Synthesis of novel macrocyclic lanthanide chelates derived from bis-pyrazolylpyridine.

Article abstract of DOI:10.1021/ol0169527

[structure: see text] New macrocyclic chelates based on bis-pyrazolylpyridine and diethylenetriaminepentaacetic acid are synthesized, and the remarkable luminescence properties of their lanthanide chelates are reported.

Full text of DOI:10.1021/ol0169527

ORGANIC
LETTERS
2
002
Vol. 4, No. 2
13-216
Synthesis of Novel Macrocyclic
Lanthanide Chelates Derived from
Bis-pyrazolylpyridine
2
Ernesto Brunet,* Olga Juanes, Rosa Sedano, and Juan-Carlos Rodr ´ı guez-Ubis*
Departamento de Qu ´ı mica Org a´ nica, C-1, Facultad de Ciencias,
niVersidad Aut o´ noma de Madrid, 28049-Madrid, Spain
ernesto.brunet@uam.es
Received October 24, 2001
ABSTRACT
New macrocyclic chelates based on bis-pyrazolylpyridine and diethylenetriaminepentaacetic acid are synthesized, and the remarkable
luminescence properties of their lanthanide chelates are reported.
The metal-centered emission of lanthanide chelates has been
successfully applied in various analytical methods based on
ments is not an easy task, and research in this area is very
active.
3
1
2
time-resolved fluorescence (TRF) and fluoroinmmunoassay.
The design of the organic part of the chelate is paramount
in attaining the required conditions for these chelates to be
practical. A useful ligand should bear a good yield for
intersystem crossing, a reasonable matching between the
chromophore first triplet state and the resonance level of the
metal, and the closest possible metal-to-chromophore dis-
tance. Last but not least, the ligand should be reasonably
soluble in aqueous media but must effectively shield the
metal from the water OH oscillators that easily quench
lanthanide emission. The fulfillment of all these require-
Heteroaromatic rings such as pyridine, pyrazine, or pyra-
zole have revealed excellent building blocks for designing
photoactive probes, and we have already prepared a number
4
of useful chelates based on these motifs. On the other hand,
polycarboxylate units are widely used in lanthanide chelates
because of their high binding constants for lanthanides.5
(3) Saito, S.; Hoshino, H.; Yotsuyanagi, T. Bull. Chem. Soc. Jpn. 2000,
3, 1817. Yang, X. P.; Su, C. Y.; Kang, B. S.; Feng, X. L.; Xiao, W. L.;
7
Liu, H. Q. J. Chem. Soc., Dalton Trans. 2000, 3253. Nozary, H.; Piguet,
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Bunzli, J. C. G. Inorg. Chem. 2000, 39, 5286. FatinRouge, N.; Toth, E.;
Perret, D.; Backer, R. H.; Merbach, A. E.; Bunzli, J. C. G. J. Am. Chem.
Soc. 2000, 122, 10810. Cooper, M. E.; Sammes, P. G. J. Chem. Soc., Perkin
Trans. 2 2000, 1695. Magennis, S. W.; Parsons, S.; Corval, A.; Woollins,
J. D.; Pikramenou, Z. Chem. Commun. 1999, 61. Prodi, L.; Pivari, S.;
Bolletta, F.; Hissler, M.; Ziessel, R. Eur. J. Inorg. Chem. 1998, 12, 1959.
(4) Rodr ´ı guez-Ubis, J. C.; Sedano, R.; Barroso, G.; Juanes, O.; Brunet,
E. HelV. Chim. Acta 1997, 80, 86. Takalo, H.; Mukkala, V. M.; Merio, L.;
Rodriguez-Ubis, J. C.; Sedano, R.; Juanes, O.; Brunet, E. HelV. Chim. Acta
1997, 80, 372.
(
1) Harma, H.; Aronkyto, P.; Lovgren, T. Anal. Chim. Acta 2000, 410,
8
6
1
5. van Hoek, A.; Visser, A. J. W. G. Phys. Chem. Biol. Interfaces 2000,
51. Bacigalupo, M. A.; Ius, A.; Longhi, R.; Meroni, G. Analyst 2000, 125,
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K.Kimura, H. Anal. Chem. 1998, 70, 596. Hemmila, I.; Mukkala, V. M.;
Takalo, H. J. Alloys Compd. 1997, 249, 158.
(2) Werts, M. H. V.; Woudenberg, R. H.; Emmerink, P. G.; vanGassel,
R.; Hofstraat, J. W.; Verhoeven, J. W. Angew. Chem., Int. Ed. 2000, 39,
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135, 27. Martell, A. E.; Smith, R. M. Critical stability constants; Plenum
Press: New York, 1989.
4
542. Beltyukova, S. V.; Egorova, A. V.; Teslyuk, O. I. J. Anal. Chem.
000, 55, 682.
2
1
0.1021/ol0169527 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/22/2001

Scheme 1
The main goal of this work was thus to build compound
Scheme 1 shows the synthetic approach. The starting 2,6-
bis(3-bromomethylpyrazol-1-yl)pyridine was prepared as pre-
viously described from 2,6-dibromopyridine and 3-ethoxy-
6
1
derived from bis-pyrazolylpyridine and diethylenetri-
7
aminepentaacetic acid (DTPA) (Figure 1). Its molecular
4
carbonyl pyrazol. The treatment of the dibromo derivative
in standard conditions with sodium azide and further catalytic
hydrogenation of the resultant diazide led to 2,6-bis(3-
aminomethylpyrazol-1-yl)pyridine. Addition of freshly pre-
pared diethylenetriaminepentaacetic dianhydride (DTPA)
over the diamine derivative dissolved in DMSO (concentra-
tion of reactants, 37 mM) in the presence of DBN (1,5-
diazabicyclo[3.4.0]non-5-ene) afforded a mixture of the two
macrocycles.
Although the assembly of very large macrocycles with
9
DTPA has rarely been reported, the MS spectrum (MALDI-
TOF) of the crude reaction hinted its production. It showed
+
+
two main groups of peaks at m/z 627.3 (1H ), 649.2 (1Na ),
6
Figure 1. Structure and molecular model of the target macrocycle.
modeling (HyperChem, AM1 and MM+) based on published
+
65.2 (1K ) and 1253.5, 1275.5, 1291.5, the latter group
being attributable either to a noncovalent dimer of 1 or to
+
+
+
2H , 2Na , and 2K , respectively. Isolation and fragmenta-
8
tion in the mass spectrometer of the species responsible for
the peak at m/z 1253.5 led to new fragments of higher and
equal m/z ratio than that of 1, i.e., 879, 727, 653, and 627,
strongly suggesting the presence of 2 since a noncovalent
dimer of 1 is very unlikely to render fragments of m/z ratio
larger than that of 1. After several unsuccessful attempts of
separation, 2 precipitated (15-20% yield) treating the crude
product with an 1:1 water-methanol mixture containing
data for DTPA-lanthanide complexes (assuming nine-
coordination of the metals by means of the three carboxylates
and aliphatic amines) showed that the macro ring of 1 would
adequately embrace the metal, therefore suggesting that the
3+
3+
Eu and Tb complexes of 1 would very likely comply
with the stringent structural features imposed by an efficient
lanthanide luminescence.
0
.5% TFA. The residue was eluted with water over an ion-
(
6) Remui n˜ a´ n, M.; Rom a´ n, H.; Alonso M. T.; Rodr ´ı guez-Ubis, J. C. J.
Chem. Soc., Perkin Trans 2 1993, 1099.
(
(
7) Ozaki, H.; Suda, E.; Nagano, T.; Sawai, H. Chem. Lett. 2000, 312.
8) Franklin, S. J.; Raymond, K. N. Inorg. Chem. 1994, 33, 5794.
(9) Inoue, M. B.; Santacruz, H.; Inoue, M.; Fernando, Q. Inorg. Chem.
1999, 38, 1596.
214
Org. Lett., Vol. 4, No. 2, 2002

exchange AG1-X8 resin (acetate form), the key fractions
were lyophilized, and the residue was washed with methanol,
yielding 1 in 10% yield. The two macrocycles exhibited very
1
different H NMR behavior in that 1, in contrast to 2,
displayed very broad signals over the observable range of
1
0
2
temperatures in D O.
3
+
3+
The Eu and Tb complexes of the macrocycles were
prepared by the addition of the corresponding aqueous
solution of lanthanide chloride to the buffered solution (pH
-
5
8
.6) of ligand at a concentration of 3 × 10 M in water.
Ligand-to-metal stoichiometry of the complexes resulted 1:1
and 1:2 for 1 and 2, respectively, as determined by
1
1
luminescence titrations and Job’s plots (Figure 2).
3
+
Figure 3. Luminescence excitation and emission spectra of Eu
and Tb3 complexes of 1 and 2.
+
Figure 2. Job’s plots of the complexation of ligands 1 and 2 with
3
+
Tb
.
the number of water molecules in the coordination sphere
of the metals, calculated by three different methods (Hor-
1
2
13
14
Excitation of aqueous solutions of Eu3+ and Tb3+ com-
rocks, Kimura, and Parker ), was the same for the
complexes of the two ligands and only 1.1 ( 0.5. This
suggests that coordination should be very similar in the two
cases, probably not involving the aromatic heterocycles, in
agreement with the small changes observed in the UV spectra
upon complexation (vide supra).
plexes of 1 and 2 from the lowest energy absorption band
gave rise to the usual, well-structured emission of the
lanthanide cations (Figure 3). In all cases, excitation and
absorption spectra matched very well, indicating that the
ligand did transfer the absorbed photons to the metal.
However, the UV spectra of the complexes were very similar
to the those of the ligand, suggesting that the bis-pyra-
zolylpyridine moiety did not suffer major conformational
changes upon complexation.The intense Eu3 and Tb
luminescence observed at the relatively low concentrations
used (3 × 10 M) suggests that the ligand-to-metal energy
transfer should be effective. The long decay times (τ) in the
ms range (Table 1) make these complexes very serious
candidates as luminescent probes for time-resolved tech-
niques.
The larger lifetimes measured in D O (factors of ca. 3.5
2
3+
3+
and 1.7 for Eu and Tb , respectively; cf. Table 1) indicate
that the complexes were sensitive to vibronic deactivation
via O-H oscillators.
+
3+
Reconsideration of lifetimes and quantum yields in the
-
5
15
light of the equations reported by Sabbatini et al. facili-
tates the discussion of the ligand-to-metal energy transfer
process.
Despite the difference in flexibility between 1 and 2 as
shown by their different behavior in H NMR (see above),
1
Table 1. Emission (Eu3+, 616 nm; Tb3+, 546 nm) Lifetimes
(
ms) and Quantum Yields (φ) after Excitation of Metal
1
(
10) H NMR of 1 (D2O, 80 °C, broad signals) δ (ppm): 8.4 (2H, Pz-
Complexes of Ligands 1 and 2 at 304 nm in Borate Buffered
H5), 7.7 (3H, Py), 6.4 (2H, Pz-H4), 4.4 (4H, PzCH2N), 3.3-2.7 (10H,
(pH 8.6) Solutions
1
3
NCH2CO) and 2.6-2.3 (8H, NCH2CH2N). C NMR (D2O, 80 °C) δ
(
(
5
(
ppm): 179.9 and 179.0 (CO2H), 174.0 (CONH2), 152.5 (Pz-C3), 147.8
Py-C4), 141.4 (Py-C2,6), 128.6 (Pz-C5), 107.8 (Py-C3,5), 106.7 (Pz-C4),
τ(D2O)a
complex
φ
τ(H2O)
8.8, 58.3 [(NCH2CH2N, NCH2CO2H)], 52.1 (NCH2CONH) and 36.5
PzCH2N). Spectra of 2 were almost identical but displaying sharp lines at
room temperature.
11) Bishop, J. A. Anal. Chim. Acta 1973, 63, 305. Bakker, B. H.; Goes,
M.; Hoebe, N.; van Ramesdonk, H. J.; Verhoeven, J. W.; Werts, M. H. V.;
Hosftraat, J. W. Coord. Chem. ReV. 2000, 208, 3. Werts, M. H. V.;
Verhoeven, J. W.; Hofstraat, J. W. J. Chem. Soc., Perkin Trans. 2 2000,
1‚Eu 3+
0.02
0.29
0.01
0.23
0.7
1.7
0.6
1.7
2.2 (2.3)
2.9 (2.9)
2.3 (2.3)
3.0 (3.0)
3+
1
‚Tb
‚Eu
3
+
2
(
2‚Tb3
+
a
Data at 77 K in parentheses.
4
33.
Org. Lett., Vol. 4, No. 2, 2002
215

especially favored by the presence of the donor amine
3
+
nitrogens in the DTPA moiety. LMCT states for Tb are
Table 2. Reinterpretation of Parameters of Table 1 in Terms of
Sabbatini’s Equations (see text)
-
1
much less accessible, and the ca. 4000 cm difference
5
3+
-1
between the emitting D
4
level of Tb (20 490 cm ) and
1
knr(OH), s-1
ion
φM
η
knr(T), s-
the T level of the ligand minimizes the problem of metal-
1
3
+
17
1
1
2
2
‚Eu
‚Tb
‚Eu
‚Tb
0.30
0.59
0.26
0.59
0.07
0.49
0.04
0.39
20
≈0
≈0
≈0
994
243
1232
255
to ligand back energy transfer.
3
+
Apart from the sought radiative route, the metal emitting
level may be deactivated by other processes. Table 2 contains
calculated rate constants for nonradiative processes, namely
thermal [knr(T) ) (1/τ ) - (1/τ )] and O-H vibronic
deactivation [knr(OH) ) (1/τ ) - (1/τ )]. The former,
nr(T), displays negligible values showing that the studied
macrocycles do not introduce excited states which can be
thermally populated from the emitting state. The second, knr
3
+
3
+
2
D O
98
77
D O
2
2
2
98
77
D O
2
Thus, Table 2 shows values obtained for η ) φ/φ
measures the energy transfer efficiency from the S
M
, which
state of
H O
2
k
1
the ligand to the emitting state of the metal via previous
intersystem crossing (S w T ) in the ligand, where φ and
are quantum yields of emission upon ligand and metal
excitation, respectively.
Assuming that the decay process in D
-
1
1
1
8
(
OH), reveals the usual, higher efficacy of the O-H
φ
M
3
+
oscillators in deactivating Eu , even though the number of
water molecules is similar in all cases. Complexes of 2
resulted somewhat more sensitive to O-H vibronic deactiva-
tion.
We thus conclude that the described macrocyclic chelates
possess enough water solubility and remarkable luminescence
properties with Eu and Tb ions that strongly posit its
application in TRF analytical methods. Research is in
progress to provide the complexes with additional functional-
ity to allow their covalent conjugation to biomolecules.
2
O at 77 K is purely
2
98 77
298
77
radiative, φ
lifetimes in H
).
It can be seen that η is much lower for Eu than for
M
≈ τ /τ , where τ
and τ
are the
H O D O
H O
D O
2
2
2
2
2
2
O at rt and D O at 77 K, respectively (Table
1
3
+
3+
16
3+
3+
Tb . The study of a relatively large body of compounds
related to 1 revealed that, to achieve efficient energy transfer
3
+
to Eu , it is necessary for the ligand T
1
level to lie well
5
-1
2 1
above the D state of the metal (21 400 cm ). Since T of
-
1
both ligands fulfilled this condition (ca. 24 300 cm ,
measured as usual in the Gd3 complexes), the reason for
the energy transfer inefficiency to Eu3 must be found in
the effective population of nonemitting LMCT states,
+
Acknowledgment. Financial support from Comisi o´ n
Interministerial de Ciencia y Tecnolog ´ı a of Spain (CICYT;
Grants PB90-0176, PB93-0264, PB95-0172, PB98-0103) and
indirect funding from FYSE-ERCROS S.A. are gratefully
acknowledged.
+
(
12) Horrocks, W. deW., Jr.; Sudnick, D. R. J. Am. Chem. Soc. 1979,
1
16, 1155.
(
(
13) Kimura, K.; Kato, Y. J. Alloys Compds. 1998, 806.
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OL0169527
D.; Royle, L.; de Sousa, A. A.; Gareth-Williams, J. A.; Woods, M. J. Chem.
Soc., Perkin Trans. 2 1999, 493.
(17) See for example: Sammes, P. J.; Yahioglu, G. Nat. Prod. Rep. 1996,
1. Carnall, W. T. In Handbook on the Physics and Chemistry of Rare Earths;
Gscheider, K., Eyring, L., Eds.; North-Holland: Amsterdam, 1979; Vol. 3,
p 171.
(
15) Sabbatini, N.; Guardigli, M.; Lehn, J. M. Coord. Chem. ReV. 1993,
23, 201.
16) Latva, M.; Takalo, H.; Mukkala, V.-M.; Matachescu, C.; Rodr ´ı guez-
Ubis, J. C.; Kankare, J. J. Luminescence 1997, 75, 149.
1
(
(18) Kropp, J. L.; Windsor, M. W. J. Chem. Phys. 1965, 42, 1599.
216
Org. Lett., Vol. 4, No. 2, 2002