CHAPTER 16

Carboxylic Acid
Derivatives: Nucleophilic
Acyl Substitution
Reactions
Carboxylic Acid Derivatives
Carboxylic acid derivatives
 Compounds in which acyl group is bonded to an electronegative
atom or substituent that can act as a leaving group
 Converted to parent carboxylic acid by hydrolysis reaction
Carboxylic Acid Derivatives
Chemistry of all carboxylic derivatives is similar
 All undergo nucleophilic acyl substitution reaction
16-1 Naming Carboxylic Acid Derivatives
Acid Halides, RCOX
 Identify first the acyl group and then the halide
 Acyl group identified by replacing the –ic acid ending with –oyl
or the –carboxylic acid ending with –carbonyl
Naming Carboxylic Acid Derivatives
Acid Anhydrides, RCO2COR′
 Symmetrical anhydrides of monocarboxylic acids and cyclic
anhydrides of dicarboxylic acids named by replacing acid
with anhydride
Naming Carboxylic Acid Derivatives
Unsymmetrical anhydrides
 Prepared from two different carboxylic acids
 Named by citing the two acids alphabetically and then
adding anhydride
Naming Carboxylic Acid Derivatives
Esters, RCO2R′
 Esters are named by first identifying the alkyl group
attached to the oxygen and then the carboxylic acid with the
–ic acid ending replaced by -ate
Naming Carboxylic Acid Derivatives
Amides, RCONH2
 Amides with unsubstituted –NH2 group named by replacing
the –oic acid or –ic acid ending with –amide, or by replacing
the –carboxylic acid ending with -carboxamide
Naming Carboxylic Acid Derivatives
 If nitrogen is further substituted the compound is named by
first identifying the substituent groups and then the parent
amide
 Substituents are preceded by N
Naming Carboxylic Acid Derivatives
Thioesters, RCOSR′
 Thioesters are named like the corresponding esters
 If ester has common name the prefix thio- is used
 If ester has a systematic name the –oate or –carboxylate ending
is replaced by –thioate or -carbothioate
Naming Carboxylic Acid Derivatives
Acyl Phosphates, RCO2PO32- and RCO2PO3R′-
 Acyl phosphates are named by citing the acyl group and
adding the word phosphate
 If alkyl group is attached to one of the phosphate oxygens it
is identified after the name of the acyl group
Naming Carboxylic Acid Derivatives
16-2 Nucleophilic Acyl Substitution Reactions
Nucleophilic Acyl Substitution
 Nucleophile adds to carbonyl of carboxylic acid derivative forming
a tetrahedral intermediate
 C=O bond is restored by elimination of one of the two substituents
originally bonded to the carbonyl carbon leading to a net
substitution
 Overall two-step substitution that involves a tetrahedral
intermediate
Nucleophilic Acyl Substitution Reactions
Aldehydes and ketones do not undergo nucleophilic acyl
substitution reactions
 Aldehydes and ketones do not possess a suitable leaving group
 Nucleophilic attack to an aldehyde or ketone results in addition of
the nucleophile to the original carbonyl carbon
 C=O bond is not restored
 Carbon of original carbonyl group remains sp3-hybridized, singly
bonded to four substituents
Nucleophilic Acyl Substitution Reactions
Relative reactivity of carboxylic acid derivatives
 Both addition and elimination steps affect the overall rate of
nucleophilic acyl substitution reaction
 Addition step is generally rate-limiting due to steric and
electronic factors
 Sterically unhindered acid derivatives are more accessible to
approaching nucleophile
Nucleophilic Acyl Substitution Reactions
 Strongly polarized acyl groups make the C=O carbon atom
more electrophilic
Nucleophilic Acyl Substitution Reactions
Usually possible to
convert more
reactive acid
derivatives to less
reactive ones
 Acid halides and
acid anhydrides do
not persist in living
organisms because
they react rapidly
with water
Nucleophilic Acyl Substitution Reactions
Five common reactions for carboxylic acid derivatives
 Hydrolysis
 Reaction with water to yield carboxylic acid
 Alcoholysis
 Reaction with alcohol to yield ester
 Aminolysis
 Reaction with ammonia or amine to yield amide
 Reduction
 Reaction with hydride reducing agent to yield aldehyde or
alcohol
 Grignard reaction
 Reaction with organomagnesium reagent to yield alcohol
Nucleophilic Acyl Substitution Reactions
Worked Example 16.1
Predicting the Product of a Nucleophilic Acyl
Substitution Reaction
Predict the product of the following nucleophilic acyl
substitution reaction of benzoyl chloride with propan-2-ol
Worked Example 16.1
Predicting the Product of a Nucleophilic Acyl
Substitution Reaction

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 isopropyl
benzoate.
Worked Example 16.1
Predicting the Product of a Nucleophilic Acyl
Substitution Reaction

Solution
16-3 Reactions of Carboxylic Acids
Direct nucleophilic acyl substitution of a carboxylic
acid is difficult because –OH group is a poor
leaving group
 Reactivity is enhanced by
 Protonating carbonyl oxygen of carboxyl group
making the carbonyl carbon atom more electrophilic
 Converting –OH into better leaving group
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Conversion of Carboxylic Acids into Acid Halides
(RCO2H→RCOX)
Conversion to accomplished by treatment of carboxylic acid
with thionyl chloride, SOCl2, or PBr3
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
 Conversion to acid chloride proceeds through chlorosulfite
intermediate, thereby replacing the –OH group with a better
leaving group
 Chlorosulfite intermediate then reacts with a nucleophilic
chloride ion
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Conversion of Carboxylic Acids into Acid Anhydrides
(RCO2H→RCO2COR′)
 Two molecules of carboxylic acid will lose 1 equivalent of
water by heating
 Preparation is uncommon due to high temperatures required
for the dehydration
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Conversion of Carboxylic Acids into Esters
(RCO2H→RCO2R′)
 Most useful reaction of carboxylic acids
 Several methods for accomplishing transformation
 SN2 reaction with carboxylate anion with primary alkyl halide
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
 Fischer esterification reaction
 Acid-catalyzed nucleophilic acyl substitution reaction of a
carboxylic acid with an alcohol
 The need to use an excess of liquid alcohol as solvent
limits Fischer esterification to the synthesis of methyl,
ethyl, propyl, and butyl esters
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Mechanism of Fischer
esterification
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Isotopic labeling experiments provide experimental evidence
for Fischer esterification mechanism
Worked Example 16.2
Synthesizing an Ester from an Acid

How might you prepare the following ester using a Fischer

esterification reaction?
Worked Example 16.2
Synthesizing an Ester from an Acid

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
Worked Example 16.2
Synthesizing an Ester from an Acid

Solution
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Conversion of Carboxylic Acids into Amides
(RCO2H→RCONH2)
 Amides 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
 Carboxylic acids are first activated with dicyclohexylcarbodiimide
(DCC)
 Intermediate then treated with amine
 Key step in laboratory synthesis of small proteins
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Mechanism of amid formation by reaction of a carboxylic acid and an
amine with dicyclohexylcarbodiimide (DCC)
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Mechanism of amid formation by reaction of a carboxylic acid and an
amine with dicyclohexylcarbodiimide (DCC)
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Conversion of Carboxylic Acids into Alcohols
(RCO2H→RCH2OH)
 Carboxylic acids reduced by LiAlH4 to give primary alcohols
by nucleophilic acyl substitution of –H for –OH
 Reaction proceeds through reactive aldehyde intermediate
which is not isolated
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Hydride ion is a base and a nucleophile
 Reaction involves carboxylate anion and gives high-
energy dianion intermediate complexed to a Lewis acidic
aluminum species
 Reaction requires high temperatures and extended
reaction times
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids
Biological Conversions of Carboxylic Acids
 Direct conversion of carboxylic acid to acyl
derivative by nucleophilic acyl substitution does not
occur in biological chemistry
 Acid must first be activated
 In living organisms, activation often accomplished by
reaction of acid with ATP to give acyl adenosyl
phosphate, or acyl adenylate
 Acyl adenylate is a mixed anhydride between carboxylic
and adenosine monophosphate (AMP), also known as
adenylic acid
 Occurs in biosynthesis of fats
Nucleophilic Acyl Substitution Reactions of
Carboxylic Acids

Fatty-acid biosyntheses
proceeds through acyl
adenylate

Acyl adenylate
undergoes nucleophilic
acyl substitution with –SH
group on coenzyme A
16-4 Reactions of Acid Halides
Reactions of Acid Halides
 Acid halides are among the most reactive of
carboxylic acid derivatives
 Halogen can be replaced by –OH to yield an acid, by
–OCOR to yield an anhydride, by –OR to yield an
ester, by –NH2 to yield an amide, or by R′ to yield a
ketone
Reactions of Acid Halides
Conversion of Acid Halides into Acids: Hydrolysis
(RCOX→RCO2H)
 Acid chlorides react with water to yield carboxylic acids
 Water attacks the acid chloride carbonyl group
 Tetrahedral intermediate undergoes elimination of Cl - and
loss of H+ to give the product carboxylic acid
Reactions of Acid Halides
Conversion of Acid Halides into Anhydrides
(RCO2H→RCO2COR′)
 Nucleophilic acyl substitution of an acid chloride with a
carboxylate anion gives an acid anhydride
 Both symmetrical and unsymmetrical anhydrides prepared
this way
Reactions of Acid Halides
Conversion of Acid Halides into Esters: Alcoholysis
(RCOX→RCO2R′)
 Acid chlorides react with alcohols to yield esters
 Most common method for preparing esters in laboratory
 Reaction is carried out in presence of pyridine or NaOH to
react with HCl that is formed
Reactions of Acid Halides
 Reaction of alcohol with acid chloride strongly affected by
steric hindrance
 Bulky groups on either partner slow down reaction
 Often possible to esterify an unhindered alcohol selectively in
presence of hindered alcohol
Reactions of Acid Halides
Conversion of Acid Halides into Amides: Aminolysis
(RCOX→RCONH2)
 Acid halides rapidly react with ammonia and amines to form amides
 Most common laboratory preparation of amides using monosubstituted
and disubstituted amines
 Trisubstituted amines cannot be used
Reactions of Acid Halides
 Because HCl is formed during reaction, 2 equivalents of
amine must be used
 First equivalent reacts with acid chloride
 Second equivalent reacts with HCl by-product
 NaOH is used if amine reactant is valuable, as in synthesis of
trimetozine
Worked Example 16.3
Synthesizing an Amide from an Acid Chloride

How might you prepare N-methylpropanamide by reaction of

an acid chloride with an amine?
Worked Example 16.3
Synthesizing an Amide from an Acid Chloride

Strategy
As its name implies, N-methylpropanamide can be
made by reaction of methylamine with the acid
chloride of propanoic acid
Worked Example 16.3
Synthesizing an Amide from an Acid Chloride

Solution
Reactions of Acid Halides
Conversion of Acid Chlorides into Alcohols:
Reduction and Grignard Reaction
 Acid chlorides are reduced by LiAlH4 to yield primary alcohols
 Reduction occurs through aldehyde which is immediately reduced
in a second step to yield the primary alcohol
Reactions of Acid Halides
 Grignard reagents react with acid chlorides to yield
tertiary alcohols in which two of the substituents are the
same
 First equivalent of Grignard reagent yields a ketone
 Second equivalent of Grignard reagent adds to ketone
to produce an alcohol
Reactions of Acid Halides
Conversion of Acid Chlorides into Ketones:
(RCOCl→RCOR′)
 Ketone can be isolated from the reaction of an acid
chloride with a lithium diorganocopper reagent, LiR2Cu
 Carboxylic acids, ester, acid anhydrides, and amides
do not react with lithium diorganocopper reagents
Reactions of Acid Halides
 Synthesis of manicone, an ant pheromone, is accomplished by
reaction of lithium diethylcopper with (E)-2,4,dimethylhex-2-enoyl
chloride
16.5 Reactions of Acid Anhydrides
Similar chemistry to acid halides
 Acid anhydrides react more slowly than acid halides
Reactions of Acid Anhydrides
Conversion of Acid Anhydrides Into Esters
(RCO2COR′→ RCO2R′2)
 Acetic anhydride is used to prepare acetate esters from
alcohols
Reactions of Acid Anhydrides
Conversion of Acid Anhydrides Into Amides
(RCO2COR′→ RCONH2)
 Acetic anhydride is used to prepare N-substituted
acetamides from amines
16-6 Reactions of Esters
Esters are among
most widespread
of all naturally
occurring compounds

Dibutyl phthalate is
a common plasticizer

Esters undergo nucleophilic substitution reactions more slowly than acid

halides or acid anhydrides
All reactions of esters are equally applicable to acyclic and cyclic esters,
called lactones
Reactions of Esters
All reactions of esters are equally applicable to acyclic and cyclic esters,
called lactones
Reactions of Esters
Conversion of Esters into Carboxylic Acids:
Hydrolysis (RCO2R′→ RCO2H)
 Esters undergo both acidic and basic hydrolysis to yield
carboxylic acids and alcohols
Reactions of Esters
 Hydrolysis of ester in base: Saponification
 Named after the Latin word sapo, meaning soap
 Soap is made from boiling animal fat with base
 Basic hydrolysis occurs through nucleophilic acyl
substitution pathway
 Isotopic labeling experiments support mechanism
 Occurs by cleavage of C-OR′ bond rather than the CO-
R′ bond
Reactions of Esters
Mechanism of base-
induced ester hydrolysis
(saponification)
Reactions of Esters
Acid-catalyzed ester hydrolysis occurs by more than
one mechanism
 Most common mechanism is reverse of Fischer
esterification reaction
 Protonation of carboxyl oxygen activates ester
toward nucleophilic attack
 Nucleophilic addition of water occurs
 A proton is removed from the water oxygen
 The alcohol oxygen is protonated making it a better
leaving group
 Alcohol is eliminated forming the carboxylic acid
Reactions of Esters
Mechanism of acid-
catalyzed ester
hydrolysis
Reactions of Esters
Ester hydrolysis is common in biological chemistry
 Digestion of fat and oils involves two sequential nucleophilic
acyl substitution reactions
Reactions of Esters
Conversion of Esters into Amides: Aminolysis
(RCO2R′→ RCONH2)
 Esters react with ammonia and amines to yield amides
 Not as common as amide formation via reaction with acid
chlorides
Reactions of Esters
Conversion of Esters into Alcohols: Reduction and
Grignard Reaction
 Esters are reduced by treatment with LiAlH4 to yield primary
alcohols
 Reaction proceeds through an aldehyde intermediate
Reactions of Esters
 Aldehyde intermediate can be isolated if 1 equivalent of
less reactive diisobutylaluminum hydride (DIBAH) is used
 Reaction is carried out at – 78°C to avoid over reduction
of aldehyde to the alcohol

 Partial reductions of esters to aldehydes occur in numerous

biological pathways
Reactions of Esters
 Esters and lactones react with 2 equivalents of Grignard
reagent to yield tertiary alcohols
 Reaction proceeds through ketone intermediate
16-7 Reactions of Amides
Amides are abundant in proteins, nucleic acids,
and many pharmaceuticals
 Amides are the least reactive of the common carboxylic
acid derivatives and undergo relatively few nucleophilic
acyl substitution reactions
Reactions of Amides
Conversion of Amides into Carboxylic Acids:
Hydrolysis (RCONH2→ RCO2H)
 Amides undergo hydrolysis to yield carboxylic acids plus
amine on heating in aqueous acid and aqueous base
 Acidic hydrolysis occurs by nucleophilic addition of water to
protonated amide followed by the loss of water
Reactions of Amides
 Basic hydrolysis occurs by nucleophilic addition of –OH
group followed by deprotonation of –OH group and
elimination of -NH2
Reactions of Amides
 Amide hydrolysis is the initial step in the digestion of dietary
proteins
 Reaction is catalyzed by protease enzymes and occurs by
mechanism almost identical to fat hydrolysis
Reactions of Amides
Conversion of Amides to Amines: Reduction
(RCONH2→(RCH2 NH2)
 Amides are reduced by LiAlH4 to amines
 Reduction of amide carbonyl into a methylene
 (C=O CH2)
 This conversion is specific for amides
Reactions of Amides
 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
 Iminium ion intermediate is further reduced by LiAlH4 to
yield the amine
Reactions of Amides
 Aminolysis is effective with both acyclic and cyclic amides,
or lactams
 Good method for preparing cyclic amines
Worked Example 16.4
Synthesizing an Amine from an Amide

How might you prepare N-ethylaniline by reduction of an

amide with LiAlH4?
Worked Example 16.4
Synthesizing an Amine from an Amide

Strategy
Reduction of an amide with LiAlH4 yields an amine.
To find the starting material for synthesis of N-
ethylaniline, look for CH2 position next to the
nitrogen atom and replace that CH2 by C=O. In this
case, the amide is N-phenylacetamide
Worked Example 16.4
Synthesizing an Amine from an Amide

Solution
16-8 Reactions of Thioesters and AcylPhosphates:
Biological Carboxylic Acid Derivatives
Substrate for nucleophilic acyl substitution reaction in
living organisms is generally either a thioester
(RCOSR′) or an acyl phosphate (RCO2PO32- or
RCO2PO3R′-)
 Thioesters and acyl phosphates are not as reactive as acid
chlorides or acid anhydrides
 Stable enough to exist in living organisms
 Reactive enough to undergo acyl substitution
Reactions of Thioesters and AcylPhosphates:
Biological Carboxylic Acid Derivatives
Acyl CoA’s such as acetyl
CoA are most common
thioesters in nature
 Acetyl CoA is formed by
nucleophilic acyl
substitution of coenzyme
A (CoA) with acetyl
adenylate
Reactions of Thioesters and AcylPhosphates:
Biological Carboxylic Acid Derivatives
N-acetylglucosamine is synthesized by an aminolysis
reaction between glucosamine and acetyl CoA
 N-acetylglucosamine is a component of cartilage and other
connective tissue
Reactions of Thioesters and AcylPhosphates:
Biological Carboxylic Acid Derivatives
(R)-Mevaldehyde is an intermediate in terpenoid synthesis
 (R)-Mevaldehyde is synthesized by reduction of (3R)-3-hydroxy-
3-methylglutaryl CoA by hydride donation from NADPH
16-9 Polyamides and Polyesters: Step-Growth
Polymers
Chain-growth polymers
 Polymers produced by chain reactions
 Amide polymers are formed from reaction of diamines with
diacid chlorides
 Ester polymers are formed from reaction of diols with diacids
Polyamides and Polyesters: Step-Growth
Polymers
Polyamides and Polyesters: Step-Growth
Polymers
Polyamides and Polyesters: Step-Growth
Polymers
Polyamides (Nylons)
 Nylon 66 is polymer of adipic acid (hexanedioic acid) with
hexamethylenediamine (hexane-1,6-diamine)
Polyamides and Polyesters: Step-Growth
Polymers
Polyesters
 Dacron (Mylar) is polyester made by reaction between
dimethyl terephthalate (dimethyl benzene-1,4-dicarboxylate)
and ethylene glycol
 Tensile strength of Dacron (Mylar) film is nearly equal to that
of steel
Polyamides and Polyesters: Step-Growth
Polymers
Lexan is polymer of diphenyl carbonate with bisphenol A
 Unusually high impact strength
 Used in bicycle safety helmets and laptop computer cases
Polyamides and Polyesters: Step-Growth
Polymers
Sutures and Biodegradable
Polymers
 Biodegradable polymers
 Polymers that are broken
down rapidly by soil
microorganisms
 Common biodegradable
polymers include polyglycolic
acid (PGA), polylactic acid
(PLA), and
polyhydroxybutyrate (PHB)
 90/10 copolymer of PGA with
PLA is used to make
absorbable sutures
 Sutures are entirely
hydrolyzed and absorbed
by body within 90 days
after surgery
16-10 Spectroscopy of Carboxylic Acid
Derivatives
Infrared Spectroscopy
 Carboxylic acid derivatives have characteristic C=O
absorptions
Spectroscopy of Carboxylic Acid Derivatives

Nuclear Magnetic Resonance Spectroscopy

1H NMR

 Hydrogens on carbon adjacent to carbonyl group are

slightly deshielded and absorb near 2 d
Spectroscopy of Carboxylic Acid Derivatives

Nuclear Magnetic Resonance Spectroscopy

13C NMR

 Carbonyl carbon atoms of carboxylic acid derivatives absorb

in range between 160 to 180 d