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Organic Chemistry
4th Edition
Paula Yurkanis Bruice
Chapter 17
Carbonyl
Compounds I
Nucleophilic Acyl
Substitution
Irene Lee
Case Western Reserve University
Cleveland, OH
©2004, Prentice Hall
Carbonyl Compounds with Groups that
Can Be Replaced by a Nucleophile
Nomenclature of Carboxylic Acids
Acyl Halides
O
O
O
C
CH3
C
H3C
Cl
C
Cl
ethanoyl chloride
acetyl chloride
CH3CH2CHCH2
Br
3-methylpentanoyl bromide
b-methylvalerylbromide
cyclopentanecarbonyl
chloride
Acid Anhydrides
R
O
O
C
C
O
R
Esters
Salts of Carboxylic Acids
Cyclic Esters Are Known as Lactones
Amides
Amides with Substituent(s) Bonded to the Nitrogen
O
O
C
C
CH3CH2
CH3CH2CH2CH2
NH
NCH2CH3
CH3
N-cyclohexylpropanamide
N-ethyl-N-methylpentanamide
Cyclic Amides Are Known as Lactams
O
a
O
NH
a
NH
b
d
g
2-azacyclohexanone
d-valerolactam
O
b
NH
g
2-azacyclopentanone
g-butyrolactam
2-azacyclobutanone
b-propiolactam
Nitriles
CH3
CH3C
C
N
ethanenitrile
acetonitrile
methylcyanide
N
benzenecarbonitrile
benzonitrile
phenyl cyanide
CH2
CHC
propenenitrile
acrylonitrile
CH3CHCH2CH2CH2C
N
5-methylhexanenitrile
d-methylcapronitrile
isohexyl cyanide
N
Two major resonance contributors in esters,
carboxylic acids, and amides
Carboxylic acids have relatively high boiling points
because
Amides have the
highest boiling
points
The reactivity of carbonyl compounds resides in the
polarity of the carbonyl group in a nucleophilic acyl
substitution reaction
Z– will be expelled if it is a much weaker base than Y–
(k–1 >> k2)
Y– will be expelled if it is a much weaker base
(k2 >> k–1)
Reaction Coordinate Diagrams for
Nucleophilic Acyl Substitution
Reactions
(a) the Nu– is a weaker base
(b) the Nu– is a stronger base
(c) the Nu– and the leaving group have similar basicities
A Molecular Orbital Description of How
Carbonyl Compounds React
All carboxylic acid derivatives react by the same general
mechanism
The tetrahedral intermediate eliminates the weakest base
If the nucleophile is neutral …
Reactions of Acyl Halides
Formation of Amides from Acyl Halides
Tertiary amines cannot form amides
Reactions of Acid Anhydrides
Acid anhydrides do not react with sodium chloride or with
sodium bromide
Reactions of Esters
a hydrolysis reaction
a transesterification
an aminolysis reaction
There are no negatively
charged species in the
reaction
Excess water will force the equilibrium to the right
Alcohols that have low boiling points can be removed by
distillation as they are formed
Acid catalyzes the reaction by …
Esters with tertiary alkyl groups undergo hydrolysis much
more rapidly than do others
H
R
O
CH3
C
C
CH3
R
O
OH
CH3
C
C
CH3
O
CH3
CH3
H
HO
OH2
CH3
C
CH3
CH3
CH3
HO
C
CH3
CH3
Hydroxide ion increases the rate of formation of the
tetrahedral intermediate
This reaction is not reversible
Elucidating the reaction mechanism of nucleophilic acyl
substitution
Fats and Oils Are Triesters of Glycerol
Nucleophilic Acyl Substitution of
Carboxylic Acids
Carboxylic acids do not undergo nucleophilic acyl
substitution reactions with amines
Hydrolysis of Amides
Dehydration of an Amide
Dehydration reagents commonly used are SOCl2, P2O5,
or POCl3
An amide cannot be hydrolyzed without a catalyst
An acid catalyst can make a group a better leaving group
Hydrolysis of an Imide
The Gabriel Synthesis
Nitriles are harder to hydrolyze than amides
Designing the Synthesis of Cyclic
Compounds
Formation of lactones
Preparation of a compound with a ketone group attached
to a benzene ring
Preparation of a cyclic ester
Activation of Carboxylic Acids
The goal is to convert the OH group into a better leaving
group such that the acyl chloride can be prepared
The acyl halide can be used to prepare other carboxylic
acid derivatives
Activated Carboxylic Acid Derivatives
in Living Organisms
Dicarboxylic acids readily lose water when heated if they
can form a cyclic anhydride with a five- or a six-membered ring