Cookies disclaimer

I agree Our site saves small pieces of text information (cookies) on your device in order to deliver better content and for statistical purposes. You can disable the usage of cookies by changing the settings of your browser. By browsing our website without changing the browser settings you grant us permission to store that information on your device.

The most radical transformations in organic synthesis? Our top five reactions involving free radicals

May 2, 2019

 

The existence of a carbon species with a single unpaired electron was considered a radical idea in the nineteenth century. However, that changed in 1900, when Russian chemist Moses Gomberg first synthesized the carbon radical triphenylmethyl. Nowadays, we know that organic free radicals have tremendous biological and synthetic significance.

Key to the chemistry of organic radicals is their structure. The carbon atom, with its single unpaired electron, is desperate to bond with another atom to obtain its full complement of electrons. As a result, free radicals are extremely reactive and have been implicated in a wide range of biological processes including aging and cancer development. Indeed, our growing knowledge of organic free radicals has helped us to understand many natural phenomena, from DNA synthesis to sunburn.

Organic free radicals also play many vital roles in industry, as they are instrumental in producing various materials such as plastics and synthetic rubber. Reactions involving free radicals have become increasingly important in organic synthesis, and there’s now a wide range of named reactions out there – we’ve picked five of our favorites for you!

1. Hunsdiecker reaction

Our first named reaction featuring free radicals is the Hunsdiecker reaction, which describes the process by which silver salts of carboxylic acids react with a halogen to produce an alkyl halide with one fewer carbon atom. While this reaction was initially described by Russian chemist Alexander Borodin in 1861, it wasn’t until 1939 that German chemists Cläre and Heinz Hunsdieker ‘borrowed’ Borodin’s books (we assume!) and built on his work to develop a general method.

Originally, the silver salts used in this reaction were prepared by treating various carboxylic acids with silver oxide. However, it’s difficult to achieve high yields with this protocol, as the silver salts must be pure and extremely dry. Fortunately, a range of strategies have been developed to overcome this problem – for example, using acid chlorides as a more reactive functional group, or using thallium(I) carboxylates in place of silver.

Another derivation of the Hunsdiecker reaction, the Barton modification, has proved very synthetically useful as it is compatible with almost all functional groups. This reaction was employed in the asymmetric total synthesis of antimitotic agents (+)- and (-)-spirotryprostatin B.

2. Meerwein arylation

The same year that the Hunsdieckers were producing their alkyl halides, German chemist Hans Meerwein and colleagues conducted a series of experiments to study the reaction of diazo compounds with alpha, beta-unsaturated carbonyl compounds. Following their pioneering work, the arylation of substituted alkenes with aryldiazonium halides in the presence of a metal catalyst has come to be known as the Meerwein arylation.

In the Meerwein arylation, the aryldiazonium halide reagents are usually prepared through the diazotization of the aromatic amines using sodium nitrite and aqueous hydrohalic acids. Once prepared, the halides are reacted immediately with the alkenes in an organic solvent such as acetone or acetonitrile.

This versatile reaction has proved useful in several successful synthesis campaigns and was instrumental in preparing a series of peptide mimetic aldehyde inhibitors of calpain, compounds with a diverse range of therapeutic uses.

3. Keck radical allylation

Discovered over three decades after the Hunsdiecker and Meerwein reactions, the Keck radical allylation describes the coupling of an alkyl halide with allyltributyltin under radical conditions to insert an allyl group. While the reaction was first described in 1973 by Masanori Kosugi and Jean Grignon (working independently), it was American chemist Gary Keck who really discovered the reaction’s broad industrial potential. Keck determined that the reaction was generally for primary, secondary and tertiary alkyl bromides, and identified azobisisobutyronitrile (AIBN) as the most efficient catalyst to initiate the process.

The Keck radical allylation has a wide range of applications, as it is highly chemoselective, accepts a number of functional groups and is tolerant of steric hindrance. Given these useful features, it has been employed in a number of total synthesis campaigns, including that of the anticancer alkaloid manzamine A.

4. Sandmeyer reaction

Another industrially useful reaction involving free radicals is the Sandmeyer reaction, which was discovered as something of a happy accident by Swiss chemist Traugott Sandmeyer in 1884. Sandmeyer was reacting benzenediazonium chloride with copper(I) acetylide in an attempt to synthesize phenylacetylene, but in an unexpected turn of events, he produced chlorobenzene instead. On investigation, he realized that copper(I) chloride was formed in situ, which catalysed the replacement of the diazonium group with a chlorine atom. Ever since, the substitution of aryldiazonium salts with halides or pseudo halides has been known as the Sandmeyer reaction.

To prepare the aryldiazonium halides required for this reaction, diazotization of the corresponding arylamines is normally carried out under anhydrous conditions. After this, the aryldiazonium compounds can be reacted in situ with copper(I) chloride, bromide or cyanide to produce the corresponding aryl halide or nitrile.

Since its unexpected discovery, the Sandmeyer reaction has been applied in a range of successful synthesis campaigns. Flupentixol, an antipsychotic drug, and neoamphimedine, a compound with anticancer properties, were both prepared using the Sandmeyer reaction.

5. Wohl‒Ziegler bromination

Taking its name from two German chemists, the Wohl–Ziegler bromination describes the addition of bromine at the allylic position of olefins or at the benzylic position of alkylated aromatic or heteroaromatic compounds. The reaction was first reported in 1919 by Alfred Wohl, but it was Karl Ziegler’s later work in 1942 that revealed its true synthetic value.

Ziegler provided a comprehensive study of the utility of N-bromosuccinimide (NBS) as a reagent. NBS is still the most effective reagent commercially available today, as it generates relatively small amounts of side products. However, the choice of solvents has moved on since Wohl and Ziegler’s early work: while benzene and carbon tetrachloride were once widely used, they’re not so popular today due to safety and environmental concerns. These days, chemists tend to use ionic liquids or even solvent-free systems.

Like many of the other free radical reactions we’ve highlighted in this blog, the Wohl‒Ziegler bromination has proved valuable in several total synthesis campaigns. For example, James M. Cook used the Wohl–Ziegler bromination to prepare (-)-tryprostatin A, a marine natural product that shows anticancer activity.

Other free radical reactions

If you’re looking for more organic reactions involving free radicals, there are loads to choose from! Other notable named reactions include the Barton radical decarboxylation, the Barton–McCombie radical deoxygenation, the Barton nitrite ester reaction, the Hofmann–Löffler–Freytag reaction and the Minisci reaction. To find out more, visit our dedicated radical reactions page.


Chemicals

Life Science

Metals & Materials

Catalysts

Analytical & Labware