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Chapter 16
Carboxylic Acid Derivatives:
Nucleophilic Acyl Substitution
Reactions
© 2006 Thomson Higher Education
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
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
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
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 substitution
Nucleophilic Acyl Substitution
Reactions
Aldehydes and ketones do not undergo nucleophilic acyl substitution
reactions
• Aldehydes and ketones do not possess a suitable leaving group
• 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
Four common reactions
for carboxylic acid
derivatives
•
Hydrolysis
•
•
Alcoholysis
•
•
Reaction with alcohol to
yield ester
Aminolysis
•
•
Reaction with water to
yield carboxylic acid
Reaction with ammonia
or amine to yield amide
Reduction
•
Reaction with hydride
reducing agent to yield
aldehyde or alcohol
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
16.3 Nucleophilic Acyl Substitution
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 Chlorides
• Laboratory conversion accomplished by treatment of
carboxylic acid with thionyl chloride, SOCl2
Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
• Reaction 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
• 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
• 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
Excess liquid alcohol used as solvent limits
reaction to methyl, ethyl, propyl and butyl
esters
Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
Mechanism of Fischer
esterification reaction
Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
Isotopic labeling experiments provide experimental
evidence for Fischer esterification mechanism
Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
Conversion of Carboxylic Acids into Amides
•
•
•
•
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
Amides 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 amide
formation by reaction
of carboxylic acid with
DCC
Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
Conversion of Carboxylic Acids into Alcohols
• Carboxylic acids reduced by LiAlH4 to give primary
alcohols by nucleophilic acyl substitution of –H for –OH
• Reaction proceeds through reactive aldehyde
intermediate
Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
Hydride ion is a base and a nucleophile
• Reaction involves carboxylate anion and gives highenergy 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 Chemistry of Acid Halides
Conversion of Acid Halides into Acids: Hydrolysis
•
•
•
Acid halides are among the most reactive of carboxylic acid
derivatives
Acid chlorides react with water to give tetrahedral intermediate
Tetrahedral intermediate expels Cl- and loses H+ to give
carboxylic acid and HCl
Chemistry of Acid Halides
Conversion of Acid Halides into Anhydrides
• Nucleophilic acyl substitution of an acid chloride with
a carboxylate anion gives an acid anhydride
• Both symmetrical and unsymmetrical anhydrides
prepared this way
Chemistry of Acid Halides
Conversion of Acid Halides into Esters: Alcoholysis
• 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
Chemistry 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
Chemistry of Acid Halides
Conversion of Acid Halides into Amides: Aminolysis
•
•
•
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
Chemistry 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
16.5 Chemistry of Acid Anhydrides
Similar chemistry to acid anhydrides
• Acid anhydrides react more slowly than acid halides
Chemistry of Acid Anhydrides
• Acetic anhydride is used to prepare acetate esters
from alcohols and N-substituted acetamides from
amines
•
More nucleophilic –NH2 group reacts rather than less
nucleophilic –OH group
16.6 Chemistry 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
Chemistry of Esters
Conversion of Esters into Carboxylic Acids: Hydrolysis
• Esters undergo both acidic and basic hydrolysis to
yield carboxylic acids and alcohols
• Saponification
•
•
•
Basic ester hydrolysis
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
Chemistry of Esters
Mechanism of baseinduced ester
hydrolysis
(saponification)
Chemistry 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
Chemistry of Esters
Mechanism of acidcatalyzed ester
hydrolysis
Chemistry of Esters
Ester hydrolysis is common in biological chemistry
• Digestion of fat and oils involves two sequential
nucleophilic acyl substitution reactions
Chemistry of Esters
Conversion of Esters into Amides: Aminolysis
• Esters react with ammonia and amines to yield
amides
• Not as common as reaction with acid chlorides
Chemistry 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
Chemistry 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
Chemistry of Esters
• Esters and lactones react with 2 equivalents of
Grignard reagent to yield tertiary alcohols
•
Reaction proceeds through ketone intermediate
16.7 Chemistry 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
Chemistry of Amides
Conversion of Amides into Carboxylic Acids:
Hydrolysis
• 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
Chemistry of Amides
•
Basic hydrolysis occurs by nucleophilic addition of –OH
group followed by deprotonation of –OH group and
elimination of -NH2
Chemistry 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
Chemistry of Amides
Conversion of Amides to Amines: Reduction
• Amides are reduced by LiAlH4 to amines
•
•
•
Reduction of amide carbonyl into a methylene
(C=O
CH2)
This conversion is specific for amides
Chemistry 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
Chemistry of Amides
• Aminolysis is effective with both acyclic and cyclic
amides, or lactams
• Good method for preparing cyclic amines
16.8 Chemistry 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
Chemistry 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
Chemistry 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
Chemistry of Thioesters and AcylPhosphates:
Biological Carboxylic Acid Derivatives
(R)-Mevaldehyde is an intermediate in terpenoid synthesis
•
(R)-Mevaldehyde is sythesized by reduction of (3R)-3hydroxy-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 (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 benzene1,4-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
1H
NMR
• Hydrogens on carbon adjacent to carbonyl group are
slightly deshielded and absorb near 2d
Spectroscopy of Carboxylic
Acid Derivatives
13C
NMR
• Carbonyl carbon atoms of carboxylic acid derivatives
absorb in range between 160 to 180 d