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Oxidation reactions are chemical transformations that result in a substrate losing electrons and increasing its oxidation state. They involve the use of an oxidizing agent or oxidant—a reagent in its higher oxidation state that is capable of gaining electrons, and is itself reduced in the reaction.
The term oxidation takes its name from the process of adding oxygen to compounds using oxygen gas (the first known oxidizing agent). But while the addition of oxygen in this way meets the modern definition of oxidation, oxygen gas is far from the only oxidizing agent. A wide range of oxidants exist, including reagents as diverse as hydrogen peroxide, permanganate salts, chromate salts and osmium tetroxide, to name just a few. Even reagents that don’t include oxygen atoms, such as halogens like fluorine and chlorine, can be powerful oxidants.
Amongst the earliest named oxidation reactions to be developed is the Tishchenko reaction. Reported in 1906 by Russian chemist Vyacheslav Tishchenko, the transformation involves the formation of esters from two equivalents of aldehydes in the presence of magnesium or aluminum alkoxides. Tishchenko’s findings built on earlier work by German chemist Rainer Ludwig Claisen on the formation of benzyl benzoate from benzaldehyde in the presence of sodium alkoxides.
The last century has seen the development of a remarkable array of oxidation reactions that play a vital role in organic synthesis. We thought we’d highlight five of our favorites!
We can’t think of a better reaction to open our blog with than the Oppenauer oxidation! In 1937, Austrian chemist Rupert Oppenauer used catalytic amounts of aluminum tert-butoxide to convert steroids with secondary alcohol functionality into their corresponding ketones. Oppenauer’s method, which built on studies by Hans Meerwein, Wolfgang Ponndorf and Albert Verley on the reduction of carbonyl compounds using aluminum alkoxides, was high yielding and mild compared to other reactions, making it a highly useful addition to the organic chemist’s toolbox. Today, the oxidation of primary and secondary alcohols to aldehydes and ketones using metal alkoxides are known as Oppenauer oxidations. The reaction is particularly advantageous for stereochemical syntheses as the secondary alcohols are oxidized much faster than primary alcohols, allowing complete chemoselectivity to be achieved.
In 1946, Welsh chemist Sir Ewart Jones and co-workers discovered that, when they were treated with chromic acid, alkynyl carbinols generated the corresponding ketone without oxidizing the substrate’s sensitive triple bond. Since then, the oxidation of primary and secondary alcohols to carboxylic acids and ketones, respectively, using chromic acid have come to be known as Jones oxidations. The chromic acid used in the reaction is typically generated by mixing chromium trioxide or dichromate salts with sulfuric or acetic acid. For more acid-sensitive substrates, reactions based on milder chromium oxide reagents, such as the Sarett and Collins oxidation, have been developed.
1974 was a bumper year for oxidation reactions, with chemists George Rubottom, Adrian Brook and Alfred Hassner independently developing methods for the preparation of alpha-hydroxy aldehydes and ketones by the oxidation of silyl enol ethers using meta-chloro peroxy benzoic acid (mCPBA). This high-yielding reaction has come to be known as the Rubottom oxidation and, while improvements to the method have been made to allow other oxidants to be used (including catalytic amounts of methyltrioxorhenium in the presence of stoichiometric hydrogen peroxide), mCPBA remains the most common oxidizing agent for the reaction. The Rubottom reaction has been used to add alpha-hydroxyl functionality in the chemical synthesis of a wide variety of natural products, providing a synthetic shortcut to a wealth of potentially therapeutically-useful compounds.
In 1980, Karl Sharpless and Tsutomu Katsuki reported a method for the asymmetric epoxidation of a broad range of allylic alcohols. They found that when prochiral and chiral allylic alcohols were treated with a mixture of enantiomerically enriched diethyl tartrate, tert-butyl hydroperoxide and titanium (IV) tetraisopropoxide, enantiopure 2,3-epoxy alcohols could be generated in high yields. The oxidizing agent in the reaction is tert-butyl hydroperoxide, while catalytic titanium (IV) tetraisopropoxide serves to bind the allylic alcohol, asymmetric tartrate ligand and hydroperoxide to produce the enantiopure epoxide products. The Sharpless asymmetric expoxidation is an incredibly useful reaction that has played a pivotal role in the synthesis of a broad range of natural products, including a number of important terpenes, pheromones and antibiotics.
In the 1980s, the need for more selective, mild and environmentally-friendly oxidation reactions led researchers to develop a new family of oxidants based on hypervalent iodine. Amongst the most important hypervalent iodine reagents are those derived from pentacoordinate iodine. Known as periodinanes, examples include 2-iodoxybenzoic acid (IBX) and Dess–Martin periodinane (DMP). While IBX had been known for some time, its insolubility in most organic solvents inhibited its use in organic synthesis. In 1983, American chemists Daniel Benjamin Dess and James Cullen Martin reported the synthesis and use of DMP, a more soluble alternative. DMP has since become the go-to reagent for the oxidation of alcohols to their corresponding carbonyl compounds, and the transformation itself has come to be known as the Dess–Martin oxidation.
The named reactions highlighted here aren’t the only important oxidations at synthetic chemists’ disposal. Over the years, a wide range of oxidizing agents have been developed to enable transformations such as the Baeyer–Villiger oxidation, Corey–Kim oxidation, Kornblum oxidation, Ley–Griffith oxidation, Pfitzner–Moffatt oxidation, Pinnick oxidation, Swern oxidation and Wacker oxidation. To find out more, visit our dedicated oxidation reaction page.