Novel Macrocyclic Eu II Complexes: Fast Water Exchange Related to an Extreme MO water Distance

Eu II complexes are potential candidates for pO 2 ‐responsive contrast agents in magnetic resonance imaging. In this regard, we have characterized two novel macrocyclic Eu II chelates, [Eu II (DOTA)(H 2 O)] 2− and [Eu II (TETA)] 2− (H 4 DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid, H 4 TETA=1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetraacetic acid) in terms of redox and thermodynamic complex stability, proton relaxivity, water exchange, rotation and electron spin relaxation. Additionally, solid‐state structures were determined for the Sr II analogues. They revealed no inner‐sphere water in the TETA and one inner‐sphere water molecule in the DOTA complex. This hydration pattern is retained in solution, as the 17 O chemical shifts and 1 H relaxation rates proved for the corresponding Eu II compounds. The thermodynamic complex stability, determined from the formal redox potential and by pH potentiometry, of [Eu II (DOTA)(H 2 O)] 2− (lg K Eu(II) =16.75) is the highest among all known Eu II complexes, whereas the redox stabilities of both [Eu II (DOTA)(H 2 O)] 2− and [Eu II (TETA)] 2− are inferior to that of 18‐membered macrocyclic Eu II chelates. Variable‐temperature 17 O NMR, NMRD and EPR studies yielded the rates of water exchange, rotation and electron spin relaxation. Water exchange on [Eu II (DOTA)(H 2 O)] 2− is remarkably fast ( k $\rm{_{ex}^{298}}$ =2.5×10 9 s −1 ). The near zero activation volume (Δ V ≠ =+0.1±1.0 cm 3 mol −1 ), determined by variable‐pressure 17 O NMR spectroscopy, points to an interchange mechanism. The fast water exchange can be related to the low charge density on Eu II , to an unexpectedly long MO water distance (2.85 Å) and to the consequent interchange mechanism. Electron spin relaxation is considerably slower on [Eu II (DOTA)(H 2 O)] 2− than on the linear [Eu II (DTPA)(H 2 O)] 3− (H 5 DTPA=diethylenetriaminepentaacetic acid), and this difference is responsible for its 25 % higher proton relaxivity ( r 1 =4.32 m M −1 s −1 for [Eu II (DOTA)(H 2 O)] 2− versus 3.49 m M −1 s −1 for [Eu II (DTPA)(H 2 O)] 3− ; 20 MHz, 298 K).