MEDICAL CHEMISTRY 1

Carboxylic acids
derivatives
by Tamas Lorand

2017/18.
Carboxylic acids derivatives

NHCOCH3

OH

paracetamol
 Learning objectives

Term of carboxylic acid derivatives, their structure, the acyl group. Reactivity of
carboxylic acid derivatives, their chemical reactions: substitution at the carbonyl
carbon.
Carboxylic acid anhydrides - nomenclature, preparation and chemical reactions-
acylation.
Esters- nomenclature, classification, preparation, physical and chemical properties
(base catalysed hydrolysis); biochemical importance of thioesters.
Phosphate and sulphate esters –their physiological importance (signal
transduction and biotransformation).
Amides - nomenclature, preparation, structure, physical and chemical properties
(acid-base character, hydrolysis, dehydration to nitriles; lactams).
 Introduction

The term: acyl group

O O O
R C R C H3C C
OH
carboxylic acid acyl group acetyl group
 Classification of the carboxylic acid
derivatives I

Derivatives of acetic acid O

H3C C
Formula Name X
O
H3C C acetyl chloride
Cl
O
H3C C
O acetic anhydride
H3C C
O
Classification of the carboxylic acid
derivatives II

Formula Name
O
H3C C methyl acetate
O
H3C
O
H3C C acetamide
NH2

H3C C N acetonitril
 Reactivity of carboxylic acid derivatives

carboxylic acid anhydrides > esters > carboxylic acid > amides > salts of
carboxylic acids

General scheme for their reactions

Substitution on the carbonyl carbon (addition + elimination)

O O O
R C + Nu R C X R C + X
X Nu Nu

X= OR, etc.
Nucleophile: ammonia, - OH, water
 Carboxylic acid anhydrides

Nomenclature: name of the acid + anhydride

Physical properties: they are more volatile (their boiling point is lower
than that of the corresponding carboxylic acid).
Chemical properties: acylation- reaction with water=hydrolysis,
reaction with alcohols = formation of ester, reaction with amines =
formation of amides, etc.
O

CH3C O
O + CH3 CH2OH CH3C + CH3COOH
CH3C ethanol OCH2CH3
O
acetic anhydride ethyl acetate
 Esters I

Classification of esters (esters of carboxylic acids)

fruit esters

waxes

triglycerides
 Esters II

Direct esterification

O
CO OH + H O CH3 C
H
+ OCH3 + H2O

benzoic acid methyl benzoate

 Esters III

Carboxylic acid anhydride + phenol

COOH
H3C O
C COOH
O + O + CH3COOH
C
OH C CH
H3C O 3
O
acetic salicylic
acetylsalicylic acid
anhydryde acid
(aspirin)
 Esters IV

Nomenclature: name of the alkyl or aryl group + name of the acid

replacing –ic acid with suffix –ate or -oate.
e.g. ethyl butyrate O ethyl butyrate
CH3 CH2 CH2 C
O CH2 CH3
Classification of ester
Fruit esters: esters of short chain alcohols with short chain fatty
acids
(ethyl butyrate - in pineapple aroma)
Waxes: esters of long chain alcohols with long chain fatty acids

H31C15 COO C31H63 myricyl palmitate

 Esters V

Triglycerides: esters of glycerol with long chain fatty acids

O
O CH2 O C (CH2)14 CH3
H3C (CH2)7 CH CH (CH2)7 C O C H
CH2 O C (CH2)16 CH3
triglyceride O
 Esters VI

Physical properties: only weak van der Waals forces, they are more
volatile than the carboxylic acids, some of them have pleasant odour
(fragrances are composed of esters)

Solubility: they are soluble in apolar organic solvents

Esters VII Components of a banana aroma
 Esters VIII

Chemical properties

Hydrolysis (acid or base catalysed= saponification, it is not reversible)

O

CH3CH2C + NaOH(aq) CH3CH2COONa + CH3CH2OH
O CH2CH3
sodium
ethyl propionate ethanol
propionate
 Esters IX

Reaction mechanism of base catalysed hydrolysis (saponification)

Methyl acetate + NaOH(aq)

addition

O elimination O
Elimináció
CH3 C OCH3 CH3 C OH + CH3O
OH
O
proton transfer
Átprotonálódás
CH3 C O + CH3OH
 Thioesters

Structure, biological importance (Acetyl-CoA)

O O-
C R' C R'
R S R S
+
thioesters no resonance stabilization

O O-
C R' C R'
R O R O
+
esters: resonance stabilized structure
 Inorganic esters I Sulphate esters

Alkylsulphates - Detergents or tenzides

O
CH3 (CH2)10 CH2 O S O- Na+
O

Sodium dodecyl sulphate

(or sodium lauryl sulphate, SDS)
The sulphate ester group occur in some polysaccharides.
In addition, the sulphate esters are involved in some metabolic processes. (steroids)
 Inorganic esters II Phosphate esters

Esters of orthophosphoric acid

The monosaccharide phosphates occur in each cell, but they play an
important role in the metabolism of amino acids, too. Some alkyl
phosphate behave as strong nerve agents.

phosphoenol-
glycerol-3-phosphate glyceraldehyde-3-phosphate
pyruvate
 Amides I

Nomenclature

IUPAC name: replace the ending-ic acid, or –oic acid with suffix –
amide. In the case of cyclic amides use the suffix: carboxamide.

(trivial names: similarly)

O
HC CH3
N
CH3CONH2 CH3
ethaneamide (acetamide) N,N-dimethylformamide

CONH2

cyclohexanecarboxamide
 Amides II

Structure and stereochemistry of amides

It is conjugated structure that can be described with two resonance
structures. The C-N bond is not a single bond; six atoms are in one
plane. (structure of peptides and proteins)

O R O R
C N C N
Q H Q H
 R
O 
C N
Q H
 Amides III

Preparation of amides I

Method: acylation of ammonia or amines using a carboxylic acid

anhydride

H3C O
O
C
CH3C
O + H2N + CH3COOH
C N
H3C O H
acetic anhydride aniline acetanilide
 Amides IV

Preparation of amides II

Method: from an amine or ammonia and a carboxylic acid

O -
O O
+ 
R C + H2N R' R C H3N R' R C + H2O
OH O NH R'

carboxylic
acid amine salt amide
 Amides V

Physical properties R
association with H-bond N H O
Q C C Q
cyclic dimer O H N
(cis-amide, rare in the nature) R

R
R N H
R N H O C
N H O C Q
O C Q polymeric associated amide
Q (trans-amide)
 Amides VI

Chemical reactions I

Acid-base properties: they are not basic compounds, they

behave as very weak acids.

Hydrolysis (acid or base catalysed)

O O

CH3C + H3O+ CH3C + NH4+
NH2 OH
acetamide
 Amides VII

Chemical reactions II

Dehydration: preparation of nitriles

O

CH3C - H2O CH3 C N
NH2
acetamide acetonitrile
 Amides VIII

Lactams (cyclic amides)

O O
C C
OH 
NH
NH2 -H2O

g-aminobutyric acid g-butyrolactam

 Summary

Term of carboxylic acid derivatives, their structure, the acyl group

Reactivity of carboxylic acid derivatives, their chemical reactions:
substitution at the carbonyl carbon.
Carboxylic acid anhydrides- nomenclature, preparation and chemical
reactions- acylation.
Esters- nomenclature, classification, preparation, physical and
chemical properties (base catalysed hydrolysis); thioesters. Inorganic
esters. Amides - nomenclature, preparation, structure, physical and
chemical properties (acid-base character, hydrolysis, dehydration to
nitriles; lactams).