Solution Structures, Stabilities, Kinetics, and Dynamics of DO3A and DO3A–Sulphonamide Complexes

The Gd3+-DO3A–arylsulphonamide (DO3A–SA) complex is a promising pH-sensitive MRI agent. The stability constants of the DO3A–SA and DO3A complexes formed with Mg2+, Ca2+, Mn2+, Zn2+, and Cu2+ ions are similar, whereas the logKLnL values of Ln­(DO3A–SA) complexes are 2 orders of magnitude higher than those of the Ln­(DO3A) complexes. The protonation constant (log KMHL) of the sulphonamide nitrogen in the Mg2+, Ca2+, Mn2+, Zn2+, and Cu2+ complexes is very similar to that of the free ligand, whereas the logKLnHL values of the Ln­(DO3A–SA) complexes are lower by about 4 logK units, indicating a strong interaction between the Ln3+ ions and the sulphonamide N atom. The Ln­(HDO3A–SA) complexes are formed via triprotonated *Ln­(H3DO3A–SA) intermediates which rearrange to the final complex in an OH–-assisted deprotonation process. The transmetalation reaction of Gd­(HDO3A–SA) with Cu2+ is very slow (t1/2 = 5.6 × 103 h at pH = 7.4), and it mainly occurs through proton-assisted dissociation of the complex. The 1H and 13C NMR spectra of the La-, Eu-, Y-, and Lu­(DO3A–SA) complexes have been assigned using 2D correlation spectroscopy (COSY, EXSY, HSQC). Two sets of signals are observed for Eu-, Y-, and Lu­(DO3A–SA), showing two coordination isomers in solution, that is, square antiprismatic (SAP) and twisted square antiprismatic (TSAP) geometries with ratios of 86–14, 93– 7, and 94–6%, respectively. Line shape analysis of the 13C NMR spectra of La-, Y- , and Lu­(DO3A–SA) gives higher rates and lower activation entropy values compared to Ln­(DOTA) for the arm rotation, which indicates that the Ln­(DO3A–SA) complexes are less rigid due to the larger flexibility of the ethylene group in the sulphonamide pendant arm. The fast isomerization and the lower activation parameters of Ln­(DO3A–SA) have been confirmed by theoretical calculations in vacuo and by using the polarizable continuum model. The solid state X-ray structure of Cu­(H2DO3A–SA) shows distorted octahedral coordination. The coordination sites of Cu2+ are occupied by two ring N- and two carboxylate O-atoms in equatorial position. The other two ring N-atoms complete the coordination sphere in axial positions. The solid state structure also indicates that a carboxylate O atom and the sulphonamide nitrogen are protonated and noncoordinated.