Chapter 21. Carboxylic Acid Derivatives

Industrial Organic Chemistry
Chapter 21.
Carboxylic Acid Derivatives:
Nucleophilic Acyl Substitution Reactions

핵심심
Instructor: Prof. Junhwan Choi

Introduction
• Carboxylic acid derivatives: compounds in which an acyl group is bonded to
an electronegative atom or substituent that can act as a leaving group.
• Many kinds of acid derivatives: acid halides, acid anhydrides, esters, amides,
thioesters and acyl phosphates.
21-1. Naming Carboxylic Acid Derivatives
Acid Halides, RCOX
• First identifying the acyl group and then the halide.
• Naming carboxylic acid derivative is based on carboxylic acid.
• Replacing the –ic acid or –oic acid ending with –oyl, or the –carboxylic acid
ending with –carbonyl.
Acid Anhydrides, RCO2COR’
• Replacing the word acid with anhydride.
• Unsymmetrical anhydrides: named by listing the two acids alphabetically and

then adding anhydride.
Esters, RCO2R’
• First identifying the alkyl group attached to oxygen and replacing the –ic acid
ending with –ate.
ㅇ 0 이R
!
없다맨다상하지있다 ,
Amides, RCONH2
• Replacing the –oic acid or –ic acid with –amide, or by replacing the –carboxylic
acid ending with –carboxamide.
• If the nitrogen atom is further substituted, the compound: first identifying the
substituents groups and the parent amide. The letter N is added.
Thioesters, RCOSR’
• Thioesters are named like the corresponding esters.
• The prefix thio– is added: for example, acetate becomes thioacetate.
• The –oate or –carboxylate ending is replaced by –thioate or –carbothioate.
Acyl Phosphate, RCO2PO3 and RCO2PO3R’
• 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.
• Summary of naming carboxylic acid derivatives.
21-2. Nucleophilic Acyl Substitution Reactions
• When a nucleophile adds to an aldehyde or ketone, the initially formed
tetrahedral intermediate can be protonated to yield an alcohol.
• However, in a carboxylic acid derivative, the tetrahedral intermediate
eliminates one of the two substituents: nucleophilic acyl substitution.
Net effect: a substitution of the

nucleophile for the –Y group
originally bonded to the acyl
carbon.
• 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.
Relative Reactivity of Carboxylic Acid Derivatives
• Both the initial addition and the subsequent elimination can affect the overall
rate of a nucleophilic acyl substitution reaction.
• The addition is generally the rate-limiting step.
• Any factor that makes carbonyl group more reactive toward nucleophiles
favors the substitution process: steric and electronic factors.
• Steric factor: unhindered, accessible carbonyl groups react more readily.
• Electronically, strongly polarized acyl compounds react more readily.
• Thus, acid chlorides are the most reactive due to the electronegative atom,
whereas amides are the least reactive.
• The polarization of a carbonyl group: similar to the reactivity of aromatic ring.

• A chlorine substituent inductively withdraws electrons from an acyl group.
• Amino, methoxy and methylthio substituents donate electrons to acyl groups.
• It is usually possible to convert a more reactive acid derivative into a less
reactive one (not vice versa).
• General reaction chemistry of carboxylic acid derivatives.
Hydrolysis: reaction with water (a carboxylic acid).
Alcoholysis: reaction with an alcohol (an ester).
Aminolysis: reaction with ammonia or an amine (an amide).
Reduction: reaction with a hydride reducing agent (an aldehyde or an alcohol).
Grignard reaction: reaction with an organometallic reagent (a ketone or an alcohol).
• Example: Predict the product of the following nucleophilic acyl substitution
reaction of benzoyl chloride with 2-propanol.
칙체
핵
• Acid chloride: nucleophilic acyl substitution.

• Identify the leaving group (Cl ) and the nucleophile (an alcohol).
• Example: Predict the product of the following nucleophilic acyl substitution
reaction of benzoyl chloride with 2-propanol.
• Example: Rank the compounds in each of the following sets in order of their
expected reactivity toward nucleophilic acyl substitution.
(a) Electronegative chloride withdraws electrons from acyl group (inductive effect),
whereas –OCH3 in ester and –NH2 in amide donate electrons to acyl group
(resonance effect).
(b) All three compounds are ester. A compound has more electronegative group
would show higher reactivity (inductive effect).
• Example: Rank the compounds in each of the following sets in order of their
expected reactivity toward nucleophilic acyl substitution.
More reactive
More reactive
21-3. Reactions of Carboxylic Acids
• The direct nucleophilic acyl substitution of a carboxylic acid is difficult
because –OH is a poor leaving group: it is necessary to enhance the reactivity
of the carboxylic acid.
• Protonation of the carboxyl group by using a strong acid and make it a better
acceptor (better site to be attacked by nucleophile) or by converting –OH into
a better leaving group.
• Acid chloride, anhydrides, esters and amins can be prepared from carboxylic
acid by nucleophilic acyl substitution.
Conversion of Carboxylic Acids into Acid Chlorides
• Carboxylic acids are converted into acid chlorides by treatment with thionyl
chloride, SOCl2.
• The carboxylic acid is first converted into an acyl chlorosulfite intermediate,

thereby replacing the –OH group into a better leaving group.
• The chlorosulfite then reacts with a nucleophilic chloride ion.
매좋은
/avcag 그룹으로
바꿔줌 ,
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.
Conversion of Carboxylic Acids into Esters

• The SN2 reaction of a carboxylate anion with a primary alkyl halide gives ester.
• Esters can also be synthesized by a nucleophilic acyl substitution of a carboxylic
acid with an alcohol: Fischer esterification reaction.
• Carboxylic acids are not reactive enough to undergo nucleophilic addition, but
their reactivity is greatly enhanced with a strong acid catalyst.
• The acid protonates the carbonyl oxygen atom, thereby giving a positive
charge to the carboxylic acid and making it much more reactive.
• The net effect of Fischer esterification is substitution of an –OH group by –OR’.

• All steps are reversible: ester
formation is favored with a large excess
of alcohol, but carboxylic acid is favored
with a large excess of water (hydrolysis).
• The
carboxylic acid and
are broken.
• Example: How might you prepare the following ester using a Fischer
esterification reaction?
• Identify the two parts of the ester: the acyl part comes from the carboxylic
acid and the –OR part comes from the alcohol.
• Example: How might you prepare the following ester using a Fischer
esterification reaction?
Conversion of Carboxylic Acids into Amides
• Amides are difficult to prepare by direct reaction of carboxylic acids with amines
because amines are bases.
• Amides are usually prepared by activating the carboxylic acid with
dicyclohexylcarbodiimide , followed by addition of the amine.
뺏어음
크더이상산뜸동할수와
새를
• The carboxylic acid
사
first adds to a C=N of
DCC.
• Nucleophilic attack of
the amine gives a
tetrahedral
intermediate.
• The intermediate
loses
dicyclohexylurea and
gives the amide. 좋은리빙그룹으로
벼하
D
Conversion of Carboxylic Acids into Alcohols
• The reduction of carboxylic acids is a nucleophilic acyl substitution reaction.
• –OH to give an aldehyde and further reduction to a primary
alcohol by nucleophilic addition.
• The aldehyde intermediate is much more reactive, so it reacts immediately
and is not isolated.
• 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 the intermediate, the two oxygens are complexed to a Lewis acidic aluminum.
21-4. Chemistry of Acid Halides
Preparation of Acid Halides
• Acid chlorides are prepared from carboxylic acids by reaction with thionyl
2 . Similar reaction with 3 yields

the acid bromide.
Reactions of Acid Halides
• Acid halides are the most reactive of carboxylic acid derivatives and can be
converted into many other kinds of compounds by nucleophilic acyl
substitution mechanisms.
• We will see only for acid chlorides, similar processes take place with other acid
halides.
• Acid chlorides react with water to yield carboxylic acid.

• A typical nucleophilic acyl substitution process: it is initiated by attack of
water on the acid chloride carbonyl group. Elimination of Cl and loss of H+
give the product carboxylic acid.
• HCl is formed during hydrolysis: this reaction is often carried out with a base
(pyridine or NaOH) to remove the HCl.
• 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.
alcoholysis
• Acid chlorides react with alcohols to yield esters (similar to carboxylic acid
formation): the most common method for preparing esters.
• Alcoholysis reactions are usually carried out in the presence of pyridine or NaOH
to remove HCl by-product.
• Alcoholysis is strongly affected by steric hinderance: a reactivity order among
alcohols of primary > secondary > tertiary.
• It becomes often possible to selectively esterify an unhindered alcohol in the
presence of a more hindered one.
aminolysis
• Acid chlorides react with ammonia and amines to give amides.
• Both monosubstituted and disubstituted amines can be used but not
trisubstituted (R3N) because amine loses proton during the reaction.
• Two equivalents of the amine must be used: one equivalent reacts with the
acid chloride and one equivalent reacts with HCl by-product.
• If the amine component is valuable (expensive), amide synthesis is often carried
out using one equivalent of an inexpensive base (NaOH).
• Example: How might you prepare N-methylpropanamide by reaction of an acid
chloride with an amine?
• As its name implies,

N-methylpropanamide: methyl group is substituted on the amide nitrogen (amine).
N-methylpropanamide : acyl group is propanoyl group (acid chloride)
• Example: How might you prepare N-methylpropanamide by reaction of an acid
chloride with an amine?
Conversion of Acid Chlorides into Alcohols: Reduction and Grignard
Reaction
• Acid chlorides are reduced by LiAlH4 to yield primary alcohols.
• Reduction occurs via a typical nucleophilic acyl substitution mechanism in
which adds to the carbonyl group (tetrahedral intermediate)
and expels Cl .
• Grignard reagents react with acid chlorides to yield tertiary alcohols with two
identical substituents.
• Grignard reagent adds to the acid chloride, loss of Cl from the tetrahedral
intermediate yields a ketone.
• A second equivalent of Grignard reagent immediately adds to the ketone to
produce a tertiary alcohol.
Conversion of Acid Chlorides into Ketones: Diorganocopper Reaction
• Initial nucleophilic acyl substitution on the acid chloride by the diorganocopper
anion to yield an acyl diorganocopper intermediate, followed by loss of R’Cu
and formation of the ketone (A ketone can be isolated in this reaction).
• The diorganocopper reaction occurs only with acid chlorides.

• Carboxylic acids, esters, acid anhydrides and amides do not react with lithium
diorganocopper reagents.
21-5. Chemistry of Acid Anhydrides
Preparation of Acid Anhydrides
• Acid anhydrides are typically prepared by nucleophilic acyl substitution reaction
of an acid chloride with a carboxylate anion.
• Both symmetrical and unsymmetrical acid anhydrides can be prepared.
Reactions of Acid Anhydrides
• The chemistry of acid anhydrides is similar to that of acid chlorides
(anhydrides react more slowly): hydrolysis, alcoholysis, aminolysis and
reduction.
• Acetic anhydrides react with alcohols to yield acetate esters.
• Acetic anhydrides react with amines to yield N-substituted acetamides (only half
of the anhydride molecule is used, inefficient).
21-6. Chemistry of Esters
Preparation of Esters
• Methods to prepare esters
SN2 reaction of a carboxylate ion with a primary alkyl halide
Fischer esterification of a carboxylic acid with an alcohol (+ acid catalyst)
Reaction between acid chloride and alcohol in the presence of bases
SnL
O
접수문에
공간적
4
만가능
6
Reactions of Esters
• Esters undergo the same kinds of reactions for other carboxylic acid
derivatives, but they are less reactive than acid chloride and anhydrides.
• An ester is hydrolyzed to yield a carboxylic acid and an alcohol (by aqueous

base or aqueous acid).
• Ester hydrolysis in basic solution is called saponification (soap is made by

boiling animal fat with aqueous base to hydrolyze the ester).
• Ester hydrolysis: a typical
nucleophilic acyl substitution.
• Hydroxide ion nucleophile
adds to the ester carbonyl group
to give a tetrahedral intermediate.
• Loss of alkoxide ion gives a
carboxylic acid, which is
deprotonated to give the
.
• Addition of aqueous HCl
protonates the carboxylate ion
and gives the carboxylic acid.
• Saponification occurs by cleavage of the C–OR bond in a carboxylic acid
rather than CO–R bond.
• Acid-catalyzed ester hydrolysis: the
reverse of a Fischer esterification.
• The ester is activated by
protonation of the carboxyl
oxygen atom.
• Nucleophilic addition of water.
• Transfer of a proton and
elimination of alcohol yields the
carboxylic acid.
aminolysis
• Esters react with ammonia and amines to yield amides (starting with an acid
chloride is easier).
• Esters are easily reduced with LiAlH4 to yield primary alcohols.

• Ester reduction: a hydride ion first adds to the carbonyl group and elimination
of alkoxide ion to yield an aldehyde. Further reduction gives alcohol.
• The aldehyde intermediate can be isolated if 1 equivalent of diisobutylaluminum

hydride ( °C to avoid further reduction).
• Example: What product would you expect from the reaction of butyrolactone with
LiAlH4? With DIBAH?
• Ester reduction by LiAlH4 gives alcohol, whereas reduction with DIBAH gives
aldehyde.
• Example: What product would you expect from the reaction of butyrolactone with
LiAlH4? With DIBAH?
• Esters react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol.

• A typical nucleophilic acyl substitution and two substituents are identical.
• The reaction occurs to give an intermediate ketone and further reaction with
Grignard reagent yields a tertiary alcohol.
21-7. Chemistry of Amides
• Amides are abundant in all living organisms because they are stable (amides
are the least reactive of the carboxylic acid derivative).
Preparation of Amides
• Amides can be prepared by reaction of an acid chloride with an amine
(ammonia, monosubstituted amines and disubstituted amines).
Reactions of Amides
• Amides undergo hydrolysis to yield carboxylic acids and ammonia (or amine)
upon heating in either aqueous acid or aqueous base (amides are least reactive).
• Acidic hydrolysis: nucleophilic addition of water to the protonated amide,
transfer of a proton to make the nitrogen a better leaving group and
subsequent elimination.
• Basic hydrolysis: nucleophilic addition of OH to the amide carbonyl group,
NH2 and subsequent deprotonation of the initially
formed carboxylic acid by ammonia.
• than acid-catalyzed reaction because amide
ion is a very poor leaving group.
• Amides can be reduced by LiAlH4. However, the product of the reduction is an

amine rather than an alcohol.
• The net effect of an amide reduction is the conversion of the amide carbonyl
2 .
• Amide reduction: nucleophilic addition of hydride ion to the carbonyl group,
expulsion of the oxygen atom as an aluminate anion leaving group to give an
iminium ion intermediate and further reduction by LiAlH4 gives the amine.
• Example: How could you prepare N-ethylaniline by reduction of an amide with
LiAlH4?
• Reduction of an amide with LiAlH4 yields an amine.

• Look for a CH2 position next to the nitrogen atom and replace that CH2 by C=O.
• Example: How could you prepare N-ethylaniline by reduction of an amide with
LiAlH4?
21-8. Chemistry of Thioesters and Acyl Phosphates
• A nucleophilic acyl
substitution in living
organisms: thioesters or acyl
phosphate.
• Example: reaction of coenzyme
A with an acyl adenylate (acyl
phosphate) gives acyl CoA.
21-9. Polyamides and Polyesters: Step-Growth Polymers
• When an amine reacts with an acid chloride, an amide is formed.
• If a diamine and a diacid chloride react, two amide bonds would form, linking
more and more molecules together until giant polyamide resulted.
• Step-growth polymers (vs. chain-growth polymers): the key bond-forming

step is often a nucleophilic acyl substitution of a carboxylic acid derivative.
• A step-growth polyamides (Nylons) are prepared by heating a diamine

(hexamethylenediamine) and a diacid (adipic acid).
Polyesters
• A step-growth polyesters are prepared by reaction between a dicarboxylate
(dimethyl terephthalate) and a diol (ethylene glycol).
• All are polyesters and are therefore susceptible to hydrolysis of their ester links.
• Absorbable sutures:
hydrolyzed and absorbed by
the body within 90 days after
surgery.
• Biodegradable electronics
Science, 2022, 376, 1006-1012.

Summary of Chapter 21
• Carboxylic acid derivatives and their nucleophilic acyl substitution reactions.
• Reactivity of an acid derivative depends on steric environment and on the

electronic nature of substituent Y.
Reactivity order: acid halide > acid anhydride > thioester > ester > amide.
• The most common reactions
Hydrolysis: substitution by water to yield an acid.
Alcoholysis: substitution by alcohol to yield an ester.
Aminolysis: substitution by amine to yield an amide.
Reduction: substitution by hydride ion to yield an alcohol.
Grignard reaction: substitution by organomagnesium halide to yield an alcohol.

Chapter 21. Carboxylic Acid Derivatives

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Chapter 21. Carboxylic Acid Derivatives

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Industrial Organic Chemistry

Carboxylic Acid Derivatives:

Nucleophilic Acyl Substitution Reactions

Instructor: Prof. Junhwan Choi

• Unsymmetrical anhydrides: named by listing the two acids alphabetically and

Net effect: a substitution of the

• The polarization of a carbonyl group: similar to the reactivity of aromatic ring.

• Acid chloride: nucleophilic acyl substitution.

• The carboxylic acid is first converted into an acyl chlorosulfite intermediate,

Conversion of Carboxylic Acids into Esters

• The net effect of Fischer esterification is substitution of an –OH group by –OR’.

2 . Similar reaction with 3 yields

• Acid chlorides react with water to yield carboxylic acid.

• Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate

• As its name implies,

• The diorganocopper reaction occurs only with acid chlorides.

• Acetic anhydrides react with alcohols to yield acetate esters.

• An ester is hydrolyzed to yield a carboxylic acid and an alcohol (by aqueous

• Ester hydrolysis in basic solution is called saponification (soap is made by

• Esters are easily reduced with LiAlH4 to yield primary alcohols.

• The aldehyde intermediate can be isolated if 1 equivalent of diisobutylaluminum

• Esters react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol.

• Amides can be reduced by LiAlH4. However, the product of the reduction is an

• Reduction of an amide with LiAlH4 yields an amine.

• Step-growth polymers (vs. chain-growth polymers): the key bond-forming

• A step-growth polyamides (Nylons) are prepared by heating a diamine

Science, 2022, 376, 1006-1012.

• Reactivity of an acid derivative depends on steric environment and on the

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