The Mitsunobu reaction uses triphenylphosphine (PPh3) and diethyl azodicarboxylate (DEAD) to convert a 1° or 2° alcohol into a wide variety of final products, dependent on the mildly acidic nucleophile (H-Nuc) used. H-Nuc transfers its proton to the zwitterionic adduct formed from PPh3 attacking the DEAD. The resulting phosphonium intermediate is then attacked by the 1° or 2° alcohol, kicking off the DEAD to form a smaller phosphonium ion. In SN2 fashion, the anionic nucleophile attacks the phosphonium ion, forming the substitution product and a by-product with a newly formed P=O bond (triphenylphosphine oxide), which drives the reaction forward.
- Reagents: PPh3 or P(n-Bu)3, DEAD or Diisopropy Azodicarboxylate (DIAD), Solvent (THF, Dioxane, DCM, Toluene, etc.)
- Reactant: 1° or 2° Alcohol, H-Nuc (pka ≤ 15)
- Product: Substitution Product, Triphenylphosphine Oxide
- Type of Reaction: SN2
Lab Tips
- Secondary alcohols undergo complete inversion of configuration. Most tertiary alcohols do not undergo the reaction, except for certain propargylic alcohols.
- Sterically hindered substrates may require temperatures over 25°C.
- Among oxygen nucleophiles, carboxylic acids give rise to esters, alcohols and phenols to ethers, while thiols and thiophenols yield thioethers.
- Common nitrogen nucleophiles include imides, hydroxamates, nitrogen heterocycles and hydrazoic acid.
Mechanism
Original Paper
Top Citations
- The Mitsunobu Reaction: Origin, Mechanism, Improvements, and Applications. Chemistry – An Asian Journal 2007, 2 (11), 1340–1355.
- Efficacious Modification of the Mitsunobu Reaction for Inversions of Sterically Hindered Secondary Alcohols. Tetrahedron Letters 1991, 32 (26), 3017–3020.
- 1,1′-(Azodicarbonyl)Dipiperidine-Tributylphosphine, a New Reagent System for Mitsunobu Reaction. Tetrahedron Letters. 1993,34 (10), 1639–1642.
Related Reactions
- Appel Reaction
- Staudinger Reaction
- Synthesis of Esters
