Acylation
Acid Chlorides and Acid Anhydrides
An ACYL group is the CARBONYL group with an ALKYL group attached so that the spare bond to attach to other
molecules is from the carbonyl carbon.
Like this:bond to other molecules
The introduction of the group into another molecule is called ACYLATION.
The reaction is used in the
pharmaceutical (aspirin) and the textile (cellulose acetate or rayon) industries. Carboxylic acids contain the ACYL
group but the OH group bonded to the ACYL group is a very poor leaving group and so carboxylic acids are not
used as ACYLATING agents. Instead, two carboxylic acid derivatives are used.
They are ACID CHLORIDES (or ACYL CHLORIDES) and ACID ANHYDRIDES.
Of the two, ACID ANHYDRIDES are the preferred choice because: they are cheaper to manufacture;
 they are less reactive so the ACYLATING reactions are less dangerous and easier to control;
 ACYL CHLORIDES produce HCl as a product of ACYLATION, and this is a corrosive molecule, whereas
ACID ANHYDRIDES produce a molecule of WATER.
 water easily hydrolyses ACYL CHLORIDES as is seen in the next section. ACID ANHYDRIDES are much
less susceptible to hydrolysis.
The main disadvantage of using ACID ANHYDRIDES is that the bi-product is either ETHANOIC ACID (for the
reactions with WATER and ALCOHOLS) or the AMMONIUM or AMINE salts of ETHANOIC ACID (for the reactions
with AMMONIA and AMINES). These bi-products are not very easy to remove, whereas the other reaction product
with ACID CHLORIDES is HCl, which is volatile and easily separated.
ACYL CHLORIDES or ACID CHLORIDES
Acid (or acyl) chlorides have the structure: -
The electron withdrawing effect of the carbonyl oxygen atom, coupled with that of the chlorine atom, make the
carbonyl carbon atom quite positively charged and susceptible to nucleophilic attack

by water (hydrolysis) to give the acid;

by alcohols to give the ester;

by ammonia to give the acid amide;

by amines to give substituted amides.
This is especially so because, in addition, the Cl atom is a good leaving group.
They are made by the action of SULPHUR DICHLORIDE OXIDE (thionyl chloride) SOCl2 on CARBOXYLIC
ACIDS.
CH3COOH
+
SOCl2
CH3COCl
+
SO2
+
HCl
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ACID ANHYDRIDES
The structure of ACID ANHYDRIDES is shown on the right. They are called ANHYDRIDES of
ACIDS because if the atoms of one molecule of water are added to a molecule of an ACID
ANHYDRIDE, two molecules of the CARBOXYLIC ACID are formed.
They are not made by dehydrating carboxylic acids, but rather by ACYLATING their SODIUM SALTS. The ‘Na+’ ion
of the sodium salt is replaced by the ACYL group.
The equations and mechanisms follow. The mechanisms for the ACYLATION reactions using ACID ANHYDRIDES
are not necessary for the course, only mechanisms using ACID CHLORIDES are required. Equations will be
required for BOTH acid chlorides AND anhydrides.
1. Water
CH3COCl + H2O
CH3COOH
+
HCl
The reaction is essentially a NUCLEOPHILIC ADDITIONELIMINATON reaction.
1. The lone pair from a
water oxygen attacks
the + carbon atom
and the CARBONYL
(C=O) double bond
breaks. This is the
ADDITION part of the
reaction.
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2. The C–Cl bond
breaks and the Cl
atom
leaves.
Simultaneously,
the
C=O double bond
reforms. This is the
ELIMINATION part of
the reaction.
3. A proton leaves
to produce the final
neutral molecule.
The NUCLEOPHILE (water,
in this case) has undergone a
NUCLEOPHILIC
SUBSTITUTION.
A HYDROGEN has been
replaced by an ACYL group.
Water is said to have been
ACYLATED.
The NUCLEOPHILE (water, in this case) has undergone a NUCLEOPHILIC
SUBSTITUTION. A HYDROGEN has been replaced by an ACYL group. Water is
said to have been ACYLATED.
(repeated because it is important that the meaning of “ACYLATION” is understood. What has been “ACYLATED”?
 WATER. The ACYL group has substituted a HYDROGEN atom in water)
The corresponding ACID ANHYDRIDE EQUATION:-
(CH3CO)2O
+
H2O
CH3COOH
+
CH3COOH
The “left-over”
product from the
ANHYDRIDE.
The product from
ACYLATING water.
2. Alcohols
CH3COCl
+
CH3OH
CH3COOCH3
+
HCl
In industry, ETHANOIC ANHYDRIDE is used instead of ETHANOYL CHLORIDE for the reasons previously
outlined. The equation is:-
(CH3CO)2O
ethanoic anhydride
+
CH3OH
CH3COOCH3
methanol
methyl ethanoate
+
CH3COOH
ethanoic acid
The carboxylic acid can be removed by the addition of SODIUM CARBONATE which neutralises it and converts it
to the SODIUM SALT which is not volatile. The ESTER can be distilled off.
This method is a much more satisfactory method of producing ESTERS than the CARBOXYLIC ACID plus
ALCOHOL method because unlike the acid plus alcohol method, the ACYLATION method is rapid, not reversible,
does not require a catalyst and produces a very good yield.
ASPIRIN
It has been known for some 2 400 years that chewing the leaves or the bark of Willow trees
was found to relieve pain and suppress the symptoms of mild fever. In the mid eighteen
hundreds, it was shown that the active ingredient responsible contained in the leaves was
SALICYLIC ACID or 2-HYDROXYBENZOIC ACID. (right)
A German scientist, KOLBE, discovered a very easy and cheap method of
manufacturing SALICYLIC ACID.
His method involved heating PHENOL
(structure shown here on the left) with CARBON DIOXIDE under pressure. Unfortunately, the drug was
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found to have some unpleasant side effects, such as irritation of the mouth, throat and stomach. Hofmann, another
German scientist, investigated many derivatives of SALICYLIC ACID to find one that relieved pain in a similar way
to SALICYLIC ACID, but without the unacceptable side effects. Eventually, ACYLATION of the PHENOLIC group
(the OH) provided the answer. Here, the ‘H’ of the OH group is replaced by the ACYL group, CH3CO
The systematic name for ASPIRIN is 2-ethanoyloxybenzenecarboxylic acid.
Ethanoic Anhydride is used instead of ethanoyl chloride and the corresponding equation is shown below.
3. Ammonia
CH3COCl
+
2 NH3
CH3CONH2
+
NH4 Cl
An amide  ETHANAMIDE
A second molecule of ammonia is involved in the last stage. Being basic it can remove the proton.
The equivalent reaction involving the ACID ANHYDRIDE is:-
(CH3CO)2O
+
2 NH3
CH3CONH2
+
CH3COO NH4
ammonium ethanoate
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When ALKYL groups replace ‘H’ atoms in AMMONIA, the new amine molecule becomes even more susceptible to
attack by + carbon atoms. Expressed another way, the amine molecule is a more powerful nucleophile than the
ammonia molecule it was made from and this leads to further ‘H’ atoms being replaced by alkyl groups. This is
because the replacement of an ‘H’ in ammonia by an alkyl group makes the lone pair of electrons on the ‘N’ atom
more available for nucleophilic attack because of the +I effect of alkyl groups. (see Reactions of Haloalkanes with
ammonia).
The reaction mechanism is reproduced here for convenience.
This is followed by a further reaction where a molecule of chloromethane is attacked by the newly formed amine in
preference to being attacked by ammonia because the amine is a stronger nucleophile. The +I inductive effect of
the alkyl group makes the lone pair of electrons on the nitrogen atom more available for nucleophilic attack.
In the reaction between ammonia and ethanoyl chloride where ETHANAMIDE is produced, the
reaction stops at this stage and further substitution of the ‘H’ atoms in the NH2 group does
NOT occur because the electron WITHDRAWING effect, or I, of the carbonyl group makes
the lone pair of electrons on the ‘N’ atom LESS available for further nucleophilic attack.
4. Amines
aminomethane
primary
Nmethylaminomethane
secondary
N,Ndimethylaminomethane
tetramethylammonium ion
tertiary
quaternary
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CH3COCl
(CH3CO)2O
+
2 C6H5NH2
CH3CONHC6H5
+ C6H5NH3+ Cl
phenylamine
N-phenylethanamide
phenylammonium chloride
+ 2 C6H5NH2
CH3CONHC6H5 + CH3COO [NH3 C6H5]+
phenylammonium ethanoate
The Mechanism
The proton is removed by another molecule of the amine, which, being BASIC, can remove the ACIDIC proton.
The reaction stops at this stage, unlike in the case of reactions with HALOALKANES, which can form TERTIARY
and even QUATERNARY AMINES, as described above.
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