Conformational Characterization of Lanthanide(III)−DOTA Complexes by ab Initio Investigation in Vacuo and in Aqueous Solution

Abstract

The conformational behavior of four [Ln(DOTA)(H(2)O)](-) systems (Ln = La, Gd, Ho, and Lu) has been characterized by means of ab initio calculations performed in vacuo and in aqueous solution, the latter by using the polarizable continuum model (PCM). Calculated molecular geometries and conformational energies of the [Ln(DOTA)(H(2)O)](-) systems, and interconversion mechanisms, barriers, and (13)C NMR spectra of the [Lu(DOTA)](-) complex are compared with experimental values. For each system, geometry optimizations, performed in vacuo and in solution at the HF/3-21G level and using a 46+4f(n) core electron effective core potential (ECP) for lanthanides, provide two minima corresponding to a square antiprismatic (A) and an inverted antiprismatic (IA) coordination geometry. All the systems are nonacoordinated, with the exception of the IA isomer of the Lu complex that, from in solution calculations, is octacoordinated, in agreement with experimental data. On comparing the in vacuo relative free energies calculated at different theory levels it can be seen that the nonacoordinated species dominates at the beginning of the lanthanide series while the octacoordinated one does so at the end. Furthermore, on passing along the series the IA isomer becomes less and less favored with respect to A and for the Lu complex a stabilization of the IAisomer is observed in solution (but not in vacuo), in agreement with the experimental data. Investigation of the A<-->IA isomerization process in the [Lu(DOTA)](-) system provides two different interconversion mechanisms: a single-step process, involving the simultaneous rotation of the acetate arms, and a multistep path, involving the inversion of the cyclen cycle configuration. While in vacuo the energy barrier for the acetate arm rotation is higher than that involved in the ring inversion (23.1 and 13.1 kcal mol(-)(1) at the B3LYP/6-311G level, respectively), in solution the two mechanisms present comparable barriers (14.7 and 13.5 kcal mol(-)(1)), in fairly good agreement with the experimental values. The NMR shielding constants for the two isomers of the [Lu(DOTA)](-) complex have been calculated by means of the ab initio GIAO and CSGT methods, and using a 46-core-electron ECP for Lu. The calculated (13)C NMR chemical shifts are in close agreement with the experimental values (rms 3.3 ppm, at the HF/6-311G level) and confirm the structural assignment of the two isomers based on experimental NMR spectra in solution. The results demonstrate that our computational approach is able to predict several physicochemical properties of lanthanide complexes, allowing a better characterization of this class of compounds for their application as contrast agents in medical magnetic resonance imaging (MRI).

Isotropic and anisotropic NMR chemical shifts in liquid water: a sequential QM/MM study

“…The isotropic and anisotropic gas-liquid chemical shifts of the X atom are determined by (4) and (5) In experimental NMR spectra, a standard system is chosen as a reference, thus the chemical shift is taken as the difference between the shielding of the atom of interest and the corresponding atom in the reference system. In theoretical calculations, the magnetic shielding must then be subtracted from the shielding in the reference system (both obtained at the same level).…”

“…Using the auto-correlation function of the energy, 21 the structures selected for subsequent quantum calculations were taken with an interval of 5×10 4 MC steps and 10 ps in MD simulations. This procedure provides configurations with less than 15% of statistical correlation between each other in both cases.…”

“…[2][3][4][5]13,14 We used it in this work to describe the isotropic and anisotropic chemical shifts in liquid water. As a first approach, we have employed the hybrid functional B3LYP 36,37 with the purpose of studying the convergence with the number of water molecules used (cluster size).…”

“…The advances in computational resources and the improvement in the theoretical methods provide important refinements to estimate the chemical shielding, such as inclusion of the electron correlation effects and the possibility of studying systems that are more complex than isolated molecules or small clusters. Presently the determination of the chemical shifts for nuclei in proteins, solids and liquids through current methodologies [1][2][3][4][5] are very convincing.…”

Electronic fine structure calculation of [Gd(DOTA)(H2O)]– using LF-DFT: The zero field splitting

“…The geometry of [Gd(DOTA)(H 2 O)] -has been taken from the published crystal structure [22] and therefore the SA isomer in its ∆(λλλλ) form (=A1, M1 in [23]). The DFT calculations correspond to a single molecule in vacuum.…”