Structural Variations Across the Lanthanide Series of Macrocyclic DOTA Complexes: Insights into the Design of Contrast Agents for Magnetic Resonance Imaging

It was early shown that the macrocyclic Ln(DOTA) complexes (DOTA = 1,4,7,10-tetra-azacyclododecane-N,N‘,N‘ ‘,N‘ ‘‘-tetraacetic acid) exists in solution as a mixture of two enantiomeric pairs of diastereoisomers differing in the ligand
conformation, namely, square antiprismatic (SA) and twisted square antiprismatic (TSA) geometries, respectively.
Later, extensive 1H NMR investigations suggested that a coordination change may be superimposed on this
conformational equilibrium involving two additional structures in which the metal ion possesses a coordination
number of eight (CN 8). It was predicted that these two species, lacking the apical coordinated water molecule,
would maintain the SA and TSA coordination geometries, and therefore, they have been labeled as SA‘ and TSA‘,
respectively. In this work we report the X-ray solid-state crystal structure determination of six Ln(DOTA) complexes
representative of all four coordination geometry typologies deduced from NMR solution studies. A distinctive structural
feature that discriminates SA (and SA‘) and TSA (and TSA‘) structures is represented by the twist angle between
the two square planes of the antiprism, the basal four nitrogen, and the apical four oxygen planes. [Ce(DOTA)(H2O)]-
displays a TSA structural typology with a twist angle of 25° and a Ce−Owater distance of 2.59 Å. The SA-type
structure has been found in the case of complexes with Pr(III), Nd(III), and Dy(III), where the twist angle is 39, 39,
and 38°, respectively, and the metal−water oxygen distance varies significantly (Pr−Ow 2.529 Å; Nd−Ow 2.508 Å;
and Dy−Ow 2.474 Å). [Tm(DOTA)]- displays a TSA‘-type structure with a twist angle of 24°. As compared with the
TSA structure of the corresponding Ce(III) complex, the Tm(III) complex shows an overall marked shrinkage of all
metal−nitrogen and metal−oxygen distances (ca. 0.2 Å), which reflects the contraction of the metal ionic radius
across the series but also the effect associated with the decrease of the CN from 9 to 8. In [Sc(DOTA)]-, the even
smaller ionic radius of Sc(III) shifts the geometry of the coordination cage to the more compact SA‘ typology with
a twist angle of 41°, a value very similar to that found in the SA structures of lanthanide(III) ions with CN 9. Finally,
an investigation was made into the hydration spheres of the complexes with SA and TSA geometries to account
for the experimental evidence of a markedly different rate of water exchange for the two isomeric structures. This
is of fundamental importance to the understanding of the corresponding Gd(III) complexes as MRI contrast agents.