Thermodynamics of the acid dissociation of BOPTA. Determination of equilibrium constants by means of 13C NMR spectroscopy

Abstract

BOPTA, (9R,S)-2,5,8-Tris(carboxymethyl)-12-phenyl-11-oxa-2,5,8-triazadodecane-1,9-dicarboxylic acid, is a chelating agent whose gadolinium complex can be used as a magnetic resonance imaging contrast agent (MRI-CA) specific for the liver. The stepwise deprotonation constants for BOPTA were determined from a series of 13 C NMR measurements by means of the new computer program HYPNMR and also from potentiometric titration data by means of the program HYPERQUAD. The first three stepwise protonation constants obtained by the NMR method are in very good agreement with those determined by potentiometry. In very acidic solutions the NMR method gave more reliable results because the glass electrode is susceptible to interference at low pH.The enthalpy changes for the protonation reactions have also been measured by microcalorimetry. The first two protonation reactions are exothermic, indicating that protonation occurs on amine nitrogen atoms, while the following protonation steps, being athermic, involve carboxylate groups.

Chelation versus Binucleation: Metal Complex Formation with the Hexadentate all‐cis‐N1,N2‐Bis(2,4,6‐trihydroxy‐3,5‐diaminocyclohexyl)ethane‐1,2‐diamine

“…[14][15][16] The particularly strong shift observed for H1 and H5 in the range of 2 pH 4 together with the negligi- x + (x % 5.6) at pH* = 3.0. [43] The significant H2-C4 and H4-C2 coupling (black arrows) and the non-observance of H1-C3 and H3-C1 coupling (circles) indicate a chair conformation with axial hydroxy groups; the H1-C5 and H5-C1 couplings (white arrows) prove the interlinking of the two taci moieties by an ethylene bridge. The numbering scheme is given in the structural representation on top.…”

“…1 m). After each addition of base, the pH* was measured, [43] and a 0.6 mL aliquot was taken for the recording of a 1 H NMR spectrum. A total of 41 spectra were recorded.…”

“…The last fraction was evaporated to dryness and dried in vacuo for 24 h. The product was isolated as a white, hydrated trihydrochloride P4·3 HCl·5 H 2 O (1.01 g, 1.60 mmol, 68 %). 1 J = 2 Hz, 4 H), 3.93 (t, J = 2 Hz, 2 H), 3.96 (t, J = 6 Hz, 2 H), 4.21 ppm (dd, J 1 = 6, J 2 = 2 Hz, 4 H); 13 C NMR (D 2 O, pH* < 2): [43] Regeneration of the unreacted P3: The filtered solid was dissolved in a minimal amount of H 2 O and acidified to a pH of 1 with aqueous HCl. This solution was sorbed on Dowex 50W-X2, and the column was eluted with H 2 O, 0.2 m aqueous HCl and 0.5 m aqueous HCl.…”

“…1 H NMR (D 2 O, pH* > 12): [43] d = 2.71 (s, 4 H), 3.12 (t, J = 6 Hz, 2 H), 3.58 (m', 4 H), 3.81 (dd, J 1 = 6, J 2 = 2 Hz, 4 H), 3.85 ppm (t, J = 2 Hz, 2 H); 13 C NMR (D 2 O, pH* > 12): [43] …”

“…[43] d = 3.73 (m, 2 H), 3.81 (t, J = 6 Hz, 1 H), 3.93 (t, J = 2.5 Hz, 1 H), 4.10 ppm (dd, J 1 = 2.5, J 2 = 6 Hz, 2 H); 13 C NMR (D 2 O, pH* < 2): [43] …”