H-1-NMR AND PROTONATION CONSTANTS OF NEW METAL-CHELALING MACROCYCLES,OXOCYCLOPOLYAMINES WITH PENDANT CARBOXYMETHYL GROUPS, AND THE STABILITIES OF THEIR MG2+ AND CA2+ COMPLEXES

Potentiometry and H-1 NMR have been used to study the protonation of a new series of 12-, 13-, 15-, 16- and 17-membered metal-chelating macr ocycles with two or three pendant carboxymethyl groups. In the 12- and 13-membered macrocycles, ethylenediamimetetraacetate and ethylenediam ine or propanediamine units are linked by two amide groups; in the 15- , 16-, and 17-membered macrocycles, diethylenetriaminepentaacetate and diamine units are linked by two amide groups. The protonation constan ts K-n (n = 1, 2, 3) of these new macrocyclic ligands are significantl y smaller than the corresponding values for tetraaza and triaza macroc ycles such as 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraace tic acid (DOTA) and 1,4,7-triazacyclononane-N,N',N''-triacetic acid (N OTA). The protonation sites have been identified by measuring the H-1 NMR chemical shifts at different pD values. Protonation corresponding to K-1 occurs on the amine nitrogen atoms. Tn the successive protonati ons, protons are distributed on the amine nitrogen atoms and the carbo xylate oxygen atoms so as to minimize electrostatic repulsion. The low basicities of the amine nitrogen atoms in these new macrocycles are a ttributable to the introduction of amide groups into the ring system. As a consequence of the low basicities of the macrocycles, the formati on constants of their Mg2+ and Ca2+ chelates are much lower than the c orresponding values of EDTA. The ratio of the two formation constants, K-f(Ca)/K-f(Mg), varies in an unpredictable manner with the size of t he macrocyclic ligand.