4,4′-Bis(trifluoromethyl)-2,2′-bipyridine-a multipurpose ligand scaffold for lanthanoid-based luminescence/19F NMR probes

Article abstract of DOI:10.1039/c3dt50842k

The tetradentate ligand 4,4′-bis(trifluoromethyl)-2,2′- bipyridine-6,6′-dicarboxylic acid (H₂1) and three corresponding anionic rare earth complexes [RE(1)₂]^- (RE = Y, Tb, Dy) were synthesized. The terbium and dysprosium complexes show lanthanoid-centered luminescence in aqueous solution, as well as paramagnetically enhanced longitudinal magnetic relaxation of the ¹⁹F nuclei.

Full text of DOI:10.1039/c3dt50842k

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4,4’-Bis(trifluoromethyl)-2,2’-bipyridine –
a multipurpose ligand scaffold for lanthanoid-
based luminescence/19F NMR probes†
Cite this: Dalton Trans., 2013, 42, 13882
Tuba Güden-Silber, Kathrin Klein and Michael Seitz*
Received 28th March 2013,
Accepted 20th July 2013
The tetradentate ligand 4,4’-bis(trifluoromethyl)-2,2’-bipyridine-6,6’-dicarboxylic acid (H21) and three
corresponding anionic rare earth complexes [RE(1)2]− (RE = Y, Tb, Dy) were synthesized. The terbium and
dysprosium complexes show lanthanoid-centered luminescence in aqueous solution, as well as paramag-
netically enhanced longitudinal magnetic relaxation of the 19F nuclei.
DOI: 10.1039/c3dt50842k
www.rsc.org/dalton
by inner-sphere H2O. A potentially very attractive alternative,
Introduction
which could be helpful to avoid this problem, is the use of 19F
1
Molecular lanthanoid complexes are very attractive for the (instead of H) nuclei, which have a number of favorable NMR
development of bioanalytical probes because of the unique characteristics (e.g. 100% natural abundance, spin 1/2 and
photophysical and magnetic properties that these building high gyromagnetic ratio). While the great potential of 19F MRI
blocks can provide. In this context, 1H MRI contrast agents has been recognized for quite some time, the remaining chal-
based on gadolinium are nowadays one of the most widely lenges (high probe concentrations/long acquisition times
used classes of metal complexes in clinical diagnosis,1 while necessary) have to date precluded its wider application.5
complexes with a variety of lanthanoids (e.g. Eu, Tb) have Parker et al. have recently introduced the idea of paramagnetic
made considerable progress as luminescent probes in a great relaxation enhancement in fluorinated lanthanoid complexes
number of bioanalytical settings.2 Every method has advan- in order to enhance the sensitivity of 19F MRI/MRS probes.6
tages but also specific intrinsic limitations. The use of analyti- According to their concept, fluorine nuclei are positioned
cal probes, however, which can be addressed by two different within a distance of ca. 7.5 Å to a paramagnetic lanthanoid.
modalities in one molecular entity, is therefore potentially of This substantially decreases the longitudinal relaxation time
great value. In the optimal case, these bimodal probes allow T1, making more scans per time interval possible. Provided
the synergistic combination of all the advantages of the indi- that the signal broadening associated with concomitant short-
vidual methods while alleviating the disadvantages.3 One very ening of the transverse relaxation time T2 is not too severe,
attractive possibility is the combination of magnetic and signal enhancement of one order of magnitude or more has
photophysical properties. Not surprisingly, several examples of been shown with this approach.6 Some of the lanthanoids suit-
such molecular, bimodal 1H MRI/optical probes have been able for use in 19F MRI are potentially also good candidates for
reported recently.4 In almost all instances, however, bimodality the development of luminescence probes. The two most
is only achieved by the application of a mixture of different promising lanthanoids in this respect are the highly para-
lanthanoids (e.g. Gd/Eu) with one ligand architecture. In magnetic Tb (μeff = 9.7 μB) and Dy (μeff = 10.6 μB), which exhibit
addition, for this particular combination the requirements for emission in the visible spectral region upon photoexcitation.
both modalities are mutually detrimental. While Gd-based The structural and electronic requirements for the realization
contrast agents need to have at least one water molecule of both modalities in a single ligand architecture are not easy
bound to the metal center, luminescence is severely quenched to fulfill, especially if some generality with respect to the
lanthanoid used is to be achieved. On the one hand, for
maximum sensitivity, one would ideally like to have as many
chemically and magnetically equivalent 19F nuclei present,
Inorganic Chemistry I, Department of Chemistry and Biochemistry, Ruhr-University
Bochum, 44780 Bochum, Germany. E-mail: michael.seitz@rub.de;
which also have to be positioned within a certain distance
range from the lanthanoid center. On the other hand, the elec-
Fax: +49 (0)234 32-14378
†Electronic supplementary information (ESI) available: Calculation of weighted
tronic structure of the ligand must be appropriate for the sen-
terbium–fluorine distances in Tb-7, determination of T1 relaxation times of RE-7
(RE = Y, Tb, Dy). CCDC 920406 (4) and 920407 (Tb-7). For ESI and crystallo-
sitization of lanthanoid luminescence by the antenna effect.
As a promising candidate for the development of such ligands,
graphic data in CIF or other electronic format see DOI: 10.1039/c3dt50842k
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Fig. 1 Ligand H21 based on a 4,4’-bis(trifluoromethyl)-2,2’-bipyridine scaffold.
we envisioned the simple model system H21 (Fig. 1) featuring
six equivalent fluorine nuclei and a 2,2′-bipyridine moiety, the
latter being among the most commonly used synthetic plat-
forms in lanthanoid coordination chemistry.7
Fig. 2 Thermal ellipsoid plot for 4 (Ortep 3 for Windows,10 50% probability
level). The hydrogen atoms are omitted for clarity.
In addition, it is known that 2,2′-bipyridine-6,6′-dicarboxylic
acid can act as an antenna for the sensitization of Tb lumine-
scence.8 Here, we show in a proof-of-concept study that the
4,4′-bis(trifluoromethyl)-2,2′-bipyridine scaffold in H21 is
indeed suitable for the implementation of both modalities
(19F NMR and lanthanoid luminescence) in a single lantha-
noid complex.
give the desired ligand H21. Complexation with the rare earths
Dy, Tb, and Y (as a diamagnetic, photoinactive reference)
yielded the analytically pure complexes RE-7.
The structure of the complexes was confirmed by X-ray ana-
lysis on single crystals of Tb-7, featuring two deprotonated
ligands binding to the eight-coordinate metal center in an
almost ideal trigonal-dodecahedral coordination geometry
(idealized symmetry D2d) (Fig. 3) with all four CF3 groups
being essentially equivalent. The complexes in the solid state
are anionic with triethylammonium as the countercation.
Importantly, the distances rTb–F are between 7.25 Å and 7.43 Å
reflecting the possible range upon rotation of the CF3 groups.
Results and discussion
Ligand synthesis
The ligand H21 was synthesized in a linear sequence over five The weighted, average distance is rmean = 7.35 Å (weighting by
steps starting from 2-bromo-6-methyl-4-trifluoromethyl-pyri-
−6, see the ESI†). This distance is rather long but would still
dine (2) (Scheme 1). Nickel(0)-mediated coupling of 2 to the be within the potentially useful range for 19F NMR probes.6
corresponding bipyridine 3 was rather efficiently achieved
Preliminary 19F NMR measurements of RE-7 (RE = Y, Tb,
r
using the conditions developed by Furue et al. for electron- Dy) in D2O showed only a single fluorine resonance in every
poor pyridines.9 Oxidation of the benzylic methyl groups case suggesting that the complex stayed intact upon dissolu-
directly to H21 proved to be impractical because of very low tion. Expectedly, however, this simple model system is not
yields and the formation of mixtures of different species that stable enough under more demanding conditions such as a
were difficult to separate. Instead, we used another sequence challenge with high-denticity competing ligands. For example,
involving oxidation to the corresponding N,N′-dioxide
4
a 1.5 mM solution of Y-7 (10 mM HEPES, pH 7.4) shows com-
(crystal structure in Fig. 2), Boekelheide rearrangement to 5, plete decomplexation upon the addition of 10 equivalents of
saponification to 6, and oxidation of bis(alcohol) 6 to cleanly Na2H2EDTA.
Fig. 3 Thermal ellipsoid plot for Tb-7 (Ortep 3 for Windows,10 50% probability
level). The hydrogen atoms and the isolated Et3NH+ cation are omitted for
Scheme 1 Synthesis of ligand H21 and the complexes RE-7.
clarity.
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Table 1 19F NMR data (5.87 T, 298 K) and quantum yields for Tb-7 and Dy-7
(10 mM HEPES buffer, pH 7.4)
Luminescence spectroscopy
The energy of the ligand-centered triplet state in the complexes
RE-7 was estimated from the low-temperature phosphor-
escence spectra of Y-7 (Fig. 4). Fitting of the band structure
yielded a zero-phonon transition energy (excited triplet →
ground state singlet) of 22 700 cm−1. This relatively high value,
Complex
δF a [ppm]
R1a,b [Hz]
Δω1/2 [Hz]
Φd [%]
Tb-7
Dy-7
−72.5
−74.8
63.8(1.8)
99.5(2.1)
41c
82c
0.9
0.7
a Y-7: δF = −64.7 ppm; R1 = 1.18(0.04) Hz. b Sample standard deviation
while above the emitting states of Tb (5D4 at ca. 20 500 cm−1 11
)
in parentheses (with Bessel correction). c In CD3OD (see text). 10%,
d
and Dy (4F9/2 at ca. 21 100 cm−1),11 is very likely to be not
sufficient to avoid problems of thermally activated back energy
transfer associated with energy gaps smaller than ca.
2000 cm−1 between the triplet state of the antenna moiety and
the corresponding accepting lanthanoid state. This pheno-
menon is likely to be responsible for the relatively small
quantum yields of Tb-7 and Dy-7 (vide infra) and has also been
observed previously for terbium in the non-fluorinated
complex analogue with the ligand 2,2′-bipyridine-6,6′-dicar-
boxylic acid.8
measured relative to quinine sulfate in 0.5 M H2SO4 (Φ = 54.6%) as the
standard.13
quite respectable since dysprosium complexes usually show
quantum yields in aqueous systems well below 5% even for
optimized systems.12 On the other hand, the relatively poor
luminescence efficiency of Tb-7 is rather surprising, but in the
light of the previously reported value of only 6.3% for the
terbium complex with the ligand 2,2′-bipyridine-6,6′-dicar-
boxylic acid, is not entirely unexpected.8 The low overall
efficiencies for both complexes, however, are more than
enough to ensure straightforward luminescence detection,
keeping in mind that the concentrations for 19F NMR measure-
ments would be in the mM range which is much higher than
usually necessary for luminescence probes.
Steady state luminescence spectra of Tb-7 and Dy-7 in
aqueous solution show the typical emission bands for both
lanthanoids (Fig. 5). Quantum yield measurements gave values
of 0.9% for Tb and 0.7% for Dy (Table 1). The value for Dy-7 is
19F NMR spectroscopy
19F NMR measurements in aqueous buffer solutions showed
moderate paramagnetic shifts of ca. 8–10 ppm for Tb-7 and
Dy-7 relative to the diamagnetic Y-7 (Table 1). Measurements
of the longitudinal relaxation rates R1 (B = 5.87 T, T = 298 K)
gave values of 63.8 Hz for Tb-7 and 99.5 Hz for Dy-7 (Table 1).
These rates are rather high for fluorine nuclei at a distance of
ca. 7.35 Å from the lanthanoid and high enough for potential
paramagnetic 19F probes. The signals of Tb-7 and Dy-7 in
aqueous solution, however, are rather broad (with signal
widths at half height Δω1/2 > 350 Hz). This, however, is not an
intrinsic property of the 2,2′-bipyridine unit. In CD3OD, the
Fig. 4 Low-temperature (77 K) steady state emission spectrum of Y-7 in
MeOH–EtOH (1 : 1, v/v) after excitation at λexc = 310 nm (solid line: cumulative
fit function; dashed lines: individual Gaussians).
signals are relatively sharp (Tb: Δω1/2 = 41 Hz, Dy: Δω1/2
=
82 Hz) in a similar range compared to previously reported suc-
cessful examples of 19F MRI probes,6 indicating that the broad-
ening in aqueous solution is due to exchange processes rather
than paramagnetic acceleration of the transverse relaxation.
Conclusions
In conclusion, we have synthesized a model ligand H21 that is
based on the new 4,4′-bis(trifluoromethyl)-2,2′-bipyridine
scaffold. We have shown that lanthanoid complexes based on
this molecular entity could in principle be used simul-
taneously in paramagnetically enhanced 19F NMR and in Tb/
Dy luminescence measurements. The incorporation of this
new building block into more elaborate ligand architectures
promises great potential for the development of practical
bimodal 19F MRI/optical imaging probes.
Fig. 5 Steady state emission spectrum of Tb-7 (solid line) and Dy-7 (dashed
line) in H2O after excitation at λexc = 306 nm.
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2-Bromo-6-methyl-4-trifluoromethylpyridine (2)
Experimental section
Under N2, PBr3 (37.2 mL, 107.1 g, 395.7 mmol, 3.2 equiv.) was
added to 6-methyl-4-trifluoromethyl-2-pyridone (21.90 g,
123.6 mmol, 1.0 equiv.) and the light-yellow suspension was
heated to 160 °C (bath temperature). After three hours, the
reaction was discontinued, at room temperature the colorless
sublimate that had formed was mechanically pushed down
into the reaction phase, and heating was continued for an
additional 4 h at 160 °C. After cooling to ambient temperature,
the orange solution was poured onto crushed ice (ca. 250 g)
and the resulting aqueous phase was treated cautiously with
solid Na2CO3 until pH 5 was reached. The voluminous precipi-
tate was filtered off with suction. The filtrate was extracted
with CHCl3 (4 × 100 mL), and the combined organic layers
were dried (MgSO4) and concentrated. The remaining orange
oil was distilled under reduced pressure (p = 72 mbar, bp
96–97 °C) to yield a light-yellow liquid (12.63 g, 43%).
Chemicals were purchased from commercial suppliers and
used as received unless stated otherwise. NMR solvents had
deuterium contents >99.8% D. Other solvents were dried by
standard procedures (EtOH: Mg/I2). Air-sensitive reactions
were carried out under a dry, dioxygen-free atmosphere of N2
using the Schlenk technique. Column chromatography was
performed with silica gel 60 (Merck, 0.063–0.200 mm). Analyti-
cal thin layer chromatography (TLC) was done on silica gel
60 F254 plates (Merck, coated on aluminium sheets).
ESI mass spectrometry was done using Bruker Daltonics
Esquire6000. NMR spectra were measured using Bruker
DPX-250 (1H: 250 MHz, 13C: 62.9 MHz, 19F: 235 MHz) and
Bruker DPX-200 (1H: 200 MHz, 13C: 50.3 MHz). UV/vis spectra
were recorded on a Jasco-670 spectrophotometer using 1.0 cm
quartz cuvettes.
1H NMR (250 MHz, CDCl3): δ = 7.54 (s, 1 H), 7.34 (s, 1 H),
2.65 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 161.6,
141.9, 140.7 (q, 2JF–C = 32.2 Hz), 122.0 (q, 1JF–C = 274 Hz), 121.1
(q, 3JF–C = 3.6 Hz), 118.0 (q, 3JF–C = 3.4 Hz), 24.3 ppm.
3-Cyano-6-methyl-4-trifluoromethyl-2-pyridone
1,1,1-Trifluoroacetylacetonate (100.23 g, 650.5 mmol,
1.0 equiv.) and cyanoacetamide (60.16 g, 715.5 mmol,
1.1 equiv.) were suspended in EtOH (400 mL, technical grade)
and the mixture was heated to gentle reflux. Diethylamine
(74.3 mL, 52.33 g, 715.5 mmol, 1.1 equiv.) was added dropwise
over 60 min. Stirring and heating were continued for an
additional 90 min and the dark brown solution was allowed to
come to ambient temperature. The solid was broken up, the
mixture was immersed in an ice-bath, and 1 M HCl (800 mL)
was added slowly with stirring. After 30 minutes of stirring,
the suspension was stored at 4 °C overnight. The precipitate
was collected, washed with water, and dried under reduced
pressure (1 mbar) at 60 °C (bath temperature) to yield the
product as a light-yellow solid (117.74 g, 90%). The analytical
data agree with previously reported literature data.14
6,6′-Dimethyl-4,4′-bis(trifluoromethyl)-2,2′-bipyridine (3)
Under N2, a two-necked Schlenk flask was charged with
[NiBr2(PPh3)2] (4.46 g, 6.00 mmol, 0.30 equiv.), zinc powder
(1.96 g, 30.0 mmol, 1.5 equiv.), and Et4NI (5.14 g, 20.0 mmol,
1.0 equiv.). Dry, degassed THF (40 mL, three freeze–pump–
thaw cycles) was added by a syringe and the suspension was
stirred at ambient temperature for 30 min. A solution of
2-bromo-6-methyl-4-trifluoromethylpyridine (2) (4.80 g,
20.0 mmol, 1.0 equiv.) in dry, degassed THF (20 mL) was
added and the dark-brown suspension was heated to 55 °C
(bath temperature) for 24 h. At ambient temperature, aqueous
ammonia (2 M, 200 mL) and CH2Cl2 (200 mL) were added, stir-
ring was continued for 10 min, and the mixture was filtered.
The aqueous layer of the filtrate was extracted with CH2Cl2
(2 × 200 mL), the combined organic phases were dried
(MgSO4) and concentrated. The residue was subjected to
column chromatography (SiO2, hexanes–CHCl3 5 : 1 → 1 : 1,
preloading onto SiO2). The product was obtained as colorless
needles (1.94 g, 61%).
1H NMR (250 MHz, CDCl3): δ = 6.63 (s, 1 H), 2.38 (s, 3 H)
ppm. Anal. Calcd for C8H5F3N2O (Mr = 202.13): C, 47.54; H,
2.49; N, 13.86. Found: C, 47.85; H, 2.65; N, 14.04.
6-Methyl-4-trifluoromethyl-2-pyridone15
3-Cyano-6-methyl-4-trifluoromethyl-2-pyridone
(31.90
g,
Mp 153–156 °C. 1H NMR (250 MHz, CDCl3): δ = 8.52 (s,
2 H), 7.41 (s, 2 H), 2.73 (s, 6 H) ppm. 13C NMR (62.9 MHz,
157.9 mmol, 1.0 equiv.) was added in portions to 50% H2SO4
(300 mL). The suspension was heated to 150 °C (bath tempera-
ture) for 20 h. The resulting yellow solution was cooled, cau-
tiously diluted with cold water to a volume of ca. 1.6 L, and
neutralized with solid Na2CO3. The resulting colorless precipi-
tate was collected, washed with cold water, and dried in vacuo
(50 °C, 0.5 mbar, 4 h). The product was obtained as a colorless
solid (24.99 g, 89%).
2
CDCl3): δ = 159.8, 156.0, 139.8 (q, JC–F = 34 Hz), 123.2 (q,
3
3
1JC–F = 273 Hz), 119.4 (q, JC–F = 3.5 Hz), 114.3 (q, JC–F
=
3.6 Hz), 24.8 ppm. 19F NMR (235 MHz, CDCl3): δ = −64.7 ppm.
MS (ESI+): m/z (%) = 342.9 (100, [M + Na]+). Anal. Calcd for
C14H10F6N2 (Mr = 320.23): C, 52.51; H, 3.15; N, 8.75. Found: C,
52.73; H, 2.83; N, 8.72. TLC: Rf = 0.14 (SiO2, hexanes–CHCl3
5 : 1, detection: UV).
1H NMR (250 MHz, CDCl3): δ = 6.67 (s, 1 H), 6.22 (s, 1H),
2.42 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 165.5,
2
1
6,6′-Dimethyl-4,4′-bis(trifluoromethyl)-2,2′-bipyridine-
N,N′-dioxide (4)
148.2, 143.7 (q, JC–F = 33 Hz), 122.4 (q, JC–F = 274 Hz), 114.2
3
3
(q, JC–F = 4.0 Hz), 101.8 (q, JC–F = 3.0 Hz), 19.3 ppm. Anal.
Calcd for C7H6F3NO (Mr = 177.12): C, 47.47; H, 3.41; N, 7.91. 6,6′-Dimethyl-4,4′-bis(trifluoromethyl)-2,2′-bipyridine (3) (3.19 g,
Found: C, 47.51; H, 3.21; N, 7.95.
10.0 mmol, 1.0 equiv.) was suspended in glacial acetic acid
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(70 mL) and aqueous hydrogen peroxide (30%, 5.0 mL, 1.65 g, onto SiO2). The product was obtained as a colorless solid
45.8 mmol, 4.6 equiv.) was added dropwise. The mixture was (0.40 g, 16%).
heated at 80 °C (bath temperature) for 20 h. Another aliquot of
Mp 176–178 °C. 1H NMR (200 MHz, CD3OD): δ = 8.66 (s,
aqueous hydrogen peroxide (30%, 4.0 mL, 1.32 g, 36.6 mmol, 2 H), 7.90 (s, 2 H), 4.94 (s, 4 H) ppm. 13C NMR (50.3 MHz,
2
3.7 equiv.) was added at ambient temperature and the reaction CD3OD): δ = 165.0, 156.7, 141.2 (q, JC–F = 33 Hz), 124.6 (q,
was heated at 80 °C for an additional 24 h. The clear solution 1JC–F = 273 Hz), 117.7 (q, JC–F = 3.6 Hz), 116.1 (q, JC–F
=
3
3
was cooled down and immersed in an ice-bath, and the 3.6 Hz), 65.7 ppm. MS (ESI+): m/z (%) = 374.9 (100, [M + Na]+).
mixture was treated with sodium thiosulfate pentahydrate Anal. Calcd. for C14H10F6N2O2 (Mr = 352.23): C, 47.74; H, 2.86;
(ca. 2 g) in portions. After stirring for 10 min, an aqueous solu- N, 7.95. Found: C, 47.25; H, 3.14; N, 7.79. TLC: Rf = 0.39 (SiO2,
tion of NaOH (50 g in 250 mL H2O) was added dropwise over CH2Cl2–MeOH 9 : 1, detection: UV).
the course of ca. 40 min, and the resulting suspension was
4,4′-Bis(trifluoromethyl)-2,2′-bipyridine-6,6′-dicarboxylic acid
monohydrate (H21)
extracted with CH2Cl2 (3 × 100 mL). The combined organic
layers were dried (MgSO4) and concentrated. The product was
obtained as a colorless solid (3.41 g, 97%) and was used in the 6,6′-Bis(hydroxymethyl)-4,4′-bis(trifluoromethyl)-2,2′-bipyridine
next step without further purification. Crystals suitable for (6) (323 mg, 917 μmol, 1.0 equiv.) was added in portions to
X-ray analysis were obtained by slow evaporation of methanolic conc. H2SO4 (4 mL) and the mixture was heated to 65 °C (bath
solutions of the title compound.
temperature). CrO3 (367 mg, 3.67 mmol, 4.0 equiv.) was added
Mp 204–206 °C. 1H NMR (200 MHz, CD3OD): δ = 8.06 (s, at a certain rate so that the internal temperature did not rise
2 H), 8.03 (s, 2 H), 2.65 (s, 6 H) ppm. 13C NMR (62.9 MHz, above 70 °C. After complete addition, the dark solution was
2
CD3OD): δ = 152.4, 144.7, 128.0 (q, JC–F = 35 Hz), 124.0 (q, heated at 70 °C (bath temperature) for an additional 60 min.
3
3
1JC–F = 272 Hz), 125.5 (q, JC–F = 3.7 Hz), 124.0 (q, JC–F
=
The mixture was poured onto crushed ice (ca. 350 g), and the
3.9 Hz), 30.7, 22.4, 17.8 ppm. MS (ESI+): m/z (%) = 374.9 (100, precipitate was collected on a filter, washed with cold water,
[M + Na]+). TLC: Rf = 0.23 (SiO2, CH2Cl2–MeOH 24 : 1, detec- and dried under reduced pressure at 100 °C for several hours.
tion: UV).
The product was obtained as an off-white solid (295 mg, 81%).
1H NMR (200 MHz, DMSO-d6): δ = 9.01 (d, J = 0.9 Hz, 2 H),
8.40 (d, J = 0.9 Hz, 2 H) ppm. 13C NMR (62.9 MHz, DMSO-d6):
6,6′-Bis(acetoxymethyl)-4,4′-bis(trifluoromethyl)-2,2′-bipyridine
(5)
δ = 164.5, 154.8, 150.0, 140.0 (q, 2JC–F = 34 Hz), 122.5 (q, 1JC–F
=
273 Hz), 121.2 (q, 3JC–F = 3.0 Hz), 119.6 (q, 3JC–F = 3.8 Hz) ppm.
19F NMR (235 MHz, DMSO-d6): δ = −63.4 ppm. MS (ESI−): m/z
(%) = 378.8 (100, [M − H]−). Anal. Calcd for C14H6F6N2O4·H2O
(Mr = 398.21): C, 42.23; H, 2.02; N, 7.03. Found: C, 42.72; H,
2.08; N, 7.12.
Under N2, 6,6′-dimethyl-4,4′-bis(trifluoromethyl)-2,2′-bipyri-
dine-N,N′-dioxide (4) (3.41 g, 9.68 mmol, 1.0 equiv.) was dis-
solved in Ac2O (50 mL) and the solution was heated to 120 °C
(bath temperature) for 14 h. After cooling to room temperature,
volatiles were removed under reduced pressure and the result-
ing brown oil was purified by column chromatography (SiO2,
CH2Cl2–MeOH 200 : 1, detection: UV). The product was
obtained as a light-yellow solid (3.07 g, 73%).
Yttrium complex [Y(1)2](HNEt3)·3H2O (Y-7)
4,4′-Bis(trifluoromethyl)-2,2′-bipyridine-6,6′-dicarboxylic acid
monohydrate (H21) (53.2 mg, 134 μmol, 2.0 equiv.) was sus-
pended in dry MeOH (6 mL), and a solution of YCl3·6H2O
(20.3 mg, 66.8 μmol, 1.0 equiv.) in dry MeOH (2 mL) was
added. The cloudy solution was stirred at ambient temperature
for 15 min and concentrated to dryness under reduced
pressure, and the remaining residue was resuspended in H2O
(8 mL). After the addition of NEt3 (93 μL, 67.6 mg, 668 μmol,
10 equiv.), the mixture was heated to reflux and filtered hot,
and the filtrate was concentrated to a volume of ca. 5 mL. The
suspension was cooled in an ice-bath for 1 h, and the light-
yellow solid was collected on a membrane filter (nylon,
0.45 μm) and washed with a minimum of ice-cold water. The
1
Mp 88–90 °C. H NMR (200 MHz, CDCl3): δ = 8.63 (s, 2 H),
7.62 (s, 2 H), 5.39 (s, 4 H), 2.23 (s, 6 H) ppm. 13C NMR
2
(50.3 MHz, CDCl3): δ = 170.5, 157.6, 155.6, 140.6 (q, JC–F
=
34 Hz), 123.0 (q, 1JC–F = 274 Hz), 117.7 (q, 3JC–F = 3.6 Hz), 116.4
3
(q, JC–F = 3.6 Hz), 66.3, 21.0 ppm. MS (ESI+): m/z (%) = 458.9
(100, [M + Na]+). Anal. Calcd. for C18H14F6N2O4 (Mr = 436.31):
C, 49.55; H, 3.23; N, 6.42. Found: C, 49.69; H, 2.90; N, 6.75.
TLC: Rf = 0.85 (SiO2, CH2Cl2–MeOH 24 : 1, detection: UV).
6,6′-Bis(hydroxymethyl)-4,4′-bis(trifluoromethyl)-2,2′-
bipyridine (6)
6,6′-Bis(acetoxymethyl)-4,4′-bis(trifluoromethyl)-2,2′-bipyridine pasty solid was transferred to a sublimation apparatus and
(5) (3.04 g, 6.97 mmol, 1.0 equiv.) was dissolved in MeOH heated at 70 °C (bath temperature) under reduced pressure
(100 mL) and K2CO3 (4.81 g, 34.8 mmol, 5.0 equiv.) was added. (p ≈ 0.3 mbar) for ca. 1 h. The sublimate (triethylammonium
The yellow suspension was stirred at ambient temperature for chloride) was discarded. The title compound was obtained as
12 h. The solvent was removed, water (100 mL) was added, and the remaining colorless solid (40 mg, 60%).
the mixture was extracted with CH2Cl2 (3 × 100 mL). The com-
1H NMR (200 MHz, CD3OD): δ = 9.41 (s, 2 H), 8.53 (s, 2 H),
bined organic phases were dried (MgSO4) and concentrated. 3.23 (q, 3 H, J = 7.3 Hz), 1.34 (t, 4 H, J = 7.3 Hz) ppm. 19F NMR
The resulting brown oil was purified by column chromato- (235 MHz, D2O): δ = −64.8 ppm. MS (ESI−): m/z (%) = 844.70
graphy (SiO2, CH2Cl2–MeOH 24 : 1, detection: UV, preloading (100, [Y(1)2]−). Anal. Calcd for C34H24F12N5O8Y·3H2O (Mr
=
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1001.52): C, 40.77; H, 3.02; N, 6.99. Found: C, 40.85; H, 3.38; X-ray crystallography
N, 6.92.
Crystals were mounted on glass fibers using perfluoropo-
lyether oil. The measurement was carried out on a RIGAKU
XtaLAB mini diffractometer using monochromated Mo-Kα radi-
ation (λ = 0.71075 Å). Data were collected at a temperature of
173(2) K. Frames corresponding to an arbitrary hemisphere of
data were collected using ω scans. An empirical absorption
correction based on the comparison of redundant and equi-
valent reflections was applied. The structure was solved within
the Wingx16 package by direct methods (SIR9217) and
expanded using Fourier techniques (SHELXL-9718) on F2. All
non-hydrogen atoms were refined anisotropically. The hydro-
gen atoms were included but not refined. They were positioned
geometrically, with distances C–H = 0.93 Å for aromatic hydro-
gens, C–H = 0.97 Å for CH2 moieties, and C–H = 0.96 Å for
methyl groups. For the methyl groups in 4, the rotation
around the corresponding C–C bond was refined (HFIX 137).
All hydrogens were constrained to ride on their parent carbon
atoms. Uiso(H) values were set at 1.2 times Ueq(C). In Tb-7, the
triethylammonium cation shows considerable disorder result-
ing in rather high Ueq or Uiso parameters for all carbon and
connected hydrogen atoms, respectively.
Terbium complex [Tb(1)2](HNEt3)·2H2O (Tb-7)
4,4′-Bis(trifluoromethyl)-2,2′-bipyridine-6,6′-dicarboxylic acid
monohydrate (H21) (96.4 mg, 242 μmol, 1.9 equiv.) was sus-
pended in dry MeOH (10 mL) and a solution of TbCl3·6H2O
(47.3 mg, 127 μmol, 1.0 equiv.) in dry MeOH (3 mL) was
added. The cloudy solution was stirred at ambient temperature
for 15 min and concentrated to dryness under reduced
pressure, and the remaining residue was resuspended in H2O
(ca. 80 mL). After the addition of NEt3 (177 μL, 128 mg,
1.27 mmol, 10 equiv.), the mixture was heated to reflux and fil-
tered hot, and the filtrate was concentrated to a volume of
ca. 5 mL. The suspension was cooled in an ice-bath for 1 h,
and the light-yellow solid was collected on a membrane filter
(nylon, 0.45 μm) and washed with a minimum of ice-cold
water. The pasty solid was transferred to a sublimation appar-
atus and heated at 70 °C (bath temperature) under reduced
pressure (p ≈ 0.3 mbar) for ca. 1 h. The sublimate (triethyl-
ammonium chloride) was discarded. The title compound was
obtained as the remaining yellow solid (75 mg, 59%). Crystals
suitable for X-ray analysis were obtained by slow evaporation of
methanolic solutions of the title compound.
Crystallographic data for 4 (CCDC 920406): C14H10F6N2O2,
Mw = 352.24 g mol−1, colorless plate (0.20 × 0.10 × 0.10 mm3),
T = 173(2) K, tetragonal, space group P41212, a = b = 11.873(5)
Å, c = 9.961(6) Å, α = β = γ = 90°, V = 1404.2(12) Å3, Z = 4, 12 062
reflections measured, 1235 unique (Rint = 0.0700), R(Fo) =
1H NMR (250 MHz, CD3OD): δ = 20.9 (br, 4 H), 5.13 (br, 6
H), 3.00 (br, 9 H), −66.2 (br s, 4 H) ppm. 19F NMR (235 MHz,
CD3OD): δ = −76.2 ppm. MS (ESI−): m/z (%) = 914.94 (100,
[Tb(1)2]−). Anal. Calcd for C34H24F12N5O8Tb·2H2O (Mr
=
2
0.0573 (observed 983 reflections, I > 2σ(I)), Rw(Fo ) = 0.1352
1053.52): C, 38.76; H, 2.68; N, 6.65. Found: C, 38.95; H, 2.35;
N, 6.58.
(all data), GoF = 1.108, the largest peak and hole: 0.164 e Å−3
and −0.211 e Å−3
.
Crystallographic data for Tb-7 (CCDC 920407): [Tb-
(C14H4F6N2O4)2](HNEt3), Mw = 1017.29 g mol−1, colorless plate
(0.31 × 0.16 × 0.15 mm3), T = 173(2) K, triclinic, space group
Dysprosium complex [Dy(1)2](HNEt3)·2H2O (Dy-7)
4,4′-Bis(trifluoromethyl)-2,2′-bipyridine-6,6′-dicarboxylic acid
monohydrate (H21) (67.7 mg, 170 μmol, 2.0 equiv.) was sus-
pended in dry MeOH (7 mL) and a solution of DyCl3·6H2O
(32.0 mg, 85.0 μmol, 1.0 equiv.) in dry MeOH (2 mL) was
added. The cloudy solution was stirred at ambient temperature
for 15 min and concentrated to dryness under reduced
pressure, and the remaining residue was resuspended in H2O
(8 mL). After the addition of NEt3 (118 μL, 86.0 mg, 850 μmol,
10 equiv.), the mixture was heated to reflux and filtered hot,
ˉ
P1, a = 10.18(1) Å, b = 11.59(1) Å, c = 16.46(2) Å, α = 78.15(3)°,
β = 85.49(3)°, γ = 84.13(3)°, V = 1887(4) Å3, Z = 2, 19 245 reflec-
tions measured, 8479 unique (Rint = 0.0542), R(Fo) = 0.0718
2
(observed 7024 reflections, I > 2σ(I)), Rw(Fo ) = 0.207 (all data),
GoF = 1.088, the largest peak and hole: 3.367 e Å−3 and
−1.847 e Å−3 (both close to Tb).
and the filtrate was concentrated to a volume of ca. 5 mL. The Luminescence spectroscopy
suspension was cooled in an ice-bath for 1 h, and the light-
Steady state emission spectra were acquired on a PTI Quanta-
yellow solid was collected on a membrane filter (nylon,
0.45 μm) and washed with a minimum of ice-cold water. The
pasty solid was transferred to a sublimation apparatus and
heated at 70 °C (bath temperature) under reduced pressure
(p ≈ 0.3 mbar) for ca. 1 h. The sublimate (triethylammonium
chloride) was discarded. The title compound was obtained as
the remaining colorless solid (61 mg, 68%).
master QM4 spectrofluorimeter using 1.0 cm quartz cuvettes
at RT. The excitation light source was a 75 W continuous
xenon short arc lamp. Emission was monitored at 90°. Spectral
selection was achieved using single grating monochromators
(excitation: 1200 grooves per mm, blazed at 300 nm; emission:
1200 grooves per mm, blazed at 400 nm). Quantum yields were
determined in HEPES buffer (10 mM, pH 7.4) using quinine
sulfate in sulfuric acid (Φabs = 54.6%)13 as the quantum yield
1H NMR (250 MHz, CD3OD): δ = 19.9 (br, 4 H), 5.02 (br,
6 H), 2.99 (br, 9 H), −107.1 (br s, 4 H) ppm. 19F NMR
(235 MHz, CD3OD): δ = −85.8 ppm. MS (ESI−): m/z (%) =
919.28 (100, [Dy(1)2]−). Anal. Calcd (Found) for C34H24DyF12-
N5O8·2H2O (Mr = 1057.09): C, 38.63; H, 2.67; N, 6.63. Found: C,
38.51; H, 2.80; N, 6.57.
standard after excitation at λexc = 315 nm for Tb-7 and at λexc
=
313 nm for Dy-7. Quantum yields were measured by the opti-
cally dilute method using the following equation:
2
Φx ¼ Φr ðGradx=GradrÞ ðnx2=nr Þ
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Dalton Transactions
where n is the refractive index and Grad is the linearly fitted
slope from the plot of the integrated luminescence intensity
versus the absorbance at the excitation wavelength. The sub-
scripts ‘x’ and ‘r’ refer to the sample and the reference, respect-
ively. The estimated uncertainties in Φ are 10%.
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Acknowledgements
5 (a) S. Temme, F. Bönner, J. Schrader and U. Flögel,
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The authors gratefully acknowledge financial support from:
DFG (Emmy Noether Fellowship M.S.) and Fonds der Che-
mischen Industrie (Liebig Fellowship M.S.). M.S. thanks Prof.
Dr Nils Metzler-Nolte (Ruhr-University Bochum) for his conti-
nued support. Financial support from the Research Depart-
ment Interfacial Systems Chemistry (Ruhr University Bochum)
is also acknowledged.
7 J. Hovinen and P. M. Guy, Bioconjugate Chem., 2009, 20,
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8 J.-C. G. Bünzli, L. J. Charbonniere and R. F. Ziessel,
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13888 | Dalton Trans., 2013, 42, 13882–13888
This journal is © The Royal Society of Chemistry 2013