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Substitution reactions are one of organic chemistry’s most powerful tools. With substitutions, chemists can swap one functional group in a molecule for another, and otherwise-common organic compounds can be transformed into tailor-made molecules that are suitable for custom uses. As such, substituted products are often used as intermediates and precursors in a wide range of important pharmaceutical, agrochemical, and industrial applications.
In this blog, we will look at the influential electrophilic aromatic substitution known as the Friedel-Crafts reaction, and the reactions that were discovered as a result of Friedel and Crafts’ pioneering work. Not only did this reaction pave the way for substitutions in general, but Friedel-Crafts substitutions still have a profound impact on modern organic chemistry and underpin a huge number of current chemical processes.
While exchanging functional groups may sound straightforward, substitutions are very sensitive to which reagents and conditions are used. They are either electrophilic or nucleophilic depending on the reagents involved, and are subdivided into aliphatic or aromatic substitutions depending on the bonding structure of the substrate. Of these, one of the most useful substitution types is the electrophilic aromatic substitution.
Electrophilic aromatic substitutions exchange can take an atom connected to an aromatic ring (usually hydrogen) and replace it with an electrophile. This means that everyday aromatic hydrocarbons like benzene and toluene can be revamped into something far more exciting! In fact, the applications of this reaction encompass such a broad scope, that it can be used in anything from anticancer drugs to industrial plastics!
In 1877, Charles Friedel and James Crafts were attempting to assess the effect of aluminum metal on organic chlorides. The two chemists noticed that the reaction didn’t go as they had predicted, and various unexpected hydrocarbons were being produced. After some further experimentation, the pair uncovered the explanation—aluminum chloride had been formed in the reaction and was acting as a catalyst for further reactions.
Friedel and Crafts then set about understanding the mechanism of this catalyzed reaction and discovered that it was perfectly suited for swapping electrophilic substituents on aromatic compounds. The substituents could be alkyl or acyl, but either way, they needed the presence of aluminum chloride or a strong Lewis acid to proceed (sometimes called Friedel-Crafts catalysts in this context). This major breakthrough in electrophilic aromatic substitution is the basis of all Friedel-Crafts reactions today.
The genius of Friedel-Crafts alkylation and acylation is that it allows chemists to easily extend aromatic compounds into larger organic molecules with additional functional groups and different properties. As an example, the most widespread use of a Friedel-Crafts reaction in industry is the ethylation of benzene. Ethylbenzene is the precursor to the common plastic polystyrene, meaning this particular Friedel-Crafts reaction is employed to produce tens of millions of tons of ethylbenzene every year.
When Friedel-Crafts reactions were discovered, they opened the door for many other similar electrophilic aromatic substitutions to be developed. These newer reactions all owe their origins to the pioneering work of Friedel and Crafts, and have since become incredibly useful tools for organic chemists in their own right. Below, we’ll look at some of the most common.
In 1897, two decades after the pioneering work performed by Friedel and Crafts, another pair of scientists named Ludwig Gattermann and Julius Arnold Koch were further investigating electrophilic aromatic substitutions. They made the discovery that carbon monoxide, hydrochloric acid and a Friedel-Crafts catalyst can be employed in electrophilic aromatic substitutions to produce aromatic aldehydes. Synthesizing aromatic aldehydes in this way became known as the Gattermann-Koch reaction, which can be used to make common flavonoids like cinnamaldehyde and vanillin for the perfume industry.
Ten years after his work with Koch, Gattermann went on to further this research and discover a way to formylate aromatic compounds. He found that aromatic compounds undergo a substitution reaction with hydrogen cyanide in the presence of a Friedel-Crafts catalyst. This became known simply as the Gattermann reaction, and has also become invaluable in many modern industrial and pharmaceutical processes, such as the synthesis of the antifungal agent 7-iodo-8-quinolinol.
Houben-Hoesch reactions built on the foundation of Friedel-Crafts, and are very similar in principle to the Gattermann reaction. The reaction is named after Kurt Hoesch and Josef Houben who both independently reported their discoveries in 1915 and 1926 respectively. With a combination of nitrile and arene compounds, the Houben-Hoesch reaction can form an aryl ketone in the presence of hydrogen chloride and a Friedel-Crafts catalyst.
We can see an example of the Houben-Hoesch reaction in action with the synthesis of 2,4,6-trihydroxyacetophenone from phloroglucinol. On its own, phloroglucinol is a drug with antispasmodic properties and is also used in the synthesis of explosives. However, if it undergoes treatment with the Houben-Hoesch reaction, it forms phloroglucinol—a drug that has plasma cholesterol-lowering activity in animals.
While not technically an electrophilic aromatic substitution reaction, the Fries rearrangement is so closely linked with Friedel-Crafts reactions that it deserves special mention. Named after the German chemist Karl Theophil Fries, the Fries rearrangement was discovered in 1908, and is a rearrangement of a phenolic ester to a hydroxy aryl ketone in the presence of a Friedel-Crafts catalyst. Despite many attempts to figure out exactly how it works, how the reaction proceeds is still unknown.
What we do know is that the Fries rearrangement involves a migration of an acyl group of phenol ester to the aryl ring. This reaction is important in industry for many things, including the synthesis of hydroxyarylketones, which are vital intermediates for several pharmaceuticals. An application of this rearrangement is in the synthesis of the potent protein kinase C inhibitor balanol, which is being studied for its novel therapeutic properties in a range of diseases.
If you’d like to find out more about the reagents and catalysts needed to perform everything from Friedel-Crafts reactions to the Fries rearrangement, then why not check out our electrophilic substitution named reactions pages?