Jones M., Fleming S.A. Organic Chemistry

17.7 Reactions of Carboxylic Acids 849

In practice, this method of esterification is restricted to the synthesis of methyl

esters because other diazo compounds are relatively unstable.

A final note about ester formation addresses the case when an alcohol and a car-

boxylic acid in the same molecule undergo esterification.The result is a cyclic ester,

known as a lactone.As usual, the relatively unstrained five- and six-membered rings

are formed more easily than other sized rings. Figure 17.33 gives an example of

lactone formation.

..

O

..

O

HCl

H

2

O

C

H

OH

O

C

H

A lactone

H

..

C

WEB 3D

FIGURE 17.33 A lactone can be

formed via an intramolecular Fischer

esterification.

PROBLEM 17.14 Write a detailed mechanism for the reaction in Figure 17.33.

PROBLEM 17.15 Treatment of the compound in the figure below with I

2

/KI and

Na

2

CO

3

in water leads to a neutral molecule of the formula C

8

H

11

IO

2

. Propose

a structure for the product and a mechanism for its formation.

..

I

2

/KI

Na

2

CO

3

/H

2

O

C

8

H

11

IO

2

OH

..

O

Lactones are commonly named in reference to the acid containing the same

number of carbon atoms, with “olide” added as a suffix. Thus a butanolide has four

carbons, a pentanolide has five, and so on. A Greek letter is used to designate the

size of the ring. An α-lactone has one carbon joining the oxygen and carbonyl car-

bon,a β-lactone has two carbons,a γ-lactone three carbons, and so on.In the IUPAC

systematic naming protocol, lactones are called oxacycloalkanones (Fig. 17.34).

..

O

C

Ethanoic acid

(acetic acid)

OH

H

3

C

..

O

C

Propanoic acid

(propionic acid)

OH

CH

3

CH

2

..

O

C

Butanoic acid

(butyric acid)

OH

CH

3

CH

2

CH

2

..

O

C

Pentanoic acid

OH

CH

3

CH

2

CH

2

CH

2

Oxacyclopropanone

an ethanolide

(an α-lactone)

..

O

..

O

α

O

2-Oxacyclohexanone

a pentanolide

(a δ-lactone)

..

O

..

α

β

γ

δ

..

2-Oxacyclobutanone

a propanolide

(a β-lactone)

..

O

α

β

..

O

2-Oxacyclopentanone

a butanolide

(a γ-lactone)

O

..

α

β

γ

..

FIGURE 17.34 The naming options for lactones.

850 CHAPTER 17 Carboxylic Acids

2

As noted on p. 249, there is potential for confusion here.There are two kinds of amides, the carbonyl deriv-

ative shown here ( ) and the negatively charged ions,



NR

2

. You need to know the context

of the discussion to know which is meant. In this case we are referring to .R

O

CO

O

NHR

R

O

CO

O

NHR

17.7b Formation of Amides Although carboxylic acids do react with primary

or secondary amines to form amides,

2

in general, this reaction is not a very useful

process. The dominant reaction between the basic amine and the carboxylic acid is

proton transfer to give the ammonium salt of the carboxylic acid. Heating of the

salts has been used as a source of amides (Fig. 17.35). However, the amount of heat

needed is more than 200 °C. Such conditions are often too harsh for the organic

compounds and result in degradation of the material.

..

O

R

..

O

+

–

+

C

..

O

R

..

O

H

NH

2

NH

3

R +C

..

O

R

H

2

O

R

ΔΔΔ

Acid Base An ammonium salt An amide

NHR

Notice loss of water—this

reaction is a dehydration

FIGURE 17.35 The formation of amides through the heating of ammonium

salts of carboxylic acids.

Amide formation from the carboxylic acid is much easier if the acid is first acti-

vated. Several activating agents have been developed that greatly facilitate amide

formation. Dicyclohexylcarbodiimide (DCC) is used most often (Fig. 17.36).

C

DCC

Amide

N

+

CH

2

NH

2

H

3

C

..

O

OH

C

H

3

C

..

O

NHCH

2

WEB 3DWEB 3D

FIGURE 17.36 The use of DCC, an activating agent, to produce amides.

N

–

+

A

C

..

O

R

H

..

O

..

C H

..

O

C

N

R

O

..

+

Overall change; better

leaving group formed

..

N

C

N

+

..

C

..

O

R

..

O

..

N

H

C

N

..

proton

transfer

FIGURE 17.37 The first step in the DCC mechanism is proton transfer.This reaction is followed by addition of the carboxylate

to one of the carbon–nitrogen double bonds. The transformation involves a change of leaving group from OH to OR to give

the activated acid A.

The strategy is to convert the poor leaving group,OH, into a better one.We used

this technique extensively in Chapter 7 (p. 282), when we discussed the transfor-

mation of alcohols. Here, the carboxylate adds to one carbon–nitrogen double bond

of DCC, accomplishing the transformation of the leaving group (Fig. 17.37).

17.7 Reactions of Carboxylic Acids 851

Two mechanistic pathways are now possible. In the simpler one, the primary or

secondary amine adds to the carbon–oxygen double bond to give a tetrahedral inter-

mediate that expels a relatively stable ion to generate the amide (Fig. 17.38).

If the amide is made from an amine and a carboxylic acid in the same molecule,

then a cyclic amide is formed. Cyclic amides are called lactams.

addition

step

+

–

deprotonation

Good

leaving group

elimination step

Amide

O

C

NH

2

O

..

C

NH

..

N

..

C

NH

..

N

..

C

N

H

..

N

..

R

O

C

NH

2

O

..

R

O

C

NH

O

..

R

Stable ion

–

C

N

H

..

N

..

O

..

R

O

C

N

H

..

R

+

A

FIGURE 17.38 Addition of the amine to intermediate A leads

to a tetrahedral intermediate that can decompose to give the

amide. Can you see why the leaving group is so good in this

reaction?

PROBLEM 17.16 There is another, more complicated (and accepted), mechanism for

the reaction of the activated acid A. The initially formed activated acid reacts not

with the amine,as in Figure 17.38, but with another molecule of carboxylic acid.The

result is an anhydride.The anhydride is the actual reagent that reacts with the amine

to give the product amide. Sketch mechanisms for anhydride and amide formation.

O

C

..

An anhydride

A

protonate

Amide

O

C

O

..

C

NH

..

N

..

NH

..

NH

..

R

O

C

O

..

O

..

R

O

C

..

O

C

..

R

C

OH

R

O

..

NH

2

..

NH

..

R

HO

C

+

C

NH

..

N

..

O

..

–

+

Summary

You have learned several methods to make carboxylic acids. We have also dis-

cussed how to make esters and amides from organic acids. Notice the similar-

ity between amide formation and ester formation. Amide formation is in fact

merely a collection of steps closely resembling those in Fischer esterification.

We are beginning to see the generality of the addition–elimination process.The

addition–elimination reaction will continue to be prominent throughout this

and other chapters.

852 CHAPTER 17 Carboxylic Acids

Nylon 6,6

OH

HO

H

2

N

O

–

O

–

O

O O O

Δ

O

–

O

NH

3

+

H

3

N

+

N N O

N

H

(CH

2

)

6

(CH

2

)

6

NH

2

H

2

N

(CH

2

)

6

(CH

2

)

4

(CH

2

)

4

NH

2

H

3

N

NH

3

HO

O

OH

O

(CH

2

)

4

Adipic acid Hexamethylenediamine

N

HH H

FIGURE 17.39 Formation of the polyamide nylon 6,6.The compound in the third line is shown truncated, which is

what the squiggly line through the bond means.

17.7c Polyamides (Nylon) and Polyesters The reaction shown at the

start of Section 17.7b, the heating of the ammonium salt of a carboxylic acid to

give an amide, is at the heart of the synthesis of a set of polyamides collectively

known as nylons. This reaction is certainly not insignificant, as evidenced by the

fact that the annual worldwide production of nylon is 4 million tons.

3

In one

example of nylon synthesis, a double-headed amine, hexamethylenediamine,

reacts with a double-headed acid, adipic acid, to form a salt (Fig. 17.39).

Pyrolysis (extreme heating) of this salt at 275 °C produces the long-chain poly-

mer known as nylon 6,6. Nylons of other chain lengths are also produced by the

chemical industry.

3

This information is obtained from Yarns and Fibers Exchange (YNFX), 2007.

Polyesters are similarly made through the reactions of diacids with diols—simple

Fischer esterification reactions that produce a polymeric structure.For example,Dacron

and Mylar are trade names for different polyesters that are made from ethylene glycol

and terephthalic acid (Fig. 17.40). This type of polyester, polyethylene terephthalate

(PET), is also used to make clear recyclable plastic bottles. It is more recyclable and

therefore more environmentally friendly than most other kinds of polymers.

17.7 Reactions of Carboxylic Acids 853

HO

Fischer esterificationTerephthalic acid

OH

HO

OH

HO

O

HO

O

HO

O

FIGURE 17.40 Polyester synthesis.

This particular polyester is used in

many consumer products.

17.7d Formation of Acid Chlorides We saw acid chlorides in our study of

Friedel–Crafts acylation (p. 643). One can make an acid chloride in good yield by

treatment of a carboxylic acid with thionyl chloride or phosphorus pentachloride

(Fig. 17.41).This reaction closely resembles the formation of chlorides by the reaction

O

OH

SOCl

2

100 ⬚C

(>90%)

..

O

Cl

..

O

OH

PCl

5

NO

2

100 ⬚C

(93%)

..

O

Cl

NO

2

..

SOCl

2

Recall from Chapter 7: R OH R Cl

..

SPECIFIC EXAMPLES

WEB 3D

O

OHR

SOCl

2

..

O

ClR

..

THE GENERAL CASE

FIGURE 17.41 The reaction of

carboxylic acids with thionyl chloride

(SOCl

2

) or phosphorus pentachloride

(PCl

5

) gives acid chlorides. The

reaction of alcohols with SOCl

2

is similar.

854 CHAPTER 17 Carboxylic Acids

of alcohols with thionyl chloride (p. 284). Once again, the key concept in acid

chloride formation is activation of the carboxylic acid by the transformation of a

very poor leaving group, OH, into a better one. In the first step of the acid chloride

formation using SOCl

2

, a chloride is displaced to form an activated acid interme-

diate, in this case a chlorosulfinic acid derivative (Fig. 17.42).

O

..

O

C

..

O

..

R

O

C

..

R

S

..

+

..

OH

..

.. ..

Cl

..

Cl

O

..

S

..

Cl

..

HCl

The activated acid,

a chlorosulfite ester

Thionyl chlorideCarboxylic

acid

+

FIGURE 17.42 An activated acid is

formed in the first step of acid

chloride formation.

O

S

..

O

C

O

..

.. .. ..

R

..

Cl

H

O

S

..

O

C

O

..

R

..

Cl

..

Cl

H

+

–

_

SO

2

O

C

Cl

..

R

..

Cl

H

+

++

+

protonation

Activated acid

Acid chloride

addition

deprotonation

O

S

..

O

C

O

..

R

..

Cl

..

Cl

H

elimination

Good leaving

group

..

O

C

Cl

..

R

..

Cl

..

Cl

FIGURE 17.43 Hydrogen

chloride protonates the

carbonyl group, and

chloride attacks this strong

electrophile. In the crucial

step, sulfur dioxide and

chloride ion are lost as the

acid chloride is formed.

Esters

A

mides

Carboxylic

acids

AlcoholsAcid

chloride

C

R

Cl

R

R R

R

..

O

..

O

..

NH

2

O

..

OH

O

..

CH

2

OH

..

OH

NH

3

2. H

2

O

..

H

2

O

1. LiAlH

4

C

FIGURE 17.44 Some

compounds formed from

addition–elimination

reactions between

different nucleophiles

and acid chlorides. See

Problem 17.18.

PROBLEM 17.17 Write a mechanism for the formation of the product in Figure

17.42. Watch out for the details! Almost everyone makes a small error the first

time on this problem.

The hydrogen chloride generated in the formation of the activated acid proto-

nates the carbonyl oxygen, and the chloride ion adds to the strong electrophile.The

tetrahedral intermediate then breaks down into chloride, sulfur dioxide,and the acid

chloride. Notice the change in leaving group induced by the overall transformation

of OH into OSOCl (Fig. 17.43).

Acid chlorides contain a good potential leaving group, the chloride; and the

addition–elimination process can lead to all manner of acyl derivatives, ,

as we will see in Chapter 18 (Fig. 17.44).

R

O

CO

O

X

Acid chloride formation

Acid chloride aminolysis

17.7 Reactions of Carboxylic Acids 855

PROBLEM 17.18 Write a mechanism for the transformation of an acid chloride

into a primary alcohol as shown in Figure 17.44.

PROBLEM 17.19 Another excellent synthesis of acid chlorides from carboxylic acids

uses either phosgene ( ) or oxalyl chloride ( )

as the reactive agent. Suggest a mechanism for the reaction with phosgene.

Cl

O

CO

O

CO

O

ClCl

O

CO

O

Cl

Oxalyl chloride

Phosgene

Cl

C

OH

..

O

..

+

O

..

CO

2

+ CO + HCl

+ CO

2

+ HCl

Cl

..

C

O

..

Cl

..

Cl

..

C

Cl

..

C

OH

..

O

..

R R

O

..

O

..

O

..

C

WEB 3D

PROBLEM 17.20 Phosgene (see Problem 17.19) is a most effective poison.Can you

guess its mode of action? What happens when phosgene is absorbed by moist

lung tissue?

Two carboxylic

acids

Anhydride Water

.. ..

O

..

O

..

.. ..

OH

O

HO

..

H

2

O

..

O

..

RR R

R

+=C

C

FIGURE 17.45 A comparison

between two carboxylic acids and

acid anhydrides.

17.7e Anhydride Formation Acid anhydrides are, as the name suggests,

related to carboxylic acids by a formal loss of water. An anhydride is “two carboxylic

acids less a molecule of water” (Fig. 17.45).

+

(80%)

O

60 ⬚C

benzene

..

O

..

O

..

O

..

–

O

..

O

..

Cl

FIGURE 17.46 Anhydride formation

through the reaction of a carboxylate

salt with an acid chloride.

Carboxylic acids and their conjugate bases, the carboxylate anions, react with acid

halides to give acid anhydrides (Fig. 17.46).

–

addition elimination

Tetrahedral

intermediate

Anhydride

..

O

..

O

..

+

..

Cl

..

–

C

O

..

Cl

..

R

..

O

..

R

..

O

..

O

..

RRR

R

..

+

Cl

..

–

CC C CC

FIGURE 17.47 The mechanism of anhydride formation involves the generation of a tetrahedral intermediate and

loss of chloride ion.

Phthalic acid

melt

Phthalic anhydride

200 ⬚C

O

..

O

..

H

2

O

..

O

..

+

H

..

O

H

..

O

..

WEB 3D

FIGURE 17.48 Dehydration of a dioic acid can form a cyclic anhydride.

O

H

1. 2 equiv. Li

O

..

C

O

..

O

H

O

..

O

..

1. 2 equiv. (CH

3

)

3

CLi

pentane, 25 °C

2. H

2

O

..

2. H

2

O

C(CH

3

)

3

(67%)

R

RR

THE GENERAL CASE

A SPECIFIC EXAMPLE

C

CC

FIGURE 17.49 A general ketone synthesis from a carboxylic acid and an organolithium reagent. Note again

the convention that differentiates sequential reactions (written 1. RLi; 2. H

2

O) from “dump ’em all together”

reactions (written RLi, H

2

O).

856 CHAPTER 17 Carboxylic Acids

The mechanisms for these reactions involve addition of the carboxylate anion to

the carbonyl group of the acid chloride to give a tetrahedral intermediate that can

lose a chloride ion, which is a good leaving group (Fig. 17.47).

Other reagents such as DCC or P

2

O

5

can be used to form anhydrides. Such

reagents are called dehydrating reagents. Cyclic anhydrides can be formed by pyrol-

ysis, or thermal dehydration, of the diacid (Fig. 17.48).

17.7f Reactions with Organolithium Reagents and Metal Hydrides

In a useful synthetic reaction that was mentioned on p. 837, organic acids react

with two equivalents of an organolithium reagent to give the corresponding ketone

(Fig. 17.49).

The first step in the reaction is the formation of the lithium salt of the carboxylic

acid.Although this species already bears a negative charge,the organolithium reagent

is a strong enough nucleophile to add to it to give the “dianion” (Fig. 17.50).

17.7 Reactions of Carboxylic Acids 857

deprotonation

protonation

addition

Dianion

C

O

H

Li

O

1

..

+

–

..

–

O

OC

..

Li

+

Li

+

R

Li

R

C

O

1

..

R

Hydrate

Ketone

C

R

..

OH

H

3

O

H

2

O

..

C

+

R

..

O

..

FIGURE 17.50 The first step in the reaction is formation of the carboxylate anion. In a second step, the organolithium

reagent is a strong enough nucleophile to add to the carboxylate anion to give a lithium-stabilized dianion. When

water is added to the reaction, a hydrate is formed. Hydrates are generally unstable compared to ketones.The

equilibrium favors the final product of the reaction, the ketone.

What can happen to the product dianion in this basic solution? This question

is one of the rare instances when the answer really is, “nothing.”There is no possi-

ble leaving group, because neither R



nor O

2

can be lost. So, the dianion remains

in solution until water is added to the reaction mixture, at which point a hydrate is

formed. Hydrates are unstable relative to their ketone precursors (p.777), and so the

end result is the ketone.

O

C

+

Li

+

Li

+

Li

+

–

C

O

–

..

O

R

Leaving groups?

No!

This reaction is fine, as long as L is a good leaving group

O

C

+

Li

+

Li

+

Li

+

–

C

O

2–

..

R

O

C

+

R R

–

C

L

O

R

O

..

FIGURE 17.51 The dianion from

Figure 17.50 is foiled in any attempt

to expel a negative charge because

of the absence of a possible

leaving group.

PROBLEM 17.21 What reagent(s) would you use to synthesize acetophenone from

acetic acid?

The key to the formation of the ketone is the inability of the dianionic inter-

mediate to expel a leaving group. Compare this nonreaction with a general process

in which a leaving group is present (Fig. 17.51). We have already seen many reac-

tions of this type, and in Chapter 18 we will see many more.

858 CHAPTER 17 Carboxylic Acids

C

1. LiAlH

4

2. H

2

O

OHR

RCH

2

(97%)

1. excess

LiAlH

4

2. H

2

O

HOOC COOH(CH

2

)

8

HOCH

2

CH

2

OH(CH

2

)

8

OH

..

O

..

THE GENERAL CASE

A SPECIFIC EXAMPLE

FIGURE 17.52 The reduction of carboxylic acids to alcohols.

O

C

LiAlH

4

+ H

2

+ AlH

3

+

Tetrahedral

intermediate

Carboxylic

acid

O

H

R

..

O

C

R

C

O

R

LiAlH

4

Aldehyde

(cannot survive

in LiAlH

4

)

–

Li

+

Li

+

Li

+

–

O

–

OAlH

2

R

H

AlH

2

H

..

O

..

O

..

C

LiAlH

4

C

R

H

2

O

H

..

OAlH

2

..

C

R

H

HO

–

..

OH

..

FIGURE 17.53 Deprotonation to give the carboxylate anion is followed by hydride

addition to give a “dianion” bound to aluminum. Loss of LiOAlH

2

leads to an

intermediate aldehyde, which is reduced by a hydride. At the conclusion of the reaction,

protonation by water gives the alcohol.

17.7g Decarboxylation Some carboxylic acids easily lose carbon dioxide in a

reaction logically called decarboxylation. The best examples are β-keto acids, and

1,3-diacids such as malonic acid (propanedioic acid) in which there is also a car-

bonyl group β to the acid (Fig. 17.54). The reactions often take place at room tem-

perature or on gentle heating. Note that the decarboxylation reaction of a β-keto

acid provides a new route for syntheses of a ketone and the decarboxylation of a

1,3-diacid is a new route for formation of carboxylic acids.

Reduction of carboxylic acids by lithium aluminum hydride, followed by

hydrolysis, gives the corresponding primary alcohols (Fig. 17.52). There is no

unanimity on the details of the reaction mechanism, but the first step must

be formation of the carboxylate anion and hydrogen. Anion formation is followed

by addition of hydride to the carbonyl group. The result is another “dianion.” In

this case, the aluminum is undoubtedly tightly bound to one of the oxygen anions.

Now, unlike the “dianion” in Figure 17.50, a molecule of aluminum oxide can be

lost to generate the aldehyde (Fig. 17.53). Because the LiAlH

4

can continue to

provide hydride (some experiments show 3.8 equivalents of hydride come from

LiAlH

4

), the newly formed aldehyde cannot survive for long (p. 801). Another

addition of hydride gives the alkoxide.The alkoxide is stable in the basic environ-

ment and subsequent addition of water forms the primary alcohol.

Jones M., Fleming S.A. Organic Chemistry

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