Nuclear magnetic resonance studies of the protonation sequence of cyclic tetra-azatetra-acetic acids

Abstract

The protonation sequence of a cyclic tetra-azatetra-acetic acids(cDOTA, cTRITA, cTETA, and cPENTA) was studied by means of n.m.r. titration spectroscopy. The methods previously used for non-cyclic polyaminocarboxylates and for the most symmetrical members of the series, cDOTA and cTETA, did not prove adequate for the entire series. The shielding parameters C_N and C_N′ are different for each type of proton in the tetra-aza ring and acetate groups and vary with the pH of the medium. This behaviour can be attributed to changes in the conformation equilibria with the protonation of the various basic centres, in which electrostatic repulsions and hydrogen-bond formation play a role, and to the more restricted flexibility of these compounds compared to their non-cyclic analogues. C_N and C_N′, were estimated as functions of the probabilities of protonation of the carboxylate groups and used as such to derive protonation sequences of the cyclic polyaminocarboxylates by solving systems of linear equations relating chemical shifts to pH and to the number of equivalents of added acid. The results confirm that two nitrogens are protonated first in all four compounds and no protonation of the carboxylate groups occurs; further acidification results in preferential protonation of these groups from cDOTA to cTETA but not for cPENTA, which preferentially accepts a third proton in one nitrogen. cDOTA and cTRlTA do not protonate further in their nitrogens but such a tendency can be observed in cTETA and clearly in cPENTA which can be fully protonated in their nitrogens and carboxylates. The sequence of protonation in this case lends support to the formation of hydrogen bonds between protonated nitrogens and non-protonated carboxylates.