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 S_N2 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.

• 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.

• 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: S_N2

Mechanism

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