The solution structure and dynamics of metal-bound water exchange have been investigated in a series of lanthanide complexes of primary, secondary, and tertiary tetraamide derivatives of 1,4,7,10-tetraazacyclododecane. In the gadolinium complexes at ambient pH, water exchange lifetimes (τ(m)) determined by 17O NMR were sufficiently long (19 μs for [Gd · 2]3+, 298 K, 17 μs for [Gd · 3]3+, and 8 μs for [Gd · 4]3+) to limit the measured relaxivity. Direct 1H NMR observation of the bound water resonance is possible for the corresponding Eu complexes at low temperature in CD3CN, and the rate of water proton exchange is about 50 times faster in the twisted square antiprismatic isomer (m) than in the isomeric square antiprismatic (M) complex. The ratio of these two isomers in solution is sensitive to the steric demand of the amide substituent, with m/M = 2 for [Eu · 4]3+, but 0.25 for [Eu · 2]3+. The slowness of coordinated water exchange has allowed the rate of prototropic exchange to be studied: in basic media deprotonation of the bound water molecule or of proximate ligand amide NH protons leads to relaxivity enhancements, whereas in acidic media, hydration around the strongly ion-paired complexes is perturbed, facilitating water exchange. The X-ray crystal structure of ligand 3 reveals a hydrogen-bonded structure with two pairs of ring N-substituents related in a trans arrangement, contrasting with the structure of diprotonated DOTA in which the ligand is predisposed to bind metal ions. In the dysprosium complex [Dy · 3 · OH2](PF6)3, the metal ion adopts a regular monocapped square antiprismatic coordination geometry, with a water Dy-O bond length of 2.427(3) Å, and a PF6 counterion is strongly hydrogen-bonded to this bound water molecule.
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