Jones M., Fleming S.A. Organic Chemistry

18.6 Reactions of Acid Chlorides: Synthesis of Acyl Compounds 889

downfield in the

13

C NMR spectra (Table 18.3). Carbon NMR spectroscopy is a

useful tool for differentiating between a ketone (or aldehyde) and an acid derivative

because the carbonyl carbon of a ketone appears near δ 200 ppm and the acid deriv-

ative appears near δ 170 ppm.

PROBLEM SOLVING

The words “NMR spectrum” and a change in the spectrum with temperature

always mean that some groups in the molecule are interchanging positions

through some sort of molecular motion, typically bond rotation (as here) or ring

flipping in cyclohexanes.

..

H N(CH

3

)

2

O

..

C

N,N-Dimethylformamide

(DMF)

PROBLEM 18.2 In the room temperature

1

H NMR spectrum of N,N-dimethyl-

formamide (DMF), two methyl signals are observed. As the temperature is raised

they merge into a single signal. Explain.

18.6 Reactions of Acid Chlorides: Synthesis

of Acyl Compounds

As mentioned before, all acyl compounds participate in the addition–elimination

process. Acid chlorides are especially reactive toward nucleophiles.Their carbonyl

groups, being the least stabilized by resonance, have the highest energy and are

the most reactive. So, an initial addition reaction with a nucleophile is relatively

easy. The chloride atom of acid chlorides is an excellent leaving group, and

sits poised, ready to depart once the tetrahedral intermediate has been formed

H

␣

C

O

HH

3

C

H

␣

C

O

ClH

3

C

TABLE 18.3 Some NMR Properties of Carbonyl Compounds and CH

3

CN (ppm, CDCl

3

)

H

␣

C

O

CH

3

H

3

C

Compound

Acetaldehyde

Acetone

Acetyl chloride

Ethyl acetate

H

␣

C

O

OCH

2

CH

3

H

3

C

H

␣

CNH

3

C

H

␣

C

O

N(CH

3

)

2

H

3

C

Compound

N,N-Dimethylacetamide

Acetonitrile

199

205

169

13

C ␦

(C O, C N)

2.25

2.18

2.66

␦ (H

␣

)

169

170

117

13

C ␦

(C O, C N)

2.05

2.09

2.05

␦ (H

␣

)

Acid chloride aminolysis

890 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

SOME SPECIFIC EXAMPLES

C

Tetrahedral intermediate

–

Nu

..

–

..

R

Cl

O

..

Cl

..

O

..

C

..

R

Cl

O

..

C +

addition

of Nu

–

THE GENERIC ADDITION–

ELIMINATION REACTION

elimination

of chloride

Primary amide

Secondary amide

Tertiary amide

..

RCl

O

..

C

..

ROH

O

..

C

Acids

Esters

RN

3

N

3

O

..

C

Acyl azides

R

O

..

C

R

O

..

C

R

O

..

C

RCN

O

..

CN

..

C

Acyl nitriles

..

O

..

HOR

..

HOH

Anhydrides

R

O

..

C

..

O

R

O

..

C

R

O

..

C

..

R

H

N

..

R

N

O

..

C

GENERAL REACTIONS

..

NH

2

NH

3

..

NH

2

R

..

NHR

2

..

OR

pyridine

0 ⬚C

..

H

3

C

H

3

C

Cl

O

..

C

..

C

H

C

CH

3

CH

2

S

CH

3

CH

2

OH

Cl

O

..

C

H

3

C

..

CC

CH

3

CH

2

S

OCH

2

CH

3

O

..

C

H

3

C

O

..

C

+

NH

2

CH

3

H

3

CCH

3

..

NH

CH

3

Amide (80%)

Ester (100%)

..

H

2

O

H

..

CC

PhS

Cl

O

..

C

..

CC

PhS

OH

O

..

.. ..

..

.. ..

..

C

Acid (82%)

H

3

CCH

3

FIGURE 18.22 Addition–elimination

reactions of acid chlorides. Note the

synthetic potential.

(Fig. 18.22). The result is an exceedingly facile and common example of the

addition–elimination mechanism.

PROBLEM 18.3 Acid chlorides often smell like hydrochloric acid. Explain.

18.6 Reactions of Acid Chlorides: Synthesis of Acyl Compounds 891

Many nucleophiles are effective in the addition–elimination reaction of acid chlo-

rides, and a great many acyl compounds can be made using acid chlorides as start-

ing materials.

Of course,strong nucleophiles such as organolithium compounds,Grignard reagents,

and the metal hydrides also react rapidly with acid chlorides. The problem here is one

of controlling secondary reactions.For example,reduction of an acid chloride with lithi-

um aluminum hydride initially gives an aldehyde. But the newly born aldehyde finds

itself in the presence of a reducing agent easily strong enough to reduce it further to the

alkoxide, and hence to the primary alcohol after water is added (Fig. 18.23).

THE GENERAL CASE

A SPECIFIC EXAMPLE

The aldehyde is born

in the presence of LiAlH

4

and must react further

Final product

primary alcohol

..

H

2

O

C

Li H AlH

3

H

+

Li

+

–

..

R

Cl

O

..

Cl

..

O

..

C

–

RH

..

O

H

..

–

..

OH

+

..

CH

2

..

OH

R

..

C

R

O

..

–

..

Cl

..

C

addition

LiAlH

4

addition

again

elimination

protonation

C

..

Cl

O

..

Cl

..

O

..

CH

2

OH

(95%)

..

CH

2

OH

..

1. LiAlH

4

ether

2. H

3

O /H

2

O

+

FIGURE 18.23 The reaction of an

acid chloride with lithium aluminum

hydride leads to a primary alcohol.

The hydride adds twice.

Similarly, reaction of an acid chloride with an organometallic reagent, ,

initially gives a ketone that usually reacts with a second equivalent of to give

the tertiary alcohol (Fig. 18.24). Note that this reaction must give a tertiary alcohol

in which at least two R groups are the same.

R

O

M

R

O

M

THE GENERAL CASE

A SPECIFIC EXAMPLE

..

H

2

O

This ketone is born in the presence of an

organolithium reagent and must react further

C

LiR

R

+

Li

+

–

..

R

Cl

O

..

Cl

..

Cl

O

..

C

CH

2

CH

3

CH

2

CH

3

OH

..

(93%)

O

..

CR

..

OH

..

C

R

O

..

–

..

Cl

..

C

addition

1. 2 equiv.

CH

3

CH

2

MgBr

ether

2. H

3

O /H

2

O

+

1. RLi

2.

elimination

FIGURE 18.24 The reaction of an

acid chloride with an organometallic

reagent proceeds all the way to the

tertiary alcohol.The organometallic

reagent adds twice.

892 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

All is fine if we are trying to make these particular alcohols, but often we are not.

How to stop the process at the aldehyde or ketone stage is the problem, and several

solutions have been found over the years. Less reactive organometallic reagents or

metal hydrides allow the isolation of the intermediate aldehydes or ketones.The reac-

tivity of lithium aluminum hydride can be attenuated by replacing some of the hydro-

gens with other groups.For example,use of lithium aluminum tri-tert-butoxyhydride

allows isolation of the aldehyde (Fig. 18.25). Presumably, the bulky metal hydride is

unable to reduce the aldehyde, which is less reactive than the original acid chloride.

THE GENERAL CASE

A SPECIFIC EXAMPLE

Lithium aluminum

tri-tert-butoxyhydride

C

H

..

R

Cl

O

..

Cl

..

Cl

O

..

(85%)

C

R

O

..

–

..

C

Stable under

these conditions

+

addition

1. LiAl[OC(CH

3

)

3

]

3

H

–78 ⬚C

2. H

2

O

elimination

Li H Al[OC(CH

3

)

3

]

3

+

–

C

NO

2

..

H

O

..

C

NO

2

Cl

..

Li

+

–

..

O

..

FIGURE 18.25 Lithium aluminum

tri-tert-butoxyhydride is not reactive

enough to add to the initially formed

aldehyde.

Catalytic reduction of an acid chloride using a deactivated, or “poisoned” cata-

lyst is called the Rosenmund reduction after Karl W. Rosenmund (1884–1964)

(Fig. 18.26). In this reaction, only the more reactive acid chloride is reduced.

THE GENERAL CASE

A SPECIFIC EXAMPLE

H

..

RCl

O

..

C

R

O

..

C

H

2

/Pd

Quinoline

a catalyst poison

quinoline

145 ⬚C

C

..

Cl

O

..

C

(77%)

H

O

..

H

2

/ BaSO

4

/Pd

, S

..

N

FIGURE 18.26 The Rosenmund

reduction of an acid chloride gives

an aldehyde.

18.6 Reactions of Acid Chlorides: Synthesis of Acyl Compounds 893

The more stable, less reactive aldehyde can be isolated. Although this is not the same

poisoned catalyst used for hydrogenation of an alkyne to give the cis alkene (Lindlar

catalyst, p. 452), they are very similar.

Organocuprates react with acid chlorides but are not reactive enough to add to

the product ketones (Fig. 18.27).

THE GENERAL CASE

A SPECIFIC EXAMPLE

C

Li

+

..

R

Cl

O

..

Cl

..

Cl

..

C

R

O

..

–

..

Cl

..

C

addition

Bu

2

CuLi

elimination

LiR

2

Cu

R

+

–

Li

+

–

..

O

..

O O

(79%)

..

FIGURE 18.27 Cuprates are reactive

enough to add R



to the carbonyl

group of the acid chloride, but not

reactive enough to attack the product

ketones.

THE GENERAL CASE

A SPECIFIC EXAMPLE

..

RCl

O

..

C

R

O

..

C

AlCl

3

..

H

3

CCl

O

..

C

CH

3

O

..

C

(97%)

AlCl

3

FIGURE 18.28 Friedel–Crafts acylation of benzene produces an aromatic ketone.

Finally, don’t forget that acid chlorides are used in the synthesis of aromatic ketones

through Friedel–Crafts acylation (p.643).This very useful reaction is shown in Figure 18.28.

PROBLEM 18.4 Write a mechanism for the formation of the product of Figure 18.28.

PROBLEM 18.5 Starting with acetyl chloride, devise a synthesis of each of the

following molecules.

H

3

CCl

O

C

Acetyl chloride

H

3

C OCH

3

O

C

(a)

H

3

COH

O

C

H

3

C

O

C

(b)

H

3

CO

O

C

CH

3

O

C

(c)

(e)

H

3

CCH

3

CH

3

OH

CH

2

CH

3

C

(d)

894 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

Summary

The presence of the good leaving group (chloride) attached directly to the

carbon–oxygen double bond makes all manner of addition–elimination reactions

possible for acid chlorides. The acid chloride can be used to make anhydrides,

esters, carboxylic acids, amides, aldehydes, ketones, and alcohols.

18.7 Reactions of Anhydrides

The reactivity of anhydrides is similar to that of acid chlorides. A carboxylate anion

is the leaving group in a variety of syntheses of acyl derivatives,all of which are exam-

ples of the addition–elimination process (Fig. 18.29). One reaction of this kind is

the basic hydrolysis of phthalic anhydride to phthalic acid. Here the leaving group

is an internal carboxylate anion.

THE GENERAL CASE

A SPECIFIC EXAMPLE

+

K

+

OH

Carboxylate

leaving group

..

H

3

O

..

+

/H

2

O

Nu

..

–

C

Phthalic anhydride Phthalic acid

O

..

C

O

..

O

..

O

..

O

..

C

R

O

..

C

RRO

..

O

..

C

R

O

..

C

O

..

C

RR

–

OH

..

–

..

O

..

–

..

addition

elimination

protonation

elimination

O

C

O

OH

C

O

..

O

..

OH

..

O

C

O

..

O

..

OH

..

OH

..

/H

2

O

..

FIGURE 18.29 Addition–elimination reactions of an anhydride.

PROBLEM 18.6 Provide a mechanism for the formation of N-phenylmaleimide

from maleic anhydride and aniline. Be sure you give a structure for the interme-

diate A, and account for the role of the acetic anhydride in the second step.

NH

2

Maleic

anhydride

O

..

O

..

O

..

O

..

O

A

Aniline

acetic

anhydride

+

H

..

N

N -Phenylmaleimide

H

WEB 3D

18.8 Reactions of Esters 895

Like acid chlorides, anhydrides can be used in the Friedel–Crafts reaction

(Fig. 18.30). Once again, a strong Lewis acid catalyst such as aluminum chloride is

used to activate the anhydride. The mechanism follows the pattern of the Friedel–

Crafts reactions we saw earlier (p. 643).

PROBLEM 18.7 Write a mechanism for the reaction of Figure 18.30.

THE GENERAL CASE

A SPECIFIC EXAMPLE

+

O

..

C

O

..

C

AlCl

3

AlCl

3

RR

O

..

C

(96%)

R

O

..

C

O

..

C

H

3

CCH

3

CH

3

CH

3

CH

3

FIGURE 18.30 A Friedel–Crafts reaction using an anhydride as the source of the acyl group.

18.8 Reactions of Esters

Esters are less reactive than acid chlorides and anhydrides in addition reactions, but

more reactive than amides. Esters can be converted into their parent carboxylic acids

under either basic or acidic aqueous conditions in a process called, logically enough,

ester hydrolysis. In base, the mechanism is the familiar addition–elimination one

(Fig. 18.31). Hydroxide ion attacks the carbonyl group to form a tetrahedral

intermediate. Loss of alkoxide then gives the acid, which is rapidly deproto-

nated to the carboxylate anion in basic solution. Notice that this reaction, saponi-

fication (p. 862), is not catalytic.The hydroxide ion used up in the reaction is not

regenerated at the end. To get the carboxylic acid itself, a final acidification step

is necessary.

..

H

3

O

..

+

/H

2

O

..

H

2

O +

HO

..

–

O

..

OH

..

C

R

O

..

C

R

O

..

C

Tetrahedral

intermediate

R

–

..

addition

elimination

acidification

OR

..

OR

..

ROH

..

–

deprotonation of

the carboxylic acid

..

O

..

C

R

..

O

+

O

..

C

R

..

OH

H

FIGURE 18.31 The base-induced

ester hydrolysis reaction,

saponification.

Ester hydrolysis

896 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

Esters can also be converted into carboxylic acids in acid (Fig. 18.32). The

carbonyl oxygen is first protonated to give a resonance-stabilized cation to which

water adds. Water is by no means as nucleophilic as hydroxide, but the protonated

carbonyl is a very strong electrophile and the overall reaction is favorable. The

reaction concludes with proton transfers and loss of alcohol.

H

3

O

..

+

..

H

2

O

..

H

2

O

+

OH

..

O

..

C

R

OH

..

C

R

..

OH

..

OH

..

addition

elimination protonation

deprotonation

..

H

3

O

+

/H

2

O

protonation

OR

OH

..

C

R

+

OH

+

OH

..

C

R

+

OR

..

HOH

2

H

O

..

C

ROR

O

..

C

ROH

..

C

ROR

OR

HO

..

OH

..

C

R

..

H

O

..

ROH+

OH

2

..

+

H

deprotonation

FIGURE 18.32 The acid-catalyzed ester hydrolysis reaction.

Have you seen this reaction before? You certainly have. It is the exact reverse of

the mechanism for Fischer esterification (p. 841), so there is nothing new here at all.

What determines where the overall equilibrium settles out? The structure of the ester

is an important factor, but much more important are the reaction conditions. Excess

water favors the acid; excess alcohol favors the ester. Le Châtelier’s principle is at

work here, and the chemist has the ability to manipulate this equilibrium (Fig. 18.33)

to favor either side. In practice, most acids and esters are easily interconvertible.

Fischer

esterification

ester hydrolysis

..

H

3

O

..

+

/H

2

O

..

C

ROR

O

..

O

..

C

ROH

..

.. ..

ROH

2

/ ROH

FIGURE 18.33 Acids and esters are

usually interconvertible.

PROBLEM 18.8 Where appropriate, draw resonance forms for the intermediate

species in the reactions of Figure 18.33.You will have to write mechanisms for the

reactions first.

A reaction closely related to acid-catalyzed ester hydrolysis is acid-catalyzed

transesterification. In this reaction, an ester is treated with an excess of an alcohol

and an acid catalyst.The result is replacement of the ester OR group with the alco-

hol OR group (Fig. 18.34). Like ester hydrolysis, transesterification can be carried

out under either acidic or basic conditions.The mechanisms are extensions of those

you have already seen in the ester hydrolysis reactions or Fischer esterification.

..

C

ROR

O

..

C

ROR

O

..

–

..

.. ..

ORHOR /

base catalyzed

..

C

ROR

O

..

+

acid catalyzed

..

.. ..

H

2

OR / HOR

FIGURE 18.34 Base- and acid-

catalyzed transesterification.

18.8 Reactions of Esters 897

PROBLEM 18.9 Write mechanisms for acid- and base-induced transesterification.

WORKED PROBLEM 18.10 There is an important difference between the reaction

of an ester with hydroxide (



OH) and of an ester with alkoxide (



OR).The reac-

tion with hydroxide is neither catalytic nor reversible, whereas the reaction with

alkoxide is both catalytic and reversible. Analyze the mechanisms of these reac-

tions and explain these observations.

ANSWER Look at the final products of the two reactions. Reaction with hydroxide

leads to a carboxylic acid (pK

a

4.5) and an alkoxide ion. These two species

must react very rapidly to make the more stable carboxylate anion (resonance sta-

bilized) and the alcohol (pK

a

17). The hydroxide reagent is consumed in this

reaction, and the overall process is so thermodynamically favorable that it is irre-

versible in a practical sense.

'

O

..

–

..

C

OR

R

..

OR

..

O

..

C

R

..

O

..

C

OH

H

R

..

OH

–

(–)

–

+

..

OR

O

..

With an alkoxide reagent, things are different. Now the product is not a car-

boxylic acid but another ester. There is no proton that can be removed, and there

is a new molecule of alkoxide generated. The reaction is approximately ther-

moneutral. The reaction is reversible.

OR

+

O

..

C

OR

R

..

–

..

+

O

..

C

R

..

–

..

OR

WORKED PROBLEM 18.11 Given that there are acid- and base-catalyzed transester-

ification reactions, should there not be both acid- and base-catalyzed Fischer

esterifications as well? Explain clearly why there is no base-catalyzed version of

Fischer esterification (i.e., RCOOH  RO



RCOOR  HO



does not occur).

ANSWER The reaction of a carboxylic acid with an alkoxide can’t proceed by

addition–elimination to give an ester because there is another much easier reac-

tion available; that reaction is simple removal of the carboxylic acid hydroxyl

proton to give the resonance-stabilized carboxylate anion. They don’t call these

compounds “acids” for nothing! The lesson in this problem is that you have to

“think simple.” Look first for “trivial” reactions (loss of the proton) before pro-

ceeding on to more complicated processes (addition–elimination).

U

OR

..

O

..

C

R

..

O

..

C

OH

H

R

..

–

..

OR

O

..

pK

a

~4.5 pK

a

~17

+

O

..

C

R

–

..

O

..

–

..

RO

–

..

HO

O

..

C

OR

R

..

O

..

OH

R

..

C

++

898 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

PROBLEM 18.12 Esters can also react with amines to give amides. Write a mecha-

nism for the reaction of methyl acetate (CH

3

COOCH

3

) and ammonia to form

acetamide (CH

3

CONH

2

).

Summary

Anhydrides react with water to generate carboxylic acids, with alcohols to give

esters, and with amines to form amides. Esters behave similarly. There are both

acid-catalyzed and base-induced reactions of esters with water (ester hydrolysis)

to give carboxylic acids. There are both acid- and base-catalyzed versions of the

reaction of esters with alcohols (transesterification) that generate new esters.

Esters also react with amines to form amides.

Esters react with amines to make

amides. One of the most important

synthetic polymers is nylon. It can

be made through the reaction of a

diester with a diamine.The

resulting polymer is a polyamide

(p. 852).This electron microscope

photo illustrates the binding

mechanism for Velcro, which is

a polyamide.

+

H

3

O

..

+

..

The relatively reactive ketone

cannot usually be isolated

C

Tetrahedral

intermediate

Alcohol

MgBrR

R

BrMg

+

..

R

OR

O

..

OR

..

C

–

R

..

O

..

R

CR

..

OH

..

C

R

O

..

C

first

addition

second

addition

elimination

BrMg

+

–

..

O

..

RO

FIGURE 18.35 The reaction of an ester with a Grignard reagent to form a tertiary alcohol.

Organometallic reagents and metal hydrides react with esters in still another

example of the addition–elimination process.Usually, these strong nucleophiles react

further with the ketones that are the initial products of the reactions (Fig. 18.35).

The ketones are not as well stabilized by resonance as are the esters and so are more

reactive in the addition reaction.

The reaction shown in Figure 18.35 is another general synthesis of complex

tertiary alcohols (compare with Fig. 18.24). Here are the possibilities for the

Jones M., Fleming S.A. Organic Chemistry

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