O-TRENSOX, a New Tripodal Iron Chelator Based on 8-Hydroxyquinoline Subunits: Thermodynamic and Kinetic Studies

Abstract

The thermodynamic stability of Fe(III) complexes with a new hexadentate tripodal ligand (O-TRENSOX) incorporating three 8-hydroxyquinoline ("oxine") subunits, linked to a tetraamine ("TREN") via an amide connection, has been investigated by the use of UV−vis spectrophotometry and potentiometric methods. O-TRENSOX has been found to form, at pH < 1, a protonated complex FeLH52+ (orange color) which deprotonates, over the pH range 1−2, to a green complex FeLH2- through a four-proton process. The first protonation constant of ferric O-TRENSOX has been determined to be 5.60. The stability constant log β110 has been determined to be 30.9. A pFe (pFe = − log [Fe3+]) value of 29.5 has been calculated at pH = 7.4, [ligand]tot = 10 μΜ, and [Fe3+]tot = 1 μM, indicating that O-TRENSOX is one of the most powerful among the iron synthetic chelators. Cyclic voltammetry experiments have shown that the system FeIII−O-TRENSOX/FeII−O-TRENSOX is quasi reversible, with a redox potential of 0.087 V vs NHE. This value is related to the high complexing ability of O-TRENSOX for both the ferric and ferrous iron redox states, making it relevant for biological uses. The kinetics of formation and acid hydrolysis of the ferric O-TRENSOX complex have been investigated in acidic medium using the diode array stopped-flow spectrophotometry technique in 2.0 M NaClO4/HClO4 at 25 °C. The determining step for the complex formation involves the reaction of FeOH2+ with the LH7+ ligand species, with a rate constant of 789 ± 17 M-1 s-1. The acid hydrolysis of the FeLH2- complex in 0.02−1.0 M HClO4 and ionic strength 2.0 M NaClO4/HClO4 leads to the FeLH52+ complex, indicating that O-TRENSOX is a very strong chelating agent for Fe(III) in acidic medium. The kinetic data have been interpreted by a stepwise mechanism related to the successive protonation of four binding sites. The spectroscopic change is consistent with removal of one arm of the ligand followed by a shift from a bis(oxinate) to a bis(salicylate) mode of coordination.