Synthesis, chirality and complexation phenomena of two diastereoisomeric dinuclear lanthanide(III) complexes

Article abstract of DOI:10.1002/ejic.201000243

Two diastereoisomeric ditopic ligands have been synthesised by linking (SSS)-hepatadenate triamide derivative of cyclen with a central (SS)- or (SR)- 1, 2-diphenyl-1, 2-diaminoethane derivative. Complexes of selected Ln ^III ions (Ln = Eu, Tb, Yb) have been characterized and circularly polarised luminescence spectra of the Eu systems revealed significant differences, consistent with a change in overall complex chirality associated with the local helicity at the metal centre. Stepwise binding constants for the formation of 1:1 and 2:1 ternary adducts with (S)-lactate and (S)-O-phospho-tyrosine have been determined, by least-squares analysis of spectral titration data, and emission and ¹H NMR spectroscopic data compared with the mononuclear analogue.

Full text of DOI:10.1002/ejic.201000243

FULL PAPER
DOI: 10.1002/ejic.201000243
Synthesis, Chirality and Complexation Phenomena of Two Diastereoisomeric
Dinuclear Lanthanide(III) Complexes
Benjamin S. Murray,[a] David Parker,*[a] Cidália M. G. dos Santos,[b] and
Robert D. Peacock[c]
Keywords: Lanthanides / Europium / Luminescence / Chirality
Two diastereoisomeric ditopic ligands have been synthesised
by linking (SSS)-heptadentate triamide derivative of cyclen
with a central (SS)- or (SR)-1,2-diphenyl-1,2-diaminoethane
derivative. Complexes of selected LnIII ions (Ln = Eu, Tb, Yb)
have been characterized and circularly polarised lumines-
cence spectra of the Eu systems revealed significant differ-
ences, consistent with a change in overall complex chirality
associated with the local helicity at the metal centre. Step-
wise binding constants for the formation of 1:1 and 2:1 ter-
nary adducts with (S)-lactate and (S)-O-phospho-tyrosine
have been determined by least-squares analysis of spectral
titration data, and emission and 1H NMR spectroscopic data
compared with the mononuclear analogue.
found,[8,9] notably with a 30:1 selectivity for O-phospho-
tyrosine over phosphorylated serine and threonine amino
acid residues.
Introduction
Metal complexes of dinucleating ligands may afford un-
predictable physical properties or chemical selectivity pro-
files, as a consequence of specific interactions involving
each metal centre. Within the domain of lanthanide coordi-
nation complexes, examples have been reported of dinuclear
complexes of GdIII, assessing their utility as contrast agents
in MRI.[1,2] Related work has examined the anion complex-
ation behaviour of ditopic systems, based on two hepta-
dentate moieties, seeking unusual binding affinities for di-
anions such as dicarboxylates.[3,4] Other studies have sought
evidence for co-operativity in the catalysis of phosphate di-
In seeking to extend the scope of such complexes as emis-
sive probes, ditopic systems based on L1 were envisaged that
might allow simultaneous binding to two O-phospho-tyr-
osine sites. This could occur in a suitable peptide where the
two phosphorylated residues are close in space, either by
virtue of their constitution, e.g. (1,2) systems or as a result
of the local helicity of the peptide chain, e.g. residues in a
(1,4) or (1,5) relationship within an α-helical segment. In
favourable circumstances, this might allow regioselective
binding of the ditopic lanthanide complex to selected phos-
pho-tyrosine sites. NMR Studies of the binding of
[Eu·L1]3+ to the [5, 9, 10] triphosphorylated insulin-receptor
dodecapeptide fragment revealed evidence for regioselective
binding to the phosphorylated Tyr in the 9-position.[8] In
related work, achiral dinuclear complexes of zinc(II) have
been studied that are designed to bind simultaneously to
two phospho-Tyr residues groups on proximate amino ac-
ids.[12]
Here, we report a concise synthetic approach to such sys-
tems, together with an assessment of the overall chirality of
the complex and a preliminary assessment of anion affinity.
The first step in this task was to prepare the ditopic ligands
L2a and L2b. In each case, the denticity of the ligand L1 is
conserved at the macrocyclic binding site, with a common
(SSS)-configuration at each of the stereogenic carbon
centres. The linking group possess either an (SS)- or (SR)-
configuration generating a pair of diastereoisomers (Fig-
ure 1). The configuration of the short, rigid linking moiety
determines the preferred conformation of the derived dinu-
clear complexes, with the (SS)-linker giving rise to “con-
ester cleavage, using dinuclear complexes of EuIII [5]
.
Neutral heptadentate macrocyclic ligands form triposi-
tive complexes with LnIII ions in aqueous solution, and the
coordination at the metal is typically made up to nine by
binding to water or certain counter-anions. The affinity of
such complexes for a given anion can be modulated by vari-
ation of the structure of the ligand substituent and the se-
lection of the LnIII ion. Using the chiral ligand, L1, for ex-
ample, anion affinity profiles have been assessed in de-
tail,[6–9] and adducts characterised by crystallography and
NMR spectroscopy.[10,11] A particular aspect of this work
was the chemoselectivity profile exhibited by [Eu·L1]3+
where a marked preference for certain phospho-anions was
,
[a] Department of Chemistry, Durham University,
South Road, Durham, DH1 3LE, UK
E-mail: david.parker@durham.ac.uk
[b] School of Chemistry, Trinity College Dublin,
Dublin 2, Ireland
[c] Department of Chemistry, Glasgow University,
Glasgow, G12 8QQ, UK
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B. S. Murray, D. Parker, C. M. G. dos Santos, R. D. Peacock
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cave“ complexes. The (SR)-isomer was envisaged to form in the presence of EDC led to formation of 2a in 75% yield.
an open structure, more typical of the rather flexible, achi- The same reaction with the (SR)-isomer did not proceed to
ral ditopic systems that have been explored previously.[3–5]
completion and the more reactive uronium coupling agent,
TBTU, was required to drive the reaction to completion
and allow the desired product 2b to be isolated (Scheme 1).
Subsequent removal of the Boc protecting groups allowed
L2a and L2b to be isolated in protonated form, as their tri-
fluoroacetate salts. The differing stereotopism of ligand hy-
1
drogens was evident in H NMR spectra (Figure 2). With
L2a, the methine resonances of the linking moiety are
homotopic, and resonate as a doublet by virtue of coupling
to the vicinal amide proton. The two amide protons associ-
ated with the ring pendant arms are non-equivalent and
two amide NH multiplets are observed, as each ring is ren-
dered equivalent by the C2-axis. With L2b, the linker meth-
ine resonances are diastereotopic and give rise to a pair of
overlapping doublet of doublets. In addition, four amide
NH resonances are observed for the NH protons of the ring
amide substituents.
Figure 1. Newman projections of (SS)-L2a (left) and (SR)-L2b high-
lighting likely preferred conformations based on steric demand.
Ligand and Complex Synthesis and
Characterization
The synthesis of each ligand was undertaken from the
common intermediate, 1, that was previously reported in
studies of emissive intracellular probes.[13] Reaction of two
Complexation of L2a/L2b with lanthanide(III) ions re-
equivalents of (SS)-1,2-diphenyl-1,2-diaminoethane with 1, quired rather forcing conditions to drive the reaction to
Scheme 1.
Figure 2. Partial 1H NMR spectra of (SS)-L2a (left) and (SR)-L2b (TFA salt, 3 m; 700 MHz, 295 K) highlighting the homotopic methine
protons of the linker (δH = 5.67 ppm) for L2a, and the corresponding diastereotopic methine protons about 5.35 ppm for L2b. For L2a,
two CHMe multiplets are observed, whereas for L2b each CHMe proton is non-equivalent.
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Diastereoisomeric Dinuclear Lanthanide(III) Complexes
Figure 3. Observed (top) and experimental (bottom) mass spectral isotope patterns for diacetate adducts of [Eu2·L2a]6+ (left; [M + 2OAc –
2H]2+) and [Yb2·L2b]6+ (right, [M + 2OAc – 2H]2+).
completion. Typically, six equivalents of Eu(CF3SO3)3, trum was virtually identical, consistent with the presence
TbCl3 or Yb(OAc)3 was used. Excess salt was removed by of a common coordination environment around each EuIII
dialysis, using benzoylated dialysis tubing with a 2000 MW centre.[6,15] Circularly polarised emission spectroscopy is
cut-off. Where appropriate, ion exchange chromatography, used to probe the chirality of the metal excited state, offer-
led to isolation of the water-soluble chloride salt. Analysis ing advantages of sensitivity over ground state CD stud-
of the product by HPLC and electrospray mass spectrome- ies.[15] The CPL spectra of [Eu·L1]3+ and (SR)-[Eu2·L2b]6+
try confirmed that complexation had proceeded to comple- were very similar (Figure 4) but that of (SS)-[Eu2·L2a]6+ was
tion. Mass spectral analyses were carried out in the pres- significantly different and much weaker in intensity, espe-
ence of the weak acid ammonium acetate, and gave rise to cially in the electric-dipole allowed ∆J = 2 transitions
characteristic isotope patterns for the di-acetate salts of the around 612 nm. Various emission dissymmetry factors (gem
)
given complex (Figure 3). Adducts were detected as either were recorded (Table 1). For certain transitions, the sign of
triply or doubly charged species, formed through the loss the observed CPL was opposite for [Eu2·L2a]6+ compared
of either one or two protons.[14] In every case, two acetate to [Eu2·L2b]6+ and [Eu·L1]3+. The differences strongly sug-
anions were associated with the complex, suggesting that in gest that opposite local helicities exist at the two Eu centres
the observed species, each metal centre is bound to one in [Eu2·L2a]6+. This leads to a reduced overall CPL. In con-
acetate anion. Previously, the crystal structure of [Yb·L1- trast, the CPL spectrum for [Eu2·L2b]6+ is consistent with
(OAc)]2+ has been reported, revealing acetate chelation at each Eu centre behaving independently and identically to
the Yb centre.[10]
the mononuclear complex, [Eu·L1]3+. Given that the X-ray
Proton NMR spectra of the Yb and EuIII complexes of structure of the diaqua complex (SSS)-[Eu·L1(OH2)2]3+
-
L2a and L2b were examined as their chloride salts (CF3SO3)3 has been determined, confirming the presence of
(500 MHz, 295K D2O 2 m complex) and revealed signifi- a nine-coordinate complex with a ∆ configuration, and that
cant differences between the isomers. Spectra of [Eu2·L2b]6+ the CPL analysis in solution has been shown to be consis-
and [Yb2·L2b]6+ were found to be the simplest, with one tent with this assignment,[7,15] such behaviour accords with
major species evident in which the paramagnetically shifted the hypothetical conformational analysis presented above
protons of the two macrocycles were non-equivalent. With (Figure 1).
[Eu2·L2a]6+ and [Yb2·L2a]6+, two species were observed (ra-
The excited state radiative lifetimes of the Eu and TbIII
tio 3:1) for each of which a similar number of paramagneti- complexes were measured in H2O and D2O, and in the pres-
cally shifted resonances was observed. No particular spec- ence of selected anions (Table 2) in order to deduce appar-
tral simplification was observed at 278 K, and at 323 K sig- ent hydration states, q.[16] The chloride salts of Eu/Tb gave
nificant line-broadening was evident.
q values in the range 1.3 to 1.4, notably lower than the
Total emission and circularly polarised luminescence values of 2.1 observed with [Ln·L1]3+ [6]
Such behaviour
.
(CPL) spectra were recorded for [Eu2·L2a]6+ and [Eu2· could indicate the presence of two isomeric complexes of
L2b]6+. The form of the metal-based total emission spec- differing hydration number, associated with the increased
Eur. J. Inorg. Chem. 2010, 2663–2672
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Figure 4. Circularly polarised luminescence (CPL) spectra for [Eu·L1]3+ (top) compared to [Eu2·L2a]6+ (left) and [Eu2·L2b]6+ (right) (295 K,
D2O, 1 m, λex = 255 nm). The CPL spectra are scaled by a factor of 18 compared to the total emission spectra.
Table 1. Emission disymmetry values gem from CPL spectra (D2O, tate anion chelates to the lanthanide centre, displacing
295 K, λexc = 397 or 255 nm).
water and that phospho-anions, such as O-phospho-Tyr,
form a ternary adduct where one water molecule remains
Complex
Observed transition
∆J = 1 (588 nm) ∆J = 1 (592 nm) ∆J = 2 (613 nm)
weakly bound.[5,6,17]
[Eu·L1]3+
+0.04
–0.03
+0.03
–0.05
–0.03
–0.05
+0.03
+0.003
+0.025
[Eu2·L2a]6+
[Eu2·L2b]6+
Anion Binding Revealed by NMR and CPL
Emission Studies
Incremental addition of various anions to [Yb2·L2a]6+
was monitored by H NMR spectroscopy. Analysis of the
hydrophobicity of the ditopic ligands, L2a and L2b com-
pared to L1. Addition of a ten-fold excess of (S)-lactate and
(S)-O-phospho-tyrosine to the terbium complexes of L2a/
L2b gave rise to complete and partial water displacement
respectively, with apparent hydration numbers of a similar
1
data was hampered by considerable line broadening
(500 MHz, 295 K) and by the tendency of certain anions to
induce precipitation. Such behaviour had not been evident
with the mononuclear system [Yb·L1]3+ [8,9] Accordingly,
magnitude to those measured for [Tb·L1]3+ [6]
In the latter
.
.
1
only a restricted set of anions could be studied. H NMR
case, it has been unequivocally demonstrated that the lac-
spectra for the dinuclear Yb complexes of L2a/L2b were re-
corded in the presence of ten equivalents of tyrosine, O-
phospho-tyrosine and hydrogen carbonate (Figure 5). This
allowed a comparison with the spectrum of the aqua com-
plex, obtained with a chloride counterion that does not co-
ordinate to the metal ion. Spectral analysis focused on the
behaviour of the most paramagnetically shifted “axial” ring
proton, Hax, resonating to higher frequency of all other res-
onances. The mean chemical shift of this resonance is a sen-
sitive reporter of the lanthanide(III) coordination environ-
ment, particularly the nature and polarisability of the “cap-
ping” axial donor substituent, in the mono-capped square
antiprismatic coordination environment.[18,19] Mean chemi-
cal shift values obtained, for Hax (Table 3) highlight the dif-
Table 2. Rate constants k for the decay of the excited states of
europium(III) and terbium(III) complexes and derived apparent
hydration states q in the presence of the stated anion [295 K, 50 µ
complex, 500 µ anion (Na+ or K+ salt), λexc = 397 or 255 nm].
Complex/anion
kH2O/ms–1
kD2O /ms–1
q (Ϯ20%)
[Eu2·L2a]6+/Cl–
2.78
2.86
0.72
0.79
0.58
0.59
0.77
0.68
1.22
1.22
0.47
0.48
0.49
0.47
0.65
0.49
1.3
1.4
0.9
1.2
0.1
0.3
0.3
0.6
[Eu2·L2b]6+/Cl–
[Tb2·L2a]6+/Cl–
[Tb2·L2b]6+/Cl–
[Tb2·L2a]6+/lactate
[Tb2·L2b]6+/lactate
[Tb2·L2a]6+/OPTyr
[Tb2·L2b]6+/OPTyr
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Diastereoisomeric Dinuclear Lanthanide(III) Complexes
1
Figure 5. Partial H NMR spectra (500 MHz, D2O, 295 K, pD 7.8, 2 m complex) of chloride salts of [Yb2·L2a]6+ (left) and [Yb2·L2b]6+
–
(right) in the presence of the indicated anions (10 m) highlighting the formation of ternary adducts with HCO3 and O-phospho-Tyr
only.
ferences between [Yb·L1]3+ and the dinuclear complexes.
Addition of hydrogen carbonate caused significant con-
1
For example, addition of tyrosine does not significantly per- traction of the H NMR spectral width for each Yb com-
turb the NMR spectrum of the dinuclear Yb, aqua species, plex, consistent with a reduction in the second order crystal
whereas with [Yb·L1]3+ an “N–O” chelate was formed un- field coefficient that determines the size of the paramag-
der these conditions, with displacement of bound water; the netic dipolar shift. Chelation of carbonate at each metal
mean chemical shift value for Hax was 36 ppm.[8,9,11] Such centre replaces the “hard” water molecule with a more pol-
a chelated species, with an “axial” coordinated amino group arisable charged oxygen donor in the “axial” capping
(evident in related X-ray analyses[11]) was also a competitive site.[14,18] Binding of inorganic phosphate to the Eu and Yb
binding mode in complexation of [Yb·L1]3+ with O-phos- complexes of L2a/L2b led to precipitation, inhibiting spec-
pho-Tyr. This behaviour was not evident for each dimeric tral studies. However, the addition of glucose-6-phosphate
mean
complex (Figure 5) and the value of δ
was consistent and glucose-1,6-diphosphate did not cause any solid to
ax
1
1
with selective monodentate phosphate ligation. A further form, permitting H NMR and CPL spectral studies. H
feature was evident in the behaviour of [Yb2·L2a]6+. In the NMR spectra of [Eu2·L2b]6+ recorded in the presence of
aqua complex, one major species was observed, in which these anions were sharp and resembled those obtained un-
the Hax resonances for each ring appeared to be chemical der the same conditions with [Eu·L1]3+; the number of reso-
shift equivalent (Figure 5). In the O-phospho-Tyr adduct nances observed was consistent with formation of a dinu-
this shift-equivalence was removed, and four resonances for clear O-phospho-bound ternary adduct, in which each
the Hax protons in each 12-N-4 ring were clearly discerned. metal centre is non-equivalent. With [Eu2·L2a]6+, the ad-
dition of glucose-1,6-diphosphate gave rise to a spectrum
with broad resonances, possibly due to the formation of
Table 3. Selected 1H NMR chemical shift data for ternary anion
1:1 and 2:1 adducts in intermediate exchange on the NMR
adducts (295 K, pD = 7.8, 500 MHz; 2 m complex, 10 m stated
timescale. CPL spectra of the dinuclear europium aqua
anion) examining the mean value for the most shifted ring pro-
ton.[a]
complexes, in the absence and presence of the phosphoryl-
ated glucose species, were also obtained (Figure 6). Spectra
Complex
Anion/mean δH (ppm) for Hax
for [Eu2·L2b]6+ resembled those obtained with [Eu·L1]3+ [9a]
,
–
Cl– or CF3SO3
O-phospho-Tyr
Tyr
consistent with a common ∆-configuration at both Eu
centres in each species. In contrast, CPL spectra for
[Eu2·L2a]6+ (Figure 6, upper part) were very weak and dif-
fered in sign for the ∆J = 1, magnetic-dipole allowed transi-
tions observed. Such behaviour suggests that the local helic-
ities at the two Eu centres in [Eu2·L2b]6+ are of opposite
[Yb·L1]3+
75
56
65
95(40)
85
80
39
(SS)-[Yb2·L2a]6+
(SR)-[Yb2·L2b]6+
55[b]
64[b]
[a] Values for minor species are given in parenthesis. [b] Data sug-
gest that the aqua species remains present, with little or no evidence
for coordination of the tyrosine carboxylate or primary amine
group.
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Figure 6. CPL spectra (1 m complex, D2O, 295 K, λexc 255 nm) highlighting the magnetic-dipole-allowed ∆J = 1 transitions for:
1) [Eu2·L2a]6+; 2) [Eu2·L2a]6+/10 eqs glucose-6-phosphate; 3) [Eu2·L2a]6+/10 eqs glucose-1,6-diphosphate; 4) [Eu2·L2b]6+; 5) [Eu2·L2b]6+/10
eqs glucose-6-phosphate; 6) [Eu2·L2b]6+/10 eqs glucose-1,6-diphosphate. For 1) to 3) CPL spectra are ϫ60 with respect to the shown total
emission spectra; = for 4) to 6) this factor is ϫ18.
sense, consistent with the presence of ∆(λλλλ) and Λ(δδδδ) sociated with SPECFIT,[21,22] based on successive 1:1 and
stereoisomeric species, specifying the elements of chirality
associated with the ligand NCCO and NCCN torsion
angles, respectively.[14,18]
2:1 binding models (Table 4). The binding curve for associa-
tion of O-phospho-Tyr with [Tb2·L2a]6+ and [Tb2·L2b]6+
(Figure 7, centre/upper, left) reached a maximum after ad-
dition of two equivalents of the phospho-anion, consistent
with the Job plot data (not shown). Lower values for the
stability of the 1:1 and 2:1 adducts were found for [Tb2·
L2a]6+ compared to [Tb2·L2b]6+, consistent with the more
open structure in the latter case, in which the metal centres
behave independently. With [Tb2·L2a]6+, the more concave
structure may lead to some degree of steric inhibition of
anion binding.
Analysis of Luminescence Spectral Titrations
The tyrosine chromophore is well known to sensitise the
terbium emission efficiently.[20] Accordingly, binding of O-
phospho-Tyr to the Tb complexes of L1, L2a and L2b was
monitored following excitation at 275 nm, observing modu-
lation of terbium emission intensity at 545 nm. Job plots
were used to establish the 1:1 stoichiometry of association
of O-phospho-Tyr with [Tb·L1]3+, and the 2:1 stoichiometry
A similar series of titrations was undertaken with the (S)-
lactate anion (Table 4). Estimated affinity constants were
for the dinuclear systems (Figure 7). Spectral titrimetric lower than for O-phospho-Tyr, consistent with the less
data were analysed using least-squares fitting methods, as- favourable electrostatic contribution to the free energy of
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Diastereoisomeric Dinuclear Lanthanide(III) Complexes
Figure 7. Binding curves (left) and equilibrium species distribution diagrams (right) characterising complexation of terbium complexes
with O-phospho-tyrosine (295 K, pH 7.4, λexc 275 nm). Top: [Tb2·L2a]6+ (50 µ); centre: [Tb·L2b]6+ (50 µ); bottom: [Tb·L1]3+ (110 µ).
The Job plot, is consistent with 1:1 stoichiometry of complexation for [Tb·L1]3+/O-phospho-Tyr.
Table 4. Formation constants for association of TbIII complexes
Summary and Conclusions
with (S)-lactate and O-phospho-(S)Tyr (295 K, pH 7.4).[a]
The dinuclear lanthanide(III) complexes of the stereoiso-
meric ligands L2a and L2b possess different local helicities
at the metal centre as revealed by the CPL studies. This
can be attributed to their differing solution conformations,
dictated by the configuration of the linking moiety. The
structure of the dinuclear complexes of (SS)-L2a must be
concave, leading to the creation of local metal helicities of
opposite sign. With the complexes of (SR)-L2b, the CPL
and solution complexation behaviour echo the behaviour of
Complex
[lactate]–
logβML
[O-phospho-Tyr]2–
logβML2
logβML
logβML2
[Tb·L1]3+
3.80(0.01)
–
4.88(0.10)
4.60(0.03)
5.67(0.30)
–
[Tb2·L2a]6+ 4.50(0.10)
[Tb2·L2b]6+ 4.58(0.13)
7.70(0.27)
7.60(0.19)
8.14(0.10)
10.45(0.29)
[a] Defining “M” as the Tb complex, and “L” as the anion, with
standard deviations in parenthesis.
binding for the mono-anion lactate, offset somewhat by the the mononuclear complex of L1; thus, the two metal centres
more favourable energy term associated with lactate chela- in [Ln2·L2b] behave independently.
tion and displacement of bound water.[10] The logβ values
The high positive charge of these dinuclear complexes
for each stereoisomeric terbium complex were similar in leads to the formation of rather insoluble complexes with
magnitude, suggesting a lesser role for any steric effect. The several anions (e.g., HPO42–, ATP4–) curtailing more de-
1:1 formation constant for [Tb·L1]3+ was lower than for the tailed analyses. Future work on such systems will embrace
dinuclear systems, consistent with a bigger electrostatic more hydrophilic derivatives, obtained by introducing sulfon-
binding energy term, as a result of the greater positive ate or carboxylate groups into either the two central or the
charge of the latter systems.
four peripheral aryl rings. It is more likely that the concave
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(1S,2S)-(–)-1,2-diphenylethylenediamine (0.024 g, 0.113 mmol) was
added to the solution which was stirred for a further 10 h then
washed with satd. NaHCO3 (aq) (10 mL) followed by H2O (10 mL).
The clear organic solution was dried, solvent removed under re-
duced pressure and the residue purified by column chromatography
(alumina using a DCM/MeOH solvent system starting from 100%
DCM then increasing the volume of MeOH by 0.5% every 50 mL
thereafter) to yield the desired product as a clear glassy solid
(0.126 g, 0.085 mmol, 75%); RF (Alumina, DCM/MeOH, 99:1):
systems based on the (SSS)-mononuclear complex linked
by an (SS)-diamide sub-unit, i.e., L2a will give rise to the
desired chemoselectivity for (1,4)- or (1,5)-di-phosphoryl-
ated species. The diastereoisomeric complexes of L2b may
serve simply as a cross-linking agent between two anion
binding sites.
1
0.80; m.p. 89–91 °C. H NMR (CDCl3, 400 MHz): δ = 9.82 (br. s,
1 H, NH), 9.08 (br. s, 1 H, NH), 7.88 (br. s, 4 H, arm NH), 7.18–
7.28 (br. m, 30 H, arm and linker Ar protons), 5.39 and 5.53 (br.
s, 2 H, linker CH), 5.01 (br. s, 4 H, arm CH), 2.03–3.30 (br. m, 44
H, cyclen CH2, amide arm CH2CO and linker CH2CO), 1.39 (br.
m, 30 H, amide arm CH3 and tBu CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 170.8 (br. m, 6 C, amide arms C=O and linker
C=O), 156.1 (2 C, Boc C=O), 143.6 (6 C, amide arms and linker
Ph(q)), 128.9, 127.6, 126.6 (br., 30 C, amide arm and linker Ph),
80.0 (2 C, Boc(q)), 46.9–62.6 (br., 24 C, cyclen CH2, amide arm
CH2, linker CH2 and linker stereocentre C), 28.7 (6 C, Boc CH3),
22.3 (4 C, amide arm CH3) ppm. MS (ES–) m/z 1480.4 [M – H]–
35%, 1517.5 [M + Cl]– 50%. HRMS (ES+) m/z found 1481.910 [M
+ H]+ C84H117O10N14 requires 1481.907.
Experimental Section
Determination of Binding Constants: To examine the influence of
some biologically common anions on complexes, titrations were
carried out examining separate solutions containing either O-phos-
pho-(S)-tyrosine or sodium (S)-lactate. Each measurement was car-
ried out by adding the anion as a concentrated stock solution such
that the incremental volume change was 0.1–0.5% of the original
solution volume, thereby avoiding any significant increase in sam-
ple volume. At each stage the pH was corrected to 7.40 (Ϯ0.04) by
using either concd. aqueous HCl or sodium hydroxide solution.
Each emission spectrum was corrected for dilution.
Every binding constant was calculated using the non-linear least-
squares programme SPECFIT/32TM [21]
The fitting methodology,
.
Ligand L2a: A colourless solution of 2a (0.093 g, 0.063 mmol) in
DCM/TFA (50:50, 5 mL) was stirred for 12 h in a sealed flask. The
resultant yellow-tinged solution was dried under reduced pressure
to yield the TFA salt of the desired product, as a glassy yellow
solid, in quantitative yield. 1H NMR (CD3CN, 500 MHz): δ = 9.77
(d, J = 9.5 Hz, 2 H, cyclen NH), 7.77 (br. s, 4 H, arm NH), 7.04–
7.48 (m, 30 H, arm and linker Ar), 5.67 (d, J = 9.0 Hz, 2 H, linker
CH), 5.05 (m, 2 H, arm CH), 4.69 (m, 2 H, arm CH), 3.92 (d, J =
15.5 Hz, 2 H, linker CH2), 3.71 (d, J = 15.5 Hz, 2 H, linker CH2),
2.62–3.29 (m, 40 H. cyclen CH2 and arm CH2), 1.46 (d, J = 7.0 Hz,
6 H, arm CH3), 1.24 (d, J = 7.0 Hz, 6 H, arm CH3) ppm. 13C
NMR (CD3CN, 125 MHz): δ = 170.7 (4 C, arm C=O), 164.4 (2 C,
linker C=O), 160.4 (q, 2 C, TFA C=O), 144.7, 144.4 (4 C, arm
Ar(q)), 139.8 (2 C, linker Ar(q)), 129.7, 129.5, 129.3, 128.8, 2ϫ128.0,
127.1, 127.0 (30 C, arm and linker Ar), 115.7 (q, 2 C, TFA CF3),
58.7 (2 C, linker CH), 56.7, 55.9, 53.0, 52.3, 51.8, 50.8, 49.1, 48.4
(16 C, cyclen CH2), 55.4 (2 C, linker CH2), 49.8, 49.7 (4 C, arm
CH), 43.8, 43.7 (4 C, arm CH2), 22.6, 22.1 (4 C, arm CH3) ppm.
MS (ES+) m/z 641.4 [M + 2H]2+ 100%. HRMS (ES+) m/z found
641.4055 [M + 2H]2+ C74H102O6N14 requires 641.4048.
which relies on the use of various mathematical parameters, uses
the Levenberg–Marquardt procedure to minimise the least-squares
residuals between the data set and the model system.[22]
Reverse-Phase HPLC and Dialysis: Reverse phase HPLC analyses
were performed at 298 K using a Perkin–Elmer Series 200 set up,
with a diode array and fluorescence detector. A Phenomenex Sy-
nergi Fusion RP 80 Å analytical column (4.6 mmϫ150 mm; 4 µm)
was used with a flow rate of 1 mLmin–1. The solvent system used
had the following time profile, with linear solvent gradient for the
period 5 to 25 min: 0–5 min: 100% 0.1% TFA in water; 5 to 20 min:
100% of 0.1% TFA/water declining to 0% with 0.1% TFA/MeCN
rising over the same time interval; 20.1 to 2 5 min: return to start
with 100% water/0.1% TFA.
Excess LnCl3 or Ln(OAc)3 salts were removed from the dinuclear
complexes of L2a and L2b using benzoylated dialysis tubing (9 mm
flat width, MWCO 2000) (Sigma–Aldrich). Typically the dialysis
tubing was washed with H2O, the solid complex was dissolved in
H2O (1 mL) and the solution was transferred to the tubing that
was sealed by clamping at both ends. The tubing was submerged
in stirring H2O (500 mL) and the H2O was exchanged four times
over 72 h followed by the removal and filtering of the tubing con-
tents. The aqueous solution was then frozen and lyophilized to
yield the desired complex.
[Eu2·L2a(H2O)4]Cl6·xH2O: Compound L2a as its TFA salt (0.082 g,
0.064 mmol, molar mass of ligand as its free base used) and Eu-
(OTf)3 (0.230 g, 0.384 mmol) in dry MeCN (1.75 mL) were heated
at reflux for 36 h under an atmosphere of argon. The solution was
then cooled to room temperature followed by removal of the sol-
vent under reduced pressure. The solid was sonicated in DCM
(2ϫ5 mL) followed by collection of the solid by centrifugation,
decanting the DCM phase; the solid was dried under reduced pres-
sure. The grey solid left was sonicated in water (5 mL), the water
was decanted followed by the drying of the remaining solid under
reduced pressure. The solid was made water soluble by the ex-
change of the triflate anions for chloride anions using ion exchange
resin (0.2 g of DOWEX 1ϫ8 200–400 mesh Cl). The crude com-
Emission and CPL Spectroscopy: Emission spectra were recorded
with a Fluorolog-3 spectrofluorimeter; CPL spectra were recorded
with a custom-modified Spex Fluoromax-2 spectrometer at the
University of Glasgow.
Synthetic Procedures
[7-(tert-Butoxycarbonyl)-4,10-bis(2-oxo-2-{[(1S)-1-phenylethyl]-
amino}ethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic Acid (1):
This intermediate was synthesised as described in the literature.[13]
Di-tert-butyl 7,7Ј-{[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis[imino(2- plex was isolated from excess EuCl3 using benzoylated dialysis tub-
oxoethane-2,1-diyl)]}bis[4,10-bis(2-oxo-2-{[(1S)-1-phenylethyl]-
amino}ethyl)-1,4,7,10-tetraazacyclododecane-1-carboxylate] (2a):
Compound
0.282 mmol), HOBt (10 mg) and NEt3 (0.1 mL, 0.717 mmol) in
CHCl3 (5 mL) were stirred at room temperature. After 25 min
ing, to yield the desired product as a white powder (0.089 g,
0.047 mmol, 74%). MS (ES+, excess ammonium acetate) m/z 567.1
1
(0.166 g, 0.254 mmol), EDC·HCl (0.054 g, [M + 2CH3CO2 – H]3+ 95%, 850.2 [M + 2CH3CO2 – 2H]2+ 100%.
HRMS (ES+) m/z found 849.3217 [M + 2CH3CO2 – 2H]2+
C78H104O10N14151Eu2 requires 849.3223; HPLC: tR = 8.5 min.
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Diastereoisomeric Dinuclear Lanthanide(III) Complexes
[Tb2·L2a(H2O)4]Cl6·xH2O: Compound L2a as its TFA salt (0.017 g,
0.013 mmol, molar mass of ligand as its free base used) and
TbCl3·6H2O (0.031 g, 0.083 mmol) in dry MeOH (1.5 mL) were
heated at reflux for 36 h under argon. The solution was then cooled
to room temperature followed by removal of the solvent under re-
duced pressure. The solid was sonicated in DCM (2ϫ5 mL), the
solid collected by centrifugation and the solid was dried under re-
duced pressure. The residual grey solid was sonicated in water
(5 mL), the water decanted and the remaining solid dried under
reduced pressure. The complex was isolated from excess TbCl3
using benzoylated dialysis tubing (9 mm flat width) to yield the
(m, 34 H, arm and linker Ar and arm NH), 5.32 (m, 2 H, linker
CH), 5.08 (m, 1 H, amide arm CH), 4.90 (m, 1 H, amide arm CH),
4.77 (m, 1 H, amide arm CH), 4.66 (m, 1 H, amide arm CH), 2.45–
3.62 (m, 44 H, cyclen CH2, arm CH2 and linker CH2), 1.49, 1.44,
1.22 (m, 12 H, arm CH3) ppm. 13C NMR (CD3CN, 125 MHz): δ
= 171.2, 170.8 (4 C, arms C=O), 163.6, 163.5 (2 C, linker C=O),
159.7 (q, 4 C, TFA C=O), 144.8, 144.3 (4 C, arm Ar(q)), 139.5,
139.2 (2 C, linker Ar(q)), 129.8, 129.5, 129.4, 129.2, 129.1, 128.1,
128.0, 127.1 (30 C, arm and linker Ar), 116.4 (q, 4 C, TFA CF3),
58.8 (2 C, linker CH), 47.0–56.6 (br. m, 22 C, cyclen CH2, linker
CH2, arm CH), 44.0 (4 C, arm CH2), 22.9, 22.6, 22.1, 22.0 (4 C,
desired product as a white powder (0.020 g, 0.010 mmol, 80%). MS arm CH3) ppm. MS (ES+) m/z 641.6 [M + 2H]2+ 100%. HRMS
(ES+ with ammonium acetate) m/z 571.7 [M + 2CH3CO2
–
(ES+) m/z found 641.4048 [M + 2H]2+ C74H102O6N14 requires
641.4048.
H]3+ 90%, 857.2 [M + 2CH3CO2-2H]2+ 100%. HRMS (ES+) m/z
found 857.3270 [M + 2CH3CO2 – 2H]2+ C78H104O10N14159Tb2 re-
quires 857.3278; HPLC: tR = 8.7 min.
[Eu2·L2b(H2O)4]Cl6·xH2O: Ligand L2b as its TFA salt (0.019 g,
0.015 mmol, molar mass of ligand as its free base used) and
Eu(OTf)3 (0.053 g, 0.088 mmol) in dry MeCN (1.75 mL) were
heated at reflux for 72 h under argon. The solution was cooled to
room temperature and solvent removed under reduced pressure.
The crude material was purified as described above to yield the
desired product as a white solid (10 mg, 0.005 mmol, 33%). MS
(ES+; excess ammonium acetate) m/z 567.3 [M + 2CH3CO2 – H]3+
100%, 850.5 [M + 2CH3CO2 – 2H]2+ 50%. HRMS (ES+, +
[Yb2·L2a(OAc)2]OAc4·xH2O: Compound L2a as its TFA salt
(0.044 g, 0.034 mmol, molar mass of ligand as free base used) and
Yb(OAc)3·4H2O (0.086 g, 0.20 mmol) in MeOH/H2O (2 mL, 50:50)
were heated at reflux for 48 h under argon. The solution was cooled
to room temperature and solvent removed under reduced pressure.
The complex was isolated from excess Yb(OAc)3 using benzoylated
dialysis tubing to yield the desired product as a white solid (0.055 g,
0.028 mmol, 82%); m.p. 191–192 °C (dec.). MS (ES+, excess am-
monium acetate) m/z 581.6 [M + 2CH3CO2 – H]3+ 100%, 872.2 [M
+ 2CH3CO2 – 2H]2+ 5%. HRMS (ES+) m/z found 869.3400 [M +
2CH3CO2 – 2H]2+ C78H104O10N14Yb2 requires 869.3391; HPLC:
tR = 8.4 min.
NH4OAc) m/z found 849.3222 [M
+ 2CH3CO2 –
2H]2+
C78H104O10N14151Eu2 requires 849.3223; HPLC: tR = 8.8 min.
[Tb2·L2b(H2O)4]Cl6·xH2O: Ligand L2b as its TFA salt (0.008 g,
0.006 mmol, molar mass of ligand its free base used) and
TbCl3·6H2O (0.014 g, 0.037 mmol) in dry MeOH (1 mL) were
heated to reflux for 48 h under argon. The solution was cooled to
room temperature and solvent removed under reduced pressure.
The complex was isolated as described above to yield a white pow-
der (0.007 g, 0.0036 mmol, 60%). MS (ES+ excess ammonium acet-
ate) m/z 572.3 [M + 2CH3CO2 – H]3+ 83%, 857.6 [M + 2CH3CO2 –
2H]2+ 100%. HRMS (ES+, + NH4OAc) m/z found 857.3284 [M +
2CH3CO2 – 2H]2+ C78H104O10N14159Tb2 requires 857.3278; HPLC:
tR = 8.9 min.
Ligand 2b: Compound 1 (0.070 g, 0.107 mmol), TBTU (0.034 g,
0.106 mmol), HOBt·xH2O (0.014 g, 0.104 mmol) and NEt3
(0.03 mL, 0.215 mmol) in MeCN (1.5 mL) were stirred, under ar-
gon, at room temperature for 15 min followed by the addition of
meso-1,2-diphenylethylenediamine (0.011 g, 0.052 mmol). The pale
yellow solution was stirred at room temperature for 24 h followed
by removal of solvent under reduced pressure. The remaining yel-
low residue was taken up in DCM (10 mL) to give a solution that
was washed with HCl(aq) (0.1 , 20 mL), satd. NaHCO3 (10 mL)
then H2O (10 mL). The organic solution was concentrated to a
volume of 1 mL under reduced pressure then dripped into cold
diethyl ether (15 mL). The pale yellow precipitate was collected by
centrifugation and dried under reduced pressure to yield a cream
coloured powder (0.042 g, 0.028 mmol, 54%); m.p. 92–94 °C. 1H
NMR (CDCl3, 500 MHz): δ = 7.73 (br. s, 1 H, amide NH), 7.14–
7.29 (br. m, 35 H, arm and linker Ar protons and amide NH), 5.40
(m, 2 H, linker CH), 5.12 (br. m, 4 H, arms CH), 2.25–3.23 (br. m,
44 H, cyclen CH2, arms CH2CO and linker CH2CO), 1.46 (br. m,
12 H, arms CH3), 1.41 (br. m, 18 H, tBu CH3) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 170.6 and 170.5 (br., 6 C, arms and linker
C=O), 156.3 (2 C, Boc C=O), 143.5 and 138.8 (br., 6 C, arms and
linker Ph(q)), 128.9, 128.5, 127.9, 126.8, 126.6 (30 C, arms and
linker Ph), 80.1 (2 C, Boc(q)), 60.3, 58.0, 57.2, 54.3, 53.2, 48.7 (br.,
28 C, cyclen CH2, arms CH2, linker CH2 and arms and linker CH),
28.8 (6 C, Boc CH3), 22.3, 21.7 (4 C, amide arm CH3) ppm. MS
(ES+) m/z 742.0 [M + 2H]2+ 100%, 1481.8 [M + H]+ 5%, 1503.8
[M + Na]+ 3%. HRMS (ES+) m/z found 1481.906 [M + H]+
C84H117O10N14 requires 1481.907.
[Yb2·L2b(OAc)2]OAc4·xH2O: Ligand L2b as its TFA salt (0.063 g,
0.049 mmol, molar mass of ligand its free base used) and Yb-
(OAc)3·4H2O (0.123 g, 0.29 mmol) in MeOH/H2O (2 mL, 50:50)
were heated to reflux for 48 h, under argon. The complex was iso-
lated as described above to yield a white solid (0.065 g, 0.031 mmol,
64%); m.p. 196–197 °C (dec.). MS (ES+, excess ammonium acetate)
m/z 581.6 [M + 2CH3CO2 – H]3+ 100%, 872.0 [M + 2CH3CO2 –
2H]2+ 15%. HRMS (ES+) m/z found 869.3392 [M + 2CH3CO2
–
2H]2+ C78H104O10N14Yb2 requires 869.3391; HPLC: tR = 8.7 min.
Acknowledgments
We thank Engineering and Physical Sciences Research Council
(EPSRC), the Royal Society of Chemistry (RSC), the ESF Cost
Action 38 for support and Professor T. Gunnlaugsson for access
to facilities (CS).
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Eur. J. Inorg. Chem. 2010, 2663–2672
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: March 1, 2010
Published Online: May 6, 2010
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Eur. J. Inorg. Chem. 2010, 2663–2672