carboxylic acid

Chem.

any organic acid containing one or more carboxyl groups.

[1900-05; CARBOXYL + -IC]

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Any organic compound with the general chemical formula ―COOH in which a carbon (C) atom is bonded to an oxygen (O) atom by a double bond to make a carbonyl group (―C=O; see functional group) and to a hydroxyl group (―OH) by a single bond (see bonding).

The fourth bond on the carbon links it to a hydrogen (H) atom (for formic acid), a methyl (―CH₃) group (for acetic acid), or another natural or synthetic monovalent group. Carboxylic acids occur widely in nature. In fatty acids, the fourth group is a hydrocarbon chain. In aromatic acids (see aromatic compound), it is a ring-structured hydrocarbon. In amino acids, it contains a nitrogen atom. Carboxylic acids participate in chemical reactions as acids, usually fairly weak. Many carboxylic acids (acetic acid, citric acid, lactic acid) are intermediates in metabolism and can be found in natural products; others (e.g., salicylic acid) are used as solvents and to prepare many chemical compounds. Important carboxylic-acid derivatives include esters, anhydrides, amides, halides (see halogen), and salts (see soap).

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▪ chemical compound

Introduction

 any of a class of organic compounds (organic compound) in which a carbon (C) atom is bonded to an oxygen (O) atom by a double bond and to a hydroxyl group (−OH) by a single bond. A fourth bond links the carbon atom to a hydrogen (H) atom or to some other univalent combining group. The carboxyl (COOH) group is so-named because of the carbonyl group (C=O) and hydroxyl group.

      The chief chemical characteristic of the carboxylic acids is their acidity. They are generally more acidic than other organic compounds containing hydroxyl groups but are generally weaker than the familiar mineral acids (e.g., hydrochloric acid, HCl, sulfuric acid, H₂SO₄, etc.).

      Carboxylic acids occur widely in nature. The fatty acids (fatty acid) are components of glycerides, which in turn are components of fat. Hydroxyl acids, such as lactic acid (found in sour-milk products) and citric acid (found in citrus fruits), and many keto acids are important metabolic products that exist in most living cells (cell). Proteins (protein) are made up of amino acids (amino acid), which also contain carboxyl groups.

      Compounds in which the −OH of the carboxyl group is replaced by certain other groups are called carboxylic acid derivatives, the most important of which are acyl halides, acid anhydrides, esters (ester), and amides (amide).

 Carboxylic acid derivatives have varied applications. For example, in addition to its use as a disinfectant, formic acid, the simplest carboxylic acid, is employed in textile treatment and as an acid reducing agent. acetic acid is extensively used in the production of cellulose plastics (plastic) and esters. aspirin, the ester of salicylic acid, is prepared from acetic acid. Palmitic acid and stearic acid are important in the manufacture of soaps, cosmetics, pharmaceuticals, candles, and protective coatings. Stearic acid also is used in rubber manufacture. Acrylic acid is employed as an ester in the production of polymers (polymer) (long-chain molecules) known as acrylates. Methacrylic acid serves as an ester and is polymerized to form Lucite. Oleic acid is used in the manufacture of soaps and detergents and of textiles.

nomenclature of carboxylic acids and their salts

      The IUPAC name of a carboxylic acid is derived from that of the longest carbon chain that contains the carboxyl group by dropping the final -e from the name of the parent alkane and adding the suffix -oic followed by the word “acid.” The chain is numbered beginning with the carbon of the carboxyl group. Because the carboxyl carbon is understood to be carbon 1, there is no need to give it a number. For example, the compound CH₃CH₂COOH has three carbon atoms and is called propanoic acid, from propane, the name for a three-carbon chain, with -oic acid, the suffix for this class of compounds, appended. If the carboxylic acid contains a carbon-carbon double bond, the ending is changed from -anoic acid to -enoic acid to indicate the presence of the double bond, and a number is used to show the location of the double bond.

       Straight-chain saturated acids and their methyl esters Straight-chain saturated acids and their methyl estersMost simple carboxylic acids, rather than being called by their IUPAC names, are more often referred to by common names that are older than their systematic names. Most simple carboxylic acids were originally isolated from biological sources; because their structural formulas were often unknown at the time of isolation they were given names that were generally derived from the names of the sources. For example, CH₃CH₂CH₂COOH, butyric acid, first obtained from butter, was named after the Latin butyrum, meaning “butter.” The acids containing an odd number of carbon atoms greater than nine generally do not have common names. The reason is that long-chain carboxylic acids were originally isolated from fats (which are carboxylic esters), and generally these fats contain carboxylic acids with only an even number of carbon atoms (because the process by which living organisms synthesize such fatty acids puts the molecules together in two-carbon pieces).

      When common names are used, substituents on the hydrocarbon chain are designated by Greek letters rather than by numbers, and counting begins not with the carboxyl carbon but with the adjacent carbon. For example, the common name of the following compound γ-aminobutyric acid, abbreviated GABA. Its IUPAC name is 4-aminobutanoic acid. GABA is an inhibitory neurotransmitter in the central nervous system (nervous system, human) of humans.

      Salts of carboxylic acids are named in the same manner as are the salts of inorganic compounds (chemical compound); the cation is named first and then the anion, as in sodium chloride. For carboxylic acids, the name of the anion is derived by changing the ending -oic acid of the IUPAC name or -ic acid of the common name to -ate. Some examples are sodium acetate, CH₃COONa; ammonium formate, HCOONH₄; and potassium butanoate (potassium butyrate), CH₃CH₂CH₂COOK.

Properties of carboxylic acids

Acidity

      The most important property of carboxylic acids, and the one that is responsible for naming them such, is their acidity. An acid is any compound that donates a hydrogen ion, H⁺ (also called a proton), to another compound, termed a base. Carboxylic acids do this much more readily than most other classes of organic compounds, so they are said to be stronger acids, even though they are much weaker than the most important mineral acids—sulfuric (sulfuric acid) (H₂SO₄), nitric (nitric acid) (HNO₃), and hydrochloric (hydrochloric acid) (HCl). The reason for the enhanced acidity of this group of compounds can best be demonstrated by a comparison of their acidity with that of alcohols (alcohol), both of which contain an −OH group. Alcohols are neutral compounds in aqueous solution. When an alcohol donates its proton, it becomes a negative ion called an alkoxide ion, RO⁻. When a carboxylic acid donates its proton, it becomes a negatively charged ion, RCOO⁻, called a carboxylate ion.

      A carboxylate ion is much more stable than the corresponding alkoxide ion because of the existence of resonance (resonance, theory of) structures for the carboxylate ion which disperse its negative charge. Only one structure can be drawn for an alkoxide ion, but two structures can be drawn for a carboxylate ion. When two or more structures that differ only in the positions of valence electrons (electron) can be drawn for a molecule or ion, it means that its valence electrons are delocalized, or spread over more than two atoms (atom). This phenomenon is called resonance, and the structures are called resonance forms. A double-headed arrow is used to show that the two or more structures are related by resonance. Because there are two resonance forms but only one real ion, it follows that neither of these forms is an accurate representation of the actual ion. The real structure incorporates aspects of both resonance structures but duplicates neither. Resonance always stabilizes a molecule or ion, even if charge is not involved. The stability of an anion determines the strength of its parent acid. A carboxylic acid is, therefore, a much stronger acid than the corresponding alcohol, because, when it loses its proton, a more stable ion results.

      Some atoms or groups, when attached to a carbon, are electron-withdrawing, as compared with a hydrogen atom in the same position. For example, consider chloroacetic acid (Cl−CH₂COOH) compared with acetic acid (H−CH₂COOH). Because chlorine has a higher electronegativity than hydrogen, the electrons in the Cl−C bond are drawn farther from the carbon than the electrons in the corresponding H−C bond. Thus, chlorine is considered to be an electron-withdrawing group. This is one example of the so-called inductive effect, in which a substituent affects a compound's distribution of electrons. There are a number of such effects, and atoms or groups may be electron-withdrawing or electron-donating as compared with hydrogen. The presence of such groups near the COOH group of a carboxylic acid often has an effect on the acidity. In general, electron-withdrawing groups increase acidity by increasing the stability of the carboxylate ion. In contrast, electron-donating groups decrease acidity by destabilizing the carboxylate ion. For example, the methyl group, −CH₃, is generally regarded as electron-donating, and acetic acid, CH₃ COOH, is about 10 times weaker as an acid than formic acid, HCOOH. Similarly, chloroacetic acid, ClCH₂ COOH, in which the strongly electron-withdrawing chlorine replaces a hydrogen atom, is about 100 times stronger as an acid than acetic acid, and nitroacetic acid, NO₂CH₂ COOH, is even stronger. (The NO₂ group is a very strong electron-withdrawing group.) An even greater effect is found in trichloroacetic acid, Cl₃CCOOH, whose acid strength is about the same as that of hydrochloric acid.

Solubility

      The solubility of carboxylic acids in water is similar to that of alcohols, aldehydes (aldehyde), and ketones (ketone). Acids with fewer than about five carbons dissolve in water; those with a higher molecular weight are insoluble owing to the larger hydrocarbon portion, which is hydrophobic. The sodium, ammonium, and potassium salts of carboxylic acids, however, are generally quite soluble in water. Thus, almost any carboxylic acid can be made to dissolve in water by converting it to such a salt, which is easily done by adding a strong base—most commonly sodium hydroxide (NaOH) or potassium hydroxide, (KOH). The calcium and sodium salts of propanoic (propionic) acid are used as preservatives, chiefly in cheese, bread, and other baked goods.

boiling point

      Carboxylic acids have much higher boiling points (boiling point) than hydrocarbons, alcohols, ethers (ether), aldehydes, or ketones of similar molecular weight. Even the simplest carboxylic acid, formic acid, boils at 101 °C (214 °F), which is considerably higher than the boiling point of ethanol ( ethyl alcohol), C₂H₅OH, which boils at 78.5 °C (173 °F), although the two have nearly identical molecular weights. The difference is that two molecules of a carboxylic acid form two hydrogen bonds with each other (two alcohol molecules can only form one). Thus, carboxylic acids exist as dimers (pairs of molecules), not only in the liquid state but even to some extent in the gaseous (gas) state.

      Therefore, boiling a carboxylic acid requires the addition of more heat than boiling the corresponding alcohol, because (1) if the dimer persists in the gaseous state, the molecular weight is in effect doubled; and, (2) if the dimer is broken upon boiling, extra energy is required to break the two hydrogen bonds. Carboxylic acids with higher molecular weights are solids (solid) at room temperature (e.g., benzoic (benzoic acid) and palmitic acids). Virtually all salts of carboxylic acids are solids at room temperature, as can be expected for ionic compounds.

Odour

      Unbranched-chain carboxylic acids (fatty acids (fatty acid)) that are liquids at room temperature, especially those from propanoic (C₃) to decanoic (C₁₀) acid, have very foul, disagreeable odours. An example is butanoic (butyric) acid (butyric acid) (C₄), which is the main ingredient in stale perspiration and thus the chief cause of “locker-room” odour.

Classes of carboxylic acids

Saturated aliphatic (aliphatic compound) acids

  formic acid, HCOOH, is found not only in ants (ant) but also in the droplets on the tiny hairs of the stinging nettle plant (in the family Urticaceae), and the acidity of this compound causes the stinging sensation felt when these hairs are touched.

   acetic acid, CH₃COOH, has been known to humankind for thousands of years (at least in water solution). It is the compound that gives the sourness to vinegar and is produced by the bacterial oxidation of ethanol in wine. Household vinegar contains about five percent acetic acid. Acetic acid is important in the metabolic processes of humans and, indeed, of all animals and plants. In these processes, the CH₃CO (acetyl) group of the acetic acid molecule is attached to a large biochemical molecule called coenzyme A; the entire compound is known as acetyl coenzyme A. In the metabolism of food materials (the body's conversion of food to energy), the carbon atoms of carbohydrates (carbohydrate), fats, and, to some degree, proteins are converted to acetyl groups that are bonded to coenzyme A to form acetyl coenzyme A. The acetyl groups of acetyl coenzyme A are then converted, by means of the tricarboxylic acid cycle and oxidative phosphorylation (see metabolism), to energy (in the form of adenosine triphosphate, or ATP) and carbon dioxide (CO₂), which is exhaled. Not all the acetyl groups of acetyl coenzyme A of an organism is converted to energy. Some is used to synthesize fatty acids (fatty acid), terpenes (terpene), steroids (steroid), and other needed molecules. The carboxylic acids that occur in fats have an even number of carbon atoms because they are synthesized entirely from the two-carbon acetyl units of acetyl coenzyme A.

      The even-numbered fatty acids (fatty acid) from 4 to 10 carbon atoms are mostly found in milk fats. Butanoic (butyric (butyric acid)) acid, CH₃CH₂CH₂COOH, is an important component of cow's milk. Goat's milk (goat) is rich in fats containing the 6-, 8-, and 10-carbon acids: hexanoic (caproic), octanoic (caprylic), and decanoic (capric) acids, respectively. Common names for these three acids are derived from the Latin caper, meaning “goat.” Some hard cheeses (e.g., Swiss cheese) contain natural propanoic acid. The higher even-numbered saturated acids, from C₁₂ to C₁₈ (lauric, myristic, palmitic, and stearic (stearic acid)), are present in the fats and oils of many animals and plants, with palmitic and stearic acids being the most prevalent. Lauric acid (C₁₂) is the main acid in coconut oil (45–50 percent) and palm kernel oil (45–55 percent). Nutmeg butter is rich in myristic acid (C₁₄), which constitutes 60–75 percent of the fatty-acid content. Palmitic acid (C₁₆) constitutes between 20 and 30 percent of most animal fats and is also an important constituent of most vegetable fats (35–45 percent of palm oil). Stearic acid (C₁₈) is also present in most fats but usually in smaller amounts than palmitic. cocoa butter is unusually rich in stearic acid (35 percent).

      Even-numbered saturated fatty acids higher than C₁₈ are much less common in fats but do occur in some waxes (wax). Waxes obtained from animal and plant sources typically consist of carboxylic esters derived from long-chain acids and long-chain alcohols. For example, beeswax contains, among other components, the ester made from cerotic acid (C₂₆) and the unbranched-chain alcohol containing 30 carbons, triacontanol. Odd-numbered fatty acids have been found only in trace amounts in natural compounds, but many have been produced synthetically in the laboratory.

Unsaturated aliphatic acids

      A number of acids important in organic chemistry contain carbon-carbon double bonds.

      There exist α,β-unsaturated acids, in which the double bond is between the second and third carbons of the chain, as well as unsaturated acids, in which the double bond occurs in other positions. Although many of these latter acids occur in nature, they are less easy to synthesize than α,β-unsaturated acids. Esters of acrylic acid (ethyl and butyl acrylate) and methacrylic acid (methyl methacrylate) are important monomers (monomer) for the synthesis of polymers (polymer). Methyl methacrylate polymerizes to yield a strong transparent solid that is used as a plastic under such proprietary names as Plexiglas and Lucite. The trans isomer of crotonic acid is found in croton oil. The cis isomer does not occur in nature but has been synthesized in the laboratory. Angelic and tiglic acids are a pair of cis-trans isomers. Angelic acid is found as an ester in angelica root, whereas tiglic acid occurs in croton oil and in several other natural products.

      Ricinoleic acid, an unsaturated hydroxy acid (i.e., one containing an −OH group), occurs in castor oil. When this acid is pyrolyzed (heated in the absence of air), it breaks down to give undecylenic acid and n-heptaldehyde.

      The zinc salt of undecylenic acid is used to treat fungal infections of the skin, especially tinea pedis (athlete's foot) (athlete's foot). Esters of this acid are used in perfumery. Sorbic acid, CH₃CH=CHCH=CHCOOH, which has two double bonds in conjugation (that is, two double bonds separated only by one single bond), and its potassium salt (potassium sorbate) are used as preservatives (preservative) in many food products as well as in their packaging materials, since they inhibit the growth of molds (mold) and other fungi (fungus).

      Many unsaturated acids occur in fats (fat).

      These naturally occurring unsaturated fatty acids (fatty acid) have certain characteristics. (1) If there are two or more carbon-carbon double bonds, each double bond is separated from the next by a CH₂ (called methylene) group. (2) Virtually all double bonds in these and other naturally occurring unsaturated fatty acids have the cis configuration. (3) Linoleic and linolenic acids are needed by the human body, but the body cannot synthesize them. They must be obtained in the diet and, therefore, are called essential fatty acids. (4) Many unsaturated fatty acids are liquids at room temperature, in contrast to the saturated stearic (C₁₈) and arachidic (C₂₀) acids, which are solids. The reason is that the regular nature of the saturated hydrocarbon chains allows the molecules in the solid to stack in a close parallel arrangement, while the presence of cis double bonds in the unsaturated hydrocarbon chains breaks up this arrangement and forces the molecules to remain farther apart. Since the molecules in the unsaturated fatty acids are not as close to each other, less energy is needed to separate them, and a lower melting-point (melting point) results. This situation is paralleled in the fats themselves, which are esters (ester) of these long-chain carboxylic acids where the alcohol component is glycerol, (HOCH₂)₂CHOH. Solid fats, obtained mostly from animal sources, have a high percentage of saturated fatty acids. Liquid fats (often called oils), obtained mainly from plant or fish sources, have a high percentage of unsaturated fatty acids. An exception is coconut oil, which, though obtained from a plant, has only a low percentage of unsaturated acids. The liquidity in this case is because of the high percentage of lauric acid (C12), which has a low molecular weight. Polyunsaturated fats may be defined as those containing an average of more than one double bond per fatty acid molecule.

      Arachidonic acid is important because the human body uses it as a starting material in the synthesis of two kinds of essential substances, the prostaglandins (prostaglandin) and the leukotrienes, both of which are also unsaturated carboxylic acids. Examples are PGE₂ (a prostaglandin) and LTB₄ (a leukotriene). The symbol PG represents prostaglandin, E indicates the presence of a keto group on the five-membered ring, and the subscript ₂ indicates two double bonds. Similarly, LT represents leukotriene, B is one form, and the subscript 4 indicates four double bonds.

      Prostaglandins and leukotrienes are made in small amounts, but they are significant because they act as hormone mediators. Some prostaglandins raise blood pressure, whereas others lower it. PGE₂ induces labour in pregnant women and is used medicinally for this purpose, as well as for therapeutic abortions (abortion). The PGEs, along with several other PGs, suppress gastric ulceration and appear to heal peptic ulcers (peptic ulcer). The PGE₁ analog, misoprostol, is currently used to prevent ulceration associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

      Unsaturated acids exhibit chemical properties expected of compounds that contain both a COOH group and one or more carbon-carbon double bonds. Like all carboxylic acids, they are acidic; can be reduced to alcohols; can be converted to acid derivatives; and, like other compounds containing double bonds, can undergo the normal double-bond addition reactions (addition reaction) and oxidation-reduction reactions (oxidation–reduction reaction).

Aromatic acids

      Aromatic acids include compounds that contain a COOH group bonded to an aromatic ring. The simplest aromatic acid is benzoic acid.

      Aromatic carboxylic acids show not only the acidity and other reactions expected of carboxylic acids (as an acid, benzoic acid is slightly stronger than acetic acid) but, similar to other aromatic compounds (aromatic compound), also undergo electrophilic substitution reactions. The COOH group is deactivating, meaning electrophilic substitutions take place less readily than with benzene itself (Friedel-Crafts reactions do not occur), and meta-directing, meaning that the incoming entity will enter at a position meta to the COOH group, rather than at an ortho or para position, as in, for example, the nitration of benzoic acid.

      Benzoic acid, a solid at room temperature (melting point 122 °C [252 °F]), was first described in 1560, having been prepared by distilling gum benzoin, a resin obtained from certain Asian trees. It occurs in various plants, both in free acid form and in ester form. It is also a constituent of the urine of certain animals, especially horses, as an amide of glycine called hippuric acid, C₆H₅CONHCH₂COOH. The sodium salt, sodium benzoate, is used as a preservative in many foods.

      Some other important aromatic acids include the following:

       salicylic acid is both a carboxylic acid and a phenol, so it can be esterified in two ways, with both giving rise to familiar products. In methyl salicylate (oil of wintergreen), the COOH group of salicylic acid is esterified with methanol (CH₃OH), whereas in acetylsalicylic acid (aspirin) the acid component of the ester is acetic acid, and salicylic acid contributes the phenolic −OH group.

       gallic acid is found in tea, as well as in other plants, and it also occurs as part of a larger molecule, called tannin, which is present in galls (gall) (such as the swellings of the tissue of oak trees caused by the attack of wasps). Tannins are used in making leather, and gallic acid is employed in the production of inks. Three of the most important aromatic dicarboxylic acids are called phthalic (phthalic acid), isophthalic, and terephthalic acid, for the ortho, meta, and para isomers, respectively. Phthalic acid is converted to its anhydride simply by heating (see below Polycarboxylic acids (carboxylic acid)). Phthalic anhydride is used to make polymeric resins called alkyd resins, which are used as coatings, especially for appliances and automobiles. The para isomer, terephthalic acid, is also used to make polymers—namely, polyesters (polyester) (see below Derivatives of carboxylic acids: Carboxylic esters (carboxylic acid)).

      Several important acids contain an aromatic ring but, because the carboxyl group is not bonded directly to it, they are not considered to be aromatic acids.

      Phenylacetic acid is used to synthesize many other organic compounds. Mandelic acid is toxic to bacteria in acidic solution and is used to treat urinary infections. Cinnamic acid, an unsaturated carboxylic acid, is the chief constituent of the fragrant balsamic resin storax. ibuprofen and naproxen are important painkilling and anti-inflammatory drugs. Ibuprofen is sold over-the-counter under proprietary names such as Advil and Nuprin. Naproxen is sold under names such as Aleve. Both ibuprofen and naproxen have a stereocentre and are chiral. The physiologically active stereoisomer of each is the S enantiomer.

Polycarboxylic acids

       Straight-chain dicarboxylic acids Straight-chain dicarboxylic acidsUnbranched-chain dicarboxylic acids contain two COOH groups. As a result they can yield two kinds of salts. For example, if oxalic acid, HOOCCOOH, is half-neutralized with sodium hydroxide, NaOH (i.e., the acid and base are in a 1:1 molar ratio), HOOCCOONa, called sodium acid oxalate or monosodium oxalate, is obtained. Because one COOH group is still present in the compound, it has the properties of both a salt and an acid. Full neutralization (treatment of oxalic acid with NaOH in a 1:2 acid-to-base molar ratio) yields NaOOCCOONa, sodium oxalate. If desired, the half-neutralization can be done with one base and the rest with another, to produce a mixed salt, as, for example, KOOCCOONa—sodium potassium oxalate. All dicarboxylic acids can be neutralized or half-neutralized in a similar manner.

      The first three simple unbranched-chain dicarboxylic acids give very different results upon heating.

      Oxalic acid decomposes by losing carbon dioxide (CO₂) to give formic acid (HCOOH), which itself decomposes to yield carbon monoxide (CO) and water (H₂O). malonic acid loses carbon dioxide by a mechanism in which three electron pairs (covalent bonds (covalent bond)) move around a ring.

      A hydrogen atom of the unstable initial enol product moves from an oxygen atom to a carbon atom (a property known as tautomerism) to give the stable acetic acid. Not only malonic acid but all carboxylic acids with two COOH groups on the same carbon atom react in the same manner. With succinic acid, the two COOH groups combine with the loss of a water molecule to produce succinic anhydride. Glutaric acid, with five carbon atoms, behaves similarly to yield glutaric anhydride. These reactions produce five- and six-membered rings, respectively, which are in general the easiest ring sizes to produce. Because adipic (six carbons) and longer-chain dicarboxylic acids would give rings of seven or more members, heating of these acids does not generally lead to cyclic anhydrides, though this conversion sometimes can be accomplished by using special techniques. Upon heating, phthalic acid readily yields phthalic anhydride (with a five-membered ring), but isophthalic and terephthalic acids do not undergo this reaction.

      Oxalic acid, in the form of its monopotassium salt, is found in many vegetables (vegetable) and fruits (fruit)—in considerable amounts in spinach and rhubarb but also to a lesser degree in cabbages, tomatoes, and grapes, among others.

      Of much greater importance than malonic acid is its diethyl ester (ethyl ether), CH₂(COOCH₂CH₃)₂, called diethyl malonate. This compound is used in a synthetic process to produce a variety of monosubstituted and disubstituted derivatives of acetic acid.

      The series of reactions in the formation of acetic acid derivatives (called the malonic ester synthesis) is feasible because a methylene group connected to two carbonyl groups (carbonyl group) (as in diethyl malonate) is somewhat more acidic than similar groups connected to only one carbonyl group and can lose a hydrogen ion to a strong base such as sodium ethoxide (C₂H₅ONa). When heated with urea and sodium ethoxide, diethyl malonate yields barbituric acid.

      A number of derivatives of barbituric acid have powerful sedative and hypnotic effects. One such derivative is pentobarbital. As with other derivatives of barbituric acid, pentobarbital is quite insoluble in water and body fluids. To increase its solubility in these fluids, pentobarbital is converted to its sodium salt, which is given the name Nembutal.

      Other examples of barbiturates (barbiturate) are secobarbital and thiopental, each of which is most commonly administered as its sodium salt. Thiopental is similar in structure to pentobarbital, except that an atom of sulfur is substituted for an oxygen in one of the C=O groups of the six-membered ring.

      Barbiturates have two principal effects. In small doses, they are sedatives (tranquilizers (tranquilizer)); in larger doses they induce sleep. Pentothal is used as a general anesthetic. Pentobarbital and secobarbital are often used as a preanesthetic to prepare patients for surgery. Barbituric acid has none of these effects.

      Succinic acid occurs in many plants; its name comes from the Latin succinum, meaning “amber,” from which it was first isolated. It is an important component of the tricarboxylic acid cycle (or Krebs cycle), a part of the process by which animals convert food to energy. Adipic acid, HOOC(CH₂)₄COOH, is used in the manufacture of nylon-6,6, the most common form of nylon (see below Derivatives of carboxylic acids: Amides (carboxylic acid)).

      Several important di- and polycarboxylic acids contain one or more hydroxyl groups.

      Malic acid is found in many fruits, including apples; tartaric acid occurs in grapes; and citric acid is present in lemons, oranges, and other citrus fruits. The monopotassium salt of tartaric acid, commonly called cream of tartar, is obtained from wine casks, where it crystallizes as a hard crust. In the past, it was used in baking powders (baking powder) as a leavening agent, but this application has largely (though not entirely) been superseded by cheaper substances such as monocalcium phosphate. Similar to succinic acid, malic and citric acids are components of the tricarboxylic acid cycle.

      The two most important unsaturated dicarboxylic acids are fumaric and maleic acids, a pair of cis-trans isomers.

      Although these two acids have the same structural formula and differ only in the three-dimensional geometry of their molecules, their properties are very different. maleic acid melts at 130 °C (266 °F) and fumaric acid at 286 °C (547 °F); at room temperature, maleic acid is about 100 times more soluble in water and about 15 times as strong an acid (although fumaric acid gives up its second proton more readily than maleic acid does). Only maleic acid forms an anhydride; fumaric acid does not. Fumaric acid occurs in nature and is a component of the tricarboxylic acid cycle, whereas maleic acid is not a natural product. Maleic anhydride, which is made industrially by oxidation of benzene (C₆H₆), is often used as a dienophile (isolated alkene component) in Diels-Alder reactions.

Hydroxy and keto acids

      The 2-, 3-, 4-, and 5-hydroxycarboxylic acids all lose water upon heating, although the products are not the same. The 2-hydroxy acids form cyclic dimeric esters (formed by the esterification of two molecules of the acid) called lactides, whereas the 3- and 4-hydroxy acids undergo intramolecular esterification to give cyclic esters called lactones (lactone). These reactions take place so readily, even without heating, that in most cases the only way to keep these kinds of hydroxy acids from forming cyclic esters is to convert them to their sodium or potassium salts. 2-Hydroxy acids lose water upon heating to yield α,β-unsaturated acids.

      The simplest hydroxy acids, glycolic and lactic, occur in nature.

       lactic acid is formed when milk turns sour (hence the name, from Latin lactis, “milk”) and was first isolated from sour milk by the Swedish chemist Carl Wilhelm Scheele (Scheele, Carl Wilhelm) in 1780. It occurs in plants as well. Lactic acid in the form of its salt (lactate) is produced in muscle tissue as a result of the anaerobic breakdown of glucose. Excess lactate is the cause of muscle soreness produced after strenuous exercise when the body's supply of oxygen is reduced. Lactic and glycolic acids can be copolymerized to give a type of polyester that can be made into absorbable surgical sutures.

      Traditional suture materials such as catgut must be removed by a health care specialist after they have served their purpose. These polyester sutures, however, are hydrolyzed slowly over a period of approximately two weeks. By the time the torn tissues have healed, the sutures have hydrolyzed, and no surgical removal is necessary. Glycolic and lactic acids formed during this hydrolysis are metabolized and excreted by the body.

      Pyruvic acid and acetoacetic acid are the simplest and most important of the α-keto and β-keto acids, respectively.

      Pyruvic acid (in the form of its salt pyruvate) is involved in the normal metabolism of carbohydrates (carbohydrate) as the final product of a series of some 11 or 12 steps starting from glucose or fructose. It is then converted (by loss of carbon dioxide) to acetyl coenzyme A, which enters the tricarboxylic acid cycle. Pyruvate is also used by the body to synthesize alanine, an amino acid required for the synthesis of proteins.

      Acetoacetic acid (in the form of its ethyl ester, called ethyl acetoacetate) is the starting compound in a series of reactions (the acetoacetic ester synthesis) that is parallel to the malonic ester synthesis.

      The product in this case is an α-substituted acetone (acetone is (CH₃)₂C=O), and many mono- and disubstituted acetones have been made by this procedure. Like 2,4-pentanedione, ethyl acetoacetate exists predominantly in the enol form owing to stabilization by internal hydrogen bonding. Acetoacetic acid itself is unstable and loses carbon dioxide to give acetone: CH₃COCH₂COOH → CH₃COCH₃+ CO₂. In severe diabetes (diabetes mellitus) the body converts acetyl coenzyme A to acetoacetic acid and its decarboxylation product, acetone—excess quantities of which are secreted in the urine. These two compounds, along with β-hydroxybutyric acid (in which the acids are in the form of their salts), are collectively called ketone bodies, although the third of these is not a ketone; they are used to diagnose diabetes.

Amino acids (amino acid)

      Compounds containing both a carboxyl group and an amino group are called amino acids (amino acid). Twenty of these are found in proteins, all of which are α-amino acids with the following formula:

       glutamic acid is one of the amino acids found in proteins (protein), and its sodium salt, monosodium glutamate (MSG), is often used as a food additive. Although it imparts no flavour of its own, it enhances the flavours of meats, fish, and vegetables. Some people experience an allergic reaction to MSG; the allergy is commonly known as “Chinese restaurant syndrome,” because MSG has been a widely used ingredient in the cuisine of many Chinese restaurants.

      Because carboxyl groups are acidic and amino groups are basic, amino acids undergo internal acid-base reactions (acid–base reaction) and exist in the form of internal salts known as zwitterions (from German zwitter, “hybrid”). Because they are internal salts, amino acids are all solids at room temperature, and most of them are soluble in water.

      Para-aminobenzoic acid (-aminobenzoic acid (para-aminobenzoic acid), PABA) is an aromatic amino acid that is a part of the folic acid molecule.

      Folic acid is required by many organisms. Humans cannot synthesize it and must obtain it from their diet (it is a B vitamin). bacteria produce folic acid, using PABA in this synthesis. In the 1930s it was discovered that when certain disease-causing bacteria are fed sulfanilamide, a compound with a structure similar to that of PABA, the bacterial enzymes (enzyme) involved in the incorporation of PABA into folic acid combine with sulfanilamide instead of PABA. Thus, the enzymes are inhibited from catalyzing the synthesis of folic acid and, deprived of folic acid, the bacteria die. Sulfanilamide proved unsuitable for use as a drug, but some of its derivatives (the sulfa drugs (sulfa drug)) are used to cure many bacterial diseases.

Synthesis of carboxylic acids

      Most of the methods for the synthesis of carboxylic acids can be put into one of two categories: (1) hydrolysis of acid derivatives and (2) oxidation of various compounds.

hydrolysis of acid derivatives

      All acid derivatives can be hydrolyzed (cleaved by water) to yield carboxylic acids; the conditions required range from mild to severe, depending on the compound involved.

      The easiest acid derivatives to hydrolyze are acyl chlorides, which require only the addition of water. Carboxylic acid salts are converted to the corresponding acids instantaneously at room temperature simply on treatment with water and a strong acid such as hydrochloric acid (shown as H⁺ in the equations above). Carboxylic esters (ester), nitriles (nitrile), and amides (amide) are less reactive and typically must be heated with water and a strong acid or base to give the corresponding carboxylic acid. If a base is used, a salt is formed instead of the carboxylic acid, but the salt is easily converted to the acid by treatment with hydrochloric acid. Of these three types of acid derivatives, amides are the least reactive and require the most vigorous treatment (i.e., higher temperatures and more prolonged heating). Under milder conditions, nitriles can also be partially hydrolyzed, yielding amides: RCN → RCONH₂.

Oxidation

      The oxidation of primary alcohols is a common method for the synthesis of carboxylic acids: RCH₂OH → RCOOH. This requires a strong oxidizing agent, the most common being chromic acid (H₂CrO₄), potassium permanganate (KMnO₄), and nitric acid (HNO₃). Aldehydes (aldehyde) are oxidized to carboxylic acids more easily (by many oxidizing agents), but this is not often useful, because the aldehydes are usually less available than the corresponding acids. Also important is the oxidation of alkyl side chains of aromatic rings by strong oxidizing agents such as chromic acid, potassium permanganate, and nitric acid to yield aromatic carboxylic acids. Regardless of the number of carbon atoms in the side chain or the presence of any groups attached to them, if the first carbon in the alkyl chain is bonded to at least one hydrogen (and not to another aromatic ring), all but one of the carbons are removed, and only a COOH group remains bonded to the aromatic ring. Examples are the oxidations of toluene and 1-chloro-3-phenylpropane.

      Terephthalic acid for the production of the polymer poly(ethylene terephthalate), abbreviated PET, is made by the catalyzed air oxidation of 1,4-dimethylbenzene (p-xylene). Treatment of this dicarboxylic acid or its dimethyl ester with ethylene glycol gives PET. PET can be fabricated into textile fibers (Dacron polyester), into film ( Mylar), and into recyclable beverage containers.

Other synthetic methods

      Grignard reagents (Grignard reagent) react with carbon dioxide (either in the gaseous form, which is bubbled through the solution, or as the solid dry ice) to give magnesium salts of carboxylic acids, which are converted to the acids themselves upon treatment with acid: RMgBr + CO₂→ RCOO^{− +}MgBr + HCl → RCOOH. Unlike the methods previously mentioned, this method adds one carbon atom to the carbon skeleton. A Grignard reagent is prepared from an alkyl or aryl halide; e.g., RBr + Mg → RMgBr. An alternative way to accomplish the same result is to treat the halide with potassium cyanide (KCN) or sodium cyanide (NaCN) and then hydrolyze the resulting nitrile, as mentioned above; e.g., RBr + KCN → RCN → RCOOH. The two procedures are complementary. Although all nitriles can be hydrolyzed to the corresponding acid and all Grignard reagents react with carbon dioxide, the halide reactions are more limited. Many types of halides (including aromatic halides) do not react with NaCN or KCN. On the other hand, while Grignard reagents can be made from many of the halides that do not react with NaCN or KCN (including aryl halides), they cannot be made from halides that contain certain other functional groups (functional group), such as alcohol, carboxylic ester, aldehyde, or ketone groups. Other methods for the synthesis of carboxylic acids have already been mentioned, including the malonic ester synthesis (see above Classes of carboxylic acids: Polycarboxylic acids (carboxylic acid)), the haloform reaction, and the Cannizzaro reaction.

Principal reactions of carboxylic acids

      Because many carboxylic acids can be obtained from natural sources, they are frequently used as starting materials for other types of compounds. The most important chemical property of carboxylic acids, their acidity, was discussed above (see above Properties of carboxylic acids: Acidity (carboxylic acid)). Other important reactions are discussed in the following sections.

Conversion to acid derivatives

      Treatment of a carboxylic acid with thionyl chloride, SOCl₂ (often in the presence of an amine such as pyridine, C₅H₅N), converts the carboxyl group to the corresponding acyl chloride (RCOOH → RCOCl).

      Several other reagents (e.g., PCl₃, PCl₅) can also be used, but thionyl chloride is usually the most convenient because the other products of the reaction, hydrogen chloride (HCl) and sulfur dioxide (SO₂), are gases, making isolation of the acyl chloride simple. This is an important reaction because several types of acid derivatives (mainly carboxylic esters (ester) and amides) are more easily made from the acyl chloride than from the carboxylic acid.

      Esters can be prepared by treatment of a carboxylic acid with an alcohol in the presence of an acid catalyst, most commonly sulfuric acid or hydrochloric acid, in a reaction known as Fischer esterification. Treatment of 4-aminobenzoic acid with ethanol ( ethyl alcohol) in the presence of an acid catalyst, for example, gives the topical (surface) anesthetic benzocaine.

      Fischer esterification has the disadvantage that it is an equilibrium reaction (as shown by the equilibrium arrows ⇌), meaning that the reaction stops before completion, with substantial amounts of carboxylic acid and alcohol still present. However, there are several ways to drive such reactions to completion, including the removal of the water by distillation and the use of a large excess of one of the reactants. Therefore, this reaction is frequently used to synthesize carboxylic esters, although the use of acyl chlorides (see below Derivatives of carboxylic acids: Carboxylic esters: Synthesis (carboxylic acid)) is often more convenient. Conversion of carboxylic acids directly to amides (amide) or anhydrides (anhydride) is generally not feasible; acyl chlorides are commonly used for these purposes. Treatment of a carboxylic acid with ammonia (NH₃) or an amine (RNH₂) does not give an amide but yields instead the salt (RCOOH + NH₃→ RCOO⁻NH₄⁺).

      There are certain compounds that can be added to produce an amide, the most important being dicyclohexylcarbodiimide (DCC):

      Diimides of this type, however, are expensive and are generally used only when small quantities are involved and very high yields are important. (Yields in the acyl chloride method are usually somewhat lower.) The DCC method is most commonly employed in the synthesis of proteins. Heating a carboxylic acid does not produce an anhydride, except for those dicarboxylic acids that yield five- or six-membered cyclic anhydrides (see above Classes of carboxylic acids: Polycarboxylic acids (carboxylic acid)).

reduction

      Although carboxylic acids are more difficult to reduce than aldehydes (aldehyde) and ketones (ketone), there are several agents that accomplish this reduction, the most important being lithium aluminum hydride (LiAlH₄) and borane (BH₃). The product is a primary alcohol (RCOOH → RCH₂OH).

      There are no known general methods of reducing carboxylic acids to aldehydes, though this can be done indirectly by first converting the acid to the acyl chloride and then reducing the chloride.

Other reactions

      Similar to aldehydes and ketones, carboxylic acids can be halogenated at the alpha (α) carbon by treatment with a halogen (Cl₂ or Br₂) and a catalyst, usually phosphorus trichloride (PCl₃).

      This reaction, called the Hell-Volhard-Zelinskii reaction, actually takes place on the acyl halide rather than on the acid itself. The purpose of the catalyst is to convert some of the acid molecules to the acyl halide, which is the compound that actually undergoes the α-halogenation. The acyl halide is then converted to the α-halogenated carboxylic acid product by an exchange reaction (RCOOH + R′COCl → RCOCl + R′COOH, where R′ represents the α-halogenated group).

      When the silver salt of a carboxylic acid is treated with bromine (Br₂) or iodine (I₂), carbon dioxide is lost, and an alkyl bromide or iodide is produced in a reaction called the Hunsdiecker reaction; e.g., RCOOAg + Br₂→ RBr + AgBr + CO₂). This is a useful way of cleaving a single carbon atom from a carbon skeleton.

Derivatives of carboxylic acids

      The carboxylic acid derivatives discussed here (with the exception of nitriles (nitrile)) share the RCO structure with aldehydes (aldehyde), ketones (ketone), and carboxylic acids themselves.

      All these compounds are subject to attack by nucleophilic reagents owing to the polarity of the carbonyl group. For acyl chlorides, anhydrides (anhydride), esters (ester), and amides (amide), this first step is almost invariably followed by loss of a species with its pair of electrons (electron) (Z is a general symbol here representing Cl, OCOR, OR, and NH₂, respectively, for the four types of compounds mentioned):

      This is the most common mechanism for reactions of these four types of compounds. Aldehydes (aldehyde) and ketones undergo the first step (attack by a nucleophile) but not generally the second, because R groups and hydrogen atoms are extremely unlikely to leave, as the resulting ions are highly unstable. Carboxylic acids themselves do not undergo even the first step, because nucleophiles, rather than attacking the carbonyl group, act as bases and remove hydrogen ion (H⁺) from the acid instead, converting it to the salt. The four types of acid derivative differ greatly in their reactivities in nucleophilic substitutions. Acyl chlorides are the most reactive, and anhydrides are somewhat less so. Carboxylic esters are much less reactive, and amides are by far the least reactive.

Carboxylic esters (ester)

nomenclature

      The functional group of a carboxylic ester is an acyl group bonded to OR or OAr, where R represents an alkyl group and Ar represents an aryl group. Both IUPAC and common names of esters are derived from the names of the parent carboxylic acids. The alkyl or aryl group bonded to oxygen is named first, followed by the name of the acid in which the suffix -ic acid is replaced by -ate.

Synthesis

      Many carboxylic esters are made by Fischer esterification; that is, by heating a mixture of the carboxylic acid and alcohol together with a strong acid (often sulfuric) as a catalyst. It has been established that, in this reaction, the OR oxygen atom of the ester in most cases comes from the alcohol and not from the carboxylic acid. This evidence was provided through isotopic-labeling experiments, in which the oxygen atom of the alcohol used was oxygen-18 (¹⁸O). In the product of the esterification, the ¹⁸O remained with the R group of the alcohol.

      The equilibrium problem associated with Fischer esterification is frequently avoided by treating the alcohol with the corresponding acyl chloride or anhydride instead of the carboxylic acid. Yields in these cases are generally very high, and a catalyst is not needed. Phenolic esters (RCOOAr) cannot usually be made directly from carboxylic acids; in these cases, it is necessary to begin with the acyl chloride or anhydride. As mentioned above (see above Classes of carboxylic acids: Hydroxy and keto acids (carboxylic acid)), carboxylic acids with OH groups on carbons 4 (γ) or 5 (δ) spontaneously form cyclic esters (lactones (lactone)).

      Carboxylic esters can also be synthesized by treatment of a salt of a carboxylic acid with an alkyl halide (RCOOM + R′Βr → RCOOR′, where M is a metal ion such as sodium or potassium) in the solvent hexamethylphosphoric triamide. Alternatively, a special process called phase-transfer catalysis, which involves a transfer of ions from an aqueous phase to an organic phase, can be used.

Properties

 Because the molecules of a carboxylic ester cannot form hydrogen bonds with one another (as both carboxylic acids and alcohols do), the boiling point of an ester RCOOR′ is usually lower than that of the corresponding acid RCOOH, especially when R′ is a methyl or ethyl group. For example, the boiling point of acetic acid (CH₃COOH) is 118 °C (244 °F), while that of ethyl acetate (CH₃COOCH₂CH₃) is 77 °C (171 °F). Carboxylic esters are neutral compounds—i.e., neither acidic nor basic. In sharp contrast to carboxylic acids (see above Properties of carboxylic acids: Odour (carboxylic acid)), carboxylic esters usually have odours that are sweet and pleasant. The odours and flavours of many fruits are due to the carboxylic esters they contain. The natural odours and flavours are the result of complex mixtures of esters and (often) other types of compounds as well. Chemists have created synthetic flavourings that attempt to duplicate the natural ones, but in most cases these are much simpler and not as full-bodied. The simple esters ethyl acetate and butyl acetate, CH₃COO(CH₂)₃CH₃, are used industrially as solvents, as, for example, in nail-polish remover. Fats, vegetable oils, and plant and animal waxes are mixtures of carboxylic esters of high molecular weight.

Reactions

      The most important reaction of carboxylic esters is one that has been known for more than 2,000 years—namely, hydrolysis under basic conditions.

      Esters can also be hydrolyzed under acidic conditions, but hydrolysis under basic conditions is generally preferred because it is not reversible. The acidic process—the reverse of Fischer esterification—gives an equilibrium mixture of the starting compounds and products.) The hydrolysis is base is called saponification, because soap (Latin: sapo) has always been manufactured by heating fats (fat) (which are carboxylic esters) with water and a basic substance (originally wood ash). Soap is a mixture of salts of long-chain fatty acids (fatty acid). Whether hydrolyzed with an acid or a base, the products are the corresponding carboxylic acid (or its salt) and alcohol. Carboxylic esters also can be converted to amides, by heating with ammonia or an amine (e.g., RCOOR′ + NH₃→ RCONH₂).

      Reduction of carboxylic esters (RCOOR′ → RCH₂OH + R′OH) can be accomplished by several reducing agents, most commonly lithium aluminum hydride. The acid portion of the ester is reduced to a primary alcohol; the alcohol portion appears as the free alcohol.

      Carboxylic esters react with Grignard reagents (Grignard reagent) to give tertiary alcohols, with the exception of formate esters, HCOOR, which yield secondary alcohols.

      When treated with a strong base such as sodium ethoxide, two molecules of a carboxylic ester with two α hydrogens combine to give a β-keto ester in a reaction called the Claisen condensation.

Lactones (lactone)

      Cyclic esters are called lactones (lactone). In these cases the COOH and OH groups that combine to form water are part of the same molecule (see above Classes of carboxylic acids: Hydroxy and keto acids (carboxylic acid)). Lactones are known with rings of all sizes from 3 to 20 or more, although 3-membered rings are extremely unstable. The easiest to synthesize are five- and six-membered lactones, but many larger ones are found in nature. For example, the antibiotic erythromycin possesses a 14-membered lactone ring in addition to other functional groups. Lactones are generally named after the carboxylic acid by using the suffix -lactone.

      A Greek letter is used to indicate the ring size. Thus, all γ-lactones have five-membered rings and all ε-lactones have seven-membered rings.

Polyesters (polyester)

      When a carboxylic acid with two carboxyl groups is esterified with an alcohol containing two hydroxyl groups, long chains called polyesters (polyester) can be made. Some of these materials have major industrial uses. In the most important example, the dicarboxylic acid terephthalic acid is esterified with ethylene glycol.

      The crude polyester can be melted, extruded, and then cold-drawn to form the textile fibre Dacron polyester, outstanding features of which are its stiffness (about four times that of nylon-6,6), very high tensile strength, and remarkable resistance to creasing and wrinkling. Because the early Dacron polyester fibres were harsh to the touch due to their stiffness, they were usually blended with cotton or wool to make acceptable textile fibres. Improved fabrication techniques have produced less-harsh Dacron polyester textile fibres. PET is also fabricated into Mylar film and recyclable plastic beverage containers. Mylar sheets are used for photographic film, and they provide the backing for audio and videotape.

      Polycarbonates, the most familiar of which is Lexan, are a class of commercially important engineering polyesters. Lexan is formed by reaction between the disodium salt of bisphenol A and phosgene. Lexan is a tough, transparent polymer with high impact and tensile strengths, and it retains its properties over a wide temperature range. It has found significant use in sporting equipment, such as bicycle, football, motorcycle, and snowmobile helmets, as well as hockey and baseball catchers' face masks. In addition, it is used to make light, impact-resistant housings for household appliances and automobile and aircraft equipment, and it is used in the manufacture of safety glass and unbreakable windows.

Amides

Nomenclature

      The functional group of an amide is an acyl group bonded to a trivalent nitrogen atom. Amides are named by dropping the suffix -oic acid from the IUPAC name of the parent acid, or -ic acid from its common name, and replacing it by -amide. If the nitrogen atom of an amide is bonded to an alkyl or aryl group, the group is named and its location on nitrogen is indicated by N-. Two alkyl or aryl groups on nitrogen are indicated by N,N-di. Amide bonds are the key structural feature that joins amino acids (amino acid) together to form polypeptides and proteins (protein).

      Cyclic amides are called lactams. Their common names are derived in a manner similar to those of lactones, with the difference that the suffix -olactone is replaced by -olactam. Caprolactam is the starting material for the synthesis of nylon-6.

      Penicillins (penicillin)—the most effective antibiotics (antibiotic) of all time—are a family of compounds, all of which have in common a four-membered β-lactam ring fused to a five-membered thiazolidine ring. The penicillins owe their antibiotic activity to a common mechanism that inhibits the synthesis of a vital part of bacterial cell walls.

      The cephalosporins (cephalosporin), another class of β-lactam antibiotics, have an even broader spectrum of antibiotic activity than the penicillins and are effective against many penicillin-resistant bacterial strains.

Synthesis

      The only important practical method for preparing amides is to treat an acyl chloride or anhydride with ammonia or a primary (RNH₂) or secondary (R₂NH) amine. Two moles of ammonia or amine are required—one to form the amide and one to neutralize the HCl or carboxylic acid by-product.

      As mentioned previously (see above Principal reactions of carboxylic acids: Conversion to acid derivatives (carboxylic acid)), amides can be made directly from ammonia or an amine and a carboxylic acid with the use of DCC or a similar compound.

Properties

      With the exceptions of formamide (HCONH₂) and some of its N-substituted derivatives, all amides are solids at room temperature. They are neutral compounds, neither acidic nor basic. An amide called acetaminophen (N-para-hydroxyphenylacetamide) is a pain reliever sold without prescription under several different proprietary names, one of which is Tylenol.

Reactions

      Like all other acid derivatives, amides can be hydrolyzed to yield carboxylic acids (under acidic conditions) or the salts of carboxylic acids (under basic conditions), but, because amides are less reactive, these reactions require more strenuous conditions than hydrolysis of the other derivatives. Lithium aluminum hydride reduction of amides can be used to prepare primary, secondary, or tertiary amines, depending of the degree of substitution of the amide. Reduction of octanamide, for example, gives a primary amine.

      Amides are also reduced by hydrogen in the presence of a transition metal catalyst. At one time, the major commercial preparation of 1,6-hexanediamine, one of the two monomers (monomer) needed for the synthesis of nylon-6,6, was by catalytic reduction of hexanediamide.

      Amides without substituents on the nitrogen can be dehydrated to nitriles (nitrile) (RCONH₂→ RC≡N + H₂O) with many dehydrating agents, of which phosphorus pentoxide (P₄O₁₀) is the most common.

Polyamides

      Polyamides can be formed by two different methods. The first is the condensation (condensation reaction) of molecules that contain both a carboxyl and an amino (NH₂or NH) group. This is the method by which proteins are synthesized in nature. The carboxyl group of one amino acid molecule forms an amide bond with the amino group of the next amino acid, producing chains which may be long or short. In the second method, a molecule that contains two carboxyl groups is combined with another molecule that has two amino groups. When adipic acid for example is combined with hexamethylenediamine, the resulting polymer is called nylon-6,6, the number coming from the fact that each monomer molecule has six carbon atoms in its chain.

      The nylons (nylon) are a family of polymers, the members of which have subtly different properties that suit them to one use or another. The two most widely used members of this family are nylon-6,6 and nylon-6. Nylon-6, so named because it is synthesized from caprolactam, a six-carbon monomer, is fabricated into fibres, brush bristles, rope, high-impact moldings, and tire cords.

      In 1971 DuPont introduced Kevlar, a polyaromatic amide (an aramid) fibre synthesized from terephthalic acid and p-phenylenediamine.

      One of the remarkable features of Kevlar is its light weight, compared with other materials of similar strength. For example, a 7.6 cm (3 inch) cable woven of Kevlar has a strength equal to that of a similarly woven 7.6-cm (3-in) steel cable. Whereas the steel cable weighs about 30 kg per metre (20 pounds per foot), the Kevlar cable weighs only 6 kg per metre (4 pounds per foot). Kevlar is used in such articles as anchor cables for offshore oil-drilling rigs and as reinforcement fibres for automobile tires. Kevlar is also woven into a fabric that is so tough that it can be used for bulletproof vests, jackets, and raincoats.

Related compounds

      Other acid derivatives include hydrazides, hydroxamic acids, and acyl azides. These compounds are formally derived from carboxylic acids and, respectively, hydrazine (NH₂NH₂), hydroxylamine (NH₂OH), and hydrazoic acid (HN₃). Imides are compounds with two RCO groups on a single nitrogen atom. The most common ones are cyclic, such as succinimide and phthalimide.

      Imides are more acidic than amides (it is the −NH group that loses the hydrogen) but less acidic than carboxylic acids. Sulfonamides (sulfonamide) are amides of sulfonic acids; (sulfonic acid) for example,

      Sulfonic acids are organic compounds containing the −SO₃H group. These acids are very strong (with an acidity comparable to that of sulfuric acid), but sulfonamides, like the amides of carboxylic acids, are neutral.

Acyl halides

Nomenclature and synthesis

      The functional group of an acyl halide ( acid halide) is an acyl group (RCO−) bonded to a halogen (halogen element) atom. They are named by changing the suffix -ic acid in the name of the parent carboxylic acid to -yl halide. Because acyl chlorides are the least expensive to make and are reactive enough, the other acyl halides (bromides, iodides, fluorides) are of only minor importance.

      The chloride of formic acid (formyl chloride) cannot be isolated, because it decomposes to carbon monoxide (CO) and hydrogen chloride (HCl). The only practical way to synthesize acyl chlorides is to treat a carboxylic acid with a compound such as thionyl chloride (see above Principal reactions of carboxylic acids: Conversion to acid derivatives (carboxylic acid)).

Reactions

      Acyl chlorides are the most reactive of the acid derivatives and can be used to make all the other derivatives (except nitriles (nitrile)), as well as other compounds. Acyl chlorides are easily hydrolyzed by water to give carboxylic acids. In fact, low-molecular-weight acyl chlorides react so readily with the water vapour in the air that they must be kept in airtight bottles so that they are not converted into carboxylic acid in the bottle. Another reason for using airtight bottles is that some of these low-molecular-weight acyl chlorides are volatile, and their vapours are irritating if they reach the eyes, nose, or mouth where they react with moisture to produce hydrochloric acid as well as the carboxylic acid. Such compounds are called lacrimators (i.e., compounds that produce tears (tear duct and glands)) and can cause pain as well as eye damage. Acyl chlorides also readily react with alcohols (alcohol) or phenols (phenol) to give esters; with ammonia or amines (amine) to give amides; with carboxylic acid salts to give anhydrides (anhydride); with sodium azide (NaN₃) to give acyl azides; with aromatic rings in the presence of aluminum chloride (AlCl₃) to give ketones (ketone) in a reaction known as Friedel-Crafts acylation; and with lithium dialkylcopper reagents (R′₂CuLi) to give ketones.

      Acyl chlorides can be reduced to aldehydes (RCOCl → RCHO) with lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH₃)₃]₃, and to primary alcohols (RCOCl → RCH₂OH) with lithium aluminum hydride (LiAlH₄) or sodium borohydride (NaBH₄).

Anhydrides (anhydride)

Nomenclature and synthesis

      The functional group of a carboxylic anhydride is two acyl groups bonded to an oxygen atom. The anhydride may be symmetrical (two identical acyl groups), or it may be mixed (two different acyl groups).

      Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.

      Cyclic anhydrides in which the ring contains five or six members are made by heating the corresponding dicarboxylic acid. The most common methods for the synthesis of noncyclic anhydrides are (1) the reaction of an acyl chloride with the salt of a carboxylic acid (RCOCl + R′COONa → RCOOCOR′) and (2) the addition of a carboxylic acid to a ketene. Acetic anhydride, the most important industrial noncyclic anhydride, is prepared by adding acetic acid to ketene.

Reactions

      Anhydrides give essentially the same reactions as the acyl chlorides, although they generally react more slowly. This can be an advantage or a disadvantage. The reason that anhydrides are less frequently used in these reactions is due more to availability considerations than to reactivity. In most cases, the acyl chloride is easier or less expensive to obtain than the corresponding anhydride. Acid anhydrides are most often used to prepare carboxylic esters and amides and in Friedel-Crafts acylations. Cyclic anhydrides have the advantage that one carboxyl group remains after a reaction, allowing the preparation of monoesters or monoamides of dicarboxylic acids. Treatment of phthalic anhydride, for example, with 1-butanol (n- butyl alcohol) gives the monoester, butyl acid phthalate. The most important use of phthalic acid esters with C4 to C10 alcohols is as plasticizers, which are used to transform hard, brittle thermoplastics into soft ductile, elastic materials for processing.

      Acetic anhydride, like acetyl chloride, reacts with the water in the air and is a lacrimator.

Nitriles (nitrile)

Nomenclature

      Nitriles (nitrile), RC≡N, are organic cyanides (cyanide). They are named after the corresponding carboxylic acids by changing -ic acid to -onitrile, or -nitrile, whichever preserves a single letter o. Thus, CH₃CN is acetonitrile (from acetic acid), whereas C₆H₅CN is benzonitrile (from benzoic acid).

Synthesis

      There are several methods of synthesizing nitriles. A common one is the treatment of an alkyl halide with sodium or potassium cyanide (RBr + KCN → RCN). Another method is the dehydration of the corresponding amide with a dehydrating agent such as phosphorus pentoxide (RCONH₂→ RCN). An aldehyde can be used to prepare a nitrile by first being converted to an oxime (RCH=NHOH) by treatment with hydroxylamine (NH₂OH), followed by dehydration of the oxime (RCHO → RCH=NHOH → RCN), most often with acetic anhydride. Aldehydes can be converted to nitriles in one step by treatment of the aldehyde with hydroxylamine together with formic acid, as well as by several other methods.

Reactions

      Nitriles are easily hydrolyzed with water, in the presence of an acid or a base, to yield the corresponding carboxylic acid or its salt, respectively. (This chemical property is the reason nitriles are considered to be acid derivatives.)

      An amide is an intermediate and can be isolated under certain conditions, so this is also a method for the synthesis of amides. Nitriles can be reduced to primary amines (RCN → RCH₂NH₂) with many reducing agents, among them lithium aluminum hydride and hydrogen in the presence of a transition metal catalyst. Nitriles can also be reduced in a different manner to yield aldehydes (aldehyde) (RCN → RCHO). Several methods are known for accomplishing this, one of which is treatment with stannous chloride (SnCl₂) and hydrochloric acid, followed by hydrolysis. In this method, RC=NH is an intermediate. Nitriles react with Grignard reagents (Grignard reagent) to give, after hydrolysis, ketones (RCN + R′MgBr → RCOR′).

Jerry March William H. Brown

Additional Reading

Studies of the subject include F.D. Gunstone, Fatty Acid and Lipid Chemistry (1995); Saul Patai (ed.), The Chemistry of Acid Derivatives (1979); and Jacob Zabicky (ed.), The Chemistry of Amides (1970).Jerry March

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