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The best organic reactions on offer: Five great reductions

Feb. 4, 2019

Reduction reactions play a vital role in organic synthesis. Historically, a reaction was considered a reduction if hydrogen was gained or oxygen lost. Nowadays, reduction is more broadly defined as a transformation when a compound gains one or more electrons – basically, a generalization of the original idea.

In these reactions, a ‘reducing agent’ donates electrons to another chemical species. Particularly generous electron donors include the earth metals and metal hydrides. Since the reducing agent loses electrons, it is itself oxidized in the process. Therefore reduction and oxidation always occur together, as electrons lost by one species must be gained by another.

Amongst the earliest named reduction reactions is the Tishchenko reaction, first reported in the early 1900s by the Russian organic chemist Vyacheslav Tishchenko. This reaction is still industrially relevant today as it is used to convert acetaldehyde into the commercially important solvent ethyl acetate.

Since Tishchenko’s discovery, many more industrially useful reduction reactions have been developed – here are some of our favorites. There’s a lot of interesting chemistry to choose from, but we’ve ‘reduced’ the list down to five for you!

1.The Clemmensen reduction

Named after the Danish chemist Erik Christian Clemmensen, who reported the reaction in 1913, the Clemmensen reduction describes a new method of converting carbonyl groups to the corresponding methylene group.

Clemmensen’s method produced alkanes from the reaction of simple aldehydes or ketones with amalgamated zinc (Zn/Hg) after several hours under reflux conditions. The reaction was initially conducted in a hydrophobic solvent in the presence of 40% aqueous hydrochloric acid, however these harsh conditions are not conducive to acid-sensitive substrates. Subsequent modifications, such as those developed by Yamamura and colleagues, use milder conditions to expand the functional group tolerance and make this reduction more synthetically useful.

Many heterocyclic 1,3-dicarbonyl compounds with alkyl substituents at the electronegative “2” position have interesting biological properties. Using a variation of the Clemmensen reduction, several of these compounds have been synthesized.

2.The Luche reduction

Discovered some 65 years after Clemmensen’s work, the Luche reduction is another reaction with widespread industrial uses. The pioneering work of French chemist Jean Louis Luche in 1978 led to the discovery that a mixture of cerium chloride and sodium borohydride could be used to convert alpha, beta-unsaturated ketones to allylic alcohols. Since then, this method to convert enones into the corresponding allylic alcohols has been known as the Luche reduction.

Luche’s method was a significant step forward as it exclusively synthesized the 1,2- reduction product in good yield, whereas previous methods had produced a mixture of 1,2- and 1,4- reduction products. The reaction conditions allow for the presence of many functional groups and also enable the chemoselective reduction of ketones in the presence of aldehydes.

The Luche reduction has proved important in the total synthesis of several amaryllidaceae alkaloids such as narciclasine.

3.The Meerwein–Ponndorf–Verley reduction

The mid-1920s were an exciting time in the history of reduction reactions! Between 1925 and 1926, three independent researchers carried out the reduction of carbonyl compounds using aluminum alkoxides. In a spirit of fairness, the reaction was named after all three of them – so nowadays the reduction of aldehydes and ketones using metal alkoxides such as aluminum isopropoxide is known as the Meerwein–Ponndorf–Verley reduction (or MPV for short). This is the reverse of the Oppenauer oxidation, in which alcohols are oxidized to aldehydes and ketones.

It’s the high selectivity of the MPV reduction that makes it so synthetically useful, giving it a significant advantage over the use of metal hydride reducing agents. The reaction is very chemoselective for aldehydes and ketones, and other functional groups such as esters and acetals are unchanged. The reduction has developed a myriad of uses, including synthesizing the furochromone ammiol and determining the stereochemistry of rutamycin antibiotics.

4.The Staudinger reaction

Another synthetically useful reduction is the Staudinger reaction, named after the work of Hermann Staudinger and Jules Meyer in 1919. Amongst a series of experiments, they described the reaction between phenyl azide and triphenylphosphine to generate phosphinimine. Since then, the reaction of organic azides with trivalent phosphorus compounds such as triphenylphosphine to generate the corresponding aza-ylides has come to be known as the Staudinger reaction.

The Staudinger reaction has developed many synthetic uses as it is extremely fast and high-yielding and does not form side-products. The reaction can be used to generate iminophosphorane compounds, which are stable and versatile intermediates – for example, their hydrolysis with water gives primary amines. The reaction has been used in the synthesis of a number of natural products, including the marine indole alkaloid (+)-hamacanthin B and the antiviral product (–)-hennooxazole A.

5.The Wolff–Kishner reduction

Following the pioneering work of chemists Ludwig Wolff and Nikolai Kishner in 1911–12, the deoxygenation of aldehydes and ketones to their corresponding hydrocarbons has been called the Wolff–Kishner reduction.

In the original methodology, the carbonyl compound was mixed with neat hydrazine in a high-boiling solvent such as ethylene glycol in the presence of excess base such as sodium ethoxide. However, the reaction often required refluxing for several days, as one of the by-products was water which reduced the reaction temperature. Subsequent modifications using milder reaction conditions have increased the yields that can be obtained and expanded the range of substrates that can be used. For example, the Huang–Minion modification removes the water and excess hydrazine via distillation, dramatically shortening the reaction time to just a few hours and allowing the use of cheaper reagents and water-soluble bases.

Amongst the applications of the Wolff–Kishner reduction is the total synthesis of dysidiolide, the first compound found to be a natural inhibitor of protein phosphatase cdc25A, which is essential for cell proliferation.

Other reduction reactions

There are a whole host of reduction reactions available to organic chemists – the named reactions here are just the start! Other well-known reduction reactions include the Birch reduction, Corey–Bakshi–Shibata reduction, Eschweiler–Clarke methylation, Midland Alpine borane reduction, Novori asymmetric hydrogenation and Stephen aldehyde synthesis. To find out more, visit our dedicated reduction reactions page.

 

 


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