III. 3.3. [Sc(Y)-DOTA] 3+ /[Sc(Y)-DOTA(H 2 O)] 3+ complexes
III.4. Study of the phosphonic derivatives of DOTA-type ligands
III.4.2. Scandium and yttrium–complexes with monophosphonic DOTA analogs 164
As referred before, polyazamacrocycles with different pendant arms, such as DOTA, DOTA - derivatives or DOTP strongly chelate lanthanide ions. Moreover, the thermodynamically stable complexes formed with such chelators are also, in general, kinetically inert, a desirable feature for their in vivo application, as bifunctional chelating agent [135]. Thus, substitution of one acetic acid arm in DOTA for a phosphonic/phosphinic acid arm may lead to a faster complex formation while preserving thermodynamic stability and kinetic inertness of the complexes formed [37]. Thus, we decided to study the monophosphonic/phosphinic acid derivatives principally the H5DO3AP and H5DO3APPrA ligands (figure 5), in order to understand the influence of the phosphonic acid pedant arm on the Scandium complexes formed, and compare the results with the Sc(DOTA) complexes. Simultaneously, in order to determine the effect that can have the atomic radius, we were also interested in studying complexation of these ligands with yttrium (III) ion.
Figure 5: Structure of the studied ligands
For scandium(III) and yttrium(III) complexes with both H5DO3AP and H5DO3APPrA ligands, a first optimisation step was carried out using the B3LYP chemical model with a AugCCpVDZ basis set (BS2), but the computation time was so long and convergence criteria are not met. For this reason, we have performed again structure optimization using the small basis set 6-31G* (BS0). For comparison, calculations were also performed with DOTA ligand using the same basis set with both scandium(III) and yttrium(III) ions.
165
Binding energies of the macrocyclic ligands in the corresponding complexes were calculated as the energy of the complex less than that of the metal ion and that of the ligand, including non-potential-energy contributions (zero-point energies) obtained through frequency analysis.
The results obtained for both Sc(III) and Y(III) with selected ligands , such as complexation energy and distance between the metal ion and the surrounding atoms are summarized in Table 5. The optimized structures for all the complexes studied either with Sc(III) or Y(III) are given in Figure 6 .
Figure 6: Structures of the Sc (Y)-monophosphonic DOTA analogs complexes (C1 symmetry)
[Sc-HDO3AP]-1
[Y-HDO3AP]-1
[Sc-HDO3APPrA]-1
[Y-HDO3APPrA]-1
166 Table 5
Sc (Y)-DOTA and monophosphonic DOTA analogs binding energy, Sc-N/Y-N and Sc-O/Y- O average distance, Sc-P/Y-P distance for Sc (Y)-complexes with studied ligands
complex symmetry BS0
ΔE(KJ/mol) R(M-O), Å (CH3PO3)-2
R(M-O), Å (CH3CO2)-1
R(M-N), Å R(M-P), Å
[Sc-DOTA]-1 C4_SAP -6431.294 / 2.088x4 2.650x4 /
[Sc-DO3AP]-2 C1 -7101.595 1.942 2.137
2.127 2.152
2.666 2.835 2.624 2.843
3.278
[Sc-HDO3AP]-1 C1 -6274.841 2.090 2.091
2.086 2.072
2.622 2.658 2.747 2.666
3.308
[Sc-DO3APPrA]-2 C1 -8419.996 2.020 2.102
2.106 2.106
2.733 2.662 2.759 2.664
3.298
[Sc-HDO3APPrA]-1 C1 -6312.667 2.074 2.086
2.107 2.074
2.640 2.658 2.603 2.753
3.321
[Y-DOTA]-1 C4_SAP -5195.559 / 2.267x4 2.711x4 /
[Y-DO3AP]-2 C1 -6673.686 2.138 2.308
2.329 2.304
2.730 2.832 2.688 2.845
3.425
[Y-HDO3AP]-1 C1 -5837.285 2.270 2.254
2.264 2.269
2.718 2.696 2.776 2.728
3.458
[Y-DO3APPrA]-2 C1 -7990.067 2.210 2.289
2.285 2.280
2.785 2.718 2.727 2.769
3.437
[Y-HDO3APPrA]-1 C1 -5872.863 2.256 2.256
2.281 2.264
2.711 2.775 2.720 2.686
3.460
167
In the case of DFT calculations, we have used the optimized structure of DOTA with a C4 symmetry and SAP configuration, then replaced a carboxylic group with a monophosphonic group, after optimization a structure with C1 symmetry was obtained for both monophosphonic DOTA analogs complexes with Sc(III) and Y(III) ions respectively. Several X-ray structures of lanthanide complexes with the HDO3AP ligand, in which the phosphonate group was protonated, were reported [136,137].
The first structure of the [Sc-DO3AP]-2complex was obtained. The three Sc-O distances from the acetate arms are relatively higher than those of the Sc-DOTA complex. However the Sc-O distance from the carboxylate in the phosphorus acid chain is the lowest one compared to the Sc-O distance from the acetate arms. The Sc-N distances are relatively the same or higher than the Sc-DOTA complex. However, for the [Sc-HDO3AP]-1 complex, practically all the Sc-O and Sc-N distance remain unchanged compared to the [Sc-DOTA]-1 complex, the binding energy is lower in the presence of the DOTA moiety relative to the DO3AP once protonated.
In the case of [Sc-HDO3APPrA]-1 complex, binding energy is somewhat lower than the [Sc- HDO3AP]-1 but higher than that obtained for the [Sc-DOTA]-1 complex. Thus, the [Sc- DOTA]-1 complex remains more stable compared to the Sc(III) complexes with the monophosphonic DOTA analogs, in which the phosphonate group was protonated.
In contrast, DFT calculations performed on Y(III)-complexes with selected ligands, show that both [Y-DO3AP]-2 and [Y-HDO3AP]-1 form complexes with the lowest binding energy thus more stable than the Y(III) complex formed with DOTA moiety. However all the complexes formed with Y(III) ions are somewhat less stable compared to that formed with Sc(III) ion.
168
Conclusion
In this chapter, we were interested principally to study the Sc(III) complexes formed with different molecules and ligands. The studies performed consist on ab initio calculations in vacuo, using hybrid DFT with the restricted B3LYP exchange correlation functional and the Gaussian 09 package. First studies were performed on [Sc(H2O)n]3+ (n=1-10) clusters, the present results indicate that the Sc3+ ion is primarily hexa-coordinated; the presence of six water molecules in the first coordination shell contributes more to the stability of the scandium complexes. Then, In order to more understand the affinity of both ammonia and water molecules to the Sc(III) ion, the [Sc(NH3)n]3+ complexes were studied and some exchange reactions were performed. Results obtained show that, ammonia bond less strongly than water.
We have then, studied the complexes formed from Cyclen moiety which constitutes the basis of the DOTA chelator with scandium (III) ion, then compared the results with complexes obtained with yttrium (III) ion. For both (M-Cyclen)3+ complexes , one conformer with C4
geometry gives the lowest binding energy. However Sc(III) form more stable complex with Cyclen compared to Y(III) ion.
Finally, studies performed on Sc (III) and Y(III) complexes with DOTA and phosphonic derivatives of DOTA-type ligands, showed that both Sc (III) and Y(III) complexes share similar structures. However the Sc(III) ion forms most stable complexes with studied ligands compared the Y(III) ion. Also, complexes formed with DOTA chelator are somewhat more stable than those formed with monophosphonic DOTA analogs.
169