Extraordinary kinetic inertness of lanthanide(iii) complexes of pyridine-rigidified 18-membered hexaazamacrocycles with four acetate pendant arms

Abstract

Large polyazamacrocycles are used for the complexation of large metal ions. However, their coordination chemistry has not been frequently studied until now. An eighteen-membered macrocycle with two rigidifying pyridine rings and four aliphatic amino groups substituted with four acetic acid pendants, H₄pyta, provides a large ligand cavity and coordination number (CN) up to 10. Trivalent lanthanides were chosen to study the effect of metal ion size on the properties of H₄pyta complexes. The complexes were formed under relatively mild conditions and two isomers were observed, depending on the Ln(iii) ion, in different mutual ratios during the synthesis. Going to smaller Ln(iii) ions, the CN decreases from 10 to 9. Stability constants of Ln(iii)-H₄pyta complexes with CN 10 are comparable with those of Ln(iii)-H₄dota complexes despite the lower overall basicity of H₄pyta. In the ten-coordinated isomers, Ln(iii) ions are perfectly 3D-wrapped inside the ligand cavity, and the ligand is minimally distorted. It leads to extreme kinetic inertness of the complexes. Dissociation of the Ln(iii)-H₄pyta complexes in 5 M HClO₄ and at 90 °C is very slow and requires up to several hours; the inertness is 10²-10⁴ times higher than that of the Ln(iii)-H₄dota complexes. The solid-state structures point to the symmetric wrapping of metal ions and CN 10 being responsible for the stability of species multiply protonated on the coordinated acetate groups. The results suggest that H₄pyta can be considered a leading scaffold for the future development of ligands intended for large metal ion binding in nuclear medicine, e.g. for α-emitting radioisotopes from the bottom of the periodic table.

Fig. 1. Structures of ligands mentioned in the text.

Fig. 2. Molecular structures of the ²²[Eu(pyta)]⁻ anion (CN 10) found in the crystal structure of Na²²[Eu(pyta)]·13.5H₂O (A) and one of the two structurally independent ²¹[Eu(Hpyta)] molecules (CN 9) present in the crystal structure of ²¹[Eu(Hpyta)]·3H2O (B). Superscripts 22 and 21 refer to complexes with CN 10 and 9, respectively (for more explanation, see the text). Carbon-bound hydrogen atoms are omitted for clarity. Colour codes: Eu: green, O: red, N: blue, C: dark grey, and H: white. A complete atom labelling scheme is given in the ESI (Fig. S8†).

Fig. 3. Compositions of the final reaction mixtures after synthesis (pH 6–7 and 60 °C) of the Ln(iii)–H₄pyta complexes determined by analytical HPLC. The 22 isomers are in blue and the 21 isomers are in green. The error bars and the average abundances are based on three independent preparations.

Fig. 4. Half-lives ^dτ_1/2 (in minutes) of acid-assisted decomplexation of the [Ln(pyta)]⁻ complexes (spectrophotometry, 5.0 M HClO₄, 90 °C). Simultaneous isomerisation and decomplexation were observed for Dy(iii)–Lu(iii) and Y(iii) complexes; their experimentally observed half-lives are in italics.

Fig. 5. Comparison of decomplexation rates for the selected [Ln(pyta)]⁻, [Ce(dota)]⁻ and [La(macropa)]⁺ complexes at different solution acidities.

Scheme 1. Decomplexation pathway of the [Ln(pyta)]⁻ complexes (large Ln(iii) ions) in strongly acidic solutions.

Fig. 6. Molecular structures of the ²²[Pr(H₂pyta)]⁺ cation found in the crystal structure of ²²[Pr(H₂pyta)]Cl·5H₂O (A) and the ²²[Pr(H₃pyta)]²⁺ cation present in the crystal structure of ²²[Pr(H₃pyta)]Cl₂·3H₂O; two of the O–H hydrogen atoms have half occupancy (B). Carbon-bound hydrogen atoms are omitted for clarity. Colour codes: Pr: green, O: red, N: blue, C: dark grey, and H: white. A complete atom labelling scheme is given in the ESI (Fig. S11 and S12†).