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]+ <i>trans</i>-[Ru^IIICl₄(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 ¹H and ¹³C 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 twocomponent DFT approach was used. The paramagnetic contributions to the ¹³C NMR chemical shifts are correlated with the distribution of spin density in the ligand moiety and the ¹³C isotropic hyperfine coupling constants, A_iso (¹³C), 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.