chapter 19 carboxylic acid derivatives: nucleophilic acyl substitution copyright © the mcgraw-hill...
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Chapter 19Chapter 19Carboxylic Acid Derivatives:Carboxylic Acid Derivatives:
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Nomenclature of Carboxylic Acid DerivativesNomenclature of Carboxylic Acid Derivatives
Acyl Halides
RC
O
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
CH3CCl
O
Acetyl chloride
3-butenoyl chlorideor but-3-enoyl chloride
O
H2C CHCH2CCl O
CBrF p-fluorobenzoyl bromideor 4-fluorobenzoyl bromide
Acid Anhydrides
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.
RCOCR'
O O
Acid Anhydrides
Acetic anhydride
Benzoic anhydride
Benzoic heptanoic anhydride
CH3COCCH3
O O
C6H5COCC6H5
O O
C6H5COC(CH2)5CH3
O O
Esters
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.
RCOR'
O
Esters
CH3COCH2CH3
O
Ethyl acetate
Methyl propanoate
2-chloroethyl benzoate
O
CH3CH2COCH3
COCH2CH2Cl
O
Amides Having an NH2 Group
Identify the corresponding carboxylic acid.
Replace the -ic acid or -oic acid ending with –amide.
RCNH2
O
Amides Having an NH2 Group
CH3CNH2
O
Acetamide
3-Methylbutanamide
O
(CH3)2CHCH2CNH2
CNH2
O Benzamide
Amides Having Substituents on N
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).
RCNHR'
O
and RCNR'2
O
Amides Having Substituents on N
CH3CNHCH3
O
N-Methylacetamide
N-Isopropyl-N-methylbutanamide
CN(CH2CH3)2
O N,N-Diethylbenzamide
O
CH3CH2CH2CNCH(CH3)2
CH3
Nitriles
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).
RC N
Nitriles
CH3C NEthanenitrileor: Acetonitrileor: Methyl cyanide
C6H5C N Benzonitrile
NC
CH3CHCH3 2-Methylpropanenitrileor: Isopropyl cyanide
Structure and ReactivityStructure and Reactivity
ofof
Carboxylic Acid DerivativesCarboxylic Acid Derivatives
© 2013 Pearson Education, Inc. Chapter 21 16
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.
© 2013 Pearson Education, Inc. Chapter 21 17
Mechanism of Acyl SubstitutionStep 1: Addition of the nucleophile forms the tetrahedral intermediate.
Step 2: Elimination of the leaving group regenerates the carbonyl.
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CH3C
O
Cl
CH3C
O
OCCH3
O
CH3C
O
OCH2CH3
CH3C
O
NH2
Most
reactive
Least
reactive
Least
stabilized
Most
stabilized
RC
O
X••
••••
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:
–
RC
O
X••
••••••
+
RC
O
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
RC
O
X••
•••• –
RC
O
X••
••••••
+
RC
O
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
RCO–
O
least stabilized C=O
most stabilized C=O
RCCl
O
RCOCR'
O O
RCOR'
O
RCNR'2
O
Reactivity is Related to Structure
RCOCR'
O ORCCl
O
RCOR'
O
RCNR'2
O
Stabilization
very small
small
large
moderate
Relative rate
of hydrolysis
1011
107
< 10-2
1.0
The more
stabilized the
carbonyl group,
the less reactive
it is.
Nucleophilic Acyl Substitution
In general:
O•• ••
CR X
+ HY
O•• ••
CR Y
+ HX
Reaction is feasible when a less stabilized
carbonyl is converted to a more stabilized
one (more reactive to less reactive).
RCO–
O
least stabilized C=O
most stabilized C=O
RCCl
O
RCOCR'
O O
RCOR'
O
RCNR'2
OA carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table.
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
in Acyl Chloridesin Acyl Chlorides
Preparation of Acyl Chlorides
From carboxylic acids and thionyl chloride(Section 12.7)
(CH3)2CHCOH
OSOCl2
heat(CH3)2CHCCl
O
+ SO2 + HCl
(90%)
RCO–
O
RCCl
O
RCOCR'
O O
RCOR'
O
RCNR'2
O
Reactions of Acyl Chlorides
Reactions of Acyl Chlorides
+ R'COH
O
RCOCR'
O O
+ HCl
Acyl chlorides react with carboxylic acids to giveacid anhydrides:
via: CR
O
Cl
OCR'
HO
RCCl
O
CH3(CH2)5CCl
O
Example
+ CH3(CH2)5COH
O
pyridine
CH3(CH2)5COC(CH2)5CH3
O O
(78-83%)
Reactions of Acyl Chlorides
+ RCOR'
O
+ HCl
Acyl chlorides react with alcohols to give esters:
R'OH via: CR
O
Cl
OR'
H
RCCl
O
Example
+ (CH3)3COHpyridine
(80%)
C6H5COC(CH3)3
O
C6H5CCl
O
Reactions of Acyl Chlorides
+ RCNR'2
O
+ H2O
Acyl chlorides react with ammonia and aminesto give amides:
R'2NH + HO–
+ Cl– via: CR
O
Cl
NR'2
H
RCCl
O
Example
C6H5CCl
O
+NaOH
(87-91%)
H2O
HN
C6H5CN
O
Reactions of Acyl Chlorides
+ RCOH
O
+ HCl
Acyl chlorides react with water to givecarboxylic acids (carboxylate ion in base):
H2O
+ RCO–
O
+ Cl–2HO–
+ H2O
RCCl
O
RCCl
O
RCCl
O
Reactions of Acyl Chlorides
+ RCOH
O
+ HCl
Acyl chlorides react with water to givecarboxylic acids (carboxylate ion in base):
H2O
via: CR
O
Cl
OH
H
Example
C6H5CH2CCl
O
+ H2O C6H5CH2COH
O
+ HCl
Reactivity
C6H5CCl
O
C6H5CH2Cl
Acyl chlorides undergo nucleophilic
substitution much faster than alkyl chlorides.
Relative rates ofhydrolysis (25°C)
1,000 1
Nucleophilic Acyl Substitution Nucleophilic Acyl Substitution
in in
Acid AnhydridesAcid AnhydridesAnhydrides can be prepared from acyl Anhydrides can be prepared from acyl
chlorides as described in previous slideschlorides as described in previous slides
Some Anhydrides are Industrial Chemicals
CH3COCCH3
O O
Aceticanhydride
O
O
O
O
O
O
Phthalicanhydride
Maleicanhydride
From Dicarboxylic Acids
Cyclic anhydrides with 5- and 6-membered
rings can be prepared by dehydration of
dicarboxylic acids:
C
C
H
H COH
COH
O
O
O
O
O
H
H
tetrachloroethane
130°C
(89%)
+ H2O
RCO–
O
RCOCR'
O O
RCOR'
O
RCNR'2
O
Reactions of Anhydrides
Reactions of Acid Anhydrides
+ RCOR'
O
+
Carboxylic acid anhydrides react with alcoholsto give esters:
R'OH RCOH
O
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.
RCOCR
O O
Reactions of Acid Anhydrides
+ RCOR'
O
+
Carboxylic acid anhydrides react with alcoholsto give esters:
R'OH RCOH
O
via:CR
O
OCR
OR'
H
O
RCOCR
O O
Example
(60%)
H2SO4
+CH3COCCH3
O O
CH3CHCH2CH3
OH
CH3COCHCH2CH3
O
CH3
Reactions of Acid Anhydrides
+ RCNR'2
O
+
Acid anhydrides react with ammonia and aminesto give amides:
2R'2NH RCO–
O
R'2NH2
+
via:CR
O
OCR
NR'2
H
O
RCOCR
O O
Example
(98%)
+CH3COCCH3
O O H2N CH(CH3)2
O CH3CNH CH(CH3)2
Reactions of Acid Anhydrides
+ 2RCOH
O
Acid anhydrides react with water to givecarboxylic acids (carboxylate ion in base):
H2O
+ 2RCO–
O
+2HO– H2O
RCOCR
O O
RCOCR
O O
Reactions of Acid Anhydrides
+ 2RCOH
O
Acid anhydrides react with water to givecarboxylic acids (carboxylate ion in base):
H2ORCOCR
O O CR
O
OCR
OH
H
O
Example
+ H2O
O
O
O
COH
O
COH
O
Sources of EstersSources of Esters
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
CH3COCH2CH2CH2CH3
O
Esters are Very Common Natural Products
butyl acetate
Contributes to characteristic pear odor.
Esters of Glycerol
R, R', and R" can be the same or different.
Called "triacylglycerols," "glyceryl triesters," or "triglycerides“.
Fats and oils are mixtures of glyceryl triesters.
RCOCH
CH2OCR'O
CH2OCR"
O
O
Esters of Glycerol
CH3(CH2)16COCH
CH2OC(CH2)16CH3O
CH2OC(CH2)16CH3
O
O
Tristearin: found in manyanimal and vegetable fats.
Cyclic Esters (Lactones)
(Z)-5-Tetradecen-4-olide(sex pheromone of female Japanese beetle)
OO
H
H
CH2(CH2)6CH3
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
Preparation of Esters
Baeyer-Villiger OxidationBaeyer-Villiger Oxidation
The Baeyer-Villiger Oxidation is the oxidative cleavage The Baeyer-Villiger Oxidation is the oxidative cleavage of a carbon-carbon bond adjacent to a carbonyl, which of a carbon-carbon bond adjacent to a carbonyl, which converts ketones to esters and cyclic ketones to converts ketones to esters and cyclic ketones to lactones. The Baeyer-Villiger can be carried out with lactones. The Baeyer-Villiger can be carried out with peracids, such as MCBPA, or with hydrogen peroxide peracids, such as MCBPA, or with hydrogen peroxide and a Lewis acid.and a Lewis acid.
Physical Properties of EstersPhysical Properties of Esters
Boiling Points
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.
CH3CHCH2CH3
CH3
CH3COCH3
O
CH3CHCH2CH3
OH
28°C
57°C
99°C
Boilingpoint
Solubility in Water
Esters can form
hydrogen bonds to
water, so low molecular
weight esters have
significant solubility in
water.
Solubility decreases
with increasing number
of carbons.
CH3CHCH2CH3
CH3
CH3COCH3
O
CH3CHCH2CH3
OH
~0
33
12.5
Solubility(g/100 g)
Reactions of Esters:Reactions of Esters:A PreviewA Preview
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)
Reactions of Esters
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.
Acid-Catalyzed Ester Hydrolysis
RCOH
O
+ R'OHRCOR'
O
+ H2OH+
Is the reverse of Fischer esterification:
Example
HCl, heat
+ H2O
O
CHCOCH2CH3
Cl
+ CH3CH2OH
O
CHCOH
Cl
(80-82%)
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).
Ester Hydrolysis in Aqueous BaseSaponification
RCO–
O
+ R'OHRCOR'
O
+ HO–
Example
water, methanol, heat
(95-97%)
CH2OCCH3
CH3
O
+ NaOH CH2OH
CH3
O
CH3CONa+
Example
(87%)
+CCOH
CH3
O
H2C
1. NaOH, H2O, heat
2. H2SO4
CH3OH
CCOCH3
CH3
O
H2C
Soap-Making
CH3(CH2)yCOCH
CH2OC(CH2)xCH3O
CH2OC(CH2)zCH3
O
O
Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids.
These salts are soaps.
K2CO3, H2O, heat
CH3(CH2)xCOK
O
CH3(CH2)yCOK
O
CH3(CH2)zCOK
O
Which Bond is Broken when Esters areHydrolyzed in Base?
••
••RCO
O
+R'••
–OH••••
••••
RCO
O
+ 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 areHydrolyzed in Base?
+••
–OH••••••
RC
O
••OR'
••••
+••OR'
–••••
A second possibility is nucleophilic acyl substitution.
RC
O••••
••
••OH
18O Labeling Gives the Answer
18O retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution is mechanism.
CH3CH2COCH2CH3
O
NaOH+
CH3CH2CONa
O
CH3CH2OH+
Stereochemistry Gives the Same Answer
Alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution is mechanism.
not SN2 CH3COK
O
+
CH3C
O
CO
HC6H5
CH3
C
HO
HC6H5
CH3
KOH, H2O
Reactions of EstersReactions of Esterswith Ammonia and Amineswith Ammonia and Amines
RCOR'
O
RCNR'2
O
RCO–
O
Reactions of Esters
Reactions of Esters
+ RCNR'2
O
+
Esters react with ammonia and aminesto give amides:
R'2NHRCOR'
O
R'OH
via: CR
O
OR'
NR'2
H
Example
(75%)
+CCNH2
CH3
O
H2C CH3OH
CCOCH3
CH3
O
H2C + NH3
H2O
Example
(61%)
+FCH2COCH2CH3
O NH2
+ CH3CH2OHFCH2CNH
O heat
R
MgX
Grignard reagents react with esters to yield tertiary alcohols
C
O••
•• –MgX+
– +R C
••O••
••
diethylether
OCH3••
•• OCH3••
••
R'R'
but species formed is unstable and dissociates under the reaction conditions to form a ketone
R
MgX
••
Grignard reagents react with esters
C
O••
•• –MgX+
– +R C
••O••
••
diethylether
OCH3••
•• OCH3••
••
R'R'
–CH3OMgX
C
O
R R'
••
This ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol.
Example
2 CH3MgBr + (CH3)2CHCOCH3
O
1. diethyl ether
2. H3O+
(CH3)2CHCCH3
OH
CH3
(73%)
Two of the groups attached to the tertiary carbon come from the Grignard reagent.
Lithium aluminum hydride preferred forlaboratory reductions.
Sodium borohydride reduction is too slowto be useful.
Catalytic hydrogenolysis used in industrybut conditions difficult or dangerous to duplicate in the laboratory (special catalyst, hightemperature, high pressure).
Reduction of Esters with LiAlH4
Gives Primary Alcohols
Example: Reduction of an Ester
1. LiAlH4
diethyl ether
2. H2O
(90%)
O
COCH2CH3
CH3CH2OH
CH2OH +
AmidesPhysical Properties of Amides
Amides are less reactive toward nucleophilic
acyl substitution than other acid derivatives.
C
O
H NH
H
C
O
H NH
H
C
O
H NH
HFormamide
Physical Properties of Amides
Amides are capable of hydrogen bonding.
C
O
H NH
HC
O
H NH
H
C
O
H NH
H
Acyl chlorides (Table 19.1)
Anhydrides (Table 19.2)
Esters (Table 19.4)
Preparation of Amides
Amides are prepared from amines by acylation
with:
Preparation of Amides
Amines do not react with carboxylic acids to give
amides. The reaction that occurs is proton-transfer
(acid-base).
RCOH
O
+ R'NH2 RCO
O
+ 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).
RCOH
O
+ R'NH2 RCO
O
+ R'NH3
+–
heat
RCNHR'
O
+ H2O
Example COH
O
+
H2N
225°C
+ H2O
(80-84%)
CNH
O
© 2013 Pearson Education, Inc. Chapter 21 92
Hydrolysis of Amides
Amides are hydrolyzed to the carboxylic acid under acidic or basic conditions.
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© 2013 Pearson Education, Inc. Chapter 21 93
Acid Hydrolysis of Amides
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Example: Acid Hydrolysis
(88-90%)
CH3CH2CHCNH2
O CH3CH2CHCOH
O H2O
H2SO4
heat
+ NH4
+HSO4
–
© 2013 Pearson Education, Inc. Chapter 21 95
Basic Hydrolysis of Amides
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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Example: Basic Hydrolysis
(95%)
CH3COK
OKOH
H2O
heat
+
CH3CNH
O Br
NH2
Br
© 2013 Pearson Education, Inc. Chapter 21 97
Reduction of an Amide to an Amine
Amides will be reduced to the corresponding amine by LiAlH4.
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© 2013 Pearson Education, Inc. Chapter 21 98
Formation of Lactams
Five-membered lactams (-lactams) and six-membered lactams (-lactams) often form on heating or adding a dehydrating agent to the appropriate -amino acid or -amino acid.
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© 2013 Pearson Education, Inc. Chapter 21 99
-Lactams
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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© 2013 Pearson Education, Inc. Chapter 21 100
Mechanism of -Lactam Acylation
The nucleophile attacks the carbonyl of the four-membered 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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© 2013 Pearson Education, Inc. Chapter 21 101
Action of -Lactam Antibiotics
The -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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Nucleophilic substitution by cyanide onalkyl halides (Sections 8.1 and 8.11)
Cyanohydrin formation (Section 17.7)
Dehydration of amides
Preparation of Nitriles
Nitriles are prepared by:
Example
(95%)
CH3(CH2)8CH2ClKCN
ethanol-water
CH3(CH2)8CH2C N
SN2
Example
(75%)
KCN
H+CH3CH2CCH2CH3
O
CH3CH2CCH2CH3
OH
C N
© 2013 Pearson Education, Inc. Chapter 21 105
Dehydration of Amides to Nitriles
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
Hydrolysis of nitriles resembles the hydrolysis
of amides. The reaction is irreversible.
Ammonia is produced and is protonated to
ammonium ion in acid solution.
+ NH4
+RCOH
O
RCN + 2H2O H+ +
Example: Acid Hydrolysis
(92-95%)
O
H2O
H2SO4
heat
CH2CN
NO2
CH2COH
NO2
© 2013 Pearson Education, Inc. Chapter 21 108
Hydrolysis of Nitriles
Heating with aqueous acid or base will hydrolyze a nitrile to a carboxylic acid.
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Example: Basic Hydrolysis
(80%)
CH3(CH2)9COH
O
CH3(CH2)9CN1. KOH, H2O, heat
2. H+
© 2013 Pearson Education, Inc. Chapter 21 110
Reduction of Nitriles to Primary Amines
Nitriles are reduced to primary amines by catalytic hydrogenation or by lithium aluminum hydride reduction.
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© 2013 Pearson Education, Inc. Chapter 21 111
Reaction of Nitriles with Grignards
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
(79%)
F3C
C N + CH3MgI
1. diethyl ether
2. H3O+, heat F3C
CCH3
O