Amides

Type of physical science: Chemistry

Field of study: Chemical compounds

Amides are derivatives of organic acids combined with ammonia or amines. The amide bond is very important in the living world (in peptides), in pharmaceuticals (in drugs and barbiturates), and in polymers (in nylon and polyamides).

Overview

When the gydroxyl group (-OH) in a carboxylic acid (RCOOH) is replaced with an amino (-NH₂) group, a compound of the general formula (RCONH₂) arises and is known as simple, or primary, (1 degree) amide. If, in the above structure, one or more organic radicals (R') replace one or both of the hydrogens on the nitrogen, the amide is called secondary or tertiary, respectively, and has the general formula (RCONHR) or RCONR₂. The organic radicals can be the same or different with that of the parent carboxylic acid.

Amides are named by replacing the -ic or -oic acid ending in the name of the parent carboxylic acid with the suffix -amide. Thus, CH₃CONH is named ethanamide (or acetamide), from the corresponding ethanoic (or acetic) acid. Any substituents on the nitrogen are named by using the prefix N (for nitrogen). For example, CH₃CH₂CH₂CONHCH₃ is called N,N-dimethylbutanamide (or N,N-dimethylbutyramide). When the amide functional group is part of a ring, the compound is generally known as lactam. The structure is named by adding a Greek letter as a prefix to the word lactam; that letter indicates the position in which the nitrogen is attached in the parent acid.

Thus, γ-amino propionic acid yields γ-propiolactam.

Because of the possibility of intermolecular hydrogen bonding, all simple amides (except for formamide, which is a liquid) are relatively low-melting solids that are stable and more or less neutral; only the low-molecular-weight ones are soluble in water. As a result of their ease of formation, amides are often used in the identification of unknown carboxylic acids in qualitative analysis.

Commercially, amides are prepared by the thermal dehydration of ammonium salts of carboxylic acids. Thus, heating ammonium acetate, CH₃COO-NH₄⁺, produces water and acetamide, CH₃CONH₂. Another synthetic route involves the partial hydrolysis of nitriles (cyanocompounds), RC=N. As a result, propionitrile, CH₃CH₂C≡N , yields propionamide, CH₃CH₂CONH₂ when carefully refluxed under acidic or basic conditions.

Amines can be converted to amides by reacting them with a reactive derivative of carboxylic acids, such as anhydride or an acyl halide. For example: It should be noted that in both of the above reactions, higher yields are obtained when a base scavenger, such as pyridine or a tertiary amine, is used. Its purpose is to trap the formed acid (in the above cases, acetic and hydrochloric, respectively).

The electronegativity of the oxygen atom in the amide bond creates a dipole that pulls the unshared pair of electrons in amide nitrogen toward the oxygen. As a result, those electrons are not available to accept a proton provided by acid solutions. Consequently, the amide nitrogen is less basic than the amine nitrogen, and amides are insoluble in dilute acids.

Compared with all other derivatives in carboxylic acids (esters, anhydrides, acyl halides), amides hydrolyze very slowly in water to the parent acid and amine. The hydrolysis is speeded up by the use of strong acid and basic media. Biologically, this occurs in the presence of specific enzymes.

Amides can be dehydrated (made to lose water) by reaction with a strong dehydrating agent, such as phosphorus pentoxide (P₂O₅), to yield nitriles. These are compounds that are, generally, very toxic because of the cyano group, -C=N group, they carry. An exception is laetrile; this controversial drug, which contains a cyano group, is found in the pits of many fruits and is used for the treatment of cancer.

The amides formed by the substitution of the gydroxyl group (-OH) of a sulfonic acid (RSO₃H) with an amino group (-NH2) are called sulfonamides (RSO₂NH₂) and are of particular importance in pharmacology.

Equally important are the urea derivatives. Urea (H₂NCONH₂) is a diamide of carbonic acid (H₂CO₃), and its reaction product with malonic acid is barbituric acid, whose salt is the parent member of the family of barbiturates.

When the amide linkage occurs between the amino group of one aminoacid and the carboxyl (-COOH) group of another, it is called a peptide bond, or peptide link.

A sequence of peptide linkages leads to a polypeptide, which is the backbone for the structure of proteins. In other words, the amide bond is the principal bond that joins the individual units (the amino acids) together in molecules of proteins.

Applications

Amides are important chemical intermediates because of the variety of reactions they undergo and the great number of products they can form. Industrially, nylon 66 was one of the first commercially successful polymers. Polymers are high-molecular-weight substances whose structure consists of many repeating structural units. They can be made by letting the unit parts, called monomers, react with one another to link together successively many times in a polymerization reaction. In nylon 66, the units are adipic acid and hexamethylenediamine. The fibers are stretched so that the nylon molecules line up parallel to one another and hold their position via intermolecular hydrogen bonding. For a useful, fiber-forming polymer, each nylon-66 molecule should contain between fifty and ninety of each of the monomer units; otherwise, weaker and brittle fibering occurs. Because of the ability of the polymer to be spun into very fine, strong fibers, nylon 66 was used as a substitute for the scarcer and more expensive natural silk in women's sheer hosiery. Nylon 66 has been largely replaced by nylon 6, the polymer of 6-aminohexanoic acid, which has similar properties but is cheaper and easier to produce. Nylon 6 is used in making fibers for carpeting, tire cord, and textiles. It is also molded in solid objects such as gears, bearings, and zippers, as well as in the preparation of sutures and various types of plastic tubing. Many electrical fixtures are made out of polyamides such as Nomex, the polymer of isophthalic acid and m-phenylenediamine. In general, nylons are named according to the number of carbon atoms in each monomer unit. There are six each in 1,6-hexanediamine and adipic acid, which produce nylon 66. Nylon 6 is made out of one monomer that contains six carbons. Their strength is attributed to the ordered, relatively rigid arrangement of their long molecules, as well as to the polar functional groups.

The amides of the straight, long-chain carboxylic acids are especially useful in industry because of the variety of properties that can be obtained by changing the nitrogen substituents.

These compounds are extensively used as waterproofing agents, lubricant additives, detergents, emulsifiers, and wetting agents.

Amides play a significant role in pharmacology and biochemistry. Acetaminophen and its derivative, phenacetin, which are popular analgesics, as well as lidocaine, a widely used local anesthetic, carry the amide group. Caffeine, xylocaine (a local anesthetic used in dentistry and obstetrics), and folic acid (a compound required by bacteria for development) are also amides. So is nicotinamide, one of the B vitamins that are required for the metabolism of carbohydrates.

One of the most important groups of amidelike compounds is the barbiturates, the best-known and most frequently abused sedatives. Barbituric acid and all its derivatives are as acidic as acetic acid (commonly known as vinegar). For this reason, they are prescribed as sodium salts. Despite the fact that medicinal chemists have synthesized thousands of variations on the parent structure, only about two dozen barbiturates are actually clinically useful and are prescribed to patients. Barbital (also known as Veronal) is a long-acting barbiturate; a 0.3 gram dose leads to a six-hour sleep for an adult. On the other hand, thiopental (sodium pentothal) has a brief effect and is used extensively in surgery. Especially rapid-acting barbiturates are Nembutal (also known as pentobarbital) and Seconal (secobarbital). Two popular antianxiety agents prescribed are meprobamate (Miltown) and chlordiapezoxide (Librium), which have significant muscle relaxant effects. They have the tendency to hydrolyze easily, thus depressing the central nervous system and cause both breathing and heartbeat to slow down. As a result, the amount required to produce the effects may approach a fatal dose, since barbiturates also depress respiration.

Two of the most important classes of antibiotics contain a reactive, four-membered lactam ring (β-lactam). These are the cephalosporins and the penicillins. Both types are powerful bactericides that were originally isolated from fungi but now are available as semisynthetic derivatives. They work by interfering with the growing bacterium's synthesis of cell walls. The imperfectly constructed cell walls permit leakage of the cell's cytoplasm, which results in the death of the organism. Penicillin acts by acylating one of the enzymes involved in cell wall biosynthesis, mainly because the angle strain in the antibiotic ring makes it exceptionally reactive.

Urea has been, historically, an important organic compound in biochemistry. The ammonia, carbon dioxide, and water that result from the deamination and oxidation of the aminoacids are combined to form urea in the liver by a complex set of reactions first described by Sir Hans Krebs and his co-workers. As urea is formed in the liver it is removed by the blood stream, carried to the kidneys, and excreted in the urine. Urea is the main end product of protein catabolism, and accounts for 80 to 90 percent of nitrogen that is excreted in the urine.

Sulfa drugs, an example of sulfonamides, function by interfering with an important enzyme in several disease-causing bacteria. The bacteria require p-aminobenzoic to synthesize folic acid for their development, unlike human beings, who need folic acid intact in their diet.

Several sulfa drugs look enough like p-aminobenzoic acid to the bacteria, which use it to prepare a coenzyme that apparently inhibits an important metabolic process and kills them. Such sulfa drugs are sulfanilamide, sulfapyridine, and sulfathiazole.

Context

The amide functional group has had a great impact in organic and biochemistry. Urea, synthesized in 1828 by Friedrich Wohler, was the very first organic compound prepared and is considered as the keystone in the development of organic chemistry. It is manufactured in large quantities, industrially, for the eventual production of fertilizer, livestock supplements, plastics, and barbiturate sedatives.

Barbiturates are among the oldest known synthetic hypnotics. Barbituric acid was first synthesized by Adolf von Baeyer in 1863. One legend suggests that Baeyer named the compound for a girlfriend named Barbara. Another one involves a group of artillery officers that Baeyer befriended, who proposed the name of their patron saint, St. Barbara. Joseph von Mering, a German chemist who was the first to investigate the pharmacological effects of barbiturates, gave the name of the city of Verona to Veronal.

Phamacologically, several amides and barbiturates have been (and will be) commonly prescribed for cases that require temporarily affecting the nervous system. Extensive research on the side effects will always be necessary to control the availability of such drugs in the market.

Thalidomide, for example, which is an imide, was prescribed in the early 1960's to many European and Canadian mothers a few weeks after conception. In December, 1962, a connection was discovered between a type of fetal malformation and the drug, which eventually led to stricter regulations on the clinical testing of drugs. This was the first known example of fetal damage produced by giving chemicals to pregnant women. The mechanism of sulfa drugs on bacteria seems well established, and they have become the primary weapons against infections since the early 1940's. The β-lactam antibiotics, penicillins and cephalosporins, have been established because of the reactivity of the four-member ring as the premier "bacteria killers" since the time of World War II. Finally, urea plays a fundamental role in the human body, as the form in which the body disposes of excess nitrogen in the urine. Its high water solubility and low toxicity make it ideal for this purpose.

Nylon 66 was first discovered and developed by Wallace H. Carothers and his associates at the DuPont research laboratories during the 1930's. The significance of its strength characteristics is evident in the great number of industrial applications, in hosiery, in tires, and in brushes, to name a few. Silk and wool, which are natural protein fibers, are also polyamides and, like nylon, so far have proved themselves to have a superior tensile strength to that of polyethylene.

Principal terms

AMINE: an organic compound that can be considered as derived from ammonia (NH3), by replacement of one or more hydrogens with an organic radical

BARBITURATES: a branch of the amide family whose members are used as sedatives

CARBOXYLIC ACID: a compound of the general formula R-COOH, from which and amide id produced by replacing the hydroxyl (-OH) with an amino (-NH2) group

LACTAM: a cyclic amide

SULFONAMIDE: the amide produced by the reaction of a sulfonic acid (R-SO3H) group with ammonia or an amine

Bibliography

Hill, John W. CHEMISTRY FOR CHANGING TIMES. 4th ed. New York: Macmillan, 1984. A textbook written for the lay person, with excellent sections on various subjects taken from everyday life. Chapter 12 deals extensively with polymers; chapters 11 and 18 cover, briefly, amides and proteins.

Holum, John R. ELEMENTS OF GENERAL AND BIOLOGICAL CHEMISTRY. 6th ed. New York: Wiley, 1983. An introductory text for health science students, with a brief discussion on amides (section 12.4). It also covers several applications under "special topics," such as nylon (12.3), barbiturates (12.4), and sulfa drugs (16.1).

Loudon, G. Marc. ORGANIC CHEMISTRY. Reading, Mass.: Addison-Wesley, 1984. An undergraduate text in organic chemistry that discusses, mechanistically, the different organic families. Chapter 24 covers the derivatives of carboxylic acids. Section 24.13B gives an account of the origin of names for barbituric acid and Veronal.

Matta, Michael S., and A. C. Wilbraham. GENERAL, ORGANIC, AND BIOLOGICAL CHEMISTRY. 2d ed. Menlo Park, Calif.: Benjamin/Cummings, 1986. An excellent introductory textbook, with several sections titled "Closer Look" in which applications of phenomena and laws in everyday events are highlighted. Sections 15.4 through 15.6 cover the nomenclature, synthesis, hydrolysis, and polymerization of amides. Section 15.10 discusses the barbiturates, while "closer look" 15.1 gives an account of the amide local anesthetics.

Stacy, Gardner W., and C. C. Wamser. ORGANIC CHEMISTRY: A BACKGROUND FOR THE LIFE SCIENCES. Dubuque, Iowa: Kendall/Hunt, 1985. A simple and easy-to-read text of basic organic chemistry for the health science courses. Sections 15.10 and 15.11 deal with amides and their applications.

Weininger, Stephen J., and F. R. Stermitz. ORGANIC CHEMISTRY. Orlando, Fla.: Academic Press, 1984. An organic chemistry text with a section on the derivatives of carboxylic acids and a special section (17.8) on β-lactam antibiotics.

Amines converting to amides

Creation of a peptide bond

Polymers.