Organic chemistry

Radical catalysis

The domination of metals in catalysis is under threat as organic catalysts gain ground. The latest example may expand chemical reactivity beyond the achievements of traditional metal complexes.

Chemists are currently excited about a different take on organic synthesis, in which purely organic molecules are used as catalysts, rather than metals or enzymes. This previously neglected strategy holds great promise in areas such as drug discovery and materials science, and has already been used in several valuable reactions. But so far, these processes have involved only charged intermediates. Reporting in Science, MacMillan and colleagues1 now describe a general strategy for organocatalysis using radical intermediates — molecules that contain reactive single electrons. The principle behind this could lead to a new family of useful reactions.

Most naturally occurring compounds are chiral: they are not superimposable on their mirror images. Using enzymes as catalysts, nature is the uncontested master at producing chiral compounds as just one mirror-image version — in enantiomerically pure form, to use the technical jargon. Chemists, however, have to rely on different approaches to render their reactions enantioselective, although their inspiration may still come from nature. Early efforts emulated metal-containing enzymes, and many metal catalysts have been developed that induce one particular chirality in a wide range of chemical transformations2. But half of all known enzymes are metal-free, and it is these that organic chemists seek to mimic. Organocatalysis has now emerged as a promising strategy that avoids using protein catalysts or potentially toxic and expensive metals3,4. Not only does it complement established methods, but it sometimes also overcomes their limitations, so that many unprecedented transformations can be realized.

MacMillan and co-workers' radical reactions1 are catalysed by chiral amines — organic compounds that contain a basic nitrogen atom. Such organocatalysis is related to that seen in certain enzymes that are crucial for sugar metabolism, and has ancient synthetic roots5. But although amines and amino acids were used in a narrow context as chiral catalysts in the 1970s, a clear understanding of their catalytic behaviour was lacking. It was another 30 years before the mechanistic principle was realized; this was termed 'enamine catalysis', after the intermediate that forms during the process6. The true potential of this approach then became apparent with the discovery of several valuable and predictable transformations. A related method, known as iminium catalysis, was developed in parallel7. These two concepts are collectively known as aminocatalysis8.

To understand how aminocatalysis works, one has to know a little about molecular orbitals. Two need to be considered — the most energetic orbital that contains electrons (known as the HOMO) and the least energetic orbital that doesn't contain electrons (the LUMO). Enamine formation increases the HOMO energy of the starting materials (aldehydes and ketones), whereas iminium ion formation lowers the LUMO energy. Both catalytic modes activate the substrates towards reaction and facilitate attack from reagents that seek areas of negative or positive charge. But these modes of action are based on the natural polarity of the reactants, which limits organocatalysis to transformations that are — at least in principle — also possible with metal-based catalysis.

MacMillan and co-workers1 overcome this limitation by introducing a third mode of aminocatalysis, based on radical intermediates. Amines and aldehydes react to form iminium ions, which may convert into enamines in an equilibrium process (Fig. 1a); this equilibrium has been exploited in enantioselective reactions that sequentially react by enamine and iminium catalysis9. But enamines can be intercepted by an oxidizing agent, which removes an electron from the intermediate to generate a positively charged radical; the highest-energy orbital of this radical cation contains a single electron, and is known as a SOMO. The radical intermediate is more susceptible to subsequent chemical attack than the aldehyde starting material.

Figure 1: A radical mode of organocatalysis.
figure1

a, In organocatalysis, an aldehyde reacts with an amine catalyst to generate an iminium ion intermediate, which can be in equilibrium with an enamine. MacMillan and colleagues1 use an oxidizing agent to remove a single electron from the enamine, so producing an enamine radical cation that is more prone to subsequent reaction than the original aldehyde. Ph represents a phenyl group; dots represent reactive electrons. b, The radical organocatalytic system is used in this reaction to add an allyl group (red) to an aldehyde, where ceric ammonium nitrate (CAN) is the oxidizing agent. One of the two possible mirror-image products (enantiomers) is formed preferentially.

Such SOMO-activation was previously known only in a single example of a light-driven enantioselective reaction10 and in reactions that were not enantioselective and which required a whole equivalent of amine per mole of the starting material11. MacMillan and colleagues1 have revisited this concept, and have improved it by developing an enantioselective version that requires much less amine. The amine catalyst used (an imidazolidinone; Fig. 1a) had previously been developed by their group7.

The authors chose several reactions to demonstrate the generality of their concept. All of them result in the formation of carbon–carbon bonds adjacent to the carbonyl group (C=O) of aldehydes, a transformation that is extremely useful in organic synthesis. One of these reactions was studied in great detail — the addition to aldehydes of hydrocarbon fragments that are based on a three-carbon unit called an allyl group (Fig. 1b). Several aldehydes were reacted with structurally diverse allyl reagents, to give products with good chemical yields and enantioselectivities. Previously, such reactions were restricted to using 'electrophilic' reagents that generate allyl cations12. The new approach opens up fresh possibilities by permitting the use of reagents that would normally generate allyl anions.

Impressive as this work is, there are still limitations. For example, each mole of aldehyde requires two equivalents of the oxidizing agent. It would be more efficient if the oxidant could be recycled during the reaction, so that a much smaller amount could be used. Such an approach has recently been described13 for an enantioselective reaction that forms carbon–oxygen bonds, using SOMO-activation by a chiral amine catalyst. That report, taken together with the work of MacMillan and colleagues1, clearly marks the beginning of a new aminocatalytic concept, with many applications expected in the near future. This mode of reaction will surely have a major impact on organic synthesis.

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Mukherjee, S., List, B. Radical catalysis. Nature 447, 152–153 (2007). https://doi.org/10.1038/447152a

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