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The active ingredients in these two nonprescription pain relievers are derivatives of arylpropanoic acids. See Chemical Connections 13A, “From Willow Bark to Aspirin and Beyond.” Inset: A model of ( S )-ibuprofen. (Charles D. Winters)
Carboxylic Acids
13.1 What Are Carboxylic Acids?
13.2 How Are Carboxylic Acids Named?
13.3 What Are the Physical Properties of Carboxylic Acids?
13.4 What Are the Acid–Base Properties of Carboxylic Acids?
13.5 How Are Carboxyl Groups Reduced?
13.6 What Is Fischer Esterification?
13.7 What Are Acid Chlorides?
13.8 What Is Decarboxylation?
H O W T O 13.1 How to Predict the Product of a Fischer Esterification 13.2 How to Predict the Product of a B -Decarboxylation Reaction
C H E M I C A L C O N N E C T I O N S 13A From Willow Bark to Aspirin and Beyond 13B Esters as Flavoring Agents 13C Ketone Bodies and Diabetes
K E Y Q U E S T I O N S
CARBOXYLIC ACIDS ARE another class of organic compounds containing the carbonyl group. Their occurrence in nature is widespread, and they are important components of foodstuffs such as vinegar, butter, and vegetable oils. The most important chemical property of carboxylic acids is their acidity. Furthermore, carboxylic acids form numerous important derivatives, including es- ters, amides, anhydrides, and acid halides. In this chapter, we study carboxylic acids themselves; in Chapters 14 and 15, we study their derivatives.
458 C H A P T E R 1 3 Carboxylic Acids
13.1 What Are Carboxylic Acids?
The functional group of a carboxylic acid is a carboxyl group , so named because it is made up of a carb onyl group and a hydr oxyl group (Section 1.7D). Following is a Lewis structure of the carboxyl group, as well as two alternative representations of it:
C COOH CO 2 H
O
O H
The general formula of an aliphatic carboxylic acid is RCOOH; that of an aromatic carbox- ylic acid is ArCOOH.
13.2 How Are Carboxylic Acids Named?
A. IUPAC System We derive the IUPAC name of a carboxylic acid 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 (Section 3.5). We number the chain beginning with the carbon of the carboxyl group. Because the carboxyl car- bon is understood to be carbon 1, there is no need to give it a number. If the carboxylic acid contains a carbon–carbon double bond, we change the infix from - an - to - en - to indicate the presence of the double bond, and we show the location of the double bond by a number. In the following examples, the common name of each acid is given in parentheses:
it is not necessary to indicate that the alkene occurs at position 2 because there is no other position where it can occur
COOH
3-Methylbutanoic acid (Isovaleric acid)
C 6 H 5
COOH
trans -3-Phenylpropenoic acid (Cinnamic acid)
In the IUPAC system, a carboxyl group takes precedence over most other functional groups (Table 12.1), including hydroxyl and amino groups, as well as the carbonyl groups
of aldehydes and ketones. As illustrated in the following examples, an J OH group of an
alcohol is indicated by the prefix hydroxy -, an J NH 2 group of an amine by amino -, and an
O group of an aldehyde or ketone by oxo -:
5-Hydroxyhexanoic acid
OH
COOH
O
COOH
4-Aminobutanoic acid 5-Oxohexanoic acid
H 2 N COOH
Dicarboxylic acids are named by adding the suffix - dioic , followed by the word acid , to the name of the carbon chain that contains both carboxyl groups. Because the two carboxyl groups can be only at the ends of the parent chain, there is no need to number them. Following are IUPAC names and common names for several important aliphatic dicarboxylic acids:
Carboxyl group A J COOH group.
460 C H A P T E R 1 3 Carboxylic Acids
some characteristic property. Table 13.1 lists several of the unbranched aliphatic carboxylic acids found in the biological world, along with the common name of each. Those with 16, 18, and 20 carbon atoms are particularly abundant in fats and oils (Section 19.1) and the phospholipid components of biological membranes (Section 19.3). When common names are used, the Greek letters a, b, g, d, and so forth are often added as a prefix to locate substituents. The a position in a carboxylic acid is the position next to the carboxyl group; an a substituent in a common name is equivalent to a 2-sub- stituent in an IUPAC name. GABA , short for g amma- a mino b utyric a cid, is an inhibitory neurotransmitter in the central nervous system of humans:
OH
O
H 2 N
OH
O
4-Aminobutanoic acid (g-Aminobutyric acid, GABA)
5
d b g 3 a 1 4 2
g
In common nomenclature, the prefix keto - indicates the presence of a ketone carbonyl in a substituted carboxylic acid (as illustrated by the common name b ketobutyric acid):
3-Oxobutanoic acid (b-Ketobutyric acid; Acetoacetic acid)
Acetyl group (Aceto group)
O
OH
O
CH 3 C ¬
O
An alternative common name for 3-oxobutanoic acid is acetoacetic acid. In deriving this
common name, this ketoacid is regarded as a substituted acetic acid, and the CH 3 C( O) J
substituent is named an aceto group.
T A B L E 1 3. 1 Several Aliphatic Carboxylic Acids and Their Common Names Structure IUPAC Name Common Name Derivation HCOOH Methanoic acid Formic acid Latin: formica , ant CH 3 COOH Ethanoic acid Acetic acid Latin: acetum , vinegar CH 3 CH 2 COOH Propanoic acid Propionic acid Greek: propion , first fat CH 3 (CH 2 ) 2 COOH Butanoic acid Butyric acid Latin: butyrum , butter CH 3 (CH 2 ) 3 COOH Pentanoic acid Valeric acid Latin: valere, to be strong CH 3 (CH 2 ) 4 COOH Hexanoic acid Caproic acid Latin: caper , goat CH 3 (CH 2 ) 6 COOH Octanoic acid Caprylic acid Latin: caper , goat CH 3 (CH 2 ) 8 COOH Decanoic acid Capric acid Latin: caper , goat CH 3 (CH 2 ) 10 COOH Dodecanoic acid Lauric acid Latin: laurus , laurel CH 3 (CH 2 ) 12 COOH Tetradecanoic acid Myristic acid Greek: myristikos , fragrant CH 3 (CH 2 ) 14 COOH Hexadecanoic acid Palmitic acid Latin: palma , palm tree CH 3 (CH 2 ) 16 COOH Octadecanoic acid Stearic acid Greek: stear , solid fat CH 3 (CH 2 ) 18 COOH Icosanoic acid Arachidic acid Greek: arachis , peanut
Fotosearch RF/Getty Images, Inc. Formic acid was first obtained in 1670 from the destructive distillation of ants, whose genus is Formica. It is one of the components of the venom of stinging ants.
Aceto group A CH 3
O C group.
E X A M P L E 13.
Write the IUPAC name for each carboxylic acid:
(a )
CH 3 (CH 2 ) 7 (CH 2 ) 7 COOH
C C
H H
(b)
COOH
OH
(c) (^) H C CH 3
COOH
OH
(d) ClCH 2 COOH
1 3. 3 What Are the Physical Properties of Carboxylic Acids? 461
P R O B L E M 13.
Each of the following compounds has a well-recognized common name. A derivative of glyceric acid is an intermediate in glycolysis (Section 21.3). Maleic acid is an intermediate in the tricarboxylic acid (TCA) cycle. Mevalonic acid is an intermediate in the biosynthesis of steroids (Section 19.4B).
HO
COOH
HO H
Glyceric acid
(a) (b) COOH
COOH
Maleic acid
(c) (^) HO
COOH
HO CH 3
Mevalonic acid
Write the IUPAC name for each compound. Be certain to show the configuration of each.
S T R AT E G Y
Identify the longest chain of carbon atoms that contains the carboxyl group to determine the root name. The suffix - e is then changed to - anoic acid. For cyclic carboxylic acids, carboxylic acid is appended to the name of the cycloalkane (without drop- ping the suffix - e ). As usual, remember to note stereochemistry ( E/Z, cis/trans , or R/S ) where appropriate.
S O L U T I O N
(a) cis -9-Octadecenoic acid (oleic acid) (b) trans -2-Hydroxycyclohexanecarboxylic acid (c) ( R )-2-Hydroxypropanoic acid [( R )-lactic acid] (d) Chloroethanoic acid (chloroacetic acid)
See problems 13.9–13.12, 13.
13.3 What Are the Physical Properties of Carboxylic Acids?
In the liquid and solid states, carboxylic acids are associated by intermolecular hydrogen bonding into dimers, as shown for acetic acid:
O H
H O
CH 3 C
O
O
hydrogen bonding in the dimer
C CH 3
d– d±
d± d–
Carboxylic acids have significantly higher boiling points than other types of organic com- pounds of comparable molecular weight, such as alcohols, aldehydes, and ketones. For example, butanoic acid (Table 13.2) has a higher boiling point than either 1-pentanol or pentanal. The higher boiling points of carboxylic acids result from their polarity and from the fact that they form very strong intermolecular hydrogen bonds. Carboxylic acids also interact with water molecules by hydrogen bonding through both their carbonyl and hydroxyl groups. Because of these hydrogen-bonding interactions, car- boxylic acids are more soluble in water than are alcohols, ethers, aldehydes, and ketones with comparable molecular weight. The solubility of a carboxylic acid in water decreases as its molecular weight increases. We account for this trend in the following way: A carboxylic acid consists of two regions of different polarity—a polar hydrophilic carboxyl group and, except
1 3. 4 What Are the Acid–Base Properties of Carboxylic Acids? 463
As we discussed in Section 2.5B, carboxylic acids (p K a 4 5) are stronger acids than alcohols (p K a 16 18) because resonance stabilizes the carboxylate anion by delocalizing its negative charge. No comparable resonance stabilization exists in alkoxide ions.
ROH RO
R O
O
R O
O
H^
H^ resonance stabilization delocalizes the negative charge
no resonance stabilization
p K a 16–
p K a 4–
R OH
O
Substitution at the a carbon of an atom or a group of atoms of higher electronega- tivity than carbon increases the acidity of carboxylic acids, often by several orders of mag- nitude (Section 2.5C). Compare, for example, the acidities of acetic acid (p K a 4.76) and chloroacetic acid (p K a 2.86). A single chlorine substituent on the a carbon increases acid strength by nearly 100! Both dichloroacetic acid and trichloroacetic acid are stronger acids than phosphoric acid (p K a 2.1):
O
Cl
the inductive effect of an electronegative atom delocalizes the negative charge and stabilizes the carboxylate ion
Formula:
Name: Acetic Chloroacetic Dichloroacetic Trichloroacetic acid acid acid acid 4.76 2.86 1.48 0.
Increasing acid strength
p K a :
CH 3 COOH ClCH 2 COOH Cl 2 CHCOOH Cl 3 CCOOH
O
The acid-strengthening effect of halogen substitution falls off rather rapidly with increasing distance from the carboxyl group. Although the acid ionization constant for 2-chlorobutanoic acid (p K a 2.83) is 100 times that for butanoic acid, the acid ionization constant for 4-chlorobutanoic acid (p K a 4.52) is only about twice that for butanoic acid:
Decreasing acid strength
COOH
Cl 2-Chlorobutanoic acid (p K a 2.83)
Cl COOH
3-Chlorobutanoic acid (p K a 3.98)
Cl COOH
4-Chlorobutanoic acid (p K a 4.52)
COOH
Butanoic acid (p K a 4.82)
v
E X A M P L E 13.
Which acid in each set is the stronger?
OH
O
Propanoic acid
(a) or OH
O
OH
2-Hydroxy- propanoic acid (Lactic acid)
(b) or OH
O
OH
2-Hydroxy- propanoic acid (Lactic acid)
OH
O
O
2-Oxopropanoic acid (Pyruvic acid)
464 C H A P T E R 1 3 Carboxylic Acids
B. Reaction with Bases All carboxylic acids, whether soluble or insoluble in water, react with NaOH, KOH, and other strong bases to form water-soluble salts:
COOH+NaOH ¡H 2 O COO Na±^ +H 2 O
Benzoic acid (slightly soluble in water)
Sodium benzoate (60 g/100 mL water)
Sodium benzoate, a fungal growth inhibitor, is often added to baked goods “to retard spoilage.” Calcium propanoate is used for the same purpose. Carboxylic acids also form water-soluble salts with ammonia and amines:
COOH+NH 3 H
2 O
¡ COO NH 4 ±
Benzoic acid (slightly soluble in water)
Ammonium benzoate (20 g/100 mL water)
As described in Section 2.2, carboxylic acids react with sodium bicarbonate and sodi- um carbonate to form water-soluble sodium salts and carbonic acid (a relatively weak acid). Carbonic acid, in turn, decomposes to give water and carbon dioxide, which evolves as a gas:
CH 3 COOH Na HCO 3 ^ H 2 O CH 3 COONa H 2 CO (^3) H 2 CO 3 CO 2 H 2 O CH 3 COOH Na HCO 3 ^ CH 3 COONa CO 2 H 2 O
P R O B L E M 13.
Match each compound with its appropriate p K a value:
2,2-Dimethyl- Trifluoro- 2-Hydroxy- propanoic acid acetic acid propanoic acid (Lactic acid)
CH 3 p K a values= 5 .03, 3.8 5 , and 0.22.
O
ƒ C
H
CH 3 CF 3 COOH HCOOH
C
ƒ C ƒ C
H 3
COOH
H 3
S T R AT E G Y
Draw the conjugate base of each acid and look for possible stabilization of the ion via resonance or inductive effects. The conjugate base that is more greatly stabilized will indicate the more acidic carboxylic acid.
S O L U T I O N (a) 2-Hydroxypropanoic acid (p K a 3.85) is a stronger acid than propanoic acid (p K a 4.87) because of the electron-withdrawing inductive effect of the hydroxyl oxygen. (b) 2-Oxopropanoic acid (p K a 2.06) is a stronger acid than 2-hydroxypropanoic acid (p K a 3.08) because of the greater electron- withdrawing inductive effect of the carbonyl oxygen compared with that of the hydroxyl oxygen.
See problems 13.20–13.22, 13.
466 C H A P T E R 1 3 Carboxylic Acids
13.5 How Are Carboxyl Groups Reduced?
The carboxyl group is one of the organic functional groups that is most resistant to reduc- tion. It is not affected by catalytic reduction (H 2 /M) under conditions that easily reduce aldehydes and ketones to alcohols and that reduce alkenes to alkanes. The most common reagent for the reduction of a carboxylic acid to a primary alcohol is the very powerful reducing agent lithium aluminum hydride (Section 12.10).
Mixture of Benzyl alcohol and Benzoic acid CH 2 OH CO 2 H
Benzyl alcohol bp 205 °C
Benzoic acid mp 122 °C
CH 2 OH CO 2 H
Ether layer containing benzyl alcohol
Distill ether
Water layer containing sodium benzoate
Acidify with 0.1 M HCl and filter solid
Dissolve in diethyl ether
Mix with 0.1 M NaOH
benzoic acid reacts with NaOH and is converted to sodium benzoate
sodium benzoate reacts with HCI and is converted to benzoic acid
FIGURE 13. Flowchart for separation of benzoic acid from benzyl alcohol.
Chemical Connections (^) 13A
FROM WILLOW BARK TO ASPIRIN AND BEYOND
The active component of willow bark was found to be salicin, a compound composed of salicyl alcohol joined to a unit of b D glucose (Section 17.2). Hydro- lysis of salicin in aqueous acid gives salicyl alcohol, which can then be oxidized to salicylic acid, an even more effective reliever of pain, fever, and inflamma- tion than salicin and one without its extremely bitter taste:
CheChCh micalii ll ConnectionsCo ect o s
The first drug developed for widespread use was as- pirin, today’s most common pain reliever. Americans alone consume approximately 80 billion tablets of aspirin a year! The story of the development of this modern pain reliever goes back more than 2, years: In 400 B.C .E., the Greek physician Hippocrates recommended chewing bark of the willow tree to alle- viate the pain of childbirth and to treat eye infections.
1 3. 5 How Are Carboxyl Groups Reduced? 467
naproxen and Rhone–Poulenc in France developed ketoprofen:
( S )-Ibuprofen
COOH
H CH 3
( S )-Naproxen
CH 3 O
COOH
H CH 3
( S )-Ketoprofen
COOH
O H CH 3
Notice that each compound has one stereocen- ter and can exist as a pair of enantiomers. For each drug, the physiologically active form is the S enantio- mer. Even though the R enantiomer of ibuprofen has none of the analgesic or anti-inflammatory activity, it is converted in the body to the active S enantiomer. In the 1960s, scientists discovered that aspirin acts by inhibiting cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglan- dins (Section 19.5). With this discovery, it became clear why only one enantiomer of ibuprofen, naproxen, and ketoprofen is active: Only the S enantiomer of each has the correct handedness to bind to COX and inhibit its activity. The discovery that these drugs owe their effec- tiveness to the inhibition of COX opened an entirely new avenue for drug research. If we know more about the structure and function of this key enzyme, might it be possible to design and discover even more effec- tive nonsteroidal anti-inflammatory drugs for the treat- ment of rheumatoid arthritis and other inflammatory diseases? And so continues the story that began with the dis- covery of the beneficial effects of chewing willow bark.
Question Draw the product of the reaction of salicylic acid with (a) one equivalent of NaOH, (b) two equivalents of NaOH, and (c) two equivalents of NaHCO 3.
Salicin
O
H
O
HO
H
H
HO
H
OH
H
CH 2 OH
CH 2 OH
CH 2 OH
OH
Salicyl alcohol Salicylic acid
O OH
OH
C^ ¬
“
Unfortunately, patients quickly recognized salicylic acid’s major side effect: It causes severe irritation of the mucous membrane lining the stomach. In the search for less irritating, but still effective, derivatives of salicylic acid, chemists at the Bayer division of I. G. Farben in Germany prepared acetyl- salicylic acid in 1883 and gave it the name aspirin , a word derived from the German spirsäure (salicylic acid), with the initial a for the acetyl group:
Salicylic acid Acetic anhydride
COH
O
O
O
OH
+CH 3 COCCH 3
Acetyl salicylate (Aspirin)
COH
O
O
OCCH 3
O
+CH 3 COH
Aspirin proved to be less irritating to the stomach than salicylic acid and also more effective in reliev- ing the pain and inflammation of rheumatoid arthritis. Bayer began large-scale production of aspirin in 1899. In the 1960s, in a search for even more effective and less irritating analgesics and anti-inflammatory drugs, the Boots Pure Drug Company in England stud- ied compounds related in structure to salicylic acid. They discovered an even more potent compound, which they named ibuprofen, and soon thereafter, Syntex Corporation in the United States developed
1 3. 5 How Are Carboxyl Groups Reduced? 469
See problems 13.30–13.32, 13.
Provide the product formed when each of the following is treated with:
(i) H 2 /Pd (ii) 1. LiAlH 4 , ether (iii) 1. NaBH 4 , EtOH
- H 2 O 2. H 2 O
Presume that an excess of reagent is available for each reaction.
H
O
O
O
(a)
HO
C
O
(b) HO
P R O B L E M 13.
S T R AT E G Y
Remember that carboxyl groups are only reduced by LiAlH 4 , alkenes are only reduced by H 2 /M, aldehydes and ketones are reduced by all metal hydride reducing agents, and benzene rings are resistant to each of these reducing reagents. Remember to consider stereochemistry in the outcome of each reaction.
S O L U T I O N
Here are structural formulas for the major product produced in each reaction:
(a) OH
O
OH
O
OH
OH
CH 3 O
H 2 /Pd
H 2 O
LiAlH 4 , ether
OH
CH 3 O
H 2 O
NaBH 4 , EtOH (no reaction)
OH
O O
OH
O
O O
O
OH
OH
OH
OH
OH
OH
OH
OH
(no reaction)
(b) H 2 /Pd
H 2 O
LiAlH 4 , ether
H 2 O
NaBH 4 , EtOH
470 C H A P T E R 1 3 Carboxylic Acids
13.6 What Is Fischer Esterification?
Treatment of a carboxylic acid with an alcohol in the presence of an acid catalyst—most commonly, concentrated sulfuric acid—gives an ester. This method of forming an ester is given the special name Fischer esterification after the German chemist Emil Fischer (1852–1919). As an example of Fischer esterification, treating acetic acid with ethanol in the presence of concentrated sulfuric acid gives ethyl acetate and water:
Ethanoic acid Ethanol Ethyl ethanoate (Acetic acid) (Ethyl alcohol) (Ethyl acetate)
CH 3
O
C OH + CH 3 CH 2 OH
H 2 SO (^4) CH (^3)
O
C OCH 2 CH 3 + H 2 O
removal of OH from the acid and H from the alcohol gives the ester
We study the structure, nomenclature, and reactions of esters in detail in Chapter 14. In the present chapter, we discuss only their preparation from carboxylic acids. Acid-catalyzed esterification is reversible, and generally, at equilibrium, the quantities of remaining carboxylic acid and alcohol are appreciable. By controlling the experimental conditions, however, we can use Fischer esterification to prepare esters in high yields. If the alcohol is inexpensive compared with the carboxylic acid, we can use a large excess of the alcohol to drive the equilibrium to the right and achieve a high conversion of carboxylic acid to its ester.
Fischer esterification The process of forming an ester by refluxing a carboxylic acid and an alcohol in the presence of an acid catalyst, commonly sulfuric acid.
HOW TO 13.
(a) In the Fischer esterification, the J OR portion of an alcohol replaces the J OH portion of a carboxylic acid. O
OH
HOR H 2 O
H 2 SO 4
O
OR
(b) This simple fact of the mechanism allows us to predict the product of any type of Fischer esterification. For example, in the following Fischer esteri- fication, the alcohol is already a part of the molecule. In cases of intramo- lecular Fischer esterifications, it is often helpful to number the atoms in the molecule.
OH
O
HO
O
1 2 3 4 5
6
in this case, the R group is ultimately connected to the carboxyl group undergoing esterification
numbering the atoms allows us to see that atom- will form a new bond to atom-1, resulting in the formation of a six-membered ring
1 2
3 4 5 6
O
H 2 SO 4
Predict the Product of a Fischer Esterification
Ken Karp for John Wiley & Sons These products all contain ethyl acetate as a solvent.
472 C H A P T E R 1 3 Carboxylic Acids
Chemical Connections (^) 13B
ESTERS AS FLAVORING AGENTS
few of them is sufficient to make ice cream, soft drinks, or candy taste natural. (Isopentane is the common name for 2-methylbutane.) The table shows the struc- tures of a few of the esters used as flavoring agents:
Question Show how each of the esters in the table can be synthesized using a Fischer esterification reaction.
CheChCh micalii ll ConnectionsCo ect o s
Flavoring agents are the largest class of food additives. At present, over a thousand synthetic and natural fla- vors are available. The majority of these are concen- trates or extracts from the material whose flavor is desired and are often complex mixtures of from tens to hundreds of compounds. A number of ester flavoring agents are synthesized industrially. Many have flavors very close to the target flavor, and adding only one or a
Structure Name Flavor
H O
O
Ethyl formate Rum
O
O
Isopentyl acetate Banana
O
O
Octyl acetate Orange
O
O
Methyl butanoate Apple
O
O
Ethyl butanoate Pineapple
NH (^2)
O
O
Methyl 2-aminobenzoate (Methyl anthranilate)
Grape
Mechanism
Fischer Esterification
STEP 1: Add a proton. Proton transfer from the acid catalyst to the carbonyl oxygen increases the electrophilicity of the carbonyl carbon:
R C
O
OH
H O
CH 3
H
±
±
H
O
CH 3
H
R C
O
OH
1 3. 7 What Are Acid Chlorides? 473
STEP 2: Reaction of a nucleophile and an electrophile to form a new covalent bond. The carbonyl carbon is then attacked by the nucleophilic oxygen atom of the alcohol to form an oxonium ion:
O
CH 3
H
± H
R C
O
OH
(an electrophile) (a nucleophile) (oxonium ion)
H
R C O
O
H
O
H
CH 3
±
STEP 3: Take a proton away. Proton transfer from the oxonium ion to a second molecule of alcohol gives a tetrahedral carbonyl addition intermediate (TCAI):
O H O
CH 3
H
O
CH 3
H
R C^ +^ Δ +
O
H
O
H
O
CH 3
R C
O
H
O
H
CH 3
H
± ±
STEP 4: Add a proton. Proton transfer to one of the J OH groups of the TCAI gives a new oxonium ion:
O ^ H O^
CH 3
O
CH 3
R C
O
H
O
H
CH 3
H
± R C
O
H
O
H H
O
CH 3
± H
STEP 5: Collapse of the tetrahedral carbonyl addition intermediate to eject a leaving group and regenerate the carbonyl group. Loss of water from this oxonium ion gives the ester and regenerates the acid catalyst:
R C
O
H
O
H H
O
CH 3
± H
O
O
CH 3
R C O
CH 3
+ H O
CH 3
H
± + O
H H
13.7 What Are Acid Chlorides?
The functional group of an acid halide is a carbonyl group bonded to a halogen atom. Among the acid halides, acid chlorides are the most frequently used in the laboratory and in industrial organic chemistry:
Functional group Acetyl chloride Benzoyl chloride of an acid halide
CCl
O
CH 3
O
¬ C Cl
O
C ¬ X
We study the nomenclature, structure, and characteristic reactions of acid halides in Chapter 14. In this chapter, our concern is only with their synthesis from carboxylic acids.
1 3. 8 What Is Decarboxylation? 475
dioxide and HCl. The mechanism shown below is a common mode of reactivity for functional derivatives of carboxylic acids (Chapter 14).
R
O
Sulfochloridous acid
R (^) O¬S¬Cl
O
H
O-
Cl Cl
O
H
¬^ SO^2 +^ HCl
E X A M P L E 13.
Complete each equation:
O
(a) (^) OH+SOCl 2 ¡
O
(b) (^) OH+SOCl 2 ¡
S T R AT E G Y
Thionyl chloride effectively causes J OH groups (for exam- ple, those of alcohols and carboxylic acids) to be replaced by Cl. Don’t forget to show the by-products of the reaction (SO 2 and HCl).
S O L U T I O N
Following are the products for each reaction:
O
O
(a) Cl+SO 2 +HCl
(b) (^) Cl+SO 2 +HCl
Complete each equation:
(a) (b)
COOH
OCH 3
OH
+SOCl 2 ¡ +SOCl 2 ¡
P R O B L E M 1 3. 6
See problems 13.30, 13.
13.8 What Is Decarboxylation?
A. B -Ketoacids
Decarboxylation is the loss of CO 2 from a carboxyl group. Almost any carboxylic acid, heated to a very high temperature, undergoes decarboxylation:
R
O
C OH
decarboxylation (^) " (high temperature) RH^ +^ CO^2
Most carboxylic acids, however, are quite resistant to moderate heat and melt or even boil without decarboxylation. Exceptions are carboxylic acids that have a carbonyl group b to the carboxyl group. This type of carboxylic acid undergoes decarboxylation quite readily
Decarboxylation Loss of CO 2 from a carboxyl group.
476 C H A P T E R 1 3 Carboxylic Acids
on mild heating. For example, when 3-oxobutanoic acid (acetoacetic acid) is heated mod- erately, it undergoes decarboxylation to give acetone and carbon dioxide: O
OH
O O
warm +CO 2 3-Oxobutanoic acid (Acetoacetic acid)
a b Acetone
Decarboxylation on moderate heating is a unique property of 3-oxocarboxylic acids (b ketoacids) and is not observed with other classes of ketoacids.
Mechanism
Decarboxylation of a B -Ketocarboxylic Acid
STEP 1: Rearrangement of bonds. Redistribution of six electrons in a cyclic six-membered transition state gives carbon dioxide and an enol:
O
O
O
H
O
H
C
O
O
O
(A cyclic six-membered transition state)
¡^ (1)^ +CO 2
(2)
enol of a ketone
STEP 2: Keto–enol tautomerism. Tautomerism (Section 12.8A) of the enol gives the more stable keto form of the product:
CH 3
C
C
O
H
H
H CH 3 ¬ C ¬ CH 3
O
Chemical Connections (^) 13C
KETONE BODIES AND DIABETES
3-Hydroxybutanoic acid and 3-oxobutanoic acid are known collectively as ketone bodies. The concentration of ketone bodies in the blood of healthy, well-fed humans is approximately 0.01 mM/L. However, in persons suffering from starvation or diabetes mellitus, the concentration of ketone bodies may increase to as much as 500 times normal. Under these conditions, the concen- tration of acetoacetic acid increases to the point where it undergoes spontaneous decarboxylation to form acetone and carbon dioxide. Acetone is not
ChChChemical ii ll ConnectionsCo ect o s
3-Oxobutanoic acid (acetoacetic acid) and its reduction product, 3-hydroxybutanoic acid, are synthesized in the liver from acetyl-CoA, a product of the metabolism of fatty acids (Section 21.5C) and certain amino acids: O
OH
O OH
OH
O
3-Oxobutanoic acid (Acetoacetic acid)
3-Hydroxybutanoic acid (b-Hydroxybutyric acid)
