Transcript Example

Chapter 19
Carboxylic Acid Derivatives:
Nucleophilic Acyl Substitution
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Nomenclature of Carboxylic Acid Derivatives
Acyl Halides
O
RC
X
Name the acyl group and add the word chloride,
fluoride, bromide, or iodide as appropriate.
Acyl chlorides are, by far, the most frequently
encountered of the acyl halides.
Acyl Halides
O
Acetyl chloride
CH3CCl
O
H2C
CHCH2CCl
3-butenoyl chloride
or but-3-enoyl chloride
O
F
CBr
p-fluorobenzoyl bromide
or 4-fluorobenzoyl bromide
Acid Anhydrides
O O
RCOCR'
When both acyl groups are the same, name the
acid and add the word anhydride.
When the groups are different, list the names of the
corresponding acids in alphabetical order and add
the word anhydride.
Acid Anhydrides
O O
CH3COCCH3
Acetic anhydride
O O
C6H5COCC6H5
Benzoic anhydride
O O
C6H5COC(CH2)5CH3
Benzoic heptanoic anhydride
Esters
O
RCOR'
Name as alkyl alkanoates.
Cite the alkyl group attached to oxygen first (R').
Name the acyl group second; substitute the suffix
-ate for the -ic ending of the corresponding acid.
Esters
O
CH3COCH2CH3
Ethyl acetate
O
CH3CH2COCH3
Methyl propanoate
O
COCH2CH2Cl
2-chloroethyl benzoate
Amides Having an NH2 Group
O
RCNH2
Identify the corresponding carboxylic acid.
Replace the -ic acid or -oic acid ending with –amide.
Amides Having an NH2 Group
O
CH3CNH2
Acetamide
O
(CH3)2CHCH2CNH2
3-Methylbutanamide
O
CNH2
Benzamide
Amides Having Substituents on N
O
RCNHR'
O
and
RCNR'2
Name the amide as before.
Precede the name of the amide with the name of
the appropriate group or groups.
Precede the names of the groups with the letter N(standing for nitrogen and used as a locant).
Amides Having Substituents on N
O
N-Methylacetamide
CH3CNHCH3
O
CN(CH2CH3)2
N,N-Diethylbenzamide
O
CH3CH2CH2CNCH(CH3)2
CH3
N-Isopropyl-N-methylbutanamide
Nitriles
RC
N
Add the suffix -nitrile to the name of the parent
hydrocarbon chain (including the triply bonded carbon
of CN).
or: Replace the -ic acid or -oic acid name of the
corresponding carboxylic acid with –onitrile.
or: Name as an alkyl cyanide (functional class name).
Nitriles
CH3C
C6H5C
N
N
CH3CHCH3
C
N
Ethanenitrile
or: Acetonitrile
or: Methyl cyanide
Benzonitrile
2-Methylpropanenitrile
or: Isopropyl cyanide
Structure and Reactivity
of
Carboxylic Acid Derivatives
Nucleophilic Acyl Substitution
 Interconversion of acid derivatives occurs by
nucleophilic acyl substitution.
 Nucleophile adds to the carbonyl, forming a
tetrahedral intermediate.
 Elimination of the leaving group regenerates the
carbonyl.
 This is an addition–elimination mechanism.
 Nucleophilic acyl substitutions are also called
acyl transfer reactions because they transfer the
acyl group to the attacking nucleophile.
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Chapter 21
16
Mechanism of Acyl Substitution
Step 1: Addition of the nucleophile forms the tetrahedral intermediate.
File Name: AAALCMJ0
Step 2: Elimination of the leaving group regenerates the carbonyl.
File Name: AAERSTX0
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Chapter 21
17
Most
reactive
O
CH3C
O
CH3C
Cl
Least
stabilized
O
OCCH3
O
CH3C
OCH2CH3
O
Least
reactive
CH3C
NH2
Most
stabilized
Electron Delocalization and the Carbonyl Group
The main structural feature that distinguishes acyl
chlorides, anhydrides, thioesters, esters, and
amides is the interaction of the substituent with the
carbonyl group. It can be represented in
resonance terms as:
•• –
•• O ••
••
O ••
RC
••
X
RC
+
•• –
•• O ••
••
X
RC
+
X
Electron Delocalization and the Carbonyl Group
The extent to which the lone pair on X can be
delocalized into C=O depends on:
1) The electronegativity of X
2) How well the lone pair orbital of X interacts
with the  orbital of C=O
••
•• –
•• –
•• O ••
•• O ••
O ••
RC
••
X
RC
+
••
X
RC
+
X
Orbital Overlaps in Carboxylic Acid Derivatives
orbital of carbonyl group
Orbital Overlaps in Carboxylic Acid Derivatives
lone pair orbital
of substituent
Orbital Overlaps in Carboxylic Acid Derivatives
electron pair of substituent delocalized into
carbonyl orbital
least stabilized C=O
O
RCCl
O O
RCOCR'
O
RCOR'
O
RCNR'2
O
RCO–
most stabilized C=O
Reactivity is Related to Structure
Stabilization
Relative rate
of hydrolysis
RCCl
O O
very small
1011
RCOCR'
small
107
RCOR'
O
moderate
1.0
RCNR'2
large
< 10-2
O
O
The more
stabilized the
carbonyl group,
the less reactive
it is.
Nucleophilic Acyl Substitution
In general:
••
••
O ••
R
C
O ••
+
X
HY
R
C
+
Y
Reaction is feasible when a less stabilized
carbonyl is converted to a more stabilized
one (more reactive to less reactive).
HX
least stabilized C=O
O
RCCl
O O
RCOCR'
O
A carboxylic acid
RCOR'
derivative can be
O
converted by
RCNR'2
O
nucleophilic acyl
substitution to any other
RCO–
type that lies below it in
this table.
most stabilized C=O
Nucleophilic Acyl Substitution
in Acyl Chlorides
Preparation of Acyl Chlorides
From carboxylic acids and thionyl chloride
(Section 12.7)
O
(CH3)2CHCOH
O
SOCl2
heat
(CH3)2CHCCl + SO2 + HCl
(90%)
Reactions of Acyl Chlorides
O
RCCl
O O
RCOCR'
O
RCOR'
O
RCNR'2
O
RCO–
Reactions of Acyl Chlorides
Acyl chlorides react with carboxylic acids to give
acid anhydrides:
O O
O
O
RCCl + R'COH
RCOCR'
H
via:
R
O
O
C
OCR'
Cl
+
HCl
Example
O
O
CH3(CH2)5CCl +
CH3(CH2)5COH
pyridine
O O
CH3(CH2)5COC(CH2)5CH3
(78-83%)
Reactions of Acyl Chlorides
Acyl chlorides react with alcohols to give esters:
O
O
RCCl + R'OH
RCOR'
H
O
via:
R
C
Cl
OR'
+
HCl
Example
O
O
C6H5CCl + (CH3)3COH
pyridine
C6H5COC(CH3)3
(80%)
Reactions of Acyl Chlorides
Acyl chlorides react with ammonia and amines
to give amides:
O
O
RCCl + R'2NH + HO–
RCNR'2 + H2O
H
+ Cl–
O
via:
R
C
Cl
NR'2
Example
O
O
C6H5CCl + HN
NaOH
H2O
C6H5CN
(87-91%)
Reactions of Acyl Chlorides
Acyl chlorides react with water to give
carboxylic acids (carboxylate ion in base):
O
RCCl + H2O
O
RCCl + 2HO–
O
RCOH
+
HCl
+
Cl–
O
RCO–
+ H2O
Reactions of Acyl Chlorides
Acyl chlorides react with water to give
carboxylic acids (carboxylate ion in base):
O
O
RCCl + H2O
RCOH
H
O
via:
R
C
Cl
OH
+
HCl
Example
O
C6H5CH2CCl + H2O
O
C6H5CH2COH + HCl
Reactivity
Acyl chlorides undergo nucleophilic
substitution much faster than alkyl chlorides.
O
C6H5CCl
Relative rates of
hydrolysis (25°C)
1,000
C6H5CH2Cl
1
Nucleophilic Acyl Substitution in
Acid Anhydrides
Anhydrides can be prepared from acyl
chlorides as described in previous slides
Some Anhydrides are Industrial Chemicals
O O
O
O
CH3COCCH3
O
Acetic
anhydride
Phthalic
anhydride
O
O
O
Maleic
anhydride
From Dicarboxylic Acids
Cyclic anhydrides with 5- and 6-membered
rings can be prepared by dehydration of
dicarboxylic acids:
O
H
COH
C
H
C
H
tetrachloroethane
O
130°C
COH
O
O
H
O
(89%)
+ H2 O
Reactions of Anhydrides
O O
RCOCR'
O
RCOR'
O
RCNR'2
O
RCO–
Reactions of Acid Anhydrides
Carboxylic acid anhydrides react with alcohols
to give esters:
O O
RCOCR + R'OH
O
RCOR'
O
+ RCOH
Normally, symmetrical anhydrides are used
(both R groups the same).
Reaction can be carried out in presence of
pyridine (a base) or it can be catalyzed by acids.
Reactions of Acid Anhydrides
Carboxylic acid anhydrides react with alcohols
to give esters:
O O
O
RCOCR + R'OH
RCOR'
H
O
via:
R
OR'
C
OCR
O
O
+ RCOH
Example
O O
CH3COCCH3
+ CH3CHCH2CH3
OH
H2SO4
O
CH3COCHCH2CH3
CH3
(60%)
Reactions of Acid Anhydrides
Acid anhydrides react with ammonia and amines
to give amides:
O
O O
RCNR'2 + RCO–
RCOCR + 2R'2NH
H
+
R'2NH2
O
via:
O
R
NR'2
C
OCR
O
Example
O O
CH3COCCH3
+ H2N
CH(CH3)2
O
CH3CNH
CH(CH3)2
(98%)
Reactions of Acid Anhydrides
Acid anhydrides react with water to give
carboxylic acids (carboxylate ion in base):
O O
RCOCR
O
+ H2O
O O
RCOCR
2RCOH
O
+ 2HO–
2RCO–
+
H2O
Reactions of Acid Anhydrides
Acid anhydrides react with water to give
carboxylic acids (carboxylate ion in base):
O O
RCOCR
O
+ H2O
2RCOH
H
O
R
OH
C
OCR
O
Example
O
O
COH
O + H2O
COH
O
O
Sources of Esters
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Esters are Very Common Natural Products
O
CH3COCH2CH2CH2CH3
butyl acetate
Contributes to characteristic pear odor.
Esters of Glycerol
O
O CH2OCR'
RCOCH
CH2OCR"
O
R, R', and R" can be the same or different.
Called "triacylglycerols," "glyceryl triesters," or
"triglycerides“.
Fats and oils are mixtures of glyceryl triesters.
Esters of Glycerol
O
O CH2OC(CH2)16CH3
CH3(CH2)16COCH
CH2OC(CH2)16CH3
O
Tristearin: found in many
animal and vegetable fats.
Cyclic Esters (Lactones)
O
O
CH2(CH2)6CH3
H
H
(Z)-5-Tetradecen-4-olide
(sex pheromone of female Japanese beetle)
Preparation of Esters
Fischer esterification (Sections 15.8 and 18.14)
From acyl chlorides (Sections 15.8 and 19.4)
From acid anhydrides (Sections 15.8 and 19.5)
Baeyer-Villiger oxidation of ketones
Baeyer-Villiger Oxidation
The Baeyer-Villiger Oxidation is the oxidative cleavage
of a carbon-carbon bond adjacent to a carbonyl, which
converts ketones to esters and cyclic ketones to
lactones. The Baeyer-Villiger can be carried out with
peracids, such as MCBPA, or with hydrogen peroxide
and a Lewis acid.
Physical Properties of Esters
Boiling Points
CH3
CH3CHCH2CH3
O
CH3COCH3
Boiling
point
28°C
57°C
OH
CH3CHCH2CH3
99°C
Esters have higher
boiling points than
alkanes because they
are more polar.
Esters cannot form
hydrogen bonds to
other ester molecules,
so have lower boiling
points than alcohols.
Solubility in Water
CH3
Solubility
(g/100 g)
CH3CHCH2CH3
O
~0
CH3COCH3
33
OH
CH3CHCH2CH3
12.5
Esters can form
hydrogen bonds to
water, so low molecular
weight esters have
significant solubility in
water.
Solubility decreases
with increasing number
of carbons.
Reactions of Esters:
A Preview
Reactions of Esters
With Grignard reagents (Section 19.12)
Reduction with LiAlH4 (Section 19.13)
With ammonia and amines (Sections 19.11)
Hydrolysis (Sections 19.9 and 19.10)
Acid-Catalyzed Ester Hydrolysis
Is the reverse of Fischer esterification:
O
RCOR'
+
H+
H2O
O
RCOH + R'OH
Maximize conversion to ester by removing water.
Maximize ester hydrolysis by having large excess of water.
Equilibrium is closely balanced because carbonyl group of
ester and of carboxylic acid are comparably stabilized.
Example
O
CHCOCH2CH3 + H2O
Cl
HCl, heat
O
CHCOH
Cl
(80-82%)
+ CH3CH2OH
Ester Hydrolysis in Aqueous Base
Saponification
O
RCOR'
O
+
HO–
RCO– + R'OH
Is called saponification
Is irreversible, because of strong stabilization of carboxylate
ion
If carboxylic acid is desired product, saponification is followed
by a separate acidification step (simply a pH adjustment).
Example
O
CH2OCCH3
CH3
+
NaOH
water, methanol, heat
O
CH2OH
(95-97%)
CH3
+
CH3CONa
Example
O
H2C
CCOCH3
CH3
1. NaOH, H2O, heat
2. H2SO4
O
H2C
(87%)
CCOH
CH3
+
CH3OH
Soap-Making
Basic hydrolysis
of the glyceryl
triesters (from
fats and oils)
gives salts of
long-chain
carboxylic acids.
These salts are
soaps.
O
CH3(CH2)xCOK
O
CH2OC(CH2)xCH3
O
CH3(CH2)yCOCH
CH2OC(CH2)zCH3
O
K2CO3, H2O, heat
O
CH3(CH2)yCOK
O
CH3(CH2)zCOK
Which Bond is Broken when Esters are
Hydrolyzed in Base?
••
••
•• O
••
RCO
••
– ••
R' + •• OH
••
•• O
••
•• •–
RCO • + R'OH
••
••
One possibility is an SN2 attack by hydroxide on
the alkyl group of the ester. Carboxylate would
be the leaving group.
Which Bond is Broken when Esters are
Hydrolyzed in Base?
••
••
•• O
RC
– ••
OR' + •• OH
••
••
••
•• O
RC
– ••
OH + •• OR'
••
••
••
A second possibility is nucleophilic acyl
substitution.
18O
Labeling Gives the Answer
O
CH3CH2COCH2CH3 +
NaOH
O
CH3CH2CONa
18O
+
CH3CH2OH
retained in alcohol, not carboxylate; therefore
nucleophilic acyl substitution is mechanism.
Stereochemistry Gives the Same Answer
H
O
CH3C
Alcohol has same
configuration at
chirality center as
ester; therefore,
nucleophilic acyl
substitution is
mechanism.
C6H5
O
C
KOH, H2O
O
CH3COK + HO
CH3
H
C6H5
C
CH3
not SN2
Reactions of Esters
with Ammonia and Amines
Reactions of Esters
O
RCOR'
O
RCNR'2
O
RCO–
Reactions of Esters
Esters react with ammonia and amines
to give amides:
O
O
RCOR'
+ R'2NH
RCNR'2 +
H
O
via:
R
C
OR'
NR'2
R'OH
Example
O
H2C
CCOCH3 +
NH3
CH3
H2O
O
H2C
(75%)
CCNH2
CH3
+
CH3OH
Example
O
FCH2COCH2CH3
+
NH2
heat
O
FCH2CNH
(61%)
+
CH3CH2OH
Grignard reagents react with esters
to yield tertiary alcohols
R'
••
R' + OCH
diethyl
3
– R
••
R C
ether
C
MgX O ••
••
••
OCH3
••
• O • + MgX
• •• •–
but species formed is
unstable and dissociates
under the reaction
conditions to form a ketone
Grignard reagents react with esters
– R
R'
••
+ OCH
3
••
C
R'
diethyl
ether
R
OCH3
••
• O • + MgX
• •• •–
MgX O ••
••
This ketone then goes
on to react with a
R
second mole of the
Grignard reagent to
give a tertiary alcohol.
C
••
–CH3OMgX
R'
C
O ••
••
Example
O
2 CH3MgBr + (CH3)2CHCOCH3
1. diethyl ether
2. H3O+
OH
(CH3)2CHCCH3
CH3
(73%)
Two of the groups
attached to the
tertiary carbon
come from the
Grignard reagent.
Reduction of Esters with LiAlH4
Gives Primary Alcohols
Lithium aluminum hydride preferred for
laboratory reductions.
Sodium borohydride reduction is too slow
to be useful.
Catalytic hydrogenolysis used in industry
but conditions difficult or dangerous to duplicate
in the laboratory (special catalyst, high
temperature, high pressure).
Example: Reduction of an Ester
O
COCH2CH3
1. LiAlH4
diethyl ether
2. H2O
CH2OH +
(90%)
CH3CH2OH
Amides
Physical Properties of Amides
Amides are less reactive toward nucleophilic
acyl substitution than other acid derivatives.
Physical Properties of Amides
Amides are capable of hydrogen bonding.
Preparation of Amides
Amides are prepared from amines by acylation
with:
Acyl chlorides (Table 19.1)
Anhydrides (Table 19.2)
Esters (Table 19.4)
Preparation of Amides
Amines do not react with carboxylic acids to give
amides. The reaction that occurs is proton-transfer
(acid-base).
O
RCOH + R'NH2
O
–
RCO
+
+ R'NH3
If no heat-sensitive groups are present, the
resulting ammonium carboxylate salts can be
converted to amides by heating.
Preparation of Amides
Amines do not react with carboxylic acids to give
amides. The reaction that occurs is proton-transfer
(acid-base).
O
O
RCOH + R'NH2
–
RCO
+
+ R'NH3
heat
O
RCNHR' + H2O
Example
O
COH +
H2N
225°C
O
+ H2O
CNH
(80-84%)
Hydrolysis of Amides
File Name: AAALCNU0
Amides are hydrolyzed to the carboxylic acid under acidic or
basic conditions.
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92
Acid Hydrolysis of Amides
File Name: AAALCNW0
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93
Example: Acid Hydrolysis
O
O
CH3CH2CHCNH2
CH3CH2CHCOH
H2O
H2SO4
heat
+
+ NH4 HSO4–
(88-90%)
Basic Hydrolysis of Amides
File Name: AAALCNV0
 Similar to the hydrolysis of an ester.
 The hydroxide ion attacks the carbonyl, forming a
tetrahedral intermediate.
 The amino group is eliminated and a proton is
transferred to the nitrogen to give the carboxylate salt.
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Chapter 21
95
Example: Basic Hydrolysis
O
NH2
CH3CNH
O
KOH
H2O
heat
Br
CH3COK +
Br
(95%)
Reduction of an Amide to an Amine
File Name: AAALCOE0
 Amides will be reduced to the corresponding
amine by LiAlH4.
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Formation of Lactams
File Name: AAALCPQ0
 Five-membered lactams (g-lactams) and sixmembered lactams (-lactams) often form on
heating or adding a dehydrating agent to the
appropriate g-amino acid or -amino acid.
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b-Lactams
File Name: AAALCPS0
 Unusually reactive four-membered ring amides are
capable of acylating a variety of nucleophiles.
 They are found in three important classes of
antibiotics: penicillins, cephalosporins, and
carbapenems.
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Mechanism of b-Lactam
Acylation
File Name: AAALCPR0
 The nucleophile attacks the carbonyl of the fourmembered ring amide, forming a tetrahedral
intermediate.
 The nitrogen is eliminated and the carbonyl reformed.
 Protonation of the nitrogen is the last step of the
reaction.
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Action of b-Lactam Antibiotics
File Name: AAALCPT0
 The b-lactams work by interfering with the synthesis
of bacterial cell walls.
 The acylated enzyme is inactive for synthesis of the
cell wall protein.
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101
Preparation of Nitriles
Nitriles are prepared by:
Nucleophilic substitution by cyanide on
alkyl halides (Sections 8.1 and 8.11)
Cyanohydrin formation (Section 17.7)
Dehydration of amides
Example
KCN
CH3(CH2)8CH2Cl
ethanolwater
SN2
CH3(CH2)8CH2C
(95%)
N
Example
O
OH
KCN
CH3CH2CCH2CH3
H+
CH3CH2CCH2CH3
C
N
(75%)
Dehydration of Amides to Nitriles
File Name: AAALCPO0
 Strong dehydrating agents can eliminate the
elements of water from a primary amide to give
a nitrile.
 Phosphorus oxychloride (POCl3) or phosphorus
pentoxide (P2O5) can be used as dehydrating
agents.
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Hydrolysis of Nitriles
O
RCN + 2H2O + H
+
+
RCOH + NH4
Hydrolysis of nitriles resembles the hydrolysis
of amides. The reaction is irreversible.
Ammonia is produced and is protonated to
ammonium ion in acid solution.
Example: Acid Hydrolysis
O
CH2CN
CH2COH
H2O
H2SO4
heat
NO2
NO2
(92-95%)
Hydrolysis of Nitriles
File Name: AAALCNX0
 Heating with aqueous acid or base will hydrolyze
a nitrile to a carboxylic acid.
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Example: Basic Hydrolysis
O
CH3(CH2)9CN
1. KOH, H2O, heat
2. H+
CH3(CH2)9COH
(80%)
Reduction of Nitriles to Primary
Amines
File Name: AAALCOG0
 Nitriles are reduced to primary amines by
catalytic hydrogenation or by lithium aluminum
hydride reduction.
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Reaction of Nitriles with Grignards
File Name: AAALCON0
 A Grignard reagent or organolithium reagent
attacks the cyano group to form an imine,
which is hydrolyzed to a ketone.
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Example
C
N + CH3MgI
F3C
1. diethyl ether
2. H3O+, heat
O
CCH3
F3C
(79%)