A cyclen-based ligand containing trans-acetate and trans- methylenephosphonate pendant groups, H6DO2A2P, was synthesized and its protonation constants (12.6, 11.43, 5.95, 6.15, 2.88, and 2.77) were determined by pH-potentiometry and 1H NMR spectroscopy. The first two protonations were shown to occur at the two macrocyclic ring N-CH 2-PO32- nitrogens while the third and fourth protonations occur at the two phosphonate groups. In parallel with protonation of the two -PO32- groups, the protons from the NH +-CH2-PO32- are transferred to the N-CH2-COO- nitrogens. The stability constants of the Ca2+, Cu2+, and Zn2+ (ML, MHL, MH2L, and M2L) complexes were determined by direct pH-potentiometry. Lanthanide(III) ions (Ln3+) form similar species, but the formation of complexes is slow; so, "out-of-cell" pH-potentiometry (La 3+, Eu3+, Gd3+, Y3+) and competitive spectrophotometry with Cu(II) ion (Lu3+) were used to determine the stability constants. By comparing the log KML values with those of the corresponding DOTA (H4DOTA = 1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid) and DOTP (H8DOTP = 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) complexes, the order DOTA < DO2A2P < DOTP was found for all the metal ion complexes examined here with the exception of the Ca2+ complexes, for which the order is reversed. The relaxivity of Gd(DO2A2P) decreases between pH 2 and 7 but remains constant in the pH range of 7 < pH < 12 (r1 = 3.6 mM-1 s-1). The linewiths of the 17O NMR signals of water in the absence and presence of Gd(DO2A2P) (at pH = 3.45 and 8.5) between 274 and 350 K are practically the same, characteristic of a q = 0 complex. Detailed kinetic studies of the Ce3+ and Gd3+ complexes with DO2A2P showed that complex formation is slow and involves a high stability diprotonated intermediate Ln(H2DO2A2P)*. Rearrangement of the diprotonated intermediate into the final complex is an OH- assisted process but, unlike formation of Ln(DOTA) complexes, rearrangement of Ln(H2DO2A2P)* also takes place spontaneously likely as a result of transfer of one of the protons from a ring nitrogen to a phosphonate group. The order of the OH- assisted formation rates of complexes is DOTA > DO2A2P > DOTP while the order of the proton assisted dissociation rates of the Gd3+ complexes is reversed, DOTP > DO2A2P > DOTA. 1H and 13C NMR spectra of Eu(DO2A2P) and Lu(DO2A2P) were assigned using two-dimensional correlation spectroscopy (2D COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear chemical shift correlation (HETCOR), and exchange spectroscopy (EXSY) NMR methods. Two sets of 1H NMR signals were observed for Eu(DO2A2P) characteristic of the presence of two coordination isomers in solution, a twisted square antiprism (TSAP) and a square antiprism (SAP), in the ratio of 93% and 7%, respectively. Line shape analysis of the 1H NMR spectra of Lu(DO2A2P) gave lower activation parameters compared to La(DOTP) for interconversion between coordination isomers. This indicates that the Ln(DO2A2P) complexes are less rigid probably due to the different size and spatial requirements of the carboxylate and phosphonate groups.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Inorganic Chemistry