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Catalysis

Raising the gold standard

Nature volume 449, pages 292293 (20 September 2007) | Download Citation

Gold is the current star of metal catalysis, but most gold catalysts cannot control which mirror-image version of a molecule forms during a reaction. The answer lies with the positive catalyst's negative counter-ion.

Catalysts are crucial to almost every area of chemistry, often enabling reactions to occur that would otherwise be impossible. Even better, some catalysts can control molecular chirality — they determine which of two mirror-image versions a reaction product will take. Most soluble catalysts of this type are complexes, in which ligand molecules bind tightly to a transition metal; if these complexes are positively charged, the negative counter-ion generally has little effect on the chiral outcome of the reaction. But reporting in Science, Toste and colleagues1 describe excellent chiral control in organic reactions catalysed by cationic gold complexes that have chiral counter-ions. If the same principle can be extended to other metals, this discovery could spark a revolution in catalysis, with potential applications for synthesis and the chemical industry.

Many three-dimensional molecules are chiral — they can exist in two forms known as enantiomers that are not superimposable on each other. Each enantiomer may have different properties, which is often of great significance in biology, medicine or materials science. This creates a challenge for chemists: how to devise enantioselective syntheses of such compounds in which the formation of one of the enantiomers is highly preferred. Nature uses enzymes for this purpose, and antibodies can also be developed as catalysts for synthetic reactions. But enzymes and antibodies are complex molecules with high molecular weights. Chemists prefer to use smaller, more easily available catalysts, such as transition-metal complexes or small organic molecules (organocatalysts).

Gold is the latest metal to enter the arena of transition-metal catalysis2,3. Gold catalysts have developed impressively over the past few years, and have already provided some valuable contributions. Early examples4,5 used cationic gold complexes that incorporated phosphorus-containing ligands known as phosphines, in combination with non-chiral counter-ions. Most gold catalysts still conform to this design. Despite the success of gold catalysts, surprisingly few enantioselective gold-catalysed reactions have been reported.

Toste and colleagues1 now describe cationic gold complexes with chiral, negatively charged counter-ions that are based on a phosphate group. In several different reactions commonly catalysed by gold complexes, the authors used their catalysts to obtain chiral products with large excesses of one enantiomer over the other (Fig. 1a). The yields and enantiomeric ratios of these reactions far exceed the high standards required for successful chiral reactions, even when 'problematic' reagents were used that do not react under previously available conditions. This impressive chiral induction is a direct result of using a chiral counter-ion.

Figure 1: Chiral counter-ions in gold catalysis.
Figure 1

Chiral compounds can exist as one of two mirror-image forms (enantiomers). Certain catalysts can control which of these enantiomers forms during a reaction. a, In reactions such as the one shown at the top, Toste and colleagues1 find that a cationic gold complex (blue), which ordinarily does not induce chirality, can promote the formation of a desired enantiomer in the presence of a chiral counter-ion (green). b, During catalysis, reaction substrates and ligand molecules bind to gold (Au) cations on opposite sides of the metal, so the ligands are too distant to induce chirality on the substrate. The authors propose1 that counter-ions associate with the gold complex by charge attraction. This brings them close enough to the substrate to control the enantiomeric outcome of the reaction.

The authors found that the enantioselectivity of their reactions was enhanced if the cationic gold complex incorporated a chiral ligand — but only if the 'correct' enantiomer of that ligand was used. Perhaps most strikingly, the authors observed that the influence of the counter-ion can be stronger than the influence of chiral ligands covalently bound directly to the gold centre, which flies in the face of accepted chemical wisdom.

The idea of using counter-ions in catalysts to induce chirality is not new — the strategy has already been successfully used in organocatalysis6. The basic principle has even been established in transition-metal catalysis with copper complexes, although the enantioselectivity obtained was so low as to be practically useless7,8,9. Gold and copper are from the same family of elements, and might therefore be expected to exhibit similar catalytic behaviour. So why are gold catalysts so much better at chiral induction in these systems?

The gold ions — known as gold(I) ions — used in gold catalysts1 differ from most other metal centres because usually only two molecules can bind to them at once; most metals can accommodate four or six molecules. During catalysis, the gold ion binds to the reaction substrate and to another ligand, with the two molecules arranged as far apart as possible on opposite sides of the metal (Fig. 1b). In transition-metal catalysis, good chiral induction occurs only when the ligand and the substrate are close together on the metal. But on gold(I) ions the bound molecules are so far apart that only low enantioselectivity can generally be obtained.

Toste and colleagues' catalysts overcome this problem by using a counter-ion to induce chirality. The authors' spectroscopic studies1 indicate that the cationic gold complex associates closely with the counter-ion in solution, as a result of charge interactions. As long as solvent molecules do not interfere, the chiral counter-ion can occupy the free space between the ligand and the substrate (Fig. 1b). The counter-ion thus probably ends up close to the substrate and so can induce chirality during the reaction. This is similar to a previously reported effect10 in which two independent ligand units cooperate to induce excellent chiral control in transition-metal-catalysed reactions.

The coming months will show how far this concept can be extended to other metals, but there will undoubtedly be difficulties to overcome. For example, because other metals can bind to more ligands than gold(I) ions, this will make it more difficult for a counter-ion to approach the metal centre and occupy a defined position close to the substrate. Nevertheless, the simple conditions developed by Toste and colleagues1 should allow a broad range of counter-ions and ligands to be screened rapidly. Perhaps a catalytic revolution is just around the corner.

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  1. A. Stephen K. Hashmi is at the Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany. hashmi@hashmi.de

    • A. Stephen K. Hashmi

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