mL) was reacted at 130 °C for 2–4 h. After cooling, the inorganic salts were
discarded by filtration and the solvent removed under reduced pressure. The
residue was taken up with dilute HCl (0.1 M, 20 mL) and the formed solid
collected and recrystallized from H2O. 1 (78%): mp 213 °C; 1H NMR (300
MHz, DMSO-d6): d 8.79 (dd, J = 5.0, 1.7, H-6); 8.22 (d, J = 8.0, H-3); 8.08
(td, H-4); 7.63 (dd, J = 8.0, H-5). 3 (76%): mp > 240 °C; 1H NMR (300
MHz, DMSO-d6): d 9.18 (d, J = 2.0, H-2); 8.47 (dd, J = 8.3, 2.0, H-4); 8.44
(d, J = 8.0, –CONH–); 8.32 (d, J = 8.0, H-5); 4.70 (s, OH); 4.01 (dtt, J =
8.0, 5.8, 5.8, CH); 3.60–3.48 (m, CH2). Ligands 2 and 4. A mixture of parent
pyridyltetrazole (6.8 mmol) and m-chloroperbenzoic acid (11.6 mmol) in
MeOH (200 mL) was reacted overnight at room temperature without
stirring. 2 (66%) was isolated by filtration and recrystallized from H2O. mp
> 240 °C; 1H NMR (300 MHz, DMSO-d6): d 8.56 (d, J = 6.4, H-6); 8.41
(dd, J = 7.8, 2.1, H-3); 7.66 (td, H-4); 7.63 (dd, J = 7.7, H-5). 4 (80%) was
isolated by evaporating the solvent and, after washing the solid with CH2Cl2
(300 mL), recrystallized from EtOH/H2O. mp > 240 °C; 1H NMR (300
MHz, DMSO-d6): d 8.97 (s, H-2); 9.49 (d, J = 8.5, H-4); 8.53 (d, J = 8.5,
– CONH–); 7.92 (d, J = 8.5, H-5); 4.70 (s, OH); 4.01 (m, CH); 3.60–3.40
(m, CH2).
Fig. 1 Crystal structure of Gd(12)3 and Gd(22)3.
ligands and three/two H2O molecules, respectively. The different
coordination number probably reflects the dissimilar steric require-
ments3 of a five- versus a six-membered chelation motif for 1 and
2, respectively. Interestingly, three/five additional H2O molecules
are present in the second coordination sphere, suggesting large
relaxivity values. The geometry of Zn(22)2 (Figure S2†) is
octahedral with two equatorial ligands and two H2O molecules in
the axial positions.
Ligands 1–4 and the corresponding Gd(III) chelates are highly
soluble in H2O. Chelate solubility increases going from the
unsubstituted 1 (2.1 g L21) and 2 (4.7 g L21)) to the hydroxyalkyl-
substituted 3 (25.6 g L21) and 4 (21.2 g L21) systems. An
additional requirement for practical application of Gd(III) com-
plexes is thermodynamic stability, to avoid toxicity of the metal.
Potentiometric data obtained by titration of a Gd:LH (LH = 1 and
2, Figs. S3 and S4†) mixture in the pH range of 2–5 (T = 298 K,
I = 0.1 M) can be fitted assuming the stepwise addition of up to
three L2 to the Gd ion,7 leading to a cumulative stability constant
(logb) values of 6.7(2) and 8.66(7) for Gd(12)3 and Gd(22)3,
respectively. As expected, these values are lower than those of
approved CAs based on macrocycle octadentate ligands ( >
15.8).3
Finally, the relaxivity r1 is the key property of a potential contrast
agent. Measurements were performed at pH = 5.7–7.2 and r1
values (mM21 s21) were obtained from the slope of a plot of 1/T1
vs. [GdL3] (concentration range 0.2–1 mM, Fig. S5†) and were
found to be: Gd(12)3 (9.98); Gd(22)3 (9.25); Gd(32)3 (10.79);
Gd(42)3 (17.72). These very high values cannot be explained solely
on the basis of a large number of water molecules probably
coordinating the metal ion in aqueous solution. Rather, very fast
exchange between inner/outer sphere water molecules with the bulk
H2O might be involved, as suggested for complexes of heptadentate
ligands.8
§ Crystal Structure. All measurements were made on a Bruker SMART
CCD diffractometer with graphite monochromated MoKa (0.71073 Å)
radiation. The data were collected at a temperature of 153(2) K and the
structures were solved by direct methods and expanded using Fourier
techniques using SHELXTL. All non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were included in idealized positions and
not refined. Intensities were corrected for absorption. Gd(12)3. Monoclinic,
P2(1)/n, Z = 4. Cell dimensions: a = 9.0273(9) Å; b = 17.714(3) Å; c =
16.7480(19) Å; a = 90°; b = 99.819(9)°; g = 90.00°. V = 2639.0(6) Å3,
rcalcd = 1.794 g cm23, total/independent reflections = 24502/6489, R(int)
= 0.0415, R = 0.0280. Zn(22)2. CCDC 232483.Monoclinic, C2/c, Z = 8.
Cell dimensions: a = 31.01(2) Å; b = 8.561(4) Å; c = 7.546(3) Å; a =
90°; b = 100.65(5)°; g = 90°. V = 1968.8(18) Å3, rcalcd = 1.875 g cm23
,
total/independent reflections = 8819/2401, R(int) = 0.0564, R = 0.0469.
Gd(22)3. CCDC 232481. Monoclinic, P2(1)/n, Z = 4. Cell dimensions: a =
7.847(3) Å; b = 39.783(7) Å; c = 9.092(3) Å; a = 90°; b = 96.50(3)°; g
= 90.00°. V = 2820.0(2) Å3, rcalcd = 1.780 g cm23, total/independent
reflections = 18878/5168, R(int) = 0.0393, R = 0.0762. CCDC 232482.
in .cif or other electronic format.
1 (a) The Chemistry of Contrast Agents in Medical Magnetic Resonance
Imaging, eds. A. Merbach and E. Toth, John Wiley and Sons, New York,
2001; (b) S. Aime, M. Botta, M. Fasano and E. Terreno, Acc. Chem. Res.,
1999, 32, 941; (c) P. Caravan, J. J. Ellison, T. J. McMurry and R. B.
Lauffer, Chem. Rev., 1999, 99, 2293; (d) S. H. Koenig and R. D. Brown
III, Prog. NMR Spectrosc., 1990, 22, 487; (e) B. L. Engelstad and G. L.
Wolf, in Magnetic Resonance Imaging, eds. D. D. Stark and W. G.
Bradley, Jr., The C. V. Mosby Company, St. Louis, 1988.
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Vander Elst, M. Port, I. Raynal, C. Simonot and R. N. Muller, Eur. J.
Inorg. Chem., 2003, 2495; (c) K. Kimpe, T. N. Parac-Vogt, S. Laurent, C.
Pierart, L. Vander Elst, R. N. Muller and K. Binnemans, Eur. J. Inorg.
Chem., 2003, 3021; (d) R. D. Bolskar, A. F. Benedetto, L. O. Husebo, R.
E. Price, E. F. Jackson, S. Wallace, L. J. Wilson and J. M. Alford, J. Am.
Chem. Soc., 2003, 125, 5471; (e) M. K. Thompson, M. Botta, G. Nicolle,
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J., 2001, 7, 600.
In summary, we described here new bidentate ligand motifs
based solely on heteroaromatic units and leading to water-soluble
neutral chelates. The Gd(III) complexes exhibit a large number of
coordinated H2O molecules and Gd(42)3 exhibits the highest r1
values reported to date for a low molecular weight molecule.
Thanks to the facile functionalization of the pyridine ring,
incorporation of these chelating motifs into a single tripodal
hexadentate structure should greatly improve stability (necessary
for application) and retain the intrinsic high relaxivity. Starting
from these large values, r1 can be further improved by ligand
incorporation into slower rotational motion substrates such as
proteins, dendrimers, and polysaccharides,1,2 as demonstrated
successfully for functionalized DTPA-protein bound (r1 ~ 50
3 Contrast Agents I/Magnetic Resonance Imaging., Ed. W. Krause, Topics
in Current Chemistry, Springer, Berlin, 2002, Vol 221.
4 (a) R. N. Muller, B. Raduchel, H. R. Maecke and A. E. Merbach, Eur. J.
Inorg. Chem., 1999, 1949; (b) É. Tóth, F. Connac, L. Helm, K. Adzamli
and A. E. Merbach, J. Biol. Inorg. Chem., 1998, 3, 606; (c) S. Aime, M.
Botta, S. G. Crich, G. Giovenzana, M. Sisti and E. Terreno, J. Biol. Inorg.
Chem., 1997, 2, 470; (d) É. Tóth, D. Pubanz, S. Vauthey, L. Helm and A.
E. Merbach, Chem. Eur. J., 1996, 2, 1607; (e) V. S. Vexler, O. Clement,
H. Schmitt-Willich and R. C. Brasch, J. Magn. Res. Imaging, 1994, 4,
381.
mM21 21 4a
s
)
and DOTA-dendrimer (r1 ~ s )
15–19 mM21 21
systems.4d Efforts in this direction are in progress.
This work was supported by grants MURST II (0103-97) and
NSF CHE-0078998.
5 A. R. Katritzky in, Handbook of Heterocyclic Chemistry, Pergamon
Press, Oxford, 1985.
6 J. M. Mc Manus and R. M. Herbst, J. Org. Chem., 1959, 24, 1462.
7 Potentiometric data were analysed using HYPERQUAD program . P.
Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739.
Notes and references
‡
Synthetic details. Ligands 1 and 3. A mixture of parent cyanopyridine
8 Y. Bretonniere, M. Mazzanti, J. Pecaut, F. A. Dunand and A. E. Merbach,
Chem. Commun., 2001, 621.
(5.3 mmol), NaN3 (8.0 mmol), NH4Cl (8.0 mmol) in anhydrous DMF (27
C h e m . C o m m u n . , 2 0 0 4 , 1 7 7 0 – 1 7 7 1
1771