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

Sina K Goetzfried,Klaus Wurst,Maren Podewitz,Ronald Gust,Monika Cziferszky,Radu A Talmazan,Klaus R Liedl,Caroline M Gallati

doi:10.1021/acs.inorgchem.0c02298

Abstract

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)AuIBr, 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)2AuI]+, 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)2AuIIIBr2]+, 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)AuIBr)2 dimer (2) that rearranges to the T-shaped intermediate Br(NHC)2AuI–AuIBr (3). The dissociation of Br– from 3 and recombination lead to (NHC)2AuI–AuIBr2 (5) followed by the separation into [(NHC)2AuI]+ (7) and [AuIBr2]− (8). [AuIBr2]− is not stable in an aqueous environment and degrades in an internal redox reaction to Au0 and Br2. The latter in turn oxidizes 7 to the gold(III) species 9. The reported ligand rearrangement of the (NHC)AuIBr 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.

Highlights

Discovering gold(I) and gold(III) complexes as catalysts,[1] luminescence agents,[2−4] and more recently as anticancer and antibacterial agents in medicinal chemistry[5−9] pushed forward the research in gold chemistry
Complexes bearing phosphine and/or thiol ligands with the famous representative auranofin,[10,11] cyclometalated gold(III) complexes with C, N donor ligands, and N-heterocyclic carbene (NHC) gold(I) complexes arose in the past as auspicious compounds against abnormal cell growth.[7,12−14] In particular, (NHC)AuIX and related complexes came into the focus of medicinal chemists and were examined for their suitability as chemotherapeutic agents.[6,9,15−19] The straightforward synthesis of the NHC ligands, the possibility of fine-tuning the physicochemical properties, and the reactivity of the resulting (NHC) gold(I) complexes make the latter to attractive lead structures for the development of novel metal-based drugs
The stability of 1 in pure ACN (1 mM) at RT was studied by HPLC at 0, 24, 48, and 72 h

Summary

Introduction

Discovering gold(I) and gold(III) complexes as catalysts,[1] luminescence agents,[2−4] and more recently as anticancer and antibacterial agents in medicinal chemistry[5−9] pushed forward the research in gold chemistry. Complexes bearing phosphine and/or thiol ligands with the famous representative auranofin,[10,11] cyclometalated gold(III) complexes with C, N donor ligands, and N-heterocyclic carbene (NHC) gold(I) complexes arose in the past as auspicious compounds against abnormal cell growth.[7,12−14] In particular, (NHC)AuIX and related complexes came into the focus of medicinal chemists and were examined for their suitability as chemotherapeutic agents.[6,9,15−19] The straightforward synthesis of the NHC ligands, the possibility of fine-tuning the physicochemical properties, and the reactivity of the resulting (NHC) gold(I) complexes make the latter to attractive lead structures for the development of novel metal-based drugs. Ligand exchange reactions were investigated for various (NHC)AuIX complexes[17,27] indicating a strong trans effect of the NHC and a preferred exchange of X as leaving group. It is well accepted that the observed biological response depends on the ligand exchange rate.[28−30] the suitability of NHCs as leaving groups was investigated, too. Dos Santos et al, for instance, studied the Received: August 3, 2020 Published: October 2, 2020

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