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

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-[RuIIICl4(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 (δorb, temperature-independent) and paramagnetic
(δpara, temperature-dependent) contributions to the
total NMR chemical shifts, a relativistic two-component 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, Aiso(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 δpara, 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.

钌基化合物作为抗癌金属药物候选物具有潜在的应用价值。中心钌原子可处于+2价态（例如，RAPTA、RAED）或+3价态（例如，NAMI、KP）。在本研究中，我们聚焦于一类具有通用结构[4-R-pyH]+trans-[RuIIICl4(DMSO)­(4-R-py)]−的顺磁性NAMI类似物，其中4-R-py代表4位取代的吡啶。由于顺磁性体系通常被认为难以通过核磁共振波谱进行详细表征，因此我们对含有不同取代吡啶的复杂体系进行了系统的结构和方法的核磁共振研究。通过温度依赖性的核磁共振实验和密度泛函理论（DFT）计算，系统地研究了这些复杂体系的顺磁性对1H和13C核磁共振化学位移的影响。为了理解影响总核磁共振化学位移的轨道（δorb，温度不依赖）和顺磁性（δpara，温度依赖）贡献的电子因素，采用了相对论双组分DFT方法。顺磁性对13C核磁共振化学位移的贡献与配体部分的磁矩密度分布以及单个碳原子的13C各向同性超精细耦合常数Aiso(13C)相关。为了分析配体中自旋分布的机制，讨论并解释了分子自旋轨道（MSOs）对超精细耦合常数的贡献以及在相对论四组分DFT水平上计算的MSOs中z分量自旋密度的空间分布。展示了取代基和溶剂对δpara，尤其是接触贡献的显著影响。本研究应有助于进一步理解电子结构与开放壳体系核磁共振化学位移之间的联系，包括在本研究中探讨的钌基金属药物。