N-Heterocyclic Carbene Gold(I) Complexes: Mechanism of the Ligand Scrambling Reaction and Their Oxidation to Gold(III) in Aqueous Solutions

[Image: see text] 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.