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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
pKa ~ 4-5
Compare
pKa of H2O ~ 16
pKa of H2CO3 ~ 7
pKa of HF ~ 3
2014 by John Wiley & Sons, Inc. All rights reserved.
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
CH3CH2 O H + H2O
A2
O O
O
H
+ H2O
(NO resonance
stabilization)
O O Na
H
+ NaOH
(soluble in water)
O
H
+ NaOH No Reaction
(immiscible
with H2O)
2014 by John Wiley & Sons, Inc. All rights reserved.
O
H
+ NaHCO
3 No Reaction
O
H
+ NaHCO
3 No Reaction
O O O O
Cl Cl Cl H
>
>
>
O > Cl O > H O > H O
> >
Cl
>
Cl H H H
>
> > >
OH OH
>Cl
2-Chlorobutanoic acid 3-Chlorobutanoic acid
(pKa = 2.85) (pKa = 4.05)
O
Cl > > > >
OH
4-Chlorobutanoic acid
(pKa = 4.50)
2014 by John Wiley & Sons, Inc. All rights reserved.
2E. Esters
Nomenclature of Esters
Rules
Ester as parent (suffix):
ending with oate
Examples
Example
Example
O
C H3C C N
H3C NH2
172.6 117.4
2014 by John Wiley & Sons, Inc. All rights reserved.
reparation of Carboxylic Acids
By oxidative cleavage of alkenes
Using KMnO4
Using ozonolysis
2. H3O+ O
O
O O
H2CrO4
H or OH OH
2014 by John Wiley & Sons, Inc. All rights reserved.
By oxidation of alkyl benzene
O
HCN H+
Br CN C
H2O, heat OH
1. CO2
2. H3O+
O
OH
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.
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
2014 by John Wiley & Sons, Inc. All rights reserved.
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)
2014 by John Wiley & Sons, Inc. All rights reserved.
Steric factor
e.g.
O O
reactivity of >
Cl Cl
Electronic factor
The strongly polarized acid
derivatives react more
readily than less polar ones
COOH
COO-
2014 by John Wiley & Sons, Inc. All rights reserved.
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
2014 by John Wiley & Sons, Inc. All rights reserved.
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
H
O B: O
B H +
R OH R OH
O O
R'2NH
(amide)
R Cl R NR'2
O
O O
R' O Na
(acid anhydride)
R O R'
2014 by John Wiley & Sons, Inc. All rights reserved.
Carboxylic Acid Anhydrides
A.Synthesis of Carboxylic Acid
Anhydrides
O O
+ +
R OH R' Cl N
O O
+ Cl
R O R'
N
H
2014 by John Wiley & Sons, Inc. All rights reserved.
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%)
2014 by John Wiley & Sons, Inc. All rights reserved.
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'
H
O H2O O OH O
+ R'COOH
R OH R OH R O R'
OH
H
O O
R O R'
O O
+
R2'NH R NR'2 R O NR'2H2
O + O
H
+ R'OH + H2O
R OH R OR'
H
O H2O O OH2
Cl
+ EtOH +
N
Benzoyl
chloride O
OEt
+ Cl
N
Ethyl benzoate
(80%) H
2014 by John Wiley & Sons, Inc. All rights reserved.
Esters from carboxylic acid
e.g. anhydrides
O O
OH
+
O
Acetic Benzoyl
anhydride alcohol
O
O
O
+
OH
Benzoyl acetate
2014 by John Wiley & Sons, Inc. All rights reserved.
B. Base-Promoted Hydrolysis of
Esters: Saponification
Hydrolysis of esters under basic
conditions: saponification
R OR' R OR'
OH
HO
O
H + OR'
R O
O H+ O
R'OH +
R OH R O
O H+ O
+ R'OH
H2O
R OR' R OH
H
O H2O O OH
+ R'OH R'
R OH R OH R O
OH
H
R Cl R Cl
H N R"
:NHR'R" R'
O
R"
:Cl:
R N R'
H
R"R'HN:
2014 by John Wiley & Sons, Inc. All rights reserved.
8C. Amides from Carboxylic
Anhydrides
H2O NH2
O + 2 NH3
warm O NH4
O O Ammonium
Phthalamic O
anhydride phthalamate
(94%)
NH2 H3O+
OH (- NH4+)
Phthalamic acid
O
(81%)
NH2 150-160oC
N H
OH
+ H2O O
O
Phthalamic acid Phthalimide
(~ 100%)
e.g. O O
Me
OMe MeNH2 N
heat H
+ MeOH
2014 by John Wiley & Sons, Inc. All rights reserved.
Amides from Carboxylic Acids and
Ammonium Carboxylates
O O
+ NH3
R OH R O NH4
heat
O
H2O +
R NH2
O O
1. DCC
R' + DCU
R OH 2. R'NH2 R N
H
:
H+ H2O
:
H O
H
H
:O: O : OH
+ NH3:
R OH R OH R NH3
HO
O OH O O
H + NH2
R NH2 R NH2 R O
HO
O
NH3 +
R O
O
C N
NH2 P4O10
dehydration
NaCN
Br CN
DMSO
1o alkyl bromide
SN2 reaction
with CN
works fine
2014 by John Wiley & Sons, Inc. All rights reserved.
CN
But synthesis of
Br NaCN
No Reaction!
DMSO
3o alkyl bromide
No SN2 reaction
Br 1. Mg, Et2O
OH
2. CO2
+
3. H3O
O 1. SOCl2
2. NH3
CN
NH2
P4O10
dehydration
2014 by John Wiley & Sons, Inc. All rights reserved.
8H.Hydrolysis of Nitriles
O
base or acid
R C N
H2O, heat R OH
H2SO4 OH
CN
H2O,
O
(82%)
:
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
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
2014 by John Wiley & Sons, Inc. All rights reserved.
Polyesters and Polyamides:
Step-Growth Polymers
Polyesters O O
HO OH + HO n OH
m
-H2O
O O
O O
n
m
(a polyester)
2014 by John Wiley & Sons, Inc. All rights reserved.
Polyamides
O O
+ n
H2N N H Cl Cl
m
H
-HCl
H H O O
N N
n
m
(a polyamide)
2014 by John Wiley & Sons, Inc. All rights reserved.
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
200oC
O
O
O + 2n CH3OH
O
n
(Dacron)
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
2014 by John Wiley & Sons, Inc. All rights reserved.
Reactions of acyl chlorides
O
R OH
H2O
R Cl
R'OH, base
R'COOH
base
O O O
R O R' R OR'
2014 by John Wiley & Sons, Inc. All rights reserved.
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'
2014 by John Wiley & Sons, Inc. All rights reserved.
Reactions of acid anhydrides
O O
+
R OH HO R'
H2O
O O
R O R'
R OH
R OH
1. LiAlH4
H2O, H+,
2. H3O+
OH O
R NH2 R OR"
2014 by John Wiley & Sons, Inc. All rights reserved.
Reactions of nitriles
O
R NH2
R OH
O 1. LiAlH4
R' 2. H3O+
R N
R'
R NR'2
Increasing reactivity
Reactivity of the
carbonyl carbon
How + or
electrophilic
is the carbon?