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Relative Reactivity of Carboxylic Acid
Derivatives1
Nucleophiles react more readily with unhindered carbony l groups
More electrophilic carbony l groups are more reactiv e to addition (acy l halides are most reactiv e, amides are least)
The intermediate with the best leav ing group decomposes f astest
Conversion of Carboxylic Acids into Acid
Chlorides2
Reaction with thiony l chloride, SOCl2
Mechanism of Thionyl Chloride Reaction
3
Nucleophilic acy l substitution pathway
Carboxy lic acid is conv erted into a chlorosulfite
which then reacts with chloride
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Conversion of Carboxylic Acids into Acid
Anhydrides4
Acid anhy drides can be deriv ed f rom two molecules of carboxy lic acid by strong heating to remov e water
Conversion of Carboxylic Acids into
Esters5
Methods include reaction of a carboxy late anion with a primary alky l halide
Fischer Esterification6
Heating a carboxy lic acid in an alcohol solv ent
containing a small amount of strong acid produces an
ester f rom the alcohol and acid
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Mechanism of the Fischer Esterification
7
The reaction is an acid-cataly zed, nucleophilic acy l substitution of a carboxy lic acid
When 18O-labeled methanol reacts with benzoic acid, the methy l benzoate produced is 18O-labeled but the water produced is unlabeled
Acid Halides8
Chemistry of Acid Halides9
Acid chlorides are prepared f rom carboxy lic acids by reaction with SOCl2
Reaction of a carboxy lic acid with PBr3 y ields the acid bromide
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Reactions of Acid Halides10
Nucleophilic acy l substitution
Halogen replaced by OH, by OR, or by NH2
Reduction y ields a primary alcohol
Grignard reagent y ields a tertiary alcohol
Hydrolysis: Conversion of Acid Halides
into Acids11
Acid chlorides react with water to y ield carboxy lic
acids
HCl is generated during the hy droly sis: a base is
added to remov e the HCl
Substitution in Synthesis12
We can readily conv ert a more reactiv e acid deriv ativ e into a less reactiv e one
Reactions in the opposite sense are possible but require more complex approaches
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Conversion of Acid Halides to Esters13
Esters are produced in the reaction of acid chlorides with alcohols in the presence of py ridine or NaOH. This is called Alcoholysis
The reaction is better with less steric bulk
Aminolysis: Conversion of Acid Halides
into Amides14
Amides result f rom the reaction of acid chlorides with
NH3, primary (RNH2) and secondary amines (R2NH)
The reaction with tertiary amines (R3N) giv es an
unstable species that cannot be isolated
HCl is neutralized by the amine or an added base
Reduction: Conversion of Acid Chlorides
into Alcohols15
LiAlH4 reduces acid chlorides to y ield aldehy des and
then primary alcohols
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Reaction of Acid Chlorides with Grignard
Reagent gives a 3º Alcohol16
Grignard reagents react with acid chlorides to y ield tertiary alcohols in which two of the substituents are the same
Formation of Ketones from Acid Chlorides
17
Reaction of an acid chloride with a lithium
diorganocopper (Gilman) reagent, Li+ R2Cu
Addition produces an acy l diorganocopper
intermediate, f ollowed by loss of R Cu and f ormation
of the ketone
Conversion of Acid halide to Acid
Anhydrides18
Prepared by nucleophilic acyl substitution of
a carboxylate w ith an acid chloride
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Reactions of Acid Anhydrides19
Similar to acid chlorides in reactivity
Acetylation20
Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines
Chemistry of Esters21
Many esters are pleasant-smelling liquids: f ragrant odors of f ruits and f lowers
Also present in f ats and v egetable oils
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Preparation of Esters22
Esters are usually prepared f rom carboxy lic acids
Reactions of Esters23
Less reactive tow ard nucleophiles than are
acid chlorides or anhydrides
Cyclic esters are called lactones and react
similarly to acyclic esters
Hydrolysis: Conversion of Esters into
Carboxylic Acids24
An ester is hy droly zed by aqueous base or aqueous acid to y ield a carboxy lic acid plus an alcohol
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Mechanism of Ester Hydrolysis25
Hy droxide cataly sis v ia an addition intermediate
Aminolysis of Esters26
Ammonia reacts with esters to f orm amides
Reduction: Conversion of Esters into
Alcohols27
Reaction with LiAlH4 y ields primary alcohols
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Mechanism of Reduction of Esters28
Hy dride ion adds to the carbony l group, f ollowed by
elimination of alkoxide ion to y ield an aldehy de
Reduction of the aldehy de giv es the primary alcohol
Reaction of Esters with Grignard
Reagents29
React with 2 equiv alents of a Grignard reagent to
y ield a tertiary alcohol
Chemistry of Amides30
Amides are abundant in all living
organisms…proteins, nucleic acids, and other
pharmaceuticals have amide functional groups
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Preparation of Amides31
Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines
Reactions of Amides32
Heating in either aqueous acid or aqueous base produces a carboxy lic acid and amine
Acidic hy droly sis by nucleophilic addition of water to the protonated amide, f ollowed by loss of ammonia
Basic Hydrolysis of Amides33
Addition of hy droxide and loss of amide ion
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Reduction: Conversion of Amides into
Amines34
Reduced by LiAlH4 to an amine rather than an
alcohol
Conv erts C=O CH2
Mechanism of Reduction35
Addition of hy dride to carbony l group
Loss of the oxy gen as an aluminate anion to giv e an
iminium ion intermediate which is reduced to the
amine
Uses of Reduction of Amides36
Works with cy clic and acy clic
Good route to cy clic amines
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Conversion of Amide to Nitrile37
Reaction of primary amides RCONH2 with SOCl2 or
POCl3
Not limited by steric hindrance or side reactions (as is
the reaction of alky l halides with NaCN)
Mechanism of Dehydration of Amides38
Nucleophilic amide oxy gen atom attacks SOCl2f ollowed by deprotonation and elimination
Naming Carboxylic Acid
Derivatives
Thioesters, RCOSR’
Names similar to the corresponding esters
Prefix thio- is added to carboxylate if ester has a
common name
–oate or carboxylate is replaced by –thioate or
carbothioate if ester has a systematic name
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Chemistry of Thioesters and AcylPhosphates:
Biological Carboxylic Acid Derivatives40
Nucleophilic carboxyl
substitution in nature
often involves a
thioester or acyl
phosphate
Acetyl CoA’s are most
common thioesters in
nature