Chapter 2

Chapter II: Carboxylic acid and its derivatives

2.1 Carboxylic acid
2.1.1 Definition, nomenclature and structure

2.1.1.1 Definition
- Carboxylic acids are organic compounds having the functional group COOH (carboxyl group)
- Carboxylic acids can be classified based on the structure of

hydrocarbon part
+ Saturated carboxylic acid
+ Unsaturated carboxylic acid
+ Aromatic carboxylic acid

2.1.1.2 Nomenclature
- Common name: Many carboxylic acids have common names that are
derived from Latin or Greek words that indicate one of their natural sources.
+ In common names, the positions of substituents are named using

Greek letters
- IUPAC name : location and name of substituents+ name of

corresponding hydrocarbon + oic
- Aromatic acids of the form Ar -COOH are named as

derivatives of benzoic acid, Ph-COOH. As with other aromatic
compounds, the prefixes ortho-, meta-, and para may be used to
give the positions of additional substituents
2.1.1.3 Structures
- Formic acid is almost planar. There are three stabilized resonance structures
- Carboxylic acid exists in dimer form in most

conditions
- The OH and carbonyl groups of the carboxyl group

are both polar
- The OH makes the C=O bond less polar and more

difficult towards nucleophylic addition reaction
- The C=O makes the OH bond more polar and makes

carboxylic acid is much more acidic in comparison with
alcohol
- Structure of carboxylate ion: Carboxylate ion is much more

stable than alkolate due to delocalization
electrostatic potential maps

- Carboxylic acids are less reactive than carbonyl

compounds towards nucleophilic addition
- Carboxylic acids are much more acidic than
alcohol due to effect of the carbonyl group
- Carboxylate ion is much more stable than alkolate
due to delocalization
2.1.4 Preparation
2.1.4.1 Oxidize alkenes, alkynes, primary alcohols, aldehydes, ketones and alkyl benzene
- Oxidation of alkenes
- Ozonolysis of alkyne followed by hydrolysis

- Oxidation of primary alcohol

- Oxidation of aldehyde: many reagents can be used

for this transformation
- Oxidation of ketones: The reaction can form a

mixture of carboxylic acid
- Oxidation of alkylbenzene: The α carbon must have hydrogen atom

2.1.4.2. Hydrolysis of carboxylix acid derivatives
- Hydrolysis of gem-trihalogen, ester, amide

- Hydrolysis of nitrile: This is an important method because

nitries can be obtained by many methods. General reaction
+ Examples
2.1.4.3. Carboxylation of Grignard reagent followed by hydrolysis
- This is a convenient for the preparation of carboxylic acid
+ Firstly, nucleophilic addition of Grignard reagent to carbon

dioxide forms the magnesium salt
+ This salt is hydrolyzed to generate the corresponding carboxylic
acid
- Attention
+ The reaction must be performed in dry conditions
+ The Grignard reagent can be conveniently prepared from the

corresponding halide
+ The synthesis from halide can be perform in one pot
+ This synthesis is applicable to primary, secondary, tertiary,

allyl, benzyl, and aryl halides, provided they have no groups
that are incompatible with a Grignard reaction
- Examples
2.1.4.4. Special method
- Industrial preparation of formic acid from methanol
and carbomonoxide Phương pháp đặc biệt
yêu cầu:
- rẻ, dễ kiếm
- phản ứng thoả mãn yêu cầu quy mô lớn
- hiệu suất lớn
- Industrial preparation of acetic acid from methanol

and carbon monoxide
- Preparation of adipic acid and terephthalic acid

- Preparation of maleic acid
- Preparation of malonic acid

2.1.3 Physical properties
2.1.3.1 Boiling point
- Boiling points and melting points of carboxylic acid are much higher than those of
corresponding alcohol because of stronger hydrogen bonds between acid molecules.
- Boiling points and melting points increase when

molecular weight increases
- Carboxylic acids, especially those possessing relatively low

molecular weights and correspondingly high volatility, exhibit
characteristically strong odors.
+For example, the presence of butanoic acid contributes to the
characteristic strong flavor of many cheeses,
+ (E)-3-methyl-2-hexenoic acid is one of the principal compounds
responsible for the smell of human sweat.
2.1.3.2 Solubility Tính tan
- Carboxylic acids are more soluble than corresponding alcohols (make stronger hydrogen
bond with water ).
- Three types of hydrogen bonds can be formed
- Solubility decreases when molecular weight increases

2.1.4 Chemical properties
2.1.4.1 Acidic property
Tính acid tỉ lệ nghịch với pKa
- Acidity is determined by pKa value. Acidity is indirectly proportional to pKa
- The –C effect of the CO group causes the OH more polar. Thus carboxylic acids are
much stronger acidic than corresponding alcohol.
- In addition, carboxylate anion is much more stable than corresponding alkolate

due to delocalization sự giải toả điện tích
delocalization in carboxylate anion

- Electron withdrawing groups increase acidity. Conversely electron donating

groups decrease acidity
+ Alkanoic acid
pKa càng nhỏ thì tính acid

càng mạnh
+ Monochlorobutanoic acid
+ Chloroacetic acid
+ Unsaturated acids are more acidic than saturated carboxylic acids

không no có tính acid mạnh hơn no
+ Strong electron-withdrawing groups make acids more acidic
+ Acidity of aromatic carboxylic acid

+ Acidity of dicarboxylic acid

- Some reactions show acidity of carboxylic acid

+ turn blue litmus paper red
+ reacts with base
+ reacts with some salts
- Carboxylate salts
+ A carboxylate salt, the product of reaction between a

carboxylic acid and a strong base, is named as follows:
• The positive ion is named first.
• The carboxylate ion is named by changing the ending of the
acid’s name (either IUPAC or common) from -ic acid to -ate.
2.1.4.2 Property at the carbonyl group

* Fisher esterification reaction
Phản ứng este hoá
- Mechanism:
proton hoá
Step 1: The carboxylic acid is protonated on its carbonyl oxygen. The
proton donor shown in the equation for this step is an alkyloxonium
ion formed by proton transfer from the acid catalyst to the alcohol.
Step 2: Protonation of the carboxylic acid increases the positive

character of its carbonyl group. A molecule of the alcohol acts
as a nucleophile and bonds to the carbonyl carbon.
Step 3: The oxonium ion formed in step 2 loses a proton to give the
tetrahedral intermediate in its neutral form. This concludes the first stage
in the mechanism.
Step 4: The second stage begins with protonation of the tetrahedral
intermediate on one of its hydroxyl oxygens.
Step 5: The hydroxyl-protonated tetrahedral intermediate dissociates to a

molecule of water and gives the protonated form of the ester.
Step 6: Deprotonation of the protonated ester gives the ester.
Acid-catalyzed esterification is reversible, and generally the quantities of

both carboxylic acid and alcohol remaining at equilibrium are appreciable
It methanol enriched in the mass-18 isotope of oxygen is esterified with

benzoic acid, the methyl benzoate product will contained all the 18O label
that was originally present in the alcohol
Esterification may be driven to the right either by using an excess of one of the
reactants or by removing one of the products. For example, in forming ethyl
esters, excess ethanol is often used to drive the equilibrium as far as possible
toward the ester. Alternatively, water may be removed either by distilling it out
or by adding a dehydrating agent such as magnesium sulfate or molecular
sieves (dehydrated zeolite crystals that adsorb water).
- Ability of acids and alcohol in esterification reaction follows these orders
- Hydroxy acids, compounds that contain both a hydroxyl and a carboxylic acid
function, have the capacity to form cyclic esters called lactones. This
intramolecular esterification takes place spontaneously when the ring that is formed
is five- or six-membered. Lactones that contain a five-memberedcyclic ester are
referred to as γ-lactones; their six-membered analogs are known as δ-lactones.
Carboxylic acids are converted to their methyl esters very simply by adding an
ether solution of diazomethane. The only by-product is nitrogen gas, and any
excess diazomethane also evaporates. Purification of the ester usually involves
only evaporation of the solvent. Yields are nearly quantitative in most cases.
2.1.4.3 Reactions to break C-O bond
- With SOCl2, PCl5, PCl3 or PBr3 to form acyl halide. Reaction mechanism is
shown in the preparation of acyl chloride
- Dehydration to form anhydride acid: Carboxylic acids can be converted into

acid anhydrides with excessive heating.
- Reaction to form amide

2.1.4.4 Decarboxylation reaction
Decarboxylation is the loss of CO2 from the carboxyl group of a molecule.

Almost any carboxylic acid, heated to a very high temperature, undergoes
thermal decarboxylation. Most carboxylic acids, however, are quite resistant
to moderate heat and melt or even boil without decarboxylation. Exceptions
are carboxylic acids that have a carbonyl group β to the carboxyl group. This
type of carboxylic acid undergoes decarboxylation quite readily on mild
heating. For example, warming 3-oxobutanoic acid brings about its
decarboxylation to give acetone and carbon dioxide.
β-Dicarboxylic acids (1,3-dicarboxylic acids, also called malonic

acids) decarboxylate readily for reasons similar to β-keto acids
- Thermolysis of carboxylate salts is much more easier
2.1.4.5 Reaction at hydrocarbon part

Alpha Bromination of Carboxylic Acids: The Hell-Volhard-Zelinsky
Reaction
It is believed to occur via the following sequence of events:

- This reaction is used to prepare α hydroxyacid or α aminoacid

* Reactions of unsaturated and aromatic acids
1) Prepare the following compounds
2) Complete these transformations
3) Complete following series of reactions

2.1.4.6 Introduce some acids
* Formic acid HCOOH
- Colourless liquid, pungent odor

- Present in some ants’ venom (ant acid)
- Prepared from CO in industry
* Acetic acid CH3COOH
- Colourless liquid. Pleasant odor, sour taste

- Aqueous 3-5% solution is called vinegar (vinegar acid)
- Widely used in organic synthesis to prepare ester acetate, acetate salts
- Easily prepared from ethanol by fermentation
* Oxalic acid HOOC-COOH
* Malonic acid HOOC-CH2-COOH
- Widely used in organic synthesis in the form of diethylmalonate
- Prepared from chloroacetic acid as following
* Adipic acid HOOC-(CH2)4-COOH
- Widely used in textile industry nylon - 6, nylon- 6,6

- Prepared in industry by oxidation of cyclohexanone
2.2 Carboxylic acid derivatives
2.2.1 Nomenclature, structures and physical properties
* Ester
- Products formed when replace the OH group of carboxylic acid by hydrocarbon part
- Nomenclature :
+ Common names: of hydrocarbon part of alcohol (alkyl) + Common name of carboxylate part
+ IUPAC names: of hydrocarbon part of alcohol (alkyl) + IUPAC name of carboxylate part
2.2.2. Acyl halide, anhydride acid, and amide
2.2.2.1 Definition and nomenclature

-Acyl halide: Products formed when replacing OH
group of carboxylic acid by halogen
- Common name : common name of acid, change “ic– yl” + halide

- IUPAC name : IUPAC name acid, change “ic-yl” + halide
- Acid anhydride: The functional group of a carboxylic anhydride is

two acyl groups bonded to an oxygen atom (RCO)2O
- Nomenclature : anhydride + corresponding acid

- Amide: Compound formed by replacing OH group of acid by amine

or ammonia. The functional group of an amide is an acyl group
bonded to a nitrogen atom
+ Amides can be classified as primary, secondary, and tertiary amides
+ Nomenclature : For primary amides: Name of corresponding acid,
change “ic – amide”. For secondary and tertiary amides: add substituents
bonding to N atom
+ A cyclic amide is called lactam

2.2.2.2 Structure
- These compounds contain polar CO bond

- The stability and reactivity of these compounds follow this order

- Physical properties : These compounds have lower boiling points and melting points
than corresponding carboxylic acid does, except for amide( because they can not
form hydrogen bonding between molecules)
- Amides have high boiling point because of dipole-dipole

interaction and hydrogen bond (for primary and secondary
amides)
- Solubilities : chloride acid and anhydride acid react violently with water.
Small molecule ester, amide are soluble in water.
2.2.3 Chemical properties

2.2.3.1 Hydrolysis reactions
* Hydrolysis of ester in acidic media
- The AAc2 mechanism

Step 1: Protonation of the carbonyl oxygen of the ester
Step 2: Nucleophilic addition of water to the protonated ester

Step 3: Deprotonation of TI–H+ to give the neutral form of the

tetrahedral intermediate (TI)
Step 4: Protonation of the alkoxy oxygen of the

tetrahedral intermediate
Step 5: Dissociation of the protonated form of the tetrahedral intermediate
gives the alcohol and the protonated form of the carboxylic acid
Step 6: Deprotonation of the protonated carboxylic acid

completes the process
When ethyl benzoate, labeled with the mass-18 isotope of the carbonyl oxygen,
then subjected it to acid-catalyzed hydrolysis in ordinary (unlabeled) water. He
found that ethyl benzoate, recovered from the reaction before hydrolysis was
complete, had lost a portion of its isotopic label. This observation is consistent
only with the reversible formation of a tetrahedral intermediate under the reaction
conditions:
- The AAl1 mechanism : applied for ester from tertiary alcohol
- Base- catalyzed hydrolysis – The saponification reaction
- General mechanism
Step 1: Nucleophilic addition of hydroxide to the carbonyl group
Step 2: Dissociation of the anionic tetrahedral intermediate TI-

Step 3: Proton transfers yield an alcohol and a carboxylate ion

- The saponification of ester is irreversible because the last step is irreversible

* Hydrolysis of the other derivatives

- General mechanism
- Anhydride acids and chloride acids are completely hydrolyzed, while amides barely
hydrolyzed except for base-catalyzed hydrolysis
mechanism
Step 1: Protonation of the carbonyl oxygen of the amide
Step 2: Nucleophilic addition of water to the protonated amide
Step 3: Deprotonation of TI–H+ to give the neutral form of the tetrahedral

intermediate (TI)
Step 4: Protonation of TI at its amino nitrogen
Step 5: Dissociation of the N-protonated form of the tetrahedral intermediate to

give ammonia and the protonated form of the carboxylic acid
Step 6: Proton-transfer processes give the carboxylic acid and
ammonium ion
Hydrolysis in basic media

Step 1: Nucleophilic addition of hydroxide ion to the
carbonyl group
Step 2: Proton transfer to the anionic form of the

tetrahedral intermediate
Step 3: Protonation ofthe amino nitrogen
Step 4: Dissociation ofthe N-protonated form of the tetrahedral

intermediate
Step 5: Irreversible formation of the carboxylate anion
2.2.3.2 Nucleophilic substitution reaction
- Order of reactivity
- Anhydride acids and chloride acids react easily with alcohols to form esters
- Reaction between ester and alcohol, the transesterification reaction

Esters undergo transesterification, in which one alkoxy group substitutes
for another, under either acidic or basic conditions. When an ester of one
alcohol is treated with a different alcohol in the presence of acid or base,
the two alcohol groups can interchange. An equilibrium results, and the
equilibrium can be driven toward the desired ester by using a large excess
of the desired alcohol or by removing the other alcohol.
- React with ammonia or amines to form amides
+ Acyl chloride
+ Acid anhydride
+ Ester
- React with organometallic compounds

+ Ester
2.2.3.3 Reduction of carboxylic acid derivatives

- LiAlH4 can reduce these derivatives to primary alcohols
Acid chlorides are more reactive than other acid derivatives, and they are
reduced to aldehydes by mild reducing agents such as lithium tri-tert-
butoxyaluminum hydride. Diisobutylaluminum hydride (DIBAL-H)
reduces esters to aldehydes at low temperatures, and it also reduces nitriles
to aldehydes.
Lithium aluminum hydride reduces amides and nitriles to amines, providing

some of the best synthetic routes to amines. Primary amides and
nitriles are reduced to primary amines. Secondary amides are reduced to
secondary amines, and tertiary amides are reduced to tertiary amines.
2.2.3.4 Substitution reactions at Cα

4) Draw structures of products of following reactions
5) Complete these reactions

6) Write products of following reactions
2.2.3.5 The Claisen condensation between esters
The Claisen reaction is the second general reaction of enolates with other
carbonyl compounds. In the Claisen reaction, two molecules of an ester react
with each other in the presence of an alkoxide base to form a a-keto ester
Mechanism
- Claisen condensation between different esters: usually a non Cα-H ester is

employed to avoid forming mixture of products
- Reactions between ester and ketone
A directed Claisen condensation can be performed in which LDA is

used as a base to irreversibly form an ester enolate, which is then
treated with a different ester
- Intramolecular Claisen condensation – the Diecmann condensation

2.2.3.6 The Michael addition
α,β-Unsaturated carbonyl compounds have unusually electrophilic double

bonds. The β carbon is electrophilic because it shares the partial positive
charge of the carbonyl carbon atom through resonance.
- α,β – unsaturated carboxylic derivatives can take part in nucleophilic
addition at the C=C bond
Addition of carbanion or anion enolate

Addition of Lithium Diorganocopper Reagents
Lithium diorganocopper reagents undergo 1,4-addition to a,b-unsaturated

aldehydes and ketones in a reaction that is closely related to the Michael
reaction. Yields are highest with primary alkyl, allylic, vinyl, and aryl
organocopper reagents
* Addition of amines - the aza-Michael addition

2.2.3.7 Other reactions

- Dehydration of amide to form nitrile
- Hoppmann rearrangement of amide

+ Proposed mechanism
- Acylation to aromatic hydrocarbon of chloride acid and anhydride acid
2.2.2 c Preparation
- Acyl chloride: Chlorination of carboxylic acid with SOCl2 or PCl5 or PCl3
or cyanuric chloride
- Acid anhydride:
+ Dehydration of carboxylic acid
+ Reaction between chloride acid and carboxylic acid

+ Reaction between chloride acid and carboxylate salt
+ Reaction between ketene and carboxylic acid

- Amide
+ Reaction between ester, chloride acid or anhydride acid with amines

+ Reaction between carboxylic acid with amines

+ Reaction between alcohols and ester

+ Reaction between carboxylate salt and alkyl halide
+ Bayaer- Villiger oxidation of ketone

7) Complete following reactions
8) From m- bromotoluene, prepare the following insecticide

9) Complete following series of reactions
10) Prepare following reacrtions

Chapter 2

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Chapter 2

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Chapter II: Carboxylic acid and its derivatives

Chapter II: Carboxylic acid and its derivatives

2.1.1 Definition, nomenclature and structure

- Carboxylic acids can be classified based on the structure of

+ Unsaturated carboxylic acid

+ Aromatic carboxylic acid

+ In common names, the positions of substituents are named using

- IUPAC name : location and name of substituents+ name of

- Aromatic acids of the form Ar -COOH are named as

- Carboxylic acid exists in dimer form in most

- The OH and carbonyl groups of the carboxyl group

- The OH makes the C=O bond less polar and more

- The C=O makes the OH bond more polar and makes

- Structure of carboxylate ion: Carboxylate ion is much more

electrostatic potential maps

- Carboxylic acids are less reactive than carbonyl

- Ozonolysis of alkyne followed by hydrolysis

- Oxidation of primary alcohol

- Oxidation of aldehyde: many reagents can be used

- Oxidation of ketones: The reaction can form a

- Oxidation of alkylbenzene: The α carbon must have hydrogen atom

2.1.4.2. Hydrolysis of carboxylix acid derivatives

- Hydrolysis of gem-trihalogen, ester, amide

- Hydrolysis of nitrile: This is an important method because

2.1.4.3. Carboxylation of Grignard reagent followed by hydrolysis

- This is a convenient for the preparation of carboxylic acid

+ Firstly, nucleophilic addition of Grignard reagent to carbon

+ The reaction must be performed in dry conditions

+ The Grignard reagent can be conveniently prepared from the

+ The synthesis from halide can be perform in one pot

+ This synthesis is applicable to primary, secondary, tertiary,

- Industrial preparation of acetic acid from methanol

- Preparation of adipic acid and terephthalic acid

- Preparation of maleic acid

- Preparation of malonic acid

- Boiling points and melting points increase when

- Carboxylic acids, especially those possessing relatively low

- Solubility decreases when molecular weight increases

- In addition, carboxylate anion is much more stable than corresponding alkolate

delocalization in carboxylate anion

- Electron withdrawing groups increase acidity. Conversely electron donating

pKa càng nhỏ thì tính acid

+ Unsaturated acids are more acidic than saturated carboxylic acids

+ Strong electron-withdrawing groups make acids more acidic

+ Acidity of aromatic carboxylic acid

+ Acidity of dicarboxylic acid

- Some reactions show acidity of carboxylic acid

+ A carboxylate salt, the product of reaction between a

2.1.4.2 Property at the carbonyl group

Step 2: Protonation of the carboxylic acid increases the positive

Step 5: The hydroxyl-protonated tetrahedral intermediate dissociates to a

Acid-catalyzed esterification is reversible, and generally the quantities of

It methanol enriched in the mass-18 isotope of oxygen is esterified with

- Ability of acids and alcohol in esterification reaction follows these orders

2.1.4.3 Reactions to break C-O bond

- Dehydration to form anhydride acid: Carboxylic acids can be converted into

- Reaction to form amide

2.1.4.4 Decarboxylation reaction

Decarboxylation is the loss of CO2 from the carboxyl group of a molecule.

β-Dicarboxylic acids (1,3-dicarboxylic acids, also called malonic

- Thermolysis of carboxylate salts is much more easier

2.1.4.5 Reaction at hydrocarbon part

It is believed to occur via the following sequence of events: