Mitsunobu Reaction: Procedure, Reactions, Mechanism and Advantages

The Mitsunobu reaction is an organic reaction converting alcohol into various functional groups, such as ester, using triphenylphosphine, and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). The reaction was discovered and thus named after a Japanese professor, Oyo Mitsunobu. The reaction allows the conversion of primary and secondary alcohols to esters, phenyl ethers, thioethers, and different other compounds. Here we will emphasize the procedure, reaction mechanism and advantages of the Mitsunobu reaction, and discuss some important questions. 

Key takeaways: Mitsunobu reaction, organic reaction, ester, triphenylphosphine, nucleophiles, carboxylic acid, diethyl azodicarboxylate (DEAD), di-isopropyl azodicarboxylate (DIAD)

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What is Mitsunobu Reaction?

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The Mitsunobu reaction is a condensation-dehydration reaction, with the loss of a water molecule from the alcohol and the carboxylic acid. This results from the strong affinity for oxygen by TPP, and for hydrogen by DEAD. For the reaction, the typical protocol is to add the phosphine and azodicarboxylate together at -10C, typically in THF or toluene, until a white precipitate forms. This white, cloudy suspension is the ylide. Then a solution of the nucleophile and alcohol are added together and the reaction can, in most cases, be heated to reflux.

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Mitsunobu Reaction Procedure

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Although Mitsunobu reaction follows nucleophilic substitution reaction, the substitution mechanism is not direction. This is because alcohol; (-OH) is not a good leaving group. The alcohol-containing hydrocarbon usually shows retention in the configuration of the final product due to its bad leaving group characteristic. This is because it has to go through SN1 mechanism. SN2 mechanism shows inversion in the configuration of the final product and the rate of the reaction depends on both the substrate and the nucleophile, that is, the order is 2.

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Mechanism of Mitsunobu Reaction

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The reaction mechanism of the Mitsunobu reaction is complex, and the identity of reagents and their roles has been the subject of debate.

Initially, the triphenylphosphine makes a nucleophilic attack upon diethyl azodicarboxylate and produces a betaine intermediate. This deprotonates the carboxylic acid, forming the ion pair. Diethyl azodicarboxylate (DEAD) itself deprotonates the alcohol to form an alkoxide that can form the key oxyphosphonium ion. The ratio and interconversion of the intermediates depend on the carboxylic acid pKa and the polarity of the solvent. Despite several phosphorus intermediates being present, only the attack of the carboxylate anion upon intermediate can form the desired product and triphenylphosphine oxide. The overall rate of reaction is controlled by carboxylate basicity and solvation.

Typically, the alcohol, carboxylic acid, and triphenylphosphine are dissolved in tetrahydrofuran or any other suitable solvent, such as diethyl ether. This is cooled to 0 °C using an ice bath. Then the DEAD dissolved in THF is slowly added and stirred at room temperature for several hours. Sometimes, this process does not succeed, in which case, the betaine may be performed. This can be done by adding DEAD to triphenylphosphine in tetrahydrofuran at 0 °C, followed by adding the alcohol and finally the acid.

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Conditions of Mitsunobu Reaction

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Following are the conditions for successfully performing the Mitsunobu reaction:

1. The pKa value of the nucleophile should be 12 or less than 12, in order to avoid the alkylation of azodicarboxylate.
2. The reaction should take place in a neutral condition where the conditions are not too acidic or basic and the temperature can also be easily maintained. The reaction can be successfully carried out at 0°C to room temperature.
3. Standard non-polar solvents like THF and dichloromethane or polar solvents like DMF must be used for the reaction.

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Intramolecular Mitsunobu Reaction

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As its name suggests, the intramolecular Mitsunobu reaction does not take place between two substrates but is rather produced from the reaction in the substrate itself. The final product of this reaction is cyclic. On activation of the phenolic oximes by the triphenylphosphine and DEAD at a mild neutral condition at 0°C, the cyclic product is obtained. This product is a heteroatom consisting of both oxygen and nitrogen, that is, oxazoles.

The intramolecular Mitsunobu reaction has been used by several groups to prepare 6- and 7- membered cyclic ethers, but this is believed to be the first example of the formation of an optically active 2- substituted chroman-4-one via such an approach.

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Advantages of using DEAD/ DIAD

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Following are the advantages of using DEAD or DIAD as a reagent in Mitsunobu reaction:

1. They are solid in nature, which helps in the better study of the Mitsunobu reaction.
2. The polarity of the by-product is totally different.

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Things to Remember

• Many functional groups such as hydrazoic acid and imide can serve as nucleophiles besides carboxylic acids. For the reaction to be successful, the nucleophile must have a pKa less than 15.
• Bruce H. Lipshutz has developed an alternative to DEAD, called di-(4-chlorobenzyl)azodicarboxylate (DCAD), where the hydrazine by-product can be easily removed by filtration and recycled back to DCAD.
• It has been proved been that triphenylphosphine and diethyl azodicarboxylate can be combined into one reagent: a phosphorane ylide. The ylide acts as the reducing agent as well as the base. The by-products are acetonitrile and trialkyl phosphine oxide.
• The Mitsunobu reaction has been used for the synthesis of quinine, morphine, colchicine, sarain, stigmatellin, eudistomin, oseltamivir, strychnine, and nupharamine.

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