Organic chemistry

Single molecules put a ring on it

Article metrics

A variant of a classical reaction has been used to generate short-lived chemical species called arynes, allowing the one-step synthesis of structurally complex benzene derivatives from simple precursors. See Article p.208

The reactions of arenes — benzene and its derivatives — have long been exploited by organic chemists for practical applications ranging from the production of simple commodity chemicals, such as polymers and dyes, to the synthesis of pharmaceuticals and other structurally complex compounds. One approach to the synthesis of arenes involves the generation of benzyne, a highly reactive, short-lived intermediate that can undergo a variety of chemical transformations. On page 208 of this issue, Hoye and co-workers1 describe a clever strategy for the generation of arynes (benzyne-containing intermediates) that involves the heat-induced isomerization of a starting material, without the need for additional reagents. This transformation is complementary to existing methods for aryne generation, and could expand the synthetic utility of these well-studied intermediates.

Arynes have been of theoretical and practical interest to chemists for the past century. However, it was not until 1953 that an isotopic-labelling study conducted by the US chemist Jack Roberts and co-workers2 provided the first compelling experimental evidence for the intermediacy of benzyne in a reaction. Organic chemists soon recognized the synthetic utility of arynes, and considerable effort has been devoted to the development of methods to generate these highly reactive species3.

Classically, arynes are generated from haloarenes — arenes in which one or more hydrogen atoms have been replaced by halogen atoms — using either strong bases or reactive organometallic reagents (Fig. 1). Although these methods work well for simple haloarenes, the use of a strong base (or a reactive organometallic reagent) can lead to unwanted side reactions when arenes containing certain chemical groups are employed. Alternatively, arynes can be generated under 'milder' conditions that are compatible with a wider range of groups by oxidizing compounds known as aminobenzotriazoles, or by heating arenediazonium carboxylate salts (Fig. 1). However, the former substrates can be difficult to synthesize, whereas the latter can explode when handled.

Figure 1: Methods for preparing arynes.
figure1

Arynes are synthetically useful chemical intermediates that can be prepared from a variety of starting materials using the general reactions shown. The groups highlighted in red are eliminated to provide arynes when subjected to the reagents or conditions indicated. In each case, the starting material contains a benzene ring. R represents any chemical group; X, X1 and X2 can be any halogen atom; Me is a methyl group. The chemical bond extending from the centre of each benzene (or aryne) ring indicates that the bond could be attached to any of the carbon atoms on the ring that is not depicted as having a chemical group attached.

A breakthrough for the practical application of arynes was the discovery4 that exposure of compounds known as aryl silyl triflates to fluoride salts produces arynes at room temperature under nearly neutral conditions (Fig. 1). This mild reaction enables the use of complex aryne precursors and reaction partners, and has inspired a renaissance in aryne chemistry5.

The strategies highlighted above can all be considered elimination reactions, in which a precursor arene loses one or more groups to form an aryne. Hoye and colleagues' approach, however, depends on a classic reaction known as the Diels–Alder cycloaddition6, and therefore represents a fundamentally different strategy. The Diels–Alder cycloaddition is the most widely studied and used method for synthesizing compounds that contain rings of six atoms7 (Fig. 2a). It involves the simultaneous formation of two carbon–carbon bonds between a diene (a molecule that contains four carbon atoms and two carbon–carbon double bonds) and a dienophile (which has two atoms and one double bond) to make a six-membered ring. The reaction works for a wide range of dienes and dienophiles, proceeds with predictable isomeric selectivity, and is highly atom-economical: all of the atoms present in the reactants appear in the product, minimizing waste.

Figure 2: A fresh twist on the Diels–Alder reaction.
figure2

a, In the classic Diels–Alder cycloaddition reaction, a diene (red) reacts with a dienophile (blue) to form a cyclic product. b, While attempting to prepare a ketotetrayne, Hoye et al.1 instead isolated a tricyclic arene. They propose that a diyne group (red) in the ketotetrayne undergoes a hexadehydro-Diels–Alder reaction with a diynophile group (blue) in the same molecule. The resulting compound can be thought of as a hybrid of two 'resonance' forms (double-headed arrow indicates resonance), one of which contains an aryne (purple). A pendant silyl ether group (orange) then reacts with the aryne to form the tricyclic arene, in which the aryne has become a benzene ring (green). Curly arrows indicate electron movement, and the dots on the oxygen atom in the silyl ether represent a pair of electrons. Me, methyl; tBu is a tertiary butyl group, CMe3.

As is the case for many scientific advances, Hoye and colleagues' discovery of their 'hexadehydro-Diels–Alder' (HDDA) reaction occurred serendipitously, during their efforts to prepare a compound known as a ketotetrayne. Instead of the ketotetrayne, they obtained a tricyclic arene as the major product (Fig. 2b). They recognized that a cycloaddition process was taking place: two carbon–carbon triple bonds (alkynes) were reacting with a third alkyne triple bond from the same molecule to generate an aryne fused to one other ring. In terminology analogous to the diene and dienophile of the classical Diels–Alder reaction, the first two alkynes comprise a diyne group, whereas the third alkyne reacts as a diynophile. The transiently formed aryne then reacted with a fortuitously positioned silyl ether group in the molecule to yield the tricyclic arene as the final product.

Realizing the potential power of this new reaction to generate arynes, Hoye et al. investigated the scope and limitations of the transformation. The reaction tolerates substrates containing a variety of chemical groups, demonstrating the generality of the reagent- and by-product-free conditions for aryne formation. The authors found that electron-withdrawing groups on the diynophile accelerate the reaction, an effect that is characteristic of standard Diels–Alder cycloadditions. In addition to silyl ethers, the aryne intermediates can react with a variety of other chemical groups, such as alcohols (which contain OH groups), olefins (which contain carbon–carbon double bonds), amides (which contain NH groups), bromide ions (Br) and aromatic rings.

Hoye and colleagues' reactions are generally high yielding, and they provide rapid access to complex arenes that could be challenging to prepare by more conventional means. Although the HDDA reaction has been the subject of previous theoretical and experimental studies8,9, the authors' report is the first to demonstrate practical applications of the transiently generated aryne intermediates and to thoroughly explore the substrate scope of these transformations.

The diyne and diynophile in the described HDDA reactions are contained within the same molecule, but one can imagine that a reaction between a diyne and diynophile from two different molecules would be an even more powerful method to construct structurally complex arenes. The prospect of such a reaction, and of myriad new aryne-reaction modes that will be enabled by the reagent-free conditions, will undoubtedly encourage continued interest in and investigation of aryne chemistry for years to come.

References

  1. 1

    Hoye, T. R., Baire, B., Niu, D. Willoughby, P. H. & Woods, B. P. Nature 490, 208–212 (2012).

  2. 2

    Roberts, J. D. et al. J. Am. Chem. Soc. 75, 3290–3291 (1953).

  3. 3

    Kitamura, T. Aust. J. Chem. 63, 987–1001 (2010).

  4. 4

    Himeshima, Y., Sonoda, T. & Kobayashi, H. Chem. Lett. 12, 1211–1214 (1983).

  5. 5

    Tadross, P. M. & Stoltz, B. M. Chem. Rev. 112, 3550–3577 (2012).

  6. 6

    Diels, O. & Alder, K. J. Liebigs Ann. Chem. 460, 98–122 (1928).

  7. 7

    Nicolaou, K. C. et al. Angew. Chem. Int. Edn 41, 1668–1698 (2002).

  8. 8

    Cahill, K. J., Ajaz, A. & Johnson, R. P. Aust. J. Chem. 63, 1007–1012 (2010).

  9. 9

    Kawano, T., Inai, H., Miyawaki, K. & Ueda, I. Tetrahedron Lett. 46, 1233–1236 (2005).

Download references

Author information

Correspondence to Sarah E. Reisman.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yeoman, J., Reisman, S. Single molecules put a ring on it. Nature 490, 179–180 (2012) doi:10.1038/490179a

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.