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Acylation

Acylation

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Acid derivatives are close cousins of carboxylic acids, and they can take part in acylation reactions. In an acylation reaction, the acyl group is added to another molecule. This acyl group comes from an acid derivative, which is attacked by a nucleophile in an addition-elimination reaction.

So, what does all this mean? To start, a nucleophile is a molecule that can donate a pair of electrons to form a new bond. The acid derivative donates the acyl group, and the nucleophile donates the pair of electrons. The result is the addition of the acyl group onto the nucleophile.

Friedel-Crafts acylation is a type of acylation reaction that involves the addition of an acyl group to an aromatic ring. The first step of this reaction is the formation of the acylium ion, which then reacts with benzene to form a complex. The third step involves the departure of the proton in order for aromaticity to return to benzene.

In summary, acylation is a reaction that involves adding the acyl group to another molecule. The acyl group comes from an acid derivative, which is attacked by a nucleophile in an addition-elimination reaction. Friedel-Crafts acylation is a type of acylation reaction that involves the addition of an acyl group to an aromatic ring.

What are acid derivatives?

Acid derivatives are molecules that are similar to carboxylic acids. They have a structure that includes the carbonyl group and a different group called Z instead of the hydroxyl group found in carboxylic acids. Carboxylic acids have the structure which includes the carboxyl functional group made up of the carbonyl and hydroxyl groups. So, acid derivatives have the structure .

Acid derivatives are closely related to carboxylic acids

All acid derivatives are polar molecules because of the electronegativity difference between the oxygen atom and carbon atom in the double bond. Oxygen is more electronegative than carbon and attracts the shared pair of electrons towards itself, becoming partially negatively charged. As a result, the carbon atom becomes partially positively charged. The Z group, being more electronegative than carbon, also contributes to the partial positive charge on the carbon atom. This creates a polar molecule as shown below.

Relative reactivity and polarity of carboxylic acid derivatives. X = halide  | Download Scientific Diagram
The polarity of acid derivatives

We’ll focus on two common types of acid derivatives: acyl chlorides and acid anhydrides.

Acyl chlorides

Acyl chlorides have a chlorine atom as their functional group, meaning that they all contain the functional group -C(=O)Cl. They’re made by reacting a carboxylic acid with a chlorinating agent such as phosphorus(V) chloride.

To name an acyl chloride, count the number of carbon atoms in its carbon chain and give it the appropriate root name. Add the suffix -oyl followed by the word chloride. For example, ethanoyl chloride has the formula CH3COCl and the following structure:

Ethanoyl chloride
Ethanoyl chloride

Struggling with nomenclature? Check out Organic Compounds for a more detailed guide.

Acid anhydrides

Acid anhydrides are a type of acid derivative made in an elimination reaction between two carboxylic acids, which also produces water. This reaction occurs when two carboxylic acid molecules lose a water molecule and join together via a covalent bond between the carbonyl carbon atoms. To name an acid anhydride, find the carboxylic acid it is based on and add the word "anhydride". For example, the acid anhydride based on methanoic acid is called methanoic anhydride, and has the following structure:

File:Formic acetic anhydride skeletal.svg - Wikimedia Commons
Methanoic anhydride

That's correct! When an acid anhydride is formed from two different carboxylic acid molecules, we list the names based on both acids in alphabetical order, followed by the word "anhydride". For example, the acid anhydride made from one molecule each of ethanoic acid and propanoic acid is called ethanoic propanoic anhydride. It has the following structure:

Ethanoic anhydride, left, and ethanoic propanoic anhydride, right
Ethanoic anhydride, left, and ethanoic propanoic anhydride, right

Nucleophilic addition-elimination

We learnt above that 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
The polarity of acid derivatives

This means that the molecule can be attacked by nucleophiles.

A nucleophile is an electron pair donor, containing a lone pair of electrons and a negative or partially negative charge.

In this case, nucleophiles are attracted to the acid derivative’s partially positively charged carbon atom.

Some common nucleophiles are water, alcohols, ammonia, and primary amines. They can all react with acid derivatives in nucleophilic addition-elimination reactions. These are two-step mechanisms.

In the first step, the nucleophile adds onto the acid derivative. In the second step, the Z group is eliminated from the molecule.

We’ll explore these reactions below.

Acyl chlorides are a lot more reactive than acid anhydrides. Nucleophilic addition-elimination reactions involving acyl chlorides are vigorous at room temperature, whereas ones involving acid anhydrides are a lot slower.

Acylation of water

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

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, and hydrochloric acid, .

Acylation of water using an acyl chloride
Acylation of water using an acyl chloride

To make acid anhydrides, we used an elimination reaction between two carboxylic acids. Reacting an acid anhydride with water is simply the reverse of this reaction. You should only have to know the reaction with a symmetrical anhydride - one made from two molecules of the same carboxylic acid. In this case, both carboxylic acid molecules are reformed. For example, reacting ethanoic anhydride with water produces two molecules of ethanoic acid.

The reaction between ethanoic anhydride and water
The reaction between ethanoic anhydride and water

Most exam boards don’t require you to know the mechanism for this reaction, but make sure you check yours so you don’t get caught out!

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.

Nucleophilic addition-elimination reactions with alcohols
Nucleophilic addition-elimination reactions with alcohols

Let’s take ethanoyl chloride and methanol as an example. The reaction produces hydrochloric acid and an ester, methyl ethanoate.

Acylation of methanol using ethanoyl chloride
Acylation of methanol using ethanoyl chloride

Remember that when naming esters, the first part of the name comes from the alcohol. In acylation reactions, the second part comes from the acid derivative. 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.

The reaction between methanol and ethanoic anhydride
The reaction between methanol and ethanoic anhydride

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. Look at the reaction between ethanoyl chloride and ammonia. The initial reaction produces ethanamide and hydrochloric acid, but the hydrochloric acid reacts further with another ammonia molecule to produce an ammonium salt, ammonium chloride. Ammonium chloride is produced in all reactions between acyl chlorides and ammonia.

The acylation of ammonia using an acyl chloride
The acylation of ammonia using an acyl chloride

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. Amides are organic molecules that contain the amine group, NH2, next to the carbonyl group, . You’ll meet them further in Amines, but we’ll briefly look at how you name amines now.

Count the number of carbon atoms in the carbon chain that contains the  double bond - even if this chain isn’t the longest. This gives you the amine’s root name. Check to see if there are any additional carbon chains attached to the nitrogen atom. If there are, name them like side chains. But instead of using a number to indicate their position, place the letter N before them. This shows that they come from the nitrogen atom instead of the carbon chain.

Amides with an additional carbon chain attached to the nitrogen atom are known as N-substituted amides.

Here, the carbon chain containing the  group has one carbon atom, giving the root name -meth-. It is circled in red to help you identify it. The molecule on the left is therefore called methanamide. But the second molecule also contains an ethyl group attached to its nitrogen atom, giving it the name N-ethylmethanamide. The ethyl group is circled in blue.

Methanamide, left, and N-ethylmethanamide, right
Methanamide, left, and N-ethylmethanamide, right

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. For example, the reaction between ethanoic anhydride and ammonia produces ethanamide and ammonium ethanoate.

Acetic anhydride and ammonia gives the product :
The reaction between ethanoic anhydride and ammonia

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 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.

Reacting propanoyl chloride with methylamine gives N-methylpropanamide and methylammonium chloride.

The reaction between propanoyl chloride and methylamine
The reaction between propanoyl chloride and methylamine

The reaction between propanoyl chloride and methylamine.

The reaction between propanoyl chloride and methylamine
The reaction between propanoyl chloride and methylamine

Reacting propanoic anhydride with methylamine produces N-methylpropanamide too. The initial reaction also produces a carboxylic acid based off of 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.

acid anhydrides with ammonia or primary amines
The reaction between propanoic anhydride with methylamine

Comparing nucleophilic addition-elimination reactions

Phew - you made it!

The following table should help consolidate your newfound knowledge of nucleophilic addition-elimination reactions, comparing reactants and products.

 

A table comparing various nucleophilic addition-elimination reactions
A table comparing various nucleophilic addition-elimination reactions

Remembering all the different reactions can be tricky. However, they all follow similar mechanisms. Instead of trying to remember each one individually, learn how to apply a few examples to a variety of different combinations of reactants.

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.

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 will therefore happen a lot faster than those involving water.

Uses of acylation

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, 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 , which is a corrosive gas.

One 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. This produces aspirin - an ester - and ethanoic acid.

File:Aspirin-skeletal.svg - Wikimedia Commons
The skeletal structure of aspirin

Aspirin is scientifically known as 2-acetyloxybenzoic acid, but it is also called acetylsalicylic acid, or ASA. The salicylic part of its name gives you a clue to its origins - willow trees. Willows are trees in the family Salicaceae. Chewing willow bark has been a known source of pain relief for centuries. In fact, medicines made from willow and other salicylate-rich plants are even recorded in the Ebers Papyrus from ancient Egypt!

You might synthesise and purify aspirin in class. This involves various different stages of heating, cooling, and filtering, all with the aim of getting a pure product. You can then calculate your percentage yield. It is hard to get a 100 percent yield on such a small scale in a laboratory - can you think of possible reasons why?

Acylation - Key takeaways Acid derivatives are molecules that are derived from carboxylic acids. They all contain a  double bond and have the general formula . Examples include acyl chlorides and acid anhydrides. Acylation reactions add the acyl group, , to another molecule. In nucleophilic addition-elimination acylation, the acyl group from an acid derivative is added on to a nucleophile, producing a variety of different products. Acyl chlorides are much more reactive than acid anhydrides and react readily with nucleophiles at room temperature. The rate of acylation depends on the partial charge of the carbon atom, the leaving ability of the Z group, and the strength of the nucleophile used.

Acylation

What is acylation?

Acylation is a type of reaction that involves adding the acyl group, -RCO-, to another molecule.

What is the acyl group?

The acyl group is an organic group with the formula -RCO-. It consists of a carbon atom bonded to an oxygen atom with a double bond, and an R group with a single bond.

How do you make acyl chlorides from carboxylic acids? 

You can make acyl chlorides by reacting carboxylic acids with either solid phosphorus(V) chloride or liquid phosphorus(III) chloride.

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