Preparing amines

Reducing nitro compounds. A nitro group, –NO₂, is reduced to –NH₂ with H₂ over a catalyst (Pd, Pt or Ni), or with a metal and acid: Sn/HCl or Fe/HCl. Nitrobenzene gives aniline this way, and Fe with HCl is the preferred method.

Ammonolysis of alkyl halides. Heat an alkyl halide with ammonia and the NH₃ replaces the halogen. But the amine formed is itself a nucleophile and reacts again, so you get a mixture of primary, secondary and tertiary amines and a quaternary ammonium salt, R₄N⁺X⁻. Using a big excess of ammonia favours the primary amine.

Reducing nitriles and amides.

• A nitrile, R–C≡N, reduced with LiAlH₄ or H₂/Ni, gives R–CH₂NH₂. Since the nitrile was made from a halide with cyanide, this route adds one carbon.
• An amide, R–CONH₂, reduced with LiAlH₄, gives R–CH₂NH₂ with the same number of carbons.

Gabriel phthalimide synthesis. Phthalimide is treated with KOH and then with an alkyl halide; hydrolysis then releases a pure primary amine, with none of the mixture that ammonolysis gives. It cannot make aryl amines, because aryl halides do not undergo the substitution step.

Hofmann bromamide degradation. An amide with bromine and NaOH loses its C=O carbon (as carbonate): R–CONH₂ gives R–NH₂, an amine with one carbon fewer than the amide.

So, for chain length: the cyanide route adds a carbon; the Hofmann route removes one. Picture the amide going on a diet: it loses its whole C=O and comes out one carbon slimmer.

A favourite exam question: which method makes a primary amine from an alkyl halide without changing the number of carbons? Not ammonolysis (it gives a mixture), not the cyanide route (one carbon more), not Hofmann (that starts from an amide, and loses a carbon): the answer is Gabriel phthalimide synthesis.