Complexation of GdIII with tetra-p-tert-butylthiacalix[4]arenoic acid in micellar media

Article abstract of DOI:10.1007/s11172-009-0186-0

The conditions for the formation of gadolinium(III) complexes possessing high relaxivity with various tetraacid stereoisomers based on p-tert-butylthiacalix[4]arene in micellar solutions of nonionic surfactants were established. The acid-base properties of individual isomers of the ligand were studied by pH-metric titration and UV spectroscopy. The composition and stability constants of the solubilized gadolinium(III) complexes with the obtained thiacalixarenes were determined using computer simulation of the NMR relaxation data.

Full text of DOI:10.1007/s11172-009-0186-0

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1400—1407, July, 2009
1400
Complexation of GdIII with tetraꢀpꢀtertꢀbutylthiacalix[4]arenoic acid
in micellar media
R. R. Amirov, A. B. Ziyatdinova, E. A. Burilova, A. Yu. Zhukov, I. S. Antipin, and I. I. Stoikov
Kazan State University,
18 ul. Kremlevskaya, 420008 Kazan, Russian Federation.
Fax: +7 (843) 231 5416. Eꢀmail: ramirov@ksu.ru
The conditions for the formation of gadolinium(III) complexes possessing high relaxivity
with various tetraacid stereoisomers based on pꢀtertꢀbutylthiacalix[4]arene in micellar solutions
of nonionic surfactants were established. The acidꢀbase properties of individual isomers of the
ligand were studied by pHꢀmetric titration and UV spectroscopy. The composition and stability
constants of the solubilized gadolinium(III) complexes with the obtained thiacalixarenes were
determined using computer simulation of the NMR relaxation data.
Key words: pꢀtertꢀbutylthiacalix[4]arene, gadolinium(III), NMR relaxation, complex forꢀ
mation, stability constants, micelles, nonionic surfactants.
Search for highꢀrelaxivity metal complexes is one of
the promising approaches to the design of contrast preꢀ
parations.
the most urgent problems in the development of new conꢀ
trast agents (CAs) for magnetic resonance imaging (MRI),
which is a nonꢀinvasive method for NMRꢀbased clinical
diagnostics of diseases.1 At present stable gadolinium(III)
complexes with linear and cyclic polyaminopolycarboxyꢀ
lates are used as CAs.2 A substantial drawback of these
CAs is their low relaxivity factor (3000—5000 L mol–1 s–1),
which requires the administration of large doses of the
drug to the body. Since natural biochemical cycles involvꢀ
ing Gd3+ ions are absent, the decrease in the amount of
the gadolinium compounds introduced into the body is an
important task. This requires the design of contrast agents
with high spinꢀlattice relaxivity values (relaxivity is the
paramagnetic contribution to the relaxation rate of proꢀ
tons of the solvent, R1).2,3 It is known that one of the
methods for increasing the relaxivity of solutions containꢀ
ing gadolinium ions is the retardation of their rotation
due to the formation of highꢀmolecularꢀweight particles
(aggregation, complexes) in their composition.4 It was
shown5,6 than an increase in the relaxivity in solutions of
longꢀchain alkyl sulfates in the presence of Gd3+ ions is
caused by the adsorption of the latter on the surface of
anionic micelles. The increase in the relaxivity of the
gadolinium(III) complex with the diethylenetriaminepenꢀ
taacetic acid derivative containing the cholesterol moiety
as the substituent is due to its selfꢀaggregation in waꢀ
ter with an increase in the concentration or the incorꢀ
poration of the complex in mixed aggregates with the nonꢀ
ionic surfactant.7 Thus, the choice of amphiphilic comꢀ
pounds capable of selfꢀaggregation or incorporation in
the composition of mixed aggregates seems to be one of
From this point of view, metacyclophanes, in particuꢀ
lar, calixarenes, whose ability to complexation and hydroꢀ
philic—lipophilic balance can be varied in a wide range,8—11
are very promising ligands for chelating rareꢀearth metꢀ
al ions, including gadolinium(III).12,13 Meanwhile, in a
few known works,14,15 calixarenes with insufficient lipoꢀ
philicity were used to design potential contrast agents.
However, the influence of the ligand conformation on the
stability and relaxation parameters of their complexes with
GdIII was not examined. The purpose of the present study
is to reveal the influence of the spatial arrangement of the
functional groups in the pꢀtertꢀbutylthiacalix[4]arene steꢀ
reoisomers substituted by carboxy groups at the lower rim
on the ability of such ligands to bind the Gd3+ ions to form
waterꢀsoluble complexes possessing high relaxivity. In adꢀ
dition, we attempted to evaluate the influence of the type
and concentration of the nonionic surfactant in solution
on the degree of binding of the paramagnetic probe and
relaxivity of gadolinium solutions containing calixarene—
surfactant mixed aggregates.
For this purpose, we synthesized tetraesters based on
thiacalix[4]arene in the conformations cone (1a), partial
cone (1b), and 1,3ꢀalternate (1с), from which the correꢀ
sponding stereoisomers of tetraꢀpꢀtertꢀbutylthiacalix[4]ꢀ
arenoic acid 2a—c were prepared.
It is known that the mutual conformational transforꢀ
mations of calix[4]arene (cone, partial cone, 1,2ꢀalternate,
1,3ꢀalternate) become impossible if the lower rim contains
substituents larger than or equal to the nꢀpropyl fragꢀ
ment.16,17 When synthesizing the thiacalix[4]arene stereoꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1361—1367, July, 2009.
1066ꢀ5285/09/5807ꢀ1400 © 2009 Springer Science+Business Media, Inc.

Complexation of GdIII with thiacalix[4]arene
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1401
R = Et (1), H (2)
(2c)) (general procedure). Compounds 1a—c were synthesized19
by the exhaustive alkylation of pꢀtertꢀbutylthiacalix[4]arene with
ethyl bromoacetate in boiling acetone in the presence of the
corresponding alkaline metal carbonate.
Tetraesters 1a—c were subjected to quantitative hydrolysis
to the corresponding tetraacids 2a—c by lithium hydroxide in
aqueous THF.20
Preparation of calixarene—surfactant aggregates and study of
complexation. Since thiacalixarene samples were not completely
dissolved even in a large excess of nonionic surfactant, a weighed
sample of the ligand was dissolved in water containing 4 equiv.
NaOH, and then the necessary amount of a surfactant and
4 equiv. HCl were added. When studying complexation, the pH
of the medium was changed by the addition of an aqueous soluꢀ
tion of NaOH, and the pH value was measured with a Thermo
Electron ThermoOrion 420A pHꢀmeter with an accuracy of
0.01 pH units.
isomers substituted at the lower rim, both the nature of the
substituent and the reaction conditions (solvent, temperaꢀ
ture) were taken into account.
The following nonionic surfactants were used for the
preparation of calixarene—surfactant mixed aggregates:
oxyethylated alkyl sorbates Tweenꢀ20, ꢀ40, and ꢀ60, oxyꢀ
ethylated dodecanol Brijꢀ35, and oxyethylated isoocꢀ
tylphenols Triton Xꢀ100 and Xꢀ405.
x + y = 20; n = 11 (Tweenꢀ20), 15 (Tweenꢀ40), 17 (Tweenꢀ60)
The pHꢀmetric titration was carried out using a Thermo
Electron microliter dispenser in such a way that at the end of the
experiment the increase in the solution volume due to the addiꢀ
tion of an aqueous carbonateꢀfree solution of NaOH did not
exceed 12%.
Brijꢀ35
Electronic absorption spectra of solutions were recorded
on a Perkin—Elmer Lambda EZꢀ210 instrument using an aqueꢀ
ous solution of the surfactant at the same concentration as a reꢀ
ference.
The spinꢀlattice relaxation times (T1) of water protons were
measured on a Bruker Minispec MQ20 pulse NMR relaxometer
(19.75 MHz). The error of measurement of relaxation times did
not exceed 1%. The temperature was maintained at 298 K using
a Thermo Electron Haake DC10 thermostat.
n = 10 (Triton Xꢀ100), 40 (Triton Xꢀ405)
Experimental
The spinꢀlattice relaxation rate of protons (1/T1) in aqueous
solutions containing paramagnetic ions Gd3+ includes the
diamagnetic (1/T2A ≈ 0.4 s–1, in the absence of a paramagnetic
Commercial Gd(NO3)3•6H2O (reagent grade, Reakhim)
was used in the work. The concentration of Gd3+ ions in solution
was determined by complexonometric titration.
Commercial nonionic surfactants Tweenꢀ20, ꢀ40, and ꢀ60
(Ferak), Brijꢀ35 (MP Biomedicals), Triton Xꢀ100, and Xꢀ405
(MP Biomedicals) were used.
The starting pꢀtertꢀbutylthiacalix[4]arene was synthesized
according to the previously described18 procedure by the conꢀ
densation of pꢀtertꢀbutylphenol and elementary sulfur at 260 °C
in the presence of sodium hydroxide.
Tetraꢀpꢀtertꢀbutylcalix[4]arenoic acid tetraesters (cone (1a),
partial cone (1b), and 1,3ꢀalternate (1c)) and 5,11,17,23ꢀtetraꢀ
tertꢀbutylꢀ25,26,27,28ꢀtetrakis[(hydroxycarbonyl)methoxy]ꢀ
thiacalix[4]arene (cone (2a), partial cone (2b), and 1,3ꢀalternate
impurity) and paramagnetic (1/T1p) contributions: 1/T1 = 1/T1A
+ 1/T1p. The experimental results are presented using the relaxꢀ
ivity values (R1/L mol–1 s–1 2
of solutions, namely, the paraꢀ
+
)
magnetic contribution (1/T1p) reduced to the gadolinium ion
concentration unit (СGd): R1 = 1/(СGdT1p). The spinꢀlattice reꢀ
laxivity factor (RF1)3 of gadolinium(III) equal to the relaxivity of
the solution of its aqua ions was 14 000 L mol–1 s–1. The possiꢀ
bilities of the NMR relaxation method for studying complexꢀ
ation and aggregation processes in solutions using paramagnetic
probes have been described previously.3,4
The experimental data were mathematically processed using
the CPESSP program.21

1402
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Amirov et al.
Results and Discussion
ence of a series of tetrasulfonatometacyclophanes.23—25
It was shown that the relaxivity of aqueous solutions conꢀ
taining Gd3+ ions and sulfonatocalix[n]arene23 or sulfoꢀ
natocalix[4]resorcinarenes24,25 increases considerably with
an increase in the lipophilicity of their molecules. As in
the case of anionic surfactants, this is due to the binding
of Gd3+ ions with aggregates of amphiphilic metacycꢀ
lophanes formed in water. The relaxivity also increased
upon the addition of nonionic surfactants to solutions
of the listed metacyclophanes due to the formation of
mixed micelles. The results obtained indicate that the
gadolinium complexes with very high R1 values can exist
in water.
The literature data on the relaxivity and stability of the
gadolinium(III) complexes with metacyclophanes are givꢀ
en only for two derivatives of classical calixarene 3 and 4
in the cone conformation substituted by functional groups
at the lower rim.14,15 Tetraamide 3 forms a rather lowly
stable complex with gadolinium(III) (β = 2•105, where β
is the stability constant) for which RF1 < 5000 L mol–1 s–1
(see Ref. 14). The stability of the GdIII complex with ligand
4 determined from the NMR relaxation data by competiꢀ
tive complexation is substantially higher (β ≈ 1•1013).15
The relaxivity of a solution of the GdIII complex with
ligand 4 in the pH range 4—9 is 9600 L mol–1 s–1
,
The latter, as compounds 3 and 4, have the cone conꢀ
figuration. Meanwhile, the change in the configuration of
the calixarene platform (partial cone, 1,2ꢀ and 1,3ꢀalterꢀ
nates) makes it possible to vary the composition and staꢀ
bility of the corresponding metal complexes.8—11 The
thiacalix[4]arene platform in which the phenol fragments
are sulfurꢀbridged is more appropriate for these purposes.
The efficient methods for the template synthesis of thiꢀ
acalix[4]arene stereoisomers were developed.17,26,27
Complexation in solution is the competition of the
cation and proton for binding with the donor atom of the
ligand and, hence, according to the commonly accepted
point of view, more basic functional groups form a more
stable bond with the complexing cation.28 Therefore, the
complexes with rareꢀearth metal cations with the involveꢀ
ment of the O atoms of the carboxyl groups possessing
higher electronꢀdonating ability than the O atoms of the
sulfur groups should be more stable. In this connection,
we intended to study the composition and stability of the
gadolinium(III) complexes with various stereoisomers of
pꢀtertꢀbutylthiacalixarene containing functional substituꢀ
ents with carboxyl groups at the lower rim and to deterꢀ
mine their relaxivity. In the present work, we studied three
stereoisomers of 5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26,27,28ꢀ
tetrakis[(hydroxycarbonyl)methoxy]thiacalix[4]arene:
cone (2a), partial cone (2b), and 1,3ꢀalternate (2c).
which is approximately twice as large as the RF1 values for
commercial CAs based on gadolinium polyaminocarbꢀ
oxylates.
Thiacalixarenes 2a—c are dissolved in water only upon
alkalization to form opalescent solutions. When gadoꢀ
linium(III) is added to these solutions, its hydroxide is
formed rapidly and then is slowly and partially dissolved
to give, most likely, mixed hydroxo complexes. Micelleꢀ
forming nonionic surfactants were used to transform thiaꢀ
calixarenes and their metal complexes into the waterꢀsolꢀ
uble state in neutral and acidic media. It was found
that among nonionic surfactants with various structures
(Tweenꢀ20, ꢀ40, and ꢀ60, Brijꢀ35, Triton Xꢀ100 and
Xꢀ405) polyoxyethylated dodecanol Brijꢀ35 has the best
solubilizing properties with respect to isomers of the carꢀ
boxylate derivative of pꢀtertꢀbutylthiacalixarene. An analoꢀ
gous result was obtained for the gadolinium(III) complexꢀ
es and, therefore, the results using the nonionic surfactant
Brijꢀ35 will be presented further.
As already mentioned, one of the methods for increasꢀ
ing the relaxivity of solutions of the metal complexes is the
use of ligands containing lipophilic substituents.4 Similar
complexes are capable of selfꢀaggregating in water or inꢀ
corporating in the existing ensembles of amphiphilic comꢀ
pounds (surfactants, micelles, liposomes, etc.). This apꢀ
proach has previously been applied7,22 to increase the reꢀ
laxivity (up to 25 000—40 000 L mol–1 s–1) in solutions of
gadolinium complexes in which the lipophilic derivatives
of diethylenetriaminepentaacetic acid, being a component
of the known contrast agents, are used as ligands.
The higher R1 values (about 35 000—60 000 L mol–1 s–1)
were observed for gadolinium(III) solutions in the presꢀ

Complexation of GdIII with thiacalix[4]arene
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1403
The acidꢀbase properties of compounds 2a—c in miꢀ
cellar solutions of Brijꢀ35 were studied by UV spectroscoꢀ
py in a region of 250—350 nm (Fig. 1, a—c).
The electronic absorption spectra (EAS) of three isoꢀ
mers differ noticeably in positions of the maxima. The
shape of these spectra changes differently with the change
in the pH of the medium. Interestingly, in the case of
1,3ꢀalternate 2с (see Fig. 1, c), the molar absorption coefꢀ
ficient (ε) was almost twice as large as the ε values for two
other isomers (see Fig. 1, a, b), and the spectrum remains
almost unchanged upon the deprotonation of the carboxꢀ
yl groups.
Thus, the EAS in the UV region make it possible to
identify isomers 2a—c. In particular, the EAS can be used
for the estimation of the purity of samples of all the synꢀ
thesized compounds in order to reveal impurities of other
isomers in the samples. However, insignificant changes in
the ε values depending on the acidity of the medium
(especially in the case of conformer 2c) do not allow one
to determine quantitatively the dissociation constants of
individual isomers of thiacalixarenoic tetraacid. Thereꢀ
fore, the apparent dissociation constants (рКn) for all tetꢀ
raacids were evaluated by the mathematical processing of
the pHꢀmetric titration data.
The titration curves of micellar solutions of thiacalixꢀ
arenes 2a—c are shown in Fig. 2. The shape of the initial
region of the titration curve suggests that of three isomers
the studied compound 2b has the lowest рК1 value. This
was confirmed by the computer simulation of the experiꢀ
mental data (Table 1). Evidently, the acidꢀbase properties
of three isomers of thiacalixarenes are rather similar.
Meanwhile, a different spatial arrangement of the carboxꢀ
yl substituents should result in a noticeable difference in
the ability of compounds 2a—c solubilized by nonionic
micelles to interact with Gd3+ ions, which is confirmed by
the analysis of the NMR relaxation data.
The pH dependence of the relaxivity of the
GdIII—2a—Brijꢀ35 system is shown in Fig. 3 (curve 1).
The relaxivity of the system remains almost unchanged
at pH ≤ 4 and corresponds to the RF1 value of the
free gadolinium(III) aqua ion. In acidic solutions all carꢀ
boxyl groups are protonated, which prevents their bindꢀ
ing to Gd3+ ions. At pH 4—5 the deprotonation of
the carboxyl groups of compound 2a begins and the relaxꢀ
ivity increases sharply up to R1 = 60 000 L mol–1 s–1. The
high R1 values are retained up to pH 8, after which the
A
a
0.8
0.6
0.4
0.2
275
275
275
300
300
300
325
325
325
λ/nm
A
b
0.8
0.6
0.4
0.2
λ/nm
c
A
pH
9
1.4
1.2
1.0
0.8
0.6
0.4
0.2
7
3
1
5
2
3
λ/nm
0.5
1.0
1.5
2.0
2.5VNaOH/mL
Fig. 1. Electronic absorption spectra of micellar solutions of
thiacalixarenes 2a (a), 2b (b), and 2c (c) at various pH (С2 =
= 0.05 mmol L–1, СBrijꢀ35 = 2 mmol L–1; arrows show the direcꢀ
tion of changing the spectra with an increase in pH).
Fig. 2. Titration curves of micellar solutions of compounds 2a
(1), 2b (2), and 2c (3) with a NaOH solution (С2 = 1 mmol L–1
СBrijꢀ35 = 10 mmol L–1, СNaOH = 48 mmol L–1).
,

1404
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Amirov et al.
Table 1. Apparent stepwise dissociation constants of the diꢀ
mers of pꢀtertꢀbutylthiacalix[4]arenoic acid in 10 mМ solutions
of Brijꢀ35
When choosing the nonionic surfactant concentration
necessary for the solubilization of the complex, it was found
that even small additives of Brijꢀ35 increase the relaxivity
of the system (Fig. 4, curve 1).
Equilibrium
pKa
To obtain transparent stable solutions of the gadoliniꢀ
um complexes with thiacalixarene 2a, it is enough that the
2a
2b
2c
Brijꢀ35 concentration would be equal to 10 mmol L–1
.
←
H4L → H3L– + H+
4.74 0.01 4.03 0.02 5.80 0.02
The further addition of the nonionic surfactant does not
reflect the relaxation parameters of the complexes, indiꢀ
cating that the nearest environment of the Gd3+ ion is
retained. This influence of the nonionic surfactant differs
from that observed in the case of mixed ionic and nonionic
micelles,29 where an excess of the nonionic component
results in the displacement of ions of the paramagnetic
probe from the surface of the micellar aggregate into water
and, hence, in a decrease in the relaxivity to the values
characteristic of the aqua ion.
The study of the dependence of the relaxivity on the
concentration of ligand 2a at pH 6 (Fig. 5) showed that
the addition of even small amounts of the ligand (curve 1)
to a micellar aqueous solution of Brijꢀ35 containing Gd3+
ions results in a sharp increase in the R1 values.
The addition of ligand 2a in an amount exceeding the
equimolar thiacalixarene to metal ion ratio exerts almost
no effect on the measured times of proton spinꢀlattice
relaxation. Earlier, when studying the complexation of
paramagnetic cations with lowꢀmolecularꢀweight ligands,
the relaxivity of solutions usually decreased due to a deꢀ
crease in the number of water molecules, which are reꢀ
placed by the electronꢀdonating atoms in the ligand, in
the first coordination sphere of the probing ion.3
H3L– ←→ H2L2– + H+ 5.76 0.02 5.50 0.02 6.10 0.10
H2L2– ←→ HL3– + H+ 6.40 0.04 6.77 0.04 6.88 0.06
HL3– ←→ L4– + H+
6.55 0.04 7.08 0.05 7.70 0.10
relaxivity decreases sharply, which is due, most likely, to
hydrolysis.
R1/L mol–1 s–1
2
1
80000
60000
40000
20000
3
2
3
4
5
6
7
8
9
10 pH
We observed the increase in the relaxivity for both inꢀ
dividual anionic surfactants6 and their mixtures with nonꢀ
ionic surfactants,29 tetraalkyl derivatives of sulfonate
calix[n]arenes,23 and calix[4]resorcinarenes25 capable of
binding paramagnetic probes by their own aggregates
Fig. 3. Dependences of the relaxivity (R1) on the pH of micellar
solutions of compounds 2a (1), 2b (2), 2c (3) (СGd
=
III
= 0.1 mmol L–1, С2 = 0.25 mmol L–1, СBrijꢀ35 = 10 mmol L–1).
R1/L mol–1 s–1
2
R1/L mol–1 s–1
100000
2
120000
100000
80000
60000
40000
20000
0
80000
1
60000
1
3
40000
20000
10
20
30
CBrijꢀ35/mmol L–1
0.1
0.2
0.3
C2/mmol L–1
Fig. 4. Dependences of the relaxivity (R1) of aqueous soluꢀ
tions of thiacalixarenes 2a (1) and 2b (2) on the nonionic surꢀ
Fig. 5. Dependences of the relaxivity (R1) of micellar solutions
of Brijꢀ35 on the concentration of thiacalixarenes 2a (1), 2b (2),
factant Brijꢀ35 concentration (СGd = 0.1 mmol L–1, С2
=
and 2c (3) (СGd = 0.1 mmol L–1, СBrijꢀ35 = 10 (1, 3) and
III
III
= 0.25 mmol L–1, pH 6.5).
50 mmol L–1 (2), рН 6.5).

Complexation of GdIII with thiacalix[4]arene
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1405
R1/L mol–1 s–1
formed in an aqueous solution. Therefore, a reason for the
fourfold increase in the relaxivity in the studied system
compared to the aqua ion can also be the binding of Gd3+
ions to the aggregate of thiacalixarene with the nonionic
surfactant. The relaxivity growth upon binding with the
solubilized ligands3 is due to the fact that the relaxation
rate of protons in a solution of the gadolinium(III) comꢀ
plex is controlled by its rotation. A similar effect achieved
upon the binding of the gadolinium complex to a protein
globule (in particular, albumin) is used in magnetic resoꢀ
nance imaging.2,4
100000
80000
60000
40000
20000
1
2
3
The pH dependence of the relaxivity for micellar soluꢀ
tions of gadolinium(III) ions containing thiacalixarene 2b
is shown in Fig. 3 (curve 2). The general shape of the
relaxation curves is similar for compounds 2b and 2a. Howꢀ
ever, in the latter case, the formation of highꢀrelaxivity
complexes begins somewhat earlier. Although the pK1
value for ligand 2b is lower than that for 2a, the result obꢀ
tained indicates the lower ability of thiacalixarene 2b to
complexation with gadolinium. The complexes with ligand
2b manifest high relaxivity and exist in a wide pH range of
5—8. However, the precipitation was prevented only by the
reaction of a considerable excess of surfactant. Note that the
increase in the surfactant concentration makes it possible
2
3
4
5
6
7
8
9
10 pH
Fig. 6. Influence of the type of the nonionic surfactant on the
dependence of the relaxivity on the pH of solutions of the Gd
complexes and ligand 2a: nonionic surfactant (NSurf) is Brijꢀ35
(1), Triton Xꢀ405 (2), and Tweenꢀ20 (3) (СGdIII = 0.1 mmol L–1
СNSurf = 20 mmol L–1, С2a = 0.25 mmol L–1).
,
suggests that the stability of the complex of the GdIII
ion with ligand 2a is independent of the type of the nonꢀ
ionic surfactant.
to achieve higher relaxivities (up to 110 000 L mol–1 s–1
;
The gadolinium(III) complexes with the 1,3ꢀalternate
stereoisomer exist in a narrower pH range (see Fig. 3,
curve 3). In this case, high relaxivity values are achieved at
considerably higher concentrations of ligand 2с in soluꢀ
tion compared to the other isomers (see Fig. 5, curve 3). In
addition, solutions of the complexes of compound 2c manꢀ
ifested rather low relaxivity and opalescence even in a nonꢀ
ionic surfactant excess. This suggests that isomer 2c is of
little promise for the formation of highꢀrelaxivity comꢀ
plexes with Gd3+ ions.
It was initially assumed that stereoisomer 2c, whose
molecule contains two carboxyl substituents directed to
the opposite sides from the calixarene platform, can act as
a bridging ligand linking the metal cations to form an
infinite chain (Scheme 1).
see Fig. 4, curve 2). The latter value is close to the theoretꢀ
ical maximum value R1 = 110 000—120 000 L mol–1 s–1
obtained from the Solomon—Bloembergen—Morgan theꢀ
ory2). Meanwhile, in the case of ligand 2a, the maximum
relaxivity of the gadolinium(III) complex is independent of
the nonionic surfactant concentration (see Fig. 4, curve 1).
An analysis of the influence of the ligand concentration on
the proton relaxation times showed (see Fig. 5) that the
distinct inflection in the saturation curve is observed at the
equimolar Gd3+ to ligand ratio only for isomer 2a. The
less steeper curves for stereoisomers 2b and 2c possibly
indicate a lower stability of their complexes with the
gadolinium(III) ion compared to the complexes formed by
ligand 2a.
This interaction should favor an increase in the conꢀ
centrations of the components in the solution. It could
be expected that high R1 values would be achieved in
the case of the Gd3+ ion (with allowance for the aggregaꢀ
tion of the monomeric complexes). We studied the deꢀ
pendences of the relaxivity on the concentrations of ligand
2c and Gd3+; however, no increase in the relaxivity
was observed.
The relaxivity values exceeding that of the aqua ion
were also detected in micellar solutions of other nonionic
surfactants: oxyethylated isooctylphenol (Triton) and alkyl
sorbate (Tween). However, no such high R1 values as
for Brijꢀ35 were observed (Fig. 6). The solutions beꢀ
came turbid at neutral pH followed by precipitation. Nevꢀ
ertheless, the character of the rise was the same for all
the three relaxation curves in acidic solutions, which
Scheme 1

1406
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Amirov et al.
Table 2. Logarithms of the apparent equilibrium constants for
the formation of the gadolinium(III) complexes with ligands 2a
and 2b in 10 mМ solutions of Brijꢀ35
Federation in the framework of the Target Program "Deꢀ
velopment of Scientific Potential of Higher School for
2006—2008" (Project No. 2.1.1.4794).
Equilibrium
logK
References
2a
2b
←
Gd3+ + H4L → [GdHL]0 + 3 H+
–8.4 0.1 –9.52 0.04
–13.34 0.1 –15.63 0.1
1. P. A. Rinck, Magnetic Resonance in Medicine, Blackwell Wisꢀ
senschafts Verlag, Berlin—Vienna, 2001.
←
Gd3+ + H4L → [GdL]– + 4 H+
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Chem. Rev., 1999, 99, 2293.
3. A. A. Popel´, Magnitnoꢀrelaksatsionnyi metod analiza neorꢀ
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nenie v MRꢀtomografii i khimii rastvorov [Metal Compounds
As Magnetic Relaxation Probes for Highly Organized Meꢀ
dia: Application in Magnetic Resonance Imaging and Soluꢀ
tion Chemistry], Novoe Znanie, Kazan, 2005, 316 pp.
(in Russian).
Table 3. Logarithms of the apparent stability constants and the
RF1 values of the GdIII complexes with ligands 2a and 2b
Equilibrium
logβ
RF1
/L mol–1 s–1
2a
2b
2a
2b
Gd3+ + HL3– ←→ [GdHL]0 8.5 0.1 6.8 0.1 60000 110000
Gd3+ + L4– ←→ [GdL]–
10.1 0.1 7.8 0.1 60000 110000
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The stability of the complexes formed in micellar soluꢀ
tions of the surfactant was estimated by the computer simꢀ
ulation of the pH dependences of the relaxivity. The comꢀ
plex analysis of the data showed that in acidic and neutral
media the Gd3+ ions form successively two highꢀrelaxivity
equimolar complexes with the triꢀ and tetraanions of the
ligands. The equilibria constants of complex formation
are given in Table 2.
The stability constants calculated using the acidꢀbase
properties of the studied thiacalixarenes (see Table 1) and
the relaxivity factors of the gadolinium complexes are listꢀ
ed in Table 3. As can be seen, the cone isomer (2a) forms
somewhat more stable complexes with gadolinium(III)
than the partial cone (2b) does.
Thus, to form highꢀrelaxivity complexes with gaꢀ
dolinium(III) ions, it is necessary that the molecule of the
tertꢀbutylthiacalix[4]arene ligand contains at least three
carboxyl substituent at the lower rim. The results obtained
showed that the cone and partial cone isomers are of most
interest as ligands for the design of potential contrast agents
in magnetic resonance imaging.
All studied complexes of thiacalixarene 2 possess high
spinꢀlattice relaxivity R1 (up to 60 000—110 000 L mol–1 s–1)
considerably exceeding the RF1 values of the commercial
contrast agents (3000—5000 L mol–1 s–1). However, inꢀ
sufficient stability (logβ ≤ 10) of these complexes does not
allow them so far to be proposed for practical use as conꢀ
trast agents (for the stability constants of the latter the
condition logβ ≥ 20 should be fulfilled).2
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 06ꢀ03ꢀ32063)
and the Ministry of Science and Education of the Russian
22. M. Nicolle, E. Toth, K.ꢀP. Eisenwiener, H. R. Macke, A. E.
Merbach, J. Biol. Inorg. Chem., 2002, 7, 757.

Complexation of GdIII with thiacalix[4]arene
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Received August 12, 2008;
in revised form January 15, 2009