Interpreting the Paramagnetic NMR Spectra of Potential Ru(III) Metallodrugs: Synergy between Experiment and Relativistic DFT Calculations

Abstract

Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The central ruthenium atom can be in the oxidation state +2 (e.g., RAPTA, RAED) or +3 (e.g., NAMI, KP). In this study we focus on paramagnetic NAMI analogs of a general structure [4-R-pyH](+)trans-[Ru(III)Cl4(DMSO)(4-R-py)](-), where 4-R-py stands for a 4-substituted pyridine. As paramagnetic systems are generally considered difficult to characterize in detail by NMR spectroscopy, we performed a systematic structural and methodological NMR study of complexes containing variously substituted pyridines. The effect of the paramagnetic nature of these complexes on the (1)H and (13)C NMR chemical shifts was systematically investigated by temperature-dependent NMR experiments and density-functional theory (DFT) calculations. To understand the electronic factors influencing the orbital (δ(orb), temperature-independent) and paramagnetic (δ(para), temperature-dependent) contributions to the total NMR chemical shifts, a relativistic two-component DFT approach was used. The paramagnetic contributions to the (13)C NMR chemical shifts are correlated with the distribution of spin density in the ligand moiety and the (13)C isotropic hyperfine coupling constants, Aiso((13)C), for the individual carbon atoms. To analyze the mechanism of spin distribution in the ligand, the contributions of molecular spin-orbitals (MSOs) to the hyperfine coupling constants and the spatial distribution of the z-component of the spin density in the MSOs calculated at the relativistic four-component DFT level are discussed and rationalized. The significant effects of the substituent and the solvent on δ(para), particularly the contact contribution, are demonstrated. This work should contribute to further understanding of the link between the electronic structure and the NMR chemical shifts in open-shell systems, including the ruthenium-based metallodrugs investigated in this account.

DFT investigation of the effect of spin-orbit coupling on the NMR shifts in paramagnetic solids

“…Substantial progress has been made in the theoretical description of various contributions to the NMR shift of molecular systems with a single paramagnetic centre. After the pioneering work of Kurland and McGarvey [16], Moon and Patchkovski derived a formalism to describe the entire shift tensor including the effects of spin-orbit coupling [19], later ex-tended to the presence of zero-field splitting by Vaara et al [20,21] and Soncini and Van den Heuvel [22], with the consequent extensive study of the NMR shift of paramagnetic molecules [23][24][25][26][27][28]. The shift mechanisms in paramagnetic transition metal-containing extended solids have been studied by Carlier, Grey and co-workers and the effects of multiple paramagnetic centres on the isotropic Fermi contact shift and its relation to the bulk magnetic properties of the solid have been qualitatively [13], and subsequently more quantitatively [29], rationalised.…”

Four-component relativistic density functional theory with the polarisable continuum model: application to EPR parameters and paramagnetic NMR shifts

“…e Experimental data measured in dimethylformamide and taken from Ref. [67] f Mean absolute error between calculated and experimental data. f Mean absolute error between calculated and experimental data.…”

“…[24] and Ref. [67], respectively. Structures of the Ru and Os nitrosyl complexes were optimized in the Turbomole program using the PBE0 [105,106] hybrid functional with Grimme's atom-pairwise D3 dispersion corrections [107] and Becke-Johnson (BJ) damping [108].…”

“…As model systems, we selected two Ru(III) low-spin d 5 complexes (S=1/2) studied comprehensively for their 1 H and 13 C NMR shifts in highly polar dimethylformamide (DMF) as a function of temperature. [67] Experimental temperature-dependent pNMR shifts along with computed data in vacuo and in solution are collected in Table 3. A significant improvement of the computed pNMR shifts upon inclusion of bulk solvent e↵ects can be noticed; the mean-absolute error (MAE) is reduced from 10-20 ppm to about 2-4 ppm.…”

“…The importance of relativistic and solvent e↵ects on magnetic resonance parameters is recognized both experimentally and computationally. [51,[67][68][69][70][71][72][73][74][75] Heavyelement containing compounds are often large, and in order to treat these compounds in solution, the computational protocol must be cost e cient and able to reliably describe both the e↵ects of the environment and relativity. Several groups extensively studied strategies for the calculation of NMR shieldings and nuclear spin-spin couplings using the ZORA or Dirac-Coulomb Hamiltonians.…”