| Summary: | This work describes work related to the search for new and improved MRI contrast agents. It is
a focused study that describes the synthesis and characterization of three novel macrocyclic
ligands, two of which incorporates a pendant β-amino alcohol (cyclohexyl) arm for complexation
with Eu3+ and Gd3+. The target products were synthesized successfully in quantitatively high
yields and confirmed using general analytical characterization techniques including NMR, ESIMS,
FTIR and in some cases X-ray crystallography.
Crystal structures of two of the N-substituted cyclen based ligands, namely molecules 2 and 3 are
reported. They both formed in the monoclinic crystal system and found to be in the P21/c and
P21/n space group, respectively. Although 2 crystallized as a free base, 3 formed a complex with
sodium with iodide as a counter ion. In addition, three lanthanide crystal structures are reported
and each adopts a distorted capped square anitiprismatic geometry. Molecule 2 formed crystals
with both Eu3+ and Gd3+ to give molecule 5 and 6, respectively. They both formed in the
triclinic and orthorhombic crystal system and found to be in the P-1 and Pcca space group,
respectively. Efforts to grow lanthanide crystals with 7 failed, however its Eu3+ complex was
satisfactorily synthesized. For comparative purposes molecule 9 was synthesized and the crystal
structure is reported.
In an effort to elucidate the solution structure of these new Eu3+ complexes in the absence and
presence of KHP, their interaction with the metal center and ligand were studied further using
luminescence and UV-visible analyses to determine pKas spectroscopically. Comparing the pKa
for the hydrolysis of water in 5 and 9 in MCB with KHP, it was observed that the pKa for 5 is
larger. This increase is attributed to the compression induced by the cyclohexyl moiety which
consequently causes an overall decrease in bond distance between the metal center and amidic
oxygen donors as shown in the solid-state data. Furthermore, the hydrophobic nature of the
cyclohexyl side arm which replaces one of the acetamide arms in 9 also contributes to the overall
decrease in pKa observed. Comparing the pKa for the hydrolysis of water in 5 and 7 in MCB
excluding KHP, again it was observed that the pKa for 5 is larger. The coordinated water in 5 appears to be more acidic than for 7, possibly due to the weaker inductive effect of 7 which
possess arms that are of a sp3 nature and impossible to deprotonate.
In addition, the number of coordinated water molecules (q) to the metal center were determined
using luminescent lifetime measurements and corrected for the estimation according to structural
functionalities innate to the complexes in this study. In solution, the q values obtained agreed
well with the proposition that the phthalate moiety coordinates with the central Eu3+ ion in a
unidentate fashion and maintains a nine coordination number. The q values also agree with
luminescent spectroscopic data which shows two valid spectroscopic pKas; the deprotonation of
the phthalate carboxylate and the deprotonation of the water molecule coordinated to the metal
center. The mean pKa values were found to be pK1 = 4.67 ± 0.06 and pK2 = 8.69 ± 0.12,
respectively. The q values obtained for 5 in MCB with KHP from pH 4.710 and 9.484 ranged
from 1.77 to 0.70 using Equation 3.1 and from 1.79 to 0.72 using Equation 3.2, respectively. It
is proposed that the due to the coordination of the phthalate moiety the hydroxyl group of the
cyclohexyl moiety no longer coordinates itself to the metal center. The q values obtained for 5 in
water from pH 4.375 and 8.645 ranged from 0.94 to 0.55 using Equation 3.1 and from 0.95 to
0.56 using Equation 3.2, respectively. The slight increase in the q value is attributed to the
hydrogen bonding the cyclohexyl group is involved in with water molecules in the second
coordination sphere which is very close to 0.5.
Finally, the electrochemical behavior of complex 5 and 9 across the pH range were investigated
using CV. Only a single electrochemically active species exists for both complexes. The results
for 5 show that the metal is encapsulated between pH 3 to 10 (E1/2 = -0.83 V), however above pH
11 the complex is demetalated (E1/2 = -1.02 V). The results for 9 show that the metal is
encapsulated between pH 3 to 10 (E1/2 = -0.83 V), however below pH 11 the complex shows a
decrease in overall current (E1/2 = -0.90 V). This result shows that complex 9 is more resistant to
oxidation as compared to complex 5, meaning that having four acetamide arms at higher pH is
better than having three. This difference can also be related to the role and tautomeric effect of
the amidic arms in stabilizing the complex. In addition, the standard rate constant was
determined for electron transfer and is close to 1.0 for both complexes investigated, which means
the reductions in both complexes are not diffusion controlled but the electrochemically active species are adsorbed on the electrode surface. The above electrochemical results show that the
metal remains encapsulated for most of the pH range and only becomes toxic free metal above
pH 11. This vast pH range of complex intactness is a favorable attribute if it were to be
considered in its application as a potential MRI agent.
Key words: MRI, europium(III), gadolinium(III), polyazamacrocycles, luminescence, cyclic
voltammetry, MRI contrast agent.
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