N -Heterocyclic carbene (NHC) gold(I) complexes offer great prospects in medicinal chemistry as antiproliferative, anticancer, and antibacterial agents. However, further development requires a thorough understanding of their reaction behavior in aqueous media. Herein, we report the conversion of the bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I) ((NHC)Au I Br, 1 ) complex in acetonitrile/water mixtures to the bis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I) ([(NHC) 2 Au I ] + , 7 ), which is subsequently oxidized to the dibromidobis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(III) ([(NHC) 2 Au III Br 2 ] + , 9 ). By combining experimental data from HPLC, NMR, and (LC-)/HR-MS with computational results from DFT calculations, we outline a detailed ligand scrambling reaction mechanism. The key step is the formation of the stacked ((NHC)Au I Br) 2 dimer ( 2 ) that rearranges to the T-shaped intermediate Br(NHC) 2 Au I –Au I Br ( 3 ). The dissociation of Br – from 3 and recombination lead to (NHC) 2 Au I –Au I Br 2 ( 5 ) followed by the separation into [(NHC) 2 Au I ] + ( 7 ) and [Au I Br 2 ] − ( 8 ). [Au I Br 2 ] − is not stable in an aqueous environment and degrades in an internal redox reaction to Au 0 and Br 2 . The latter in turn oxidizes 7 to the gold(III) species 9 . The reported ligand rearrangement of the (NHC)Au I Br complex differs from that found for related silver(I) analogous. A detailed understanding of this scrambling mechanism is of utmost importance for the interpretation of their biological activity and will help to further optimize them for biomedical and other applications.

Bromido[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(i) complexes (8a–h) with methoxy, methyl and fluorine substituents at different positions in the 4-aryl ring were synthesized and characterized.

The significance of the halido ligand (Cl-, Br-, I-) in halido[3-ethyl-4-phenyl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complexes (2, 3, 4) in terms of ligand exchange reactions, including the ligand scrambling to the bis[3-ethyl-4-phenyl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complex (5)...

The known ruthenium complex [Ru(tpy)(bpy)(Hmte)](PF6)2 ([1](PF6)2, where tpy = 2,2’:6’,2″-terpyridine, bpy = 2,2’-bipyridine, Hmte = 2-(methylthio)ethanol) is photosubstitutionally active but non-toxic to cancer cells even upon light irradiation. In this work, the two analogs complexes [Ru(tpy)(NN)(Hmte)](PF6)2, where NN = 3,3'-biisoquinoline (i-biq, [2](PF6)2) and di(isoquinolin-3-yl)amine (i-Hdiqa, [3](PF6)2), were synthesized and their photochemistry and phototoxicity evaluated to assess their suitability as photoactivated chemotherapy (PACT) agents. The increase of the aromatic surface of [2](PF6)2 and [3](PF6)2, compared to [1](PF6)2, leads to higher lipophilicity and higher cellular uptake for the former complexes. Such improved uptake is directly correlated to the cytotoxicity of these compounds in the dark: while [2](PF6)2 and [3](PF6)2 showed low EC50 values in human cancer cells, [1](PF6)2 is not cytotoxic due to poor cellular uptake. While stable in the dark, all complexes substituted the protecting thioether ligand upon light irradiation (520 nm), with the highest photosubstitution quantum yield found for [3](PF6)2 (Φ[3] = 0.070). Compounds [2](PF6)2 and [3](PF6)2 were found both more cytotoxic after light activation than in the dark, with a photo index of 4. Considering the very low singlet oxygen quantum yields of these compounds, and the lack of cytotoxicity of the photoreleased Hmte thioether ligand, it can be concluded that the toxicity observed after light activation is due to the photoreleased aqua complexes [Ru(tpy)(NN)(OH2)]2+, and thus that [2](PF6)2 and [3](PF6)2 are promising PACT candidates. Graphic abstract

A series of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complexes (2a-f) containing methyl, fluoro or methoxy substituents at various positions in the 4-aryl ring were synthe-sized and evaluated for their anti-cancer properties in A2780 (wild-type...

The ligand scrambling reaction of gold(I) complexes is a phenomenon occurring primarily in L–Au I –X (L = phosphine, N -heterocyclic carbene (NHC), and thiol; X = halide and thiol) complexes and has been observed among others for e.g., the bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2 H -imidazol-2-ylidene]gold(I) complex ( 7a ), which underwent ligand rearrangement in aqueous solutions. In this study, we investigated the influence of substituents on the 4-aryl ring of the related (NHC)Au I Br complexes ( 1a – 9a ) in terms of the conversion to the [(NHC) 2 Au I ] + ( 1b – 9b ) and [(NHC) 2 Au III Br 2 ] + ( 1c – 9c ) species. Furthermore, the influence of external factors such as solvent, temperature, concentration, and presence of halides (Cl – , Br – , and I – ) or hydroxyl ions was studied to gain a deeper understanding of the ligand rearrangement reaction. The substituent on the 4-aryl ring has a marginal impact on the scrambling reaction. Out of the investigated organic solvents (dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), and acetonitrile (ACN)), only ACN separates single complex molecules. In all other solvents, relatively stable ((NHC)Au I Br) 2 dimers are present. The addition of water to ACN solutions forces the formation of such dimeric units, starting the transformation to [(NHC) 2 Au I ] + and [(NHC) 2 Au III Br 2 ] + . The rate-determining step is the release of Br – from a T-shape intermediate because an excess of KBr terminates this reaction. Furthermore, it is obvious that only single molecules react with halides. The aurophilic interactions between two (NHC)Au I Br molecules are too strong in the presence of water and largely impeded reaction with halides. As a single molecule, the reaction with Cl – (e.g., in a 0.9% NaCl solution) is notable, while I – even leads to a fast and quantitative conversion to (NHC)Au I I and finally to [(NHC) 2 Au I ] + .