Oxidatively stable, aqueous europium(II) complexes through steric and electronic manipulation of cryptand coordination chemistry

Article abstract of DOI:10.1002/anie.201002789

A series of cryptands has been prepared and they demonstrate the relationship between oxidative stability of aqueous Eu^II and ligand properties (see figure). One of these Eu^II complexes is more stable than Fe^II in hemoglobin and appears to be the most oxidatively-stable aqueous Eu^II species known. The high stability of Eu^II is expected to enable the use of the unique magnetic and optical properties of this ion in vivo.

Full text of DOI:10.1002/anie.201002789

Angewandte
Chemie
DOI: 10.1002/anie.201002789
Cryptands
Oxidatively Stable, Aqueous Europium(II) Complexes through Steric
and Electronic Manipulation of Cryptand Coordination Chemistry**
Nipuni-Dhanesha H. Gamage, Yujiang Mei, Joel Garcia, and Matthew J. Allen*
The magnetic and optical properties of the divalent state of
europium make this ion extremely attractive for use in
materials,[1] catalysis,[2] luminescence,[3] magnetic,[4] and diag-
nostic-medical[5] applications. A major hin-
drance to the use of EuII in many of these
applications is the extreme propensity of the
ion to oxidize to EuIII, especially in aqueous
solution. Research efforts aimed at increas-
ing the stability of aqueous EuII have yielded
little success:[6,7] even the most stable aque-
ous EuII complex reported (4,7,13,16,21,24-
hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane
europium(II), 1-Eu) is not stable enough in
aqueous solution for practical use.[8,9] Our
research group has generated EuII com-
plexes in aqueous solution, and here we
report the most oxidatively-stable aqueous
EuII complexes known.
cryptand 1 to coordinate EuII over EuIII. To implement these
strategies, we studied cryptands 1–6 (Scheme 1).
Scheme 1. Ligands used to observe trends in oxidative stability of aqueous EuII.
Our strategy for favoring EuII over EuIII
in aqueous solution involves the synthesis
and use of ligands that would preferentially
coordinate to large, soft, electron-rich
metals like EuII. The template for our ligand design was
cryptand 1 because 1-Eu is the most oxidatively-stable,
aqueous EuII complex previously reported.[8] The stability of
1-Eu is partially due to the better size match of the cavity of
cryptand 1 (1.4 ꢀ) to the EuII ion (1.25 ꢀ) relative to the EuIII
ion (1.07 ꢀ).[10] We hypothesized that further oxidative
stabilization could be achieved by modifying the structure
of cryptand 1 using four principles of coordination chemistry
to stabilize electron-rich metals.[6,11] Specifically, our goals
were 1) to increase the steric bulk surrounding cryptand 1 to
minimize interactions between EuII and its environment; 2) to
reduce the Lewis basicity of cryptand 1 to favor the electron-
rich EuII over EuIII; 3) to change the cavity size of the
cryptand to match the size of the EuII ion preferentially; and
4) to modify the hard–soft, acid–base (HSAB) properties of
To increase the steric bulk of 1, methyl groups were added
to the ethylene carbon atoms between the oxygen atoms
resulting in ligand 2. This methyl substitution pattern was
chosen because metal–environment interactions occur
between the unmodified ethylene groups.[8] Furthermore, to
examine the influence of Lewis basicity on oxidative stability,
phenyl rings were introduced to decrease the electron-
donating ability of the adjacent oxygen atoms of ligands 3–5
by a resonance withdrawing effect.[12] The extent of electron
withdrawal was modulated by varying the electron density of
the phenyl ring through the addition of a fluorine atom (4) or
by increasing the number of rings (5). Phenyl-ring-containing
cryptands 3–5 also have an influence on cavity size because
each phenyl ring decreases the cavity size of the cryptand. We
expected the seemingly minor influence of the phenyl rings on
cavity size to have a noticeable effect on the oxidative
stability of EuII because of selectivity studies with Group 2
cations using cryptands 1, 3, and 5.[13] Finally, relatively soft
sulfur-atom donors were introduced in cryptand 6 in place of
oxygen-atom donors to explore the HSAB preferences for the
softer EuII ion relative to the harder EuIII ion.
[*] N.-D. H. Gamage, Dr. Y. Mei, J. Garcia, Prof. M. J. Allen
Department of Chemistry
Wayne State University
5101 Cass Avenue, Detroit, MI 48202 (USA)
Fax: (+1)313-577-8822
E-mail: mallen@chem.wayne.edu
Homepage: http://chem.wayne.edu/allengroup
To synthesize the diverse set of cryptands 1–6, a three-step
procedure was devised that involved common intermediates
7, 9, and 11 (Scheme 2).[14] Briefly, the synthesis involved the
conversion of the appropriate ethylenediols or catechols into
the corresponding ditosylates (7, 9, and 11) and subsequent
ring closure with 1,4,10,13-tetraoxa-7,16-diazacyclooctade-
cane, 2,2’-(ethylenedioxy)bis(ethylamine), or 1,4,10,13-tetra-
[**] This research was supported by start-up funds from Wayne State
University and a Pathway to Independence Career Transition Award
(R00EB007129) from the National Institute of Biomedical Imaging
and Bioengineering of the National Institutes of Health.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002789.
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8923

Communications
oxygen atoms (better for
electron-rich metals) and
the reduction in cavity size
caused by the phenyl ring
(better match for the size of
the EuII ion). However, the
addition of a second phenyl
ring (5) caused no differ-
ence in the anodic peak
potential compared to the
monophenyl cryptand
3
(p = 0.76). This effect is
likely due to reduction of
the cavity size counteract-
ing the decreased basicity
of the ligand, thus suggest-
ing that a minimum cavity
size for EuII stabilization
was achieved with cryptand
3. Further decrease in
Lewis basicity through the
addition of a fluorine sub-
stituent to the phenyl ring
Scheme 2. Synthetic route to cryptands 2 and 4–6 using common intermediates 7, 9, and 11.
thia-7,16-diazacyclooctadecane. Metal complexation was ach-
(4) led to 129 mV greater stability than what was observed
with unsubstituted monophenyl cryptand 3. In addition, the
oxidative stability of 4-Eu is not different from that of FeII in
hemoglobin (p = 0.45).
Finally, replacement of the harder oxygen atoms with
softer sulfur atoms (6) produced the most dramatic stabiliza-
tion effect of our cryptand series. This modification increased
the oxidative stability of EuII by 173 mV compared to the
structurally similar cryptand 3. The cavity size of cryptand 6
ieved in situ by mixing Eu(NO3)3·5H2O and the desired
cryptand (1–6) in aqueous solution under an Ar atmosphere.
The resulting solution was placed in a standard three-
electrode cell (glassy-carbon working electrode, platinum-
wire auxiliary electrode, and Ag/AgCl (1.0m KCl) reference
electrode). The potential at the carbon electrode was held at
À0.8 V (vs. Ag/AgCl) while stirring to produce EuII in situ for
metalation.[7] After metalation, cyclic voltammograms were
obtained for each complex in solution with ferrocene as an
internal standard:[9,15] a new anodic peak was observed for
each complex at a more positive potential than the peak
corresponding to oxidation of the aqueous EuII (Table 1).
These data indicate that each cryptand imparted additional
stability to EuII as hypothesized.
À
increases slightly because of the increased bond length of C S
À
compared to C O, thus suggesting that a decrease in stability
should be observed based on the difference between crypt-
ands 1 and 3. However, the effect of cavity size is small
relative to the influence of HSAB matching between EuII and
sulfur. Cryptand 6 with EuII produces an oxidative potential
that is 666 mV more positive than the aqueous EuII and
35 mV more positive than FeII in hemoglobin. To the best of
our knowledge, this oxidative stability of EuII is the highest
reported in aqueous solution and indicates the potential for
the use of EuII in vivo.
Table 1: Anodic peak potentials (Epa) with respect to ferrocene/ferroce-
nium (Fc/Fc+).
Sample
Epa (V vs. Fc/Fc+)[a] Sample
Epa (V vs. Fc/Fc+)[a]
We observed dramatic oxidative stabilization of EuII using
modified cryptands. These trends in stability suggest that
further stabilization of aqueous EuII and other lanthanide ions
is possible. We are currently pursuing these avenues of
research in addition to measuring the thermodynamic stabil-
ity of the EuII complexes reported here. Finally, our most
stable complex, with an oxidation potential indicative of
biological oxidative stability, opens the door for the use of the
magnetic and spectroscopic properties of EuII in vivo.
1
2
3
4
Eu(NO3)3 À0.701Æ0.030
5
6
7
8
2-Eu
4-Eu
À0.169Æ0.006
À0.079Æ0.007
1-Eu
5-Eu
3-Eu
À0.336Æ0.016
À0.211Æ0.004
À0.208Æ0.009
hemoglobin À0.070Æ0.003
6-Eu
À0.035Æ0.010
[a] Potentials are listed as mean Æ standard error.
The cyclic voltammetric data of europium-containing
solutions of 1 and 2 demonstrate that the increased steric
bulk in cryptand 2 leads to increased oxidative stability over
unmodified cryptand 1. Furthermore, a more targeted exami-
nation of the influence of Lewis basicity on oxidative stability
was achieved by examining the impact of ligands 3–5. We
observed that one phenyl ring on cryptand 3 was sufficient to
stabilize EuII oxidatively by 128 mV with respect to the
unmodified cryptand 1-Eu. This stabilization is likely due to a
combination of the decrease in Lewis basicity of the adjacent
Received: May 8, 2010
Revised: August 23, 2010
Published online: October 6, 2010
Keywords: chelates · cryptands · europium · lanthanides ·
.
redox chemistry
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