Occurrence and sources of amines

Aliphatic amines occur in nature, principally as products of the putrefaction of protein material, but they are also present in living tissue (e.g., histamine, a cyclic aliphatic amine). The methylamines occur in small amounts in some plants. Many polyfunctional amines (i.e., those having other functional groups in the molecule) occur as alkaloids in plants—for example, mescaline, 2-(3,4,5-trimethoxyphenyl)ethylamine; the cyclic amines nicotine, atropine, morphine, and cocaine; and the quaternary salt choline, N-(2-hydroxyethyl)trimethylammonium chloride, which is present in nerve synapses and in plant and animal cells.

Large quantities of aliphatic amines are made synthetically. The most widely used industrial method is the reaction of alcohols with ammonia at a high temperature, catalyzed by metals or metal oxide catalysts (e.g., nickel or copper). Mixtures of primary, secondary, and tertiary amines are thereby produced. Some amines—such as hexamethylenediamine, used in the manufacture of nylon-6,6—are made by catalytic addition of hydrogen to nitriles, R≡CN.

Aniline and some other aromatic amines were at one time obtained from coal tar but are today synthesized from benzene, C₆H₆, or other hydrocarbons. Benzene is first converted to nitrobenzene (C₆H₅NO₂) or chlorobenzene (C₆H₅Cl). The former is reduced to aniline by treatment with hydrogen over a catalyst or by means of other reagents, such as iron or hydrogen sulfide (Fe and H₂S, respectively). Aniline is made from chlorobenzene by treatment with ammonia at a high temperature in the presence of copper compounds.

On a smaller scale, such as in the pharmaceutical industry or the research laboratory, the foregoing methods may not be suitable because of the engineering costs and the formation of a mixture of products. For the synthesis of single products and small-scale operations, other reactions are available. The reaction of alkyl halides, R―X, where X is a halogen, or analogous reagents with ammonia (or amines) is useful with certain compounds. A mixture of mono-, di-, and trialkylated amines, and sometimes also the quaternary ammonium salt, often results:

RCH₂X + NH₃→

RCH₂NH₂, (RCH₂)₂NH, (RCH₂)₃N, (RCH₂)₄N⁺X⁻

Not all alkyl halides are effective reagents; the reaction is sluggish with secondary alkyl groups and fails with tertiary ones. Its usefulness is largely confined to primary alkyl halides (those having two hydrogen atoms on the reacting site). To avoid the problem of multiple alkylation, methods have been devised for “blocking” substitution so that only one alkyl group is introduced. The Gabriel synthesis is one such method; it utilizes phthalimide, C₆H₄(CO)₂NH, whose one acidic hydrogen atom has been removed upon the addition of a base such as KOH to form a salt.

Although phthalimide itself is not reactive, its anion will react with alkyl halides, but only once. Hydrolysis of the resulting alkylphthalimide releases the primary amine.

Primary amines having a tertiary alkyl group (R₃CNH₂) are difficult to prepare with most methods but are made industrially by the Ritter reaction. In this method a tertiary alcohol reacts with hydrogen cyanide (HCN) in the presence of a concentrated strong acid; a formamide, RNH―CHO, is formed first, which then undergoes hydrolysis.

Reaction of ammonia with alkenes at high temperatures and pressure, catalyzed by zeolites, is also employed industrially.

Reduction of nitro compounds, RNO₂, by hydrogen or other reducing agents produces primary amines cleanly (i.e., without a mixture of products), but the method is mostly used for aromatic amines because of the limited availability of aliphatic nitro compounds. Reduction of nitriles and oximes (R₂C=NOH) also yields primary amines. Imines, R₂C=NR′, may be used to prepare secondary amines, commonly in a process in which the imine is formed from a primary amine and an aldehyde or ketone and then reduced by hydrogen and a nickel catalyst. Amides, RCONR′₂, can be reduced to amines by lithium aluminum hydride (LiAlH₄), which replaces the oxygen with two hydrogens. If there is no substituent on the nitrogen (i.e., R′ = H), a primary amine results. When one or both R′ groups are not hydrogen, secondary or tertiary amines, respectively, are produced.

Prominent among rearrangement reactions is the Hofmann reaction, in which an amide is treated with chlorine or bromine and an aqueous alkali (base).

A series of steps takes place quickly. In an intermediate step, an R group moves from the carbonyl carbon to the nitrogen, displacing the halogen ion; the final step, the loss of a CO₃²⁻ group, leads to a primary amine of one less carbon atom (i.e., RCONH₂ becomes RNH₂). The Beckmann rearrangement, by which a ketoxime, R₂C=NOH, is rearranged to an amide, RCONHR, can be used to prepare primary amines when followed by hydrolysis.

Tertiary amines are typically made by direct alkylation of secondary amines by alkyl halides:

Alternatives are reduction of disubstituted amides or reduction of a mixture of a secondary amine and an aldehyde by formic acid (known as the Leuckart reaction):

R₂NH + R^′₂C=O + HCOOH → R₂N―CHR^′₂+ CO₂