Carboxylic acid derivatives: Acyl Chlorides and Acid Anhydrides

Acyl Chlorides Acid Anhydrides

Acid anhydrides have a similar reactivity to
O Acyl chlorides are much acyl chlorides and therefore bring about the
O
CH3 C more reactive than same changes in functional groups.
carboxylic acids CH3 C
Cl
ethanoyl chloride O
The main difference is the by-products.
CH3 C Acyl chlorides mostly give off HCl. Acid
O anhydrides give off RCOOH
ethanoic anhydride.

Explaining reactivity
Many of the reactions of the carboxylic acid derivatives follow the pattern below with
an attack by an nucleophile.
O O

CH3 C + :X- CH3 C + :W- On a simplistic level, the stronger the

electron attracting power of ‘W’, the
W X more positive the carbon, and the
more attractive the carbon is to
Where –W: and :W- can be –Cl and Cl- (acyl chlorides) nucleophiles.
or -OCH3 and OCH3- (esters) The relative attractive powers of the –W: are
`or -NH2 and NH2- (amides) -Cl > -OH > -OCH3 > -NH2

Therefore in the case of hydrolysis reactions, acyl chlorides are highly reactive and will be hydrolysed by weak
nucleophiles such as water.
Amides and Esters contain only weak electron attracting W groups and need strong nucleophiles such as hydroxide
ions in NaOH to hydrolyse.
This difference in reactivity is caused by a combination of two factors
1. the electronegativity of the Cl’s, N’s and O’s causing electron density to be withdrawn from the carbon
making the carbon more positive and more attractive to nucleophiles- This factor makes them more reactive.
2. delocalisation of the lone pairs on these atoms into the carbonyl system which reduces the reactivity.

Comparing the reactivity of Acyl chlorides to amides

Acyl Chloride O O
Amide
CH 3 C CH3 C

Cl
NH2

Acyl chloride are more reactive than amides

Cl and N have similar electronegativities and so should attract electron density from the carbon by similar
amounts, making the carbons equally positive.
However, the lone pair on the nitrogen delocalises with the π bond in the carbonyl group which decreases its
reactivity.

The Cl is too big (3p orbital rather than 2p orbital in N) to be able to delocalise. This difference in the ability to
delocalise explains the difference in reactivity.

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 Reaction with water

Change in functional group: acyl chloride  Change in functional group: acid anhydride 
carboxylic acid carboxylic acid
Reagent: water Reagent: water
Conditions: room temp. Conditions: room temp.

RCOCl (l) + H2O  RCO2H + HCl (g) (RCO)2O + H2O  2RCO2H

O
O O
CH3 C O
CH3 C + H2O  CH3 C + HCl (g)
O + H2O  2 CH3 C
Cl OH
CH3 C OH
Observation: Steamy white fumes of HCl are
given off O

Nucleophilic Addition Elimination Mechanism

Oδ- : O- O
O
CH3 C δ+ + +
H3 C C OH H3 C C OH CH 3 C
Cl δ-
:OH H H OH
Cl
H

Reaction with alcohol

Change in functional group: acyl chloride  ester Change in functional group: acid anhydride  ester
Reagent: alcohol Reagent: alcohol
Conditions: room temp. Conditions: room temp.

RCOCl (l) + CH3CH2OH  RCO2CH2CH3 + HCl (g)

(RCO)2O + CH3CH2OH  RCO2CH2CH3 +RCO2H
O H O H H
O
CH 3 C + CH3CH2OH  H C C O C C H + HCl H O H H
CH3 C
Cl H H H O + CH CH OH  H C C O C C H
3 2
CH3 C H H H
Observation: Steamy white fumes of HCl
O + CH3CO2H
are given off

:O
-
δ- O
O O
+ +
CH3 C δ+ H3C C OCH2CH3 H3 C C OCH 2CH 3 C
H3C OCH2CH3
Cl Cl H H
: OCH CH
2 3
Nucleophilic Addition Elimination Mechanism
H

This reaction for making esters is much better than using carboxylic acids as the reaction is much quicker and it is not a
reversible reaction.

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Reaction with ammonia

Change in functional group: acyl chloride  Change in functional group: acid anhydride 
primary amide primary amide
Reagent: ammonia Reagent: ammonia
Conditions: room temp. Conditions: room temp.

RCOCl (l) +2NH3  RCONH2 + NH4Cl (s) (RCO)2O + 2NH3  RCONH2 + RCO2-NH4+
O O O
CH3 C O
CH3 C + 2NH3  CH3 C + NH4Cl (s)
O + 2NH3  CH3 C + CH3CO2-NH4+
Cl NH2
CH3 C NH2
Observation: white smoke of NH4Cl is given off
O

Nucleophilic Addition Elimination Mechanism

O
δ- :O - O O
δ+ + +
CH3 C H3C C NH2 H3 C C NH 2 C
Cl H3C NH2
Cl H H
: NH3
Reaction with primary amines

Change in functional group: acyl chloride  Change in functional group: acid anhydride 
secondary amide secondary amide
Reagent: primary amine Reagent: primary amine
Conditions: room temp. Conditions: room temp.

RCOCl +2CH3NH2  RCONHCH3 + CH3NH3+Cl- (RCO)2O +2CH3NH2  RCONHCH3 + RCO2-CH3NH3+

O O
O + CH3NH3+Cl- CH3 C O
CH3 C + 2CH3NH2  CH3 C NH CH3 + CH3CO2-CH3NH3+
O +2CH3NH2 
Cl CH3 C NH CH3
N-methylethanamide CH3 C
N-methylethanamide
O

Nucleophilic Addition Elimination Mechanism

δ- :O
O O
+ +
CH3 C δ+ H3C C NHCH2CH3 H3C C NHCH2CH3
Cl H
Cl H
:NHCH CH
2 3

H
O
C
H3C NHCH2CH3

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Reaction with phenol

Change in functional group: acyl chloride  ester Phenols do not easily form esters with carboxylic
Reagent: phenol acids but do so readily with acyl chlorides.
Conditions: room temp.

RCOCl (l) + C6H5OH  RCO2C6H5 + HCl (g)

O
O O
CH 3 C + OH C
+ HCl
Cl
H3C
Observation: Steamy white fumes of HCl
are given off
O
O C
 + HCl
OH + C O
Cl

phenol Benzoyl Phenyl

chloride benzoate

Making Aspirin

Aspirin is made from 2-hydroxybenzoic acid which contains a phenol group. In the reaction the
phenol group is turned into an ester by reacting it with the reactive ethanoic anhydride.

O
CO2H
CO2H CH3 C O

OH
+ O  O C CH3 + CH CO H
3 2
CH3 C
O Aspirin

Ethanoic anhydride is used instead of acid chlorides because it is cheaper, less

corrosive, less vulnerable to hydrolysis, and less dangerous to use.

Making Paracetamol

Paracetamol is made by the reaction of an aromatic amine with

an acyl chloride to produce an amide.
O
CH3 C
Cl O
HO NH2 HO NH C CH3

Paracetamol

4
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Detailed method for Preparation of Aspirin Aspirin is made from 2-hydroxybenzoic
O acid which contains a phenol group. In the
CO2H
CO2H CH3 C O
reaction the phenol group is turned into an
ester by reacting it with the reactive
OH
+ O  O C CH3 + CH CO H
3 2
ethanoic anhydride
CH3 C
O Aspirin Ethanoic anhydride is used instead of
Add to a 50 cm3 pear-shaped flask 2.0 g of 2-hydroxybenzoic acid and acid chlorides because it is cheaper, less
4 cm3 of ethanoic anhydride. corrosive, less vulnerable to hydrolysis,
To this mixture add 5 drops of 85% phosphoric(v) acid and swirl to and less dangerous to use.
mix, Fit the flask with a reflux condenser and heat the mixture on a
The excess ethanoic anhydride will
boiling water bath for about 5 minutes. Without cooling the mixture,
hydrolyse and the contents of the flask
carefully add 2 cm3 of water in one portion down the condenser.
will boil.
When the vigorous reaction has ended, pour the mixture into 40 cm 3
of cold water in a 100 cm3 beaker, stir and rub the sides of the beaker
with a stirring rod necessary to induce crystallisation and, finally,
allow the mixture to stand in ice bath to complete crystallisation.
Collect the product by suction filtration and wash it with a little water.

Purification stage: recrystallisation

Using a measuring cylinder, measure out 15 cm3 of ethanol into a
boiling tube.
Prepare a beaker half-filled with hot water from a kettle at a Avoid naked flames due to
temperature of approximately 75 °C. flammability of ethanol
Use a spatula to add the crude aspirin to the boiling tube with ethanol
and place the tube in the beaker of hot water.
Stir the contents of the boiling tube until all of the aspirin dissolves
into the ethanol.
Pour the hot solution containing dissolved aspirin through a warmed This step will remove any insoluble
filter funnel and fluted filter paper to hot filter impurities and heat will prevent crystals
Then pour filtrate into 40 cm3 of water in a conical flask. reforming during filtration
Allow the conical flask to cool slowly and white needles of aspirin
should separate. Soluble impurities will remain in solution form
Cool the whole mixture in an ice bath. because they are present in small quantities
Filter off the purified solid under reduced pressure and allow it to dry so solution is not saturated. Ice will increase
on filter paper. the yield of crystals
Record the mass of the dry purified solid

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