Acidity of Carboxylic Acids -
PROBLEM How would you prepare the following compounds from benzene? More than one step is needed in 20-46 each case.
(a) $m$-Chlorobenzoic acid
(b) p-Bromobenzoic acid
(c) Phenylacetic acid, $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{H}$

PROBLEM Predict the product of the reaction of $p$-methylbenzoic acid with each of the following:
20-47 (a) $\mathrm{LiAlH}_{4}$, then $\mathrm{H}_{3} \mathrm{O}^{+}$
(b) $N$-Bromosuccinimide in $\mathrm{CCl}_{4}$
(c) $\mathrm{CH}_{3} \mathrm{MgBr}$ in ether, then $\mathrm{H}_{3} \mathrm{O}^{+}$
(d) $\mathrm{KMnO}_{4}, \mathrm{H}_{3} \mathrm{O}^{+}$

PROBLEM Using ${ }^{13} \mathrm{CO}_{2}$ as your only source of labeled carbon, along with any other compounds needed, how
20-48 would you synthesize the following compounds?
(a) $\mathrm{CH}_{3} \mathrm{CH}_{2}{ }^{13} \mathrm{CO}_{2} \mathrm{H}$ (b) $\mathrm{PRODCH}_{3}{ }^{13} \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{H}$

PROBLEM How would you carry out the following transformations?
20-49

PROBLEM Which method-Grignard carboxylation or nitrile hydrolysis-would you use for each of the 20-50 following reactions? Explain.
(a)

(b)

(c)

(d) $\mathrm{HOCH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{Br} \longrightarrow \mathrm{HOCH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{H}$


Acidity of Carboxylic Acids -
PROBLEM 1,6-Hexanediamine, a starting material needed for making nylon, can be made from 1,3-butadiene.
20-51 How would you accomplish the synthesis?

PROBLEM 3-Methyl-2-hexenoic acid (mixture of $E$ and $Z$ isomers) has been identified as the substance 20-52 responsible for the odor of human sweat. Synthesize the compound from starting materials having five or fewer carbons.


Spectroscopy -
PROBLEM Propose a structure for a compound $\mathrm{C}_{6} \mathrm{H}_{12} \mathrm{O}_{2}$ that dissolves in dilute NaOH and shows the following 20-53 ${ }^{1} \mathrm{H}$ NMR spectrum: $1.08 \delta(9 \mathrm{H}$, singlet), $2.2 \delta(2 \mathrm{H}$, singlet), and $11.2 \delta(1 \mathrm{H}$, singlet $)$.

PROBLEM What spectroscopic method could you use to distinguish among the following three isomeric acids?
20-54 Tell what characteristic features you would expect for each acid.
$\mathrm{CH}_{3}\left(\mathrm{CH}_{2}\right)_{3} \mathrm{CO}_{2} \mathrm{H}$
$\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CHCH}_{2} \mathrm{CO}_{2} \mathrm{H}$

Pentanoic acid
3-Methylbutanoic acid
2,2-Dimethylpropanoic acid
PROBLEM How would you use NMR (either ${ }^{13} \mathrm{C}$ or ${ }^{1} \mathrm{H}$ ) to distinguish between the following pairs of isomers?
20-55 (a)

and

(c) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{H}$ and
$\mathrm{HOCH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CHO}$
(d)
$\left(\mathrm{CH}_{3}\right)_{2} \mathrm{C}=\mathrm{CHCH}_{2} \mathrm{CO}_{2} \mathrm{H}$
and

PROBLEM Compound $\mathbf{A}, \mathrm{C}_{4} \mathrm{H}_{8} \mathrm{O}_{3}$, has infrared absorptions at 1710 and 2500 to $3100 \mathrm{~cm}^{-1}$ and has the ${ }^{1} \mathrm{H}$ 20-56 NMR spectrum shown. Propose a structure for A.


General Problems -
PROBLEM A chemist in need of 2,2-dimethylpentanoic acid decided to synthesize some by reaction of 20-57 2-chloro-2-methylpentane with NaCN , followed by hydrolysis of the product. After the reaction sequence was carried out, however, none of the desired product could be found. What do you suppose went wrong?

PROBLEM Show how you might prepare the anti-inflammatory agent ibuprofen starting from 20-58 isobutylbenzene. More than one step is needed.

PROBLEM The following synthetic schemes all have at least one flaw in them. What is wrong with each?
20-59 (a)

(b)

(c)

PROBLEM p-Aminobenzoic acid (PABA) was once widely used as a sunscreen agent. Propose a synthesis of
20-60 PABA starting from toluene.
PROBLEM Propose a synthesis of the anti-inflammatory drug fenclorac from phenylcyclohexane.


20-61 -
PROBLEM The $\mathrm{p} K_{\mathrm{a}}$ 's of five $p$-substituted benzoic acids $\left(\mathrm{YC}_{6} \mathrm{H}_{4} \mathrm{CO}_{2} \mathrm{H}\right)$ are listed below. Rank the corresponding
20-62 substituted benzenes $\left(\mathrm{YC}_{6} \mathrm{H}_{5}\right)$ in order of their increasing reactivity toward electrophilic aromatic substitution. If benzoic acid has $\mathrm{p} K_{\mathrm{a}}=4.19$, which of the substituents are activators and which are deactivators?

| Substituent $\mathbf{Y}$ |  |
| :---: | :---: |
| $-\mathrm{Si}\left(\mathrm{CH}_{3}\right)_{3}$ | 4.27 |
| $-\mathrm{CH}=\mathrm{CHC} \equiv \mathrm{N}$ | 4.03 |
| $-\mathrm{HgCH}_{3}$ | 4.10 |
| $-\mathrm{OSO}_{2} \mathrm{CH}_{3}$ | 3.84 |
| $-\mathrm{PCl}_{2}$ | 3.59 |

PROBLEM How would you carry out the following transformations? More than one step is needed in each case.

20-63 (a)

(b)

PROBLEM The following $\mathrm{p} K_{\mathrm{a}}$ values have been measured. Explain why a hydroxyl group in the para position 20-64 decreases the acidity while a hydroxyl group in the meta position increases the acidity.

$\mathrm{p} K_{\mathrm{a}}=4.48$

$\mathrm{p} K_{\mathrm{a}}=4.19$

$\mathrm{p} K_{\mathrm{a}}=4.07$

PROBLEM Identify the missing reagents a-f in the following scheme:


20-65 -
PROBLEM Propose a structure for a compound, $\mathrm{C}_{4} \mathrm{H}_{7} \mathrm{~N}$, that has the following IR and ${ }^{1} \mathrm{H}$ NMR spectra:
20-66

PROBLEM The two ${ }^{1} \mathrm{H}$ NMR spectra shown here belong to crotonic acid (trans $-\mathrm{CH}_{3} \mathrm{CH}=\mathrm{CHCO}_{2} \mathrm{H}$ ) and 20-67 methacrylic acid $\left[\mathrm{H}_{2} \mathrm{C}=\mathrm{C}\left(\mathrm{CH}_{3}\right) \mathrm{CO}_{2} \mathrm{H}\right]$. Which spectrum corresponds to which acid? Explain.
(a)

(b)

PROBLEM The ${ }^{1} \mathrm{H}$ and ${ }^{13} \mathrm{C}$ NMR spectra below belong to a compound with formula $\mathrm{C}_{6} \mathrm{H}_{10} \mathrm{O}_{2}$. Propose a 20-68 structure for this compound.
(a)

(b)


20-65 -
(b)

PROBLEM Propose structures for carboxylic acids that show the following peaks in their ${ }^{13}$ C NMR spectra.
20-69 Assume that the kinds of carbons $\left(1^{\circ}, 2^{\circ}, 3^{\circ}\right.$, or $\left.4^{\circ}\right)$ have been assigned by DEPT-NMR.
(a) $\mathrm{C}_{7} \mathrm{H}_{12} \mathrm{O}_{2}: 25.5 \delta\left(2^{\circ}\right), 25.9 \delta\left(2^{\circ}\right), 29.0 \delta\left(2^{\circ}\right), 43.1 \delta\left(3^{\circ}\right), 183.0 \delta\left(4^{\circ}\right)$
(b) $\mathrm{C}_{8} \mathrm{H}_{8} \mathrm{O}_{2}: 21.4 \delta\left(1^{\circ}\right), 128.3 \delta\left(4^{\circ}\right), 129.0 \delta\left(3^{\circ}\right), 129.7 \delta\left(3^{\circ}\right), 143.1 \delta\left(4^{\circ}\right), 168.2 \delta\left(4^{\circ}\right)$

PROBLEM Carboxylic acids having a second carbonyl group two atoms away lose $\mathrm{CO}_{2}$ (decarboxylate) through 20-70 an intermediate enolate ion when treated with base. Write the mechanism of this decarboxylation reaction using curved arrows to show the electron flow in each step.

An enolate ion


CHAPTER 21 <br> Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions -
FIGURE 21.1 The lives of rock climbers depend on their ropes, typically made of a nylon polymer prepared by a nucleophilic acyl substitution reaction. (credit: modification of work "110823-A-NR754-001" by USASOC News Service/Flickr, CC BY 2.0)


CHAPTER CONTENTS - 21.1 Naming Carboxylic Acid Derivatives
21.2 Nucleophilic Acyl Substitution Reactions
21.3 Reactions of Carboxylic Acids
21.4 Chemistry of Acid Halides
21.5 Chemistry of Acid Anhydrides
21.6 Chemistry of Esters
21.7 Chemistry of Amides
21.8 Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives
21.9 Polyamides and Polyesters: Step-Growth Polymers
21.10 Spectroscopy of Carboxylic Acid Derivatives

WHY THIS CHAPTER? Carboxylic acid derivatives are among the most widely occurring of all molecules, both in laboratory chemistry and in biological pathways. Thus, a study of them and their primary reaction-nucleophilic acyl substitution-is fundamental to understanding organic chemistry. We'll begin this chapter by first learning about carboxylic acid derivatives, and we'll then explore the chemistry of acyl substitution reactions.

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid
derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can act as a leaving group in the nucleophilic acyl substitution reaction that we saw briefly in the Preview of Carbonyl Chemistry:

Many kinds of acid derivatives are known, but we'll be concerned primarily with four of the most common ones: acid halides, acid anhydrides, esters, and amides. Acid halides and acid anhydrides are used only in the laboratory, while esters and amides are common in both laboratory and biological chemistry. In addition, carboxylic acid derivatives called thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acyl phosphates.

Acid halide ( $\mathrm{X}=\mathrm{Cl}, \mathrm{Br}$ )

Acid anhydride

Ester

Amide

Thioester

Acyl phosphate


Acid Halides, RCOX -
Acid halides are named by identifying first the acyl group and then the halide. As described in Section 20.1 and shown in TABLE 20.1, the acyl group name is derived from the carboxylic acid name by replacing the -ic acid or -oic acid ending with -oyl, or the -carboxylic acid ending with -carbonyl. To keep things interesting, however, IUPAC recognizes eight exceptions for which a -yl rather than an -oyl ending is used: formic (formyl), acetic (acetyl), propionic (propionyl), butyric (butyryl), oxalic (oxalyl), malonic (malonyl), succinic (succinyl), and glutaric (glutaryl).

Acetyl chloride

Benzoyl bromide

Cyclohexanecarbonyl chloride


Acid Anhydrides, $\mathrm{RCO}_{2} \mathrm{COR}^{\prime}$ -
Symmetrical anhydrides of unsubstituted monocarboxylic acids and cyclic anhydrides of dicarboxylic acids are named by replacing the word acid with anhydride.

Acetic anhydride

Benzoic anhydride

Succinic anhydride

Unsymmetrical anhydrides-those prepared from two different carboxylic acids-are named by listing the two acids alphabetically and then adding anhydride.

Acetic benzoic anhydride


Esters, $\mathrm{RCO}_{2} \mathrm{R}^{\prime}$ -
Esters are named by first identifying the alkyl group attached to oxygen and then the carboxylic acid, with the -ic acid ending replaced by -ate.

Ethyl acetate

Dimethyl malonate

tert-Butyl cyclohexanecarboxylate


Amides, $\mathrm{RCONH}_{2}$ -
Amides with an unsubstituted $-\mathrm{NH}_{2}$ group are named by replacing the -oic acid or -ic acid ending with -amide, or by replacing the -carboxylic acid ending with -carboxamide.

Acetamide

Hexanamide

Cyclopentanecarboxamide

If the nitrogen atom is further substituted, the compound is named by first identifying the substituent groups and then the parent amide. The substituents are preceded by the letter $N$ to identify them as being directly attached to nitrogen.

N -Methylpropanamide

$N, N$-Diethylcyclohexanecarboxamide


Thioesters, RCOSR' -
Thioesters are named like the corresponding esters. If the related ester has a common name, the prefix thiois added to the name of the carboxylate: acetate becomes thioacetate, for instance. If the related ester has a systematic name, the -oate or -carboxylate ending is replaced by -thioate or -carbothioate: butanoate becomes butanethioate and cyclohexanecarboxylate becomes cyclohexanecarbothioate, for instance.

Methyl thioacetate

Ethyl butanethioate

Methyl cyclohexanecarbothioate


Acyl Phosphates, $\mathrm{RCO}_{2} \mathrm{PO}_{3}{ }^{2-}$ and $\mathrm{RCO}_{2} \mathrm{PO}_{3} \mathrm{R}^{r}$ -
Acyl phosphates are named by citing the acyl group and adding the word phosphate. If an alkyl group is attached to one of the phosphate oxygens, it is identified after the name of the acyl group. In biological chemistry, acyl
adenosyl phosphates are particularly common.

Benzoyl phosphate

Acetyl adenosyl phosphate

A summary of nomenclature rules for carboxylic acid derivatives is given in TABLE 21.1.
TABLE 21.1 Nomenclature of Carboxylic Acid Derivatives

| Functional group | Structure | Name ending |
| :---: | :---: | :---: |
| Carboxylic acid | <smiles>[R]C(=O)O</smiles> | -ic acid
 (-carboxylic acid) |
| Acid halide | <smiles>[R]C([X])=O</smiles> | -oyl halide
 (-carbonyl halide) |
| Acid anhydride | <smiles>[R]C(=O)OC([R])[R]</smiles> | anhydride |
| Amide | <smiles>R16N</smiles> | -amide
 (-carboxamide) |
| Ester | <smiles>[R]OC([R])=O</smiles> | -oate
 (-carboxylate) |
| Thioester | <smiles>[R]C(=O)[Sn]</smiles> | -thioate
 (-carbothioate) |
| Acyl phosphate | <smiles></smiles> | -oyl phosphate |

PROBLEM Give IUPAC names for the following substances:

21-1 (a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)


Acyl Phosphates, $\mathrm{RCO}_{2} \mathrm{PO}_{3}{ }^{2-}$ and $\mathrm{RCO}_{2} \mathrm{PO}_{3} \mathrm{R}^{r}$ -
PROBLEM Give IUPAC names for the following substances:

21-1 (a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

PROBLEM Draw structures corresponding to the following names:
21-2 (a) Phenyl benzoate (b) $N$-Ethyl- $N$-methylbutanamide (c) 2,4-Dimethylpentanoyl chloride
(d) Methyl 1-methylcyclohexanecarboxylate (e) Ethyl 3-oxopentanoate
(f) Methyl $p$-bromobenzenethioate (g) Formic propanoic anhydride
(h) cis-2-Methylcyclopentanecarbonyl bromide


Acyl Phosphates, $\mathrm{RCO}_{2} \mathrm{PO}_{3}{ }^{2-}$ and $\mathrm{RCO}_{2} \mathrm{PO}_{3} \mathrm{R}^{r}$ - 21.2 Nucleophilic Acyl Substitution Reactions
The addition of a nucleophile to a polar $\mathrm{C}=\mathrm{O}$ bond is the key step in three of the four major carbonyl-group reactions. We saw in the chapter on Aldehydes and Ketones: Nucleophilic Addition Reactions that when a nucleophile adds to an aldehyde or ketone, the initially formed tetrahedral intermediate can be protonated to yield an alcohol. When a nucleophile adds to a carboxylic acid derivative, however, a different reaction path is taken. The initially formed tetrahedral intermediate eliminates one of the two substituents originally bonded to the carbonyl carbon, leading to a net nucleophilic acyl substitution reaction (FIGURE 21.2).
(a) Aldehyde or ketone: nucleophilic addition

(b) Carboxylic acid derivative: nucleophilic acyl substitution

FIGURE 21.2 The general mechanisms of nucleophilic addition and nucleophilic acyl substitution reactions. Both reactions begin with addition of a nucleophile to a polar $\mathrm{C}=\mathrm{O}$ bond to give a tetrahedral, alkoxide ion intermediate. (a) The intermediate formed from an aldehyde or ketone is protonated to give an alcohol, but (b) the intermediate formed from a carboxylic acid derivative expels a leaving group to give a new carbonyl compound.

The difference in behavior between aldehydes/ketones and carboxylic acid derivatives is a consequence of structure. Carboxylic acid derivatives have an acyl carbon bonded to a group -Y that can act as a leaving group, often as a stable anion. As soon as the tetrahedral intermediate is formed, the leaving group is expelled to generate a new carbonyl compound. Aldehydes and ketones, however, have no such leaving group, however, and therefore don't undergo substitution.

A carboxylic acid derivative

An aldehyde

A ketone


Acyl Phosphates, $\mathrm{RCO}_{2} \mathrm{PO}_{3}{ }^{2-}$ and $\mathrm{RCO}_{2} \mathrm{PO}_{3} \mathrm{R}^{r}$ - 21.2 Nucleophilic Acyl Substitution Reactions
A carboxylic acid derivative

An aldehyde

A ketone

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group that was originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an $\mathrm{S}_{\mathrm{N}} 2$ reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An $\mathrm{S}_{\mathrm{N}} 2$ reaction occurs in a single step by backside displacement of the leaving group, while a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate.

PROBLEM Show the mechanism of the following nucleophilic acyl substitution reaction, using curved arrows
21-3 to indicate the electron flow in each step:


Relative Reactivity of Carboxylic Acid Derivatives -
Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition is usually the rate-limiting step. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process.

Steric and electronic factors are both important in determining reactivity. Sterically, we find within a series of similar acid derivatives that unhindered, accessible carbonyl groups react with nucleophiles more readily than do sterically hindered carbonyl groups. The reactivity order is


Reactivity -
Electronically, we find that strongly polarized acyl compounds react more readily than less polar ones. Thus, acid chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic acid derivatives indicate these differences by the relative blueness on the $\mathrm{C}=\mathrm{O}$ carbons. Acyl phosphates are hard to place on this scale because they are not often used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters.

Amide

Ester

Thioester

Acid anhydride

<

Acid chloride


Reactivity -
The way in which various substituents affect the polarization of a carbonyl group is similar to the way they affect the reactivity of an aromatic ring toward electrophilic substitution (Section 16.4). A chlorine substituent, for example, inductively withdraws electrons from an acyl group in the same way that it withdraws electrons from and thus deactivates an aromatic ring. Similarly, amino, methoxyl, and methylthio substituents donate electrons to acyl groups by resonance in the same way that they donate electrons to, and thus activate, aromatic rings.

As a consequence of these reactivity differences, it's usually possible to convert a more reactive acid derivative into a less reactive one. Acid chlorides, for instance, can be directly converted into anhydrides, thioesters, esters, and amides, but amides can't be directly converted into esters, thioesters, anhydrides, or acid chlorides. Remembering the reactivity order is therefore a way to keep track of a large number of reactions (FIGURE 21.3). Another consequence, as noted previously, is that only acyl phosphates, thioesters, esters, and amides are commonly found in nature. Acid halides and acid anhydrides react so rapidly with water that they can't exist for long in living organisms.

FIGURE 21.3 Interconversions of carboxylic acid derivatives. A more reactive acid derivative can be converted into a less reactive one, but not vice versa.

In studying the chemistry of carboxylic acid derivatives in the next few sections, we'll be concerned largely with the reactions of just a few nucleophiles and will see that the same kinds of reactions tend to reoccur (FIGURE 21.4).

- Hydrolysis
- Alcoholysis
- Aminolysis
- Reduction
- Grignard reaction

Reaction with water to yield a carboxylic acid
Reaction with an alcohol to yield an ester
Reaction with ammonia or an amine to yield an amide
Reaction with a hydride reducing agent to yield an aldehyde or an alcohol
Reaction with an organometallic reagent to yield a ketone or an alcohol

FIGURE 21.4 Some general reactions of carboxylic acid derivatives.


Predicting the Product of a Nucleophilic Acyl Substitution Reaction -
Predict the product of the following nucleophilic acyl substitution reaction of benzoyl chloride with 2-propanol:

Benzoyl chloride


Strategy -
A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group ( $\mathrm{Cl}^{-}$in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate.

Solution

PROBLEM Rank the compounds in each of the following sets in order of their expected reactivity toward 21-4 nucleophilic acyl substitution:
(a)

(b)

PROBLEM Predict the products of the following nucleophilic acyl substitution reactions:
21-5

PROBLEM The following structure represents a tetrahedral alkoxide ion intermediate formed by addition of a 21-6 nucleophile to a carboxylic acid derivative. Identify the nucleophile, the leaving group, the starting acid derivative, and the ultimate product.


Strategy - 21.3 Reactions of Carboxylic Acids
The direct nucleophilic acyl substitution of a carboxylic acid is difficult because -OH is a poor leaving group (Section 11.3). Thus, it's usually necessary to enhance the reactivity of the acid, either by using a strong acid catalyst to protonate the carboxyl and make it a better acceptor or by converting the - OH into a better leaving group. Under the right circumstances, however, acid chlorides, anhydrides, esters, and amides can all be prepared from carboxylic acids by nucleophilic acyl substitution reactions.


Conversion of Carboxylic Acids into Acid Chlorides -
In the laboratory, carboxylic acids are converted into acid chlorides by treatment with thionyl chloride, $\mathrm{SOCl}_{2}$.

2,4,6-Trimethylbenzoic acid


2,4,6-Trimethylbenzoyl -
chloride (90\%)This reaction occurs by a nucleophilic acyl substitution pathway in which the carboxylic acid is first converted into an acyl chlorosulfite intermediate, thereby replacing the -OH of the acid with a much better leaving group. The chlorosulfite then reacts with a nucleophilic chloride ion. You might recall from Section 17.6 that an analogous chlorosulfite is involved in the reaction of an alcohol with $\mathrm{SOCl}_{2}$ to yield an alkyl chloride.

Carboxylic acid

A chlorosulfite
Acid chloride


Conversion of Carboxylic Acids into Acid Anhydrides -
Acid anhydrides can be derived from two molecules of carboxylic acid by heating to remove 1 equivalent of water. Because of the high temperatures needed, however, only acetic anhydride is commonly prepared this
way.


Conversion of Carboxylic Acids into Esters -
Perhaps the most useful reaction of carboxylic acids is their conversion into esters. There are many methods for accomplishing this, including the $\mathrm{S}_{\mathrm{N}} 2$ reaction of a carboxylate anion with a primary alkyl halide that we saw in Section 11.3.


Sodium butanoate -
Methyl butanoate (97\%)
Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need for an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters.

The mechanism of the Fischer esterification reaction is shown in FIGURE 21.5. Carboxylic acids are not reactive enough to undergo nucleophilic addition directly, but their reactivity is greatly enhanced in the presence of a strong acid such as HCl or $\mathrm{H}_{2} \mathrm{SO}_{4}$. The mineral acid protonates the carbonyl-group oxygen atom, thereby giving the carboxylic acid a positive charge and rendering it much more reactive toward nucleophiles. Subsequent loss of water from the tetrahedral intermediate yields the ester product.


FIGURE 21.5 MECHANISM -
Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid.

The net effect of Fischer esterification is substitution of an -OH group by -OR'. All steps are reversible, and the reaction typically has an equilibrium constant close to 1 . Thus, the reaction can be driven in either direction by the choice of reaction conditions. Ester formation is favored when a large excess of alcohol is used as solvent, but carboxylic acid formation is favored when a large excess of water is present.

Evidence in support of the mechanism shown in FIGURE 21.5 comes from isotope-labeling experiments. When ${ }^{18} \mathrm{O}$-labeled methanol reacts with benzoic acid, the methyl benzoate produced is found to be ${ }^{18} \mathrm{O}$-labeled whereas the water produced is unlabeled. Thus, it is the $\mathrm{C}-\mathrm{OH}$ bond of the carboxylic acid that is broken during the reaction rather than the $\mathrm{CO}-\mathrm{H}$ bond and the $\mathrm{RO}-\mathrm{H}$ bond of the alcohol that is broken rather than the $\mathrm{R}-\mathrm{OH}$ bond.


Synthesizing an Ester from an Acid -
How might you prepare the following ester using a Fischer esterification reaction?


Strategy -
Begin by identifying the two parts of the ester. The acyl part comes from the carboxylic acid and the -OR part comes from the alcohol. In this case, the target molecule is propyl o-bromobenzoate, so it can be prepared by treating $o$-bromobenzoic acid with 1-propanol.


Solution -
PROBLEM How might you prepare the following esters from the corresponding acids?

21-7 (a)

(b)

(c)

PROBLEM If the following molecule is treated with acid catalyst, an intramolecular esterification reaction
21-8 occurs. What is the structure of the product? (Intramolecular means within the same molecule.)


Conversion of Carboxylic Acids into Amides -
Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions. Thus, the - OH must be replaced by a better, nonacidic leaving group to carry out a nucleophilic acyl substitution. In practice, amides are often prepared by activating the carboxylic acid with a carbodiimide ( $\mathrm{R}-\mathrm{N}=\mathrm{C}=\mathrm{N}-\mathrm{R}$ ), followed by addition of the amine. Dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide (EDEC) are commonly used.

Dicyclohexylcarbodiimide 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide

As shown in FIGURE 21.6, the acid first adds to a $\mathrm{C}=\mathrm{N}$ double bond of DCC , and nucleophilic acyl substitution by amine then ensues. Alternatively, and depending on the reaction solvent, the reactive acyl intermediate might also react with a second equivalent of carboxylate ion to generate an acid anhydride that then reacts with the amine. The product from either pathway is the same.


FIGURE 21.6 MECHANISM -
Mechanism of amide formation by reaction of a carboxylic acid and an amine with dicyclohexylcarbodiimide (DCC).

Dicyclohexylcarbodiimide is first protonated by the carboxylic acid to make it a better acceptor.

(2) The carboxylate then adds to the protonated carbodiimide to yield a reactive acylating agent.
(3) Nucleophilic attack of the amine on the acylating agent gives a tetrahedral intermediate. dicyclohexylurea and gives the amide.
(4) $\downarrow$

Amide

Dicyclohexylurea

We'll see in Section 26.7 that this carbodiimide method of amide formation is the key step in the laboratory synthesis of small proteins, or peptides. For instance, when one amino acid with its $\mathrm{NH}_{2}$ rendered unreactive and a second amino acid with its $-\mathrm{CO}_{2} \mathrm{H}$ rendered unreactive are treated with carbodiimide, a dipeptide is formed.

Amino acid 1
Amino acid 2
A dipeptide


Conversion of Carboxylic Acids into Alcohols -
We said in Section 17.4 that carboxylic acids are reduced by $\mathrm{LiAlH}_{4}$ to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which -H replaces -OH to give an aldehyde that is further reduced by nucleophilic addition to produce a primary alcohol. The aldehyde intermediate is much more reactive than the starting acid, so it reacts instantly and is not isolated.

Because hydride ion is a base as well as a nucleophile, the actual nucleophilic acyl substitution step takes place on the carboxylate ion rather than on the free carboxylic acid and gives a high-energy dianion intermediate. In this intermediate, the two oxygens are complexed to a Lewis acidic aluminum species. Thus, the reaction is relatively difficult, and acid reductions require higher temperatures and extended reaction times.

Alternatively, borane in tetrahydrofuran $\left(\mathrm{BH}_{3} / \mathrm{THF}\right)$ is a useful reagent for reducing carboxylic acids to primary alcohols. Reaction of an acid with $\mathrm{BH}_{3} / \mathrm{THF}$ occurs rapidly at room temperature, and the procedure is often preferred to reduction with $\mathrm{LiAlH}_{4}$ because of its relative ease and safety. Borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that on p-nitrophenylacetic acid. If the reduction of $p$-nitrophenylacetic acid were done with $\mathrm{LiAlH}_{4}$, both the nitro and carboxyl groups would be reduced.


Biological Conversions of Carboxylic Acids -
The direct conversion of a carboxylic acid to an acyl derivative by nucleophilic acyl substitution does not occur in biological chemistry. As in the laboratory, the acid must first be activated by converting the - OH into a better leaving group. This activation is often accomplished in living organisms by reaction of the acid with adenosine triphosphate (ATP) to give an acyl adenosyl phosphate, or acyl adenylate, a mixed anhydride combining a carboxylic acid and adenosine monophosphate (AMP, also known as adenylic acid). In the biosynthesis of fats, for example, a long-chain carboxylic acid reacts with ATP to give an acyl adenylate, followed by subsequent nucleophilic acyl substitution of a thiol group in coenzyme A to give the corresponding acyl CoA (FIGURE 21.7).


FIGURE 21.7 MECHANISM -
In fatty-acid biosynthesis, a carboxylic acid is activated by reaction with ATP to give an acyl adenylate, which undergoes nucleophilic acyl substitution with the -SH group on coenzyme A. (ATP $=$ adenosine triphosphate; $A M P=$ adenosine monophosphate.)
(1) ATP is activated by coordination to magnesium ion, and nucleophilic addition of a fatty acid carboxylate to phosphorus then yields a pentacoordinate intermediate...
(2... which expels diphosphate ion ( $\mathrm{PP}_{\mathrm{i}}$ ) as leaving group and gives an acyl adenosyl phosphate in a process analogous to a nucleophilic acyl substitution reaction.
(3) The -SH group of coenzyme A adds to the acyl adenosyl phosphate, giving a tetrahedral alkoxide intermediate . . .
(4)... which expels adenosine monophosphate (AMP) as leaving group and yields the fatty acyl CoA.

ATP
$\mathrm{Mg}^{2+}$
(1)

Pentacoordinate intermediate
(2)

Acetyl adenosyl phosphate


(acyl adenylate) -
(3)

©

Note that the first step in FIGURE 21.7-reaction of the carboxylate with ATP to give an acyl adenylate-is itself a nucleophilic acyl substitution on phosphorus. The carboxylate first adds to a $\mathrm{P}=\mathrm{O}$ double bond, giving a fivecoordinate phosphorus intermediate that expels diphosphate ion as a leaving group.


Preparation of Acid Halides -
Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride $\left(\mathrm{SOCl}_{2}\right)$, as we saw in the previous section. Similar reaction of a carboxylic acid with phosphorus tribromide ( $\mathrm{PBr}_{3}$ ) yields the acid bromide.


Reactions of Acid Halides -
Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by -OCOR to yield an anhydride, by -OR to yield an ester, by $-\mathrm{NH}_{2}$ to yield an amide, or by R' to yield a ketone. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we'll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides.


Acid anhydride -
Ester

$\mathrm{R}^{\prime} \mathrm{OH}$

Amide

Ketone

Conversion of Acid Halides into Carboxylic Acids: Hydrolysis
Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of $\mathrm{Cl}^{-}$and loss of $\mathrm{H}^{+}$to give the product carboxylic acid plus HCl .

Because HCl is formed during hydrolysis, the reaction is often carried out in the presence of a base such as pyridine or NaOH to remove the HCl and prevent it from causing side reactions.


Conversion of Acid Halides into Anhydrides -
Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared.


Conversion of Acid Halides into Esters: Alcoholysis -
Acid chlorides react with alcohols to yield esters in a process analogous to their reaction with water to yield acids. In fact, this reaction is probably the most common method for preparing esters in the laboratory. As with hydrolysis, alcoholysis reactions are usually carried out in the presence of pyridine or NaOH to react with the HCl formed.

The reaction of an alcohol with an acid chloride is strongly affected by steric hindrance. Bulky groups on either partner slow down the reaction considerably, resulting in a reactivity order among alcohols of primary > secondary > tertiary. As a result, it's often possible to selectively esterify an unhindered alcohol in the presence of a more hindered one. This can be important in complex syntheses in which it's sometimes necessary to distinguish between similar functional groups. For example,

PROBLEM How might you prepare the following esters using a nucleophilic acyl substitution reaction of an 21-9 acid chloride?
(a) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{CH}_{3}$
(b) $\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{CH}_{2} \mathrm{CH}_{3}$
(c) Ethyl benzoate

PROBLEM Which method would you choose if you wanted to prepare cyclohexyl benzoate-Fischer
21-10 esterification or reaction of an acid chloride with an alcohol? Explain.


Conversion of Acid Halides into Amides: Aminolysis -
Acid chlorides react rapidly with ammonia and amines to give amides. As with the acid chloride-plus-alcohol method for preparing esters, this reaction of acid chlorides with amines is the most commonly used laboratory method for preparing amides. Both monosubstituted and disubstituted amines can be used, but not trisubstituted amines ( $\mathrm{R}_{3} \mathrm{~N}$ ).

Because HCl is formed during the reaction, two equivalents of the amine must be used. One equivalent reacts with the acid chloride, and one equivalent reacts with the HCl by-product to form an ammonium chloride salt. If, however, the amine component is valuable, amide synthesis is often carried out using one equivalent of the amine plus one equivalent of an inexpensive base such as NaOH . For example, the sedative trimetozine is prepared commercially by reaction of $3,4,5$-trimethoxybenzoyl chloride with the amine morpholine in the presence of one equivalent of NaOH .


Synthesizing an Amide from an Acid Chloride -
How might you prepare $N$-methylpropanamide by reaction of an acid chloride with an amine?


Strategy -
As its name implies, $N$-methylpropanamide can be made by reaction of methylamine with the acid chloride of propanoic acid.


Solution -
Propanoyl Methylamine N-Methylpropanamide chloride

PROBLEM Write the mechanism of the reaction just shown between 3,4,5-trimethoxybenzoyl chloride and 21-11 morpholine to form trimetozine. Use curved arrows to show the electron flow in each step.

PROBLEM How could you prepare the following amides using an acid chloride and an amine or ammonia?
21-12 (a) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CONHCH}_{3}$
(b) $N, N$-Diethylbenzamide
(c) Propanamide


Conversion of Acid Chlorides into Alcohols: Reduction and Grignard Reaction -
Acid chlorides are reduced by $\mathrm{LiAlH}_{4}$ to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by $\mathrm{LiAlH}_{4}$ to yield alcohols.

Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion ( $\mathrm{H}:^{-}$) adds to the carbonyl group, yielding a tetrahedral intermediate that expels $\mathrm{Cl}^{-}$. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then further reduced by $\mathrm{LiAlH}_{4}$ in a second step to yield the primary alcohol.

Benzoyl chloride

Benzyl alcohol (96\%)

Grignard reagents react with acid chlorides to yield tertiary alcohols with two identical substituents. The mechanism of the reaction is similar to that of $\mathrm{LiAlH}_{4}$ reduction. The first equivalent of Grignard reagent adds to the acid chloride, loss of $\mathrm{Cl}^{-}$from the tetrahedral intermediate yields a ketone, and a second equivalent of Grignard reagent immediately adds to the ketone to produce an alcohol.

Conversion of Acid Chlorides into Ketones: Diorganocopper Reaction
The ketone intermediate formed in the reaction of an acid chloride with a Grignard reagent can't usually be isolated because addition of the second equivalent of organomagnesium reagent occurs too rapidly. A ketone can, however, be isolated from the reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, $\mathrm{Li}^{+} \mathrm{R}_{2} \mathrm{Cu}^{-}$. The reaction occurs by initial nucleophilic acyl substitution on the acid chloride by the diorganocopper anion to yield an acyl diorganocopper intermediate, followed by loss of $\mathrm{R}^{\prime} \mathrm{Cu}$ and formation of the ketone.


An acid An acyl A ketone chloride <br> diorganocopper -
The reaction is generally carried out at $-78^{\circ} \mathrm{C}$ in ether solution, and yields are often excellent. For example, manicone, a substance secreted by male ants to coordinate ant pairing and mating, has been synthesized by reaction of lithium diethylcopper with (E)-2,4-dimethyl-2-hexenoyl chloride.

Note that the diorganocopper reaction occurs only with acid chlorides. Carboxylic acids, esters, acid anhydrides, and amides do not react with lithium diorganocopper reagents.

PROBLEM How could you prepare the following ketones by reaction of an acid chloride with a lithium 21-13 diorganocopper reagent?


Preparation of Acid Anhydrides -
Acid anhydrides are typically prepared by nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion, as we saw in the previous section. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way.


Reactions of Acid Anhydrides -
The chemistry of acid anhydrides is similar to that of acid chlorides, although anhydrides react more slowly. Thus, acid anhydrides react with water to form acids, with alcohols to form esters, with amines to form amides, and with $\mathrm{LiAlH}_{4}$ to form primary alcohols. Only the ester- and amide-forming reactions are commonly used, however.

Alcoholysis
Aminolysis


Conversion of Acid Anhydrides into Esters -
Acetic anhydride is often used to prepare acetate esters from alcohols. For example, aspirin (acetylsalicylic acid) is prepared commercially by the acetylation of $o$-hydroxybenzoic acid (salicylic acid) with acetic anhydride.

Aspirin (an ester)


Conversion of Acid Anhydrides into Amides -
Acetic anhydride is also commonly used to prepare $N$-substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of $p$-hydroxyaniline with acetic anhydride. Only the more nucleophilic $-\mathrm{NH}_{2}$ group reacts rather than the less nucleophilic - OH group.

Notice in both of the previous reactions that only "half" of the anhydride molecule is used, while the other half acts as the leaving group during the nucleophilic acyl substitution step and produces acetate ion as a by-product. Thus, anhydrides are inefficient, and acid chlorides are normally preferred for introducing acyl substituents other than acetyl groups.

PROBLEM Write the mechanism of the reaction between $p$-hydroxyaniline and acetic anhydride to prepare
21-14 acetaminophen.
PROBLEM What product would you expect from reaction of one equivalent of methanol with a cyclic
21-15 anhydride, such as phthalic anhydride (1,2-benzenedicarboxylic anhydride)? What is the fate of the second "half" of the anhydride?


Phthalic anhydride - 21.6 Chemistry of Esters
Esters are among the most widespread of all naturally occurring compounds. Many simple esters are pleasantsmelling liquids that are responsible for the fragrant odors of fruits and flowers. For example, methyl butanoate is found in pineapple oil, and isopentyl acetate is a constituent of banana oil. The ester linkage is also present in animal fats and in many biologically important molecules.

$A$ fat
$\left(R=C_{11-17}\right.$ chains $)$

The chemical industry uses esters for a variety of purposes. Ethyl acetate, for instance, is a commonly used solvent, and dialkyl phthalates are used as plasticizers to keep polymers from becoming brittle. You may be aware that there is current concern about the possible toxicity of phthalates at high concentrations, although a recent assessment by the U.S. Food and Drug Administration found the risk to be minimal for most people, with the possible exception of male infants.

Dibutyl phthalate (a plasticizer)


Preparation of Esters -
Esters are usually prepared from carboxylic acids by the methods already discussed. Thus, carboxylic acids are converted directly into esters by $S_{N} 2$ reaction of a carboxylate ion with a primary alkyl halide or by Fischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters by treatment with an alcohol in the presence of base (Section 21.4).


Reactions of Esters -
Esters undergo the same kinds of reactions that we've seen for other carboxylic acid derivatives, but they are less reactive toward nucleophiles than either acid chlorides or anhydrides. All their reactions are applicable to both acyclic and cyclic esters, called lactones.


A lactone (cyclic ester) -
Conversion of Esters into Carboxylic Acids: Hydrolysis
An ester is hydrolyzed, either by aqueous base or aqueous acid, to yield a carboxylic acid plus an alcohol.

Ester hydrolysis in basic solution is called saponification, after the Latin word sapo, meaning "soap." We'll see in Section 27.2 that soap is in fact made by boiling animal fat with aqueous base to hydrolyze the ester linkages.

As shown in FIGURE 21.8, ester hydrolysis occurs through a typical nucleophilic acyl substitution pathway in which hydroxide ion is the nucleophile that adds to the ester carbonyl group to give a tetrahedral intermediate. Loss of alkoxide ion then gives a carboxylic acid, which is deprotonated to give the carboxylate ion. Addition of aqueous HCl , in a separate step after the saponification is complete, protonates the carboxylate ion and gives the carboxylic acid.


FIGURE 21.8 MECHANISM -
Mechanism of base-induced ester hydrolysis (saponification).
Nucleophilic addition of hydroxide ion
to the ester carbonyl group gives the
usual tetrahedral alkoxide
intermediate.
2 Elimination of alkoxide ion then
generates the carboxylic acid.
3 Alkoxide ion abstracts the acidic
proton from the carboxylic acid and
yields a carboxylate ion.
4 Protonation of the carboxylate ion
by addition of aqueous mineral acid
in a separate step then gives the
free carboxylic acid.

The mechanism shown in FIGURE 21.8 is supported by isotope-labeling studies. When ethyl propanoate labeled with ${ }^{18} \mathrm{O}$ in the ether-like oxygen is hydrolyzed in aqueous NaOH , the ${ }^{18} \mathrm{O}$ label shows up exclusively in the ethanol product. None of the label remains with the propanoic acid, indicating that saponification occurs by cleavage of the $\mathrm{C}-\mathrm{OR}^{\prime}$ bond rather than the $\mathrm{CO}-\mathrm{R}^{\prime}$ bond.

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). As shown in FIGURE 21.9, the ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid. Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, FIGURE 21.9 is the reverse of FIGURE 21.5.


FIGURE 21.9 MECHANISM -
Mechanism of acid-catalyzed ester hydrolysis. The forward reaction is a hydrolysis; the back-reaction is a Fischer esterification and is thus the reverse of FIGURE 21.5.

Ester hydrolysis is common in biological chemistry, particularly in the digestion of dietary fats and oils. We'll save a complete discussion of the mechanistic details of fat hydrolysis until Section 29.2 but will note for now that the reaction is catalyzed by various lipase enzymes and involves two sequential nucleophilic acyl substitution reactions. The first is a transesterification reaction in which an alcohol group on the lipase adds to an ester linkage in the fat molecule to give a tetrahedral intermediate that expels alcohol and forms an acyl enzyme intermediate. The second is an addition of water to the acyl enzyme, followed by expulsion of the enzyme to give a hydrolyzed acid and a regenerated enzyme.

PROBLEM Why is the saponification of an ester irreversible? In other words, why doesn't treatment of a
21-16 carboxylic acid with an alkoxide ion yield an ester?


Conversion of Esters into Amides: Aminolysis -
Esters react with ammonia and amines to yield amides. The reaction is not often used, however, because it's usually easier to prepare an amide by starting with an acid chloride (Section 21.4).


Conversion of Esters into Alcohols: Reduction -
Esters are easily reduced by treatment with $\mathrm{LiAlH}_{4}$ to yield primary alcohols (Section 17.4).


A lactone -
The mechanism of ester reduction is similar to that of acid chloride reduction in that a hydride ion first adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde. Further reduction of the aldehyde gives the primary alcohol.

The aldehyde intermediate can be isolated if 1 equivalent of diisobutylaluminum hydride (DIBAH, or DIBALH ) is used as the reducing agent instead of $\mathrm{LiAlH}_{4}$. The reaction has to be carried out at $-78{ }^{\circ} \mathrm{C}$ to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur
in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester.

PROBLEM What product would you expect from the reaction of butyrolactone with $\mathrm{LiAlH}_{4}$ ? With DIBAH?
21-17

PROBLEM Show the products you would obtain by reduction of the following esters with $\mathrm{LiAlH}_{4}$ :

21-18 (a)

(b)

Conversion of Esters into Alcohols: Grignard Reaction
Esters react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol in which two of the substituents are identical (Section 17.5). The reaction occurs by the usual nucleophilic substitution mechanism to give an intermediate ketone, which reacts further with the Grignard reagent to yield a tertiary alcohol.

PROBLEM What ester and what Grignard reagent might you start with to prepare the following alcohols?

21-19 (a)

(b)

(c)


A lactone - 21.7 Chemistry of Amides
Amides, like esters, are abundant in all living organisms. Proteins, nucleic acids, and many pharmaceutical agents have amide functional groups. The reason for this abundance of amides is that they are stable in the aqueous conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions.

A protein segment

Benzylpenicillin (penicillin G)

Uridine 5 '-phosphate (a ribonucleotide)


Preparation of Amides -
Amides are usually prepared by reaction of an amine with an acid chloride (Section 21.4). Ammonia, monosubstituted amines, and disubstituted amines all undergo the reaction.


Conversion of Amides into Carboxylic Acids: Hydrolysis -
Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine upon heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more extreme than those required for the hydrolysis of acid chlorides or esters, but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group, and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of $\mathrm{NH}_{3}$ in the final step.

Basic hydrolysis occurs by nucleophilic addition of $\mathrm{OH}^{-}$to the amide carbonyl group, followed by elimination of amide ion $\left({ }^{-} \mathrm{NH}_{2}\right)$ and subsequent deprotonation of the initially formed carboxylic acid by ammonia. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult.

Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to what we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate, which then undergoes hydrolysis.


Conversion of Amides into Carboxylic Acids: Hydrolysis -
Conversion of Amides into Amines: Reduction
Like other carboxylic acid derivatives, amides can be reduced by $\mathrm{LiAlH}_{4}$. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction is thus the conversion of the amide carbonyl group into a methylene group $\left(\mathrm{C}=\mathrm{O} \longrightarrow \mathrm{CH}_{2}\right)$. This kind of reaction is specific to amides and does not occur with other carboxylic acid derivatives.

$\boldsymbol{N}$-Methyldodecanamide
Dodecylmethylamine (95\%)
Amide reduction occurs by nucleophilic addition of hydride ion to the amide carbonyl group, followed by expulsion of the oxygen atom as an aluminate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is further reduced by $\mathrm{LiAlH}_{4}$ to yield the amine.

The reaction is effective with both acyclic and cyclic amides, or lactams, and is a good method for preparing cyclic amines.


Synthesizing an Amine from an Amide -
How could you prepare $N$-ethylaniline by reduction of an amide with $\mathrm{LiAlH}_{4}$ ?

$N$-Ethylaniline


Strategy -
Reduction of an amide with $\mathrm{LiAlH}_{4}$ yields an amine. To find the starting material for synthesis of N -ethylaniline, look for a $\mathrm{CH}_{2}$ position next to the nitrogen atom and replace that $\mathrm{CH}_{2}$ by $\mathrm{C}=\mathrm{O}$. In this case, the amide is $N$-phenylacetamide.

Solution

PROBLEM How would you convert $N$-ethylbenzamide to each of the following products?
21-20 (a) Benzoic acid
(b) Benzyl alcohol
(c) $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{NHCH}_{2} \mathrm{CH}_{3}$

PROBLEM How would you use the reaction of an amide with $\mathrm{LiAlH}_{4}$ as the key step in going from
21-21 bromocyclohexane to ( $N, N$-dimethylaminomethyl)cyclohexane? Write all the steps in the reaction sequence.

(N,N-Dimethylaminomethyl)cyclohexane


Strategy - 21.8 Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives
As mentioned in the chapter introduction, the substrate for a nucleophilic acyl substitution reaction in living organisms is generally either a thioester ( $\mathrm{RCOSR}{ }^{\prime}$ ) or an acyl phosphate ( $\mathrm{RCO}_{2} \mathrm{PO}_{3}{ }^{2-}$ or $\mathrm{RCO}_{2} \mathrm{PO}_{3} \mathrm{R}^{\prime-}$ ). Neither is as reactive as an acid chloride or acid anhydride, yet both are stable enough to exist in living organisms while still reactive enough to undergo acyl substitution.

Acyl CoA's, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage ( $\mathrm{O}=\mathrm{P}-\mathrm{O}-\mathrm{P}=\mathrm{O}$ ) between phosphopantetheine and adenosine $3^{\prime}, 5^{\prime}$-bisphosphate. (The prefix bis- means "two" and indicates that adenosine $3^{\prime}, 5^{\prime}$-bisphosphate has two phosphate groups, one on C3' and one on $\mathrm{C}^{\prime}$.) Reaction of coenzyme A with an acyl phosphate or acyl adenylate gives acyl CoA (FIGURE 21.10). As we saw in Section 21.3 (FIGURE 21.7), formation of the acyl adenylate occurs by reaction of a carboxylic acid with ATP and is itself a nucleophilic acyl substitution reaction that takes place on phosphorus.

Adenosine $\mathbf{3}^{\prime}$, $\mathbf{5}^{\prime}$-bisphosphate


Coenzyme A (CoA) -
Acetyl adenylate


Acetyl CoA -
FIGURE 21.10 Formation of the thioester acetyl CoA by nucleophilic acyl substitution reaction of coenzyme $A$ (CoA) with acetyl adenylate.

Once formed, an acyl CoA is a substrate for further nucleophilic acyl substitution reactions. For example, N -acetylglucosamine, a component of cartilage and other connective tissues, is synthesized by an aminolysis reaction between glucosamine and acetyl CoA.

Another example of a nucleophilic acyl substitution reaction on a thioester-this one a substitution by hydride ion to effect the partial reduction of a thioester to an aldehyde-occurs in the biosynthesis of mevaldehyde, an intermediate in terpenoid synthesis, which we'll discuss in some detail in Section 27.5. In this reaction, (3S)-3-hydroxy-3-methylglutaryl CoA is reduced by hydride donation from NADPH.

PROBLEM Write the mechanism of the reaction shown in Figure 21.10 between coenzyme A and acetyl
21-22 adenylate to give acetyl CoA.


Acetyl CoA - 21.9 Polyamides and Polyesters: Step-Growth Polymers
When an amine reacts with an acid chloride, an amide is formed. What would happen, though, if a diamine and a diacid chloride were allowed to react? Each partner would form two amide bonds, linking more and more molecules together until a giant polyamide resulted. In the same way, reaction of a diol with a diacid would lead to a polyester.

A diamine A diacid chloride

A polyamide (nylon)

A diacid
A polyester
There are two main classes of synthetic polymers: chain-growth polymers and step-growth polymers. The polyethylene and other alkene and diene polymers that we saw in Section 8.10 and Section 14.6 are called chain-growth polymers because they are produced in chain-reaction processes. An initiator adds to a $\mathrm{C}=\mathrm{C}$ bond to give a reactive intermediate, which adds to a second alkene molecule to produce a new intermediate, which adds to a third molecule, and so on. By contrast, polyamides and polyesters are step-growth polymers because each bond in the polymer is formed independently in a discrete step, often the nucleophilic acyl substitution reaction of a carboxylic acid derivative. Some commercially important step-growth polymers are shown in TABLE 21.2.

TABLE 21.2 Some Common Step-Growth Polymers and Their Uses


Acetyl CoA - 21.9 Polyamides and Polyesters: Step-Growth Polymers
TABLE 21.2 Some Common Step-Growth Polymers and Their Uses

| Monomers | Structure | Polymer | Uses |
| :---: | :---: | :---: | :---: |
| Adipic acid <br> Hexamethylenediamine | <smiles>O=CCCCCC[Ca]=O</smiles> $\mathrm{H}_{2} \mathrm{NCH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{NH}_{2}$ | Nylon 66 | Fibers, clothing, tire cord |
| Dimethyl terephthalate | <smiles>COC(=O)c1ccc(C(=O)OC)cc1</smiles> | Dacron, Mylar, Terylene | Fibers, clothing, films, tire cord |
| Ethylene glycol | $\mathrm{HOCH}_{2} \mathrm{CH}_{2} \mathrm{OH}$ |  |  |

TABLE 21.2 Some Common Step-Growth Polymers and Their Uses
Monomers


Polyamides (Nylons) -
The best known step-growth polymers are the polyamides, or nylons, first prepared in 1930 by Wallace Carothers at the DuPont Company by heating a diamine with a diacid. For instance, nylon 66 is prepared by reaction of adipic acid (hexanedioic acid) with hexamethylenediamine (1,6-hexanediamine) at $280{ }^{\circ} \mathrm{C}$. The designation " 66 " indicates the number of carbon atoms in the diamine (the first 6 ) and the diacid (the second 6).

Nylons are used both in engineering applications and in making fibers. A combination of high impact strength and abrasion resistance makes nylon an excellent metal substitute for bearings and gears. As fiber, nylon is used in a variety of applications, from clothing to tire cord to ropes.


Polyesters -
The most generally useful polyester is made by reaction between dimethyl terephthalate (dimethyl 1,4-benzenedicarboxylate) and ethylene glycol (1,2-ethanediol). The product is used under the trade name Dacron to make clothing fiber or tire cord and under the name Mylar to make recording tape. The tensile strength of poly(ethylene terephthalate) film is nearly equal to that of steel.

Lexan, a polycarbonate prepared from diphenyl carbonate and bisphenol A, is another commercially valuable polyester. Lexan has an unusually high impact strength, making it valuable for use in bicycle helmets and laptop cases.


Sutures and Biodegradable Polymers -
Because plastics are too often thrown away rather than recycled, much work has been carried out on developing biodegradable polymers, which can be broken down rapidly in landfills by soil microorganisms. Among the most common biodegradable polymers are poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(hydroxybutyrate) (PHB). All are polyesters and are therefore susceptible to hydrolysis of their ester links. Copolymers of PGA with PLA have found a particularly wide range of uses. A 90/10 copolymer of poly(glycolic acid) with poly(lactic acid) is used to make absorbable sutures, for instance. The sutures are entirely hydrolyzed and absorbed by the body within 90 days after surgery.

Glycolic acid

Poly(glycolic acid)

Lactic acid
$\downarrow$ Heat

Poly(lactic acid)

3-Hydroxybutyric acid
$\downarrow$ Heat

Poly(hydroxybutyrate)

In Europe, interest has centered particularly on poly(hydroxybutyrate), which can be made into films for packaging as well as into molded items. The polymer degrades within four weeks in landfills, both by ester hydrolysis and by an E1cB elimination reaction of the oxygen atom $\beta$ to the carbonyl group. The use of poly(hydroxybutyrate) is limited at present by its cost-about four times that of polypropylene.

PROBLEM Draw structures of the step-growth polymers you would expect to obtain from the following
21-23 reactions:
(a)

(b)

(c)

PROBLEM Kevlar, a nylon polymer prepared by reaction of 1,4-benzenedicarboxylic acid (terephthalic acid)
21-24 with 1,4 -benzenediamine ( $p$-phenylenediamine), is so strong that it's used to make bulletproof vests. Draw the structure of a segment of Kevlar.


Infrared Spectroscopy -
All carbonyl-containing compounds have intense IR absorptions in the range 1650 to $1850 \mathrm{~cm}^{-1}$. As shown in TABLE 21.3 the exact position of the absorption provides information about the specific kind of carbonyl group. For comparison, the IR absorptions of aldehydes, ketones, and carboxylic acids are included in the table, along with values for carboxylic acid derivatives.

TABLE 21.3 Infrared Absorptions of Some Carbonyl Compounds

| Carbonyl type | Example | Absorption $\left(\mathrm{cm}^{\mathbf{- 1}}\right)$ |
| :--- | :--- | :--- |
| Saturated acid chloride | Acetyl chloride | 1810 |
| Aromatic acid chloride | Benzoyl chloride | 1770 |
| Saturated acid anhydride | Acetic anhydride | 1820,1760 |
| Saturated ester | Ethyl acetate | 1735 |
| Aromatic ester | Ethyl benzoate | 1720 |
| Saturated amide | Acetamide | 1690 |
| $N$-Substituted amide | Benzamide | 1675 |
| $N, N$-Disubstituted amide | $N, N$-Dimethylacetamide | 1650 |
| Saturated aldehyde | Acetaldehyde | 1730 |
| Saturated ketone | Acetone | 1715 |
| Saturated carboxylic acid | Acetic acid | 1710 |


Infrared Spectroscopy -
Acid chlorides are easily detected by their characteristic absorption near $1810 \mathrm{~cm}^{-1}$. Acid anhydrides can be identified by a pair of absorptions in the carbonyl region, one at $1820 \mathrm{~cm}^{-1}$ and another at $1760 \mathrm{~cm}^{-1}$. Note that each of these functional groups has a strong electron-withdrawing group attached to the carbonyl. The inductive withdrawal of electron density shortens the $\mathrm{C}=\mathrm{O}$ bond, thereby raising its stretching frequency. Esters are detected by their absorption at $1735 \mathrm{~cm}^{-1}$, a position somewhat higher than that for either aldehydes or ketones. Amides, by contrast, absorb near the low-wavenumber end of the carbonyl region, with the degree of substitution on nitrogen affecting the exact position of the IR band. That is, for amides, the delocalization of
electron density (resonance) from nitrogen into the carbonyl lengthens the $\mathrm{C}=\mathrm{O}$ bond and lowers its stretching frequency.

PROBLEM What kinds of functional groups might compounds have if they show the following IR absorptions?
21-25 (a) Absorption at $1735 \mathrm{~cm}^{-1}$ (b) Absorption at $1810 \mathrm{~cm}^{-1}$
(c) Absorptions at 2500 to $3300 \mathrm{~cm}^{-1}$ and $1710 \mathrm{~cm}^{-1}$
(d) Absorption at $1715 \mathrm{~cm}^{-1}$

PROBLEM Propose structures for compounds that have the following formulas and IR absorptions:
21-26 (a) $\mathrm{C}_{6} \mathrm{H}_{12} \mathrm{O}_{2}, 1735 \mathrm{~cm}^{-1}$
(b) $\mathrm{C}_{4} \mathrm{H}_{9} \mathrm{NO}, 1650 \mathrm{~cm}^{-1}$
(c) $\mathrm{C}_{4} \mathrm{H}_{5} \mathrm{ClO}, 1780 \mathrm{~cm}^{-1}$


Nuclear Magnetic Resonance Spectroscopy -
Hydrogens on the carbon next to a carbonyl group are slightly deshielded and absorb near $2 \delta$ in the ${ }^{1} \mathrm{H}$ NMR spectrum, although the exact identity of the carbonyl group can't be determined. FIGURE 21.11 shows the ${ }^{1} \mathrm{H}$ NMR spectrum of ethyl acetate.

FIGURE 21.11 ${ }^{\mathbf{1}} \mathbf{H}$ NMR spectrum of ethyl acetate.
Although ${ }^{13} \mathrm{C}$ NMR is useful for determining the presence or absence of a carbonyl group in a molecule, the identity of the carbonyl group is difficult to determine. Aldehydes and ketones absorb near $200 \delta$, while the carbonyl carbon atoms of various acid derivatives absorb in the range 160 to $180 \delta$ (TABLE 21.4).

TABLE $21.4^{13} \mathrm{C}$ NMR Absorptions of Some Carbonyl Compounds

| Compound | Absorption (ס) |
| :--- | :--- |
| Acetic acid | 177.3 |
| Ethyl acetate | 170.7 |
| Acetyl chloride | 170.3 |
| Acetamide | 172.6 |
| Acetic anhydride | 166.9 |
| Acetone | 205.6 |
| Acetaldehyde | 201.0 |


$\boldsymbol{\beta}$-Lactam Antibiotics -
You should never underestimate the value of hard work and logical thinking, but it's also true that blind luck often plays a role in most real scientific breakthroughs. What has been called "the supreme example of luck in all scientific history" occurred in the late summer of 1928, when the Scottish bacteriologist Alexander Fleming went on vacation, leaving in his lab a culture plate recently inoculated with the bacterium Staphylococcus aureus.

While Fleming was away, an extraordinary chain of events occurred. First, a nine-day cold spell lowered the laboratory temperature to a point where the Staphylococcus in the culture plate could not grow. During this time, spores from a colony of the mold Penicillium notatum, being grown in a lab on the floor below, wafted up into Fleming's lab and landed in the culture plate. The temperature then rose, and both Staphylococcus and Penicillium began to grow. On returning from vacation, Fleming discarded the plate into a tray of antiseptic, intending to sterilize it. Evidently, though, the plate did not sink deeply enough into the antiseptic, because when Fleming happened to glance at it a few days later, what he saw changed the course of history. He noticed that the growing Penicillium mold appeared to dissolve the colonies of staphylococci.

Fleming realized that the Penicillium mold must be producing a chemical that killed the Staphylococcus bacteria, and he spent several years trying to isolate the substance. Finally, in 1939, the Australian pathologist Howard Florey and the German refugee Ernst Chain managed to isolate the active substance, called penicillin. The dramatic ability of penicillin to cure infections in mice was soon demonstrated, and successful tests in humans followed shortly thereafter. By 1943, penicillin was being produced on a large scale for military use in World War II, and by 1944 it was being used on civilians. Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine.


$\boldsymbol{\beta}$-Lactam Antibiotics -
Now called benzylpenicillin, or penicillin G, the substance first discovered by Fleming is but one member of a large class of so-called $\boldsymbol{\beta}$-lactam antibiotics, compounds with a four-membered lactam (cyclic amide) ring. The four-membered lactam ring is fused to a five-membered, sulfur-containing ring, and the carbon atom next to the lactam carbonyl group is bonded to an acylamino substituent, RCONH-. This acylamino side chain can be varied in the laboratory to provide many hundreds of penicillin analogs with different biological activity profiles. Ampicillin, for instance, has an $\alpha$-aminophenylacetamido substituent [ $\left.\mathrm{PhCH}\left(\mathrm{NH}_{2}\right) \mathrm{CONH}-\right]$.

Closely related to the penicillins are the cephalosporins, a group of $\beta$-lactam antibiotics that contain an unsaturated, six-membered, sulfur-containing ring. Cephalexin, marketed under the trade name Keflex, is an example. Cephalosporins generally have much greater antibacterial activity than penicillins, particularly against resistant strains of bacteria.

Cephalexin (a cephalosporin)

The biological activity of penicillins and cephalosporins is due to the presence of the strained $\beta$-lactam ring, which reacts with and deactivates the transpeptidase enzyme needed to synthesize and repair bacterial cell walls. With the wall either incomplete or weakened, the bacterial cell ruptures and dies.

(inactive enzyme)


Key Terms -
- acid anhydride
- acid halide
- acyl phosphate
- amide
- carboxylic acid derivative
- chain-growth polymer
- ester
- Fischer esterification reaction
- lactam
- lactone
- nucleophilic acyl substitution reaction
- saponification
- step-growth polymer
- thioester


Summary -
Carboxylic acid derivatives-compounds in which the -OH group of a carboxylic acid has been replaced by another substituent-are among the most widely occurring of all molecules and are involved in almost all biological pathways. In this chapter, we covered the chemistry necessary for understanding them and thus also necessary for understanding living organisms. Acid halides, acid anhydrides, esters, and amides are the most common such derivatives in the laboratory; thioesters and acyl phosphates are common in biological molecules.

The chemistry of carboxylic acid derivatives is dominated by the nucleophilic acyl substitution reaction. Mechanistically, these substitutions take place by addition of a nucleophile to the polar carbonyl group of the acid derivative to give a tetrahedral intermediate, followed by expulsion of a leaving group.

The reactivity of an acid derivative toward substitution depends both on the steric environment near the carbonyl group and on the electronic nature of the substituent, Y. The reactivity order is acid halide >acid anhydride $>$ thioester $>$ ester $>$ amide.

The most common reactions of carboxylic acid derivatives are substitution by water to yield an acid (hydrolysis), by an alcohol to yield an ester (alcoholysis), by an amine to yield an amide (aminolysis), by hydride ion to yield
an alcohol (reduction), and by an organomagnesium halide to yield an alcohol (Grignard reaction).
Step-growth polymers, such as polyamides and polyesters, are prepared by reactions between difunctional molecules. Polyamides (nylons) are formed by reaction between a diacid and a diamine; polyesters are formed from a diacid and a diol.

IR spectroscopy is a valuable tool for the structural analysis of acid derivatives. Acid chlorides, anhydrides, esters, and amides all show characteristic IR absorptions that can be used to identify these functional groups.


Summary of Reactions -
1. Reactions of carboxylic acids (Section 21.3)
a. Conversion into acid chlorides

b. Conversion into esters

c. Conversion into amides

d. Reduction to yield primary alcohols

2. Reactions of acid chlorides (Section 21.4)
a. Hydrolysis to yield acids

b. Reaction with carboxylates to yield anhydrides

c. Alcoholysis to yield esters

d. Aminolysis to yield amides

e. Reduction to yield primary alcohols

f. Grignard reaction to yield tertiary alcohols

g. Diorganocopper reaction to yield ketones

3. Reactions of acid anhydrides (Section 21.5)
a. Hydrolysis to yield acids

b. Alcoholysis to yield esters

c. Aminolysis to yield amides

4. Reactions of esters (Section 21.6)
a. Hydrolysis to yield acids

b. Reduction to yield primary alcohols

c. Partial reduction to yield aldehydes

d. Grignard reaction to yield tertiary alcohols

5. Reactions of amides (Section 21.7)
a. Hydrolysis to yield acids

b. Reduction to yield amines


Visualizing Chemistry -
PROBLEM Name the following compounds:
21-27
(a)

(b)

PROBLEM How would you prepare the following compounds starting with an appropriate carboxylic acid and
21-28 any other reagents needed? (reddish brown $=\mathrm{Br}$.)
(a)

(b)

PROBLEM The following structure represents a tetrahedral alkoxide-ion intermediate formed by addition of a
21-29 nucleophile to a carboxylic acid derivative. Identify the nucleophile, the leaving group, the starting acid derivative, and the ultimate product (green $=\mathrm{Cl}$ ).

PROBLEM Electrostatic potential maps of a typical amide (acetamide) and an acyl azide (acetyl azide) are
21-30 shown. Which of the two do you think is more reactive in nucleophilic acyl substitution reactions? Explain.

Acetamide


Mechanism Problems -
PROBLEM Predict the product(s) and write the mechanism for the following reactions:
21-31 (a)

(b)

PROBLEM Predict the product(s) and write the mechanism for the following reactions:


21-32 (a) -
(b)

PROBLEM Predict the product(s) and write the mechanism for each of the following reactions:
21-33 (a)

PROBLEM Predict the product(s) and write the mechanism for the following reactions:
21-34 (a)

(b)

PROBLEM Pivalic mixed anhydrides are often used to form amide bonds between amino acids. Unlike with a
21-35 symmetrical anhydride, this reaction is highly regioselective, with the nucleophile adding only to the amino-acid carbonyl. Provide the complete mechanism for the following reaction and explain the regioselectivity.

PROBLEM When 4-dimethylaminopyridine (DMAP) is added in catalytic amounts to acetic anhydride and an
21-36 alcohol, it significantly increases the rate of ester formation. The process begins with a reaction between acetic anhydride and DMAP to form a highly reactive acetylpyridinium intermediate that is more reactive than acetic anhydride itself. Propose a mechanism for this process that includes the formation and reaction of the acetylpyridinium intermediate.

PROBLEM Fats are biosynthesized from glycerol 3-phosphate and fatty-acyl CoA's by a reaction sequence that
21-37 begins with the following step. Show the mechanism of the reaction.

PROBLEM Treatment of an $\alpha$-amino acid with DCC yields a 2,5-diketopiperazine. Propose a mechanism. 21-38

PROBLEM Succinic anhydride yields the cyclic imide succinimide when heated with ammonium chloride
21-39 at $200^{\circ} \mathrm{C}$. Propose a mechanism for this reaction. Why do you suppose such a high reaction temperature is required?


21-32 (a) -
PROBLEM The hydrolysis of a biological thioester to the corresponding carboxylate is often more complex
21-40 than the overall result might suggest. The conversion of succinyl CoA to succinate in the citric acid cycle, for instance, occurs by initial formation of an acyl phosphate, followed by reaction with guanosine diphosphate (GDP, a relative of adenosine diphosphate [ADP]) to give succinate and guanosine triphosphate (GTP, a relative of ATP). Suggest mechanisms for both steps.

Succinyl CoA

Acyl phosphate

GTP

PROBLEM One step in the gluconeogenesis pathway for the biosynthesis of glucose is the partial reduction
21-41 of 3-phosphoglycerate to give glyceraldehyde 3-phosphate. The process occurs by phosphorylation with ATP to give 1,3-bisphosphoglycerate, reaction with a thiol group on the enzyme to give an enzyme-bound thioester, and reduction with NADH. Suggest mechanisms for all three reactions.

3-Phosphoglycerate

1,3-Bisphosphoglycerate

(Enzyme-bound thioester)

Glyceraldehyde 3-phosphate

PROBLEM Bacteria typically develop a resistance to penicillins and other $\beta$-lactam antibiotics (see Chemistry
21-42 Matters at the end of this chapter) due to bacterial synthesis of $\beta$-lactamase enzymes. Tazobactam, however, is able to inhibit the activity of the $\beta$-lactamase by trapping it, thereby preventing a resistance from developing.

(a) The first step in trapping is reaction of a hydroxyl group on the $\beta$-lactamase to open the $\beta$-lactam ring of tazobactam. Show the mechanism.
(b) The second step is opening the sulfur-containing ring in tazobactam to give an acyclic imine intermediate. Show the mechanism.
(c) Cyclization of the imine intermediate gives the trapped $\beta$-lactamase product. Show the mechanism.


21-32 (a) -
PROBLEM The following reaction, called the benzilic acid rearrangement, takes place by typical carbonyl-
21-43 group reactions. Propose a mechanism ( $\mathrm{Ph}=$ phenyl).

PROBLEM In the iodoform reaction, a triiodomethyl ketone reacts with aqueous NaOH to yield a carboxylate
21-44 ion and iodoform (triiodomethane). Propose a mechanism for this reaction.


Naming Carboxylic Acid Derivatives -
PROBLEM Give IUPAC names for the following compounds:
21-45
(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

PROBLEM Draw structures corresponding to the following names:
21-46 (a) $p$-Bromophenylacetamide (b) $m$-Benzoylbenzamide (c) 2,2-Dimethylhexanamide
(d) Cyclohexyl cyclohexanecarboxylate (e) Ethyl 2-cyclobutenecarboxylate
(f) Succinic anhydride

PROBLEM Draw and name compounds that meet the following descriptions:
21-47 (a) Three acid chlorides having the formula $\mathrm{C}_{6} \mathrm{H}_{9} \mathrm{ClO}$
(b) Three amides having the formula $\mathrm{C}_{7} \mathrm{H}_{11} \mathrm{NO}$

Nucleophilic Acyl Substitution Reactions
PROBLEM Predict the product, if any, of reaction between propanoyl chloride and the following reagents:
21-48
(a) $\mathrm{Li}(\mathrm{Ph})_{2} \mathrm{Cu}$ in ether
(b) $\mathrm{LiAlH}_{4}$, then $\mathrm{H}_{3} \mathrm{O}^{+}$
(c) $\mathrm{CH}_{3} \mathrm{MgBr}$, then $\mathrm{H}_{3} \mathrm{O}^{+}$
(d) $\mathrm{H}_{3} \mathrm{O}^{+}$
(e) Cyclohexanol (f) Aniline (g) $\mathrm{CH}_{3} \mathrm{CO}_{2}^{-} \mathrm{Na}^{+}$


Naming Carboxylic Acid Derivatives -
PROBLEM Answer Problem 21-48 for reaction of the listed reagents with methyl propanoate.
21-49
PROBLEM Answer Problem 21-48 for reaction of the listed reagents with propanamide.
21-50
PROBLEM What product would you expect to obtain from Grignard reaction of an excess of phenylmagnesium
21-51 bromide with dimethyl carbonate, $\mathrm{CH}_{3} \mathrm{OCO}_{2} \mathrm{CH}_{3}$ ?
PROBLEM How might you prepare the following compounds from butanoic acid?
21-52 (a) 1-Butanol (b) Butanal (c) 1-Bromobutane (d) Pentanenitrile (e) 1-Butene
(f) $N$-Methylpentanamide (g) 2-Hexanone (h) Butylbenzene (i) Butanenitrile

PROBLEM Predict the product(s) of the following reactions:

21-53 (a)

(b)
$\xrightarrow[\text { 2. } \mathrm{H}_{3} \mathrm{O}^{+}]{\text {1. } \mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{MgBr}}$ ?

(d)

(e)

(h)

PROBLEM The following reactivity order has been found for the saponification of alkyl acetates by aqueous
21-54 NaOH. Explain.
$\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{CH}_{3}>\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{CH}_{2} \mathrm{CH}_{3}>\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{CH}\left(\mathrm{CH}_{3}\right)_{2}>\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{C}\left(\mathrm{CH}_{3}\right)_{3}$

PROBLEM Explain the observation that attempted Fischer esterification of 2,4,6-trimethylbenzoic acid with
21-55 methanol and HCl is unsuccessful. No ester is obtained, and the acid is recovered unchanged. What alternative method of esterification might be successful?


Naming Carboxylic Acid Derivatives -
PROBLEM Outline methods for the preparation of acetophenone (phenyl methyl ketone) starting from the 21-56 following:
(a) Benzene
(b) Bromobenzene
(c) Methyl benzoate
(d) Benzonitrile
(e) Styrene

PROBLEM Treatment of 5 -aminopentanoic acid with DCC (dicyclohexylcarbodiimide) yields a lactam. Show 21-57 the structure of the product and the mechanism of the reaction.

PROBLEM When ethyl benzoate is heated in methanol containing a small amount of HCl , methyl benzoate is 21-58 formed. Propose a mechanism for the reaction.

PROBLEM tert-Butoxycarbonyl azide, a reagent used in protein synthesis, is prepared by treating 21-59 tert-butoxycarbonyl chloride with sodium azide. Propose a mechanism for this reaction.


Step-Growth Polymers -
PROBLEM The step-growth polymer nylon 6 is prepared from caprolactam. The reaction involves initial
21-60 reaction of caprolactam with water to give an intermediate open-chain amino acid, followed by heating to form the polymer. Propose mechanisms for both steps, and show the structure of nylon 6.

Caprolactam

PROBLEM Qiana, a polyamide fiber with a silky texture, has the following structure. What are the monomer
21-61 units used in the synthesis of Qiana?

Qiana

PROBLEM What is the structure of the polymer produced by treatment of $\beta$-propiolactone with a small amount
21-62 of hydroxide ion?

$\beta$-Propiolactone

PROBLEM Polyimides with the structure shown are used as coatings on glass and plastics to improve scratch 21-63 resistance. How would you synthesize a polyimide? (See Problem 21-39.)


A polyimide -
Spectroscopy
PROBLEM How would you distinguish spectroscopically between the following isomer pairs? Tell what 21-64 differences you would expect to see.
(a) N -Methylpropanamide and $\mathrm{N}, \mathrm{N}$-dimethylacetamide
(b) 5-Hydroxypentanenitrile and cyclobutanecarboxamide
(c) 4-Chlorobutanoic acid and 3-methoxypropanoyl chloride
(d) Ethyl propanoate and propyl acetate

PROBLEM Propose a structure for a compound, $\mathrm{C}_{4} \mathrm{H}_{7} \mathrm{ClO}_{2}$, that has the following IR and ${ }^{1} \mathrm{H}$ NMR spectra:
21-65

PROBLEM Assign structures to compounds with the following ${ }^{1} \mathrm{H}$ NMR spectra:
21-66
(a) $\mathrm{C}_{4} \mathrm{H}_{7} \mathrm{ClO}$

IR: $1810 \mathrm{~cm}^{-1}$

(b) $\mathrm{C}_{5} \mathrm{H}_{7} \mathrm{NO}_{2}$

IR: 2250, $1735 \mathrm{~cm}^{-1}$


General Problems -
PROBLEM The following reactivity order has been found for the basic hydrolysis of $p$-substituted methyl
21-67 benzoates:
$\mathrm{Y}=\mathrm{NO}_{2}>\mathrm{Br}>\mathrm{H}>\mathrm{CH}_{3}>\mathrm{OCH}_{3}$
How can you explain this reactivity order? Where would you expect $\mathrm{Y}=\mathrm{C} \equiv \mathrm{N}, \mathrm{Y}=\mathrm{CHO}$, and $\mathrm{Y}=\mathrm{NH}_{2}$ to be in the reactivity list?

PROBLEM When a carboxylic acid is dissolved in isotopically labeled water, the label rapidly becomes
21-68 incorporated into both oxygen atoms of the carboxylic acid. Explain.

PROBLEM We said in Section 21.6 that mechanistic studies on ester hydrolysis have been carried out using
21-69 ethyl propanoate labeled with ${ }^{18} \mathrm{O}$ in the ether-like oxygen. Assume that ${ }^{18} \mathrm{O}$-labeled acetic acid is your only source of isotopic oxygen, and then propose a synthesis of the labeled ethyl propanoate.

PROBLEM Treatment of a carboxylic acid with trifluoroacetic anhydride leads to an unsymmetrical anhydride
21-70 that rapidly reacts with alcohol to give an ester.

(a) Propose a mechanism for formation of the unsymmetrical anhydride.
(b) Why is the unsymmetrical anhydride unusually reactive?
(c) Why does the unsymmetrical anhydride react as indicated rather than giving a trifluoroacetate ester plus carboxylic acid?

PROBLEM Butacetin is an analgesic (pain-killing) agent that is synthesized commercially from 21-71 p-fluoronitrobenzene. Propose a synthesis.

Butacetin

PROBLEM Phenyl 4-aminosalicylate is a drug used in the treatment of tuberculosis. Propose a synthesis of this
21-72 compound starting from 4-nitrosalicylic acid.


General Problems -
Butacetin

PROBLEM Phenyl 4-aminosalicylate is a drug used in the treatment of tuberculosis. Propose a synthesis of this
21-72 compound starting from 4-nitrosalicylic acid.

PROBLEM $N, N$-Diethyl- $m$-toluamide (DEET) is the active ingredient in many insect-repellent preparations.
21-73 How might you synthesize this substance from $m$-bromotoluene?

$N, N$-Diethyl-m-toluamide

PROBLEM Tranexamic acid, a drug useful against blood clotting, is prepared commercially from
21-74 p-methylbenzonitrile. Formulate the steps likely to be used in the synthesis. (Don't worry about cis-trans isomers; heating to $300^{\circ} \mathrm{C}$ interconverts the isomers.)

PROBLEM One frequently used method for preparing methyl esters is by reaction of carboxylic acids with
21-75 diazomethane, $\mathrm{CH}_{2} \mathrm{~N}_{2}$.

The reaction occurs in two steps: (1) protonation of diazomethane by the carboxylic acid to yield methyldiazonium ion, $\mathrm{CH}_{3} \mathrm{~N}_{2}{ }^{+}$, plus a carboxylate ion; and (2) reaction of the carboxylate ion with $\mathrm{CH}_{3} \mathrm{~N}_{2}{ }^{+}$.
(a) Draw two resonance structures of diazomethane, and account for step 1.
(b) What kind of reaction occurs in step 2?

PROBLEM Draw the structure of the polymer you would expect to obtain from reaction of dimethyl 21-76 terephthalate with a triol such as glycerol. What structural feature would this new polymer have that was not present in Dacron (Table 21.2)? How do you think this new feature might affect the properties of the polymer?


General Problems -
PROBLEM Assign structures to compounds with the following ${ }^{1} \mathrm{H}$ NMR spectra:
21-77 (a) $\mathrm{C}_{5} \mathrm{H}_{10} \mathrm{O}_{2}$
IR: $1735 \mathrm{~cm}^{-1}$

(b) $\mathrm{C}_{11} \mathrm{H}_{12} \mathrm{O}_{2}$

IR: $1710 \mathrm{~cm}^{-1}$

PROBLEM Propose structures for compounds with the following ${ }^{1} \mathrm{H}$ NMR spectra:
21-78 (a) $\mathrm{C}_{5} \mathrm{H}_{9} \mathrm{ClO}_{2}$
IR: $1735 \mathrm{~cm}^{-1}$

(b) $\mathrm{C}_{7} \mathrm{H}_{12} \mathrm{O}_{4}$

IR: $1735 \mathrm{~cm}^{-1}$

PROBLEM Propose a structure for the compound with the formula $\mathrm{C}_{19} \mathrm{H}_{9} \mathrm{NO}_{2}$ and the following IR and NMR 21-79 spectra

PROBLEM Draw the structure of the compound that produced the following spectra. The infrared spectrum has 21-80 strong bands at 1720 and $1738 \mathrm{~cm}^{-1}$.

PROBLEM When an amide is formed from an acid chloride or an anhydride, two equivalents of base are
21-81 required. However, when an ester is used as the starting material, only one equivalent of base is needed. Explain this reactivity in terms of basicity of the leaving groups.

PROBLEM Epoxy adhesives are prepared in two steps. $\mathrm{S}_{\mathrm{N}} 2$ reaction of the disodium salt of bisphenol A with
21-82 epichlorohydrin forms a "prepolymer," which is then "cured" by treatment with a triamine such as $\mathrm{H}_{2} \mathrm{NCH}_{2} \mathrm{CH}_{2} \mathrm{NHCH}_{2} \mathrm{CH}_{2} \mathrm{NH}_{2}$.


General Problems -
Draw structures to show how addition of the triamine results in a strengthening of the polymer.


CHAPTER 22 -
Carbonyl Alpha-Substitution Reactions

FIGURE 22.1 Tear gas is a controversial riot-control device used by some military and police forces. It is a simple chloroketone made by a carbonyl $\alpha$-substitution reaction. (credit: modification of work "Tear Gas in CWB Hennessy Road View" by The Stand News/Wikimedia Commons, Public Domain)


CHAPTER CONTENTS - 22.1 Keto-Enol Tautomerism
22.2 Reactivity of Enols: $\alpha$-Substitution Reactions
22.3 Alpha Halogenation of Aldehydes and Ketones
22.4 Alpha Bromination of Carboxylic Acids
22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
22.6 Reactivity of Enolate Ions
22.7 Alkylation of Enolate Ions

WHY THIS CHAPTER? As with nucleophilic additions and nucleophilic acyl substitutions, many laboratory schemes, pharmaceutical syntheses, and biochemical pathways make frequent use of carbonyl $\alpha$-substitution reactions. Their great value comes from the fact that they constitute one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller precursors. In this chapter, we'll see how and why these reactions occur.

We said in the Preview of Carbonyl Chemistry that much of the chemistry of carbonyl compounds can be explained by just four fundamental reaction types: nucleophilic additions, nucleophilic acyl substitutions, $\alpha$ substitutions, and carbonyl condensations. Having studied the first two of these reactions in the past three chapters, let's now look in more detail at the third major carbonyl-group process-the $\boldsymbol{a}$-substitution reaction.

Alpha-substitution reactions occur at the position next to the carbonyl group-the $\alpha$ position-and involve the substitution of an $\alpha$ hydrogen atom by an electrophile, E, through either an enol or enolate ion intermediate. Let's begin by learning more about these two species.


CHAPTER CONTENTS - 22.1 Keto-Enol Tautomerism
A carbonyl compound with a hydrogen atom on its $\alpha$ carbon is in equilibrium with its corresponding enol isomer (Section 9.4). This spontaneous interconversion between two isomers, usually with the change in position of a hydrogen, is called tautomerism, from the Greek tauto, meaning "the same," and meros, meaning "part." The individual keto and enol isomers are called tautomers.

Note the difference between tautomers and resonance forms. Tautomers are constitutional isomers-different compounds with different structures-while resonance forms are different representations of a single compound. Tautomers have their atoms arranged differently, while resonance forms differ only in the position of their $\pi$ and nonbonding electrons.

Most monocarbonyl compounds exist almost entirely in their keto form at equilibrium, and it's usually difficult to isolate the pure enol. Cyclohexanone, for example, contains only about $0.0001 \%$ of its enol tautomer at room temperature. The percentage of enol tautomer is even lower for carboxylic acids, esters, and amides. The enol can only predominate when stabilized by conjugation or intramolecular hydrogen bonding. Thus, 2,4-pentanedione is about $76 \%$ enol tautomer. Although enols are scarce at equilibrium, they are nevertheless responsible for much of the chemistry of carbonyl compounds because they are so reactive.

Cyclohexanone


Acetone -
Keto-enol tautomerism of carbonyl compounds is catalyzed by both acids and bases. Acid catalysis occurs by protonation of the carbonyl oxygen atom to give an intermediate cation that loses $\mathrm{H}^{+}$from its $\alpha$ carbon to yield a neutral enol (FIGURE 22.2a). This proton loss from the cation intermediate is similar to what occurs during an E1 reaction when a carbocation loses $\mathrm{H}^{+}$to form an alkene (Section 11.10).

Base-catalyzed enol formation occurs because the presence of a carbonyl group makes the hydrogens on the $\alpha$ carbon weakly acidic. Thus, a carbonyl compound can act as an acid and donate one of its $\alpha$ hydrogens
to a sufficiently strong base. The resultant resonance-stabilized anion, an enolate ion, is then protonated to yield a neutral compound. If protonation of the enolate ion takes place on the $\alpha$ carbon, the keto tautomer is regenerated and no net change occurs. If, however, protonation takes place on the oxygen atom, an enol tautomer is formed (FIGURE 22.2b).


FIGURE 22.2 MECHANISM -
Mechanism of enol formation under both acid-catalyzed and base-catalyzed conditions. (a) Acid catalysis involves (1) initial protonation of the carbonyl oxygen followed by (2) removal of $\mathrm{H}^{+}$from the $\alpha$ position. (b) Base catalysis involves (1) initial deprotonation of the $\alpha$ position to give an enolate ion, followed by (2) reprotonation on oxygen.

Note that only the hydrogens on the $\alpha$ position of carbonyl compounds are acidic. Hydrogens at $\beta, \gamma, \delta$, and so on, aren't acidic and can't be removed by base because the resulting anions can't be resonance-stabilized by the carbonyl group.

PROBLEM Draw structures for the enol tautomers of the following compounds:
22-1 (a) Cyclopentanone (b) Methyl thioacetate (c) Ethyl acetate (d) Propanal (e) Acetic acid (f) Phenylacetone

PROBLEM How many acidic hydrogens does each of the molecules listed in Problem 22-1 have? Identify them. 22-2

PROBLEM Draw structures for all monoenol forms of the following molecule. Which would you expect to be 22-3 most stable? Explain.


FIGURE 22.2 MECHANISM - 22.2 Reactivity of Enols: $\boldsymbol{\alpha}$-Substitution Reactions
What kind of chemistry do enols have? Because their double bonds are electron-rich, enols behave as nucleophiles and react with electrophiles in much the same way that alkenes do. But because of resonanceelectron donation of a lone pair of electrons on the neighboring oxygen, enols are more electron-rich and correspondingly more reactive than alkenes. Notice in the following electrostatic potential map of ethenol $\left(\mathrm{H}_{2} \mathrm{C}=\mathrm{CHOH}\right)$ how there is a substantial electron density (yellow-red) on the $\alpha$ carbon.

When an alkene reacts with an electrophile, $\mathrm{E}^{+}$, initial addition gives an intermediate cation and subsequent reaction with a nucleophile, such as a halide ion, yields an addition product (Section 7.7). When an enol reacts with an electrophile, however, only the initial addition step is the same (FIGURE 22.3). Instead of reacting with a nucleophile to give an addition product, the intermediate cation loses the -OH proton to give an $\alpha$-substituted carbonyl compound.


FIGURE 22.3 MECHANISM -
General mechanism of a carbonyl $\boldsymbol{\alpha}$-substitution reaction. In step 3, the initially formed cation loses $\mathrm{H}^{+}$to regenerate a carbonyl compound.

Acid-catalyzed enol formation occurs by the usual mechanism.

2 An electron pair from the enol oxygen attacks an electrophile ( $\mathrm{E}^{+}$), forming a new bond and leaving a cation intermediate that is stabilized by resonance between two forms.

Loss of a proton from oxygen yields the neutral alpha-substitution product as a new $\mathrm{C}=\mathrm{O}$ bond is formed.
(1) $\downarrow$ Acid catalyst

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FIGURE 22.3 MECHANISM - 22.3 Alpha Halogenation of Aldehydes and Ketones
A particularly common $\alpha$-substitution reaction in the laboratory is the halogenation of aldehydes and ketones at their $\alpha$ positions by reaction with $\mathrm{Cl}_{2}, \mathrm{Br}_{2}$, or $\mathrm{I}_{2}$ in acidic solution. Bromine in acetic acid solvent is often used.

Remarkably, ketone halogenation also occurs in biological systems, particularly in marine alga, where dibromoacetaldehyde, bromoacetone, 1,1,1-tribromoacetone, and other related compounds have been found.

From the Hawaiian alga Asparagopsis taxiformis
This form of halogenation is a typical $\alpha$-substitution reaction that proceeds by acid-catalyzed formation of an enol intermediate, as shown in FIGURE 22.4.

Evidence for the mechanism shown in FIGURE 22.4 includes the observation that acid-catalyzed halogenations show second-order kinetics and follow the rate law

$$
\text { Reaction rate }=k[\text { Ketone }]\left[\mathrm{H}^{+}\right]
$$

In other words, the rate of halogenation depends only on the concentrations of ketone and acid and is independent of halogen concentration. Since halogen is not involved in the rate-limiting step, chlorination, bromination, and iodination of a given substrate all occur at the same rate.

Furthermore, if an aldehyde or ketone is treated with $\mathrm{D}_{3} \mathrm{O}^{+}$, the acidic $\alpha$ hydrogens are replaced by deuterium. For a given ketone, the rate of deuterium exchange is identical to the rate of halogenation, implying that a common intermediate-presumably the enol-is involved in both processes.


FIGURE 22.3 MECHANISM - 22.3 Alpha Halogenation of Aldehydes and Ketones
$\alpha$-Bromo ketones are useful in the laboratory because they can be dehydrobrominated by base treatment to yield $\alpha, \beta$-unsaturated ketones. For example, 2-methylcyclohexanone gives 2-bromo-2-methylcyclohexanone on halogenation, and the $\alpha$-bromo ketone gives 2-methyl-2-cyclohexenone when heated in pyridine. The reaction takes place by an E2 elimination pathway (Section 11.8) and is a good method for introducing a $\mathrm{C}=\mathrm{C}$ bond into a molecule. Note that bromination of 2-methylcyclohexanone occurs primarily on the more highly substituted $\alpha$ position because the more highly substituted enol is favored over the less highly substituted one (Section 7.6).

PROBLEM Write the complete mechanism for the deuteration of acetone on treatment with $\mathrm{D}_{3} \mathrm{O}^{+}$.
22-4

PROBLEM Show how you might prepare 1-penten-3-one from 3-pentanone.
22-5


FIGURE 22.3 MECHANISM - 22.4 Alpha Bromination of Carboxylic Acids
The $\alpha$ bromination of carbonyl compounds by $\mathrm{Br}_{2}$ in acetic acid is limited to aldehydes and ketones because acids, esters, and amides don't enolize to a sufficient extent. Carboxylic acids, however, can be $\alpha$ brominated by a mixture of $\mathrm{Br}_{2}$ and $\mathrm{PBr}_{3}$ in the Hell-Volhard-Zelinskii (HVZ) reaction.

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves $\alpha$ substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins by reaction of the carboxylic acid with $\mathrm{PBr}_{3}$ to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with $\mathrm{Br}_{2}$ in an $\alpha$-substitution reaction to give an $\alpha$-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the $\alpha$-bromo carboxylic acid product.

PROBLEM If methanol rather than water is added at the end of a Hell-Volhard-Zelinskii reaction, an ester 22-6 rather than an acid is produced. Show how you would carry out the following transformation, and propose a mechanism for the ester-forming step.


FIGURE 22.3 MECHANISM - 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
As noted in Section 22.1, a hydrogen on the $\alpha$ position of a carbonyl compound is weakly acidic and can be removed by a strong base to yield an enolate ion. In comparing acetone ( $\mathrm{p} K_{\mathrm{a}}=19.3$ ) with ethane ( $\mathrm{p} K_{\mathrm{a}} \approx 60$ ), for instance, the presence of a neighboring carbonyl group increases the acidity of the ketone over the alkane by a factor of $10^{40}$.

Acetone
$\left(p K_{a}=19.3\right)$

Ethane
( $\mathrm{p} K_{\mathrm{a}} \approx 60$ )

Proton abstraction from a carbonyl compound occurs when the $\alpha \mathrm{C}-\mathrm{H}$ bond is oriented roughly parallel to the $p$ orbitals of the carbonyl group. The $\alpha$ carbon atom of the enolate ion is $s p^{2}$-hybridized and has a $p$ orbital that overlaps the neighboring carbonyl $p$ orbitals. Thus, the negative charge is shared by the electronegative oxygen atom, and the enolate ion is stabilized by resonance (FIGURE 22.5).

FIGURE 22.5 Mechanism of enolate-ion formation by abstraction of an $\alpha$ proton from a carbonyl compound. The enolate ion is stabilized by resonance, and the negative charge (red) is shared by the oxygen and the $\alpha$ carbon atom, as indicated in the electrostatic potential map.

Because carbonyl compounds are only weakly acidic, a strong base is needed for the formation of an enolateion. If an alkoxide ion, such as sodium ethoxide, is used as base, deprotonation of acetone only takes place to the extent of about $0.1 \%$ because acetone is a weaker acid than ethanol ( $\mathrm{p} K_{\mathrm{a}}=16$ ). If, however, a more powerful base is used, then a carbonyl compound is completely converted into its enolate ion.


FIGURE 22.3 MECHANISM - 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
In practice, the strong base lithium diisopropylamide [ $\mathrm{LiN}\left(i-\mathrm{C}_{3} \mathrm{H}_{7}\right)_{2}$; abbreviated LDA] is commonly used for making enolate ions. As the lithium salt of the weak acid diisopropylamine, $\mathrm{p} K_{\mathrm{a}}=36$, LDA can readily deprotonate most carbonyl compounds. It is easily prepared by reaction of butyllithium with diisopropylamine and is soluble in organic solvents because of its two alkyl groups.

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. TABLE 22.1 lists the approximate $\mathrm{p} K_{\mathrm{a}}$ values of different types of carbonyl compounds and shows how these values compare to other acidic substances we've seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions.

| Functional group | Example | $\mathrm{p} K_{\mathrm{a}}$ |
| :---: | :---: | :---: |
| Carboxylic acid | <smiles>CC=O</smiles> | 5 |
| 1,3-Diketone | <smiles>CC(=O)C=O</smiles> | 9 |
| 3-Keto ester | <smiles>CC(=O)C=O</smiles> | 11 |
| 1,3-Diester | <smiles>CC(=O)CC(C)=O</smiles> | 13 |
| Alcohol | $\mathrm{CH}_{3} \mathrm{OH}$ | 16 |
| Acid chloride | <smiles>CC(Cl)Cl</smiles> | 16 |
| Aldehyde | <smiles>C=O</smiles> | 17 |
| Ketone | <smiles>CC(C)=O</smiles> | 19 |