ch17 CA

Chapter 17
Carboxylic Acids
and Their Derivatives
Nucleophilic
AdditionElimination
at the Acyl Carbon
Created by
Professor William Tam & Dr. Phillis
Chang
Copyright 2014 by John Wiley & Sons, Inc. All rights reserved.
1. Introduction
Carboxylic Acid Derivatives
O O O O
R OH R Cl R O R'
carboxylic acid acid chloride acid anhydride
O O
R OR' R NR'2
ester amide
2014 by John Wiley & Sons, Inc. All rights reserved.

Nomenclature and Physical
Properties
2A. Carboxylic Acids
Nomenclature of Carboxylic Acids
Rules
Carboxylic acid as parent
(suffix): ending with oic
acid
Examples

2B. Carboxylate Salts
Nomenclature of Carboxylic Salts
Rules
Carboxylate as parent
(suffix): ending with
oate
Examples

2C. Acidity of Carboxylic Acids
O
H
R O
pKa ~ 4-5
Compare
pKa of H2O ~ 16
pKa of H2CO3 ~ 7
pKa of HF ~ 3
When comparing acidity of
organic compounds, we compare
the stability of their conjugate
bases. The more stable the
conjugate base, the stronger the
acid
CH3COOH CH3CH2OH
pKa 4.75 16

O
+ H2O
CH3 O H
A1
CH3CH2 O H + H2O
A2

The conjugate base B1 is more
stable (the anion is more
delocalized) than B2 due to
resonance stabilization
O O O
CH3 O CH3 O CH3 O
Thus, A1 is a stronger acid

than A2

Acidity of Carboxylic Acids,
Phenols, and Alcohols


O O

O
H
+ H2O
(NO resonance
stabilization)

Question
You are given three unknown
samples: one is benzoic acid, one
is phenol, and one is cyclohexyl
alcohol. How would you
distinguish them by simple
chemical tests?
Recall: acidity of

O O
H + Na OH + H2O
R O R O Na
(soluble in water)
O O Na
H
+ NaOH
(soluble in water)
O
H
+ NaOH No Reaction
(immiscible
with H2O)
O
H
+ NaHCO
3 No Reaction
O
H
+ NaHCO
3 No Reaction

O O O O
Cl Cl
> > Cl > H
Cl OH Cl OH H OH H OH
Cl H H H
pKa 0.70 1.48 2.86 4.76
Stability of conjugate bases
O O O O
Cl Cl Cl H
>
>
>
O > Cl O > H O > H O
> >
Cl
>
Cl H H H

O Cl O
>
> > >
OH OH
>Cl
2-Chlorobutanoic acid 3-Chlorobutanoic acid
(pKa = 2.85) (pKa = 4.05)
O
Cl > > > >
OH
4-Chlorobutanoic acid
(pKa = 4.50)
2E. Esters
Nomenclature of Esters
Rules
Ester as parent (suffix):
ending with oate
Examples

2F. Carboxylic Anhydrides
Nomenclature of Carboxylic
Anhydrides
Rules
Most anhydrides are named
by dropping the word acid
from the name of the
carboxylic acid and then
adding the word
Example
anhydride

2G.Acyl Chlorides
Nomenclature of Acid chlorides
Rules
Acid chloride as parent
(suffix): ending with oyl
chloride
Example

2H.Amides
Nomenclature of Amides
Rules
Amide as parent (suffix):
ending with amide
Example

2I. Nitriles
Nomenclature of Nitriles
Rules
Nitrile as parent (suffix):
ending with nitrile
Example

J. Spectroscopic Properties of
Acyl Compounds
IR Spectra
The C=O stretching band occurs
at different frequencies for acids,
esters, and amides, and its
precise location is often helpful in
structure determination
Conjugation and electron-donating
groups bonded to the carbonyl
shift the location of the C=O
absorption to lower frequencies
IR Spectra
Electron-withdrawing groups
bonded to the carbonyl shift the
C=O absorption to higher
frequencies
The hydroxyl groups of carboxylic
acids also give rise to a broad
peak in the 2500-3100 cm-1 region
arising from OH stretching
vibrations
The NH stretching vibrations of
amides absorb between 3140 and
3500 cm-1
1H NMR Spectra
The acidic protons of
carboxylic acids are highly
deshielded and absorb far
downfield in the 10-12 region
The protons of the carbon of
carboxylic acids absorb in the
2.0-2.5 region

C NMR Spectra
13
The carbonyl carbon of

carboxylic acids and their
derivatives occur downfield in
the 160-180 region (see the
following examples), but not
as far downfield as for
aldehydes and ketones ( 180-
220)
The nitrile carbon is not
shifted so far downfield and
absorbs in the 115-120
C NMR chemical shifts for the
13
carbonyl or nitrile carbon atom

O O O
C C C
H3C OH H3C OEt H3C Cl
177.2 170.7 170.3
O
C H3C C N
H3C NH2
172.6 117.4
reparation of Carboxylic Acids
By oxidative cleavage of alkenes
Using KMnO4
Using ozonolysis

By oxidation of aldehydes & 1o
alcohols
e.g.H OH
1. Ag O 2
2. H3O+ O
O
O O
H2CrO4
H or OH OH
By oxidation of alkyl benzene

By hydrolysis of cyanohydrins
and other nitriles
e.g.
O
O NC HO C
HCN OH H+ OH
Ph CH3 Ph CH3 H2O Ph CH3
O
HCN H+
Br CN C
H2O, heat OH

By carbonation of Grignard
reagents
e.g.Br MgBr
Mg
Et2O
1. CO2
2. H3O+
O
OH

4. Acyl Substitution:
Nucleophilic Addition-
Elimination at the Acyl
Carbon
O O
+ Nu Nu
R Y R
Y
O
Y +
R Nu
(Y = leaving group, e.g. OR, NR2, Cl)

This nucleophilic acyl substitution
occurs through a nucleophilic
addition-elimination mechanism

This type of nucleophilic acyl
substitution reaction is common
for carboxylic acids and their
derivatives
O O O O
R OH R Cl R O R'
carboxylic acid acid chloride acid anhydride
O O
R OR' R NR'2
ester amide
Unlike carboxylic acids and their
derivatives, aldehydes and
ketones usually do not undergo
this type of nucleophilic acyl
substitution, due to the lack of an
acyl leaving group
A good
O leavin O O
g
R Y group R H R R'
a carboxylic acid
derivative Not a good
leaving
group
4A. Relative Reactivity of Acyl
Compounds
Relative reactivity of carboxylic
acid derivatives towards
nucleophilic acyl substitution
reactions
There are 2 steps in a
nucleophilic acyl substitution
The addition of the Nu
(RDS)
LG leaves (the tetrahedral
intermediate)
Steric factor
e.g.
O O
reactivity of >
Cl Cl
Electronic factor
The strongly polarized acid
derivatives react more
readily than less polar ones

Thus, reactivity of
O O O O O
> > >
R Cl R O R' R OR' R NR'2
most least
reactive reactive
Easy to move to a bad leaving group
Hard to move to a better leaving group

Substitution in Synthesis
COOH
COO-
5. Acyl Chlorides
A. Synthesis of Acyl Chlorides
Conversion of carboxylic acids to
acid chlorides
O O
R OH R Cl
Common reagents
SOCl2
(COCl)2
PCl3 or PCl5
Mechanism
O O
Cl
R O
Cl
O
O O
Cl
Cl R O
O
O O O
Cl + CO2 + CO + Cl
R O R Cl
Cl
O 2014 by John Wiley & Sons, Inc. All rights reserved.
5B. Reactions of Acyl Chlorides
Nucleophilic acyl substitution

reactions of acid chlorides
Conversion of acid chlorides to
carboxylic acids
O base O
+ H2O
R Cl R OH

Mechanism
O
H
R O
Cl H
H
O B: O
B H +
R OH R OH

Conversion of acid chlorides to
other carboxylic derivatives
O
R'OH
(ester)
pyridine R OR'
O O
R'2NH
(amide)
R Cl R NR'2
O
O O
R' O Na
(acid anhydride)
R O R'
Carboxylic Acid Anhydrides
A.Synthesis of Carboxylic Acid
Anhydrides
O O
+ +
R OH R' Cl N
O O
+ Cl
R O R'
N
H
O O O O
+ + Na Cl
R O Na R' Cl R O R'
O O
OH 300oC
O + H2O
OH
Succinic O Succinic
O acid anhydride
O O
OH 230oC
O + H2O
OH
Phthalic Phthalic anhydride O
acid O (~100%)
B. Reactions of Carboxylic Acid
Anhydrides
Conversion of acid anhydrides to
carboxylic acids
O O + O O
H
+ H2O +
R O R' R OH HO R'

Mechanism
H
O O H+ O O OH O
R O R' R O R' H2O R O R'

O
H H
H
O H2O O OH O
+ R'COOH
R OH R OH R O R'
OH
H

Conversion of acid anhydrides to
other carboxylic derivatives
O O
R'OH
+
R OR' R OH
O O
R O R'
O O
+
R2'NH R NR'2 R O NR'2H2

7. Esters
Synthesis of Esters: Esterification
O + O
H
+ R'OH + H2O
R OH R OR'

Mechanism
H
O H+ O OH
H H H
R O R O R'OH R O
OH
"activated" R'
H
O H2O O OH2
R OR' R OR' R OR'

HO

Esters from acyl chlorides
e.g. O
Cl
+ EtOH +
N
Benzoyl
chloride O
OEt
+ Cl
N
Ethyl benzoate
(80%) H
Esters from carboxylic acid
e.g. anhydrides
O O
OH
+
O
Acetic Benzoyl
anhydride alcohol
O
O
O
+
OH
Benzoyl acetate
B. Base-Promoted Hydrolysis of
Esters: Saponification
Hydrolysis of esters under basic
conditions: saponification

Mechanism
O O
R OR' R OR'
OH
HO
O
H + OR'
R O
O H+ O
R'OH +
R OH R O

Hydrolysis of esters under acidic
conditions
O H+ O
+ R'OH
H2O
R OR' R OH

Mechanism
H
O H+ O OH
R OR' R OR' H2O R OR'

O
H H
H
O H2O O OH
+ R'OH R'
R OH R OH R O
OH
H

8. Amides
8A.Synthesis of Amides
Amides can be prepared in a
variety of ways, starting with acyl
chlorides, acid anhydrides,
esters, carboxylic acids, and
carboxylate salts.
All of these methods involve
nucleophilic additionelimination
reactions by ammonia or an
amine at an acyl carbon.
B. Amides from Acyl Chlorides
O O
R Cl R Cl
H N R"
:NHR'R" R'
O
R"
:Cl:
R N R'
H
R"R'HN:
8C. Amides from Carboxylic
Anhydrides

O O
H2O NH2
O + 2 NH3
warm O NH4
O O Ammonium
Phthalamic O
anhydride phthalamate
(94%)
NH2 H3O+
OH (- NH4+)
Phthalamic acid
O
(81%)

O O
NH2 150-160oC
N H
OH
+ H2O O
O
Phthalamic acid Phthalimide
(~ 100%)

8D.Amides from Esters
O
O H R' R'
+ N R N + R'"OH
R OR'" R" R"
R' and/ or R" may be H.
e.g. O O
Me
OMe MeNH2 N
heat H
+ MeOH
Amides from Carboxylic Acids and
Ammonium Carboxylates
O O
+ NH3
R OH R O NH4
heat
O
H2O +
R NH2

DCC-Promoted amide synthesis
O O
1. DCC
R' + DCU
R OH 2. R'NH2 R N
H

8F. Hydrolysis of Amides
Acid hydrolysis of amides

Mechanism
H
:O: O OH
:
H+ H2O
R NH2 R NH2 R NH2
:
H O
H
H
:O: O : OH
+ NH3:
R OH R OH R NH3
HO

Basic hydrolysis of amides

Mechanism
O OH O O
H + NH2
R NH2 R NH2 R O
HO
O
NH3 +
R O

Nitriles from the Dehydration of
Amides
:O: P4O10 or (CH3CO)2O
R C N: + H3PO4
:
R NH2 heat (or CH3CO2H)

(a nitrile)
(H2O)
This is a useful synthetic method

for preparing nitriles that are not
available by nucleophilic
substitution reactions between
alkyl halides and cyanide ions
e.g.
O
C N
NH2 P4O10
dehydration

Example
Synthesis of
NaCN
Br CN
DMSO
1o alkyl bromide
SN2 reaction
with CN
works fine
CN
But synthesis of
Br NaCN
No Reaction!
DMSO
3o alkyl bromide
No SN2 reaction

Solution
O
Br 1. Mg, Et2O
OH
2. CO2
+
3. H3O
O 1. SOCl2
2. NH3
CN
NH2
P4O10
dehydration
8H.Hydrolysis of Nitriles
O
base or acid
R C N
H2O, heat R OH
Catalyzed by both acid and base

Examples
H2SO4 OH
CN
H2O,
O
(82%)

protonated nitrile
Mechanism H
R C N: R C NH R C NH + : O H
H
:
H O H
slow
: amide
tautomer H
:
H H H H2O
:
:
O: O: :O H
H O H +
C C
:
C
R NH2 R NH R NH
:
:
protonated
amide
H several steps O
O: + NH4
(amide hydrolysis)
C R OH
R NH2 2014 by John Wiley & Sons, Inc. All rights reserved.
:
Mechanism N
:
:
: H OH NH
:
R C N: + O H
:
:
R OH R OH
:
O H
:
:
H
O HO O HO H
:
:
R NH2 R NH2
O H OH OH OH
H
HO
HO H
O O
H OH
+ NH3 + OH
:
R NH2
R O
O 2014 by John Wiley & Sons, Inc. All rights reserved.
Decarboxylation of Carboxylic
Acids
O
decarboxylation
R H + CO2
R OH
O O o O
100-150 C
+ CO2
R OH R
A -keto acid

There are two reasons for this
ease of decarboxylation
H H
O O O O
CO2
R O R R
-keto acid enol ketone
O O O O
: : : :
CO2 HA
: :
R O: R : R
acylacetate ion
:
O
: :
resonance-stabilized
anion
R
Polyesters and Polyamides:
Step-Growth Polymers
Polyesters O O
HO OH + HO n OH
m
-H2O
O O
O O
n
m
(a polyester)
Polyamides
O O
+ n
H2N N H Cl Cl
m
H
-HCl
H H O O
N N
n
m
(a polyamide)
Example: Nylon 66 (each piece has
6C)
O
OH NH2
n HO + n H2N
O
heat
O H
N
N + 2n H2O
O H
(Nylon 66) n
Applications: clothing, fibers, bearings

Example: Dacron (Mylar)
O O
OH
n + n HO
CH3O OCH3
200oC
O
O
O + 2n CH3OH
O
n
(Dacron)
Applications: film, recording tape

13. Summary of the Reactions
of Carboxylic Acids and
Their Derivatives

Reactions of carboxylic acids
O
C
R O
NaOH or NaHCO 3
or other bases
O
O
RCH2OH
1. LiAlH4 R OH R'OH, H+, C
R OR'
+
2. H2O, H
O SOCl2 O
O O or PCl3
C C or PCl5 C
R O R' R' Cl R Cl
base
Reactions of acyl chlorides
O
R OH
H2O
R Cl
R'OH, base
R'COOH
base
O O O
R O R' R OR'
Reactions of acyl chlorides
(Contd)
R OH
1. LiAlH4
2. H3O+
O
R Cl 1. LiAlH(OtBu)3, -78oC
2. H3O+
OH 1. R'MgX O
R' 2. H3O+
R R H
R'
Reactions of acid anhydrides
O O
+
R OH HO R'
H2O
O O
R O R'

Reactions of esters
R OH
R OH
1. LiAlH4
H2O, H+,
2. H3O+
OH O
R" 1. R"MgX R OR'

R
R" 2. H3O+
NH3 R"OH, H+,

O O
R NH2 R OR"
Reactions of nitriles
O
R NH2
R OH
1. LiAlH4 H+, H2O,

2. H3O+
R C N

Reactions of amides
O 1. LiAlH4
R' 2. H3O+
R N
R'
R NR'2

Recap from chapter 17
Increasing reactivity
Reactivity of the
carbonyl carbon
How + or
electrophilic
is the carbon?

END OF CHAPTER 17

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Chapter 17

2014 by John Wiley & Sons, Inc. All rights reserved.

2014 by John Wiley & Sons, Inc. All rights reserved.

2014 by John Wiley & Sons, Inc. All rights reserved.

2014 by John Wiley & Sons, Inc. All rights reserved.

2014 by John Wiley & Sons, Inc. All rights reserved.

CH3 O CH3 O CH3 O

Thus, A1 is a stronger acid

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pKa 0.70 1.48 2.86 4.76

Stability of conjugate bases

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The carbonyl carbon of

carbonyl or nitrile carbon atom

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Ph CH3 Ph CH3 H2O Ph CH3

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Hard to move to a better leaving group

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Nucleophilic acyl substitution

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R O R' R O R' H2O R O R'

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R OR' R OR' R OR'

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R OR' R OR' H2O R OR'

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R' and/ or R" may be H.

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R NH2 R NH2 R NH2

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R NH2 heat (or CH3CO2H)