米氏反应 Mitsunobu reaction — 定义、原理与由来

定义Definition

米氏反应（光延反应）是用三苯基膦和偶氮二甲酸二乙酯（DEAD）或二异丙酯（DIAD）活化醇羟基，使其被酸性亲核试剂（羧酸、酚、酰亚胺、叠氮酸等）以 SN2 方式取代、碳中心构型翻转的反应。

The Mitsunobu reaction activates an alcohol with triphenylphosphine and diethyl (DEAD) or diisopropyl (DIAD) azodicarboxylate so that an acidic nucleophile (carboxylic acid, phenol, imide, HN₃, etc.) displaces it by SN2 with inversion of configuration.

机理Mechanism

PPh₃ 加成到 DEAD 的 N=N 上生成甜菜碱；它使酸性亲核试剂（pKa 约 < 13）去质子化，同时与醇生成烷氧基𬭸盐（好的离去基团）；亲核负离子从背面进攻碳，生成构型翻转的产物和三苯基氧膦。

PPh₃ adds to DEAD’s N=N to form a betaine, which deprotonates the acidic nucleophile (pKa ≲ 13) and converts the alcohol into an alkoxyphosphonium ion (a good leaving group); the nucleophile attacks from the back, giving the inverted product and triphenylphosphine oxide.

由来Origin

日本化学家光延旺洋于 1967 年报道。中文常音译为“米氏反应”（与米氏方程无关）。

Reported by the Japanese chemist Oyo Mitsunobu in 1967. (In Chinese it is often transliterated 米氏反应, unrelated to the Michaelis–Menten equation.)

应用与缺点Uses and drawbacks

常用于翻转仲醇构型（先酯化再水解）、合成醚、酯、叠氮化物和胺（与邻苯二甲酰亚胺结合）。缺点是原子经济性差，副产物三苯基氧膦和肼二甲酸酯难以分离；DEAD 有爆炸风险。

Used to invert secondary alcohols (esterify then hydrolyse) and to make ethers, esters, azides and amines (with phthalimide). Its atom economy is poor, Ph₃PO and hydrazine by-products are hard to remove, and DEAD is shock-sensitive.

反应Reactions

R¹R²CH–OH + H–Nu + PPh₃ + DEAD ⟶ R¹R²CH–Nu构型翻转+ Ph₃P=O + EtO₂C–NH–NH–CO₂EtR¹R²CH–OH + H–Nu + PPh₃ + DEAD ⟶ R¹R²CH–Nu+ Ph₃P=O + EtO₂C–NH–NH–CO₂Et

THF，0 °C 至室温，滴加 DEAD 或 DIAD

THF, 0 °C to room temperature, with dropwise DEAD or DIAD

PPh₃ 与 DEAD 生成甜菜碱。
PPh₃ and DEAD form a betaine.
甜菜碱夺取亲核试剂的质子。
The betaine deprotonates the nucleophile.
醇与磷结合成烷氧基𬭸盐。
The alcohol forms an alkoxyphosphonium ion.
亲核试剂 SN2 背面进攻，构型翻转。
SN2 attack with inversion.

(R)-2-辛醇 + PhCOOH ⟶ (S)-2-辛基苯甲酸酯(R)-2- + PhCOOH ⟶ (S)-2-Benzoic acid

构型翻转。

Inversion of configuration.

年表Timeline

1967
光延旺洋报道该反应
Mitsunobu reports the reaction
1981
光延发表系统综述，推动广泛应用
Mitsunobu’s review spurs wide adoption

米氏反应Mitsunobu reaction