Synthesis and Characterization of a Series of Macrocyclic Chelates Containing o and n Donors: Prospects for Use as NMR Shift Agents for Alkali-Metal Cations

A new series of polyoxa tetraaza macrocyclic tetraacetates have been prepared and characterized. These derivatives chelate lanthanides and transition-metal ions in the tetraaza tetraacetate portion of the macrocycle, leaving the polyoxa portion available for binding with alkali-metal cations. The protonation constants and metal-binding properties of these chelates have been investigated and compared to those of the parent molecule 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Molecular mechanics calculations were performed to estimate the polyoxa cavity sizes, and these results were compared to those of the crown ether series. The Dy³⁺, Ni²⁺, and Co²⁺complexes were examined for their ability to induce a paramagnetic shift in the ²³Na⁺NMR resonance of aqueous NaCl at pH 7. The Dy³⁺complex formed with the tetraoxa tetraaza macrocycle (O₄N₄) produced the largest ²³Na paramagnetic shift, opposite in direction to that produced by Dy(DOTA)⁻. This verified that Na⁺(and other alkali-metal cations) binds in the polyoxa cavity, orthorogonal to the presumed symmetry axis of the Dy³⁺cation bound within the tetraaza tetraacetate portion of the macrocycle. Competitive titrations with Ca²⁺indicate that these ligands are considerably more specific for Na⁺ions than are the more common ion-pairing ²³Na shift agents.