Chapter-20
Functional Derivatives of Carboxylic Acids Nucleophilic Acyl Substitution
Structure
Closely related to the carboxylic acids and to each other are a number of chemical families known as functional derivatives of carboxylic acids: acid chlorides> anhydrides, amides, and esters. These derivatives are compounds in which the OH of a carboxyl group has been replaced by CI, OOCR, NH2 , or
Like the acid to which it is related, an acid derivative may be aliphatic or aromatic, substituted or unsubstituted; whatever the structure of the rest of the molecule, the properties of the functional group remain essentially the same.
Nomenclature
The names of acid derivatives are taken in simple ways from either the common name or the IUPAC name of the corresponding carboxylic acid. For example:
Physical properties
The presence of the C O group makes the acid derivatives polar compounds. Acid chlorides and anhydrides (Table 20.1) and esters (Table 20.2, p. 674) have boiling points that are about the same as those of aldehydes or ketones of comparable molecular weight (see Sec. 15.4). Amides (Table 20.1) have quite high boiling points because they are capable of strong intermolecular hydrogen bonding.
The border line for solubility in water ranges from three to five carbons for the esters to five or six carbons for the amides. The acid derivatives are soluble in the usual organic solvents.
Volatile esters have pleasant, rather characteristic odors; they are often used in the preparation of perfumes and artificial flavorings. Acid chlorides have sharp, irritating odors, at least partly due to their ready hydrolysis to HC1 and carboxylase acids
Nucleophilic acyl substitution. Role of the carbonyl group
Before we take up each kind of acid derivative separately, it will be helpful to outline certain general patterns into which we can then fit the rather numerous individual facts.
Each derivative is nearly always prepared directly or indirectly from the corresponding carboxylic acid and can be readily converted back into the carboxylic acid by simple hydrolysis. Much of the chemistry of acid derivatives involves their conversion one into another, and into the parent acid. In addition, each derivative has certain characteristic reactions of its own.
The derivatives of carboxylic acids, like the acids themselves, contain the carbonyls group, C~O. This group is retained in the products of most reactions undergone by these compounds and does not suffer any permanent changes itself. But by its presence in the molecule, it determines the characteristic reactivity of these compounds, and is the Kev to the understanding of their chemistry.
It is understandable that acid derivatives are hydrolyzed more readily in either alkaline or acidic solution than in neutral solution: alkaline solutions provide hydroxide ion, which acts as a strongly nucleophilic reagent; acid solutions provide hydrogen ion, which attaches itself to carbonyl oxygen and thus renders termolecular vulnerable to attack by the weakly nucleophilic reagent, water.
Nucleophilic substitution: alkyl vs. . acyl
It is, of course, the carbonyl group that makes acyl compounds more reactive than alkyl compounds. Nucleophilic attack (SN 2) on a tetrahedral alkyl carbon involves a badly crowded transition state containing pentavalent carbon; a bond must be partly broken to permit the attachment of the nucleophile:
Nucleophilic attack on a flat acyl compound involves a relatively unhindered transition state leading to a tetrahedral intermediate that is actually a compound; since the carbonyl group is unsaturated, attachment of the nucleophile requires
breaking only of the weak TT bond, and places a negative charge on an atom quite willing to accept it; oxygen.
Preparation of acid chlorides
Acid chlorides are prepared from the corresponding acids by reaction with thionyl chloride, phosphorus trichloride, or phosphorus pentachloride, as discussed in Sec.
Reactions of acid chlorides
Like other acid derivatives, acid chlorides typically undergo nucleophilic substitution. Chlorine is expelled as chloride ion or hydrogen chloride, and its place is taken by some other basic group. Because of the carbonyl group these reactions take place much more rapidly than the corresponding nucleophilic substitution reactions of the alkyl halides. Acid chlorides are the most reactive of the derivatives of carboxylic acids
Conversion of acid chlorides into acid derivatives
Aromatic acid chlorides (ArCOCl) are considerably less reactive than the aliphatic acid chlorides. With cold water, for example, acetyl chloride reacts almost explosively, whereas Benzoyl chloride reacts only very slowly. The reaction of aromatic acid chlorides with an alcohol or a phenol is often carried out using the Schutten-Baumann technique: the acid chloride is added in portions (followed by vigorous shaking) to a mixture of the hydroxy compound and a base, usually aqueous sodium hydroxide or pyridine (an organic base, Sec. 31.11). Although the function of the base is not clear, it seems not only to neutralize the hydrogen chloride that would otherwise be liberated, but also tp catalyze the reaction.
Preparation of acid anhydrides
Only one monocarboxylic acid anhydride is encountered ^very often; however, this one, acetic anhydride, is immensely important. It is prepared by the reaction of acetic acid with ketene, CH2=C---O, which itself is prepared by high-temperature dehydration of acetic acid.
by pyrolysis of acetone, and ordinarily used as soon as it is made.
In contrast to monocarboxylic acids, certain *//carboxylic acids yield anhydrides on simple heating: in those cases where a five- or six-membered ring is produced. For example:
Ring size is crucial : with adipic acid, for example, anhydride formation would produce a seven-membered ring, and does not take place. Instead, carbon dioxide is lost and cyclopentanone, a ketone with a five-membered ring, is formed.
Reactions of acid anhydrides
Acid anhydrides undergo the same reactions as acid chlorides, but a little more slowly; where acid chlorides yield a molecule of HC1, anhydrides yield a molecule of carboxylic acid.
Compounds containing the acetyl group are often prepared from acetic anhydride; it is cheap, readily available, less volatile and more easily handled than acetyl chloride, and it does not form corrosive hydrogen chloride. It is widely used industrially for the esterification of the polyhydroxy compounds known as carbohydrates, especially cellulose (Chap. 35)
Only "half" of the anhydride appears in the acyl product; the other "half" carboxylic acid. A cyclic anhydride, we see, undergoes exactly the same reactions as any other anhydride. However, since both "halves" of the anhydride are attached to each other by carbon-carbon bonds, the acyi compound and the carboxylic acid formed will have to be part of the same molecule, Cyclic anhydrides can thus be used to make compounds containing both the acyl group and the carboxyl group: compounds that are, for example, both acids and amides, both acids and esters, etc. These difunctional compounds are of great value in further synthesis.
Preparation of amides
In the laboratory amides are prepared by the reaction of ammonia with acid chlorides or, when available, acid anhydrides (Sees. 20.8 and 20.10). In industry they are often made by heating the ammonium salts of carboxylic acids.
Reactions of amide
An amide is hydrolyzed when heated with aqueous acids or aqueous bases. The products are ammonia and the carboxylic acid, although one product or the other is obtained in the form of a salt, depending on the
Hydrolysis of amides
Hydrolysis of amides is typical of the reactions of carboxylic acid derivatives. It involves nucleophilic substitution, in which the NH2 group is replaced by OH. Under acidic conditions hydrolysis involves attack by water on the protonated
Imides
Preparation of esters
Esters are usually prepared by the reaction of alcohols or phenols with acids or acid derivatives. The most common methods are outlined below
The direct reaction of alcohols or phenols with acids involves an equilibrium and especially in the case of phenols requires effort to drive to completion (see Sec. 18.16). In the laboratory, reaction with an acid chloride or anhydride is more commonly used.
Reactions of ester
Esters undergo the nucleophilic substitution that is typical of carboxylic acid derivatives. Attack occurs at the electron-deficient carbonyl carbon, and results in the replacement of the OR' group by OH, OR*, or NH2:
These reactions are sometimes carried out in the presence of acid. In these acid-catalyzed reactions, H f attaches itself to the oxygen of the carbonyl group, and thus renders carbonyl carbon even more susceptible to nucleophilic attack.
Alkaline hydrolysis of esters
A carboxylic ester is hydrolyzed to a carboxylic acid and an alcohol or phenol when heated with aqueous acid or aqueous base. Under alkaline conditions, of course, the carboxylic acid is obtained as its salt, from which it can be liberated by addition of mineral acid.
Exchange experiments are also the basis of our estimate of the relative importance of the two steps: differences in rate of hydrolysis of acyl derivatives depend chiefly on how fast intermediates are formed, and also on what fraction of the intermediate goes on to product. As we have said, the rate of formation of the intermediate is affected by both electronic and steric factors: in the transition state, a negative charge is developing, and carbon is changing from trigonal toward tetrahedral.
Acidic hydrolysis of esters
Hydrolysis of esters is promoted not only by base but also by acid. Acidic hydrolysis, as we have seen (Sec. 18.16), is reversible,
The mechanism for acid-catalyzed hydrolysis and esterification is contained in the following equilibria:
Mineral acid speeds up both processes by protonating carbonyl oxygen and thus rendering carbonyl carbon more susceptible to nucleophilic attack (Sec. 20.4). In hydrolysis, the nucleophilic is a water molecule and the leaving group is an alcohol; in esterification, the roles are exactly reversed.
As in alkaline hydrolysis, there is almost certainly a tetrahedral intermediate or, rather, several of them. The existence of more than one intermediate is required by, among other things, the reversible nature of the reaction. Looking only at hydrolysis, intermediate II is likely, since it permits separation of the weakly basic alcohol molecule instead of the strongly basic alkoxide ion; but consideration of esterification shows that II almost certainly must be involved, since it is the product of attack by alcohol on the protonated acid
Ammonolysis of esters
Treatment of an ester with ammonia, generally in ethyl alcohol solution, yields the amide. This reaction involves nucleophilic attack by a base, ammonia, on the electron-deficient carbon; the alkoxy group, OR', is replaced by NH2 . For example:
Transesterification
In the esterification of an acid, an alcohol acts as a nucleophilic reagent; in hydrolysis of an ester, an alcohol is displaced by a nucleophilic reagent. Knowing this, we are not surprised to find that one alcohol is capable of displacing another alcohol from an ester. This alcoholics (cleavage by an alcohol) of an ester is called transesterification.
Transesterification is an equilibrium reaction. To shift the equilibrium to the right, it is necessary to use a large excess of the alcohol whose ester we wish to make, or else to remove one of the products from the reaction mixture. The second approach is the better one when feasible, since in this way the reaction can be driven to completion.
Reaction of esters with Grignard reagents
Two of the three groups attached to the carbon bearing the hydroxyl group in the alcohol come from the Grignard reagent and hence must be identical; this, of course, places limits upon the alcohols that can be prepared by this method. But, where applicable, reaction of a Grignard reagent with an ester is preferred to reaction with a ketone because esters are generally more accessible.
Like many organic compounds, esters can be reduced in two ways: (a) by catalytic hydrogenation using molecular hydrogen, or (b) by chemical reduction. In either case, the ester is cleaved to yield (in addition to the alcohol or phenol from which it was derived) a primary alcohol corresponding to the acid portion of the ester
Functional derivatives of carbonic acid
Much of the chemistry of the functional derivatives of carbonic acid is already quite familiar to us through our study of carboxylic acids. The first step in dealing with one of these compounds is to recognize just how it is related to the parent acid. Since carbonic acid is bifunctional, each of its derivatives, too, contains two functional groups; these groups can be the same or different. For example
We use these functional relationships to carbonic acid simply for convenience. Many of these compounds could just as well be considered as derivatives of other acids, and, indeed, are often so named. For example:
Analysis of carboxylic acid derivatives. Saponification equivalent
Functional derivatives of carboxylic acids are recognized by their hydrolysis under more or less vigorous conditions to carboxylic acids. Just which kind of derivative it is indicated by the other products of the hydrolysis.
Identification or proof of structure of an acid derivative involves the identification or proof of structure of the carboxylic acid formed upon hydrolysis (Sec. 18.21). In the case of an ester, the alcohol that is obtained is also identified (Sec. 16.11). (In the case of a substituted amide, Sec. 23.6, the amine obtained is identified, Sec. 23.19.
Spectroscopic analysis of carboxylic acid derivatives
Infrared. The infrared spectrum of an acyl compound shows the strong band in the neighborhood of 1 700 cm ~ l that we have come to expect of O -O stretching (see Fig.
The exact frequency depends on the family the compound belongs to (see Table 20.3, p. 689) and, for a member of a particular family, on its exact structure. For esters, for example:
Esters are distinguished from acids by the absence of the O H band. They are distinguished from ketones by two strong C O stretching bands in the 1050- 1300 cm' 1 region; the exact position of these bands, too, depends on the ester's structure.
Besides the carbonyl band, amides (RCONH2) show absorption due to N H stretching in the 3050-3550 cm" 1 region (the number of bands and their location depending on the degree of hydrogen bonding), and absorption due to N H bending in the 1600-1640 cm" J region.
Namr. As we can see in Table 13.4 (p, 421), the protons in the alkyl portion of an ester (RCOOCH2 R') absorb farther downfield than the protons in the acyl portion (RCH2COOR')
absorption by the CO NH protons of an amide appears in the range B 5-8, typically as a broad, low hump.
PROBLEMS
2. Write balanced equations, naming all jorganic products, for the reaction (if any) of /i-butyryl chloride with:
3. Answer Problem 2, parts (a) through (1) for acetic anhydride.
4. Write equations to show the reaction (if any) of succinic anhydride with :
5. Write balanced equations, naming all organic products, for the reaction (if any) of phenylacetamide
(a) hot HC1 (aq) (b) hot NaOH (aq)
6. Answer Problem 5 for phenylacetonitrile.
7. Write balanced equations, naming all organic products, for the reaction (if any) of methyl //-butyrate with :
(a) hot H2SO4 (aq) (e) ammonia
(b) hot KOH (aq) (f) phenylmagnesium bromide
(c) isopropyl alcohol -f H2SO4 (g) isobutylmagnesium bromide
(d) benzyl alcohol + QH5CH2ONa (h) LiAlH4 , then acid
8. Outline the synthesis of each of the following labeled compounds, using H2 18O as the source of 18O.
Predict the product obtained from each upon alkaline hydrolysis in ordinary H2O.
9. Outline the synthesis of each of the following labeled compounds, using 14CO2 or 14CH3OH and H2 18O as the source of the "tagged" atoms.
10. Predict the product of the reaction of y-butyrolactone with (a) ammonia, (b) LiAlH4 , (c) C2H5OH + H2SO4 .
11. When sec-butyl alcohol of rotation +13.8 was treated with tosyl chloride, and the resulting tosylate was allowed to react with sodium benzoate, there was obtained sec-butyl benzoate. Alkaline hydrolysis of this ester gave sec-butyl alcohol of rotation -13.4. In which step must inversion have taken place? How do you account for this?
12. Account for the following observations. (Hint: See Sec. 14.13, and Problem 14.9 on
13. An unknown compound is believed to be one of the following, all of which boil within a few degrees of each other. Describe how you would go about finding out which of the possibilities the unknown actually is. Where possible use simple chemical tests; where necessary use more elaborate chemical methods like quantitative hydrogenation, cleavage, neutralization equivalent, saponification equivalent, etc. Make use of any needed tables of physical constants.
15. Tell how you would separate by chemical means the following mixtures, recovering each component in reasonably pure form: (a) benzoic acid and ethyl benzoate; (b) n-valeric acid; n-valeric acid (c) ammonium benzoate and benzamide. Tell exactly what you would do and
16. Carboxyl groups are often masked by reaction with dihydropyran, which yields esters that are stable toward base but easily hydrolyzed by dilute aqueous acids. Account in detail both for the formation of these esters and for their ease of hydrolysis. (Hint: See Sec. 19.15.)
17. Treatment of 2,4-pentanedione with KCN and acetic acid, followed by hydrolysis, gives two products, A and B. Both A and B are dicarboxylic acids of formula C7 HJ2O6 . A melts at 98. When heated, B gives first a lactonic acid (C7 Hi ()O5 , m.p. 90) and finally a dilactone (C7 H8 O4 , m.p. 105). (a) What structure must B have that permits ready formation of both a monolactone and a dilactone? (b) What is the structure of A? (Hint: Use models.)
18. Give the structures (including configurations where pertinent) of compounds C through O.
19. Progesterone is a hormone, secreted by the corpus luteum, that is involved in the control of pregnancy. Its structure was established, in part, by the following synthesis from the steroid stigmasterol, obtained from soybean oil.
21. 2,5-Dimethyl-l,l-cyclopentanedicarboxylic acid can be prepared as a mixture of two optically inactive substances of different physical properties, NN and OO. When each is heated and .the reaction mixture worked up by fractional crystallization, NN yields a single product, PP, of formula C8H14O2 , and OO yields two products, QQ and RR, both of formula C8 H14O2 .
(a) Give stereochemical formulas for NN, OO, PP, QQ, and RR. (b) Describe another method by which you could assign configurations to NN and OO.
(b) When R-glyceraldehyde, CH2 OHCHOHCHO, is treated with cyanide and the resulting product is hydrolyzed, two monocarboxylic acids are formed (see Problem 12, p. 649). These acids are identical with the acids obtained by oxidation with bromine water of ( - )-threose and ( - )-erythrose.
Assign a single structure to (-)-erythrose and to (-)-threose.
23. Which (if any) of the following compounds could give rise to each of the infrared spectra shown in Fig. 20.2 (p. 695)?
24. Give a structure or structures consistent with each of the nmr spectra shown in Fig. 20.3 (p. 696).
25. Give the structures of compounds SS, TT, and UU on the basis of their infrared spectra (Fig. 20.4, p. 697) and their nmr spectra (Fig. 20.5, p. 698).
26. Give a structure or structures consistent with the nmr spectrum shown in Fig. 20.6 (p. 699).
27. Give the structure of compound VV on the basis of its infrared and nmr spectra shown in Fig. 20.7 (p. 699).
28. Give a structure or structures consistent with each of the nmr spectra shown in Fig. 20.8 (p.700).
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