Mitsunobu reaction
| Mitsunobu reaction | |
|---|---|
| Named after | Oyo Mitsunobu |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | mitsunobu-reaction |
| RSC ontology ID | RXNO:0000034 |
The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). The alcohol undergoes an inversion of stereochemistry. It was discovered by Oyo Mitsunobu (1934–2003).
Several reviews have been published.
The reaction mechanism of the Mitsunobu reaction is fairly complex. The identity of intermediates and the roles they play has been the subject of debate.
Initially, the triphenyl phosphine (2) makes a nucleophilic attack upon diethyl azodicarboxylate (1) producing a betaine intermediate 3, which deprotonates the carboxylic acid (4) to form the ion pair 5. DEAD itself deprotonates the alcohol (6) forming an alkoxide that can form the key oxyphosphonium ion 8. The ratio and interconversion of intermediates 8–11 depend on the carboxylic acid pKa and the solvent polarity. Although several phosphorus intermediates are present, the attack of the carboxylate anion upon intermediate 8 is the only productive pathway forming the desired product 12 and triphenylphosphine oxide (13).
Hughes et al. have found that the formation of the ion pair 5 is very fast. The formation of the oxyphosphonium intermediate 8 is slow and facilitated by the alkoxide. Therefore, the overall rate of reaction is controlled by carboxylate basicity and solvation.
The order of addition of the reagents of the Mitsunobu reaction can be important. Typically, one dissolves the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran or other suitable solvent (e.g. diethyl ether), cool to 0 °C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room temperature for several hours. If this is unsuccessful, then preforming the betaine may give better results. To preform the betaine, add DEAD to triphenylphosphine in tetrahydrofuran at 0 °C, followed by the addition of the alcohol and finally the acid.
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