3.

0 Carboxylic Acids and Derivatives

3.0.6 Nucleophilic Acyl Substitution Reactions

Some general reactions of carboxylic acid derivatives.

• Hydrolysis: Reaction with water to yield a carboxylic acid

• Alcoholysis: Reaction with an alcohol to yield an ester
• Aminolysis: Reaction with ammonia or an amine to yield an amide
• Reduction: Reaction with a hydride reducing agent to yield an alcohol
• Grignard reaction: Reaction with an organomagnesium reagent to yield an alcohol

Dr. Mudalungu/ Organic reactions 106

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions

Predicting the Product of a Nucleophilic Acyl Substitution Reaction

Example: Predict the product of the following nucleophilic acyl substitution reaction of benzoyl chloride with propan-2-ol:

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 (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 the ester isopropyl benzoate.

Dr. Mudalungu/ Organic reactions 107

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions-Carboxylic Acids and Their Reactions

The direct nucleophilic acyl substitution of a carboxylic acid is difficult because -OH is a poor leaving group. 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 conditions, however, acid chlorides,
anhydrides, esters, and amides can all be prepared from carboxylic acids.
Conversion of Acids into Acid Chlorides (RCO2H RCOCl)
Carboxylic acids are converted into acid chlorides by treatment with thionyl chloride, SOCl2. The 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.

Dr. Mudalungu/ Organic reactions 108

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions-Carboxylic Acids and Their Reactions

Conversion of Acids into Esters (RCO2H RCO2R′)

Perhaps the most useful reaction of carboxylic acids is their conversion into esters by reaction with an alcohol—the substitution
of -OH by -OR. Called the Fischer esterification reaction, the simplest method involves heating the carboxylic acid with an
acid catalyst in an alcohol solvent.

As shown in the mechanism (see next slide), the acid catalyst first protonates an oxygen atom of the -CO2H group, which gives
the carboxylic acid a positive charge and makes it more reactive toward nucleophiles. An alcohol molecule then adds to the
protonated carboxylic acid, and subsequent loss of water yields the ester product.

Dr. Mudalungu/ Organic reactions 109

and functional group Chemistry
2022
3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions-Carboxylic Acids and Their Reactions

Mechanism of the Fischer esterification reaction of a carboxylic acid to yield

an ester. The reaction is an acid-catalyzed nucleophilic acyl substitution.

All steps in the Fischer esterification reaction are reversible, and the position of the equilibrium can be driven either forward or
backward depending on the reaction conditions. Ester formation is favored when alcohol is used as the solvent, but carboxylic acid is
favored when the solvent is water.
Dr. Mudalungu/ Organic reactions 110
and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions-Carboxylic Acids and Their Reactions

Question: 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 propan-1-ol.

Dr. Mudalungu/ Organic reactions 111

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions-Carboxylic Acids and Their Reactions

Conversion of Acids into Amides (RCO2H RCONH2)

Amides are carboxylic acid derivatives in which the acid -OH group has been replaced by a nitrogen substituent, -NH2, -NHR, or
-NR2. Amides are difficult to prepare directly from acids by substitution with an amine because amines are bases, which convert
acidic carboxyl groups into their unreactive carboxylate anions. Thus, the -OH must be activated by making it a better,
nonacidic leaving group. In practice, amides are usually prepared by treating the carboxylic acid with dicyclohexylcarbodiimide
(DCC) to activate it, followed by addition of the amine. The DCC method for preparing amides is particularly useful for the
laboratory synthesis of proteins from amino acids.

Dr. Mudalungu/ Organic reactions 112

and functional group Chemistry
2022
3.0 Carboxylic Acids and Derivatives
3.0.6 Nucleophilic Acyl Substitution Reactions-Carboxylic Acids and Their Reactions

Conversion of Acids into Alcohols (RCO2H RCH2OH)

Carboxylic acids are reduced by lithium aluminum hydride (LiAlH4) to yield primary alcohols. The reaction occurs by initial
substitution of the acid -OH group by -H to give an aldehyde intermediate that is further reduced to the alcohol.

Dr. Mudalungu/ Organic reactions 113

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.7 Nucleophilic Acyl Substitution Reactions-Acid Halides and Their Reactions

As already seen, Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride, SOCl2

They are among the most reactive of the various carboxylic acid derivatives and can be converted into many other kinds of substances.
The halogen can be replaced by -OH to yield an acid, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, acid halides can be
reduced by LiAlH4 to give primary alcohols or allowed to react with Grignard reagents to give tertiary alcohols. Neither of these latter two processes
is often used, however, because the product alcohols can be made more conveniently from esters. Although illustrated only for acid chlorides,
similar reactions take place with other acid halides.

Some nucleophilic acyl

substitution reactions of acid
chlorides.

Dr. Mudalungu/ Organic reactions 114

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.7 Nucleophilic Acyl Substitution Reactions-Acid Halides and Their Reactions

Conversion of Acid Chlorides into Acids (RCOCl RCO2H)

Acid chlorides react with water to yield carboxylic acids—the substitution of -Cl by -OH. This hydrolysis reaction is a typical nucleophilic acyl
substitution process and is initiated by attack of the nucleophile water on the acid chloride carbonyl group. The initially formed tetrahedral
intermediate undergoes loss of HCl to yield the product.

Conversion of Acid Chlorides into Esters (RCOCl RCO2R′)

Acid chlorides react with alcohols to yield esters in a reaction analogous to their reaction with water to yield acids.

Because HCl is generated as a by-product, the

reaction is usually carried out in the presence of an
amine base such as pyridine, which reacts with the
HCl as it’s formed and prevents it from causing side
reactions.

Dr. Mudalungu/ Organic reactions 115

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.7 Nucleophilic Acyl Substitution Reactions-Acid Halides and Their Reactions

Conversion of Acid Chlorides into Amides (RCOCl RCONH2)

Acid chlorides react rapidly with ammonia and with amines to give amides—the substitution of -Cl by -NR2. Both
monosubstituted and disubstituted amines can be used. For example, 2-methylpropanamide is prepared by reaction of 2-
methylpropanoyl chloride with ammonia. Note that one extra equivalent of ammonia is added to react with the HCl generated.

Question: Show how you would prepare N-methylpropanamide by reaction of an acid chloride with an amine.
Strategy The name of the product gives a hint as to how it can be prepared. Reaction of methylamine with propanoyl chloride
gives N-methylpropanamide.

Dr. Mudalungu/ Organic reactions 116

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.8 Nucleophilic Acyl Substitution Reactions-Acid Anhydrides and Their Reactions

The best method for preparing acid anhydrides is by a nucleophilic acyl substitution reaction of an acid chloride with a
carboxylic acid anion. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way.

The chemistry of acid anhydrides is similar to that of acid chlorides.

Dr. Mudalungu/ Organic reactions 117

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.8 Nucleophilic Acyl Substitution Reactions-Acid Anhydrides and Their Reactions

Acetic anhydride is often used to prepare acetate esters of complex alcohols and to prepare substituted acetamides from
amines. For example, aspirin (an ester) is prepared by reaction of acetic anhydride with o-hydroxybenzoic acid.
Similarly, acetaminophen (an amide; the active ingredient in Tylenol) is prepared by reaction of acetic anhydride with p-
hydroxyaniline.

N/B: In both of these examples that only “half” of the anhydride molecule is used; the other half acts as the leaving group during the nucleophilic acyl substitution step
and produces carboxylate anion as a by-product. Thus, anhydrides are inefficient to use, and acid chlorides are normally used instead.

Dr. Mudalungu/ Organic reactions 118

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.8 Nucleophilic Acyl Substitution Reactions-Acid Anhydrides and Their Reactions

Question: What is the product of the following reaction?

Strategy Acid anhydrides undergo a nucleophilic acyl substitution reaction with alcohols to give esters. Reaction of
cyclohexanol with acetic anhydride yields cyclohexyl acetate by nucleophilic acyl substitution of the -OCOCH3 group of the
anhydride by the -OR group of the alcohol.

Dr. Mudalungu/ Organic reactions 119

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.9 Nucleophilic Acyl Substitution Reactions-Esters and Their Reactions

Esters are usually prepared either from acids or acid chlorides by the methods already discussed. Thus, carboxylic acids are
converted directly into esters by Fischer esterification with an alcohol, and acid chlorides are converted into esters by reaction
with an alcohol in the presence of pyridine.

Esters show the same kinds of chemistry we’ve seen for other acyl derivatives, but they’re less reactive toward nucleophiles than
acid chlorides or anhydrides.

Some reactions of esters

Dr. Mudalungu/ Organic reactions 120

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.9 Nucleophilic Acyl Substitution Reactions-Esters and Their Reactions

Conversion of Esters into Acids (RCO2R′ RCO2H)

Esters are hydrolyzed either by aqueous base or by aqueous acid to yield a carboxylic acid plus an alcohol.

Hydrolysis in basic solution is called saponification, after the Latin word sapo, “soap.” (soap is made by the base-induced ester
hydrolysis of animal fat.) Ester hydrolysis occurs by a typical nucleophilic acyl substitution pathway in which OH - nucleophile
adds to the ester carbonyl group, yielding a tetrahedral alkoxide intermediate. Loss of RO- then gives a carboxylic acid, which is
deprotonated to give the acid carboxylate plus alcohol.

Dr. Mudalungu/ Organic reactions 121

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.9 Nucleophilic Acyl Substitution Reactions-Esters and Their Reactions

Conversion of Esters into Alcohols by Reduction (RCO2R′ RCH2OH)

Esters are reduced to primary alcohols by treatment with LiAlH4. The reaction occurs by an initial nucleophilic acyl substitution
reaction in which hydride ion adds to the carbonyl group followed by elimination of an alkoxide ion to give an aldehyde
intermediate. Further reduction of the aldehyde by a typical nucleophilic addition process gives the primary alcohol.

Conversion of Esters into Alcohols by Grignard Reaction (RCO2R′ R3COH)

Grignard reagents react with esters to yield tertiary alcohols in which two of the substituents on the hydroxyl-bearing carbon are
identical.
For example, methyl benzoate reacts with 2 equivalents of CH3MgBr to yield 2-phenylpropan-2-ol. The reaction occurs by
nucleophilic addition of a Grignard reagent to the ester, elimination of alkoxide ion to give an intermediate ketone, and further
nucleophilic addition to the ketone to yield the tertiary alcohol.

Dr. Mudalungu/ Organic reactions 122

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.9 Nucleophilic Acyl Substitution Reactions-Esters and Their Reactions

Mechanism of the reaction of a Grignard reagent with an ester to yield a tertiary alcohol. A ketone intermediate is
involved.

Dr. Mudalungu/ Organic reactions 123

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.9 Nucleophilic Acyl Substitution Reactions-Esters and Their Reactions

Example: How could you use the reaction of a Grignard reagent with an ester to prepare 1,1-diphenylpropan-1-ol?
Strategy The product of the reaction between a Grignard reagent and an ester is a tertiary alcohol in which the alcohol carbon
and one of the attached groups have come from the ester and the remaining two groups bonded to the alcohol carbon
have come from the Grignard reagent. Since 1,1-diphenylpropan-1-ol has two phenyl groups and one ethyl group bonded to the
alcohol carbon, it must be prepared from reaction of a phenylmagnesium halide with an ester of propanoic acid.

Dr. Mudalungu/ Organic reactions 124

and functional group Chemistry
2022
3.0 Carboxylic Acids and Derivatives
3.0.10 Nucleophilic Acyl Substitution Reactions-Amides and Their Reactions

Amides are usually prepared by reaction of an acid chloride with an amine. They are much less reactive than acid chlorides,
acid anhydrides, and esters, and the amide bond is stable enough to link different amino acids together to form proteins.

The most common reactions of amides are their hydrolysis to give carboxylic acids and their reduction with LiAlH 4.
Interestingly, though, the reduction product of an amide is an amine rather than the expected alcohol

Dr. Mudalungu/ Organic reactions 125

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.10 Nucleophilic Acyl Substitution Reactions-Amides and Their Reactions

Conversion of Amides into Acids (RCONH2 RCO2H)

Amides undergo hydrolysis in either aqueous acid or base to yield carboxylic acids plus amine. Although the reaction is slow and
requires prolonged heating, the overall transformation is a typical nucleophilic acyl substitution of -OH for -NH2. In biochemistry,
the reaction is particularly useful for hydrolyzing proteins to their constituent amino acids.

Conversion of Amides into Amines by Reduction (RCONH2 RCH2NH2)

Like other carboxylic acid derivatives, amides are reduced by LiAlH4. The product of this reduction, however, is an amine rather
than an alcohol. For example:

The effect of amide reduction is to convert the amide carbonyl group into a methylene group (C=O CH2). This kind of reaction is specific for
amides and does not occur with other carboxylic acid derivatives.

Dr. Mudalungu/ Organic reactions 126

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.10 Nucleophilic Acyl Substitution Reactions-Amides and Their Reactions

Example: How could you prepare N-ethylaniline by reduction of an amide with LiAlH4?

Strategy Reduction of an amide with LiAlH4 yields an amine. To find the starting material for synthesis of N-ethylaniline, look for
a CH2 position next to the nitrogen atom and replace that CH2 by C=O. In this case, the amide is N-phenylacetamide.

Dr. Mudalungu/ Organic reactions 127

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.11 Nucleophilic Acyl Substitution Reactions-Nitriles and Their Reactions

Nitriles, are analogous to carboxylic acids in that both have a carbon atom with three bonds to electronegative atoms
and both contain a multiple bond.

Nitriles occur less frequently in living organisms than do acid derivatives, although more than 1000 examples are known.
Cyanocycline A, for instance, has been isolated from the bacterium Streptomyces lavendulae and found to have both
antimicrobial and antitumor activity. Lotaustralin, isolated from the cassava plant, contains a sugar with an acetal carbon, one
oxygen of which is bonded to a nitrile-bearing carbon (Sugar-O-C-CN). On hydrolysis of the acetal, hydrogen cyanide is
released, thereby acting as a natural insecticide to protect the plant.

Dr. Mudalungu/ Organic reactions 128

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.11 Nucleophilic Acyl Substitution Reactions-Nitriles and Their Reactions

The simplest method of preparing nitriles is by the SN2 reaction of cyanide ion with a primary alkyl halide

Reactions of Nitriles
Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with
nucleophiles to yield sp2- hybridized imine anions in a reaction analogous to the formation of an sp3-hybridized alkoxide ion by
nucleophilic addition to a carbonyl group. The imine anion then goes on to yield further products.

Dr. Mudalungu/ Organic reactions 129

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.11 Nucleophilic Acyl Substitution Reactions-Nitriles and Their Reactions

The most useful reactions of nitriles are hydrolysis to give a carboxylic acid plus ammonia, reduction to yield an amine, and
Grignard reaction to give a ketone

Some reactions of nitriles

Conversion of Nitriles into Carboxylic Acids (RCN RCO2H)

Nitriles are hydrolyzed in either acidic or basic solution to yield carboxylic acids and ammonia (or an amine). For example,
benzonitrile gives benzoic acid.

Dr. Mudalungu/ Organic reactions 130

and functional group Chemistry
2022
3.0 Carboxylic Acids and Derivatives
3.0.11 Nucleophilic Acyl Substitution Reactions-Nitriles and Their Reactions

Conversion of Nitriles into Amines by Reduction (RCN RCH2NH2)

Reduction of a nitrile with LiAlH4 gives a primary amine, RNH2, just as reduction of an ester gives a primary alcohol, ROH. For
example:

Conversion of Nitriles into Ketones by Reaction with Grignard Reagents

Grignard reagents, RMgX, add to nitriles to give intermediate imine anions that can be hydrolyzed to yield ketones. For
example, benzonitrile reacts with ethylmagnesium bromide to give propiophenone.

Dr. Mudalungu/ Organic reactions 131

and functional group Chemistry
2022
 3.0 Carboxylic Acids and Derivatives
3.0.11 Nucleophilic Acyl Substitution Reactions-Nitriles and Their Reactions

Example: Show how you could prepare 2-methylpentan-3-one by reaction of a Grignard reagent with a nitrile.

Strategy Look at the structure of the target ketone. The C=O carbon comes from the carbon, one of the two attached
groups comes from the Grignard reagent, and the other attached group was present in the nitrile. Thus, there are two ways to
prepare a ketone from a nitrile by Grignard addition.

Dr. Mudalungu/ Organic reactions 132

and functional group Chemistry
2022