Nucleophilic Substitution

In principle, one can replace a good leaving group with ammonia or amines leading to a more complex amine or ammonium salt. However, such reactions do not proceed in good yields except in exceptional cases.

YouTube video: preparation of amines by substitution

In general, nucleophilic substitution is not a useful method for preparing amines.

Alkylation of ammonia and amines with alkyl halides: primary, secondary and tertiary amines and quaternary ammonium salts are formed

Basicity and nucleophilicity increase from ammonia to primary, secondary and tertiary amines, so each product competes with the starting reagent

Direct S_N with ammonia does not work well because the primary amine is more nucleophilic than ammonia and competes with it. Worse still, the secondary and tertiary amines formed are even more nucleophilic, and the competition becomes even more complicated. The reaction only works well when it is used to obtain the final ammonium salt.

Bromoethane with a large excess of ammonia (16:1 molar ratio) gives only 34% of ethylamine together with other amines

Even with a large excess of ammonia, the yield of S_N reactions is low and complex mixtures of amines that are hard to separate are obtained.

Important alternative: carry out the substitution with a precursor of the amine group that can react only once. The amino group remains latent until it is "revealed".

Gabriel synthesis: potassium phthalimide displaces the halide of R–X and hydrazine releases the primary amine R–NH₂ and phthalhydrazide

Siegmund Gabriel (7 November 1851 – 22 March 1924) was a German chemist who had the idea of using phthalimide as a precursor function of an amine. The amine was "revealed" by treating the alkylphthalimide, the product of nucleophilic substitution with an R–X, with hydrazine (H₂N–NH₂).

How can phthalimide be obtained?

By heating phthalic acid with ammonia: an amide forms first, with loss of a water molecule, and then the amide nitrogen attacks the second carboxyl group and closes the ring, with loss of another water molecule.

The N–H of phthalimide is fairly acidic (pK_a = 9) because the negative charge of the anion is delocalized over the two carbonyl groups; that is why KOH easily deprotonates it to give potassium phthalimide.

Preparation of phthalimide from phthalic acid and ammonia, with loss of two water molecules; its N–H has pKa = 9

Excess ammonia converts 2-bromopropanoic acid into alanine (80%), protected as an ammonium salt

In some special cases, such as α-halocarboxylic compounds, treatment with ammonia gives excellent results for preparing α-amino acids.

Intramolecular cyclization of haloamines with Et₃N: aziridine, pyrrolidine (n = 1) or piperidine (n = 2)

The "intramolecular" attack of an NH₂ or NHR group on a carbon bearing a good leaving group gives cyclic compounds in reasonable yields.

There are other functions that carry the amine function in latent form: azide and cyanide.

Chlorocyclopentane: with NaN₃ it gives the azide (95%), which LiAlH₄ reduces to cyclopentylamine (90%); with NaCN it gives the nitrile (90%), which is reduced to cyclopentylmethylamine (85%)

Outcome of substitution with phthalimide, azide or cyanide depending on the substrate: SN2 for methyl, primary and secondary; SN1/E1 for tertiary; SN1/SN2 for allylic and benzylic

Once the substitution has taken place, reduction of the azide or nitrile functions gives the amine; in the case of cyanide, with one more carbon atom.