20.3 Preparation of Amines

This section outlines the primary methods for synthesizing amines, focusing on reactions involving alkyl halides and the reduction of various nitrogen-containing functional groups.

For background on the structure and classification of amines, refer to 20.1 AMINES→.

1. By the Reaction of Alkyl Halides with Ammonia (Ammonolysis)

When an alcoholic solution of ammonia is heated with an alkyl halide in a sealed tube at $100^{\circ }\mathrm{C}$, a nucleophilic substitution reaction occurs. Ammonia acts as a nucleophile, displacing the halide ion. However, the resulting primary amine is also nucleophilic and can further react with the alkyl halide.

This process, known as ammonolysis, typically yields a mixture of primary, secondary, and tertiary amines, along with a quaternary ammonium salt.

Stepwise Reaction:

1. Formation of Primary Amine: $R-X+\ddot{N}{H}_3\to [R-{\mathrm{NH}}_3{]}^{+}{X}^{-}\stackrel{N{H}_3}{\to }R-{\mathrm{NH}}_2+{\mathrm{NH}}_4^{+}{X}^{-}$

2. Formation of Secondary Amine: $R-{\mathrm{NH}}_2+R-X\to [R_2{\mathrm{NH}}_2{]}^{+}{X}^{-}\stackrel{N{H}_3}{\to }{R}_2\mathrm{NH}+{\mathrm{NH}}_4^{+}{X}^{-}$

3. Formation of Tertiary Amine: $R_2\mathrm{NH}+R-X\to [R_3\mathrm{NH}{]}^{+}{X}^{-}\stackrel{N{H}_3}{\to }{R}_3\mathrm{N}+{\mathrm{NH}}_4^{+}{X}^{-}$

4. Formation of Quaternary Ammonium Salt: $R_3\mathrm{N}+R-X\to [R_4\mathrm{N}{]}^{+}{X}^{-}$

2. By the Reduction of Nitrogen-Containing Functional Groups

Amines can be effectively synthesized by reducing functional groups that contain nitrogen.

a. Reduction of Nitriles (Cyanides)

Reduction of alkyl or aryl nitriles produces primary amines.

• Reagents: Common reducing agents include lithium aluminum hydride (${\mathrm{LiAlH}}_4$) or sodium metal in ethanol ($\mathrm{Na}/{\mathrm{C}}_2{\mathrm{H}}_5\mathrm{OH}$).

General Reaction: $R-\mathrm{C}\equiv \mathrm{N}\stackrel{{\mathrm{LiAlH}}_4\text{ or }\mathrm{Na}/{\mathrm{C}}_2{\mathrm{H}}_5\mathrm{OH}}{\to }R-{\mathrm{CH}}_2-{\mathrm{NH}}_2$

b. Catalytic Reduction of Nitriles

Nitriles can also be reduced using hydrogen gas in the presence of a metal catalyst.

• Catalysts: Common catalysts include Raney nickel (Raney Ni), platinum (Pt), or rhodium on alumina ($\mathrm{Rh}-{\mathrm{Al}}_2{\mathrm{O}}_3$).

General Reaction: $R-\mathrm{C}\equiv \mathrm{N}+2{\mathrm{H}}_2\stackrel{\text{Ni, Pt, or Pd}}{\to }R-{\mathrm{CH}}_2-{\mathrm{NH}}_2$

Example with Benzonitrile: ${\mathrm{C}}_6{\mathrm{H}}_5-\mathrm{C}\equiv \mathrm{N}+2{\mathrm{H}}_2\stackrel{\text{Raney Ni}}{\to }{\mathrm{C}}_6{\mathrm{H}}_5-{\mathrm{CH}}_2-{\mathrm{NH}}_2$ Benzonitrile to Benzylamine

c. Reduction of Nitro Compounds

Both aliphatic and aromatic nitro compounds can be reduced to form primary amines. This is a particularly important method for synthesizing anilines.

• Reagents:
  • Chemical Reduction: A metal (like tin, Sn, or iron, Fe) in the presence of a strong acid (like concentrated HCl).
  • Catalytic Hydrogenation: Hydrogen gas (${\mathrm{H}}_2$) with a catalyst like palladium (Pd), platinum (Pt), or nickel (Ni).

Example with Nitrobenzene: ${\mathrm{C}}_6{\mathrm{H}}_5-{\mathrm{NO}}_2+6[\mathrm{H}]\stackrel{\text{Sn/HCl or Fe/HCl}}{\to }{\mathrm{C}}_6{\mathrm{H}}_5-{\mathrm{NH}}_2+2{\mathrm{H}}_2\mathrm{O}$ Nitrobenzene to Aniline (Phenylamine)

d. Reduction of Amides

Amides can be converted to amines using two distinct methods that yield different products.

i. Reduction using $\mathbf{LiAl}{\mathbf{H}}_4$

• When an amide is treated with the strong reducing agent lithium aluminum hydride (${\mathrm{LiAlH}}_4$), the carbonyl group ($>\mathrm{C}=\mathrm{O}$) is reduced to a methylene group ($-{\mathrm{CH}}_2-$).
• This reaction forms a primary amine while keeping the carbon chain length intact.

General Reaction: $R-\mathrm{CO}-{\mathrm{NH}}_2\stackrel{1.{\mathrm{LiAlH}}_4/\text{ Ether}2.{\mathrm{H}}_2\mathrm{O}}{\to }R-{\mathrm{CH}}_2-{\mathrm{NH}}_2$

ii. Hoffmann Degradation Reaction

• When an amide is treated with bromine (${\mathrm{Br}}_2$) in the presence of a strong base (like KOH or NaOH), a degradation reaction occurs.
• This reaction, known as the Hoffmann degradation or Hoffmann bromamide reaction, produces a primary amine with one less carbon atom than the starting amide.

General Reaction: $R-\mathrm{CO}-{\mathrm{NH}}_2+{\mathrm{Br}}_2+4\mathrm{KOH}\to R-{\mathrm{NH}}_2+{\mathrm{K}}_2{\mathrm{CO}}_3+2\mathrm{KBr}+2{\mathrm{H}}_2\mathrm{O}$

Example with Acetamide: ${\mathrm{CH}}_3-\mathrm{CO}-{\mathrm{NH}}_2+{\mathrm{Br}}_2+4\mathrm{KOH}\to {\mathrm{CH}}_3-{\mathrm{NH}}_2+{\mathrm{K}}_2{\mathrm{CO}}_3+2\mathrm{KBr}+2{\mathrm{H}}_2\mathrm{O}$ Acetamide to Methylamine