In this contribution we present two ligands based on a do3a platform containing a picolinate group attached to the fourth nitrogen atom of the cyclen unit, which are designed for stable lanthanide complexation in aqueous solutions. Potentiometric measurements reveal that the thermodynamic stability of the complexes is very high (log K = 21.2-23.5), being comparable to that of the dota analogues. Luminescence lifetime measurements performed on solutions of the Eu(III) and Tb(III) complexes indicate that the complexes are nine coordinate with no inner-sphere water molecules. A combination of density functional theory (DFT) calculations and NMR measurements shows that for the complexes of the heaviest lanthanides there is a major isomer in solution consisting of the enantiomeric pair Λ(δδδδ) and Δ(λλλλ), which provides square antiprismatic coordination (SAP) around the metal ion. Analysis of the Yb(III)-induced paramagnetic shifts unambiguously confirms that these complexes have SAP coordination in aqueous solution. For the light lanthanide ions however both the SAP and twisted-square antiprismatic (TSAP) isomers are present in solution. Inversion of the cyclen ring appears to be the rate-determining step for the Λ(δδδδ) ↔ Δ(λλλλ) enantiomerization process observed in the Lu(III) complexes. The energy barriers obtained from NMR measurements for this dynamic process are in excellent agreement with those predicted by DFT calculations. The energy barriers calculated for the arm-rotation process are considerably lower than those obtained for the ring-inversion path. Kinetic studies show that replacement of an acetate arm of dota by a picolinate pendant results in a 3-fold increase in the formation rate of the corresponding Eu(III) complexes and a significant increase of the rates of acid-catalyzed dissociation of the complexes. However, these rates are 1-2 orders of magnitude lower than those of do3a analogues, which shows that the complexes reported herein are remarkably inert with respect to metal ion dissociation.

In this study we present the results of the equilibrium, dissociation kinetics, DFT and X-ray crystallographic studies performed on the complexes of metal ions of biomedical importance (Mn(2+), Cu(2+) and Gd(3+)) formed with octadentate ligands based on a cyclen platform incorporating two picolinate pendant arms (dodpa(2-) and Medodpa(2-)). The stability constants of the complexes were accessed by multiple methods (pH-potentiometry, direct and competition UV-vis spectrophotometry and (1)H-relaxometry). The stability constants of the complexes formed with dodpa(2-) and Medodpa(2-) do not differ significantly (e.g. log K[Mn(dodpa)] = 17.40 vs. log K[Mn(Medodpa)] = 17.46, log K[Cu(dodpa)] = 24.34-25.17 vs. log K[Cu(Medodpa)] = 24.74 and log K[Gd(dodpa)](+) = 17.27 vs. log K[Gd(Medodpa)](+) = 17.59), which indicates that the steric hindrance brought by the methyl groups has no significant effect on the stability of the complexes. The stability constants of the Mn(2+) complexes formed with the cyclen dipicolinates were found to be ca. 3 log K units higher than those determined for the complex of the cyclen monopicolinate (dompa(-)), which indicates that the second picolinate moiety attached to the backbone of the macrocycle is very likely coordinated to the Mn(2+) ion. However, the stability of the [Cu(dodpa)] and [Cu(Medodpa)] complexes agrees well with the stability constant of [Cu(dompa)](+), in line with the hexadentate coordination around the metal ion observed in the X-ray structure of [Cu(Medodpa)]. The [Gd(dodpa)](+) and [Gd(Medodpa)](+) complexes display a fairly high kinetic inertness, as the rate constants of acid catalysed dissociation (k1 = 2.5(4) × 10(-3) and 8.3(4) × 10(-4) M(-1) s(-1) for [Gd(dodpa)](+) and [Gd(Medodpa)](+), respectively) are smaller than the value reported for [Gd(do3a)] (k1 = 2.5 × 10(-2) M(-1) s(-1)). The [Mn(dodpa)] complex was found to be more inert than [Mn(Medodpa)]. The results of the diffusion-ordered NMR spectroscopy (DOSY) and DFT calculations of diamagnetic [La(dodpa)](+) and [Lu(dodpa)](+) complexes indicate the formation of a trinuclear entity of the La complex in aqueous solution.

The stability constants of complexes of the macrocyclic ligand do3a‐pic4– (H4do3a‐pic = 2,2′,2″‐{10‐[(6‐carboxypyridin‐2‐yl)methyl]‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl}triacetic acid) with several divalent metal ions (Pb2+, Cd2+, Zn2+, Cu2+, Ca2+, and Mg2+) have been determined by using pH‐potentiometric titrations (I = 0.1 M KCl, 25 °C). The stability of these complexes follows the trend Cu2+ > Cd2+ ≈ Pb2+ ≈ Zn2+ >> Ca2+ >> Mg2+. A particularly high stability constant has been determined for the Cu2+ complex [log KCuL = 23.20(4)]. Analysis of the titration curves indicate the presence of protonated forms of the complexes in solution, with protonation constants of log KM(HxL) = 6.9–2.0 (x = 1, 2, or 3). The structure of the complexes in solution has been investigated by using 1H and 13C NMR spectroscopy and DFT calculations performed in aqueous solution at the TPSSh/6‐31G(d) level. In the case of the Pb2+ and Cd2+ complexes, relativistic effects were considered with the use of relativistic effective core potentials. Calculations show that the complexes with the largest metal ions (Pb2+ and Ca2+) are nine‐coordinate, with their coordination polyhedra being best described as capped twisted square antiprisms. The Cd2+ and Mg2+ complexes are seven‐coordinate, with the metal ions being bound to the four nitrogen atoms of the cyclen unit and the three acetate pendant arms. Finally, in the Cu2+ and Zn2+ complexes, the metal ions are six‐coordinated, with the metal ions being asymmetrically placed inside the macrocyclic cavity of the ligand, and the coordination polyhedra can be described as an octahedron and a trigonal prism, respectively.

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