Mitsunobu reaction

The Mitsunobu reaction is to convert an organic chemical reaction to alcohol in a number of functional groups. It was developed by Oyo Mitsunobu (1934-2003) discovered and named after him.

It enables the transformation of alcohols into esters, ethers, amines, and thioethers using reagents triphenylphosphine and diethylazodicarboxylate (DEAD ) or diisopropyl azodicarboxylate ( DIAD ).

Located at the hydroxy group at a stereogenic center of the molecule, respond to such secondary alcohols in the Mitsunobu reaction with inversion at the stereocenter. In this way, the Mitsunobu benzoylation of the hydroxyl group, followed by hydrolysis of the ester thus obtained can be used in natural product chemistry for selective inversion of secondary chiral alcohols. In this context one also speaks of a Mitsunobu inversion.

Mechanism

In the initial step of triphenylphosphine (2) engages the diethylazodicarboxylate (1) and it is formed as an intermediate, a betaine (3). This betaine deprotonated carboxylic acid, and an ion pair ( 4). The alcohol, which is in the ( R) configuration, now engages this intermediate and produces a triphenylphosphonium ion alcohol (5). This will now be attacked by a SN2-type mechanism of the carboxylate ion, and there is elimination of triphenylphosphine oxide, the ester (6), which is now present in the (S ) configuration. There has been an inversion. The driving force for this reaction is the formation of very stable phosphorus -oxygen bond.

In the Mitsunobu reaction the order of addition of reagents is important. Typically, the alcohol, the carboxylic acid and triphenylphosphine in an ethereal solvent such as diethyl ether or tetrahydrofuran ( THF) and added at 0 ° C, the diazodicarboxylate. A variant in unsuccessful Mitsunobu reactions consisting of a solution of phosphine Diazodicarboxylates and at 0 ° C are added sequentially to the alcohol and the carboxylic acid.

Variants

A series of other functional groups can be prepared in the manner of alcohols, depending on the nucleophile. However, the nucleophile has to have a pKa value of less than 15.