O.M.N. Dhubhghaill

We present the results of new and previously published 17O NMR, EPR, and NMRD studies of aqueous solutions of the Gd3+ octaaqua ion and the commercial MRI contrast agents [Gd(DTPA)(H2O)]2- (MAGNEVIST, Schering AG, DTPA = 1,1,4,7,7-pentakis(carboxymethyl)-1,4,7-triazaheptane), [Gd(DTPA-BMA)(H2O)] (OMNISCAN, Sanofi Nycomed, DTPA-BMA = 1,7-bis[(N-methylcarbamoyl)methyl]-1,4,7-tris(carboxymethyl)-1,4,7-triazaheptane), and [Gd(DOTA)(H2O)]- (DOTAREM, Guerbet, DOTA = 1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). High-field EPR measurements at different concentrations give evidence of an intermolecular dipole−dipole electronic relaxation mechanism that has not previously been described for Gd3+ complexes. For the first time, the experimental data from the three techniques for each complex have been treated using a self-consistent theoretical model in a simultaneous multiple parameter least-squares fitting procedure. The lower quality of the fits compared to separate fits of the data for each of the three techniques shows that the increase in the number of adjustable parameters is outweighed by the increased constraint on the fits. The parameters governing the relaxivity of the complexes are thus determined with greater confidence than previously possible. The same approach was used to study two dimeric Gd3+ complexes [pip{Gd(DO3A)(H2O)}2] and [bisoxa{Gd(DO3A)(H2O)}2] (pip(DO3A)2 = bis(1,4-(1-(carboxymethyl)-1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl-1,4-diazacyclohexane, bisoxa(DO3A)2 = bis(1,4-(1-(carboxymethyl)-1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl))-1,10-diaza-3,6-dioxadecane) that are being developed as potential second-generation MRI contrast agents. These dimeric complexes are expected to have higher relaxivities than the monomeric contrast agents, due to their longer rotational correlation times. The results of this study show that further relaxivity gain for these complexes will be hindered by the slow rate of water exchange on the complexes. High-field EPR measurements suggest that there is a previously unrecorded intramolecular dipole−dipole mechanism of electronic relaxation, but that this additional contribution to electronic relaxation is of minor importance compared to the limiting effect of water exchange rates in the determination of proton relaxivity in MRI applications.

A temperature-dependent UV–visible spectrophotometric study on [Eu(DO3A)(H2O)n] proved the presence of a hydration equilibrium (n = 1, 2), strongly shifted towards the bisaqua species [DO3A = 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane]. The thermodynamic parameters and the reaction volume were determined for the equilibrium [Eu(DO3A)(H2O)] + H2O ⇌ [Eu(DO3A)(H2O2)] and the same results were extra-polated for the Gd(III) analogue (ΔH° = −12.6 kJ mol−1, ΔS° = −25.2 J mol−1 K−1, KEu298 = 7.7 and ΔV° = −7.5 cm3 mol−1). The variable-temperature 17O NMR data on [Gd(DO3A)(H2O)n] were analysed by two approaches: (i) with the Swift–Connick equations (two-site exchange) and (ii) with the Kubo–Sack formalism (three-site exchange). The comparison of the results obtained by the two different analyses show that, despite the crude approximation of treating the system as a two-site exchange problem, the Swift–Connick method gives a correct value for the water exchange rate. Based on previous observations on the relationship between inner sphere structure and water exchange rate, one can expect higher rates for complexes with a hydration equilibrium. Indeed, the water exchange on [Gd(DO3A)(H2O)n] is about twice as fast as on [Gd(DOTA)(H2O)]− (kex298 = 11 × 106 and 4.8 × 106 s−1, respectively), although it is still much slower than that on [Gd(H2O)8]3+ (kex298 = 804 × 106 s−1). The limited gain in the water exchange rate is explained in terms of a rigid inner sphere structure introduced by the macrocyclic ligand which makes difficult the transition from the reactant to the transition state, and consequently, results in a slower exchange as compared to the Gd3+ aqua ion. The activation parameters of the water exchange are and , and the mechanism is proposed to be dissociatively activated. Copyright © 1999 John Wiley & Sons, Ltd.

Aquation of the anticancer complex trans-[H2im][RuCl4(Him)2]1(Him = imidazole) has been studied in D2O at a range of pH*(meter reading) values between 2.4 and 10 by observation of paramagnetically shifted 1H NMR resonances. At 310 K. pH* 5.6, the half-life was 3.4 h and three products were detected, assigned as mono- and di-aqua species. The rate was similar at low pH*, but the reaction followed a different course at high pH*. Aquation was also studied by separation of the products on a reversed-phase column using HPLC, by conductivity measurements, and by EPR spectroscopy. Slow oxidation of the complex to RuIV appeared to take place in perchlorate, phosphate or acetate solutions. Cyclic voltammetric studies showed that reduction of 1 to RuII(Em–0.14 V versus the normal hydrogen electrode, pH 7) was accompanied by the uptake of two protons with associated pKa values of 6.26 and 3.87. Both aquation and the more favourable reduction of 1 at low pH may play a role in the biological activity of the complex.

An evaluation of the Bruker SMART X2S for the collection of crystallographic diffraction data, structure solution and refinement is carried out with a variety of materials with different electron densities, presenting some of the successes and challenges of automation in chemical crystallography.