Protonation scheme for some triaza macrocycles studied by potentiometry and NMR spectroscopy

Abstract

A series of triaza macrocyclic tricarboxylate ligands with ring sizes of nine to twelve (NOTA, DETA, UNTA and DOTRA) have been synthesized. Their acid-base properties and protonation sequence have been established and compared with those of the corresponding cyclic triamines and trimethyl cyclic triamines, using potentiometric measurements and l H N M R pH titrations. The first protonation constant of the carboxylate ligands is very high, and larger than the value for the parent cyclic amines. It is also very sensitive to the presence of Na' ions in solution. The first t w o protonation constants correspond to protonation of the ring nitrogens, and their increase with ring size is non-monotonic, reflecting p H-dependent conformational effects. These effects, due to electrostatic interactions as well as to hydrogen bond formation, caused difficulties in the application of methods (previously used for noncyclic polyaminocarboxylates) to obtain the protonation sequence from the 'H NM R p H titrations, similar to a previous occurrence for tetraaza macrocycles. By studying the p H dependence of the shielding parameters, C, and C,,, the protonation sequences were then obtained. For each of the four compounds studied, two nitrogen atoms are protonated before the carboxylate groups. Formation of hydrogen bonds between protonated nitrogens and non-protonated carboxylates affects the basicity of the latter, reducing the flexibility of these ligands in certain p H intervals.

Assignment of pH‐dependent NMR spectra of the scorpiand macrocycle: an application of titration profiles and spectral linewidths

“…8 We found also a close similarity of the 1 H NMR pH titration profiles for pairs b 0 /e 0 and (to some extent) d 0 /f 0 reported for the tri-Nmethylated triaza ring 2. 9 Moreover, its corresponding curve c 0 lies between curves b 0 and d 0 , as could have been expected. In fact, such an empirical approach is based on the assumption that titration curves of nuclei in comparable chemical environments have comparable shapes.…”

Determination of microscopic acid?base parameters from NMR?pH titrations

“…Linewidth variations of methylenic protons as a function of pH have also been observed for methylated cyclic triamines, caused by slow interconversion of various conformations of the partially protonated ring [179]. For a trimethylated oxatriaza macrocycle, irregular 1 H NMR-pH profiles with maxima have been observed, suggesting a redistribution of protons as described for DTPA nitrogens above [52].…”

“…(31) holds only if the protonating groups maintain a constant average orientation throughout the pH range [106]. In polyazacycloalkanes, the preferred pH-dependent conformations mean that C coefficients also vary with pH [52,178,179]. If protonation states of particular nitrogens can uniquely be identified at certain points of the NMR-pH titration curves, this information can be used to obtain a new, compound-specific set of C coefficients [52].…”

“…Protonation sequences of N-methylated cyclic polyamines have been derived from 1 H NMR titration data [179,180,181,182,183]. Linewidth variations of methylenic protons as a function of pH have also been observed for methylated cyclic triamines, caused by slow interconversion of various conformations of the partially protonated ring [179].…”

Characterisation of 67Ga3+ complexes of triaza macrocyclic ligands: biodistribution and clearance studies

“…The triazamacrocyclic ligands NOTA, NOTP, and NOTPME were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy as described elsewhere (11,15,16). Solutions of the Ga 3ϩ chelates for NMR analysis were obtained by mixing stoichiometric amounts of Ga(NO 3 ) 3 and each of the ligands in D 2 O (at 20-mM concentrations) and adjusting the pH to 7 with diluted DCl and NaOD.…”