Controlled synthesis of a novel heteropolymetallic complex with selectively incorporated lanthanide(III) ions

Article abstract of DOI:10.1021/ic402643a

A novel synthetic strategy toward a heteropolymetallic lanthanide complex with selectively incorporated gadolinium and europium ions is outlined. Luminescence and relaxometric measurements suggest possible applications in bimodal (magnetic resonance/optic

Full text of DOI:10.1021/ic402643a

Communication
pubs.acs.org/IC
Controlled Synthesis of a Novel Heteropolymetallic Complex with
Selectively Incorporated Lanthanide(III) Ions
Elke Debroye,† Matthias Ceulemans,† Luce Vander Elst,‡ Sophie Laurent,‡ Robert N. Muller,‡,§
and Tatjana N. Parac-Vogt*,†
†Department of Chemistry, KULeuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
‡Department of General, Organic and Biomedical Chemistry, University of Mons, Place du Parc 23, 7000 Mons, Belgium
§Center for Microscopy and Molecular Imaging (CMMI), 6041 Gosselies, Belgium
S
* Supporting Information
europium(III) ion for the luminescent properties (Figure 1).
DTPA has been chosen as the gadolinium(III) chelating unit and
ABSTRACT: A novel synthetic strategy toward a
heteropolymetallic lanthanide complex with selectively
incorporated gadolinium and europium ions is outlined.
Luminescence and relaxometric measurements suggest
possible applications in bimodal (magnetic resonance/
optical) imaging.
anthanide chelates are gaining growing interest in the field of
Lmolecular imaging. Gadolinium complexes have a wide-
spread application as magnetic resonance imaging (MRI)
contrast agents because they enhance the longitudinal relaxation
rate of water protons.1 Furthermore, numerous lanthanide
compounds are used as luminescent probes in the visible and
near-IR (NIR) regions for bioassay and live-cell microscopy.2
The luminescent chelates provide the advantage of long-lived
luminescence but require the insertion of an aromatic
chromophore into the ligand structure to sensitize lanthanide
emission via energy transfer.3 The chelating moieties most
commonly exist as diethylenetriaminepentaacetic acid (DTPA)
or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The
ligands not only prevent the toxicity effect of aqueous lanthanide
ions but also minimize the nonradiative deactivation of
lanthanide luminescence due to coupled O−H vibrations.
The design of lanthanide-based systems with potential
applications in bimodal imaging attracts much attention. Several
heteropolymetallic complexes combining gadolinium ions and
luminescent transition-metal ions have been developed and
investigated.4 Mixtures of complexes in which the ligand is
coordinated to paramagnetic gadolinium(III) or lanthanide ions
emitting in the visible5 or NIR region6 have been intensively
studied for their magnetic resonance/optical abilities. Alter-
natively, heterometallic complexes in which the antenna links the
chelating units bearing different luminescent lanthanide ions
have been reported.7 The aryl function can also be integrated into
one of the structures in order to achieve a dual imaging probe.8
However, the controlled site-selective synthesis of heterometallic
lanthanide complexes remains a challenge because of the very
similar coordination behavior across the lanthanide series.3
This work reports a novel synthetic strategy in order to
selectively incorporate two different lanthanide ions into a
heterotetrametallic complex, (GdL)3Eu, containing three
gadolinium(III) ions providing MRI response and one
Figure 1. Schematic representation of the compound (GdL)3Eu.
is linked to a europium(III) chelate consisting of a para-
substituted pyridine-2,6-dicarboxylate derivative via an amide
bond. In the envisioned complex, water molecules are able to
approach the paramagnetic entity in order to achieve efficient
relaxation enhancement, while water is excluded from the first
coordination sphere of europium(III) resulting in a bright
emissive compound. Furthermore, the sensitivity difference
between optical and MRI is encountered by assembling three
paramagnetic components around one luminescent metal ion.
The synthesis of the europium coordinating part starts with
the Suzuki−Miyaura coupling of t-Boc-protected 4-
(aminomethyl)phenylboronic acid pinacol ester (1) to dimethyl
4-bromo-2,6-pyridinedicarboxylate (2), resulting in the pro-
tected dipicolinate derivative 3 (Scheme 1). The t-Boc group is
selectively removed using trifluoroacetic acid in dichloromethane
in order to attach the aromatic chromophore via an amide bond
to DTPA/tert-butyl ester 4. The tert-butyl esters of the ligand
precursor 5 are selectively cleaved by stirring the product in an
aqueous HCl solution, leading to the octadentate ligand 6, which
forms the gadolinium complex Gd6 upon reaction with
gadolinium(III) chloride. Cleavage of the methyl esters is done
under alkaline conditions, and the reaction of 3 mol equiv of the
resulting GdL with europium(III) chloride yields the final
metallostar compound (GdL)3Eu.
1
The H NMR spectrum of the corresponding lanthanum
complex La6 displays shifting and splitting of the proton
Received: October 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ic402643a | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Communication
(aminocarboxylate) chelates with characteristic relative intensity
values5b (see the SI).
Scheme 1. Synthesis of the (GdL)3Eu Metallostar
Luminescence decay of the metallostar assembly in water
displays a biexponential curve, yielding lifetimes of 1.12 0.02
and 0.23 0.03 ms. These findings indicate the presence of more
than one europium(III) species in solution, suggesting that an
equilibrium between (GdL)3Eu and (GdL)2Eu has been
established under the low concentrations for the luminescence
measurements.10b The observed lifetimes for the 1:3 and 1:2
species are somewhat lower than those reported for other
europium(III) dipicolinate complexes, 1.64 and 0.31 ms,
respectively.10b The mean lifetimes obtained by single-
exponential analysis in both H2O (0.81 0.02 ms) and D2O
(2.60 0.05 ms) reveal a q value of 0.59 0.1. The hydration
number of ∼0.6 would imply a ratio of 80:20 between the 1:3 and
1:2 Eu-to-GdL species because three water molecules replace
one ligand in the inner coordination sphere. Because the
stoichiometry of the metallostar is critical for the photophysical
properties, the stability of the complex has been further explored
by monitoring the europium emission intensity and the
absorbance efficiency in a 0.1 M Tris buffer at pH 7.4 as a
function of the Eu-to-GdL ratio (see the SI). It can be seen that
the strongest luminescence is obtained in the region where 0.33
equiv of europium(III) have been added and the 1:3 complex has
been formed. At that time, no nonradiative quenching by
coordinated water molecules takes place. Adding extra
equivalents of europium(III) leads to the increased appearance
of 1:2 and 1:1 assemblies having poor luminescence. Factor
analysis indeed reveals the presence of three species, and the data
can be satisfactorily fitted according to the proposed model,
resonances in the aliphatic region, consistent with the occurrence
of several interconverting isomers. After cleavage of the methyl
esters, 1H NMR of LaL reveals controlled deprotection without
affecting the metal-ion coordination. Formation of the metal-
lostar (LaL)3Eu leads to broadening of all signals and separation
of the proton resonances in the aromatic region due to the
assembly of dipicolinate units around the paramagnetic euro-
pium ion (see the Supporting Information, SI).
The absorbance spectrum of the GdL complex displays a well-
defined absorption band with a maximum at 282 nm (ε = 4250
cm−1 M−1) corresponding to the well-known π → π* transitions
of dipicolinate-based ligands9 and a shoulder at 221 nm. The self-
assembly of three dipicolinate moieties around europium
resulted in a similarly shaped absorbance spectrum with a 2
nm red shift of the maxima and a slight decrease of the extinction
coefficient per ligand of 13% (ε284 = 11000 cm−1 M−1). The
molar absorption coefficient for (GdL)3Eu is slightly lower
resulting in log β11 = 6.5(2), log β12 = 12.8(2), and log β13
=
17.9(3). These values are slightly lower compared to other para-
substituted europium(III) dipicolinate complexes,9 but the
stability is remarkably high considering the bulky substituents
with a net negative charge at the pyridine 4 position.11b The
photophysically determined species distribution is in good
agreement with the one calculated with the program HySS
making use of the obtained stability constants (see the SI).
The europium(III) luminescence quantum yield determined
upon ligand excitation equals 9.8%. Considering the observed
and calculated radiative lifetimes, the intrinsic quantum yield has
been estimated to be 22%, resulting in a sensitization efficiency
ηsens of 47%. These values are somewhat lower compared to those
of the parent dpa2− tris-chelate with QEu = 24% and ηsens = 61%
but are in agreement with those of similar complexes reported in
the literature.9,13
compared to the one for the parent EuIIIdpa2− tris-chelate (ε271
=
16560 cm−1 M−1).10 Excitation into the benzyldipicolinate
chromophore of (GdL)3Eu at 290 nm gives rise to a
characteristic red europium-centered emission spectrum (Figure
2). Normally, for europium(III) dipicolinate complexes, the 5D0
Figure 3 depicts the 1H NMRD profiles of GdL and (GdL)3Eu
representing enhancement of the water proton relaxivity (r1) per
1 mM gadolinium(III) as a function of the magnetic field
strength. The profile of (GdL)3Eu displays a characteristic hump
Figure 2. Corrected and normalized emission spectrum of (GdL)3Eu
(λexc = 290 nm) at 298 K (2 × 10−5 M in 0.1 M NaCl, pH 7.4).
10
7
→ F1 transition is split into two bands. In the case of the
metallostar compound, the observed unsymmetrical splitting
into three bands indicates a slightly distorted D3 symmetry,
suggesting the absence of time-averaged rotational symmetry.11
In addition, the integrated emission intensity of the D0 → 7F2
5
5
7
transition is approximately 5−6 times that of the D0 → F1
transition, which is consistent with other para-substituted
europium(III) dipicolinate complexes.9,12 It is certain that
europium(III) did not replace the gadolinum(III) coordinated
to the DTPA scaffold because the studied EuL complex displays a
very different crystal-field splitting typical for acyclic poly-
Figure 3. 1H NMRD profiles of GdL and (GdL)3Eu compared to Gd-
DTPA in water at pH 7.4 and 310 K. The lines represent the fitted data.
B
dx.doi.org/10.1021/ic402643a | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Communication
between 20 and 100 MHz, which is assigned to the formation of a
supramolecular structure. At 20 MHz and 310 K, the relaxivity is
enhanced to 8.3 s−1 mM−1 for GdL and 9.6 s−1 mM−1 for
(GdL)3Eu with respect to 3.8 s−1 mM−1 for Gd-DTPA, as could
be expected given the higher molecular weight of the synthesized
chelates. Taking into account the presence of three gadolinium
ions per metallostar compound, a longitudinal relaxation rate of
28.8 s−1 mM−1 per molecule is obtained at 20 MHz. During the
theoretical fitting of the NMRD data, the inner- and outer-sphere
contributions to the paramagnetic relaxivity were taken into
account and the resulting parameters are listed in Table 1. Mainly
BELSPO, and COST Actions (D38 and TD1004), and the EMIL
Program.
REFERENCES
■
(1) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. Rev.
1999, 99, 2293.
(2) Bunzli, J.-C. G. Chem. Rev. 2010, 110, 2729.
̈
(3) Parker, D. Chem. Soc. Rev. 2004, 33, 156.
(4) (a) Dehaen, G.; Eliseeva, S. V.; Kimpe, K.; Laurent, S.; Vander Elst,
L.; Muller, R. N.; Dehaen, W.; Binnemans, K.; Parac-Vogt, T. N.
Chem.Eur. J. 2012, 18, 293. (b) Debroye, E.; Dehaen, G.; Eliseeva, S.
V.; Laurent, S.; Vander Elst, L.; Muller, R. N.; Binnemans, K.; Parac-
Vogt, T. N. Dalton Trans. 2012, 41, 10549. (c) Koullourou, T.; Natrajan,
L.; Bhavsar, H.; Pope, S. J. A.; Feng, J.; Kauppinen, R.; Narvainen, J.;
Shaw, R.; Scales, E.; Kenwright, A.; Faulkner, S. J. Am. Chem. Soc. 2008,
130, 2178.
(5) (a) Placidi, M. P.; Engelmann, J.; Natrajan, L. S.; Logothetis, N. K.;
Angelovski, G. Chem. Commun. 2011, 47, 11534. (b) Debroye, E.;
Eliseeva, S. V.; Laurent, S.; Vander Elst, L.; Petoud, S.; Muller, R. N.;
Parac-Vogt, T. N. Eur. J. Inorg. Chem. 2013, 2013, 2629.
Table 1. Parameters Obtained by Fitting the 1H NMRD Data
in Water at pH 7.4 and 310 K
a
a
Gd-DTPA
GdL
225
(GdL)3Eu
τR (ps)
τS0 (ps)
τV (ps)
54
87
25
1
3
3
4
314
82
5
1
1
112
42
1
2
30
(6) (a) Tallec, G.; Fries, P. H.; Imbert, D.; Mazzanti, M. Inorg. Chem.
2011, 50, 7943. (b) Bonnet, C. S.; Buron, F.; Caille, F.; Shade, C. M.;
́
a
Fixed values: q = 1, r = 0.31 nm, d = 0.36 nm, τM = 300 ns, and D =
3.3 × 10−9 m2 s−1.14
Drahos,
Suzenet, F.; Petoud, S.; Tot
̌
B.; Pellegatti, L.; Zhang, J.; Villette, S.; Helm, L.; Pichon, C.;
́
́
h, E. Chem.Eur. J. 2012, 18, 1419.
(7) (a) Placidi, M. P.; Villaraza, A. J. L.; Natrajan, L. S.; Sykes, D.;
Kenwright, A. M.; Faulkner, S. J. Am. Chem. Soc. 2009, 131, 9916.
(b) Sorensen, T. J.; Tropiano, M.; Blackburn, O. A.; Tilney, J. A.;
Kenwright, A. M.; Faulkner, S. Chem. Commun. 2013, 49, 783.
(8) (a) Mamedov, I.; Parac-Vogt, T. N.; Logothetis, N. K.; Angelovski,
G. Dalton Trans. 2010, 39, 5721. (b) Jones, J. E.; Amoroso, A. J.; Dorin, I.
M.; Parigi, G.; Ward, B. D.; Buurma, N. J.; Pope, S. J. A. Chem. Commun.
2011, 47, 3374.
the longer rotational correlation time τR is responsible for the
beneficially high relaxation rates. In the case of GdL, the possible
formation of intermolecular hydrogen bonds can lead to an
apparent increased molecular weight, improving the relaxivity.
In conclusion, the sequential deprotection of a newly designed
ditopic ligand allows the site-selective coordination of lanthanide
ions, leading to a unique heteropolymetallic lanthanide complex,
(GdL)3Eu, which can be considered as a potential bimodal MRI/
visible imaging agent. At the center of the metallostar, the
europium(III) ion is barely subjected to nonradiative deactiva-
tion by coordinated OH oscillators, achieving bright-red
luminescence with a quantum yield up to 10%. Furthermore,
enhanced longitudinal relaxation rates up to 31 s−1 mM−1 per
molecule at 40 MHz were obtained because of the presence of
three gadolinium ions at the periphery of the compound able to
coordinate one water molecule each. The possibility of making a
central macrocyclic ligand in order to avoid dissociation to the
(GdL)2Eu species has been considered for future work. In
general, the presented synthetic route offers broader applications
because it allows the insertion of different pairs of lanthanide ions
for further investigation of dual-optical or magnetic resonance/
optical imaging abilities.
(9) Gassner, A.-L.; Duhot, C. l.; Bunzli, J.-C. G.; Chauvin, A.-S. Inorg.
̈
Chem. 2008, 47, 7802.
(10) (a) Moore, E. G. Dalton Trans. 2012, 41, 5272. (b) Chauvin, A.-S.;
Gumy, F.; Imbert, D.; Bunzli, J.-C. G. Spectrosc. Lett. 2004, 37, 517.
̈
(11) (a) Bunzli, J.-C.; Eliseeva, S. In Lanthanide Luminescence;
̈
Hanninen, P., Harma, H., Eds.; Springer: Berlin, 2011; Vol. 7, p 1.
(b) Platas-Iglesias, C.; Piguet, C.; Andre, N.; Bunzli, J.-C. G. J. Chem.
̈
̈
̈
Soc., Dalton Trans. 2001, 3084.
(12) George, M. R.; Golden, C. A.; Grossel, M. C.; Curry, R. J. Inorg.
Chem. 2006, 45, 1739.
(13) Andres, J.; Chauvin, A.-S. Eur. J. Inorg. Chem. 2010, 2010, 2700.
(14) Vander Elst, L.; Sessoye, A.; Laurent, S.; Muller, R. N. Helv. Chim.
Acta 2005, 88, 574.
ASSOCIATED CONTENT
* Supporting Information
■
S
Details on instrumentation and methods and synthetic
procedures and characterization of ligand and complexes. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tatjana.vogt@chem.kuleuven.be.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
E.D. and T.N.P.-V. acknowledge the IWT Flanders and FWO
Flanders (Grant G.0412.09) for financial support. L.V.E., S.L.,
and R.N.M. are thankful for the ARC Programs, the FNRS,
C
dx.doi.org/10.1021/ic402643a | Inorg. Chem. XXXX, XXX, XXX−XXX