双语化学辞典Chem Lexicon
反应 · 有机化学 · 胺的合成 Organic chemistry · Amine synthesis

加布里埃尔合成Gabriel synthesis

拼音Pinyin jiā bù lǐ āi ěr hé chéng　别名Also 盖布瑞尔合成；加布里埃尔伯胺合成； Gabriel amine synthesis

定义Definition

加布里埃尔合成是用邻苯二甲酰亚胺钾盐与伯卤代烷发生 SN2 烷基化，再用肼（或酸碱水解）释放出伯胺的方法。它避免了氨直接烷基化时生成仲胺、叔胺和季铵盐的多重烷基化问题。

The Gabriel synthesis alkylates potassium phthalimide with a primary alkyl halide by SN2, then releases the primary amine with hydrazine (or acid/base hydrolysis). It avoids the over-alkylation to secondary, tertiary and quaternary products that plagues direct alkylation of ammonia.

原理Principle

邻苯二甲酰亚胺 N–H 受两个羰基活化，pKa 约 8.3，可被 KOH 去质子化成亲核的酰亚胺负离子。烷基化后氮上已没有 H，也被两个羰基拉低了亲核性，因此只发生一次烷基化。

Phthalimide’s N–H is flanked by two carbonyls (pKa ≈ 8.3), so KOH gives a nucleophilic imide anion. After alkylation nitrogen carries no H and is deactivated by the carbonyls, so alkylation stops at one.

脱保护Deprotection

1926 年英–马纳斯克改进法用肼在乙醇中回流，生成稳定的邻苯二甲酰肼沉淀并释放伯胺，条件温和；传统的强酸或强碱水解较慢且苛刻。

The Ing–Manske procedure (1926) refluxes with hydrazine in ethanol, precipitating phthalhydrazide and releasing the amine under mild conditions; classic acid or base hydrolysis is slower and harsher.

由来与局限Origin and limits

德国化学家西格蒙德·加布里埃尔于 1887 年报道。只适用于伯卤代烷（仲、叔卤代烷易消除），不能制芳胺（芳基卤不发生 SN2）。也可用于合成 α-氨基酸。

Reported by the German chemist Siegmund Gabriel in 1887. It works only with primary halides (secondary and tertiary ones eliminate) and cannot make arylamines (aryl halides do not undergo SN2). It is also used to make α-amino acids.

反应Reactions

邻苯二甲酰亚胺钾 + R–X ⟶ N-烷基邻苯二甲酰亚胺 N2H4⟶ R–NH2 + 邻苯二甲酰肼Imine + R–X ⟶ N-AlkylImine N2H4⟶ R–NH2 +

DMF 中与卤代烷加热；随后肼/乙醇回流

Heat with the alkyl halide in DMF; then hydrazine in refluxing ethanol

  1. KOH 使邻苯二甲酰亚胺去质子化。

    KOH deprotonates phthalimide.

  2. 酰亚胺负离子对卤代烷 SN2 取代。

    The imide anion does SN2 on the halide.

  3. 肼进攻羰基，形成环状酰肼，放出伯胺。

    Hydrazine attacks the carbonyls, forming the cyclic hydrazide and releasing the amine.

PhthNK + PhCH2Br ⟶ PhthNCH2Ph N2H4⟶ PhCH2NH2

制备苄胺。

Preparation of benzylamine.

反应机理图Mechanism

红色弯箭头表示一对电子的移动方向：从电子来源（孤对电子或化学键）指向电子去向。Red curly arrows show where an electron pair moves: from its source (lone pair or bond) to its destination.

1

邻苯二甲酰亚胺负离子按 SN2 进攻卤代烃，只烷基化一次

The phthalimide anion alkylates once, by SN2

2

N-烷基邻苯二甲酰亚胺

N-Alkylphthalimide

N₂H₄
3

纯的伯胺（不会多烷基化）

A clean primary amine (no over-alkylation)

年表Timeline

  • 1887

    加布里埃尔报道该方法

    Gabriel reports the method

  • 1926

    英与马纳斯克提出肼解法

    Ing and Manske introduce hydrazinolysis