Formation of Amines | 胺的制备

📚 Formation of Amines | 胺的制备

Amines are organic derivatives of ammonia in which one or more hydrogen atoms have been replaced by alkyl or aryl groups. They are classified as primary (1°), secondary (2°) or tertiary (3°) depending on how many carbon-containing substituents are bonded to the nitrogen atom. The preparation of amines is a core topic in A-Level Chemistry, requiring a clear understanding of several synthetic routes. Each method has its own selectivity, limitations and mechanistic details that must be carefully considered to obtain the target amine in good yield and purity.

胺是氨的有机衍生物，其中一个或多个氢原子被烷基或芳基取代。根据与氮原子相连的含碳取代基的数量，胺可分为伯胺（1°）、仲胺（2°）和叔胺（3°）。胺的制备是A-Level化学的核心内容，需要清楚地理解多条合成路线。每种方法都有其自身的选择性、局限性以及机理细节，必须仔细考量才能以较好的产率和纯度制得目标胺。

1. Introduction to Amine Formation | 胺的制备概述

The central challenge in synthesising a specific class of amine, particularly primary amines, is to prevent further reaction at the nitrogen atom. Amines are themselves nucleophiles, so the initial product can attack another molecule of the electrophile, leading to mixtures of secondary, tertiary amines and even quaternary ammonium salts. Synthetic strategies must therefore be designed to stop the reaction at the desired degree of alkylation. The most important laboratory and industrial routes include nucleophilic substitution of halogenoalkanes, the Gabriel synthesis, reduction of nitro compounds, nitriles and amides, reductive amination and the Hofmann rearrangement.

合成特定类型的胺，尤其是伯胺，其核心挑战在于防止在氮原子上发生进一步反应。胺本身是亲核试剂，因此初始产物可以继续进攻另一分子亲电试剂，导致生成仲胺、叔胺甚至季铵盐的混合物。因此，合成策略必须设计为将反应停止在所需的烷基化程度。最重要的实验室和工业路线包括卤代烷的亲核取代、加布里埃尔合成、硝基化合物、腈和酰胺的还原、还原胺化以及霍夫曼重排。

2. Nucleophilic Substitution of Halogenoalkanes | 卤代烷的亲核取代反应

Halogenoalkanes react with an excess of ammonia in ethanol under heat and pressure to give amines. The reaction proceeds via an S_N2 mechanism in which ammonia acts as a nucleophile, displacing the halide ion. The initially formed alkylammonium salt is then deprotonated by a second molecule of ammonia to release the free primary amine.

卤代烷与过量的氨在乙醇中加热加压反应生成胺。反应通过S_N2机理进行，氨作为亲核试剂进攻并取代卤离子。初始生成的烷基铵盐随后被另一分子氨去质子化，释放出游离的伯胺。

R–X + 2NH₃ → R–NH₂ + NH₄X

However, the primary amine produced is a stronger nucleophile than ammonia and will compete for the remaining halogenoalkane. This leads to secondary and tertiary amines, and ultimately quaternary ammonium salts. As a result, the method gives a mixture that is difficult to separate. Using a very large excess of ammonia can bias the product distribution towards the primary amine, but even then the selectivity is rarely sufficient for preparative purposes.

然而，生成的伯胺是比氨更强的亲核试剂，将与剩余的卤代烷竞争。这样就会生成仲胺和叔胺，并最终形成季铵盐。因此，该方法得到的是难以分离的混合物。使用非常大过量的氨可以使产物分布向伯胺倾斜，但即便如此，其选择性仍很少能满足制备要求。

3. The Gabriel Synthesis of Primary Amines | 加布里埃尔合成伯胺

The Gabriel synthesis offers a clean route to primary amines without over-alkylation. Phthalimide is first deprotonated with potassium hydroxide to form the nucleophilic potassium phthalimide. This salt then undergoes an S_N2 reaction with a primary alkyl halide to give an N-alkylphthalimide.

加布里埃尔合成提供了一条无需担心过度烷基化、能够干净地制得伯胺的路线。首先将邻苯二甲酰亚胺与氢氧化钾作用去质子化，生成亲核的邻苯二甲酰亚胺钾。然后该盐与伯卤代烷发生S_N2反应，得到N-烷基邻苯二甲酰亚胺。

The phthalimide protecting group is then removed by either alkaline hydrolysis or treatment with hydrazine (the Ing–Manske procedure), liberating the pure primary amine and regenerating phthalimide or a hydrazine derivative. This strategy guarantees that only primary amines are formed because the nitrogen can be alkylated only once. The method works best with primary alkyl halides; secondary and tertiary alkyl halides tend to undergo elimination under the basic conditions.

随后，通过碱性水解或用肼处理（Ing-Manske法）脱去邻苯二甲酰保护基，释放出纯的伯胺，并回收邻苯二甲酰亚胺或生成肼衍生物。这一策略确保只生成伯胺，因为氮原子只能被烷基化一次。该方法最适合伯卤代烷；仲卤代烷和叔卤代烷在碱性条件下容易发生消除反应。

4. Reduction of Nitro Compounds | 硝基化合物的还原

Aromatic primary amines are conventionally prepared by reducing the corresponding nitroarenes. The classic example is the reduction of nitrobenzene to phenylamine (aniline). The reducing system commonly used is tin and concentrated hydrochloric acid, which generates hydrogen in situ, followed by

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