Guilford Techno Consultants, Inc

Wednesday, August 2, 2023 by Guilford Techno Consultants, Inc. | Name Reactions

The Mitsunobu reaction, discovered by Oyo Mitsunobu, is a reaction in which a primary or secondary alcohol can be reacted with a nucleophile through an S_N2 mechanism. The reaction is unique in that the hydroxyl group of the alcohol is converted into a better leaving group, and the resulting electrophilic species is subsequently attacked by the negatively charged nucleophile in a “one pot” synthesis. In other words, the conversion of the hydroxyl to a better leaving group and the subsequent nucleophilic attack take place in one reaction mixture, unlike other nucleophilic displacements of the hydroxyl group that involve two separate steps (i.e., tosylate formation). 

In addition to the alcohol, there are three other reactants involved in the reaction; the nucleophile, triphenyl phosphine, and diethylazodicarboxylate (DEAD). A requirement of the nucleophile is that it has an acidic proton. Appropriate nucleophiles for the reaction include carboxylic acids, thiols, and phenols, to name a few. The anion of the nucleophile is produced through deprotonation. Triphenyl phosphine serves to convert the alcohol to the electrophilic species. Both the deprotonation of the nucleophile and conversion of the alcohol to the electrophile are facilitated by DEAD, which has several roles in the mechanism. The side products of the reaction are triphenyl phosphine oxide and the reduced form of DEAD. As the mechanism is S_N2, inversion of stereochemistry of chiral secondary alcohols is observed. The mechanism for the reaction along with practice problems can be found in the following presentation.

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