Controlled preparation of a heterometallic lanthanide complex containing different lanthanides in symmetrical binding pockets

Article abstract of DOI:10.1039/b913702e

A heterometallic lanthanide complex has been prepared by sequential deprotection and complexation of an orthogonally protected ligand: luminescence and NMR spectroscopy have been used to probe the integrity of the complex.

Full text of DOI:10.1039/b913702e

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Controlled preparation of a heterometallic lanthanide complex containing
different lanthanides in symmetrical binding pocketsw
Louise S. Natrajan,a Aaron Joseph L. Villaraza,a Alan M. Kenwrightb and
Stephen Faulkner*ac
Received (in Cambridge, UK) 9th July 2009, Accepted 10th August 2009
First published as an Advance Article on the web 20th August 2009
DOI: 10.1039/b913702e
A heterometallic lanthanide complex has been prepared by
sequential deprotection and complexation of an orthogonally
protected ligand: luminescence and NMR spectroscopy have
been used to probe the integrity of the complex.
catalyst. Compound 2 was prepared from 6 in a two step
process: reaction of 6 with chloroacetyl chloride yielded
a chloroacetamide which was then reacted with the ethyl
triester 7. Compound 2 possesses two masked DOTA–
monoamide binding sites; one of these is masked by tert-
butyl ester protecting groups, while the second is masked
by ethyl esters. These groups are mutually orthogonal in
that tert-butyl esters can be removed under acidic conditions,
while the ethyl esters can be removed by base-catalysed
hydrolysis.
Lanthanide complexes are of considerable current interest
owing to the widespread application of gadolinium complexes
as contrast agents in magnetic resonance imaging1,2 (MRI)
and luminescent lanthanide complexes in bioassay and
microscopy.3–5 Relatively simple systems can be used as
MRI contrast agents, provided that the complexes used have
sufficient kinetic stability to obviate the toxicity of lanthanide
ions in vivo.1,2,6 Though relatively simple luminescent complexes
can be used in vivo,7 lanthanide complexes have low extinction
coefficients associated with f–f transitions, and much
lower detection limits can be achieved by incorporating a
chromophore into the ligand structure and using it to sensitise
lanthanide emission.8
There are two possible approaches to the conversion
of 2 to YbTbꢀ1 (Scheme 2). Both of these were investigated.
Trifluoroacetic acid mediated cleavage of the tert-butyl esters
followed by reaction with ytterbium trifluoromethanesulfonate
Kinetically stable lanthanide complexes have also been
exploited in the preparation of d–f hybrid complexes,9 and
have been shown to be effective building blocks for more
complicated architectures, including heterometallic lanthanide
complexes10 and heterometallic complexes which combine
MRI contrast with long-lived luminescence.11
We now report the synthesis of the heterometallic complex
TbYbꢀ1 from an orthogonally protected pro-ligand, 2. In this
case alternative strategies are unsatisfactory, since reaction of
1 with terbium and ytterbium salts would yield statistical
mixtures of the complexes Yb2ꢀ1, Tb2ꢀ1 and TbYbꢀ1. In this
ligand system, orthogonal protection permits two otherwise
identical binding sites to be unmasked and complexed in a
controlled manner.
The synthesis of 2 is outlined in Scheme 1. Reaction of the
tert-butyl triester12 3 with the chloroacetamide 4 (prepared by
reaction of 4-nitroaniline with chloroacetyl chloride) yielded
compound 5, in which a DOTA–monoamide binding site is
masked by tert-butyl esters. 5 was converted into 6 by transfer
hydrogenation using hydrazine in the presence of a palladium
a School of Chemistry, University of Manchester, Oxford Road,
Manchester, UK M13 9PL
b Department of Chemistry, University of Durham, South Road,
Durham, UK DH1 3LE
c University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, UK OX1 3TA.
E-mail: Stephen.Faulkner@chem.ox.ac.uk;
Fax: +44 (0)1865 272705; Tel: +44 (0)1865 285148
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation. See DOI: 10.1039/b913702e
Scheme 1 Synthesis of the orthogonally protected pro-ligand 2.
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Fig. 1 1H NMR spectra for (a) Ybꢀ8, (b) Ybꢀ9 and (c) TbYbꢀ1.
around the metal centre. The four inequivalent resonances in
the range 110–140 ppm in both spectra may be assigned to
pseudo axial protons on the cyclen ring and to a square
antiprismatic coordination geometry (SAP isomer) by
comparison with related compounds.13 In both, a set of minor
resonances that are shifted upfield are also observed, which are
assigned to the alternate twisted square antiprismatic
(TSAP) geometric isomer.14 Although, it is clear from the
relative linewidths that the major and minor forms of the
complexes are in slow exchange, the minor isomer is in faster
conformational exchange. The rate of this exchange process
seems to be retarded in Ybꢀ9 by the presence of the tert-butyl
groups on the protected macrocycle, since these resonances are
broader in Ybꢀ8.
Scheme 2 Synthesis of TbYbꢀ1 and its precursors.
yielded Ybꢀ8. In the other pathway, Ybꢀ9 was prepared by
base-catalysed hydrolysis of 2, followed by reaction of the
product with ytterbium trifluoromethanesulfonate. The 1H
NMR spectra of the complexes (Fig. 1) show very close
similarities in the paramagnetically shifted parts of the spectrum,
where the axial and equatorial cyclen ring protons resonate,
implying that both complexes have near-identical environments
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Table 1 Photophysical properties of the complexes
ex/nm em/nm /ms
sphere hydration numbers (q) for both lanthanide ions
are again consistent with binding in DOTA–monoamide
pockets,13 with the value for Tb3+ being slightly larger; an
effect of the lanthanide contraction.
l
l
t
H2O
t
/ms
q
D2O
Ybꢀ8
337
337
337
337
260
980
980
980
980
545
1.51
1.50
1.45
1.37
5.03
6.35
8.15
6.15
0.4
0.4
0.5
0.5
0.6
Ybꢀ9
In conclusion, orthogonal protection of binding sites that
form kinetically stable lanthanide complexes allows access to
heterometallic arrays that contain different lanthanides in
otherwise equivalent binding sites. This study also illustrates
how care is needed when considering suitable protecting
groups (and indeed the order of synthetic steps) for reactions
involving DOTA–monoamide derivatives.
H3Ybꢀ1
TbYbꢀ1
1610
2270
This is borne out by the luminescence properties of the
complexes, which are summarised in Table 1. The table also
shows calculated values of q, the number of bound solvent
oscillators, using the equation
Notes and references
z In water, ATb = 5 ms, BTb = 0.06 msꢂ1, AYb = 1.0 ms and
q = ALn(1/tH ꢂ 1/tD ꢂ BLn
)
(1)
BYb = 0.1 msꢂ1
.
where tH and tD are the lifetimes observed in H2O and D2O,
respectively, and A and B are constants for a given lanthanide
15
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and solvent system.z
From Table 1 it can be seen that calculated values of q for
both complexes are identical within experimental error, and
are consistent with the binding of a small lanthanide ion in a
DOTA–monoamide binding site. The complexes were clearly
differentiated by MALDI mass spectroscopy; molecular ions
corresponding well to calculated isotopic distributions were
observed for both complexes (see ESIw).
Reaction of Ybꢀ8 with sodium hydroxide yielded H3Ybꢀ1.
However, the NMR spectrum of the crude product indicated
that partial hydrolysis (o5%) of the ligand skeleton had also
occurred to yield [YbꢀDOTA]ꢂ as a minor product, presum-
ably following hydrolysis of the amide bond in Ybꢀ8 or H3Ybꢀ1
(mediated by the Lewis acidity of the Yb3+ ion). By contrast,
cleavage of the tert-butyl esters in Ybꢀ9 proceeded cleanly, and
H3Ybꢀ1 was isolated pure. This has clear implications for the
choice of strategy when deprotecting orthogonally protected
systems for lanthanide complexation, and also restricts
the possible routes that can be used to functionalise
DOTA–monoamide complexes further.
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Reaction of H3Ybꢀ1 with terbium trifluoromethane-
sulfonate yielded TbYbꢀ1. The 1H NMR spectrum of this
complex (Fig. 1c) is very different to the other complexes,
containing a series of peaks at very large chemical shifts
corresponding to protons close to the terbium ion as well as
peaks at similar chemical shifts to those of Ybꢀ8, Ybꢀ9 and
H3Ybꢀ1. The striking difference in peak heights among the
pseudo-contact shifted peaks is a consequence of differences in
line-broadening due to differential relaxation of the protons
by the respective lanthanides. Upon closer inspection, the
linewidths of the cyclen ring protons in the binding pocket
accommodating the Yb3+ ion (100–140 ppm) are narrower
than in all the monometallic precursors and two sets of
resonances are observed. The relative intensities of these are
comparable, suggesting that they may result from the presence
of roughly equal populations of different diastereoisomers
under the conditions of the experiment.
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Furthermore, MALDI-MS revealed the presence of the
molecular ion with an isotopic distribution corresponding
closely to that predicted for TbYbꢀ1. This compound showed
sensitised luminescence from both the Tb3+ and Yb3+ metal
centres, respectively, in the visible and near IR. The inner
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6022 | Chem. Commun., 2009, 6020–6022