Lanthanide(III) complexes with a reinforced cyclam ligand show unprecedented kinetic inertness

Article abstract of DOI:10.1021/ja511331n

Lanthanide(III) complexes of a cross-bridged cyclam derivative containing two picolinate pendant arms are kinetically inert in very harsh conditions such as 2 M HCl, with no dissociation being observed for at least 5 months. Importantly, the [Ln(dota)]

Full text of DOI:10.1021/ja511331n

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Communication
Lanthanide(III) Complexes with a Reinforced Cyclam
Ligand Show Unprecedented Kinetic Inertness
Aurora Rodríguez-Rodríguez, David Esteban-Gómez, Raphael Tripier, Gyula Tircso, Zoltan
Garda, Imre Toth, Andres De Blas, Teresa Rodriguez-Blas, and Carlos Platas-Iglesias
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja511331n • Publication Date (Web): 12 Dec 2014
Downloaded from http://pubs.acs.org on December 17, 2014
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Lanthanide(III) Complexes with a Reinforced Cyclam Ligand
Show Unprecedented Kinetic Inertness
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Aurora Rodríguez-Rodríguez,† David Esteban-Gómez,† Raphaël Tripier,*,‡ Gyula Tircsó,§ Zoltán Gar-
da,§ Imre Tóth,§ Andrés de Blas,† Teresa Rodríguez-Blas† and Carlos Platas-Iglesias,*,†
†Departamento de Química Fundamental, Universidade da Coruña, Campus da Zapateira-Rúa da Fraga 10, 15008 A Coruña,
Spain
‡ Université de Bretagne Occidentale, UMR-CNRS 6521, UFR des Sciences et Techniques, 6 avenue Victor le Gorgeu, C.S.
93837, 29238 BREST Cedex 3, France
§ Department of Inorganic and Analytical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem
tér 1, H-4032 Debrecen, Hungary
Supporting Information Placeholder
shown to be somewhat more inert than the parent dota complexes,
ABSTRACT: Lanthanide(III) complexes of a cross-bridged
cyclam derivative containing two picolinate pendant arms are
kinetically inert in very harsh conditions such as 2 M HCl, with
but their thermodynamic stability is considerably lower.5
Kinetic inertness of Ln3+ complexes with functionalized
no dissociation being observed for at least 5 months. Importantly,
the [Ln(dota)]- complexes, which are recognized to be extremely
inert, dissociate under these conditions with lifetimes in the range
ca. 1 minute to 12 hours depending upon the Ln3+ ion. X-ray dif-
fraction studies reveal octadentate binding of the ligand to the
metal ion in the [Eu(cb-tedpa)]+ complex, while 1H and 13C NMR
experiments in D2O point to the presence of a single diastereoi-
somer in solution with a very rigid structure. The structure of the
complexes in the solid state is retained in solution, as demonstrat-
ed by the analysis of the Yb3+-induced paramagnetic shifts.
tetraazamacrocyclic ligands decreases by several orders of magni-
tude from the 12-membered dota to the 13-membered TRITA and
the 14-membered TETA, which is based on a cyclam platform
(Chart 1).6 An interesting approach to develop kinetically inert
complexes of transition metal complexes is the use of cross-
bridged cyclam derivatives, which commonly contain a 1,8-
ethylene unit bridging two nitrogen atoms of the tetraazamacrocy-
cle in trans positions.7 However, to the best of our knowledge
cross-bridged cyclam derivatives have never been used for Ln3+
complexation. In this contribution we report the cross-bridged
cyclam derivative cb-tedpa (Scheme 1), which forms Ln3+ com-
plexes endowed with a very high kinetic inertness.
Chart 1. Ligands discussed in the present work
Lanthanide(III) coordination chemistry in aqueous solutions is
currently receiving a great deal of attention due to the important
biomedical and bioanalytical applications of the complexes of
these metal ions. Indeed, stable Gd3+ complexes with polyam-
inocarboxylate ligands are commonly used as contrast agents in
Magnetic Resonance Imaging (MRI),1 while luminescent com-
plexes of Eu3+ and Tb3+ have found applications in fluoroinmuno-
assays and as luminescent probes for optical imaging.2 These
applications require a very robust complexation of the metal ion
in highly competitive biological media. For instance, macrobicy-
clic structures such as the famous cryptates reported by Lehn have
found application in homogeneous fluoroimmunoassays thanks to
their very low dissociation rates in biological media.3 However,
stable Ln3+ complexation is normally achieved with the use of
macrocyclic ligands based on 1,4,7,10-tetraazacyclododecane
(cyclen) such as dota [H4dota = 1,4,7,10-tetraazacyclododecane-
1,4,7,10-tetraacetic acid, Chart 1], which forms lanthanide com-
plexes of exceptionally high thermodynamic stability and kinetic
inertness.4 In spite of the intense research efforts carried out in the
last 20 years to develop stable Ln3+ chelates for medical or bio-
chemical applications, none of the systems reported to date can
rival with dota derivatives in terms of combined thermodynamic
stability and kinetic inertness. Some Ln3+ complexes of dota-
tetraamides and cyclen-based polyazaphosphinic acids were
Compound 1 was obtained from cyclam following the previ-
ously reported synthesis in 70% yield.8 Alkylation of 1 with me-
thyl 6-(chloromethyl)picolinate9 followed by deprotection of the
methyl ester groups with HCl 6 M gave the desired ligand in 92%
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yield over the two steps. Attempts to prepare Ln3+ complexes of
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cb-tedpa in 2-propanol, EtOH and H2O by reaction of equimolar
amounts of the ligand and lanthanide triflates or chlorides were
unsuccessful. However, reaction of H2cb-tedpa with lanthanide
chlorides in refluxing n-butanol in the presence of diisopro-
pylethylamine (DIPEA) resulted in the formation of compounds
of formula [Ln(cb-tedpa)]Cl (Ln = La, Eu, Gd, Tb or Yb). Even
so, the complexes were purified using reverse-phase MPLC to
remove unreacted ligand and salts. Thus, the formation of the
Ln3+ complexes of cb-tedpa appears to be rather slow, and re-
quires the use of a solvent with a high boiling point and long reac-
tion times (ca. 7 days). The high resolution mass spectra of com-
pounds [Ln(cb-tedpa)]Cl (ESI+-MS) show peaks due to the
[Ln(cb-tedpa)]+ entities, thereby confirming the formation of the
desired compounds. However, the yields obtained were rather low
(ca. 24%). To overcome this, the synthesis of the Eu3+ complex
was carried out under microwave radiation (150 ºC, 250 psi, max-
imum power 300 W) in n-butanol using DIPEA as a base and a
100% excess of EuCl3·6H2O. The formation of the complex was
quantitative after 8 h, as demonstrated by NMR spectroscopy (see
Supporting Information for details).
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Figure 1. View of the cation complex present in crystals of
[Eu(CB-TEDPA)](PF6)·2.5H2O. Hydrogen atoms are omitted for
simplicity. Selected bond distances (Å): Eu1-N1 2.490(6), Eu1-
N2 2.602(7), Eu1-N3 2.541(7), Eu1-N4 2.635(6), Eu1-N5
2.544(7), Eu1-N6 2.492(7), Eu1-O1 2.324(5), Eu1-O3 2.309(5).
Scheme 1. Synthesis of CB-TEDPA and numbering scheme
used for NMR spectral assignment
The emission spectra of the Eu3+ complex recorded in H2O and
D2O solutions show the 5D0 → 7FJ characteristic of this metal ion,
with maxima at 580 (J = 0), 592 (J=1), 617 (J = 2) and 695 nm (J
5
= 4). The emission lifetimes of the D0 excited state recorded in
H2O and D2O are 0.71 and 1.15 ms, respectively. Application of
the methodology developed by Horrocks13 and Beeby14 allowed to
calculate the number of water molecules coordinated to the Eu3+
ion in solution, which resulted to be q = 0.25 – 0.35. This result
points to the absence of water molecules in the inner coordination
sphere, in line with the X-ray structure of the complex.
The 1H and 13C NMR spectra of the diamagnetic [La(cb-
tedpa)]+ complex have been obtained in D2O solution at pD ~ 7.0
and 298 K. The proton spectrum (See Supporting Information)
consists of 17 signals corresponding to 17 magnetically non-
equivalent proton environments in the ligand (see Scheme 1 for
labelling), which points to an effective C2 symmetry of the com-
plex in solution. This is confirmed by the 13C NMR spectrum,
which shows 13 signals for the 26 carbon nuclei of the ligand
backbone. The assignments of the proton signals (Table S1, Sup-
porting Information) were based upon HMQC and HMBC 2D
heteronuclear experiments as well as standard 2D homonuclear
COSY experiments. The sharp and clear diasterotopic nature of
the 1H NMR resonances suggests the presence of a single diaster-
eoisomer in solution with no fluxional behavior being observed at
room temperature.
a
Reagents and conditions: i) Methyl 6-(chloromethyl)picolinate,
Na2CO3, CH3CN, 95%; ii)
6 M HCl, reflux, 97%; iii)
LnCl3·xH2O, nBuOH, ꢀ, DIPEA.
Addition of KPF6 to an aqueous solution of the Eu3+ complex
gave single crystals of formula [Eu(cb-tedpa)](PF6)·2.5H2O suita-
ble for X-ray diffraction analysis. A view of the structure of the
[Eu(cb-tedpa)]+ complex and bond distances of the metal coordi-
nation environment are given in Figure 1. The metal ion is fully
enveloped by the bicyclic ligand, which shows a folded cis-V
geometry.10 The Eu3+ ion is directly bound to eight donor atoms
of the ligand: the four nitrogen atoms of the macrocycle, and the
nitrogen and oxygen atoms of each of the two picolinate pendant
arms. The distances between the metal ion and the amine nitrogen
atoms of the macrocycle fall within the range 2.53 – 2.63 Å, with
an average value of 2.58 Å. A considerably longer average Eu-N
distance was observed for the nine-coordinated [Eu(dota)(H2O)]-
complex (2.68 Å),11 while a slightly longer value was found for
the eight-coordinated [Eu(TETA)]- analogue (2.62 Å).12 This
result suggests a rather strong interaction between the nitrogen
donor atoms of the macrocycle and the metal ion in [Eu(cb-
tedpa)]+.
The structure of the paramagnetic [Yb(cb-tedpa)]+ complex in
1
solution has been established by analyzing the H paramagnetic
1
shifts induced by the Yb3+ ion in the ligand nuclei. The H NMR
spectrum (D2O, pH ~ 7.0, 25 ºC) shows 17 paramagnetically
shifted resonances in the range +86 to -51 ppm, which confirms
1
the C2 symmetry of the complex in solution (Figure 2). The H
NMR shifts induced by Yb3+ are dominated by the pseudocontact
contribution, which depends upon the axial [χzz – 1/3 (χxx + χyy
+
χzz)] and rhombic (χxx – χyy) parts of the magnetic susceptibility
tensor and the location of the observed nuclei with respect to the
magnetic axes.15 The analysis of the Yb3+-induced paramagnetic
shifts has been carried out following the methodology reported
previously,16 using the 1H NMR shifts observed for the La3+ com-
plex to estimate the diamagnetic contribution. A geometrical
model of the structure of the Yb3+ complex has been obtained
using DFT calculations at the TPSSh/LCECP/6-31G(d) level. The
geometry of the [Yb(cb-tedpa)]+ complex optimized in aqueous
solution is very similar to that observed for the Eu3+ analogue in
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the solid state (Supporting Information). The calculated structure
provides an excellent agreement between the observed H NMR
M HCl shows an absorption band with a maximum at 269 nm (ε ~
1
6800 M-1cm-1), while in the spectrum of the complex this band
points at 274 nm and is considerably more intense (ε ~ 11400
M-1cm-1). This absorption band is assigned to a combination of
π→π* and n→π* transitions centered on the picolinate pendant
arms, and is very similar to those reported for different complexes
with macrocyclic ligands containing picolinate groups.19 Thus, the
spectra of the ligand and the complex recorded in HCl 2 M solu-
tion are substantially different, which allows the dissociation of
the complex to be monitored. Importantly, the spectrum of the
complex does not show any variation during a period of more than
5 months (167 days). Furthermore, the integrity of the complex
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shift and those calculated using the equation for the pseudocontact
shift (Figure 2), with [χzz – 1/3 (χxx + χyy + χzz)] = 90 30
ppm·Å3 and (χxx – χyy) = 3018 39 ppm·Å3, and an excellent
agreement factor of AFj = 0.071. This result unambiguously
proves that the [Yb(cb-tedpa)]+ complex adopts the same overall
structure observed for the Eu3+ complex in the solid state (with
shorter Ln-donor distances as a consequence of the smaller ionic
radius of the Yb3+ ion). The Yb3+-induced shifts are dominated by
the rhombic contribution, in contrast to the results obtained for
[Yb(TEDPA)]- (1/3 (χxx + χyy + χzz)] = 3237 and (χxx – χyy) =
-2526 ppm·Å3 with AFj = 0.089).17
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1
has been confirmed by NMR spectroscopy. The H NMR spec-
trum of the [Eu(cb-tedpa)]+ recorded in D2O solution at neutral
pH presents paramagnetically shifted signals in the range ~+15 -
-15 ppm. The spectrum recorded in 2 M DCl is very similar, alt-
hough some signals are slightly shifted presumably due to the
protonation of the complex. The spectrum recorded in 2 M HCl
does not show noticeable changes during 90 days (Figure S3),
which confirms an astonishing kinetic inertness of the complex in
solution. Indeed, the most inert Ln3+ complexes reported to date,
the [Ln(dota)]- complexes, do undergo dissociation under the
same conditions: The lifetime of the [Eu(dota)]- complex in 2 M
HCl can be estimated from the rate constants characterizing to
acid-catalyzed dissociation to be 6.9 h, while the corresponding
values for the Ce3+ and Gd3+ complexes under these conditions are
1.2 minutes and 11.5 hours.4,20 It has been shown that Ln3+ com-
plexes of dota-tetraamides and cyclen-based polyazaphosphinic
acids are even more inert than the parent dota complexes.5 How-
ever, the lifetimes of these complexes in acidic solutions (0.1-2 M
acid concentrations) are still in the range of a few days, highlight-
ing once more the exceptional kinetic inertness of [Ln(cb-tedpa)]+
complexes.
Figure 2. 1H NMR (300 MHz, 298 K) spectrum of [Yb(cb-
tedpa)]+ recorded in D2O solution and plot of the experimental
shifts versus those calculated with the DFT optimized geometry
and pseudocontact contributions. The solid line represents a per-
fect fit between experimental and calculated values.
An additional set of experiments was carried out to test whether
the [Eu(cb-tedpa)]+ complex undergoes dissociation in the pres-
ence of competing metal ions (Cu2+, 10 fold excess at pH=4.6),
bioligands (250 fold excess of H2PO43-/HPO42- at pH=7.4) or che-
lating ligands (250 fold excess of the ttha ligand at pH=5.0). The
absorption spectra of the samples remained unchanged throughout
the examined time period (3 weeks), confirming that the complex
does not suffer dissociation under these conditions (Figures S6-
S8, Supporting Information). The Gd3+ complex with a macrocy-
clic ligand based on a diaza-12-crown-4 platform containing two
picolinate pendant arms was shown to dissociate rather quickly
following both the proton-assisted and metal-assisted pathways.21
Thus, it is clear that the cross-bridged cyclam unit of the ligand
plays a critical role in the kinetic inertness [Ln(cb-tedpa)]+ com-
plexes.
In conclusion, we have reported a new class of very rigid Ln3+
complexes with extremely high kinetic inertness, which over-
comes by far that of the well-known [Ln(dota)]- complexes. This
property is of crucial importance for the design of Ln3+ for medi-
cal and bioanalytical applications with reduced toxicities, as the
release of the toxic free Ln3+ ion can be avoided. For instance,
Gd3+ release of the metal ion after the administration of certain
Gd3+-based CAs to patients suffering from severe renal failure has
been proved to trigger a potentially fatal disease called Nephro-
genic Systemic Fibrosis (NSF).22 Another important property of
the crossed-bridge ligand reported here is that it can be functional-
ized by introducing different groups in the β-N position, follow-
ing our straightforward methodology reported recently.23
Figure 3. UV absorption spectra of the CB-TEDPA ligand and
the [Eu(CB-TEDPA)]+ complex recorded in 2 M HCl. The spectra
of the complex obtained right after dissolution is identical to those
obtained for the same solution after 110 days (samples were ther-
mostated at 25 ºC).
Acid-catalyzed dissociation represents the main dissociation
pathway of Ln3+ complexes with macrocyclic ligands.18 Thus, the
kinetic inertness of the [Eu(cb-tedpa)]+ complex has been evaluat-
ed by following the changes of the UV-Vis absorption spectrum
in acidic solution (HCl 2 M). The spectrum of the free ligand in 2
ASSOCIATED CONTENT
Supporting Information
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Full details on the synthesis of the ligand and Ln3+ complexes,
high-resolution MS of the complexes, 1H and 13C NMR data,
excitation and emission spectra and computational details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Mato-Iglesias, M.; Roca-Sabio, A.; Palinkas, Z.; Esteban-Gomez,
D.; Platas-Iglesias, C.; Toth, E.; de Blas, A.; Rodríguez-Blas, T. Inorg.
Chem. 2008, 47, 7840-7851.
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McGregor, P. A.; Sadler, P. J. Chem Eur. J. 2003, 9, 4709-4717.
(11) Spirlet, M.-R.; Rebizant, J.; Desreux, J. F.; Loncin, M.-F. Inorg.
Chem. 1984, 23, 359-363.
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AUTHOR INFORMATION
Corresponding Authors
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I.-H. Inorg. Chim. Acta 2000, 310, 56-64.
(13) Supkowski, R. M.; Horrocks, W.D.W. Jr. Inorg. Chim. Acta
2002, 340, 44-48.
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9
carlos.platas.iglesias@udc.es
Raphael.Tripier@univ-brest.fr
gyula.tircso@science.unideb.hu
(14) Beeby, A.; Clarkson, I. M.; Dickins, R.S.; Faulkner, S.; Parker,
D.; Royle, L.; de Sousa, A. S.; Williams, J. A. G.; Woods, M. J. Chem.
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Notes
The authors declare no competing financial interests.
(16) a) Rodríguez-Rodríguez, A.; Esteban-Gómez, D.; de Blas, A.;
Rodríguez-Blas, T.; Fekete, M.; Botta, M.; Tripier, R.; Platas-Iglesias, C.
Inorg. Chem. 2012, 51, 2509-2521; b) Liu, T.; Nonat, A.; Beyler, M.;
Regueiro-Figueroa, M.; Nono, K. N.; Jeannin, O.; Camerel, F.; Debaene,
F.; Cianférani-Sanglier, S.; Tripier, R.; Platas-Iglesias, C.; Charbonnière,
L. J. Angew. Chem. Int. Ed. 2014, 53, 7259-7263; c) Doffek, C.; Alzak-
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ACKNOWLEDGMENT
A. R.-R., D. E.-G., A. de B., T. R.-B. and C. P.-I. thank Ministerio
de Educación y Ciencia (MEC, CTQ2009-10721), Fondo Europeo
de Desarrollo Regional (FEDER, CTQ2009-10721) and Xunta de
Galicia (CN 2012/011) for generous financial support and Centro
de Supercomputación de Galicia (CESGA) for providing the
computer facilities. G. T., I. T. and C. P.-I. gratefully
acknowledge support from the COST CM1006 “European F-
Element Network (EuFen) and COST TD1004 “Theragnostics
Imaging and Therapy: An Action to Develop Novel Nanosized
Systems for Imaging-Guided Drug Delivery” Actions. G. T, Z. G.,
and I. T. thank the Hungarian Scientific Research Fund (OTKA
K-84291 and K-109029) and the TÁMOP-4.2.2.A-11/1/KONV-
2012-0043 (ENVIKUT) project implemented through the New
Hungary Development Plan, co-financed by the European Social
Fund and the European Regional Development Fund. This work
was also supported by the János Bolyai Research Scholarship of
the Hungarian Academy of Sciences. R.T. and C. P.-I thank the
Université Europeene de Bretagne for the financial support. R.T.
also thanks the support of CNRS and MENSR. A. R.-R. thanks
Ministerio de Educación y Ciencia (FPU program) for a pre-
doctoral fellowship.
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