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Organic chemistry

Nickel steps towards selectivity

Hydrocarbons called alkenes are isolated from petroleum as mixtures of isomers, often making it hard to use them as reagents for synthesis. A reaction involving a migrating nickel atom offers a possible solution. See Letter p.84

On page 84, Juliá-Hernández and co-workers1 report a remarkable feat of chemical selectivity: a process that converts isomeric mixtures of compounds known as alkenes into single fatty acids, by reacting them with the greenhouse gas carbon dioxide. The process not only overcomes a problem that has long hampered the chemical processing of petroleum-derived alkenes, but also might have many applications — fatty acids are crucial ingredients in products such as rubber, soaps and plastics, and it is estimated2 that they will have a global market value of US$20 billion by 2023.

The past 100 years have witnessed remarkable discoveries that have greatly advanced the synthetic use of alkenes — simple hydrocarbons that contain carbon–carbon double bonds (C=C bonds). Reactions of C=C bonds have thus become central to the synthesis of products ranging from plastics to complex pharmaceutical agents, because they enable the ready conversion of cheap and abundant petroleum-derived alkenes to value-added products. But such alkenes are often mixtures of regioisomers, in which the C=C bond is located at different positions along a hydrocarbon backbone. Reactions of regioisomeric alkene mixtures frequently yield multiple products, which must be separated, and at great cost. Some chemical processes circumvent this problem, but reactions in which regioisomeric alkenes selectively generate single products remain rare3.

The production of fatty acids also comes with selectivity problems. Most fatty acids are prepared on industrial scales by breaking down animal- and plant-derived lipids using water4. This allows fatty acids to be used as a renewable feedstock chemical (a raw material that can be used in bulk for industrial processes), but the compounds are mainly isolated as complex mixtures of fatty acids of varying chain lengths. Separation by fractional distillation and further chemical modification are subsequently required to generate the pure, non-natural fatty acids typically required for the production of fine chemicals, such as pharmaceutical ingredients or detergents.

An alternative approach commonly adopted for making short-chain acids involves the reaction of simple alkenes with carbon monoxide (a cheap feedstock gas) and water. This process, known as hydrocarboxylation, can be promoted by metal catalysts. For example, the industrial production of propanoic acid (C2H5COOH) relies on the nickel-catalysed hydrocarboxylation of ethene (CH2=CH2), another abundant, petroleum-derived feedstock gas5. Notably, the high natural abundance of nickel makes it an economical and sustainable alternative to commonly used precious-metal catalysts. But although hydrocarboxylation works well for pure, simple alkene substrates, regioisomeric alkene mixtures generate product mixtures that are difficult to separate.

Juliá-Hernández and co-workers have developed a two-step process that converts isomeric alkenes and CO2 into single fatty acids (Fig. 1). The process begins by exposing mixtures of regioisomeric alkenes to hydrobromic acid, which adds a hydrogen and a bromine atom across the C=C bond in each isomer. In the second step, a catalyst — consisting of a nickel atom in complex with a large ligand molecule — inserts its nickel atom into the resulting carbon–bromine bond, forming an intermediate that contains a carbon–nickel (C–Ni) bond in the middle of a hydrocarbon chain. Interactions between the bulky nickel complex and neighbouring hydrocarbon groups destabilize this intermediate. Through a series of previously well-characterized organometallic processes, the nickel group subsequently 'walks' down the chain until it reaches a position that is free from these adverse interactions. The C–Ni bond then reacts with CO2 gas, a process known as carboxylation, forming a single fatty-acid product and regenerating the catalyst.

Figure 1: Synthesis of single fatty acids from mixtures of isomeric alkenes.
figure1

a, Juliá-Hernández et al.1 report a process that can convert mixtures of regioisomers of alkenes into a single fatty acid; regioisomers contain chemical groups (in this case, carbon–carbon double bonds) at different positions in a molecule. b, In the first step, the alkenes are reacted with hydrobromic acid (HBr) to form a regioisomeric mixture of alkyl bromides; only one regioisomer is shown for simplicity. Me, methyl group. c, The alkyl bromides are treated with a nickel catalyst to form a regioisomeric mixture of an unstable organonickel intermediate; [Ni] represents a nickel atom in complex with a bulky ligand molecule. d, The nickel atom then 'walks' along the hydrocarbon chain, until it forms a terminal organonickel intermediate. The same terminal intermediate forms as a result of chain walking in the other organonickel regioisomers. e, The terminal intermediate reacts with carbon dioxide to form the target fatty acid.

Central to the success of this process is the chain-walking event. Compounds that contain C–Ni bonds often decompose through a pathway called β-hydride elimination, which forms an alkene and a compound that contains a nickel–hydrogen (Ni–H) bond. Importantly, this process is reversible, which means that the nickel and hydrogen atoms in the Ni–H bond can reattach to the alkene to form one of two possible isomeric nickel-containing compounds. One of these isomers is the same species that generated the alkene, but the other contains a C–Ni bond at the next carbon atom along the hydrocarbon chain — as though the nickel atom has taken a step along the chain. Juliá-Hernández et al. have fashioned this often deleterious side reaction into the directable chain-walking event described above.

The chain-walking event is analogous to that observed with certain zirconium-containing reagents6, but Juliá-Hernández and co-workers' process is catalytic and uses a widely available, inexpensive nickel salt, which makes the process potentially economically viable for fine-chemical production. The authors also found that chain walking could be initiated directly from a wide range of alkyl bromides (the bromine-containing compounds formed as intermediates in the first step of the process), rather than from alkenes, to form diverse acids in good yields. These acids could be used as versatile intermediates for organic synthesis.

Juliá-Hernández et al. also performed their reaction using alkyl bromides that contain carbonyl (C=O) groups, which can stabilize adjacent carbon–metal bonds. The authors observed that carboxylation occurred preferentially next to the stabilizing groups in reactions carried out at 42–50 °C, whereas reactions at lower temperatures (10–25 °C) favoured carboxylation at the terminal position of the hydrocarbon chain, with modest to excellent selectivities. This provides a simple method for selectively generating either one of two products from a single set of reactants, and will be a powerful tool for synthesizing variants of structurally complex compounds.

The authors' catalytic method enables the selective synthesis of useful fatty acids from readily available building blocks. Although still at a preliminary stage, these reactions could potentially underpin a new approach to the industrial production of fatty acids. Moreover, if other chain-walking events can be designed that terminate in reactions with reagents other than CO2, this would dramatically expand the portfolio of chemicals that can be made from alkenes. At present, a two-step process is needed to convert petroleum-derived alkenes into fatty acids. But if a one-step, nickel-catalysed carboxylation can be developed for alkenes (or even for alkanes, analogues of alkenes that contain only single carbon–carbon bonds, and for which the authors also show some exciting preliminary results), it would open up these abundant chemical feedstocks for use in research in synthetic chemistry.Footnote 1

Notes

  1. 1.

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Gaunt, M., Williamson, P. Nickel steps towards selectivity. Nature 545, 35–36 (2017). https://doi.org/10.1038/545035a

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