₂(L)](PF₆)₂ ([1]-[3](PF₆)₂), where L is ligand 4, its methyl ether, 1,3-bis(methylthio)-2-methoxypropane (5), or its carboxymethyl ether, 1,3-bis(methylthio)-2-(carboxymethoxy)propane (6). Coordination of ligands 4-6 to the bis(bipyridine)ruthenium center gives rise to 16 possible isomers, consisting of 8 possible Λ diastereoisomers and their Δenantiomers. We found that the synthesis of [1]-[3](PF₆)₂ is diastereoselective, yielding a racemic mixture of the Λ-(S)-eq-(S)-ax-OH_eq-[Ru]²⁺ and δ-(R)-ax-(R)-eq-OH_eq-[Ru]²⁺ isomers. Upon irradiation with blue light in water, [1]-[3](PF₆)₂ selectively substitute their bis(thioether) ligands for water molecules in a two-step photoreaction, ultimately producing [Ru(bpy)₂(H₂O)₂]²⁺ as the photoproduct. The relatively stable photochemical intermediate was identified as cis-[Ru(bpy)₂(κ¹-L)(H₂O)]²⁺ by mass spectrometry. Global fitting of the time evolution of the UV-vis absorption spectra of [1]-[3](PF₆)₂ was employed to derive the photosubstitution quantum yields (φ₄₄₃) for each of the two photochemical reaction steps separately, revealing very high quantum yields of 0.16-0.25 for the first step and lower values (0.0055-0.0093) for the second step of the photoreaction. The selective and efficient photochemical reaction makes the photocleavable bis(thioether) ligand scaffold reported here a promising candidate for use in e.g. ruthenium-based photo-activated chemotherapy.

Full text of DOI:10.1021/acs.inorgchem.9b01669

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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Diastereoselective Synthesis and Two-Step Photocleavage of
Ruthenium Polypyridyl Complexes Bearing a Bis(thioether) Ligand
Michael S. Meijer and Sylvestre Bonnet*
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
S
* Supporting Information
ABSTRACT: Thioethers are good ligands for photoactivat-
able ruthenium(II) polypyridyl complexes, as they form
thermally stable complexes that are prone to ligand photo-
substitution. Here, we introduce a novel symmetric chelating
bis(thioether) ligand scaffold, based on 1,3-bis(methylthio)-2-
propanol (4) and report the synthesis and stereochemical
characterization of the series of novel ruthenium(II)
polypyridyl complexes [Ru(bpy)2(L)](PF6)2 ([1]−[3]-
(PF6)2), where L is ligand 4, its methyl ether, 1,3-
bis(methylthio)-2-methoxypropane (5), or its carboxymethyl
ether, 1,3-bis(methylthio)-2-(carboxymethoxy)propane (6).
Coordination of ligands 4−6 to the bis(bipyridine)ruthenium
center gives rise to 16 possible isomers, consisting of 8
possible Λ diastereoisomers and their Δ enantiomers. We
found that the synthesis of [1]−[3](PF6)2 is diastereoselective, yielding a racemic mixture of the Λ-(S)-eq-(S)-ax-OHeq-[Ru]2+
and Δ-(R)-ax-(R)-eq-OHeq-[Ru]2+ isomers. Upon irradiation with blue light in water, [1]−[3](PF6)2 selectively substitute their
bis(thioether) ligands for water molecules in a two-step photoreaction, ultimately producing [Ru(bpy)2(H2O)2]2+ as the
photoproduct. The relatively stable photochemical intermediate was identified as cis-[Ru(bpy)2(κ1-L)(H2O)]2+ by mass
spectrometry. Global fitting of the time evolution of the UV−vis absorption spectra of [1]−[3](PF6)2 was employed to derive
the photosubstitution quantum yields (Φ443) for each of the two photochemical reaction steps separately, revealing very high
quantum yields of 0.16−0.25 for the first step and lower values (0.0055−0.0093) for the second step of the photoreaction. The
selective and efficient photochemical reaction makes the photocleavable bis(thioether) ligand scaffold reported here a promising
candidate for use in e.g. ruthenium-based photo-activated chemotherapy.
bis(arylthioether) ligands, e.g. 1,3-bis(phenylthio)propane
(bptp).26−28 The photosubstitution of some bis(thioether)
ligands was previously reported to be 5−10 times more
efficient than that of comparable bis(amine) ligands.26
However, these reports do not always appreciate the two-
step nature of the photosubstitution of such bidentate ligands,
reporting the photosubstitution quantum yields as a single
number. Furthermore, the bis(thioether) ligands reported
previously often have limited options for further functionaliza-
tion, such as the attachment of anchoring groups, which can be
very useful for the development of photoactivatable ruthenium
complexes bound to inorganic surfaces or nanomaterials.
In this work, we report the coordination of the symmetric
bidentate bis(thioether) ligand 1,3-bis(methylthio)-2-propanol
(4) to ruthenium. We introduced an alcohol functionality in
this ligand to allow for future functionalization; this substituent
was added in a symmetrical position to prevent the formation
of regioisomers upon metal coordination of the ligand. To
exemplify these functionalization options, we also prepared the
INTRODUCTION
■
The use of light as a trigger for the activation of metal-based
anticancer agents has been actively researched over the last
decades.1−5 In combination with ruthenium(II) complexes,
light can be used either to drive the formation of reactive
oxygen species through the sensitization of oxygen in
photodynamic therapy (PDT)6−9 or to uncage photoactivat-
able complexes through ligand photosubstitution in photo-
activated chemotherapy (PACT).10−18 This photolability can
be enhanced through both steric and electronic effects.19 In
our group, thioether ligands have been considered with more
attention for the photocaging of bioactive ruthenium
polypyridyl complexes.13,20−22 Their softness makes thioethers
excellent ligands for ruthenium(II) ions, and their complexes
often show good thermal stability. Under blue light irradiation,
several groups have shown that thioether ligands can be
selectively substituted by solvent molecules, both for
monodentate ligands, e.g. 2-(methylthio)ethanol
(Hmte),20,23,24 and for bidentate chelating thioether li-
gands.13,25−30 Examples of the latter include combinations of
thioether sulfur donors with nitrogen donor atoms, e.g. 2-
(methylthio)methylpyridine (mtmp),13 as well as symmetric
Received: June 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b01669
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
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Scheme 1. Chemical Structures of New Ruthenium Polypyridyl Complexes [1]−[3](PF6)2 (Left) and Complexes [7]−
[10](PF6)2, Previously Reported by the Groups of Turro (Center) and Sauvage (Right)26,27
electrospray (250 °C) with resolution R = 60000 at m/z 400 (mass
range m/z 150−2000) and dioctyl phthalate (m/z 391.28428) as a
lock mass. The high-resolution mass spectrometer was calibrated prior
to measurements with a calibration mixture (Thermo Finnigan).
Ligand Synthesis. 1,3-Bis(methylthio)-2-methoxypropane (5).
Dry and deoxygenated THF (20 mL) was placed under a dinitrogen
atmosphere in a round-bottom flask containing 1,3-bis(methylthio)-2-
propanol (0.56 g, 0.50 mL, 3.70 mmol), followed by the addition of
solid NaH (296 mg, 7.40 mmol, 60% dispersion in mineral oil). The
resulting suspension was stirred at room temperature for 20 min to
allow complete deprotonation of the alcohol. Afterward the reaction
mixture was cooled to 0 °C, and iodomethane (0.63 g, 0.28 mL, 4.44
mmol) was added dropwise. The resulting suspension was stirred at
room temperature for 24 h and then quenched with saturated aqueous
NH4Cl (5 mL) to yield a light yellow solution. The solvent was
removed in vacuo, and the residue was dissolved in H2O (40 mL) and
extracted with DCM (3 × 40 mL). The organic layers were combined,
washed with brine, dried over MgSO4, and concentrated by rotary
evaporation. Separation of the product (Rf = 0.7) and unreacted
starting compound (Rf = 0.9) was performed by column
chromatography (SiO2, petroleum ether 40/60/EtOAc (4/1)),
ultimately resulting in 404 mg of compound 5 as a colorless oil
(2.43 mmol, 66%). 1H NMR (400 MHz, δ in CDCl3): 3.50 (p, J = 5.7
Hz, 1H, H3), 3.42 (s, 3H, H6), 2.74 (ddd, J = 21.4, 13.6, 5.7 Hz, 4H,
H2 + H4), 2.16 (s, 6H, H1 + H5). 13C NMR (101 MHz, δ in CDCl3):
80.6 (C3), 57.5 (C6), 37.2 (C2 + C4), 16.8 (C1 + C5). ESI-MS in
methyl- and carboxymethyl-substituted derivatives of 4, i.e. 1,3-
bis(methylthio)-2-methoxypropane (5) and 1,3-bis-
(methylthio)-2-(carboxymethoxy)propane (6). We hence
synthesized three new ruthenium polypyridyl complexes of
the general formula [Ru(bpy)2(L)](PF6)2 ([1]−[3](PF6)2),
where bpy = 2,2′-bipyridine and L = 4−6 (Scheme 1). We
investigated the stereochemistry of the complexes using
density functional theory (DFT) and NOESY NMR studies
and examined both the efficiency and selectivity of the
photochemistry of complexes [1]−[3](PF6)2 in aqueous
solution. Our results are compared to reports by the groups
of Turro and Sauvage on the related bis(thioether) chelate
complexes [Ru(bpy)2(bete)](PF6)2 ([7](PF6)2, bete = 3,6-
dithiaoctane), [Ru(bpy)2(bpte)](PF6)2 ([8](PF6)2, bpte = 1,2-
bis(phenylthio)ethane), [Ru(phen)2(bpte)](PF6)2 ([9]-
(PF6)2), and [Ru(phen)2(bptp)](PF6)2 ([10](PF6)2), all
shown in Scheme 1.26,27 In particular, we evaluate the effects
of the chelating ring size (five- vs six-membered ring), of the
size and aromaticity of the thioether substituent (methyl, ethyl,
or phenyl group), and of the addition of a substituent to the
chelating ring (i.e., the hydroxyl or ether group in complexes
[1]−[3](PF6)2) on the stereo- and photochemistry of this type
of complex.
1
CH3OH m/z exptl (calcd): 205.0 (205.0, [M + K]+). H NMR data
EXPERIMENTAL SECTION
match the literature data.31
■
General Considerations. Dry tetrahydrofuran (THF) was
collected from a Pure-Solv MD5 dry solvent dispenser (Demaco).
1,3-Bis(methylthio)-2-propanol (4) was obtained from Alfa Aesar. All
other reagents and solvents, including cis-[Ru(bpy)2Cl2], were
purchased from Sigma-Aldrich and used as received. All syntheses
were conducted under an oxygen-free atmosphere using standard
Schlenk line techniques. Syntheses of all ruthenium complexes were
performed in the absence of light. Flash column chromatography was
performed on silica gel (Screening Devices BV) with a particle size of
40−64 μm and a pore size of 60 Å. TLC analysis was conducted on
TLC aluminum foils with silica gel matrix (Supelco, silica gel 60, art.
no. 56524) with detection by UV absorption (254 nm) or basic
KMnO4 spray. Size exclusion column chromatography was performed
in acetone using Sephadex LH20, loaded into a chromatography
column (i.d. = 3−4 cm, l ≈ 60 cm).
1,3-Bis(methylthio)-2-(carboxymethoxy)propane (6). Dry and
deoxygenated THF (10 mL) was placed under a nitrogen atmosphere
in a round-bottom flask containing 1,3-bis(methylthio)-2-propanol
(0.25 g, 0.22 mL, 1.64 mmol), followed by the addition of solid NaH
(328 mg, 8.20 mmol, 60% dispersion in mineral oil) and potassium
iodide (22 mg, 0.133 mmol). The resulting suspension was stirred at
room temperature for 20 min to allow complete deprotonation of the
alcohol. Afterward the reaction mixture was cooled to 0 °C, and a
solution of bromoacetic acid (342 mg, 2.46 mmol) in dry THF (2
mL) was added dropwise. The resulting suspension was heated to
reflux, stirred for 22 h, and subsequently cooled to 0 °C and quenched
with water (10 mL) to yield a light yellow solution. The solvent was
removed in vacuo, and the residue was dissolved in H2O (30 mL) and
washed with EtOAc (3 × 30 mL). The aqueous layer was acidified to
pH ∼2 with 1 M HCl, followed by extraction with EtOAc (3 × 50
mL). The organic layers were combined, washed with brine, dried
over MgSO4, and concentrated by rotary evaporation. Acetic acid
impurities were removed from the crude product by coevaporation
with toluene (3 × 50 mL), to obtain compound 6 as a colorless oil
All NMR spectra were recorded on a Bruker AV-300, AV-400, or
AV-500 spectrometer. Chemical shifts (δ) are indicated in ppm
relative to TMS or the solvent peak. Atom numbering for NMR
attribution is shown in the Supporting Information (Schemes S1 and
S2). Mass spectra were recorded by using a MSQ Plus Spectrometer
fitted with a Dionex automatic sample injection system. High-
resolution mass spectra were recorded by direct injection (2 μL of 1
μM solution in MeOH or acetonitrile and 0.1% formic acid) in a mass
spectrometer (Thermo Finnigan LTQ Orbitrap) equipped with an
1
(327 mg, 1.55 mmol, 95%). H NMR (300 MHz, δ in CDCl3): 9.23
(s, 1H, −COOH), 4.28 (s, 2H, H6), 3.64 (p, J = 5.9 Hz, 1H, H3), 2.76
(ddd, J = 19.3, 14.2, 5.5 Hz, 4H, H2 + H4), 2.15 (s, 6H, H1 + H5). 13
C
NMR (75 MHz, δ in CDCl3): 173.4 (C7), 79.8 (C3), 67.5 (C6), 37.9
B
DOI: 10.1021/acs.inorgchem.9b01669
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Inorganic Chemistry
Article
(C2 + C4), 16.6 (C1 + C5). HR-MS in CH3OH m/z exptl (calcd):
233.0285 (233.0384, [M + Na]+).
H
D3 + HA3), 8.73 (t, J = 7.8 Hz, 2H, HB3 + HC3), 8.46 (qd, J = 8.0, 1.5
Hz, 2H, HD4 + HA4), 8.17 (tt, J = 7.9, 1.5 Hz, 2H, HB4 + HC4), 8.06
(ddd, J = 7.4, 5.7, 1.4 Hz, 2H, HD5 + HA5), 7.84 (dd, J = 5.7, 0.8 Hz,
1H, HB6), 7.78 (dd, J = 5.7, 0.8 Hz, 1H, HC6), 7.52 (dddd, J = 8.8, 7.2,
5.6, 1.3 Hz, 2H, HB5 + HC5), 4.77 (s, 1H, H3), 4.48 (d, J = 16.5 Hz,
1H, H6), 4.35 (d, J = 16.5 Hz, 1H, H6), 3.59 (dd, J = 13.2, 6.3 Hz, 1H,
H2,ax), 3.52 (dd, J = 14.1, 2.7 Hz, 1H, H4,eq), 3.26 (dd, J = 14.0, 4.8
Hz, 1H, H4,ax), 2.98 (dd, J = 13.2, 1.6 Hz, 1H, H2,eq), 1.68 (s, 3H, H5),
1.35 (s, 3H, H1). 13C NMR (101 MHz, δ in acetone-d6): 171.3 (C7),
158.7, 158.6, 157.6, 157.5 (all Cq), 154.9 (CD6), 154.8 (CA6), 152.3
Ruthenium Complex Synthesis. [Ru(bpy)2(4)](PF6)2 ([1](PF6)2).
A mixture of 1,3-bis(methylthio)-2-propanol (4, 78 mg, 0.51 mmol)
and cis-Ru(bpy)2Cl2 (50 mg, 0.103 mmol) was placed in a 25 mL
round-bottom flask, under an N2 atmosphere. A deoxygenated
mixture of EtOH and H2O (1/1 v/v, 10 mL) was added, and the
reaction mixture was refluxed in the dark for 1.5 h. The resulting
orange solution was cooled to room temperature, and EtOH was
removed in vacuo. Water (10 mL) was added to the residue, before
washing with Et2O (3 × 15 mL). A saturated aqueous KPF6 solution
(∼5 mL) was then added to the aqueous layer, and the resulting
orange suspension was extracted with DCM (6 × 20 mL). The
combined organic layers were washed once with half saturated
aqueous KPF6 and then dried by rotary evaporation. Any excess KPF6
was removed by size exclusion chromatography in acetone, and after
drying overnight under high vacuum, complex [1](PF6)2 was
obtained as an orange powder (50 mg, 0.058 mmol, 57%). TLC: Rf
(CC6), 152.0 (CB6), 140.0, 140.0, 140.0, 139.9 (CA4 + CB4 + CC4
+
CD4), 129.9, 129.2 (CA5 + CD5), 128.9, 128.8 (CB5 + CC5), 126.0,
125.8 (CA3 + CD3), 125.3, 125.2 (CB3 + CC3), 75.0 (C3), 66.7 (C6),
37.7 (C2), 36.9 (C4), 18.4 (C5), 15.9 (C1). HR-MS in CH3CN m/z
exptl (calcd): 312.0410 (312.0396, [M − 2PF6]2+); UV−vis: λmax (ε
in M−1 cm−1) in H2O: 412 nm (5.18 × 103). Anal. Calcd for
C27H30F12N4O3P2RuS2·H2O: C, 34.81; H, 3.46; N, 6.01. Found: C,
34.91; H, 3.87; N, 5.89.
Density Functional Theory. Structure minimizations were
performed using density functional theory (DFT) as implemented
in the ADF software package from SCM (version 2017). The
structures of the 16 possible Λ stereoisomers of [1](PF6)2, consisting
of eight isomers with a chairlike metallacycle (i.e., R and S
conformation for both sulfur atoms and the −OH substituent) and
eight isomers with a boatlike metallacycle, were optimized in water
using the conductor-like screening model (COSMO)32 to simulate
the effect of solvation. The BLYP functional,33,34 combined with a
TZP basis set (valence triple-ζ plus 1 polarization function) and a
small frozen core for all atoms including ruthenium,35 was employed
in all calculations. All boatlike structures were found to convert to
chairlike structures during the structure optimization process and are
thus not shown.
1
= 0.2 (SiO2, acetone/H2O/saturated aqueous KPF6 (16/4/1)). H
NMR (500 MHz, δ in acetone-d6): 9.87 (d, J = 5.1 Hz, 1H, HA6), 9.63
(d, J = 5.6 Hz, 1H, HD6), 8.88 (t, J = 8.1 Hz, 2H, HD3 + HA3), 8.74
(dd, J = 8.2, 3.5 Hz, 2H, HB3 + HC3), 8.47 (tdd, J = 7.9, 2.9, 1.4 Hz,
2H, HD4 + HA4), 8.18 (td, J = 7.9, 1.5 Hz, 2H, HB4 + HC4), 8.08
(dddd, J = 11.2, 7.4, 5.7, 1.4 Hz, 2H, HD5 + HA5), 7.84 (d, J = 5.8 Hz,
1H, HB6), 7.79 (d, J = 5.3 Hz, 1H, HC6), 7.52 (tdd, J = 7.2, 5.6, 1.3
Hz, 2H, HB5 + HC5), 5.33 (d, J = 4.4 Hz, 1H, − OH), 4.87 (br s, 1H,
H3), 3.41 (dd, J = 13.5, 3.1 Hz, 1H, H4,eq), 3.30 (dd, J = 13.1, 6.3 Hz,
1H, H2,ax), 3.01 (dd, J = 13.1, 2.1 Hz, 1H, H2,eq), 2.99−2.93 (m, 1H,
H4,ax), 1.59 (s, 3H, H5), 1.36 (s, 3H, H1); 13C NMR (101 MHz, δ in
acetone-d6): 158.8, 158.7, 157.6, 157.5 (all Cq), 154.6 (CD6), 154.4
(CA6), 152.2 (CC6), 152.1 (CB6), 140.0 (CA4 + CB4 + CC4 + CD4),
129.7, 129.1 (CA5 + CD5), 128.9, 128.8 (CB5 + CC5), 126.0, 125.9
(CA3 + CD3), 125.3, 125.2 (CB3 + CC3), 67.0 (C3), 41.2 (C2), 39.5
(C4), 18.0 (C5), 16.1 (C1). HR-MS in CH3CN m/z exptl (calcd):
303.5503 (303.5504, [M − 2PF6 + CH3CN]2+), 565.0662 (565.0669,
[M − 2PF6 − H]+). UV−vis: λmax (ε in M−1 cm−1) in H2O: 413 nm
(5.13 × 103). Anal. Calcd for C25H28F12N4OP2RuS2·H2O: C, 34.37;
H, 3.46; N, 6.41. Found: C, 34.94; H, 3.61; N, 6.36.
Photosubstitution Quantum Yields of [1]−[3](PF6)2 under
Blue Light Irradiation. UV−vis experiments on the ruthenium
complexes were performed on a Cary 50 Varian spectrometer
equipped with a Cary Single Cell Peltier for temperature control (T =
298 K) and stirring. For the irradiation, a LED light source was used
(λ = 443 nm, fwhm = 11 nm) the photon flux of which was
determined by ferrioxalate actinometry (see Table S1 in the
Supporting Information). Experiments were performed in 1.0 × 1.0
cm fluorescence cuvettes (QS-111, Hellma Analytics) containing 3.00
mL of solution. A stock solution of the desired complex was prepared
using demineralized water, which was then diluted to the desired
working concentration (Table S1) and placed in the cuvette.
Irradiations were carried out under an N2 atmosphere after
deoxygenation for 10 min by gentle bubbling of N2 through the
sample, and the sample was kept under an inert atmosphere during
the experiment by a gentle flow of N2 over the top of the cuvette. A
UV−vis absorption spectrum was measured every 6 s during the
experiment. Data were analyzed using Microsoft Excel 2010. The
quantum yields of the photosubstitution reactions (Φ443) were
calculated by fitting the time evolution of the UV−vis absorption
spectra of the irradiated solution using the Glotaran software package
(see the Supporting Information for a full description).36 Mass
spectrometry was performed after the irradiation experiments to
identify the photoproducts.
[Ru(bpy)2(5)](PF6)2 ([2](PF6)2). Complex [2](PF6)2 was synthesized
using the method described for [1](PF6)2, using a mixture of 5 (85
mg, 0.516 mmol) and cis-Ru(bpy)2Cl2 (25 mg, 0.052 mmol) in a
mixture of EtOH and H2O (1/1 v/v, 6 mL). The complex was
obtained as a light orange powder in 69% yield (31 mg, 0.036 mmol).
TLC: Rf = 0.2 (SiO2, acetone/H2O/saturated aqueous KPF6 (16/4/
1
1)). H NMR (300 MHz, δ in acetone-d6): 9.81 (d, J = 5.1 Hz, 1H,
HA6), 9.58 (d, J = 5.3 Hz, 1H, HD6), 8.88 (t, J = 7.5 Hz, 2H, HD3
+
HA3), 8.74 (dd, J = 8.2, 4.0 Hz, 2H, HB3 + HC3), 8.46 (t, J = 7.9 Hz,
2H, HD4 + HA4), 8.23−8.04 (m, 4H, HB4 + HC4 + HD5 + HA5), 7.84
(d, J = 6.2 Hz, 1H, HB6), 7.79 (d, J = 5.8 Hz, 1H, HC6), 7.51 (tdd, J =
7.4, 5.6, 1.3 Hz, 2H, HB5 + HC5), 4.48 (br s, 1H, H3), 3.54 (s, 3H,
H6), 3.53−3.44 (m, 2H, H4,eq + H2,ax), 3.16 (dd, J = 13.7, 5.6 Hz, 1H,
H4,ax), 2.97 (dd, J = 13.2, 1.6 Hz, 1H, H2,eq), 1.63 (s, 3H, H5), 1.34 (s,
3H, H1). 13C NMR (75 MHz, δ in acetone-d6): 158.8, 158.6, 157.6,
157.5 (all Cq), 155.0 (CD6), 154.1 (CA6), 152.3 (CC6), 152.1 (CB6),
140.0, 140.0, 140.0, 140.0 (CA4 + CB4 + CC4 + CD4), 129.8, 129.0 (CA5
+ CD5), 128.9, 128.8 (CB5 + CC5), 126.0, 125.9 (CA3 + CD3), 125.3,
125.2 (CB3 + CC3), 75.8 (C3), 57.2 (C6), 37.6 (C2), 36.9 (C4), 18.2
(C5), 15.8 (C1). HR-MS in CH3CN m/z exptl (calcd): 310.5584
(310.5583, [M − 2PF6 + CH3CN]2+). UV−vis: λmax (ε in M−1 cm−1)
in H2O: 412 nm (4.04 × 103). Anal. Calcd for C26H30F12N4OP2RuS2·
4H2O·0.5(CH3)2CO: C, 34.03; H 4.26; N, 5.77. Found: C, 34.00; H,
4.47; N, 5.98.
Photoirradiation Monitored by 1H NMR Spectroscopy.
Deoxygenated D2O (0.6 mL) was placed in an NMR tube containing
[1](PF6)2 (1 mg) under an N2 atmosphere, resulting in an orange
solution (2 mM). The tube was irradiated at room temperature using
a LOT 1000 W xenon arc lamp equipped with an IR short-pass filter
and a 400 nm long-pass filter. The progress of the photoreaction was
1
[Ru(bpy)2(6)](PF6)2 ([3](PF6)2). Complex [3](PF6)2 was synthesized
using the method described for [1](PF6)2, using a mixture of 6 (48
mg, 0.228 mmol) and cis-Ru(bpy)2Cl2 (52 mg, 0.107 mmol) in a
mixture of EtOH and H2O (1/1 v/v, 10 mL). The complex was
obtained as a light orange powder in 55% yield (54 mg, 0.059 mmol).
TLC: Rf = 0.2 (SiO2, acetone/H2O/saturated aqueous KPF6 (16/4/
monitored by H NMR at several time points until the steady state
was reached (at 60 min irradiation).
A reference sample of cis-[Ru(bpy)2(H2O)2](CF3SO3)2 (cis-
[14](CF3SO3)2) in D2O was prepared by the addition of a drop of
triflic acid to a suspension of [Ru(bpy)2(CO3)] in D2O in the absence
of light. The latter was prepared following a literature procedure.37
Singlet Oxygen Generation and Phosphorescence Quan-
tum Yield of [1]−[3](PF6)2. The singlet oxygen generation and
1
1)). H NMR (400 MHz, δ in acetone-d6): 9.91 (d, J = 5.6 Hz, 1H,
HA6), 9.55 (d, J = 5.2 Hz, 1H, HD6), 8.86 (dd, J = 14.6, 8.2 Hz, 2H,
C
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phosphorescence quantum yields of [1]−[3](PF6)2 were determined
by relative methods, using [Ru(bpy)3]Cl2 as the standard. A full
description is provided in the Supporting Information.
of ligands 4−6 to the ruthenium center was achieved by
refluxing an excess of the ligand (2−10 equiv) with cis-
[Ru(bpy)2Cl2] in an ethanol/water mixture. Replacement of
the two coordinating chlorides by ligands 4−6 was typically
completed within 1.5 h, as shown by the color change of the
solution from purple to orange. After anion exchange with
KPF6, complexes [1]−[3](PF6)2 were obtained in 55−69%
yield as orange solids. The complexes were all isolated as their
bis(hexafluoridophosphate) salt, as confirmed by elemental
analysis. The workup of compound [3](PF6)2 was performed
under acidic conditions (pH ∼2) to ensure protonation of the
carboxylic acid in the final solid product. All three complexes
were soluble in water, despite their apolar counteranions.
Coordination of the bis(thioether) ligand was clearly
RESULTS AND DISCUSSION
■
Synthesis. Ligands 5 and 6 were obtained in good yields
from the commercially available ligand 4 through deprotona-
tion of the alcohol with sodium hydride, followed by
nucleophilic substitution using iodomethane or bromoacetic
acid as the electrophile, respectively (Scheme 2). Coordination
Scheme 2. Synthesis of Ruthenium Complexes [1]−
a
[3](PF6)2
1
demonstrated by H NMR by a splitting of the signal of the
thiomethyl groups, e.g. from a singlet at 2.16 ppm for ligand 5
in CDCl3 to two singlets at 1.63 and 1.34 ppm for complex
[2](PF6)2 in acetone-d6. Further characterization of the
complexes was performed using high-resolution mass spec-
trometry and elemental analysis.
As we used a racemic sample of cis-[Ru(bpy)2Cl2] for the
synthesis of [1]−[3](PF6)2, we obtained racemic mixtures of
the Λ and Δ enantiomers for each complex. An additional
stereochemical complication is caused by the six-membered
ring formed by the coordination of ligands 4−6, which induces
four more sources of isomerism: the configuration (R or S) of
the two sulfur atoms, the configuration of the carbon atom
attached to the hydroxyl or ether group, leading to either an
axial or equatorial −OR substituent, and the inversion of the
six-membered metallacycle, which transforms all axial sub-
stituents on the ring into equatorial ones (see Scheme 3). With
five stereogenic centers, we would expect 32 possible isomers,
i.e. 16 Λ diastereoisomers and their respective Δ enantiomers.
However, due to the plane of symmetry in ligands 4−6,
inversion of the six-membered ring leads to the formation of
one of the other diastereoisomers: e.g., ring inversion of Λ-a-
[Ru]2+ (see Scheme 3) leads to the formation of Λ-h-[Ru]2+.
Thus, we concluded that there are eight possible Λ
diastereoisomers in total, shown in Scheme 3, all with their
respective Δ enantiomers. It should be noted that the
determination of enantiomer relationships is nontrivial for
a
Conditions: (a) NaH, iodomethane in THF, 0 °C to room
temperature, 24 h, 66%; (b) NaH, KI, bromoacetic acid in THF, 0
°C to reflux, 22 h, 95%; (c) (i) cis-[Ru(bpy)2Cl2] in EtOH/H2O (1/1
v/v), reflux, 1.5 h, (ii) KPF6, 57% ([1](PF6)2), 69% ([2](PF6)2), 55%
([3](PF6)2). Compounds [1]−[3](PF6)2 were obtained as racemic
Λ/Δ mixtures.
Scheme 3. Possible Stereoisomers of Complexes [1]−[3]2+, Resulting from the Inversion of either the Configuration of One of
the Sulfur Atoms or the Configuration of the Carbon Atom Attached to the Hydroxyl or Ether Group
D
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a
Table 1. Enantiomer Relationships for Complexes [1]−[3]2+
Λ
Δ
Λ-a-[Ru]2+
Λ-b-[Ru]2+
Λ-c-[Ru]2+
Λ-d-[Ru]2+
Λ-e-[Ru]2+
Δ-e-[Ru]2+
Λ-f-[Ru]2+
Δ-g-[Ru]2+
Λ-g-[Ru]2+
Δ-f-[Ru]2+
Λ-h-[Ru]2+
Δ-h-[Ru]2+
Δ-a-[Ru]2+
Δ-c-[Ru]2+
Δ-b-[Ru]2+
Δ-d-[Ru]2+
a
The definition of the isomers is given in Scheme 3. The enantiomer of each isomer shown in the top line corresponds to the isomer shown in the
bottom line.
these complexes. For example, whereas the mirror image of Λ-
a-[1]2+ is as expected Δ-a-[1]2+, the enantiomer of Λ-b-[1]2+ is
Δ-c-[1]2+ because the two nonequivalent sulfur atoms in
diastereoisomer b exchange with each other upon mirroring
into c. A similar exchange occurs with isomers f and g. The full
list of enantiomeric pairs is shown as Table 1 for convenience.
According to 1D and 2D 1H NMR, which showed only a single
set of 16 aromatic proton signals originating from the
bipyridine ligands, all 3 complexes were obtained as a racemic
mixture of a single diastereomer.
methyl groups are found in equatorial positions. The small
energy differences of ∼4 kJ mol−1 between these isomers is not
enough to exclude any of these four structures purely on the
basis of their computed energies.
As the DFT calculations did not provide a conclusive
1
answer, we turned to H NMR spectroscopy. The stereo-
chemistry of the carbon atom bearing the alcohol (C3 in Figure
3
1) could be found from the J coupling constants of the
Structural Characterization by NMR and DFT. In order
to gather insight into which one of the eight diastereoisomers
of [1](PF6)2 was obtained, we performed a computational
study of the stability of each of these isomers in aqueous
solution using DFT, employing the COSMO32 model to
simulate solvent effects. We minimized the structures of the
eight Λ diastereoisomers of [1]2+ shown in Scheme 3, where
the six-membered ring is in a chair conformation, as well as the
eight possible diastereoisomers with the six-membered ring in
a boat configuration. The diastereoisomers in a boat
configuration either relaxed to one of the chair configurations
shown above or resulted in a twisted-boat configuration with a
high energy. Thus, we concluded that a boat configuration is
energetically strongly disfavored for the six-membered metal-
lacycle in [1]2+ and that the product obtained must be in a
chair configuration. The optimized structures, their structural
distortion parameters, and their respective energies in water are
given in Table 2, Table S2, and Figure S1. Four of the possible
Figure 1. Structure of the most stable Λ diastereoisomer of [1]2+, Λ-
(S)-eq-(S)-ax-OHeq-[1]2+ (Λ-f-[1]2+), optimized by DFT (BLYP/
TZP) in water (COSMO), with a schematic drawing showing the
atom numbering used in the text.
protons on the adjacent carbon atom (C2). The large
3
difference between the J coupling constant of the axial (3J =
Table 2. Absolute and Relative Energies in Water
(COSMO) of the Λ Diastereoisomers of [1]2+, Optimized
by DFT
6.3 Hz) and equatorial protons (3J = 2.1 Hz) suggests that the
proton on C3 is positioned axially, and thus the −OH group
has to be equatorial. NOESY NMR spectroscopy further
confirmed the axial position of this proton (H3) by an off-
diagonal correlation with the D6 proton of the bpy ligand
(Figure S2). As the alcohol group is equatorial, the number of
possible Λ isomers of [1]2+ in solution was reduced to two, i.e.
Λ-(S)-eq-(S)-ax-OHeq-[1]2+ (Λ-f-[1]2+) and Λ-(S)-eq-(R)-eq-
OHeq-[1]2+ (Λ-e-[1]2+), which differ from each other by a
single inversion of sulfur chirality. In order to assess whether
this thiomethyl group (C1 in Figure 1) was axial or equatorial,
we examined the off-diagonal NOESY correlations of this
group (Figure S3). We found a correlation of these protons to
the A6 proton of the bpy ligand, over a distance of 3.29 Å
versus 5.00 Å for the equatorial and axial cases, respectively.
This suggested that the thiomethyl group is oriented
equatorially. However, the protons on C1 also show an off-
diagonal correlation to the axial proton on C3, a proton that is
significantly closer if the thiomethyl group is oriented axially
(3.36 Å versus 4.98 Å). Finally, a weak correlation was found
to the C3 proton on the bipyridine ring, which is closer to
thiomethyl group C1 in the axial conformation (5.19 Å versus
6.22 Å). All in all, this convinced us that this thiomethyl group
is at least predominantly oriented axially, yet an equilibrium
between its axial and equatorial positions in solution could not
be fully excluded. Thus, our NMR studies suggest that [1]2+ is
predominantly a racemic mixture of Λ-(S)-eq-(S)-ax-OHeq-
absolute energy in water/
Hartree
relative energy (ΔE) in water/
isomer
kJ mol−1
Λ-a-[1]2+
Λ-b-[1]2+
Λ-c-[1]2+
Λ-d-[1]2+
Λ-e-[1]2+
Λ-f-[1]2+
Λ-g-[1]2+
Λ-h-[1]2+
−13.05674
−13.05197
−13.05690
−13.05133
−13.05688
−13.05832
−13.05310
−13.05317
4.1
16.7
3.7
18.4
3.8
0.0
13.7
13.5
geometries, i.e. Λ-b-[1]2+, Λ-d-[1]2+, Λ-g-[1]2+, and Λ-h-[1]2+,
were significantly higher in energy, in comparison to the other
four. All of these geometries have one of the sulfur atoms in an
(R)-ax orientation that leads to a steric clash of the thiomethyl
group with one of the bipyridine ligands (Figure S1).
Diastereoisomer Λ-(S)-eq-(S)-ax-OHeq-[1]2+ (Λ-f-[1]2+ in
Scheme 3) was found to be the lowest in energy, 3.7 kJ
mol−1 lower than the diastereoisomer that is second lowest, Λ-
(S)-eq-(S)-ax-OHax-[1]2+ (Λ-c-[1]2+), obtained by inversion of
the configuration of the carbon atom bearing the alcohol
substituent. Two more diastereoisomers have relatively low
energies, namely Λ-(S)-eq-(R)-eq-OHax-[1]2+ (Λ-a-[1]2+), and
Λ-(S)-eq-(R)-eq-OHeq-[1]2+ (Λ-e-[1]2+), where both thio-
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Table 3. Lowest-Energy Absorption Maxima (λmax), Molar Absorption Coefficients at λmax (εmax) and 443 nm (ε443),
Photosubstitution Quantum Yields (Φ443) and Photosubstitution Reactivities (ξ443 = Φ443 × ε443) at 298 K in H2O, Singlet
Oxygen Quantum Yield (ΦΔ), and Phosphorescence Quantum Yield (ΦP) at 293 K in MeOD for Complexes [1]−[3](PF6)2
and Photochemical Intermediates [11]−[13](PF6)2
complex
λmax/nm (εmax/103 M−1 cm−1
)
ε443/103 M−1 cm−1
Φ443
0.24
0.0079
0.25
0.0093
0.16
0.0055
ξ443
ΦΔ
ΦP (λem/nm)
2.0 × 10−4 (624)
[1](PF6)2
[11](PF6)2
[2](PF6)2
[12](PF6)2
[3](PF6)2
[13](PF6)2
413 (5.13)
453 (7.02)
412 (4.04)
456 (5.52)
412 (5.18)
456 (6.77)
2.95
6.68
2.29
5.04
2.92
6.19
704
53
578
47
474
34
0.008
0.007
1.4 × 10−4 (620)
6 × 10−5 (620)
<0.005
[1]2+ (Λ-f-[1]2+, Figure 1) and Δ-(R)-ax-(R)-eq-OHeq-[1]2+
(Δ-g-[1]2+). This is also the enantiomeric pair that was found
to be most stable in our DFT studies (Table 2), suggesting that
the formation of the complex is under thermodynamic control.
Substitution of the alcohol does not affect the stereochemistry
of the complexes, as complexes [2](PF6)2 and [3](PF6)2 were
also found to form as a racemic mixture of the Λ-f-[Ru]2+ and
Δ-g-[Ru]2+ enantiomers, where [Ru]2+ is [2]2+ or [3]2+.
In recent work from our group we have shown that the bond
angle variance σ2 can be used as a structural distortion
parameter to quantify the steric hindrance induced by
thiomethyl groups in ruthenium polypyridyl complexes that
bear no straining pyridyl ligands.25,38 In the case of complex
[1]2+, we observed an increase in the σ2 value by at least 25
upon the introduction of an (R)-ax sulfur atom in the Λ
diastereoisomers, in comparison to their corresponding (S)-eq
isomer (e.g., σ2 = 59.4 and 87.5 for Λ-a-[1]2+ and Λ-b-[1]2+,
respectively, see Table S2). This increase correlates well with
the energies calculated by DFT (Table 2), which show an
increase by 10−15 kJ mol−1 for this inversion of the sulfur
configuration. Interestingly, we could not find a direct
correlation between the σ2 value and the DFT energy for the
conformation of the second sulfur atom. Inversion from Λ-(S)-
ax to Λ-(R)-eq for the C1 thiomethyl group led to an increase
in the σ2 value of ∼17 but resulted in virtually no increase in
DFT-calculated energy. This phenomenon could be explained
by the fact that the calculation of the σ2 value does not take
into account the intraligand interactions within bis(thioether)
ligand 4. Although the Λ-(S)-ax conformation is favorable for
relieving the octahedral strain on the ruthenium center, it does
lead to unfavorable 1,3-diaxial interactions with the H3 proton
on ligand 4, making the total energetic effect negligible.
Logically, we observed no effect of orientation of the alcohol
group on the σ2 value, since this does not affect the octahedral
strain on the ruthenium center.
Photochemistry. All three complexes form yellow
solutions in water, showing a 1MLCT absorption band around
412 nm, with molar absorption coefficients of 4.0−5.2 × 103
M−1 cm−1 (Table 3), typical for ruthenium(II) polypyridyl
complexes containing two thioether donor ligands.26 Essen-
tially no phosphorescence was observed upon irradiation of the
complexes with blue light in deuterated methanol (Figure
S4A), with phosphorescence quantum yields ΦP lower than 2.0
× 10−4. The complexes also appeared to be very poor singlet
oxygen sensitizers (ΦΔ ≤ 0.008, Figure S4B), as expected from
their photosubstitution properties (vide infra).
In the absence of light, complexes [1]−[3](PF6)2 were
found to be stable in water (Figure S5). However, all three
compounds are photoreactive under blue light irradiation in
water. We monitored the photoreactions of [1]−[3](PF6)2
with UV−vis absorption spectroscopy and mass spectrometry.
Upon irradiation of a solution of [1](PF6)2 with a blue LED (λ
= 443 11 nm), we observed a two-step bathochromic shift in
1
the MLCT absorbance band of the solution (Figure 2 and
Figure S6). First, the absorption maximum shifted from 413 to
453 nm, accompanied by three isosbestic points at 319, 364,
and 426 nm (Figure 2A). This first reaction was completed
within 5 min under the irradiation conditions used (photon
flux qp = 2.65 × 10−8 mol of photons s−1), at which point the
absorption maximum started to shift toward longer wave-
lengths again. This second reaction, in which the absorption
maximum changed from 453 to 491 nm, showed isosbestic
points at 314, 330, 389, and 466 nm and was significantly
slower than the first photoreaction (Figure 2B). Completion of
this second reaction took 1 h, at which point a steady state was
reached. Mass spectrometry of the reaction mixture after
irradiation (Figure S7) showed a peak at m/z 247.9,
corresponding to [Ru(bpy)2(CH3CN)2]2+ (calcd m/z 248.0),
formed inside the mass spectrometer from the original
photoproduct [Ru(bpy)2(OH2)2]2+ ([14]2+). No signals were
observed that match to photoproducts resulting from expulsion
of one of the bpy ligands. This result indicates that, upon blue
light irradiation of [1]2+ in water, the bis(thioether) chelate 4
is selectively substituted by two water molecules.
The intermediate species in the photoreaction was identified
by mass spectrometry, by measuring a sample after the first 5
min of irradiation (Figure S8). This sample showed the peak
for the photoproduct, as well as a peak for the starting
compound [1]2+ at m/z 282.7 (calcd m/z 283.0), and another
signal at m/z 303.1, identified as [Ru(bpy)2(4)(CH3CN)]2+
(calcd m/z 303.6), formed inside the mass spectrometer from
the original photochemical intermediate [Ru(bpy)2(4)-
(H2O)]2+. We hypothesized that the intermediate, which is
reasonably stable, is most likely six-coordinate, with ligand 4
bound in a monodentate fashion, and the second thioether
The synthesis of the related complexes [9](PF6)2 and
[10](PF6)2 was also reported to be diastereoselective by
Sauvage et al., who reported the same stereochemistry for the
sulfur atoms as we found for [1]−[3](PF6)2.27 However, in
their crystal structure the six-membered ring in [10](PF6)2 is
found in a half-chair conformation, perhaps made possible by
the lack of substitution at the C3 position. Overall, we can
conclude that the configuration of the sulfur atoms is not
influenced by the size of the ring, nor by the type of
substituents on the sulfur atoms (methyl groups in [1]−
[3](PF6)2 and phenyl groups in [9]- and [10](PF6)2) or by
substituents on the chelating ring. However, the introduction
of substituents at the C3 position on the ring does seem to
force the ring into a chair conformation.
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for ruthenium polypyridyl complexes bearing two photo-
cleavable monodentate ligands, such as cis-[Ru(bpy)2(py)2]2+
(py = pyridine),39−41 and has also been observed for the
photodissociation of the ligand bete (3,6-dithiaoctane) in
26
[7]2+ or mtmp (2-(methylthio)methyl-2-pyridine) in [Ru-
(bpy)2(mtmp)]2+.13
The identity of the final products of the photoreaction was
1
confirmed by H NMR spectroscopy (Figure 3). White light
irradiation of a sample of [1](PF6)2 in D2O in an NMR tube
resulted in the formation, at the photostationary state, of a
mixture of the free ligand 4 and of the complex cations cis-
[Ru(bpy)2(H2O)2]2+ (cis-[14]2+) and trans-[Ru-
(bpy)2(H2O)2]2+ (trans-[14]2+). Although our experimental
data do not allow us to exclude direct formation of trans-[14]2+
from the photochemical intermediate [11]2+, it is most likely
formed through photoisomerization of cis-[14]2+ to its trans
isomer, as reported previously.37,42 As both the cis and trans
isomers undergo photoisomerization, a photostationary state is
obtained at the end of the irradiation experiment. Since the
quantum yields for these cis−trans isomerization reactions of
[14]2+ are relatively high (Φ450 = 0.023−0.045 in 0.5 M
H2SO4) in comparison to the photosubstitution of [11]2+
(Table 3), we did not observe these reactions separately
(whether by NMR or by UV−vis absorption spectroscopy) but
they occur concomitantly. In addition, NMR experiments
under light irradiation were not helpful in identifying the
structure of [11]2+, as this intermediate may exist as several
highly unsymmetrical isomers, the peaks of which overlap with
those of the reagent or products (Figure 3).
Irradiation of complexes [2]2+ and [3]2+ resulted in very
similar photoreactions, as shown in Figures S9 and S10. The
UV−vis absorption spectra indicate formation of the same final
photoproduct [14]2+, passing through the monodentate
photochemical intermediates [12]2+ and [13]2+, as confirmed
by mass spectrometry (Figures S11−S14). The quantum
efficiencies of the two photochemical steps for each photo-
reaction were derived using global fitting of the time evolution
of the UV−vis absorption spectra, using the Glotaran software
package (Table 3 and Figures S15−S17).36 The photo-
substitution quantum yields Φ443 were found to be similar
across all three complexes, with Φ443 = 0.24, 0.25, and 0.16 for
the first step of the photoreaction for [1]2+, [2]2+, and [3]2+,
respectively. The second step of the photoreaction was
characterized by photosubstitution quantum yields of 0.0079,
0.0093, and 0.0055, respectively. These quantum efficiencies
are similar to those observed earlier for the second reaction
step of bidentate pyridine-thioether ligands13 and slightly lower
Figure 2. Evolution in time of the absorption spectra of a solution of
[1](PF6)2 in H2O (72 μM) upon irradiation at 298 K with a 443 nm
LED (qp = 2.65 × 10−8 mol of photons s−1) under N2, for t = 0−3.5
min (A, Δt = 12 s) and t = 3.5−60 min (B, Δt = 3.2 min), and the
time evolution of the absorbance (C) at 413 nm (red), 453 nm
(black), and 491 nm (blue) during the first 60 min of irradiation. The
vertical dashed line (t = 3.5 min) indicates the completion of the first
photosubstitution reaction.
group is replaced by water: i.e., [Ru(bpy)2(κ1-4)(H2O)]2+
([11]2+). Overall, under blue light irradiation [1](PF6)2
undergoes a two-step consecutive photochemical substitution
of the bis(thioether) ligand, passing through the rather stable
mono(aqua) intermediate [11]2+ (Scheme 4). This two-step
photoreactivity is reminiscent of the photoreactivity observed
Scheme 4. Two-Step Photosubstitution Reactions Observed upon Blue Light Irradiation of Solutions of [1]2+−[3]2+ in H2O
G
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(σ2), we hypothesize that minimization of the steric hindrance
induced by the thioether ligands is a major driving force for the
formation of this isomer. As we obtained the same
diastereoisomer that was reported for complexes [9](PF6)2
and [10](PF6)2, we conclude that the diastereoselectivity is
not determined by the nature of the thioether substituent or by
the chelate ring size. According to DFT, the substituent on the
C3 carbon in [1]−[3](PF6)2 does force the chelate ring in a
chair conformation, rather than a half-chair conformation as
observed in the X-ray structures of [9](PF6)2 and [10](PF6)2.
All three complexes were found to be stable in the dark in
aqueous solution but undergo efficient ligand substitution
reactions upon irradiation with blue light. In all three cases, a
selective substitution of the bis(thioether) ligand in two steps
was observed, leading to the formation of the bis(aqua)
complex [Ru(bpy)2(H2O)2]2+ ([14]2+). The reaction mecha-
nism was found to be identical with that reported for
complexes [7](PF6)2 and [8](PF6)2. A 30-fold difference in
efficiency between the two steps of the photoreaction was
observed, which, in combination with a high time resolution in
the irradiation experiments, allowed us to determine the
photosubstitution quantum yields for the individual steps,
rather than the overall quantum yield. It also allowed us to
identify the photochemical intermediate as the κ1-mono-
(thioether), mono(aqua) complex by mass spectrometry.
Substitution of the alcohol group by a methoxy or carboxylate
group, as in complexes [2](PF6)2 and [3](PF6)2, does not have
an effect on the diastereoselectivity of the synthesis or on the
selectivity of the photosubstitution reaction. Only small
differences were observed in the efficiency of the photo-
substitution reactions. Thus, functionalized bis(thioether)
ligands are promising candidates for the binding of cis
ruthenium-based PACT complexes to inorganic surfaces, as
they can be functionalized, do not form too many isomers, and
can be efficiently photocleaved.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01669.
■
Figure 3. Evolution of the aromatic (A, δ 9.9−6.9 ppm) and aliphatic
1
S
regions (B, δ 4.1−1.15 ppm) of the H NMR spectrum of a solution
of [1](PF6)2 (2.0 mM) in D2O upon irradiation with a Xe lamp (λirr
=
400−700 nm) for 60 min. Labeled signals correspond to the free
ligand 4 (diamonds), cis-[14]2+ (circles), and trans-[14]2+ (squares).
NMR spectra, spectroscopic details for photosubstitu-
tion, singlet oxygen generation, and phosphosrescence
quantum yield measurements, mass spectra after
irradiation, dark stability measurements of ruthenium
complexes, and computational details, including calcu-
lated geometries and structural parameters (PDF)
than those found for the substitution of monodentate thioether
ligands.20 For the photosubstitution reactions of [7]2+ and
[8]2+ in water, Turro et al. also reported a two-step
mechanism, including a quick formation of a κ1-coordinated
intermediate species. They reported overall quantum yields for
the formation of [14]2+ (Φ400) of 0.024 and 0.022,
respectively, rather than the quantum yields of the individual
steps reported above for the photosubstitution reactions in
[1]−[3]2+.26 This discrepancy in the kinetic models precludes
direct comparison of photosubstitution efficiencies.
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.B.: bonnet@chem.leidenuniv.nl.
■
ORCID
CONCLUSIONS
■
Michael S. Meijer: 0000-0003-0877-2374
Sylvestre Bonnet: 0000-0002-5810-3657
Notes
In this work, we have shown that the coordination of ligands
4−6 to the cis-Ru(bpy)2 scaffold under reflux in an EtOH/
H2O mixture is diastereoselective, yielding complexes [1]−
[3](PF6)2 as a racemic mixture of two enantiomers: namely, Λ-
(S)-eq-(S)-ax-OHeq-[Ru]2+ and Δ-(R)-ax-(R)-eq-OHeq-
[Ru]2+. DFT calculations showed this isomer to be the most
energetically favorable, suggesting that under such conditions
the synthesis is under thermodynamic control. As the obtained
isomer was also found to have the smallest bond angle variance
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The European Research Council is acknowledged for a Starting
grant to S.B. Prof. E. Bouwman is kindly acknowledged for
scientific discussion and support.
H
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photoactivatable metallodrugs: Selective and rapid light-induced
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