Acylation

You should know by now about some of the ways that carboxylic acids react (see Reactions of Carboxylic Acids for more information). In fact, they readily react like typical acids - they neutralise bases and form salts with metals or ammonia.

However, carboxylic acids don’t really take part in many other reactions. This is because they contain the hydroxyl functional group, -OH. This particular group, -OH, is a very poor leaving group. It isn’t stable on its own and prefers to be part of another molecule, such as a carboxylic acid. However, the close cousins of carboxylic acids, known as acid derivatives, react much more readily with a variety of substances - including in acylation reactions.

• This article is about acylation reactions in organic chemistry.
• We'll define acylation before looking at acid derivatives.
• We'll then learn about various nucleophilic addition-elimination acylation reactions, including their products and mechanisms.
• We'll also explore Friedel-Crafts acylation.
• Finally, we'll consider the rate of acylation and uses of acylation.

Acylation definition

In acylation reactions, we introduce the acyl group, -RCO-, to another molecule. The acyl group comes from a molecule known as an acylating agent, and the most common acylating agents are acyl chlorides and acid anhydrides. Both acyl chlorides and acid anhydrides are examples of acid derivatives.

If you take a carboxylic acid and swap the hydroxyl (-OH) group for a chlorine atom, you end up with an acyl chloride. They have the general structure RCOCl. Their Z group is a chlorine atom.

On the other hand, if you take two carboxylic acids and join them together using an oxygen atom from one of their hydroxyl groups (releasing water in the process), you end up with an acid anhydride. They have the general structure RCOOCOR'.

You can think of acid anhydrides as having two acyl functional groups, but for the purpose of these reactions, it is much easier to consider the -OCOR' group as their Z group.

The general structure of acid derivatives.StudySmarter Originals

In this article, we'll focus on how acid derivatives react in two different types of acylation reactions:

Nucleophilic addition-elimination acylation

To start, let's focus on nucleophilic addition-elimination acylation. These reactions involve acid derivatives and a specific nucleophile: either water, a primary alcohol, ammonia, or a primary amine.

Acid derivatives are polar molecules. They contain a partially negatively-charged oxygen atom and a partially positively-charged carbon atom:

The polarity of acid derivatives. StudySmarter Originals

This means that acid derivatives can be attacked by nucleophiles.

Some common nucleophiles are water, alcohols, ammonia, and primary amines. As nucleophiles, they are attracted to areas of electron deficiency. In this case, they are attracted to the acid derivative’s partially positively-charged carbon atom, and they react in a nucleophilic addition-elimination acylation reaction. This has a two-step mechanism:

• In the first step, the nucleophile adds to the acid derivative to form an intermediate.
• In the second step, the Z group is eliminated from the intermediate molecule.

Overall, one of the nucleophile's hydrogen atoms is swapped for the acid derivative's acyl groups.

Let's now look at examples of nucleophilic addition-elimination reactions with each of these nucleophiles. We'll see how they react with both acyl chlorides and acid anhydrides and will learn about the mechanism and products of each reaction.

Acylation of water

The first set of reactions we’ll look at involve water as the nucleophile.

Acylation of water with acyl chlorides

To start with, let’s take a look at the reaction between an acyl chloride and water. This is probably the simplest of the nucleophilic addition-elimination acylation reactions and shows you the reaction’s general mechanism. It produces a carboxylic acid (RCOOH) and hydrochloric acid (HCl).

The mechanism of nucleophilic addition-elimination acylation of water using an acyl chloride. StudySmarter Originals

Here's the overall equation:

\(RCOCl+H_2O\rightarrow RCOOH+HCl\)

Acylation of water with acid anhydrides

Acid anhydrides are produced using an elimination reaction between two carboxylic acids. Reacting an acid anhydride with water in a nucleophilic addition-elimination reaction is simply the reverse - it reforms both carboxylic acid molecules.

Here's the general equation:

\((RCO)_2O+H_2O\rightarrow 2RCOOH\)

For example, reacting ethanoic anhydride with water produces two molecules of ethanoic acid.

The acylation reaction between ethanoic anhydride and water. StudySmarter Originals

Once again, here's the equation:

\((CH_3CO)_2O+H_2O\rightarrow 2CH_3COOH\)

Acylation of primary alcohols

The acylation reaction between acid derivatives and a primary alcohol is very similar to their reaction with water. When drawing your mechanism, simply replace one of the hydrogen atoms on the water molecule with an alkyl group. This reaction also occurs with phenol.

Acylation of primary alcohols with acyl chlorides

Reacting a primary alcohol with an acyl chloride produces an ester (RCOOR') and hydrochloric acid (HCl). Here's the equation:

\(RCOCl+R'OH\rightarrow RCOOR'+HCl\)

Let’s take ethanoyl chloride and methanol as an example. The reaction produces hydrochloric acid and methyl ethanoate (CH₃COOCH₃).

Mechanism of nucleophilic addition-elimination acylation of methanol using ethanoyl chloride. StudySmarter Originals

Acylation of primary alcohols with acid anhydrides

Reacting acid anhydrides with a primary alcohol produces an ester and a carboxylic acid:

\((RCO)_2O+R'OH\rightarrow RCOOR'+RCOOH\)

For example, when we react ethanoic anhydride with methanol, we also get methyl ethanoate. However, the second product is a carboxylic acid based on the acid anhydride. Here we get ethanoic acid (CH₃COOH):

\((CH_3CO)_2O+CH_3OH\rightarrow CH_3COOCH_3+CH_3COOH\)

The reaction between methanol and ethanoic anhydride. StudySmarter Originals

Acylation of ammonia

Reacting acid derivatives with ammonia produces an amide and an ammonium salt. This uses the same mechanism as the two reactions above, but there is an additional step involving an additional molecule of ammonia.

Acylation of ammonia with acyl chlorides

Reacting ammonia with an acyl chloride produces an amide and hydrochloric acid. However, the hydrochloric acid then reacts with an additional molecule of ammonia to produce ammonium chloride (NH₄Cl):

\(RCOCl+2NH_3\rightarrow RCONH_2+NH_4Cl\)

Look at the reaction between ethanoyl chloride and ammonia. The initial reaction produces ethanamide (CH₃CONH₂) and hydrochloric acid; the hydrochloric acid reacts further with another ammonia molecule to produce ammonium chloride.

Mechanism of the nucleophilic addition-elimination acylation of ammonia using an acyl chloride. StudySmarter Originals

The overall reaction is between ethanoyl chloride and two ammonia molecules, producing ethanamide and ammonium chloride.

The other product of this reaction is what we call an amide. An amide is an organic molecule that contains the amine group (NH₂) next to the carbonyl group (C=O).

Acylation of ammonia with acid anhydrides

If we react an acid anhydride with an excess of ammonia, we again produce an amide. The initial reaction also produces a carboxylic acid. However, a second molecule of ammonia reacts with the carboxylic acid to produce an ammonium salt.

Here's the equation:

\((RCO)_2O+2NH_3\rightarrow RCONH_2+RCOONH_4\)

For example, the reaction between ethanoic anhydride and ammonia produces ethanamide (CH₃CONH₂) and ammonium ethanoate (CH₃COONH₄):

\((CH_3CO)_2O+2NH_3\rightarrow CH_3CONH_2+CH_3COONH_4\)

The reaction between ethanoic anhydride and ammonia. StudySmarter Originals

Acylation of primary amines

A lot of new information has been thrown at you, but we just need to look at one more type of nucleophilic addition-elimination acylation reaction: reacting acid derivatives with primary amines. This is very similar to their reactions with ammonia - when you are drawing the mechanism, simply replace one of ammonia’s hydrogen atoms with an R group.

The reaction produces an N-substituted amide and a different ammonium salt.

Acylation of primary amines with acyl chlorides

If you react an acyl chloride with a primary amine, you produce an N-substituted amide and an ammonium salt:

\(RCOCl+2NH_2R'\rightarrow RCONHR'+R'NH_3Cl\)

Reacting propanoyl chloride (CH₃CH₂COCl) with methylamine (NH₂CH₃) gives N-methylpropanamide (CH₃CH₂CONHCH₃) and methylammonium chloride (CH₃NH₃Cl):

\(CH_3CH_2COCl+2NH_2CH_3\rightarrow CH_3CH_2CONHCH_3+CH_3NH_3Cl\)

There are a lot of different R groups and carbon chains involved in this reaction, and so we've highlighted them in the diagram below to help you understand the process a little better.

The reaction between propanoyl chloride and methylamine. The R groups are highlighted, so you can understand the reaction better. StudySmarter Originals

Acylation of primary amines with acid anhydrides

If you react an acid anhydride with a primary amine, you produce an N-substituted amide and a different ammonium salt:

\((RCO)_2O+2NH_2R'\rightarrow RCONHR'+R'NH_3OCOR\)

Reacting propanoic anhydride ( (CH₃CH₂CO)₂O) with methylamine produces N-methylpropanamide too. The initial reaction also produces a carboxylic acid based on the acid derivative. Because we started with propanoic anhydride, we produce propanoic acid. This then reacts with another molecule of methylamine to produce a different ammonium salt. Here we produce methylammonium propanoate (CH₃NH₃OCOCH₂CH₃):

\((CH_3CH_2CO)_2O+2NH_2CH_3\rightarrow CH_3CH_2CONHCH_3+CH_3NH_3OCOCH_2CH_3\)

Factors affecting acylation

Some nucleophilic addition-elimination acylation reactions happen much faster than others. This is due to many different factors.

• The carbon atom’s partial charge.
• The acid derivative’s Z group.
• The strength of the nucleophile involved.

Partial charge

As we explored above, the carbon atom in the acid derivative that is joined to the oxygen atom and the Z group is partially negatively charged. The strength of this partial charge varies, depending on how electronegative the Z group is. A more electronegative Z group will attract the shared pair of electrons more strongly towards itself, increasing the carbon atom’s partial positive charge.

Imagine a tug of war between you and your friend. A piece of fabric tied around the middle of the rope represents the shared pair of electrons involved in the covalent bond between the two of you. If you are a lot stronger than your friend, you’ll be able to pull the rope and the fabric towards you. You have attracted the electrons towards yourself. We can say you are more electronegative than your friend. This leaves your friend electron-deficient and therefore partially positively charged. A carbon atom with a higher charge will be attacked by nucleophiles a lot more easily, as nucleophiles are negatively or partially negatively charged.

Leaving ability of Z group

Some Z groups are better leaving groups than others. This increases their reactivity. We won’t go into the reasons here, but it involves things like electronegativity, size, and resonance. However, you should know that chloride ions are a much better leaving group than carboxylate ions, so acyl chlorides are more reactive than acid anhydrides. For example, all of the nucleophilic addition-elimination reactions involving acyl chlorides take place at room temperature and are extremely exothermic, whilst those involving acid anhydrides must be heated gently.

Strength of nucleophile

Stronger nucleophiles will attack the acid derivative’s partially charged carbon atom more readily than weaker nucleophiles. Again, this is due to factors that we won’t go into right now, but which include charge and basicity.

We have explored reactions between acid derivatives and four different nucleophiles. These nucleophiles all vary in strength. Their relative strengths are given below:

primary amine > ammonia > primary alcohol > water

Acylation reactions involving a primary amine therefore happen a lot faster than those involving water.

Friedel-Crafts acylation of benzene

Do you remember how we said that there are two types of acylation reactions? The second is known as Friedel-Crafts acylation. It is used to add the acyl group to aromatic molecules such as benzene.

Like in nucleophilic addition-elimination acylation reactions, Friedel-Crafts acylation involves acid derivatives. But this reaction differs because it uses an electrophilic substitution mechanism. It also uses a catalyst, aluminium(III) chloride (AlCl₃).

The overall reaction has multiple steps:

• The acid derivative reacts with the catalyst to form an electrophile.
• The electrophile is attracted to the aromatic molecule's ring of delocalised electrons.
• The electrophile bonds with the aromatic molecule, which causes one of the aromatic molecule-hydrogen bonds to break.
• The hydrogen ion released is used to regenerate the catalyst.
• Overall, we substitute the electrophile for a hydrogen atom.

The products depend on the acid derivative used. We always produce an aromatic ketone with the structure C₆H₅COR; we name these molecules using the prefix phenyl-. We also produce the molecule HZ, where Z is the acid derivative's Z group. This means that if our acid derivative is an acyl chloride, we also produce hydrochloric acid (HCl). However, if our acid derivative is an acid anhydride, we also produce a carboxylic acid (RCOOH).

Friedel-Crafts acylation of benzene.StudySmarter Originals

For example, if you react benzene with ethanoyl chloride (CH₃COCl) in the presence of an aluminium(III) chloride catalyst, you produce phenylethanone (C₆H₅COCH₃) and hydrochloric acid. If you react benzene with ethanoic anhydride ((CH₃CO)₂O), you also produce phenylethanone, but instead of hydrochloric acid you produce ethanoic acid (CH₃COOH).

\(C_6H_6+CH_3COCl\rightarrow C_6H_5COCH_3+HCl\)

\(C_6H_6+(CH_3CO)_2O\rightarrow C_6H_5COCH_3+CH_3COOH\)

Uses of acylation

We'll now consider some of the uses of acylation.

First of all, you’ll notice that reacting acyl chlorides or acid anhydrides with an alcohol produces an ester. We can also make esters by reacting a carboxylic acid with an alcohol in an esterification reaction. This is reversible, whereas acylation goes to completion. Therefore, acylation is often preferred to esterification as it gives a higher yield. However, the choice of acid derivatives is important. We tend to use an acid anhydride instead of an acyl chloride to make esters for the following reasons:

• It is cheaper.
• It is a slower, more controlled reaction.
• It does not produce hydrochloric acid, which is a corrosive gas.

Esters are important parts of many perfumes and cosmetics, thanks to their fruity smells.

Similarly, acylation of ammonia or primary amines produces amides. These are useful stepping stools in the preparation of many pharmecuticals.

Another example of an important acylation reaction is the production of aspirin. Aspirin is manufactured by reacting a compound known commonly as 2-hydroxybenzoic acid, 2-hydroxybenzenecarboxylic acid or simply just salicylic acid, with ethanoic anhydride. The -hydroxy- in the name 2-hydroxybenzoic acid indicates that this molecule contains a hydroxyl group (-OH). 2-hydroxybenzoic acid is therefore a primary alcohol. Its acylation reaction with ethanoic anhydride produces aspirin - an ester - and ethanoic acid.

The skeletal structure of aspirin. commons.wikimedia.org