Water-soluble arene ruthenium complexes: From serendipity to catalysis and drug design

Dedicated to Françoise Hardy, iconic figure of style and melancholy, whose art paralleled the development of the chemistry described here, in gratitude and admiration on the occasion of her 70th birthday
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Highlights

  • The history of water-soluble arene ruthenium complexes is retraced.

  • Such complexes activate hydrogen and are catalysts or catalyst precursors in water.

  • Bioconjugates and anticancer can be developed with such complexes.

Abstract

Shortly after the discovery of benzene ruthenium dichloride and some controversy about its polymeric or dimeric nature in the 1960s, the hydrolysis of this material in water to give a mixture of benzene ruthenium aqua complexes was discovered. However, it took a long time until this reaction and the hydrolysis of other arene analogs were used as an entry to the synthesis of water-soluble arene ruthenium complexes. These complexes are able to activate molecular hydrogen in aqueous solution and allow the design of arene ruthenium bioconjugates. They can serve as catalysts or catalyst precursors for hydrogenation and transfer hydrogenation reactions in water and they are at present one of the most promising classes of metal complexes to replace cisplatin in future cancer therapy, due to their inherent cytotoxicity and their good cellular uptake, conditioned by well balanced lipophilic and hydrophilic properties.

Graphical abstract

Many arene ruthenium complexes can be handled in water thanks to the surprising inertness of the arene ruthenium bond towards hydrolysis. Arene ruthenium chloro complexes can undergo aquation to give cationic aqua complexes that are water-soluble. This historical perspective retraces the evolution of this field from the chance discovery to topical research in catalysis and drug design.

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Introduction

Arene ruthenium complexes are children of the 1960s: during his PhD project in the laboratory of Professor Günter Winkhaus at the University of Mainz, Hellmut Singer reacted ruthenium trichloride hydrate with 1,3-cyclohexadiene in dry ethanol and obtained after gentle warming (35 °C, 5 h) a brownish precipitate, which was isolated by decantation, washed with methanol and dried in high vacuum. The elemental analysis of this material, obtained in 75% yield, suggested the composition [(C6H6)RuCl2], in accordance with the IR and 1H NMR data. A polymeric structure was assumed for this compound, [(C6H6)RuCl2]x, on grounds of the unsaturated character of the (η6-C6H6)RuCl2 fragment (a 16 electron species) and of the low solubility of the compound (Fig. 1). Winkhaus and Singer published this reaction (in German) in one of the first volumes of this journal [1]. The dehydrogenation of 1,3-cyclohexadiene to benzene in this reaction was also discussed in this paper and explained by a simultaneous reduction of the formally trivalent metal to ruthenium(II); despite the modest claims and the erroneous assumption of a polymeric structure, this paper remains a milestone of organometallic chemistry (Fig. 2).

From the same reaction, but under slightly modified conditions (90% aqueous ethanol, 45 °C, 3 h), Zelonka and Baird obtained a red solid, which they believed to be different from Winkhaus' polymeric form and for which they proposed the molecular formula [(C6H6)RuCl2]2 with η6-coordinated benzene ligands on the basis of a detailed analysis of the infrared spectrum in 1972 (Fig. 1) [2], [3]. This dimeric molecule containing two terminals and two bridging chloro ligands in accordance with the 18 electron rule is present in the solid state, but the compound dissolves in coordinating solvents such as acetonitrile (L) to give monomeric complexes of the type [(C6H6)RuCl2(L)] [2], [3], [4]. These findings were confirmed by Bennett and Smith, who also showed that Baird's red dimer [(C6H6)RuCl2]2 was identical with Winkhaus' original material considered to be polymeric [5]. They also synthesized a large number of derivatives [(arene)RuCl2]2 and [(arene)RuCl2(L)] [5] and showed the more soluble p-cymene derivative [(p-MeC6H4Pri)RuCl2]2 to be dimeric in chloroform solution by osmometry [6].

While the molecular structures of various derivatives [(arene)RuCl2]2 (arene being hexamethylbenzene [7], trindane [8], ethylbenzoate [9], 1,2,3,4-tetrahydronaphthalene [10], o-toluene methylcarboxylate [11], hexaethylbenzene [12], indane [13] and p-cymene [14]) have been solved by X-ray structure analysis during the following years, the molecular structure of the parent benzene complex [(C6H6)RuCl2]2 was only confirmed in 2005 by a single-crystal X-ray analysis of the chloroform disolvate [15].

The molecule has indeed the expected dimeric structure; the two halves of the molecule are related by a crystallographic inversion center (Fig. 3). The two benzene rings are planar and the distance between the benzene centroid and the ruthenium atom is 1.646 Å. The bridging Ru–Cl distances are 2.4495(11) and 2.4580(9) Å and the terminal Ru–Cl distance is 2.3911(9) Å. The Ru⋯Ru distance is 3.7099(8) Å, there is no metal–metal bond in accordance with the electron count of 36 and the noble gas rule [15].

Section snippets

Arene ruthenium aqua complexes

By the time when this compound was discovered, organometallic chemists were trained to work with rigorous exclusion of air and water in thoroughly dried organic solvents, since organometallic compounds and water were thought to be antagonists [16]. Indeed, organometallics are in general either hydrophobic or water-sensitive, but the credo of their incompatibility with water was so prevalent that for organometallic reactions anhydrous conditions have become a general feature of laboratory

Hydrogen activation by arene ruthenium complexes in aqueous solution

The homolytic cleavage of molecular hydrogen into hydrogen atoms is energetically preferred (ΔH° = 436 kJ mol−1) over the heterolytic cleavage to give protons and hydride anions (ΔH° = 1675 kJ mol−1) in the gas phase. However, in an aqueous solution of transition metal aqua complexes, the heterolytic dihydrogen splitting may be possible, since the energies related to the hydration of the protons (ΔH° = −1084 kJ mol−1) and to the coordination of the hydrides can overcompensate the heterolytic

Catalytic hydrogenation reactions in aqueous solution

Since molecular hydrogen is activated in water by arene ruthenium complexes, it is reasonable to assume that these complexes may catalyze hydrogenation reactions in aqueous solution, thus complying with the topical demands for environmentally friendly processes [40]. In particular, the hydrogenation of carbon dioxide to give formic acid in aqueous solution is a challenging task.

A very important finding in this respect is summarized in a paper by Professor Seiji Ogo, and co-workers, then in

Arene ruthenium bioconjugates

Since water-soluble arene ruthenium complexes are at the interface between organometallic chemistry and coordination chemistry, they can be coupled with biorelevant ligands such as amino acids and peptides or nucleobases and nucleotides, thus being working horses for the emerging field of bioorganometallic chemistry, a term introduced by Professor Gérard Jaouen from the Paris Tech Chemistry School in 1985 [70].

The first arene ruthenium amino acid derivatives were synthesized in 1977 by the

Arene ruthenium complexes with anticancer activity in vitro

Water-soluble arene ruthenium complexes are easily taken up by living cells because of their amphiphilic properties, that is to say they seem to have the right balance between the hydrophilicity of the metal center and lipophilicity provided by the arene ligand. Combined with the synthetic diversity and the fact that ruthenium is a non-toxic metal, water-soluble arene complexes are ideally suited for medicinal applications [82].

Platinum-based drugs are in clinical use for cancer treatment for

Outlook

From the beginning, the history of water-soluble arene ruthenium complexes is shaped by serendipity: Discovered by chance, benzene ruthenium dichloride dimer was found to dissolve in water, the arene ruthenium bond being inert to hydrolysis. It was also by chance that water-soluble ruthenium complexes were found to be catalytically active in aqueous solution and biologically active toward cancer cells. They illustrate par excellence how science works: Progress comes from serendipity and leads

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