The amides are a class of organic compounds which can be regarded as having been derived from either acids or amines. For example, the simple aliphatic amide acetamide (CH3–CO–NH2) is related to acetic acid in the sense that the –OH group of acetic acid is replaced by an –NH2 group. Conversely, acetamide can be regarded as being derived from ammonia by replacement of one ammonia hydrogen by an acyl group. Amides can be derived not only from aliphatic or aromatic carboxylic acids but also from other types of acids—for example, sulphur- and phosphorus-containing acids.
The term substituted amides may be used to describe those amides having one or both hydrogens on the nitrogen replaced by other groups—for example, N,N-dimethylacetamide. This compound could also be regarded as an amine, acetyl dimethyl amine.
Amides are generally quite neutral in reaction compared with the acid or amine from which they are derived, and they are occasionally somewhat resistant to hydrolysis. The simple amides of aliphatic carboxylic acids (except formamide) are solids at room temperature, while the substituted aliphatic carboxylic acid amides may be liquids with relatively high boiling points. The amides of aromatic carboxylic or sulphonic acids are usually solids. A wide variety of methods are available for the synthesis of amides.
The unsubstituted aliphatic carboxylic acid amides have wide use as intermediates, stabilizers, release agents for plastics, films, surfactants and soldering fluxes. The substituted amides such as dimethylformamide and dimethylacetamide have powerful solvent properties.
Dimethylformamide is primarily used as a solvent in organic synthesis. It is also used in the preparation of synthetic fibres. It is a selective medium for the extraction of aromatics from crude oil and a solvent for dyes. Both dimethylformamide and dimethylacetamide are ingredients in paint removers. Dimethylacetamide is also used as a solvent for plastics, resins and gums, and in many organic reactions.
Acetamide is used for denaturing alcohol and as a solvent for many organic compounds, as a plasticizer, and an additive in paper. It is also found in lacquers, explosives and soldering flux. Formamide is a softener for paper and glues, and a solvent in the the plastics and pharmaceutical industries.
Some unsaturated aliphatic amides, such as acrylamide, are reactive monomers used in polymer synthesis. Acrylamide is also used in the synthesis of dyes, adhesives, paper and textile sizing, permanent press fabrics, and sewage and waste treatment. It is utilized in the metal industry for ore processing, and in civil engineering for the construction of dam foundations and tunnels. The polyacrylamides find extensive use as flocculants in water and sewage treatment, and as strengthening agents during paper manufacture in the paper and pulp industry. Aromatic amide compounds form important dye and medicinal intermediates. Some have insect repellent properties.
The wide variety of possible chemical structures of amides is reflected in the diversity of their biological effects. Some appear entirely innocuous—for example, the longer-chain simple fatty acid amides such as stearic or oleic acid amides. On the other hand, several of the members of this family are classified as Group 2A (probable human carcinogens) or Group 2B (possible human carcinogens) by the International Agency for Research on Cancer (IARC). Neurologic effects have been noted in humans and experimental animals with acrylamide. Dimethylformamide and dimethylacetamide have produced liver injury in animals, and formamide and monomethylformamide have been shown experimentally to be teratogens.
Although a considerable amount of information is available on the metabolism of various amides, the nature of their toxic effects has not yet been explained on a molecular or cellular basis. Many simple amides are probably hydrolyzed by non-specific amidases in the liver and the acid produced excreted or metabolized by normal mechanisms.
Some aromatic amides—for example, N-phenylacetamide (acetanilide)—are hydroxylated on the aromatic ring and then conjugated and excreted. The ability of a number of amides to penetrate the intact skin is especially important in considering safety precautions.
Acrylamide was initially made in Germany in 1893. Practical use of this compound had to wait until the early 1950s, when commercial manufacturing processes became available. This development occurred primarily in the United States. By the mid-1950s it was recognized that workers exposed to acrylamide developed characteristic neurologic changes primarily characterized by both postural and motor difficulties. Reported findings included tingling of the fingers, tenderness to touch, coldness of the extremities, excessive sweating of the hands and feet, a characteristic bluish-red discolouration of the skin of the extremities, and a tendency toward peeling of the skin of the fingers and hands. These symptoms were accompanied by weakness of the hands and feet which led to difficulty in walking, climbing stairs and so on. Recovery generally occurs with cessation of exposure. The time for recovery varies from a few weeks to as long as 1 year.
Neurologic examination of individuals suffering from acrylamide intoxication shows a rather typical peripheral neuropathy with weakness or absence of tendon reflexes, a positive Romberg test, a loss of position sense, a diminution or loss of vibration sense, ataxia, and atrophy of the muscles of the extremities.
Following recognition of the symptom complex associated with acrylamide exposure, animal studies were carried out in an attempt to document these changes. It was found that a variety of animal species including rat, cat and baboon were capable of developing peripheral neuropathy with disturbance of gait, disturbance of balance and a loss of position sense. Histopathologic examination revealed a degeneration of the axons and myelin sheaths. The nerves with the largest and longest axons were most commonly involved. There did not appear to be involvement of the nerve cell bodies.
Several theories have been advanced as to why these changes occur. One of these has to do with possible interference with the metabolism of the nerve cell body itself. Another theory postulates interference with the intracellular transport system of the nerve cell. An explanation is that there is a local toxic effect on the entire axon, which is felt to be more vulnerable to the action of acrylamide than is the cell body. Studies of the changes taking place within the axons and myelin sheaths have resulted in a description of the process as a drying back phenomenon. This term is used to describe more accurately the progression of changes observed in the peripheral nerves.
While the described symptoms and signs of the characteristic peripheral neuropathy associated with acrylamide exposure are widely recognized from exposure in industry and from animal studies, it appears in humans that, when acrylamide has been ingested as a contaminant in drinking water, the symptoms and signs are of involvement of the central nervous system. In these instances drowsiness, disturbance of balance, and mental changes characterized by confusion, memory loss and hallucinations were paramount. Peripheral neurological changes did not appear until later.
Skin penetration has been demonstrated in rabbits, and this may have been a principal route of absorption in those cases reported from industrial exposures to acrylamide monomer. It is felt that the hazard from inhalation would be primarily from exposure to aerosolized material.
The good solvent action of dimethylformamide results in drying and defatting of the skin on contact, with resultant itching and scaling. Some complaints of eye irritation have resulted from vapour exposure in industry. Complaints by exposed workers have included nausea, vomiting and anorexia. Intolerance to alcoholic beverages after exposure to dimethylformamide has been reported.
Animal studies with dimethylformamide have shown experimental evidence of liver and kidney damage in rats, rabbits and cats. These effects have been seen from both intraperitoneal administration and inhalation studies. Dogs exposed to high concentrations of the vapour exhibited polycythemia, decrease of the pulse rate, and a decline in systolic pressure, and showed histologic evidence of degenerative changes in the myocardium.
In humans this compound is capable of being readily absorbed through the skin, and repeated exposures can lead to cumulative effects. In addition, like dimethylacetamide, it may facilitate the percutaneous absorption of substances dissolved in it.
It should be mentioned that dimethylformamide will readily penetrate both natural and neoprene rubber gloves, so that prolonged use of such gloves is inadvisable. Polyethylene provides better protection; however, any gloves used with this solvent should be washed after each contact and discarded frequently.
Dimethylacetamide has been studied in animals and has been shown to exhibit its principal toxic action in the liver on repeated or continued excessive exposure. Skin contact may cause the absorption of dangerous quantities of the compound.
Acetamide and thioacetamide are prepared by heating ammonium acetate and aluminium sulphide, and are used in the laboratory as analytical reagents. Both compounds have been shown to produce hepatomas in rats on prolonged dietary feeding. Thioacetamide is more potent in this respect, is carcinogenic also to mice, and can also induce bile duct tumours in rats. While human data on these chemicals are not available, the extent of the experimental animal data is such that both of these substances are now considered possible human carcinogens. (Thioacetamide can also be found in the article “Sulphur compounds, organic” in this chapter.) Dimethylformamide is also classified as a Group 2B possible human carcinogen by IARC.
Acrylamide is classified as a probable human carcinogen (Group 2A) by IARC. This decision is supported by the results of bioassays in mice by several routes and yielding multiple sites of cancer, by data on genotoxicity, and by acrylamide’s ability to form adducts. The chemical structure of acrylamides also supports the probability that the chemical is a human carcinogen.
Safety and Health Measures
The potential toxic properties of any amide should be carefully considered before use or exposure commences. Owing to the general tendency of amides (especially those of lower molecular weight) to be absorbed percutaneously, skin contact should be prevented. Inhalation of dusts or vapours should be controlled. It is desirable that persons with exposure to amides be under regular medical observation with particular reference to the functioning of the nervous system and liver. The possible or probable cancer status of some these chemicals dictates that extremely prudent working conditions are needed.
Table 1 - Chemical information.
Table 2 - Health hazards.
Table 3- Physical and chemical hazards.
Table 4 - Physical and chemical properties.