Islamic University in Madinah
Department of Chemistry
CH-5
Organic Chemistry-2
Carboxylic Acids and Their Derivatives
Nucleophilic Addition–Elimination at the Acyl Carbon
Prepared By
Dr. Khalid Ahmad Shadid
&
Prof Dr. Abdelfattah Haikal
1. Introduction

O
Carboxylic Acid Derivatives
O
R
OH
carboxylic acid
O
R
Cl
acid chloride
R
OR'
ester
R
O
R'
acid anhydride
O
O
R
O
NR'2
amide
2. Nomenclature and Physical Properties
Carboxylic Acids


Nomenclature of Carboxylic Acids
●
Rules

Carboxylic acid as parent (suffix): ending with “–oic acid”
Examples
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Carboxylate Salts


Nomenclature of Carboxylic Salts
●
Rules

Carboxylate as parent (suffix): ending with “–oate”
Examples
 Acidity of Carboxylic Acids
Most unsubstituted carboxylic acids have Ka values in the range of lit 10-4 - 10-5
(pKa 4-5).
These relative acidities mean that carboxylic acids react readily with aqueous
solutions of sodium hydroxide and sodium bicarbonate to form soluble sodium
salts.
Carboxylic acids having electron-withdrawing groups are stronger
than unsuhslituled acids. The chloroacetic acids, show the
following order of acidities:
O
O
Cl
OH
Cl
>
Cl
Cl
H
0.70

> H
OH H
H
1.48
OH
H
4.76
2.86
Stability of conjugate bases
O
O
Cl
Cl
>
Cl
O
> Cl
OH H
Cl
pKa
O
Cl
H
Cl
O > Cl
O > H
H
O
O
O
O > H
H
H
The acid-strengthening effect of electron- withdrawing groups arises
from a combination of inductive effects and entropy effects.
The acid-strengthening effect decreases as distance between the
electron-withdrawing group and the carboxyl group increases.
Cl
O
O
>
O
>
OH
Cl
2-Chlorobutanoic acid
(pKa = 2.85)
OH
3-Chlorobutanoic acid
(pKa = 4.05)
Cl
OH
4-Chlorobutanoic acid
(pKa = 4.50)
 Dicarboxylic Acids
Dicarboxylic acids are named as alkanedioic acids in the IUIPAC
systematic or substitutive system.
pK
a
(at 25oC)
Common
Name
mp (oC)
pK1
pK2
Oxalic acid
189 dec
1.2
4.2
HO2CCH 2CO2H
Malonic acid
136
2.9
5.7
HO2C(CH 2)4CO2H
Adipic acid
153
4.4
5.6
Phthalic acid
206-208 dec
2.9
5.4
Structure
HO2C
CO2H
CO2H
CO2H
 Esters
The names of esters are derived from the names of the alcohol (with
the ending -yl) and the acid (with the ending -ate or -oate). The
portion of the name derived from the alcohol comes first.
Esters are polar compounds, but, lacking a hydrogen attached to
oxygen, their molecules cannot form hydrogen bonds to each other.
As a result, esters have boiling points that are lower than those of
acids and alcohols of comparable molecular weight.
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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 “anhydride”
 Example
 Acyl Chlorides
Acyl chlorides are also called acid chlorides. They are named by
dropping -ic acid from the name of the acid and then adding -yl
chloride.
Acyl chlorides and carboxylic anhydrides have boiling points in the same range as
esters of comparable molecular weight.
 Amides
Amides that have no substituent on nitrogen are named by dropping -ic acid
from the common name of the acid (or -oic acid from the substitutive name)
and then adding -amide. Alkyl groups on the nitrogen atom of amides are
named as substituents, and the named substituent is prefaced by N- or N, N-.
 Nitriles
Carboxylic acids can he converted to nitriles and vice versa. In
IUPAC substitutive nomenclature, acyclic nitriles are named by
adding the suffix -nitrile to the name of the corresponding
hydrocarbon. The carbon atom of the -CN group is assigned
number 1.
Preparation of Carboxylic Acids
1. By oxidative cleavage of alkenes
●
Using KMnO4
●
Using ozonolysis
2. By oxidation of aldehydes & 1o alcohols
H
OH
1. Ag2O
2. H3O+
O
O
O
O
H
or
OH
H2CrO4
OH
3. By oxidation of alkyl benzene
4. By Oxidation of methyl Ketones
5. By oxidation of Cyanohydrines and other Nitriles
Nitriles can also be prepared by nucleophilic substitution reactions
of alkyl halides with sodium cyanide. Hydrolysis of the nitrile yields a
carboxylic acid with a chain one carbon atom longer than the
original alkyl halide.
6. By Carbonation of Grignard Reagent
Problem
Show how each of the following compounds could be
converted to benzoic acid.
(a) Ethylbenzene
(b) Acetophenone
(c) Benzyl alcohol
(d) Bromobenzene
(e) Phenylethene
(f) Benzaldehyde
Nucleophilic Addition-Elimination at the Acyl Carbon
A characteristic reaction of aldehydes and ketones is one of
nucleophilic addition to the carbon-oxygen double bond.
Carboxylic acids and their derivatives are characterized by a
nueleophilic addition-elimination mechanism that takes place at
their acyl (carbonyl) carbon atoms.
It is after the initial nucleophilic attack has taken place
that the two reactions differ. The tetrahedral intermediate
formed from an aldehyde or ketone usually accepts a
proton to form a stable addition product.
In contrast, the intermediate formed from an acyl
compound usually eliminates a leaving group; this
elimination leads to regeneration of the carbon-oxygen
double bond and to a substitution product. The overall
process in the case of acyl substitution occurs, therefore, by
a nucleophilic addition-elimination mechanism.
Nucleophilic Addition-Elimination at the Acyl Carbon
O
O
+
R
Nu
Y
R
O
Y
+
R
Nu
(Y = leaving group, e.g. OR, NR2, Cl)

This nucleophilic acyl substitution
occurs through a nucleophilic
addition-elimination mechanism
Nu
Y
This type of nucleophilic acyl
substitution reaction is common for
carboxylic acids and their
derivatives
O
O
R
OH
carboxylic acid
O
R
Cl
acid chloride
OR'
ester
R
O
R'
acid anhydride
O
O
R
O
R
NR'2
amide
Unlike carboxylic acids and
their derivatives, aldehydes
A good leaving group
and ketones usually do not
O
O
O
undergo this type of
R
H
R
R'
Y
nucleophilic acyl substitution, R
a carboxylic acid
due to the lack of an acyl
derivative
Not a good leaving group
leaving group
Acyl compounds react as they do because they all have good, or
reasonably good, leaving groups (or they can be protonated to have
good leaving groups) attached to the carbonyl carbon atom. An
acyl chloride, for example, generally reacts by losing a chloride iona very weak base and thus a very good leaving group.
Relative Reactivity of Acyl Compounds
The general order of reactivity of acid derivatives can be explained by taking
into account the basicity of the leaving groups.
When acyl chlorides react, the leaving group is a chloride ion, and when
amides react, the leaving group is an amine (or ammonia). The chloride ions
are the weakest bases and acyl chlorides are the must reactive acyl
compounds. Amines (or ammonia) are the strongest bases and amides are the
least reactive acyl compounds.
Acyl Chlorides
synthesis of acyl chlorides
(COCl)2
Oxalyl chloride
Mechanism
Oxalyl chloride
O
R
O
Cl
R
O
O
Cl
Cl
O
O
Cl
O
O
O
R
Cl
O
O
Cl
O
O
R
Cl
+ CO2 + CO + Cl
Reactions of Acyl Chlorides
Acyl chlorides also react with water and (even more rapidly) with
aqueous base.
Mechanism
O
R
O
Cl
H
H
O
B
H +
R
H
B:
OH
R
O
OH
Carboxylic Acid Anhydrides
Synthesis of Carboxylic Acid Anhydrides
Carboxylic acids react with acyl chlorides in the presence of
pyridine to give carboxylic acid anhydrides.
O
O
+
R
OH
+
R'
Cl
N
O
O
+
R
O
R'
Cl
N
H
Sodium salts
of carboxylic
acids
R
O
O
+ Na Cl
+
O Na
R'
O
R
Cl
O
300 C
dicarboxylic acid
O
OH
Phthalic
acid
O
anhydrides
O Succinic
anhydride
O
OH
R'
O + H2O
OH
Succinic
O acid
O
Cyclic anhydrides
o
OH
dicarboxylic acid
O
O
230oC
O
Phthalic anhydride O
(~100%)
Cyclic anhydrides
+
H2O
Reactions of Carboxylic Acid Anhydrides

Conversion of acid anhydrides to carboxylic acids
by hydrolysis
O
R
O
O
R'
+ H2O
O
+
H
O
+
R
OH
HO
R'
Mechanism
O
R
O
O
O
H+
R'
R
H
O
OH
O
R'
H2O
R
H
O
R
H2O
OH
H
R
O
O
O
H
OH
O
OH
+ R'COOH
R
OH
R'
O
O
H
R'
Reactions of Carboxylic Acid Anhydrides
Because carboxylic acid anhydrides are highly reactive they can be used to
prepare esters and amides.
Esters
Synthesis of Esters: Esterification
Carboxylic acids react with alcohols to form esters through a
condensation reaction known as esterification:
Mechanism
Acid-Catalyzed Ester Hydrolysis
Esters from Acyl Chlorides
Esters from Carboxylic Acid Anhydrides
Cyclic anhydrides react with one molar equivalent
of an alcohol to form compounds that are both
esters and acids.
Base-Promoted Hydrolysis of Esters: Saponification
Lactones
Carboxylic acids
whose molecules
have a hydroxyl
group on a  or 
carbon undergo
an intramolecular
esterification to
give cyclic esters
known as  or lactones. The
reaction is acid
catalyzed:
R


O


+ H
O
O
O
OH
H
HO
O
a -hydroxyacid
A
H
O
A
H
H
O
H
R
O
O
H
O
O
+ O
H
H
R
a -lactone
H
O
R
H +
H
R
H
Lactones are hydrolyzed by aqueous base just as other
esters are.
Amides
Synthesis of Amides
 Amides from Acyl Chlorides
Amides from Acyl Chlorides
O
O
R
R
Cl
Cl
H
:NHR'R"
N
R"
R'
O
R
R"R'HN:
R"
N
H
R'
:Cl:
Amides from Carboxylic Anhydrides
Amides from Esters
Amides from Carboxylic Acids and Ammonium Carboxylates
Hydrolysis of Amides
Problem
What products would you obtain from acidic and basic
hydrolysis of each of the following arnides?
Nitriles from the Dehydration of Amides
Amides react with P4H10 (a compound that is often called
phosphorus pentoxide and written P2O5 or with boiling acetic
anhydride to form nitriles.
O
NH2
P4O10
dehydration
C
N
Hydrolysis of Nitriles
Catalyzed by both acid and base

Examples
CN
OH
H2SO4
H2O, 
O
(82%)

protonated nitrile
Mechanism
C
N:
H
R
NH
C
NH + : O
H +
:O
protonated
amide
H
(amide hydrolysis)
NH2
:
R
O:
C
O
several steps
R
+
OH
NH4
C
H
NH
:
R
NH
:
R
NH2
O:
C
H
H2O
:
O
:
H
H
slow
:
amide
tautomer
H
O:
C
C
H
:
R
O
:
H
H
R
:
R
H
H
Mechanism
+
N:
: :
O
:
O
H
R
HO
O
H
:
NH2
O
OH
HO
H
NH2
OH
OH
H
O
R
R
H
HO
HO
O
:
NH2
R
OH
H
:
R
NH
H
O
OH
R
O
+ NH3 +
OH
OH
O
:
C
OH
: :
R
H
N
:
:
:

H
Lactams
O
O
O

Cyclic amides
are called
NH

lactams. The size
of the lactam ring a -lactam
is designated by
Greek letters in a H
way that is
R
N
S
analogous to
lactone
O
N
nomenclature
O

NH


a -lactam
CH3
CH3
CO2H

NH



a -lactam
R = C6H5CH2
Penicillin G
R = C6H5CH
Ampicillin
NH2
R = C6H5OCH2
Penicillin V
-Halo Acids
The Hell-volhard-Zeliniski reaction
Aliphatic carboxylic acids react with bromine or chlorine in the
presence of phosphorus (or a phosphorus halide) to give -halo
acids through a reaction known as the Hell-Volhard-Zelinski (or HVZ)
reaction.
-Halo acids are important synthetic intermediates
because they are capable of reacting with a variety
of nucleophiles;
Decarboxylation of Carboxylic Acids
The reaction whereby a carboxylic acid loses CO2 is called
a decarboxylation.
Acids whose molecules have a carbonyl group one carbon
removed from the carboxylic acid group, called -keto acids,
decarboxylate readily when they are heated to 100-150°C. (Some
-keto acids even decarboxylate slowly at room temperature.)
1. When the carboxylate anion decarboxylates, it forms a
resonance-stabilized enolate anion:
O
R
O
CO2
-keto acid
R
ketone
enol
O
: :
O
CO2
: :
R
O
R
O
O
H
O:
HA
:
R
O
: :
O
H
R
acylacetate ion
:
O
: :
R
resonance-stabilized
anion
2. When the acid itself decarboxylates, it can do so through a sixmembered cyclic transition state:
O
H
O
R
CO2
O
-keto acid
O
R
enol
H
O
R
ketone
This reaction produces an enol directly and, the enol then
tautomerizes to a methyl ketone.
Malonic acids also decarboxylate readily for similar reasons.
Chemical Tests for Acyl Compounds

Recall: acidity of
O
R
O
O
H + Na
OH
R
O Na
+ H2O
(soluble in water)
O
H
O Na
+ NaOH
(soluble in water)
O
(immiscible
with H2O)
H
+ NaOH
No Reaction
O
O
H
H
+ NaHCO3
No Reaction
+ NaHCO3
No Reaction
Summary of the Reactions of Carboxylic
Acids and Their Derivatives
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