Game-Changing Recipe for Chemical Building Blocks

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News & views instead are used as raw materials that are ‘decorated’ with other chemical groups. Organic chemistry This is similar to how bakers think about making an apple pie. Apple pies are made using Game-changing recipe for pastry dough for the crust and apples for the filling. Apples are the only ingredient that can be used, because there is no way to make an chemical building blocks apple filling from other ingredients. Fortu- nately for bakers, apples are relatively inexpensive and widely available in most areas, but Valerie A. Schmidt the resources needed to plant, grow, harvest Chemists generally regard benzene rings as preformed units and distribute the ripened fruit are taken for that are elaborated to build larger molecules. This idea has granted. This parallels the historical use of now been challenged in reactions for making anilines — BTX as cheap, widely available ‘ingredients’ for making more-complex molecular targets. The precursors of many high-value chemical products. See p.75 time-intensive geological process by which crude oil is produced from organic material, and the many resources needed to extract the Decades of research have provided chemists bond can be replaced with a carbon–nitrogen oil, to isolate BTX from it and to distribute the with the tools to synthesize a diverse array (C–N) bond without disrupting the aromatic chemicals for use in manufacturing processes, of organic molecules in short sequences system, thus producing the nitrogenated are also taken for granted. of high-yielding reactions, making use of aromatic framework of an aniline. This But what if apples weren’t the only inexpensive and widely available chemi- method for making anilines is known as the ingredient that could be used for the filling? cal building blocks. When a new reaction is nitration–reduction pathway2 (Fig. 1a). What if apple seeds — which contain all the reported that fundamentally alters the idea of Alternatively, carbon–halogen bonds in BTX basic genetic information needed to produce what can be used as a building block, it can be a derivatives can be replaced by C–N bonds6, an apple — and a few speciality spices could game changer. On page 75, Dighe et al.1 report either using a strong base if the benzene ring is somehow be used instead, and still produce one such potentially transformative reaction highly activated, or using sophisticated metal a perfect apple pie? In this (admittedly far- that uses light and two transition-metal catalysts. Such reactions are broadly known fetched) scenario, the idea that apples are catalysts to make products known as anilines — as aromatic substitutions (Fig. 1b). Funda- the only basic ingredient of an apple pie would key ingredients for making pharmaceuticals, mentally, nitration–reduction pathways and have to be altered. Dighe et al. have essentially agrochemicals, dyes, electronic materials and aromatic substitutions both revolve around performed the chemical equivalent of making polymers2,3. the entrenched idea that complex aromatic apple pie from apple seeds. When chemists describe certain organic molecules are made only from building blocks The authors have leveraged the inherent molecules as being aromatic, they aren’t refer- that already contain aromatic rings. Aromatic propensity of nitrogen-containing com- ring to their smell. They’re actually describing frameworks are therefore generally not made pounds called amines to react with carbonyl molecules — such as those that contain from scratch during organic synthesis, but (C=O) groups to form a C–N bond. These benzene rings — that have a certain number of electrons interlocked into circular systems, thereby lowering the energy of the molecule a Nitration–reduction pathway concerned. Anilines are benzene rings with a H NO2 Hydrogen gas NH2 nitrogen atom attached, and do often have a Nitric acid Catalyst fishy smell. But their odour is one of the least R1 R1 R1 noteworthy things about them. Aniline Aniline groups were present in three b Aromatic substitution 2 of the top ten highest-grossing global R X 2 N pharmaceuticals in 2019 — Eliquis R R3 + HN (apixaban), Revlimid (lenalidomide) and 3 Base or catalyst R1 R R1 Xarelto (rivaroxaban), combined retail Amine sales of which surpassed US$28 billion (see c Dehydrogenative amination go.nature.com/2dirpwf; ref. 4). Aniline com- Iridium and R2 pounds are also precursors for one of the O R2 cobalt catalysts N 3 two monomers needed to produce poly + HN R 3 Blue light urethane materials, which in turn are used R1 R R1 to make everything from stretchy fabrics Cyclic ketone and compressible foams to the wheels of skateboards and rollercoasters5. These are all Figure 1 | Methods for synthesizing anilines. a, In the two-step nitration–reduction pathway, a hydrogen high-value commercial products, so finding atom on a benzene ring is replaced by a primary amine group (NH ); hydrogens on other carbon atoms versatile ways to make anilines from abundant 2 are not shown. b, In aromatic substitutions, a halogen atom (X) is displaced by an amine, in the presence chemicals is of great interest. of either a base or a catalyst. In a and b, the benzene ring of the aniline comes from the starting material, Simple anilines are generally derived and only groups (blue) attached to the ring are altered. c, Dighe et al.1 report dehydrogenative amination from benzene, toluene and xylenes (BTX) — reactions in which the benzene ring of the aniline is made from the ring of a cyclic ketone (rings shown in petrochemicals available at low cost in bulk red), and a carbonyl (C=O) group is converted into an amine group (blue). The reactions require a light- quantities. These building blocks contain a ben- activated iridium catalyst and a cobalt catalyst. R1 can be any chemical group; R2 and R3 represent a hydrogen zene ring in which a carbon–hydrogen (C–H) atom or any hydrocarbon group.

reactions produce compounds known as status quo, but having the freedom to choose 3. Vogt, P. F. & Gerulis, J. J. in Ullmann’s Encyclopedia of enamines that contain a non-aromatic ring, from an increased range of options for making Industrial Chemistry https://doi.org/10.1002/14356007. a02_037 (Wiley, 2000). which can readily lose an electron to a light- anilines is a wonderful thing. 4. McGrath, N. A., Brichacek, M. & Njardarson, J. T. activated iridium catalyst (see Fig. 1b of the J. Chem. Educ. 87, 1348–1349 (2010). paper1). Loss of an electron produces a reactive Valerie A. Schmidt is in the Department of 5. Szycher, M. Szycher’s Handbook of Polyurethanes 2nd edn (CRC, 2012). intermediate called an enaminium radical, Chemistry and Biochemistry, University of 6. Hartwig, J. F., Shekhar, S., Shen, Q. & which contains an unpaired electron. This California, San Diego, La Jolla, California Barrios-Landeros, F. in PATAI’s Chemistry of Functional radical then engages a cobalt catalyst, which 92093, USA. Groups (eds Rappoport, Z. et al.) https://doi. removes hydrogen atoms sequentially from e-mail: [email protected] org/10.1002/9780470682531.pat0391 (Wiley, 2009). 7. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Chem. Rev. the non-aromatic ring, thereby forming the 113, 5322–5363 (2013). aromatic ring of an aniline. This overall pro- 1. Dighe, S. U., Juliá, F., Luridiana, A., Douglas, J. J. & 8. Dempsey, L. L., Brunschwig, B. S., Winkler, J. R. & cess is termed dehydrogenative amination Leonori, D. Nature 584, 75–81 (2020). Gray, H. B. Acc. Chem. Res. 42, 1995–2004 (2009). 2. Kahl, T. et al. in Ullmann’s Encyclopedia of Industrial 9. Iosub, A. V. & Stahl, S. S. ACS Catal. 6, 8201–8213 (2016). (Fig. 1c), and it allows anilines to be produced Chemistry https://doi.org/10.1002/14356007.a02_303. 10. Liu, X., Chen, J. & Ma, T. Org. Biomol. Chem. 16, from non-aromatic precursors. pub2 (Wiley, 2011). 8662–8676 (2018). Light-activated iridium catalysts have previously been used for single-electron Archaeology oxidations7 (processes in which an electron is lost from a molecule), and cobalt catalysts have also been used to remove hydrogen 8 Evidence grows for early atoms from molecules . But by melding these two processes together, Dighe et al. have produced a reaction that is greater than the peopling of the Americas sum of its parts. Other methods for preparing aromatic rings from scratch have previously Ruth Gruhn been reported9,10, but have been challenging to use for organic synthesis. The long-debated timing of the peopling of the Americas The authors demonstrate that their comes into focus, thanks to some archaeological findings. reaction can make a wide array of anilines, What are the implications of a revised timeline for our nearly two-thirds of which contain structural motifs commonly found in biologically active understanding of these earliest inhabitants? See p.87 & p.93 compounds or pharmaceuticals. Indeed, the authors show that their reactions can be used to make seven medicines, including the local Ardelean et al.1 (page 87) and Becerra-Valdivia for many of the following decades, that anaesthetic lidocaine and the cardiovascular and Higham2 (page 93) report evidence that the earliest people in the Americas were drug vesnarinone. The use of dehydrogenative the initial human settlement of the American specialized big-game hunters who very amination to synthesize those two compounds continent happened earlier than is widely rapidly expanded into North and South avoids the problems of the current industrial accepted, and some of this evidence suggests America, within 1,000 years of initial entry13. production routes, which start from aromatic that expansion into the continent began at This model became known as the Clovis-first building blocks. least 10,000 years earlier than was generally theory. It was later established that Clovis tech- Dighe and colleagues’ reactions might suspected. A study of radiocarbon dating of nology did not reach the southern continent. be beneficial when nitration–reduction early archaeological sites by Becerra-Valdivia The time of their entry from Alaska into what is approaches do not occur selectively at a and Higham reveals that interior regions of now the continental United States was thought single C–H bond on an aromatic ring, or when Alaska, Yukon in Canada and the continental to coincide with the opening of an ice-free corri- aromatic substitutions are low-yielding or United States were already widely populated dor (Fig. 1) by around 13,000 years ago between prohibitively expensive. However, nitration– before 13,000 years ago. For decades, that the great northern continental ice sheet (called reduction pathways are generally reliable time frame was widely considered to mark the the Laurentide Ice Sheet) and the ice-covered and scalable, and use inexpensive starting earliest possible date of initial entry, until data northern Rocky Mountains (the Cordilleran materials, and have therefore enabled the from sites more than 13,000 years old in North Ice Sheet) in western Canada. industrial-scale synthesis of anilines — this and South America, first reported in the 1970s, However, beginning in the mid-1970s, is, in part, why aniline-containing com- raised the possibility of earlier arrivals3–5. researchers identified archaeological pounds are so widely used. By contrast, the Archaeological excavations in Chiquihuite sites in the Americas dated to earlier than chemical-engineering processes needed to Cave in northern Mexico by Ardelean and 13,000 years ago, especially in South America. scale up Dighe and co-workers’ light-activated, colleagues provide evidence of human occu- For example, the site of Monte Verde II iridium-catalysed chemistry is unknown, and pation about 26,500 years ago. This Mexican in south-central Chile, initially dated to will be a factor that affects how extensively site now joins half a dozen other documented 14,500 years ago3, is a well-preserved open the reactions are adopted for the production archaeological sites in northeast and central settlement with wooden structures and of commercial chemicals. Moreover, iridium Brazil that have yielded evidence suggest- artefacts indicating a lifestyle based mainly is one of the rarest elements in Earth’s crust, ing dates for human occupation between around a diet of plants (subsequent dis- limiting supplies of the catalyst and increasing 20,000 and 30,000 years ago6–12. coveries revealed earlier occupations of its cost. Following discoveries in the 1930s on the this site14). Other early archaeological sites Nevertheless, Dighe et al. have shown that American Great Plains of distinctive, well- in South America on the Pacific coast, in aniline synthesis need not be bound by con- crafted stone spear points — of a type connected the northern and central Andes, on the ventions that dictate the use of preformed with the Clovis culture — alongside bones of Caribbean coast, in the Brazilian uplands, aromatic rings. Time will tell whether the mammoths, mastodons and a now-extinct in the Amazon basin, and on the Patagonian authors’ reactions will completely replace the bison species, archaeologists maintained, steppe in Argentina indicate that all major