Carboxylic Acids

In this chapter we will consider:

• Structure and reactivity of various carboxylic acid derivatives

• Many different examples of nucleophilic acyl substitutions, a

of which proceed by a similar mechanism though they
lead to different products

• Methods for the preparation of carboxylic acid derivatives

from appropriate functional groups
 Intended Learning Objectives

•Provide IUPAC name and structure of carboxylic acid derivatives.

•Explain how substituents affect the acidity of a carboxylic acids.

•Describe the preparations of a carboxylic acid derivatives

•Describe the formation of an acyl chloride from a carboxylic acid.

•Describe the formation of an ester by reaction of a carboxylic acid

with an alcohol in the presence of an acid catalyst.
 Intended Learning Objectives

•Explain the general mechanism for a nucleophilic acyl substitution,

and describe the role of the tetrahedral intermediate.

•Describe the preparation of ester using acyl chlorides or acetic

anhydride.

•Describe the preparation of an amide by the reaction of an amine

with an acyl chloride, acetic anhydride, or an ester.

•Describe the decarboxylation process

 Carboxylic Acid Nomenclature

– systematic IUPAC names replace "-e"

ending of alkane with "oic acid"
Systematic Name
O

HCOH methanoic acid

O

CH3COH ethanoic acid

CH3(CH2)16COH octadecanoic acid

 Table 19.1 (page 737)

– common names are based on natural

origin rather than structure
Systematic Name Common Name
O

HCOH methanoic acid formic acid

O

CH3COH ethanoic acid acetic acid

CH3(CH2)16COH octadecanoic acid stearic acid

 Numbering

Select the longest continuous carbon chain and

assign the carbon of carboxylic acid as 1
O

CH3CHCOH 2-hydroxypropanoic acid

OH O

CH3 CH2COH
C C (Z)-3-pentenoic acid
H H
 Naming

Carbonyl of ketone & aldehyde will be considered

as substituent: use oxo as prefix

4-oxopentanoic acid

3-(3-oxocyclypentyl)benzoic acid
 Naming

2-chloro-4-(3-chlorobutyl)benzoic acid
 Cyclic carboxylic acid derivatives

1- Ring name as cycloalkane + Carboxylic acid

2- Numbering: Assign number 1 of cyclic carbon connected
to carboxylic group

2,4-dimethylcyclohexane carboxylic acid

Applications
 Applications

4,6-dimethyl-2-cyclohexene
carboxylic acid 2,4-dimethyl-2,4-cyclohexadiene
carboxylic acid
 Carboxylic group as Substituent

Carboxylic acid as substituent: carboxyl

 Carboxylic group as Substituent

Carboxylic acid as substituent: carboxyl

2-amino-5-carboxylbenzoic acid
Not 4-amino-3-carboxylbenzoic acid
Applications
 Applications

(2E) 3-methyl-2,4-pentadienoic acid

4,5-Epoxy-2-ethyl-4-methylheptanoic acid

2-(2-carboxylbutyl)-3-ethyl-2-methyl oxirane
 Electron Delocalization

•• •• –
R O •• R O •
C •• •
C

•O• +O •
• • •
H H

Resonance stabilizes carbonyl

group
 19.4
Acidity of Carboxylic Acids

• Most carboxylic acids have a pKa close to 5.

 Carboxylic acids are weak acids

•but carboxylic acids are far more acidic than alcohols

CH3COH CH3CH2OH

Ka = 1.8 x 10-5 Ka = 10-16

pKa = 4.7 pKa = 16
Greater acidity of carboxylic acids is attributed
stabilization of carboxylate ion by

resonance stabilization of carboxylate ion

•• •• –
O •• •O•
• •
RC RC
•• –
O •• O ••
•• ••
 19.6
Substituents and Acid Strength
 Substituent Effects on Acidity

X CH2COH

X Ka pKa

H 1.8 x 10-5 4.7

CH3 1.3 x 10-5 4.9

CH3(CH2)5 1.3 x 10-5 4.9

• alkyl substituents have negligible effect

 Substituent Effects on Acidity

X CH2COH

X Ka pKa

H 1.8 x 10-5 4.7

F 2.5 x 10-3 2.6

Cl 1.4 x 10-3 2.9

• electronegative substituents increase acidity

 Substituent Effects on Acidity

•• –
•O•
• •
X CH2C
O ••
••

• electronegative substituents withdraw

electrons from carboxyl group by inductive
effect and provide stabilization of carboxylate
ion; increase Ka
Application
 Preparation of Carboxylic Acids: Review

•oxidation of primary alcohols (KMnO4, K2Cr2O7)

•oxidation of aldehydes (KMnO4, K2Cr2O7)

 Synthesis of Carboxylic Acids

1- Carboxylation of Grignard Reagents

2- Hydrolysis of Nitrile

3- Hydrolysis of Ester
 Carboxylation of Grignard Reagents

O
Mg CO2
RX RMgX RCOMgX
diethyl
ether H3O+

• converts an alkyl (or O

aryl) halide to a
carboxylic acid having RCOH
one more carbon atom
than the starting halide
 Carboxylation of Grignard Reagents

•• ••
O •• O ••
diethyl
R C ether R C
•O• +
MgX O •• • •• •– MgX
••

H3O+ ••
O ••

R C
• OH
• ••
 Example: Alkyl Halide

1. Mg,
CH3CHCH2CH3 diethyl ether CH3CHCH2CH3
2. CO2
Cl CO2H
+
3. H3O
(76-86%)
Example: Aryl Halide

1. Mg

2. CO2
CH3 + CH3
3. H3O
Br CO2H

(82%)
 19.12
Synthesis of Carboxylic Acids
by
Hydrolysis of Nitriles
 Hydrolysis of Nitriles

– O
•C
• N •• H3O+
RX RC N •• RCOH + NH4+
SN2 heat

• converts an alkyl halide to a carboxylic acid

having one more carbon atom than the
starting halide
• Reagent: NaCN, KCN
Mechanism
Example

NaCN
CH2Cl CH2CN
DMSO
(92%)
H2O
H2SO4
O heat
CH2COH
(77%)
Example: Dicarboxylic Acid

BrCH2CH2CH2Br

NaCN H2O

NCCH2CH2CH2CN (77-86%)

H2O, HCl heat

O O

HOCCH2CH2CH2COH (83-85%)
 via Cyanohydrin

O OH
1. NaCN
CH3CCH2CH2CH3 CH3CCH2CH2CH3
2. H+
CN
Cyanohydrin
OH
HCl, heat
CH3CCH2CH2CH3 H2O

CO2H
 Saponification reaction

COCH3 + HO-

Hydrolysis of ester in basic medium:

NaOH, KOH used in excess
O

COH + CH O-
3
 Two ways to prepare benzoic acid derivatives

1-Oxidation of alkylbenzene

2-Carboxylation of halobenzene
Application
Application
 Reactions of Carboxylic Acids

•Reduction with LiAlH4

•Esterification

•Reaction with Thionyl Chloride (SOCl2)

 Reduction with LiAlH4

O
LiAlH4
CH3CH2CH2COH CH3CH2CH2CH2OH

• Lithium aluminium hydride with carboxylic acids give

alcohol derivatives
• Lithium aluminium hydride provides hydride (H-)
strong nucleophile
• Hydride attacks the carbon of carbonyl
 Acid-catalyzed Esterification

(also called Fischer esterification)

O
H+
COH + CH3OH

COCH3 + H2O

• Important fact: the oxygen of the alcohol is

incorporated into the ester as shown.
 Lactones

•Lactones are cyclic esters

•Formed by intramolecular esterification in a

compound containing a hydroxyl group and
a carboxylic acid function
 Examples

O
O
HOCH2CH2CH2COH + H2O
O

HOCH2CH2CH2CH2COH O + H2O
O
 Example

O O

CH3CCH2CH2CH2COH

NaBH4
Soft reducing agent
OH O

CH3CHCH2CH2CH2COH
 Example

O O

CH3CCH2CH2CH2COH

NaBH4

OH O
H2SO4 O
CH3CHCH2CH2CH2COH O
H3C
 Carboxylic Acid Derivatives
O

RCCl Acyl chloride

O O
Carboxylic
Acid RCOCR Anhydride
Derivatives O

RCOR' Ester
O

RCNR'2 Amide
 Acyl chloride preparation

O O

RCOH SOCl2 RCCl

R: alkyl, phenyl Acyl chloride

 Nucleophilic Acyl Substitution

involves formation and dissociation

of a tetrahedral intermediate
•• O- ••
O •• R O ••
Nu -X
C C Nu C
R X R Nu
X
X (good leaving group) = Halogen, -OCOR

Nu= HO-, ROH, RCOOH, RNH2 (amines)

 Nucleophilic Acyl Substitution

RCCl Acyl chloride

Very reactive toward
O O
Decreasing nucleophile
Reactivity RCOCR Anhydride
(Nucleophilic Acyl O
Substitution)
RCOR' Ester
O

RCNR'2 Amide
 O

RCCl Acyl chloride

O O
Increasing
stabilization RCOCR Anhydride
of C=O O

RCOR' Ester
O

RCNR'2 Amide
 Amides

•• – ••
O •• •O •
• •

C •• C +
R NR'2 R NR'2

•lone pair donation from nitrogen stabilizes the

carbonyl group of an amide
•N is less electronegative than O; therefore,
amides are more stabilized than esters and
anhydrides
 Reactions of Acyl Chlorides

Acyl chlorides react with carboxylic acids to give

acid anhydrides:

O O O O

RCCl + R'COH RCOCR' + HCl

H
O O
via: R C OCR'

Cl
Example

O O

CH3(CH2)5CCl + CH3(CH2)5COH

O O

CH3(CH2)5COC(CH2)5CH3
 Reactions of Acyl Chlorides

Acyl chlorides react with alcohols to give esters:

O O

RCCl + R'OH RCOR' + HCl

H
O

via: R C OR'

Cl
 Example

O O

C6H5CCl + (CH3)3COH C6H5COC(CH3)3

(80%)
 Reactions of Acyl Chlorides

Acyl chlorides react with ammonia and amines

to give amides:

O O

RCCl + R'2NH RCNR'2 + HCl

H
O

via: R C NR'2

Cl
 Example

O O

C6H5CCl + HN C6H5CN
 Reactions of Acyl Chlorides

Acyl chlorides react with water to give

carboxylic acids (carboxylate ion in base):

O O

RCCl + H2O RCOH + HCl

H
O

via: R C OH

Cl
 Example

O O

C6H5CH2CCl + H2O C6H5CH2COH + HCl

Example of using anhydride as acyl agent

O O

CH3COCCH3 + H2N CH(CH3)2

CH3CNH CH(CH3)2

(98%)
 Pyruvic Acid preparation

1-Nucleophilic acyl substitution

2- Hydrolysis of nitrile group
 Thioesters

Thioesters are compounds of the type:

O

RCSR'

•Thioesters are intermediate in reactivity

between anhydrides and esters.
 Thioesters

Many biological nucleophilic acyl substitutions

involve thioesters.
O O

RCSR' + Nu H RCNu + R'S H

H
O
via: R C Nu
Good leaving group
SR'
(weak base)
 Decarboxylation of Carboxylic Acids

Simple carboxylic acids do not decarboxylate

RCOH RH + CO2

But malonic acid does.

O O O

HOCCH2COH CH3COH + CO2

Mechanism of Decarboxylation of Malonic Acid

HOCCH2 + CO2
Reaction is related to the
stability of carbanion

H+/H2O

HOCCH3
 Decarboxylation of Malonic Acid derivatives

O O O

HOCCHR'
HO OH
R R' R
Groups other than H may be present.
Decarboxylation is a general reaction
for 1,3-dicarboxylic acids

CO2H CO2H
185°C

CO2H H

160°C
CH(CO2H)2 CH2CO2H
 Decarboxylation of β-keto acid gives Ketone

O O O
α
R" β OH R"CCR'
R R' R
β-keto acid
Acidic
hydrolysis
O

R"CCHR'

R
 Decarboxylation of a β-Keto Acid

O CH3 O CH3
75°C
CH3C C CO2H CH3C C H + CO2

CH3 CH3
Application
Application