A useful way of making amines is by reduction of imines (or iminium ions). This overall process, from carbonyl compound to amine, is called reductive amination. This is, in fact, one of the few successful ways, and the best way, of making secondary amines. This should be your fi rst choice in amine synthesis.

This can be done in two steps, provided the intermediate is stable, but, because the instability of many imines makes them hard to isolate, the most convenient way of doing it is to form and reduce the imine in a single reaction. The selective reduction of iminium ions (but not carbonyl compounds) by sodium cyanoborohydride makes this possible. When Na (CN)BH3 is added to a typical imine-formation reaction it reacts with the iminium ion but not with the starting carbonyl compound nor with the imine. Here is an example of an amine synthesis using reductive amination.

In the fi rst step, the ketone and ammonia are in equilibrium with their imine, which, at pH 6, is partly protonated as an iminium ion. The iminium ion is rapidly reduced by the cyanoborohydride to give the amine. Reactions like this, using ammonia in a reductive amination, are often carried out with ammonium chloride or acetate as convenient sources of ammonia. At pH 6, ammonia will be mostly protonated anyway as the pKa of NH₄ ⁺ is about 10.

In the second step of the synthesis, amine plus formaldehyde gives an imine, present as its protonated iminium form, which gets reduced. Formaldehyde is so reactive that it reacts again with the secondary amine to give an iminium ion; this too is reduced to the amine.

Living things make amino acids using imines

The amino acid alanine can be made in moderate yield in the laboratory by reductive amination of pyruvic acid.

Living things use a very similar reaction to manufacture amino acids from keto acids, but do it much more efficiently. The key step is the formation of an imine between pyruvic acid and the vitamin B₆-derived amine pyridoxamine.

This imine (biochemists call imines Schiff bases) is in equilibrium with an isomeric imine, which can be hydrolysed to pyridoxal and alanine. These reactions are, of course, all controlled by enzymes and coupled to the degradation of unwanted amino acids (the latter process converts the pyridoxal back to pyridoxamine). Nature was doing reductive aminations a long time before sodium cyanoborohydride was invented! We will come back to this in Chapter 42.

An alternative method for reductive amination uses hydrogenation (hydrogen gas with a metal catalyst) to reduce the imine in the presence of the carbonyl compound. Most of these reductions do not require such high temperatures or pressures.

مواضيع ذات صلة

Amines react with carbonyl compounds

Modifying reactivity using acetals

Cyclic acetals are more stable than acyclic acetals

Acetals hydrolyse only in the presence of acid

Making acetals

Acetals are formed from aldehydes or ketones plus alcohols in the presence of acid

Acid or base catalysts increase the rate of equilibration of hemiacetals with their aldehyde and alcohol parents

Aldehydes can react with alcohols to form hemiacetals

Making the products less reactive

Making the starting materials more reactive

A bit of shorthand

Making alcohols instead of ketones