Synthesis of four derivatives of 3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid, the stabilities of their complexes with Ca(II), Cu(II), Zn(II) and lanthanide(III) and water-exchange investigations of Gd(III) chelates

Article abstract of DOI:10.1039/b107456n

The protonation constants of four poly(aminocarboxylates), N′-pyridylmethyl (TTDA-PY), N′-2-hydroxypropyl (TTDA-HP), N′-2-hydroxy-1-phenylethyl (TTDA-H1P) and N′-2-hydroxy-2-phenylethyl (TTDA-H2P) derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), and the stability constants of their complexes formed with Ca²⁺, Zn²⁺, Cu²⁺, La³⁺, Ce³⁺, Nd³⁺, Sm³⁺, Gd³⁺, Dy³⁺, Ho³⁺, Yb³⁺ and Lu³⁺ were determined by potentiometric methods at 25.0 ± 0.1 °C and 0.10 mol dm^-3 ionic strength in Me₄NNO₃. The stability of the Gd(III) complexes follows the order TTDA-PY > TTDA-H2P ≈ TTDA-HP ≈ TTDA-H1P. The thermodynamic resistance of the gadolinium(III) complexes, at the plasma concentration used in clinical applications, towards demetallation in the presence of important components of blood plasma, such as Ca(II), Zn(II) and Cu(II), has been evaluated. The observed water proton relaxivity values of [Gd(TTDA-PY)]^-, [Gd(TTDA-HP)]^-, [Gd(TTDA-H1P)]^- and [Gd(TTDA-H2P)]^- became constant with respect to pH changes over the range of 4-10, 6-10, 6-10 and 6-10, respectively. ¹⁷O NMR shifts showed that the [Dy(TTDA-PY)]^-, [Dy(TTDA-HP)]^-, [Dy(TTDA-H1P)]^- and [Dy(TTDA-H2P)]^- complexes at pH 6.30 and 4.30 had 0.9 and 0.9; 2.2 and 3.4; 2.0 and 3.5; 1.8 and 3.0 inner-sphere water molecules, respectively. Water proton spin-lattice relaxation rates for gadolinium(III) complexes were also consistent with the number of inner-sphere water molecules. The EPR transverse electronic relaxation rate and ¹⁷O NMR transverse relaxation time were thoroughly investigated and the results obtained were compared with that previously reported for the other gadolinium(III) complex, [Gd(DTPA)(H₂O)]^2-. Short exchange lifetime values were obtained for the [Gd(TTDA)(H₂O)]^2-, [Gd(TTDA-PY)(H₂O)]^-, [Gd(TTDA-HP)(H₂O)₂]^-, [Gd(TTDA-H1P)(H₂O)₂]^- and [Gd(TTDA-H2P)(H₂O)₂]^- complexes. Their water-exchange rates are about 24-45 times faster than that for the [Gd(DTPA)(H₂O)]^2- complex, which suggested that the longer backbone of the multidentate ligand may be pulled tightly into the first coordination sphere, resulting in high steric constraints at the water binding site.

Full text of DOI:10.1039/b107456n

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of four derivatives of 3,6,10-tri(carboxymethyl)-3,6,10-
triazadodecanedioic acid, the stabilities of their complexes with
Ca(II), Cu(II), Zn(II) and lanthanide(III) and water-exchange
investigations of Gd(III) chelates†
Tsan-Hwang Cheng,a Yun-Ming Wang,*a Kuei-Tang Lina and Gin-Chung Liub
a School of Chemistry, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung,
Taiwan 807, Republic of China
b Department of Radiology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road,
Kaohsiung, Taiwan 807, Republic of China
Received 2nd August 2001, Accepted 6th September 2001
First published as an Advance Article on the web 26th October 2001
The protonation constants of four poly(aminocarboxylates), NЈ-pyridylmethyl (TTDA-PY), NЈ-2-hydroxypropyl
(TTDA-HP), NЈ-2-hydroxy-1-phenylethyl (TTDA-H1P) and NЈ-2-hydroxy-2-phenylethyl (TTDA-H2P) derivatives
of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), and the stability constants of their complexes
formed with Ca2ϩ, Zn2ϩ, Cu2ϩ, La3ϩ, Ce3ϩ, Nd3ϩ, Sm3ϩ, Gd3ϩ, Dy3ϩ, Ho3ϩ, Yb3ϩ and Lu3ϩ were determined by
potentiometric methods at 25.0 0.1 ЊC and 0.10 mol dmϪ3 ionic strength in Me4NNO3. The stability of the Gd()
complexes follows the order TTDA-PY > TTDA-H2P ≈ TTDA-HP ≈ TTDA-H1P. The thermodynamic resistance
of the gadolinium() complexes, at the plasma concentration used in clinical applications, towards demetallation
in the presence of important components of blood plasma, such as Ca(), Zn() and Cu(), has been evaluated.
The observed water proton relaxivity values of [Gd(TTDA-PY)]Ϫ, [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and
[Gd(TTDA-H2P)]Ϫ became constant with respect to pH changes over the range of 4–10, 6–10, 6–10 and 6–10,
respectively. 17O NMR shifts showed that the [Dy(TTDA-PY)]Ϫ, [Dy(TTDA-HP)]Ϫ, [Dy(TTDA-H1P)]Ϫ and
[Dy(TTDA-H2P)]Ϫ complexes at pH 6.30 and 4.30 had 0.9 and 0.9; 2.2 and 3.4; 2.0 and 3.5; 1.8 and 3.0 inner-sphere
water molecules, respectively. Water proton spin–lattice relaxation rates for gadolinium() complexes were also
consistent with the number of inner-sphere water molecules. The EPR transverse electronic relaxation rate and
17O NMR transverse relaxation time were thoroughly investigated and the results obtained were compared with that
previously reported for the other gadolinium() complex, [Gd(DTPA)(H2O)]2Ϫ. Short exchange lifetime values were
obtained for the [Gd(TTDA)(H2O)]2Ϫ, [Gd(TTDA-PY)(H2O)]Ϫ, [Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ
and [Gd(TTDA-H2P)(H2O)2]Ϫ complexes. Their water-exchange rates are about 24–45 times faster than that for the
[Gd(DTPA)(H2O)]2Ϫ complex, which suggested that the longer backbone of the multidentate ligand may be pulled
tightly into the first coordination sphere, resulting in high steric constraints at the water binding site.
oxa-5,8,11-triazatridecan-13-oic acid (BOPTA) are effective
Introduction
magnetic resonance imaging (MRI) contrast agents when
The use of paramagnetic metal complexes as contrast agents for
bound to a trivalent gadolinium ion.4–7 These gadolinium()
magnetic resonance imaging (MRI) have been developed very
complexes display good relaxivity and high stability. To avoid
complex dissociation, Gd() chelates characterized by high
rapidly and extensively.1–3 The octachelating ligands, 3,6,9-
tri(carboxymethyl)-3,6,9-triazadodecanedioic acid (DTPA),
thermodynamic stability and kinetic inertness are commonly
1,7-bis[(N-methylcarbamoyl)methyl]-1,4,7-triazaheptane-1,4,7-
sought.8–16 The acute toxicity of gadolinium() complexes with
triacetate (DTPA-BMA), 10-(2-hydroxypropyl)-1,4,7,10-tetra-
the linear poly(aminocarboxylate) ligands correlates well with
azacyclododecane-1,4,7-triacetic acid (HP-DO3A), 1,4,7,10-
tetraazacyclododecane-N,N Ј,NЉ,Nٞ-tetraacetic acid (DOTA),
3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)un-
the selectivity constant of ligand for Gd() over endogenously
available metal ions.15,16 The relaxation effect of a gadolinium-
() complex, the relaxivity, can be divided into two parts: (1)
decandicarboxylic acid (EOB-DTPA), 1,4,7-tris(carboxy-
outer-sphere relaxivity, resulting from long-range interactions
methyl)-10-(1-(hydroxymethyl)-2,3-dihydroxypropyl)-1,4,7,10-
tetraazacyclododecane (DO3A-butrol), 1,11-bis(2-methoxy-
between gadolinium() and bulk water; (2) inner-sphere relax-
ivity due to short-range interactions between gadolinium()
ethylamino)-1,11-dioxo-3,6,9-triaza-3,6,9-tris(carboxymethyl)-
and inner-sphere water molecules. The inner-sphere contri-
undecane (DTPA-BEMA), and (4-carboxymethyl)-1-phenyl-2-
bution to total relaxivity depends on the number of water
molecules in the inner-sphere, the proton-exchange rate, the
rotational correlation time, and the electronic relaxation
rate. The proton-exchange rate, as confirmed recently for
several gadolinium() complexes, can be taken as identical to
the exchange rate of all the water molecules at physiological
pH.17–19
† Electronic supplementary information (ESI) available: tables of pM
values and relaxivities; potentiometric titration curves for TTDA-PY,
TTDA-HP, TTDA-H1P and TTDA-H2P; species distribution curves,
plots of temperature dependence of transverse electronic relaxation
rates and plots of pH dependence of conditional stability constants for
Gd complexes of all four ligands and TTDA; 1H NMR and COSY
spectra of [La(TTDA-HP)]Ϫ. See http://www.rsc.org/suppdata/dt/b1/
b107456n/
17O NMR spectroscopy is an efficient technique for studying
water-exchange rate because the oxygen of the coordinated
DOI: 10.1039/b107456n
J. Chem. Soc., Dalton Trans., 2001, 3357–3366
This journal is © The Royal Society of Chemistry 2001
3357

View Article Online
water molecule, directly bound to the paramagnetic Gd3ϩ ion, is
a more sensitive antenna than protons. Another advantage of
this method is that the outer-sphere contribution to the relax-
ation is negligible.20 However, the interpretation of 17O NMR
transverse relaxation rates has faced some problems, mainly
due to the fact that the electronic relaxation parameters,
obtained only from 17O NMR transverse relaxation rates, are
rather ill-defined. Therefore, it is desirable to determine these
parameters by EPR spectroscopy as an independent technique
providing direct access to transverse electronic rates.21
General procedure for the reaction of DPTO with 2-picolyl
chloride or (S)-(؊)-propylene oxide. DPTO (5.0 g, 12.09 mmol)
was suspended in 50 cm3 of water, with stirring and the pH was
adjusted to between 11.5 and 12.0 by addition of NaOH (2.0
mol dmϪ3). The reaction mixture was kept at room temperature
and 2-picolyl chloride (1.1 equiv) or (S)-(Ϫ)-propylene oxide
(15% excess) was added. Then the mixture was stirred for one
day after which time 6 mol dmϪ3 HCl (100 cm3) was added to
remove the protecting group. In the case of 4a and 4b, the crude
product was purified with an AG 50W × 8 cation exchange resin
column (200–400 mesh, Hϩ form, 100 cm3 of resin, 4.2 cm
column diameter). All fractions containing the product were
evaporated by rotary evaporation and coevaporated three times
with 150 cm3 of water to remove the excess HCl.
The characterization of the gadolinium() complex with
bis(amide) derivatives of DTPA, NЈ-pyridylmethyl and NЈ-2-
hydroxypropyl derivatives of DTPA and 3,6,10-tri(carboxy-
methyl)-3,6,10-triazadodecanedioic acid (TTDA) have been
investigated in our earlier studies.22–28 In the continuing search
for gadolinium() chelates for use in MRI, we have modified
the central carboxylate group of TTDA with 2-pyridylmethyl,
2-hydroxypropyl, 2-hydroxy-1-phenylethyl and 2-hydroxy-2-
phenylethyl moieties and explored the protonation constants
of these ligands, the stability constants of the metal complexes
and the relaxometric investigations of gadolinium() chelates.
This report describes the synthesis of four derivatives of
TTDA, 3,10-di(carboxymethyl)-6-pyridylmethyl-3,6,10-triaza-
dodecanedioic acid (TTDA-PY), 3,10-di(carboxymethyl)-6-(2-
hydroxypropyl)-3,6,10-triazadodecanedioic acid (TTDA-HP),
3,10-di(carboxymethyl)-6-(2-hydroxy-1-phenylethyl)-3,6,10,-tri-
azadodecanedioic acid (TTDA-H1P) and 3,10-di(carboxy-
methyl)-6-(2-hydroxy-2-phenylethyl)-3,6,10-triazadodecanedioic
acid (TTDA-H2P) (Scheme 1), their protonation, thermo-
dynamic, and conditional stability constants of complexes with
lanthanide(), Cu(), Zn() and Ca() and their selectivity for
NЈ-(2-Hydroxypropyl)triazaoctane (TO-HP, 4a). Yield 1.12 g,
1
32.6%. H NMR (D2O): δ 4.19 (m, 1H, –CHOH), 3.60 (m,
2H, ethylene backbone), 3.45 (m, 2H, propylene backbone),
3.32 (m, 2H, ethylene backbone), 3.31, 3.19 (t, t, 2H, propyl-
ene backbone), 3.05 (t, 2H, –NCH2CH(OH)–), 2.11 (p, 2H,
–NCH2CH2CH2N–), 1.20 (d, 3H, –CH(OH)CH3).
NЈ-(2-Pyridylmethyl)triazaoctane (TO-PY, 4b). Yield 1.76 g,
1
42.2%. H NMR (D2O): δ 8.59, 8.35, 7.94, 7.82 (m, 4H, pyH),
4.35 (s, 2H, NCH2py), 3.15 (s, 4H, backbone), 2.80 (m, 4H,
backbone), 1.84 (p, 2H, –NCH2CH2CH2N–).
General procedure for the reaction of 4a and 4b with tert-
butylbromoacetate. A suspension of 4a, 4b, potassium carbon-
ate (10 g, 72.35 mmol) and tert-butylbromoacetate (4.1 equiv)
in CH3CN (120 cm3) was stirred at reflux for 36 h. The potas-
sium carbonate was removed by filtering the reaction mixture
with a Büchner funnel and was washed with CH3CN (20 cm3).
The filtrate was evaporated by rotary evaporation. To the resi-
due was added H2O followed by extraction with chloroform (3
× 50 cm3). The chloroform phase was evaporated under reduced
pressure and 2 mol dmϪ3 HCl (50 cm3) was added. The solution
was stirred for 6 h at ambient temperature, stripped to dryness
Gd3ϩ over endogenously available metal ions are discussed. 17
O
NMR shifts of the [Dy(TTDA-PY)]Ϫ, [Dy(TTDA-HP)]Ϫ,
[Dy(TTDA-H1P)]Ϫ and [Dy(TTDA-H2P)]Ϫ complexes and
water proton spin–lattice relaxivity r1 of the [Gd(TTDA-PY)-
( H2O)]Ϫ, [Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ
and [Gd(TTDA-H2P)(H2O)2]Ϫ are described. Their kinetic
parameters are also obtained by analysis of the 17O NMR
transverse relaxation rate data using the results of a single-
magnetic field EPR study.
1
and the acid treatment repeated three times (until H NMR
showed complete removal of the tert-butyl group). In the case
of salts 5a and 5b, the residue was dissolved in 50 cm3 of dis-
tilled water and the solution was loaded into an AG 50W × 8
cation exchange resin column (200–400 mesh, Hϩ form, 100 cm3
of resin, 4.2 cm column diameter). All fractions containing the
product were evaporated by rotary evaporation and coevapor-
ated three times with 150 cm3 of water to remove the excess
HCl. Then the products were dissolved in 30 cm3 of distilled
water and alkalized with ammonia water to pH 11.0 and the
solution applied to an AG1 × 8 anion exchange resin column
(200–400 mesh, HCO2H form, 60 cm3 of resin, 3.0 cm column
diameter). All fractions containing the products were evapor-
ated by rotary evaporation and coevaporated three times with
200 cm3 of water to remove the formic acid.
Experimental
Materials
Gadolinium oxide (>99.9%) was obtained from Aldrich
Chemical Co. and oven dried at 110 ЊC for at least 24 h before
use. All other reagents used for the synthesis of the ligands were
purchased from commercial sources unless otherwise noted.
Proton and 13C NMR spectra and elemental analyses were used
to confirm the composition of the products. 17O-enriched water
(10.5%) was purchased from Isotec Inc.
Preparations
NЈ-(2-Hydroxypropyl)di(carboxymethyl)triazadodecanedioic
acid (TTDA-HP, 5a). Yield 1.32 g, 77.2%. Anal. calc. (found)
for C15H27N3O9ؒ1.5H2O (FW = 434.44): C, 44.24 (44.61); H,
Synthesis of N,N-bis(phthalimide)triazaoctane (DPTO). To a
500 cm3 two-necked round-bottom flask was added phthalic
anhydride (36.95 g, 249.42 mmol) and chloroform (200 cm3).
The solution was cooled to 5 ЊC in an ice bath and N-(2-
aminoethyl)-1,3-propanediamine (13.92 g, 118.77 mmol) was
added. The reaction mixture became slurry within 20 min and
the mixture was stirred for 5 h. The pale yellow slurry was
filtered with a Büchner funnel, washed with CH3OH (4 × 60
cm3) and then vacuum dried to give 25.43 g (51.8%) of a white
solid, mp: 158.0–159.0 ЊC. Anal. calc. (found) for C21H19N3O4ؒ
2H2O (FW = 413.43): C, 61.01 (60.98); H, 5.61 (5.52); N, 10.16
1
7.83 (8.05); N, 9.67 (9.72)%. H NMR (D2O, pD 3.67): δ 3.99
(m, 1H, –CHOH), 3.77 (s, 4H, –CH2COOH), 3.52 (s, 4H,
–CH2COOH), 3.26 (t, 2H, propylene backbone), 3.10 (t, 2H,
ethylene backbone), 3.05 (m, 2H, ethylene backbone), 2.92 (t,
2H, propylene backbone), 2.76 (m, 2H, –NCH2CH(OH)–), 2.02
(p, 2H, –NCH2CH2CH2N–), 1.12 (d, 3H, –CH(OH)CH3).
NЈ-(2-Pyridylmethyl)di(carboxymethyl)triazadodecanedioic
1
acid (TTDA-PY, 5b). Yield 0.96 g, 42.7%. H NMR (D2O):
1
(9.96)%. H NMR (CDCl3): δ 7.00 (m, 8H, ArH), 2.95 (t, 2H,
δ 8.68, 8.49, 7.94, 7.82 (m, 4H, pyH), 4.18 (s, 2H, NCH2py),
4.03 (s, 4H, –CH2COOH), 3.92 (s, 4H, –CH2COOH), 3.47 (t,
2H, backbone), 3.25 (t, 2H, backbone), 3.04 (t, 2H, backbone),
2.71 (t, 2H, backbone), 1.90 (m, 2H, –NCH2CH2CH2N–).
ethylene backbone), 2.86, (t, 2H, propylene backbone), 2.29 (t,
2H, ethylene backbone), 2.17 (t, 2H, propylene backbone), 1.27
(p, 2H, –NCH2CH2CH2N–).
3358
J. Chem. Soc., Dalton Trans., 2001, 3357–3366

View Article Online
Scheme 1
Synthesis of NЈ-(2-hydroxy-1-phenylethyl)di(carboxymethyl)-
500 cm3 of 0.4 mol dmϪ3 formic acid and 500 cm3 of 0.5 mol
triazadodecanedioic acid and NЈ-(2-hydroxy-2-phenylethyl)di-
(carboxymethyl)triazadodecanedioic acid (TTDA-H1P, 5c and
TTDA-H2P, 5d). Compounds 4c and 4d were synthesized from
DPTO and (S)-(Ϫ)-styrene oxide (15% excess) according to the
general procedure described above for 4a and 4b. After being
vacuum dried, 1.07 g of mixed TO-H1Pؒ3HCl and TO-H2Pؒ
3HCl was obtained as a white hygroscopic powder. Compounds
5c and 5d were synthesized from 4c and 4d according to the
general procedure described above for 5a and 5b. After running
a cation exchange resin column, the product (5c, 5d) came off
in 3.5 mol dmϪ3 HCl fractions. Solvent was removed from all
fractions containing the product by rotary evaporation. The
products were dissolved in 20 cm3 of distilled water and alkal-
ized with ammonia water to pH 11.0 and the solution applied to
ananionexchangeresincolumn.Theproductwaselutedwith500
cm3 of water, 500 cm3 of 0.1 mol dmϪ3 formic acid, 500 cm3 of
0.2 mol dmϪ3 formic acid, 500 cm3 of 0.3 mol dmϪ3 formic acid,
dmϪ3 formic acid. The products 5c and 5d came off in 0.5 mol
dmϪ3 and 0.3 mol dmϪ3 formic acid, respectively. The products
were evaporated separately by rotary evaporation and coevap-
orated three times with 200 cm3 of water to remove the formic
acid to yield 0.55 g and 0.64 g of a white hygroscopic free acid
5c and 5d, respectively. Anal. calc. (found) for C21H31N3O9ؒ
1.8H2O (5c) (FW = 501.92): C, 50.25 (50.35); H, 6.95 (7.15); N,
8.37 (8.44)%. 1H NMR (D2O, pD 4.05): δ 7.38 (m, 5H, phenyl),
4.05 (t, 1H, –CHCH2OH), 3.72 (s, 2H, –CH2COOH), 3.48 (q,
4H, –CH2COOH), 3.23 (m, 2H, ethylene backbone), 3.18 (m,
2H, propylene backbone), 3.02, 2.88 (m, m, 2H, ethylene back-
bone), 2.88, 2.74, (m, m, 2H, propylene backbone), 1.96 (p, 2H,
–NCH2CH2CH2N–). Anal. calc. (found) for C21H31N3O9ؒ
1.8H2O (5d) (FW = 501.92): C, 50.25 (50.28); H, 6.95 (7.03); N,
8.37 (8.47)%. 1H NMR (D2O, pD 7.26), δ 7.38 (m, 5H, phenyl),
4.83 (t, 1H, –CHOH), 3.60 (s, 4H, –CH2COOH), 3.52 (s, 4H,
–CH2COOH), 3.18 (m, 2H, ethylene backbone), 3.12 (m, 2H,
J. Chem. Soc., Dalton Trans., 2001, 3357–3366
3359

View Article Online
propylene backbone), 2.95 (m, 2H, ethylene backbone), 2.89
(m, 2H, –NCH2CH(OH)–), 2.73 (t, 2H, propylene backbone),
1.85 (p, 2H, –NCH2CH2CH2N–).
The equilibria were slow to attain and it was necessary to allow
about 10 min for each point of the titration where the ligand–
ligand competition took place. However, complexation was
usually rapid (3–5 min per point to give a stable pH reading) in
the Cu(), Ca() and Zn() solutions. The same values of the
stability constants were obtained either by using the direct or
the back titration. The protonation constants of the ligands
were calculated using a FORTRAN computer program
PKAS35 written for polyprotonic weak acid equilibria. The
overall stability constants of the various metal complexes
formed in aqueous solution were determined from the titration
data with the FORTRAN computer program BEST.35 A value
of 13.78 was employed for the pKw at 25 ЊC. The species distri-
bution diagrams were calculated with the FORTRAN program
SPE and SPEPLOT.35
17O NMR measurements
The hydration number of [Dy(TTDA-PY)]Ϫ, [Dy(TTDA-
HP)]Ϫ, [Dy(TTDA-H1P)]Ϫ and [Dy(TTDA-H2P)]Ϫ was deter-
mined by the method of Alpoim et al.29 The 17O NMR spectra
were recorded on a Varian Gemini 300 spectrometer at 25 ЊC.
The induced 17O shift (d.i.s.) measurements were determined
using D2O as an external standard. An equimolar solution of
Dy() and ligand was prepared, and a stoichiometric amount
of standardized NaOH was added so that the complex was fully
formed. Six solutions of varying dysprosium() concentrations
were prepared by serial dilution of the stock solution.
The measurement of the 17O transverse relaxation rates was
carried out with a Varian Gemini-300 (7.05 T, 40.65 MHz)
spectrometer, equipped with a 5 mm probe, by using an external
D2O lock. The Varian temperature unit was used to stabilize the
temperature. The value of the transverse relaxation rate was
resolved by evaluating the linewidth at half-height (∆ν1/2) of the
water 17O signal (R2 = π∆ν1/2). Solutions containing 2.6% of the
17O isotope were used.
Relaxation time measurements
The gadolinium() chelate solution was prepared by combin-
ing equal molar amounts of the stock GdCl3 and the ligand
solution. A slight excess (3%) of the ligand was used and the
solution was allowed to react for at least 2 h at room temper-
ature to ensure full complexation. The Gd() chelate solutions
under various pH values were prepared by combining the buffer
solution with an appropriately diluted Gd() complex solution
in a 1 : 1 (v/v) ratio. The following buffer systems were used:
chloroacetic acid–NaOH (pH 2–3), acetic acid–NaOH (pH
4–5), PIPES (PIPES = piperazine-N,N Ј-bis-2-ethanesulfonic
acid)–NaOH (pH 6.0–8.0) and ammonia–HCl (pH 9–10).
These buffer solutions were used to maintain constant ionic
strength (i.e. 0.10 mol dmϪ3). The buffered Gd() chelate solu-
tions were all allowed to equilibrate for at least 2 h. The pH of
these solutions was determined immediately before relaxation
time T 1 measurements. Relaxation times T 1 of aqueous solu-
tions of gadolinium() complexes of ligands were measured to
determine relaxivity r1. All measurements were made using a
NMR spectrometer operating at 20 MHz and 37.0 0.1 ЊC
(NMS 120 Minispec, Bruker). Before each measurement the
spectrometer was tuned and calibrated. The values of T 1 were
measured from eight data points generated by an inversion–
recovery pulse sequence.
Solution preparations
Stock solutions of Ca(), Zn(), Cu() and lanthanide() were
prepared between 0.015 and 0.025 mol dmϪ3 from nitrate salts
with demineralized water (obtained by a Millipore/Milli-Q sys-
tem) and standardized by titration with Na2EDTA (disodium
salt of ethylenedinitrilotetraacetic acid) or atomic absorption
spectrophotometry. A stock solution was prepared by dissolv-
ing reagent grade Na2EDTA 4.65 g and diluting it to 250 cm3
with demineralized water. This was used as a titrant to stand-
ardize the solution of lanthanide() and Ca().30
Potentiometric measurements
The protonation constants of the ligands were determined by
potentiometric titrations of 1.0 mmol dmϪ3 ligand solutions
using an automatic titrator system. The stability constants of
their complexes with Ca(), Zn() and Cu() were also deter-
mined by direct pH potentiometry. The autotitrating system
consists of a 702 SM Titroprocessor, a 728 stirrer, and a PT-100
combination pH electrode (Metrohm). The pH electrode was
calibrated using three standard buffer solutions. In order to
avoid any contact with CO2, all calibrations and titrations in a
glass-jacketed vessel (20 cm3) thermostatted at 25.0 0.1 ЊC,
with an ionic strength of 0.10 mol dmϪ3 Me4NNO3 were carried
out under a nitrogen atmosphere. A CO2-free, 0.100 mol dmϪ3
NaOH solution was used as the titrant to minimize the change
of ionic strength during the titration. The purity of the ligand
was also confirmed by potentiometric titration with standard
KOH. Each titration was performed at least three times.
EPR measurements
The EPR spectra were recorded at the X-band (0.34 T) using a
Bruker ER 200D-SRC spectrometer operated in continuous-
wave mode. The samples were contained in 1 mm glass tubes.
The cavity temperature was stabilized using electronic temper-
ature control of the gas flowing through the cavity and was
verified by substituting a thermometer for the sample tube.
Measurements were made from 273 up to 363 K. The peak-to-
peak linewidth was measured from the recorded spectra using
the instrument software.
Since the lanthanide chelates are completely or almost com-
pletely formed at low pH, their stability constant could not be
determined from the normal potentiometric titration method.
Therefore, these stability constants were evaluated by a ligand–
Results and discussion
Protonation constants
ligand competition potentiometric titration in this study.31–33
A
The potentiometric titration curves for TTDA-PY, TTDA-HP,
TTDA-H1P and TTDA-H2P have been deposited as ESI (Figs.
1S–4S). Table 1 summarizes the protonation constants of
TTDA-PY, TTDA-HP, TTDA-H1P, TTDA-H2P, DTPA and
TTDA.16,25 The titration curves of TTDA-PY, TTDA-HP,
TTDA-H1P and TTDA-H2P show an increase at pH 9.5–5.0,
8.7–4.0, 9.0–4.0 and 9.0–4.0 at a = 3 (a = moles of base per mol
ligand present), respectively. This is due to the large difference
between the second (log K2) and third (log K3) protonation con-
stants, i.e. 9.25 and 5.26; 8.64 and 4.45; 9.03 and 3.55; 8.83 and
4.55, respectively. The protonation constant of TTDA-PY is
significantly higher than those of TTDA-HP, TTDA-H1P,
TTDA-H2P and DTPA and similar to that of TTDA.
1 : 1 : 1 molar ratio of lanthanide(), ligand and a reference
ligand with a known metal chelate stability was titrated. A good
reference ligand for the lanthanide() systems was found to be
EDTA.16 EDTA forms a complex with lanthanide() whose
stability constant is accurately known.34 The potentiometric
equilibrium studies were conducted on solutions of the ligand
in the absence of metal ions and then in the presence of each
metal ion which the M : L ratio was 1 : 1. The δ data were
obtained after additions of 0.005 cm3 increments of standard
0.100 mmol dmϪ3 KOH solution, and after stabilization in this
direction, equilibrium was then approached from the other
direction by adding standard 0.100 mol dmϪ3 acid solution.
3360
J. Chem. Soc., Dalton Trans., 2001, 3357–3366

View Article Online
Table 1 Protonation constants of the ligands TTDA-PY, TTDA-HP, TTDA-H1P, TTDA-H2P, DTPA and TTDA at 25.0 0.1 ЊC in aqueous
Me4NNO3 (µ = 0.10 mol dmϪ3
)
Species
log β
H
L
TTDA-PY
TTDA-HP
TTDA-H1P
TTDA-H2P
DTPAa
TTDAb
1
2
3
4
1
1
1
1
10.37(0.06)
19.62(0.02)
24.88(0.04)
27.90(0.01)
11.08(0.05)
19.72(0.04)
24.17(0.07)
26.93(0.01)
10.40(0.05)
19.43(0.07)
22.98(0.08)
25.80(0.08)
10.63(0.01)
19.46(0.01)
23.51(0.04)
26.28(0.02)
10.49
19.09
23.37
26.01
10.60
19.52
24.64
27.44
a Data were obtained from refs. 16, 34 and 36. b Ref. 25.
Table 2 Stability constants, selectivity constants and modified selectivity constants for Gd(), Zn(), Ca() and Cu() complexes of TTDA-PY,
TTDA-HP, TTDA-H1P, TTDA-H2P, DTPA and TTDA at 25.0 0.1 ЊC in aqueous Me4NNO3 (µ = 0.10 mol dmϪ3
)
Parameter
TTDA-PY
TTDA-HP
TTDA-H1P
TTDA-H2P
DTPAa
TTDAb
[GdL]/[Gd][L]
23.48(0.07)
18.65
12.02(0.03)
7.96(0.04)
2.16
20.41(0.03)
6.18(0.02)
15.58
17.14(0.03)
5.86(0.02)
12.31
17.33(0.05)
12.39
12.02(0.05)
6.29(0.03)
7.08
17.97(0.02)
3.60(0.02)
13.03
15.03(0.04)
3.93(0.03)
10.09
17.16(0.07)
12.52
12.86(0.05)
5.30(0.03)
8.22
18.40(0.09)
3.74(0.03)
13.76
17.77(0.07)
5.36(0.07)
13.13
17.44(0.05)
12.76
12.74(0.04)
4.45
8.06
18.16(0.03)
3.36
13.48
17.37(0.03)
4.04
12.70
0.07
22.46
18.14
10.75
6.11
6.43
21.38
4.81
17.0
18.70
5.60
14.38
3.76
11.71
1.08
22.77
18.04
14.45
log KGdLЈ (pH 7.4)
log ([CaL]/[Ca][L])
log βCaHL
log KCaLЈ (pH 7.4)
log [CuL]/[Cu][L]
log βCuHL
log KCuLЈ (pH 7.4)
log [ZnL]/[Zn][L]
log βZnHL
log KZnLЈ (pH 7.4)
selectivity [log K(Gd/Zn)]
selectivity [log K(Gd/Ca)]
selectivity [log K(Gd/Cu)]
log KselЈ
9.72
19.31
14.58
18.59
13.86
4.18
8.32
3.46
8.44
6.34
11.46
3.07
9.06
2.30
5.31
Ϫ0.64
5.34
Ϫ0.61
4.30
Ϫ1.24
3.66
4.70
Ϫ0.72
4.32
7.06
a Data were obtained from refs. 16, 34 and 36. b Ref. 25.
Replacement of the central acetate group in TTDA by the 2-
pyridylmethyl group results in a decrease in log K1 (0.23 units),
an increase in log K2 (0.33 units) and a decrease in log K3 (0.14
units), log K4 (0.12 units) and the ΣpKa value (0.46 units) and by
the 2-hydroxypropyl group results in an increase in log K1 (0.48
units), a decrease in log K2 (0.28 units), log K3 (0.67 units) and
the ΣpKa value (1.51 units).
Thermodynamic stability constants
The potentiometric titration curves for the complexes of Ca2ϩ,
Cu2ϩ and Zn2ϩ with TTDA-PY, TTDA-HP, TTDA-H1P and
TTDA-H2P have been deposited as ESI (Figs. 1S–4S). The
thermodynamic stability constants for metal chelate with
TTDA-PY, TTDA-HP, TTDA-H1P and TTDA-H2P are pre-
sented in Table 2.16,25,34,36 The stability constant of the Gd()
complex with TTDA-PY is slightly higher than those of the
corresponding TTDA and DTPA complexes, which may
indicate a mildly higher ligand basicity for TTDA-PY. The
stability constants of [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ
and [Gd(TTDA-H2P)]Ϫ are very similar. The lower stability
constants of the TTDA-HP, TTDA-H1P and TTDA-H2P
chelates with Gd(), Ca(), Zn() and Cu() when compared
to the DTPA, TTDA and TTDA-PY chelates may be ascribed
to the weaker donor ability of the hydroxyl group oxygen
atom. The stability constants of Gd() complexes with TTDA-
HP, TTDA-H1P and TTDA-H2P are similar to that of the
corresponding DEATA (N,N-bis(2-aminoethyl)ethylamine-
NЈ,NЈ,NЉ,NЉ-tetraacetic acid)37 (i.e. log KGdL = 17.79). A
coordination number of seven for DEATA suggests that the
hydroxyl group oxygen atoms in the TTDA-HP, TTDA-H1P
and TTDA-H2P ligands do not coordinate to the Gd() metal
Fig. 1 Variation of stability constant with ionic radius for the
lanthanide chelates of TTDA-PY (᭛), TTDA-HP (ᮀ), TTDA-H1P (᭝)
and TTDA-H2P (᭺).
methyl protons (Hb). This doublet collapses into a singlet as the
temperature increases. The protons of the terminal acetate
groups (Ha) gave four AB patterns with the baricenter at 3.52
ppm (J = 40 Hz), 3.49 ppm (J = 41 Hz), 3.16 ppm (J = 42 Hz),
and 2.94 ppm (J = 30 Hz), respectively. The lack of an AB
pattern for proton Hc indicates that the oxygen atom of the
hydroxy group is not coordinated in the lanthanide complex.
Plots of the thermodynamic stability constants (log KLnL) for
lanthanide() chelates versus lanthanide() ionic radius are
displayed in Fig. 1. The stability trend of [Ln(TTDA-HP)]Ϫ,
[Ln(TTDA-H1P)]Ϫ and [Ln(TTDA-H2P)]Ϫ is mainly because
TTDA-HP, TTDA-H1P and TTDA-H2P are more sterically
crowded or less flexible than DTPA and cannot wrap around
1
ion which is supported by the solution H-NMR and COSY
spectra of 0.1 mol dmϪ3 [La(TTDA-HP)]Ϫ in D2O, pD 7.0, 25
ЊC, see ESI (Figs. 5S and 6S).
In the ambient-temperature (25 ЊC) spectrum of [La(TTDA-
HP)]Ϫ, the doublet at 1.31 and 1.30 ppm is assigned to the
J. Chem. Soc., Dalton Trans., 2001, 3357–3366
3361

View Article Online
the smaller lanthanide() ions successfully. These results sig-
nificantly lead to a plateau in stability for Nd(), Sm(),
Gd() and Dy() for [Ln(TTDA-HP)]Ϫ, [Ln(TTDA-H1P)]Ϫ
and [Ln(TTDA-H2P)]Ϫ chelates and this is a common effect in
Ln() solution chemistry.38 The progressive increase in stability
constants for [Ln(TTDA-PY)]Ϫ along the Ln() cation series is
characteristic of ligand TTDA-PY because it possesses mildly
higher basicity and reveals increasing stability when enhancing
the charge density of the Ln() cation.
Conditional stability constants and selectivity constants
In Table 2 the conditional stability constants13,16 at pH 7.4 are
presented for the six ligands TTDA-PY, TTDA-HP, TTDA-
H1P, TTDA-H2P, TTDA and DTPA. Their order is
[Gd(TTDA-PY)]Ϫ
> ≈ >
[Gd(TTDA)]2Ϫ [Gd(DTPA)]2Ϫ
[Gd(TTDA-HP)]Ϫ ≈ [Gd(TTDA-H1P]Ϫ ≈ [Gd(TTDA-H2P)]Ϫ.
A plot of the pH dependence of the conditional stability con-
stants for the complexes [Gd(TTDA)]2Ϫ, [Gd(TTDA-PY)]Ϫ,
[Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ
has been deposited as ESI (Fig. 7S). The results of the pH
dependence study of the conditional stability constants for
[Gd(TTDA)]2Ϫ and [Gd(TTDA-PY)]Ϫ are very similar. The
conditional stability constants at pH > 11 for [Gd(TTDA)]2Ϫ
and [Gd(TTDA-PY)]Ϫ differ by a factor of 100.71 which is simi-
lar to that at pH 7.4 (100.10). This demonstrates that the stability
constant of [Gd(TTDA)]2Ϫ comes close to that of [Gd(TTDA-
PY)]Ϫ at pH 7.4. The results for [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-
H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ at pH 7.4 are very similar.
These results also show that the stability constant of [Gd-
(TTDA-PY)]Ϫ is significantly higher than those of [Gd(TTDA-
HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ at pH 7.4.
The species distribution curves of [Gd(TTDA-PY)]Ϫ,
[Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ
have been deposited as ESI (Figs. 8S–11S). The species distri-
bution curves of [Gd(TTDA-PY)]Ϫ indicate that there is still
some free Gd3ϩ at pH 1 but after pH 3 the complex is fully
formed. However, the dominant species, [Gd(TTDA-HP)]Ϫ,
[Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ chelates are
formed at pH values larger than 5.5, 6.0 and 6.0, respectively.
The pM values39 of ligands have been deposited as ESI
(Table 1S). The pGd value of TTDA-PY resembles those of
TTDA and DTPA and is larger than those of TTDA-HP,
TTDA-H1P and TTDA-H2P and significantly larger than
those of the corresponding [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-
H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ chelates. The pGd value for
[Gd(TTDA-PY)]Ϫ is similar to that of [Gd(TTDA)]2Ϫ because
the protonation constants of TTDA-PY and TTDA and the
stability of [Gd(TTDA-PY)]Ϫ and [Gd(TTDA)]2Ϫ are similar.
The pM value of [Gd(TTDA-PY)]Ϫ is larger than those of
[Ca(TTDA-PY)]2Ϫ, [Cu(TTDA-PY)]2Ϫ and [Zn(TTDA-PY)]2Ϫ,
but [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ are less than
those of [Cu(TTDA-H1P)]2Ϫ and [Zn(TTDA-H1P)]2Ϫ,
[Cu(TTDA-H2P)]2Ϫ and [Zn(TTDA-H2P)]2Ϫ, respectively.
Therefore, the competition among Gd3ϩ, Ca2ϩ, Cu2ϩ and Zn2ϩ
with TTDA-PY seems to favor Gd3ϩ at pH 7.4, indicating that
the [Gd(TTDA-PY)]Ϫ complex should be stable enough to
avoid interference by Ca2ϩ, Cu2ϩ and Zn2ϩ at physiological pH.
The logarithmic selectivity constants13,16 for TTDA-PY,
TTDA-HP, TTDA-H1P, TTDA-H2P and TTDA are also
shown in Table 2. The log K(Gd/Zn, Gd/Ca and Gd/Cu) values
of TTDA-PY are higher than those of TTDA-HP, TTDA-H1P
and TTDA-H2P indicating that TTDA-PY shows more favor-
able selectivity towards Gd3ϩ over Zn2ϩ, Cu2ϩ and Ca2ϩ. The
complexes of Gd() with TTDA-HP, TTDA-H1P and TTDA-
H2P have a much lower selectivity for Gd() over Zn(), Cu()
and Ca() which in turn leads to a high toxicity because of
Gd() displacement by endogenous Zn(), Cu() and Ca().16
However, the selectivity constants, (log K(Gd/Zn)), (log K(Gd/
Cu)) and (log K(Gd/Ca)), of Gd() complexes with TTDA-
Fig. 2 The Dy()-induced water 17O NMR shift versus Dy() chelate
concentration for solutions of [Dy(TTDA-PY)]Ϫ (pH 6.3) (᭝),
[Dy(TTDA-PY)]Ϫ (pH 4.3) (᭺), [Dy(TTDA-H2P)]Ϫ (pH 6.3) (᭛),
[Dy(TTDA-H1P)]Ϫ (pH 6.3) (ᮀ), [Dy(TTDA-HP)]Ϫ (pH 6.3) (×),
[Dy(TTDA-H2P)]Ϫ (pH 4.3) (᭿), [Dy(TTDA-HP)]Ϫ (pH 4.3) (᭜),
[Dy(TTDA-H1P)]Ϫ (pH 4.3) (ꢀ) and DyCl3 (᭹) in D2O at 25.0 0.1 ЊC.
H1P and TTDA-H2P are similar; therefore the toxicity of
these two complexes should probably be similar too. Table 2
16
also shows the modified selectivity constants (KselЈ
)
values of
TTDA-PY, TTDA-HP, TTDA-H1P, TTDA-H2P, DTPA and
TTDA at pH 7.4. The log KselЈ of TTDA-PY is higher than
those of DTPA and TTDA and is significantly higher than
those of TTDA-HP, TTDA-H1P and TTDA-H2P. Thus,
TTDA-PY forms a gadolinium() complex that is more stable
than those of [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and
[Gd(TTDA-H2P)]Ϫ toward transmetallation with Ca2ϩ, Zn2ϩ
and Cu2ϩ metal ions at pH 7.4. In other words, the toxicity of
[Gd(TTDA-PY)]Ϫ may be less than those of [Gd(TTDA-HP)]Ϫ,
[Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ.
Dy(III)-Induced 17O water NMR shifts
Fig. 2 shows the Dy()-induced water 17O NMR shifts against
Dy() chelate concentration for solutions of DyCl3,
[Dy(TTDA-PY)]Ϫ, [Dy(TTDA-HP)]Ϫ, [Dy(TTDA-H1P)]Ϫ and
[Dy(TTDA-H2P)]Ϫ in D2O at 25 ЊC. The slopes obtained at pH
= 6.30 and pH = 4.30 are Ϫ71.2(r2 = 0.994) and Ϫ71.1(r2 =
0.994) for [Dy(TTDA-PY)]Ϫ; Ϫ165.0(r2 = 0.992) and Ϫ260.3(r2
= 0.998) for [Dy(TTDA-HP)]Ϫ; Ϫ148.2(r2 = 0.997) and
Ϫ269.5(r2 = 0.992) for [Dy(TTDA-H1P)]Ϫ and Ϫ138.0(r2
=
0.998) and Ϫ231.2 ppm dm3 mmolϪ1(r2 = 0.998) for [Dy(TTDA-
H2P)]Ϫ, respectively. The slope for DyCl3 is Ϫ608.8(r2 = 1.000)
ppm dm3 mmolϪ1 and eight hydration numbers have been pro-
posed for the dysprosium() ion.40–42 Therefore [Dy(TTDA-
PY)]Ϫ, [Dy(DTPA-HP)]Ϫ, [Dy(TTDA-H1P)]Ϫ and [Dy(TTDA-
H2P)]Ϫ complexes at pH 6.30 and pH 4.30 contain 0.9 and
0.9; 2.2 and 3.4; 2.0 and 3.5; 1.8 and 3.0 inner-sphere water
molecules per Dy() ion, respectively. The number of Ln()-
bound water molecules in these complexes provides informa-
tion on the coordination mode of the ligand. The coordination
sites of Gd() ion for the [Gd(TTDA-PY)]Ϫ complex are occu-
pied by one water molecule while eight sites are available for the
TTDA-PY ligand. By binding three amine nitrogen atoms, four
carboxylates and one 2-pyridylmethyl nitrogen atom of the
TTDA-PY backbone, a similar coordination mode as found for
the coordination sites of the previously studied bis(amide)
DTPA derivative and DTPA is attained.22,23,43,44 However, two
coordination sites of Gd() are occupied by two water mol-
ecules and seven sites are available for TTDA-HP, TTDA-H1P
3362
J. Chem. Soc., Dalton Trans., 2001, 3357–3366

View Article Online
Fig. 4 pH dependence of the relaxivity for [Gd(TTDA-PY)]Ϫ), (᭹)
Fig. 3 Temperature dependence of the relaxivity for [Gd(TTDA-
PY)]Ϫ (᭿), [Gd(TTDA-HP)]Ϫ (᭹), [Gd(TTDA-H1P)]Ϫ (ᮀ), [Gd(TTDA-
H2P)]Ϫ (᭝) and [Gd(TTDA)]2Ϫ (᭺) at 20 MHz.
[Gd(TTDA-HP)]Ϫ (᭝), [Gd(TTDA-H1P)]Ϫ (ᮀ), [Gd(TTDA-H2P)]Ϫ
(᭿) and [Gd(TTDA)]2Ϫ (᭺) at 20 MHz and 37 0.1 ЊC.
and TTDA-H2P ligands. The 2-hydroxypropyl, 2-hydroxy-1-
phenylethyl and 2-hydroxy-2-phenylethyl oxygen atom may not
coordinate with Gd() metal ion in the gadolinium()
chelates. This result is also consistent with the conclusion of
the stability studies of [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ
and [Gd(TTDA-H2P)]Ϫ. Moreover, the previous results for the
stability constant values of [Ln(TTDA-PY)]Ϫ are significantly
larger than those of [Ln(TTDA-HP)]Ϫ, [Ln(TTDA-H1P)]Ϫ and
[Ln(TTDA-H2P)]Ϫ chelates.
similar, it is assumed that the outer-sphere relaxivities are simi-
lar. Thus, the observed relaxivity is primarily attributed to the
variation in the inner-sphere contribution. The inner-sphere
relaxivity is mainly dependent on the number of inner-sphere
water molecules in the gadolinium() complex. A larger num-
ber of inner-sphere water molecules leads to a higher relaxivity
r1. The q value of the complex of gadolinium() with TTDA-
PY is similar to those of [Gd(DTPA)]2Ϫ and [Gd(TTDA)]2Ϫ
leading to almost identical r1 values.25,29 The relaxivity values of
[Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ
are higher than those of [Gd(TTDA-PY)]Ϫ, [Gd(TTDA)]Ϫ and
[Gd(DTPA)]2Ϫ; this is undoubtedly due to the larger hydration
number of the gadolinium() complex.
Relaxometric studies of the Gd(III) complexes
The paramagnetic contribution of the solvent longitudinal
relaxivity is obtained using the following equation:45
The relaxivity r1 values for gadolinium() complexes at
various pH values are shown in Fig. 4. The relaxivity r1 curve
of [Gd(TTDA-PY)]Ϫ exhibits no pH dependence over the pH
range 4.0–10.5. In other words, no ligand dissociation occurred
for [Gd(TTDA-PY)]Ϫ in this pH range. It is also concluded that
the hydration number of [Gd(TTDA-PY)]Ϫ remains constant in
this pH range. The observed relaxivity trend is in qualitative
agreement with the previously obtained q values of the
[Gd(TTDA-PY)]Ϫ complex at pH 4.3 and 6.3. When the pH
range is less than 4 the [Gd(TTDA-PY)]Ϫ complex may undergo
partial dissociation resulting in higher relaxivity. The relaxivity
(r1) trends of [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and
[Gd(TTDA-H2P)]Ϫ increase with decreasing pH values over the
pH range 6.0–2.0 as shown in Fig. 4. This could be attributed to
the partial dissociation of Gd() complexes at lower pH values.
Moreover, the hydration numbers of [Gd(TTDA-HP)]Ϫ,
[Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ in the pH range 4–
5 are significantly higher than those at pH 6.3, see Fig. 4. Thus,
the dissociation of the complexes appears to be more complete
for [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-
H2P)]Ϫ than for [Gd(TTDA-PY)]Ϫ in the lower pH 2–6 range.
R1sp = Cq/[55.6(T 1M ϩ τM)]
(1)
Where, C is the molar concentration of the gadolinium()
complex, q is the number of water molecules bound to metal
ion, T 1M is the longitudinal relaxation time of the bound water
protons, and τM is the residence lifetime of the bound water.
Because of the opposite temperature dependence of T 1M and
τM two cases can be considered: (1) fast water-exchange (T 1M ӷ
is
1p
τ ), R increases with decreasing temperature; (2) slow water-
M
is
1p
exchange (T 1M Ӷ τ ), R decreases with decreasing temper-
M
ature. Fig. 3 shows the temperature dependence of the relaxivity
(r1) for the [Gd(TTDA-PY)]Ϫ, [Gd(TTDA-HP)]Ϫ, [Gd(TTDA-
H1P)]Ϫ, [Gd(DTPA-H2P)]Ϫ and [Gd(TTDA)]2Ϫ complexes at
20 MHz in the temperature range 278–343 K. A monoexponen-
tial decrease of the observed relaxivity upon increasing the
temperature in the range 278–343 K was found for these five
gadolinium() complexes. This is characteristic of the fast
chemical exchange behavior which occurs when the residence
lifetime of the coordinated water molecule is much shorter than
the longitudinal relaxation time of the bound water proton.
The longitudinal relaxivity r1 values of [Gd(TTDA-PY)]Ϫ,
[Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ, [Gd(DTPA-H2P)]Ϫ,
[Gd(TTDA)]2Ϫ and [Gd(DTPA)]2Ϫ have been deposited as
ESI (Table 2S). The r1 value of [Gd(TTDA-PY)]Ϫ is similar to
those of [Gd(DTPA)]2Ϫ and [Gd(TTDA)]2Ϫ. However, the
[Gd(TTDA-HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ
are higher than those of corresponding [Gd(DTPA)]2Ϫ, [Gd-
(TTDA)]2Ϫ and [Gd(TTDA-PY)]Ϫ under the same experimental
conditions.16,25 The relaxivity of a paramagnetic metal complex
consists of two components: the inner-sphere and outer-sphere
relaxivities. Since the basic skeleton of these ligands studied
and the shapes and sizes of the gadolinium() complexes are
Water-exchange lifetime studies of the Gd(III) complexes
The measured peak-to-peak line widths, ∆Hpp, of the derivative
spectrum can be related to the overall transverse electronic
relaxation rate, 1/T 2e, via eqn. (2), where gL is the isotropic
Landé g factor (gL = 2.0 for Gd3ϩ).46
(2)
The temperature dependence of transverse electronic relax-
ation rates at the X-band (0.34 T) at pH 7 for 50 mmol dmϪ3
J. Chem. Soc., Dalton Trans., 2001, 3357–3366
3363

View Article Online
solutions of [Gd(TTDA)]2Ϫ, [Gd(TTDA-PY)]Ϫ, [Gd(TTDA-
HP)]Ϫ, [Gd(TTDA-H1P)]Ϫ and [Gd(TTDA-H2P)]Ϫ have been
deposited as ESI (Fig. 12S). The data we obtained from each
compound were fitted simultaneously with the following results
of 17O NMR.
Analysis of the temperature dependence of the transverse
relaxation rate for the 17O water nuclei is the most accurate
method for evaluating the exchange lifetime of the water mole-
cules directly coordinated to the metal in a paramagnetic Gd3ϩ
chelate.47 In principle, the exchange lifetime for the protons on
the coordinated water may result either from the exchange rate
of the whole water molecule (1/τMo ) or/and from the protropic
exchange rate (1/τMH) shown in eqn. (3).47,48 This approach allows
(τM)Ϫ1 = (τMo )Ϫ1 ϩ (τMH)Ϫ1
(3)
assessment of the exchange lifetime of the metal-bound water
oxygen nucleus which, at neutral pH and in non-buffered solu-
tions, corresponds to the exchange lifetime of the metal-bound
water protons, i.e. τM = τMo .47,48
The paramagnetic contribution (R2op) to the observed trans-
o
verse relaxation rate (R2obs) of water 17O nuclei at variable
Fig. 5 Temperature dependence of the transverse water 17O relaxation
rate at 7.05
T and pH 7
for 50 mmol dmϪ3 solutions of
temperature is given by eqn. (4):
[Gd(TTDA)(H2O)]2Ϫ (ꢀ), [Gd(TTDA-PY)(H2O)]Ϫ (᭝), [Gd(TTDA-
HP)(H2O)2]Ϫ (᭿), [Gd(TTDA-H1P)(H2O)2]Ϫ (᭺) and [Gd(TTDA-
H2P)(H2O)2]Ϫ (᭹). The lines represent the simultaneous least-squares
fit to all data points as described in the text.
R2op = R2obs Ϫ R2od
(4)
o
where the diamagnetic term R2od is evaluated from a solution
containing a diamagnetic analogue of the chelate of interest.
R2op is related to τMo through the values of ∆ωMo (the 17O chemical
shift difference between coordinated and bulk water) and R2oM
(the transverse relaxation rate of the coordinated water oxygen)
shown in eqn. (5):19,49
τϪei1 = τMo Ϫ1 ϩ T Ϫ1
(8)
ie
For gadolinium() complexes, T ie values are basically related
to the modulation of the transient zero-field splitting (ZFS) of
the electronic spin states arising from the dynamic distortions
of the ligand field caused by the solvent collision and, accord-
ing to McLachlan,52 in the limit of ωsτv Ӷ 1 they are expressed
by eqns. (9) and (10):
(5)
The temperature dependence of of ∆ωMo is described by eqn.
(6):50
(9)
(6)
(10)
where S is the electronic spin quantum number (7/2 for Gd3ϩ),
B is the applied magnetic field strength, kB is the Boltzmann
_
constant, µB is the Bohr magneton, and A/h is the Gd–17O scalar
where ∆2 is the mean-square zero field splitting energy, τv is
the correlation time for modulation of the zero field splitting
interaction, and ωs is the electronic Larmor frequency. This
modulation may result either from rotation or from transient
distortions of the complex. The temperature dependence of
τv has an Arrhenius behavior as shown in eqn. (11):17
coupling constant, which is related to the unpaired electron spin
density at the 17O nucleus and is mainly dependent on the
distance between the metal ion and the metal-bound 17O
nucleus. For gadolinium() with poly(aminocarboxylate)
chelates this distance does not seem to vary significantly, for the
gadolinium() complexes with TTDA, TTDA-PY, TTDA-HP,
TTDA-H1P and TTDA-H2P derivatives, the same value as was
reported for the closely related [Gd(DTPA)]2Ϫ chelate (Ϫ3.8 ×
106 rad sϪ1)19 was used.
(11)
For gadolinium() chelates, R2oM is dominated by the
electron–nucleus scalar interaction, which is modulated by
the electronic relaxation times T ie (i = 1, 2) or by the exchange
lifetime given by eqn. (7):51
where the subscript j refers to the two different dynamic
processes involved (j = M, v) and ∆Hj is the corresponding
activation enthalpy.
The transverse electronic relaxation of Gd3ϩ in solution was
analyzed with the assumption that the mean transverse elec-
tronic relaxation time can be used to describe the observed line
width.21 The ZFS electronic relaxation mechanism can be due
either to a permanent ZFS modulated by rotation of the com-
plex or to a transient ZFS regulated by random distortions of
the complex.
An accurate determination of the water-exchange rate is
possible by measuring the 17O NMR transverse relaxation
rate (R2op) as a function of temperature.46,48 The results for
(7)
where τei (i = 1, 2) values are the correlation times for the
dynamic processes modulating the scalar interaction. Both the
longitudinal and transverse electronic relaxation times (T 1e and
T 2e), as well as the exchange lifetime of the metal-bound water
molecule, may modulate the scalar interaction. The correlation
time for this process is given by eqn. (8).
3364
J. Chem. Soc., Dalton Trans., 2001, 3357–3366

View Article Online
Table 3 Kinetic and NMR parameters of [Gd(TTDA)(H2O)]2Ϫ, [Gd(TTDA-PY)(H2O)]Ϫ, [Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ,
[Gd(TTDA-H2P)(H2O)2]Ϫ and [Gd(DTPA)(H2O)]2Ϫ as obtained from the simultaneous fit of 17O NMR and EPR data
Complexes
1019 ∆2/sϪ2
τv/ps
τM/ns
∆Hv/J molϪ1
[Gd(TTDA)(H2O)]2Ϫ
4.6 0.2
3.7 0.2
9.7 0.3
9.2 0.3
5.4 0.2
4.6 0.2
25
31
45
45
70
25
1
1
2
1
2
1
10.6 1.3
12.5 1.1
6.7 0.5
7.1 0.9
9.1 0.9
303 35
1.6 1.0
1.5 1.2
1.6 0.9
1.6 1.0
1.3 1.0
1.6 1.8
[Gd(TTDA-PY)(H2O)]Ϫ
[Gd(TTDA-HP)(H2O)2]Ϫ
[Gd(TTDA-H1P)(H2O)2]Ϫ
[Gd(TTDA-H2P)(H2O)2]Ϫ
[Gd(DTPA)(H2O)]2Ϫ a
a Data were obtained from ref. 19.
[Gd(TTDA)(H2O)]2Ϫ,[Gd(TTDA-PY)(H2O)]Ϫ,[Gd(TTDA-HP)-
(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd(TTDA-H2P)-
(H2O)2]Ϫ complexes are plotted in Fig. 5 with the corresponding
curves representing the results of the best fitting of the data
according to eqns. (2)–(11). As there are a large number of
parameters to be determined in the quantitative analysis of
the 17O NMR transverse relaxation rate (R2op) versus T profiles,
the increasing σ-donating strength of the coordinated ligand
leading to an increase in the water-exchange rate.55 However,
the acetate groups are weak σ-donors and the labilizing effect
of the poly(aminocarboxylate) ligands is relatively low,56,59
resulting in a decrease in the water-exchange rate.
The mechanism and the rate of the water-exchange reaction
are affected by the steric constraints of the water binding
site.60,61 The exchange lifetime of [Gd(TTDA-PY)(H2O)]Ϫ,
[Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd-
(TTDA-H2P)(H2O)2]Ϫ is similar to that of [Gd(TTDA)(H2O)]2Ϫ
as shown in Table 3. It is interesting to find that the substitution
of an acetate arm with a pyridylmethyl group, a 2-hydroxy-
propyl group, a 2-hydroxy-1-phenylethyl group or a 2-hydroxy-
2-phenylethyl group on the linear poly(aminocarboxylate)
ligand causes only a slight effect on the exchange lifetime. How-
ever, the exchange lifetime of Gd() complexes with these
five derivatives of TTDA, TTDA-PY, TTDA-HP, TTDA-H1P
and TTDA-H2P is significantly lower than that of [Gd-
(DTPA)(H2O)]2Ϫ. The [Gd(TTDA)(H2O)]2Ϫ and [Gd(DTPA)-
(H2O)]2Ϫ complexes have the same five carboxylate groups, the
longer backbone of the multidentate ligand in the [Gd-
(TTDA)(H2O)]2Ϫ and thus are pulled tightly into the first
coordination sphere. This results in high steric constraints on
the water binding site.58 The overall outcome is an acceler-
ation of the water-exchange rate by one order of magnitude.
Analogous considerations can be made to account for
[Gd(EGTA)(H2O)]Ϫ (EGTA = 3,12-bis(carboxymethyl)-6,9-
dioxa-3,12-diazatetradecanedioate).48 In this complex, two
coordinating oxygen atoms are linked by an ethylenic group,
which induces severe constraints on the atoms around the site
occupied by the water molecule, thus favoring the exchange
process.62 The hydroxyl group oxygen atom in [Gd(TTDA-HP)-
(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd(TTDA-H2P)-
(H2O)2]Ϫ is not found to be coordinated to the metal ion,
though it causes these complexes to be less crowded, and the
two inner-sphere water molecules make the water-exchange rate
faster than that of [Gd(DTPA)(H2O)]2Ϫ.53,58,63
it is convenient to fix some of them. On this basis, besides the
_
value of q and A/h, the value of ∆HM used for all these gad-
olinium() complexes with TTDA, TTDA-PY, TTDA-HP,
TTDA-H1P and TTDA-H2P is 40 kJ molϪ1.53
For these five complexes, a good fit of the data with the
parameters in Table 3 is obtained. At 298 K, the accurate
estimation of τMo values are 10.6 ns, 12.5 ns, 6.7 ns, 7.1 ns and 9.1
ns for [Gd(TTDA)(H2O)]2Ϫ, [Gd(TTDA-PY)(H2O)]Ϫ, [Gd-
(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd-
(TTDA-H2P)(H2O)2]Ϫ, respectively. These values are very close
to the optimal range for the attainment of the high relaxivities
expected when the molecular reorientational time of the com-
plexes is lengthened to the nanoseconds range.54 These five
complexes are of the same order of magnitude suggesting that,
in spite of their hydration number differing by one unit, the
water-exchange may take place through a similar mechanism.
By varying the temperature over a wide range, R2op is domin-
ated by 1/τM in the slow kinetic region at low temperature and is
dominated by 1/τei in the fast kinetic region at high temper-
ature. The maximum in the profiles corresponds to the trans-
lation from the slow to the fast kinetic regions. The maximum
in the profile of 17O NMR transverse relaxation rate (R2op)
versus T could not be found for [Gd(TTDA)(H2O)]2Ϫ, [Gd-
(TTDA-PY)(H2O)]Ϫ, [Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-
H1P)(H2O)2]Ϫ and [Gd(TTDA-H2P)(H2O)2]Ϫ, which indicates
that the water-exchange rate is very fast.
From Table 3, the correlation time for the modulation of the
ZFS (τv) for [Gd(TTDA)(H2O)]2Ϫ, is the same as that of [Gd-
(DTPA)(H2O)]2Ϫ, but smaller than those of [Gd(TTDA-PY)-
(H2O)]Ϫ, [Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ,
and [Gd(TTDA-H2P)(H2O)2]Ϫ complexes, indicating that the
modulation of the transient zero field splitting distortions is
faster for [Gd(TTDA)(H2O)]2Ϫ, and [Gd(DTPA)(H2O)]2Ϫ.
Meanwhile, the electronic relaxation time values are found to be
very short for [Gd(TTDA-HP)(H2O)2]Ϫ and [Gd(TTDA-H1P)-
(H2O)2]Ϫ mainly shown by the high value of mean-square zero
field splitting energy, ∆2.55
Conclusion
The octadentate poly(aminocarboxylate) ligand, TTDA-PY,
forms thermodynamically stable complexes with the trivalent
gadolinium cation. It does not dissociate under physiological
conditions (pH 7.4), and does not exchange with Ca(), Cu()
or Zn() to an appreciable extent. From analysis of the
17O NMR relaxometric properties, the replacement of the
ethylene backbone with a trimethylene backbone will increase
the steric constraints at the water binding site and thereby
increase the water-exchange rate. [Gd(TTDA-HP)(H2O)2]Ϫ,
[Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd(TTDA-H2P)(H2O)2]Ϫ have
higherrelaxivitythan[Gd(TTDA-PY)(H2O)]Ϫbecause[Gd(TTDA-
HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd(TTDA-H2P)-
(H2O)2]Ϫ have similar water-exchange rates and sizes, the
increased relaxivities are due to the presence of two water
molecules in the inner coordination sphere. The thermo-
dynamic studies have shown that [Gd(TTDA-HP)(H2O)2]Ϫ,
[Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd(TTDA-H2P)(H2O)2]Ϫ are
The rate of water-exchange from the inner-sphere of a metal
ion is affected strongly by the substitution of one or more water
molecules by a coordinated ligand. For the complexes of the
first-row transition elements there are a lot of experimental
data showing that multidentate ligands increase significantly
the rate of exchange of the remaining water molecules.56 Con-
trary to these results, the water-exchange rate was found to be
lower for the [Gd(TTDA)(H2O)]2Ϫ, [Gd(TTDA-PY)(H2O)]Ϫ,
[Gd(TTDA-HP)(H2O)2]Ϫ, [Gd(TTDA-H1P)(H2O)2]Ϫ and [Gd-
298
(TTDA-H2P)(H2O)2]Ϫ complexes (k = 9.4 × 107, 8.0 × 107,
ex
1.5 × 108, 1.4 × 108 and 1.1 × 108 sϪ1, respectively) than that
298
for [Gd(H2O)8]3ϩ (k
= 1.19 × 109 sϪ1).57 The data for
ex
[Gd(DTPA)(H2O)]2Ϫ, Table 3, show the same trend58 owing to
J. Chem. Soc., Dalton Trans., 2001, 3357–3366
3365

View Article Online
26 Y. M. Wang, Y. J. Wang, R. S. Sheu, G. C. Liu, W. C. Lin and J. H.
Liao, Polyhedron, 1999, 18, 1147.
27 Y. M. Wang, Y. J. Wang, G. C. Liu and Y. T. Kuo, J. Chin. Chem.
Soc., 1999, 46, 551.
28 T. H. Cheng, Y. M. Wang, W. T. Lee and G. C. Liu, Polyhedron,
2000, 19, 2027.
29 M. C. Alpoim, A. M. Urbano, C. F. G. C. Geraldes and J. A. Peters,
J. Chem. Soc., Dalton Trans., 1992, 463.
not stable enough to be MRI contrast agents. On the other
hand, [Gd(TTDA-PY)(H2O)]Ϫ has adequate relaxivity, a
slightly higher thermodynamic stability constant than
[Gd(DTPA)(H2O)]2Ϫ, and an optimal water-exchange rate which
make this chelate a very interesting blood pool contrast agent
for MRI. Moreover, these four Gd() chelates may be very
suitable for linking to high-molecular weight carriers.
30 C. A. Chang, H. G. Brittain, J. Telser and M. F. Tweedle, Inorg.
Chem., 1990, 29, 4468.
31 W. R. Harris and A. E. Martell, Inorg. Chem., 1976, 15, 713.
32 Y. Li, A. E. Martell, R. D. Hancock, J. H. Reibenspies, C. J.
Anderson and M. J. Welch, Inorg. Chem., 1996, 35, 404.
33 C. H. Taliaferro, R. J. Motekaitis and A. E. Martell, Inorg. Chem.,
1984, 23, 1188.
34 R. M. Smith and A. E. Martell, Critical Stability Constants, Plenum,
New York, 1975, vol. 1–4.
Acknowledgements
We are grateful to the National Science Council of the Republic
of China for financial support under Contract No. NSC 88-
2113-M037-016.
35 A. E. Martell and R. J. Motekaitis, Determination and Use of
Stability Constants, 2nd edn., VCH, New York, 1992.
36 D. L. Wright, J. H. Holloway and C. N. Reilley, Anal. Chem., 1965,
37, 884.
37 P. K. Tse and J. E. Powell, Inorg. Chem., 1985, 24, 2720.
38 P. Caravan, P. Mehrhodavandi and C. Orvig, Inorg. Chem., 1997, 36,
1316.
39 W. R. Harris, K. N. Raymond and F. L. Weitl, J. Am. Chem. Soc.,
1981, 103, 1316.
40 T. Kowall, F. Foglia, L. Helm and A. E. Merbach, J. Am. Chem.
Soc., 1995, 117, 3790.
References
1 P. Caravan, J. J. Ellison, T. J. McMurry and R. B. Lauffer, Chem.
Rev., 1999, 99, 2293.
2 M. Botta, Eur. J. Inorg. Chem., 2000, 399.
3 S. Aime, A. Barge, J. I. Bruce, M. Botta, J. A. K. Howard, J. M.
Moloney, D. Parker, A. S. de Sousa and M. Woods, J. Am. Chem.
Soc., 1999, 121, 5762.
4 E. Tóth, L. Burai, E. Brücher and A. E. Merbach, J. Chem. Soc.,
Dalton Trans., 1997, 1587.
5 J. Platzek, P. Blaszkiewicz, H. Gries, P. Luger, G. Michl, A.
Müller-Fahrnow, B. Radüchel and D. Sülzle, Inorg. Chem., 1997,
36, 6086.
41 C. Cossy, L. Helm, D. H. Powell and A. E. Merbach, New J. Chem.,
1995, 19, 27.
6 C. F. G. C. Geraldes, A. M. Urbano, M. C. Alpoim, A. D. Sherry,
K.-T. Kuan, R. Rajagopalan, F. Maton and R. N. Muller, Magn.
Reson. Imaging, 1995, 13, 401.
7 F. Uggeri, S. Aime, P. L. Anelli, M. Botta, M. Brocchetta, C. Haen,
G. Ermondi, M. Grandi and P. Paoli, Inorg. Chem., 1995, 34, 633.
8 C. A. Chang, Invest. Radiol., 1993, 28, S21.
9 K. Kumar and M. F. Tweedle, Pure Appl. Chem., 1992, 65, 515.
10 K. Kumar, C. A. Chang and M. F. Tweedle, Inorg. Chem., 1993, 32,
587.
11 K. Kumar and M. F. Tweedle, Inorg. Chem., 1993, 32, 4183.
12 K. Kumar, C. A. Chang, L. C. Francesconi, D. D. Dischino, M. F.
Malley, J. Z. Gougoutas and M. F. Tweedle, Inorg. Chem., 1994, 33,
3567.
42 C. Cossy, A. C. Barnes, J. E. Enderby and A. E. Merbach, J. Chem.
Phys., 1989, 90, 3254.
43 J. A. Peters, Inorg. Chem., 1988, 27, 4686.
44 S. W. A. Bligh, A. H. M. S. Chowdhury, M. McPartlin, I. J. Scowen
and R. A. Bulman, Polyhedron, 1995, 14, 567.
45 T. J. Swift and R. E. Connick, J. Chem. Phys., 1962, 37, 307.
46 J. Reuben, J. Phys. Chem., 1971, 75, 3164.
47 S. Aime, M. Botta, S. G. Crich, G. Giovenzana, R. Pagliarin, M.
Sisti and B. Terreno, Magn. Reson. Chem., 1998, 36, S200.
48 S. Aime, M. Botta, M. Fasano and E. Terreno, Acc. Chem. Res.,
1999, 32, 941.
49 S. Aime, M. Chiaussa, G. Digilio, E. Gianolio and E. Terreno,
J. Biol. Inorg. Chem. (JBIC), 1999, 4, 766.
13 K. Kumar, M. F. Tweedle, M. F. Malley and J. Z. Gougoutas, Inorg.
Chem., 1995, 34, 6472.
14 C. Paul-Roth and K. N. Raymond, Inorg. Chem., 1995, 34, 1408.
15 M. F. Tweedle, J. J. Hagan, K. Kumar, S. Mantha and C. A. Chang,
Magn. Reson. Imaging, 1991, 9, 409.
16 W. P. Cacheris, S. C. Quay and S. M. Rocklage, Magn. Reson.
Imaging, 1990, 8, 467.
50 N. Bloembergen, J. Chem. Phys., 1957, 27, 595.
51 L. Banci, I. Bertini and C. Luchinat, Nuclear and Electron
Relaxation, VCH, Weinheim, 1991.
52 A. D. McLachlan, Proc. R. Soc. London, Ser. A, 1964, 280, 271.
53 S. Aime, E. Gianolio, E. Terreno, G. B. Giovenzana, R. Pagliarin,
M. Sisti, G. Palmisano, M. Botta, M. P. Lowe and D. Parker, J. Biol.
Inorg. Chem. (JBIC), 2000, 5, 488.
17 G. González, D. H. Powell, V. Tiddières and A. E. Merbach, J. Phys.
Chem., 1994, 98, 53.
18 S. Aime, M. Botta, M. Fasano, S. Paoletti, P. M. Anelli, P. M. Uggeri
and M. Virtuani, Inorg. Chem., 1994, 33, 4707.
19 D. H. Powell, O. M. Ni Dhubhghaill, D. Pubanz, L. Helm, Y. S.
Lebedev, W. Schlaepfer and A. E. Merbach, J. Am. Chem. Soc.,
1996, 118, 9333.
54 S. Aime, M. Botta, M. Fasano and E. Terreno, Chem. Soc. Rev.,
1998, 27, 19.
55 S. Deibig, E. Tóth and A. E. Merbach, J. Am. Chem. Soc., 2000, 122,
5822.
56 D. W. Margerum, G. R. Cayley, D. C. Weatherourn and G. K.
Pagenkopf, in Coordination Chemistry, A. E. Martell, ed., American
Chemical Society, Washington, DC, 1978, vol. 2.
57 R. V. Southwood-Jones, W. L. Rari, K. E. Newman and A. E.
Merbach, J. Chem. Phys., 1980, 73, 5909.
20 K. Micskei, L. Helm, E. Brücher and A. E. Merbach, Inorg. Chem.,
1993, 32, 3844.
21 D. H. Powell, A. E. Merbach, G. González, E. Brücher, K. Micskei,
M. F. Ottaviani, K. Köhler, A. von Zelewsky, O. Ya. Grinberg and
Y. S. Lebedev, Helv. Chim. Acta, 1993, 76, 2129.
22 Y. M. Wang, T. H. Cheng, G. C. Liu and R. S. Sheu, J. Chem. Soc.,
Dalton Trans., 1997, 883.
23 Y. M. Wang, T. H. Cheng, R. S. Sheu, I. T. Chen and M. Y. Chiang,
J. Chin. Chem. Soc., 1997, 44, 123.
58 K. Micskei, D. H. Powell, L. Helm, E. Brücher and A. E. Merbach,
Magn. Reson. Chem., 1993, 31, 1011.
59 R. B. Lauffer, Chem. Rev., 1987, 87, 901.
60 D. Pubanz, G. González, D. H. Powell and A. E. Merbach, Inorg.
Chem., 1995, 34, 4447.
61 N. Graeppi, D. H. Powell, G. Laurenczy, L. Zékány and A. E.
Merbach, Inorg. Chim. Acta, 1995, 235, 311.
24 Y. M. Wang, S. T. Lin, Y. J. Wang and R. S. Sheu, Polyhedron, 1998,
17, 2021.
25 Y. M. Wang, C. H. Lee, G. C. Liu and R. S. Sheu, J. Chem. Soc.,
Dalton Trans., 1998, 4113.
62 S. Aime, A. Barge, A. Borel, M. Botta, S. Chemerisov, A. E.
Merbach, U. Müller and D. Pubanz, Inorg. Chem., 1997, 36, 5104.
63 É. Tóth, L. Helm, A. E. Merbach, R. Hedinger, K. Hegetschweiler
and A. Jánossy, Inorg. Chem., 1998, 37, 4104.
3366
J. Chem. Soc., Dalton Trans., 2001, 3357–3366