Amines as Nucleophiles & their Synthesis

This lesson covers: 

1. How aliphatic and aromatic amines are produced
2. The reaction mechanism involved in producing aliphatic amines
3. How amides are produced
4. The reaction mechanism involved in producing amides

Aliphatic amines form from halogenoalkanes or nitriles

There are two main ways to produce aliphatic amines:

• Nucleophilic substitution of halogenoalkanes
• Reduction of nitriles

Reacting halogenoalkanes with ammonia and amines

Aliphatic amines can be produced by reacting a halogenoalkane with ammonia, primary amines, secondary amines, or tertiary amines in a nucleophilic substitution reaction.

1. Reaction with ammonia to form primary amines:

Primary aliphatic amines can be produced by heating a halogenoalkane with excess ethanolic ammonia.

For example, bromoethane reacts with ammonia to give ethylamine:

CH₃CH₂Br + 2NH₃ ➔ CH₃CH₂NH₂ + NH₄Br

1. Reaction with primary amines to form secondary amines:

Secondary aliphatic amines can be produced by reacting a halogenoalkane with a primary amine.

For example, bromoethane reacts with ethylamine to give diethylamine:

CH₃CH₂NH₂ + CH₃CH₂Br ➔ (CH₃CH₂NH₂)₂NH + HBr

1. Reaction with secondary amines to form tertiary amines:

Tertiary aliphatic amines can be produced by reacting a halogenoalkane with a secondary amine.

For example, bromoethane reacts with diethylamine to give triethylamine:

(CH₃CH₂)₂NH + CH₃CH₂Br ➔ (CH₃CH₂)₃N + HBr

1. Reaction with tertiary amines to form quaternary ammonium salts:

Quaternary ammonium salts can be produced by reacting a halogenoalkane with a tertiary amine.

For example, bromoethane reacts with triethylamine to give tetraethylammonium bromide:

(CH₃CH₂)₃N + CH₃CH₂Br ➔ (CH₃CH₂)₄N⁺Br^-

Nucleophilic substitution reaction mechanism

The mechanism for these reactions involves two steps:

1. The nucleophile (ammonia or amine) attacks the halogenoalkane, displacing the halogen and forming an alkylammonium salt.
2. The alkylammonium salt is then deprotonated by a base (e.g., the nucleophile or a separate base) to form the amine product.

For example, the mechanism for the reaction between bromoethane and ammonia is:

Reducing nitriles to amines

Primary aliphatic amines can be prepared by reducing nitriles through catalytic hydrogenation. This process involves reacting the nitrile with hydrogen gas (H₂) in the presence of a metal catalyst, such as nickel or platinum. 

The general reaction for this reduction is:

R-C≡N + 4[H] ➔ R-CH₂-NH₂

For example, the reduction of ethanenitrile to ethylamine can be represented as follows:

CH₃CN + 4[H] ➔ CH₃CH₂NH₂

An advantage of catalytic hydrogenation is that it produces a purer product compared to other methods, such as the reaction of halogenoalkanes with ammonia. In catalytic hydrogenation, the primary amine formed does not undergo further substitution reactions, preventing the formation of secondary, tertiary, and quaternary ammonium compounds as byproducts.

Reacting acyl chlorides with ammonia and amines

Amides can be synthesised through the reaction of acyl chlorides or acid anhydrides with concentrated ammonia or primary amines, in a nucleophilic addition-elimination reaction.

1. With ammonia:

The reaction between acyl chlorides or acid anhydrides and ammonia produces primary amides.

For example, ethanoyl chloride reacts with ammonia to give ethanamide (CH₃CONH₂) and HCl:

CH₃COCl + NH₃ ➔ CH₃CONH₂ + HCl

Similarly, ethanoic anhydride reacts with ammonia to give ethanamide and ethanoic acid:

(CH₃CO)₂O + NH₃ ➔ CH₃CONH₂ + CH₃COOH

1. With amines:

The reaction between acyl chlorides or acid anhydrides and primary amines produces secondary amides, also known as N-substituted amides.

For example, ethanoyl chloride reacts with methylamine to give N-methylethanamide (CH₃CONHCH₃) and HCl:

CH₃COCl + CH₃NH₂ ➔ CH₃CONHCH₃ + HCl

Similarly, ethanoic anhydride reacts with methylamine to give N-methylethanamide and ethanoic acid:

(CH₃CO)₂O + CH₃NH₂ ➔ CH₃CONHCH₃ + CH₃COOH

In these reactions, the produced HCl or carboxylic acid typically reacts with any excess ammonia or amine to form ammonium salts.

Mechanism of amide formation

The formation of amides through this method involves a two-step nucleophilic addition-elimination mechanism:

1. The nitrogen's lone pair in ammonia or an amine attacks the electrophilic carbon in the carbonyl group of the acyl chloride or acid anhydride, leading to a tetrahedral intermediate.
2. The next step is the elimination of HCl (in the case of acyl chlorides) or a carboxylate anion (in the case of acid anhydrides) from the intermediate, which re-establishes the carbonyl group and results in the formation of the amide product.

For example, the mechanism for the reaction between ethanoyl chloride and ammonia is:

Aromatic amines from nitro compounds

Aromatic amines are produced by reducing nitro compounds in a two-step process:

1. The nitro compound is heated under reflux with tin and concentrated HCl to form an ammonium salt.
2. The ammonium salt is then treated with aqueous NaOH to give the free amine.

For example, nitrobenzene is reduced to phenylamine via phenylammonium chloride:

Aromatic amines like this are useful in organic synthesis for making pharmaceuticals, dyes, and other compounds.