General methods of preparation of aliphatic amines

• Aliphatic amines are organic compounds that consist of an alkyl or cycloalkyl group attached to one or more amino groups (-NH2).

• They are classified based on the number of carbon atoms connected to the nitrogen atom: primary (one carbon group), secondary (two carbon groups), and tertiary (three carbon groups).

• The preparation of aliphatic amines involves several general methods, each with its own advantages and limitations.

Here are some of the most common methods:

General methods of preparation of aliphatic amines

1. Ammonolysis of Alkyl Halides

• This process involves the reaction of an alkyl halide with ammonia. The reaction can lead to the formation of primary, secondary, and tertiary amines, along with quaternary ammonium salts, depending on the reaction conditions and the amount of ammonia used.

RX + NH3 ​→ RNH2 ​+ HX

• RX = Alkyl halide

• 3NH3​ = Ammonia

• RNH2​ = Primary amine

• HX = Hydrogen halide

• The reaction typically requires an excess of ammonia to shift the equilibrium towards the formation of the desired amine. However, this method can result in a mixture of products, necessitating further separation and purification.

2. Reduction of Nitro Compounds

• Aliphatic nitro compounds can be reduced to amines using various reducing agents, such as hydrogen gas in the presence of a catalyst (e.g., palladium on carbon), iron and hydrochloric acid, or tin and hydrochloric acid.

RNO2​ + 3H2 ​→ RNH2 ​+ 2H2​O

• RNO2​ = Nitro compound

• RNH2​ = Primary amine

• This method is widely used for the preparation of primary amines, especially when starting from readily available nitro compounds.

3. Reduction of Nitriles

• Nitriles can be reduced to primary amines using hydrogen in the presence of a suitable catalyst (e.g., nickel), or by using lithium aluminum hydride (LiAlH_4).

RCN + 2H2 ​→ RNH2 ​+ CH3​OH

• RCN = Nitrile

• RNH2​ = Primary amine

• This method is particularly useful for synthesizing primary amines with one more carbon atom than the original nitrile.

4. Gabriel Synthesis

• The Gabriel synthesis is a method for preparing primary amines that involves the reaction of potassium phthalimide with an alkyl halide, followed by hydrolysis of the resulting N-alkylphthalimide to liberate the primary amine.

C6​H4​(CO)2​N−K+ + RX → C6​H4​(CO)2​NR + KX → C6​H4​(CO)2​NR + H2​O → RNH2 ​+ C6​H4​(CO)2​OH

• This method is advantageous because it avoids the over-alkylation problems associated with direct ammonolysis of alkyl halides.

5. Reductive Amination

• Reductive amination involves the reaction of an aldehyde or ketone with ammonia or an amine, followed by reduction.

• The initial step forms an imine or iminium ion, which is then reduced to give the amine.

RCHO + NH3 ​→ RCH=NH + H2​O → RCH=NH + H2 ​→ RCH2​NH2​

• This method can be used to synthesize primary, secondary, or tertiary amines, depending on the starting materials.