Alcohol coupling — inversion
Mitsunobu reaction
How the Mitsunobu reaction works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: PPh₃, DEAD (or DIAD), acidic H–Nu (pKa < 13). Conditions: THF, 0 °C → 25 °C. Bonds formed: C–Nu; P=O; bonds broken: C–O (alcohol). Stereochemistry: Clean inversion at the alcohol carbon. Rate and selectivity: Betaine formation fast; SN2 step rate-limiting.
At a glance
Step 1: Betaine forms and deprotonates the acid
PPh₃ attacks DEAD (diethyl azodicarboxylate), and the resulting betaine deprotonates an acidic nucleophile (like a carboxylic acid), forming an activated phosphonium species.
Step 2: Alcohol O attacks P⁺
The alcohol's oxygen attacks that phosphonium center, forming an oxyphosphonium intermediate — the same kind of activated leaving group used in the Appel reaction.
Step 3: SN2 with inversion
The deprotonated nucleophile performs a backside SN2 attack, displacing triphenylphosphine oxide and giving the coupled product with clean inversion of configuration at the original alcohol carbon.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- Nu
- Nucleophile. An electron-rich species that donates an electron pair to form a new bond.
- Ph
- Phenyl. –C₆H₅.
- THF
- Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
- DEAD
- Diethyl azodicarboxylate. Mitsunobu oxidant: picks up PPh₃ to form a betaine.
- DIAD
- Diisopropyl azodicarboxylate. Mitsunobu oxidant, handier than DEAD.
- PPh3
- Triphenylphosphine. Nucleophilic phosphine; forms very strong P=O bonds, driving Wittig, Appel and Mitsunobu reactions.
- TPPO
- Triphenylphosphine oxide. The thermodynamic sink of Wittig/Mitsunobu/Appel reactions.
- SN2
- Bimolecular nucleophilic substitution. One concerted step with backside attack and inversion; rate = k[RX][Nu].
- pKa
- Acid-dissociation constant (–log). Lower pKa = stronger acid; used to judge which proton a base removes.
How it compares with related reactions
| Mitsunobu reaction | Appel reaction | Corey-House synthesis | |
|---|---|---|---|
| Reagents | PPh₃, DEAD (or DIAD), acidic H–Nu (pKa < 13) | PPh₃, CBr₄ (or CCl₄) | 2 R–Li, CuI; then R′–X (primary alkyl iodide, bromide or tosylate) |
| Conditions | THF, 0 °C → 25 °C | CH₂Cl₂, 0–25 °C | Et₂O or THF, –78 to 25 °C |
| Stereochemistry | Clean inversion at the alcohol carbon | Inversion at carbon (SN2) | Inversion at a stereogenic sp³ C–X in many cases; best with 1° halides |
| Rate / selectivity | Betaine formation fast; SN2 step rate-limiting | Driven by strong P=O bond; works best on 1° and 2° alcohols | Soft, low-polarity C–Cu bond: little elimination or carbonyl attack vs RLi |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Mitsunobu reaction?
PPh₃, DEAD (or DIAD), acidic H–Nu (pKa < 13). Conditions: THF, 0 °C → 25 °C.
Which bonds are formed and which are broken?
Formed: C–Nu; P=O. Broken: C–O (alcohol).
What is the stereochemical outcome?
Clean inversion at the alcohol carbon
What controls the rate or the selectivity?
Betaine formation fast; SN2 step rate-limiting
Study guides that help with this reaction
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go