AMIDES

 

 

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 () is related to acetic acid in the sense that the -OH group of acetic acid is replaced by an  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.

 

Uses

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.

 

Hazards

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.

 

Neurological effects

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.

 

Hepatotoxic effects

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.

 

Carcinogenesis

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.

 

 

Amides tables

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Table 104.21.       Chemical identification

 

CHEMICAL

Synonyms/ UN code

CAS-number

CHEMICAL FORMULA

ACETAMIDE

Acetic acid amide;

Acetimidic acid;

Ethanamide;

Methanecarboxamide

60-35-5

2-ACETYLAMINOFLUORENE

2-Acetaminofluorene;

Acetoaminofluorene;

N-Acetyl-2-aminofluorene;

2-(Acetylamino)fluorene;

2-Fluorenylacetamide

53-96-3

ACRYLAMIDE

Acrylic amide;

Ethylenecarboxamide;

Propenamide;

2-Propenamide;

Vinyl amide

UN2074

79-06-1

  

BENZOTHIAZYL-2-

CYCLOHEXYLSULFENAMIDE

N-Cyclohexyl-2-benzothiazolesulfenamide;

N-Cyclohexyl-2-benzothiazylsulfenamide

95-33-0

2-CHLOROACETAMIDE

Chloroacetamide;

a-Chloroacetamide;

2-Chloroethanamide

79-07-2

 

2-CHLORO-N-HYDROXYMETHYLACETAMIDE

Chloracetamide-N-metholol

2832-19-1

 

COLCHICINE

Acetamide, N-(5,6,7,9-Tetrahydro-1,2,3,10-

tetramethoxy-9-oxobenzo--(heptalen-yl)-;

N-Acetyl trimethylcolchicinic acid methylether;

Benzo(a)heptalen-9(5h)-one, 7-acetamido-6,7-dihydro-1,2,3,10-tetramethoxy-

64-86-8

 

CYCLOHEXIMIDE

b-(2-(3,5-Dimethyl-2-oxocyclohexyl)-2-

hydroxyethyl)glutarimide;

3-(2-(3,5-Dimethyl-2-oxocyclohexyl)-

2-hydroxyethyl)glutarimide

66-81-9

 

 

CYCLOPHOSPHAMIDE

Cyclophosphane;

N,n-bis(2-chloroethyl)-N’,o-propylenephosphoric

acid ester diamide;

N,N-Bis(2-chloroethyl)tetrahydro-2h-

1,3,2-oxazaphosphorin-2-amine 2-oxide;

Bis(2-chloroethyl)phosphoramide-cyclic

propanolamide ester

50-18-0

 

4,4’-DIACETYLBENZIDINE

4,4’-Diacetamidobiphenyl;

4,4’-Diacetylaminobiphenyl;

Diacetylbenzidine;

N,N’-Diacetyl benzidine

613-35-4

 

DIETHYLCARBAMOYL CHLORIDE

Diethylcarbamic chloride;

N,N-Diethylcarbamoyl chloride;

Diethylcarbamyl chloride;

Diethylchloroformamide;

N,N-Diethylchloroformamide

88-10-8

 

DIMETHYL ACETAMIDE

Acetdimethylamide;

Acetic acid, dimethylamide;

N,N-Dimethylacetamide;

Dimethylacetone amide;

Dimethylamide acetate

127-19-5

DIMETHYL CARBAMOYL CHLORIDE

Chloroformic acid dimethylamide;

(Dimethylamino)carbonyl chloride;

Dimethylcarbamic acid chloride;

Dimethylcarbamic chloride;

Dimethylchloroformamide

UN2262

79-44-7

 

DIMETHYLFORMAMIDE

N,N-Dimethyl formamide;

N,N-Dimethylmethanamide;

N-Formyldimethylamine

UN2265

68-12-2

 

N,N’-ETHYLENE BIS(STEARAMIDE)

1,2-Bis(octadecanamido)ethane;

N,N’-Ethylene distearylamide;

N,N’-Ethylene bis(octadecanamine)

110-30-5

 

FORMAMIDE

Carbamaldehyde;

Methanamide

75-12-7

 

METHYLFORMAMIDE

N-Methylformamide;

Monomethylformamide

123-39-7

SODIUM AMIDE

 

7782-92-5

 

 

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Table 104.22.     Health hazards

 

CHEMICAL NAME

CAS-NUMBER

ICSC SHORT-TERM EXPOSURE

ICSC LONG-TERM EXPOSURE

ICSC ROUTES OF EXPOSURE AND SYMPTOMS

US NIOSH TARGET ORGANS & ROUTES OF ENTRY

US NIOSH SYMPTOMS

ACETAMIDE

60-35-5

eyes; skin; resp tract

 

Inhalation: cough, shortness of breath

Skin: redness, pain

Eyes: pain, redness, blurred vision

Ingestion: sore throat, burning sensation

 

 

2-ACETYLAMINOFLUORENE

53-96-3

 

 

 

Liver; bladder; kidneys; pancreas; skin; lungs (in animals: tumors of the liver; bladder, pancreas, skin & lungs)

Inh, abs, ing, con

Reduced function of liver, kidneys, bladder, pancreas (carc)

ACRYLAMIDE

79-06-1

skin; resp tract; CNS; liver

PNS; CNS

Inhalation: cough, sore throat, weakness

Skin: may be absorbed, redness, pain

Eyes: redness, pain

Ingestion: abdominal pain, weakness

CNS; PNS; skin; eyes, repro sys (in animals: tumors of the lungs, testes, thyroid & adrenal glands)

Inh, abs, ing, con

Irrit eyes, skin; ataxia, numb limbs, pares; musc weak; absent deep tendon reflex; hand sweat; ftg, leth; repro effects (carc)

2-CHLOROACETAMIDE

79-07-2

eyes; skin; resp tract; heart; liver; spleen

skin

Inhalation: burning sensation, cough, sore throat

Skin: redness, pain

Eyes: redness, pain

Ingestion: sore throat

 

 

CYCLOPHOSPHAMIDE

50-18-0

eyes; skin; resp tract; kidneys; bladder; CVS; CNS; GI tract; liver; heart; blood

skin

Inhalation: diarrhoea, dizziness, loss of hair, darkening of skin and finger nails, nausea, vomiting

Skin: may be absorbed

 

 

DIMETHYL ACETAMIDE

127-19-5

eyes; skin; resp tract

skin; liver; kidneys

Inhalation: headache, nausea, vomiting

Skin: may be absorbed, redness

Eyes: Vapour will be absorbed, redness, pain

CNS; liver; skin

Inh, abs, ing, con

irrit skin; jaun, liver damage; depres, leth, halu, delusions

DIMETHYLFORMAMIDE

68-12-2

eyes; skin; resp tract; liver; CNS

liver

Inhalation: loss of appetite, abdominal pain, diarrhoea, dizziness, nausea, vomiting, nervous agitation, facial flushing and alcohol intolerance

Skin: may be absorbed, dry skin, redness, roughness

Eyes: redness, pain

Eyes; liver; kidneys; CVS; skin; resp sys

Inh, abs, ing, con

Irrit eyes, skin, resp sys; nau, vomit, colic; liver damage, enlarged liver; high BP; face flush; derm; in animals: kidney, heart damage

FORMAMIDE

75-12-7

lungs; CNS

liver

Inhalation: drowsiness, headache, nausea, unconsciousness

Skin: may be absorbed, redness

Eyes: redness

Ingestion: abdominal pain

Eyes; skin; resp sys; CNS; repro sys

Inh, ing, con

Irrit eyes, skin, muc memb; drow, ftg; nau, acidosis; skin eruptions; in animals: repro effects

 

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Table 104.23.      Physical and chemical hazards

 

For UN Class: 1.5 = very insensitive substances which have a mass explosion hazard; 2.1 = flammable gas; 2.3 = toxic gas; 3 = flammable liquid; 4.1 = flammable solid; 4.2 = substance liable to spontaneous combustion; 4.3 = substance which in contact with water emits flammable gases; 5.1 = oxidizing substance; 6.1 = toxic; 7 = radioactive; 8 = corrosive substance

 

CHEMICAL NAME

CAS-NUMBER

PHYSICAL

CHEMICAL

UN CLASS OR DIVISION /  SUBSIDIARY RISKS

ACETAMIDE

60-35-5

 

The substance decomposes on heating, producing toxic fumes  The solution in water is a strong base, it reacts violently with acid and is corrosive  Reacts with oxidants, reducing agents, bases, and acids

 

ACRYLAMIDE

79-06-1

 

The substance may polymerize violently due to heating or under the influence of light  The substance decomposes on heating producing toxic gases (nitrous oxides)  Reacts violently with oxidants

6.1

2-CHLOROACETAMIDE

79-07-2

 

The substance decomposes on heating producing toxic fumes including nitrogen oxides and chlorine  Reacts with strong oxidants, strong reducing agents, strong acids and strong bases

 

CYCLOPHOSPHAMIDE

50-18-0

 

The substance decomposes on heating, on contact with moisture, light, producing toxic fumes  Reacts with strong oxidants, strong acids, strong bases

 

DIMETHYL ACETAMIDE

127-19-5

 

The substance decomposes on heating producing toxic fumes (nitrogen oxides)  Attacks many plastics

 

DIMETHYL CARBAMOYL CHLORIDE

79-44-7

 

 

8

DIMETHYLFORMAMIDE

68-12-2

 

On combustion, forms toxic gases (carbon monoxide, dimethylamine and oxides of nitrogen)  Reacts with oxidants

3

N,N’-ETHYLENE BIS(STEARAMIDE)

110-30-5

Dust explosion possible if in powder or granular form, mixed with air

On combustion, forms toxic gases  The substance decomposes on heating and on burning producing toxic fumes (nitrogen oxides)  Reacts with strong oxidants

 

FORMAMIDE

75-12-7

 

On combustion, forms toxic gases (nitrogen oxides)  The substance decomposes on heating at 200 °C or above producing ammonia, water, carbon monoxide and hydrogen cyanide  Reacts vigorously with oxidizing materials  Attacks copper and natural rubber  Incompatible with iodine, pyridine and sulfur trioxide

 

 

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Table 104.24.     Physical & chemical properties

 

CHEMICAL NAME

CAS-NUMBER

COLOUR/FORM

BOILING POINT (°C)

MELTING POINT (°C)

MOLECULAR WEIGHT

SOLUBILITY IN WATER

RELATIVE DENSITY (WATER=1)

RELATIVE VAPOUR DENSITY (AIR=1)

VAPOUR PRESSURE/ (KPA)

INFLAM.

Limits

FLASH POINT (°C)

AUTO IGNITION POINT (°C)

ACETAMIDE

60-35-5

deliquescent hexagonal crystals; trigonal monoclinic crystals

222

81

59.07

1 g/0.5 ml

1.159

 

<0.1

 

 

 

2-ACETYLAMINOFLUORENE

53-96-3

tan, crystalline solid

 

194

223.26

insol

 

 

 

 

 

 

ACRYLAMIDE

79-06-1

flake-like crystals from benzene;white crystalline solid; leaf crystals from benzene

125

84.5

71.08

v sol

1.122

2.45

1 Pa

 

138 cc

424

BENZOTHIAZYL-2-

CYCLOHEXYLSULFENAMIDE

95-33-0

cream-coloured powder

 

93-100

264.41

insol

1.27

 

 

 

 

 

2-CHLOROACETAMIDE

79-07-2

crystals

225

120

93.5

sol

 

3.2

0.007

 

 

 

COLCHICINE

64-86-8

 

 

156

399.42

v sol

 

 

 

 

 

 

CYCLOHEXIMIDE

66-81-9

plates from amyl acetate, water or 30% methanol; colourless crystals

 

119.5-121

281.34

 

 

 

 

 

 

 

CYCLOPHOSPHAMIDE

50-18-0

fine, white, crystalline powder; liquifies on loss of its water of crystallization

 

49.5-53

261.10

1/25 parts

 

 

 

 

112

 

4,4’-DIACETYLBENZIDINE

613-35-4

 

 

328.3

268.30

 

 

 

 

 

 

 

DIETHYLCARBAMOYL CHLORIDE

88-10-8

liquid

187

-44

135.6

sol

 

4.1

 

 

 

 

DIMETHYL ACETAMIDE

127-19-5

colourless oily liquid

165

-20

87.12

misc

0.9366

@ 25 °C/4 °C

3.01

0.33

1.8 ll

11.5 ul

70 oc

490

DIMETHYL CARBAMOYL CHLORIDE

79-44-7

liquid

167

-33

107.5

 

1.1678

3.73

 

 

 

 

DIMETHYLFORMAMIDE

68-12-2

colourless to very slightly yellow liquid; water-white liquid

153

-60.4

73.09

misc

0.9445

@ 25 °C/4 °C

2.51

0.36

2.2 ll

15.2 ul

67 oc

354

N,N’-ETHYLENE BIS(STEARAMIDE)

110-30-5

solid

 

135-146

593.04

insol

0.97

 

 

 

280 oc

 

FORMAMIDE

75-12-7

slightly viscous, colourless oily liquid

210.5 decomp

2.55

45.04

misc

1.1334

1.6

2 Pa

 

154 oc

>500

METHYLFORMAMIDE

123-39-7

 

180-185

-3.8

59.07

v sol

1.011

@ 19 °C

 

 

 

 

 

SODIUM AMIDE

7782-92-5

white crystalline powder

400

210

39.02

sol

1.39

 

 

 

 

 

 

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