The basis of organic chemistry is the study of carbon-containing compounds with the aim of manipulating carbon atoms to generate new molecules through the formation of carbon–carbon (C–C) bonds. In a paper in Nature, Wang et al.1 report a method for harnessing a reactive form of carbon known as a carbyne (Fig. 1a), which has been underused in synthetic chemistry. The findings open the door to new types of C–C bond-formation reaction.
Conventional approaches to C–C bond formation typically involve well-studied, reactive carbon species. Carbynes, however, have been largely unexplored for C–C bond formation because their high reactivity makes them challenging to prepare and handle. Once formed, carbynes react with each other, with solvent molecules and with other substrates in an uncontrolled manner, producing myriad products. This has limited their applications, and even efforts to study these species.
Carbynes have previously been formed as complexes with metals, which can then be decomposed to release the free carbyne (see refs 2 and 3, for example). By conducting such decompositions in water at room temperature, researchers have prepared simple compounds that contain C–C triple bonds from the reactions of free carbynes with each other4. The formation of undesired side products in these reactions was minimized because the rate of reaction of the free carbynes with water was several times slower than the rate of the carbyne–carbyne reaction5. However, product yields were low, and the method has limited applications for synthesis.
Wang et al. have devised a clever means of accessing equivalents of carbynes, an approach that has broad synthetic utility. The authors prepared stable precursor compounds that contain two ‘masking’ groups (Fig. 1b). These precursors can be activated by a catalyst in a light-mediated process so that one of the masks is released, generating a carbyne equivalent. Further activation allows the carbyne equivalent to react with substrate molecules, losing the second mask and forming three new bonds in a single synthetic step.
The authors demonstrated the power of this single-step approach by transforming isobutylbenzene (a simple hydrocarbon that contains a benzene ring) into a more-complex system, installing a new ring in a process that forms two new C–C bonds and one carbon–hydrogen (C–H) bond (Fig. 1c). The reaction occurs with high selectivity at particular carbon atoms on isobutylbenzene, and under conditions that chemists would describe as very mild: at ambient temperature and pressure, and using reagents that tolerate the presence of a wide range of groups in the substrate molecule. Such conditions avoid unwanted degradation of the starting materials or the product, thus maximizing the potential product yield.
Wang and colleagues also showed that the unmasking process could be conducted in a stepwise manner by modifying the reaction conditions, allowing the isolation of compounds in which groups known as diazoacetates are attached to benzene rings; one of the masks is retained as part of the diazoacetate group (Fig. 1d). Although methods for making diazoacetates attached to benzene rings have been reported previously, they require a synthetic ‘handle’ — a reactive atom or group — to be present on a benzene ring in the starting material6. The authors’ method installs diazoacetates directly at a C–H bond on a benzene ring, and so does not require a synthetic handle. It might, therefore, allow diazoacetates to be attached to complex aromatic systems (compounds that contain a benzene ring, or a related ring system) into which synthetic handles cannot be incorporated.
The authors show that the diazoacetate-installing reaction works effectively for a range of aromatic substrates. In each case, the diazoacetate is positioned highly selectively at a particular site — even for substrates that contain bulky groups, which often erode site selectivity in other types of reaction. Moreover, the reactions tolerate the presence of a variety of chemical groups in the substrates, and give reasonable yields of products.
The diazoacetate group is especially useful for chemical synthesis because it can be converted into many other groups using metal-catalysed reactions (as Wang et al. demonstrate for diazoacetates made using their approach). The availability of a method that allows diazoacetate groups to be incorporated site selectively into structurally complex molecules will be particularly useful for researchers working in drug discovery, because it will enable variants of biologically active molecules to be made rapidly from the molecules themselves, rather than in multi-step synthetic routes from simple starting materials. Indeed, Wang et al. demonstrate effective, site-selective diazoacetate incorporation into 12 complex drug molecules.
There are some limitations to the new reactions — for example, drug compounds that contain basic amine groups tend not to be amenable to this approach. The yields obtained for diazoacetate incorporation into drug molecules are often low to moderate (10–58%) compared with the yields observed for the less-complex substrates (mostly 50–99%). Moreover, substrates that bear strongly electron-withdrawing groups on the aromatic ring also seem to reduce yields and site selectivity relative to other substrates. But these are minor issues compared with the benefits of this approach for drug discovery and development.
Wang and colleagues’ work also has more-fundamental implications for organic chemistry. It offers a new means of generating diazo compounds (the family of compounds to which diazoacetates belong) that allows access to types of diazo molecule that were not previously accessible using other chemistries. In addition, because the reactions generate three new bonds, they provide a way to convert simple reagents into structurally complex molecules in a single step. The authors’ reactions are therefore an invaluable addition to the synthetic chemist’s toolbox.
Finally, Wang et al. have reported the first evidence that carbynes can be harnessed effectively for practical organic synthesis. The findings therefore open the door to the exploration of new reactivities of carbon — either through modification of the currently reported masked carbyne equivalents, or through the development of alternative ones.
Nature 554, 36-38 (2018)
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