Mitsunobu reaction template

PPh₃ adds to DEAD; the betaine deprotonates benzoic acid, the alcohol attacks phosphorus and benzoate displaces Ph₃P=O to give the inverted ester.

Mechanism step by step

PPh₃ and DEAD activate an alcohol for SN2 by a carboxylate, with inversion

1. Betaine – PPh₃ adds to the N=N of DEAD
2. Deprotonation – The betaine takes the acid proton
3. Alcohol activation – O attacks P; the hydrazide leaves
4. Proton transfer – The alkoxyphosphonium ion
5. SN2 with inversion – Benzoate attacks from the back; Ph₃P=O leaves

Key points

• Clean inversion at the alcohol carbon: (R)-alcohol → (S)-ester.
• The nucleophile needs pKa < ~13 (carboxylic acids, phenols, imides, HN₃).
• By-products Ph₃P=O and the hydrazine dicarboxylate can be hard to remove.
• Hydrolysis of the ester gives the inverted alcohol.

Drawn with 231 atoms, 16 arrows, 7 shapes – every one editable in MolDraw.

Sources

• Mitsunobu & Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380 Original paper
• Mitsunobu, Synthesis 1981, 1 Review
• Kürti & Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier 2005 Textbook
• Clayden, Greeves & Warren, Organic Chemistry, 2nd ed., OUP 2012 Textbook