With the aim to design new water-soluble organometallic Ru(II) complexes acting as anticancer agents catalysing transfer hydrogenation (TH) reactions with biomolecules, we have synthesized four Ru(II) monocarbonyl complexes (1-4) featuring the 1,4-bis(diphenylphosphino)butane (dppb) ligand and different bidentate nitrogen (N^N) ligands, of general formula [Ru(OAc)CO(dppb)(N^N)]n (n = +1, 0; OAc = acetate). The compounds have been characterised by different methods, including 1H and 31P NMR spectroscopy, electrochemistry as well as single crystals X-ray diffraction in the case of 1 and 4. The compounds have also been studied for their hydrolysis in aqueous environment, and for the catalytic regioselective reduction of NAD+ to 1,4-NADH in aqueous solution with sodium formate as hydride source. Moreover, the stoichiometric and catalytic oxidation of 1,4-NADH have also been investigated by UV-Visible spectrophotometry and NMR spectroscopy. Overall, initial structure-activity relationships could be inferred which point towards the influence of the extension of the aromatic N^N ligand in the cationic complexes 1-3 on the TH in both reduction/oxidation processes. The neutral complex 4, featuring a picolinamidate N^N ligand, stands out as the most active catalyst for the reduction of NAD+, while being completely inactive towards NADH oxidation. The compound can also convert pyruvate into lactate in the presence of formate, albeit with scarce efficiency. In any case, for all compounds, Ru(II) hydride intermediates could be observed and even isolated in the case of complexes 1-3. Together, insight from the kinetic and electrochemical characterization suggests that, in the case of Ru(II) complexes 1-3, catalytic NADH oxidation sees the H-transfer from 1,4-NADH as the rate limiting step, whereas for NAD+ hydrogenation with formate as the H-donor, the rate limiting step is the transfer of the ruthenium hydride to the NAD+ substrate. The latter is further modulated by the presence of di-cationic aquo- or mono-cationic hydroxo-species of complexes 1-3. Instead, compound 4, stable with respect to hydrolysis in aqueous solution, appears to operate via a different mechanism. Finally, the anticancer activity and ability to form reactive oxygen species (ROS) of complexes 1-3 have been studied in cancerous and non-tumorigenic cells in vitro. Noteworthy, the conversion of aldehydes to alcohols could be achieved by the three Ru(II) catalysts in living cells, as assessed by fluorescence microscopy. Furthermore, the formation of Ru(II) hydride intermediate upon treatment of cancer cell extracts with complex 3 has been detected by 1H NMR spectroscopy. Overall, this study paves the way to the application of non-arene based organometallic complexes as TH catalysts in biological environment.

A new pathway of electrocatalytic transfer hydrogenation with neutral water as the H-donor was discovered using [(tBuPCP)Ir(H)(Cl)] (1) as the catalyst and styrene as a model substrate in THF electrolyte. Cyclic voltammetry experiments with 1 revealed that two subsequent reductions at –2.55 and –2.84 V vs. Fc+/Fc trigger the elimination of Cl– and afford the highly reactive anionic Ir(I) hydride complex [(tBuPCP)Ir(H)]– (2). The identity of 2 and its reactivity were further investigated by LIFDI-MS, which confirmed 2 as reactive species in the alkene hydrogenation cycle. Bulk electrolysis and chronoamperometry for electro-hydrogenation of styrene established ethylbenzene as the only product, formed with high faradaic efficiency of 96% and a turnover frequency of 1670 h–1 at an electrolysis potential of –3.1 V, with insignificant H2 formation. Importantly, the electro-hydrogenation performance of 1 remained constant upon addition of KOH to the electrolyte, which suggests a reaction mechanism that is independent of free H+. Instead, the reactive Ir-hydrides are regenerated by oxidative addition of H2O to the complex, which creates a reaction cascade that is reminiscent of metal-hydride formation in classical transfer hydrogenation systems. As such, the herein presented study on electrocatalytic transfer hydrogenation (e-TH) with H2O as the H-donor is different from the plethora of other electro-hydrogenation studies that operate via H+ reduction, often in low-pH electrolyte. These findings may inspire the general, pH independent use of H2O as H-donor in conjunction with electrochemistry, to replace isopropanol or formate as intrinsically reducing H-donors in the many existing examples of classical transfer hydrogenation.