There are many compounds that have ketones and aldehydes as functional groups. They are also known as carbonyl and formyl groups and are important functional groups because they cause many types of chemical reactions.
Ketones and aldehydes are highly reactive, and if nothing is done to prevent them, the carbonyl carbons will be subjected to nucleophilic attack, which will lead to a synthetic reaction. Therefore, the carbonyl and formyl groups must be protected to prevent them from reacting. These are called protecting groups (or protective groups).
Acetal is frequently used as a protecting group for carbonyl compounds. Carbonyl compounds can synthesize acetals via hemiacetals.
Why are these protective groups useful? And what are the reaction mechanisms and deprotection methods? These will be explained in this section.
Table of Contents
- 1 Ketones and Aldehydes Hydrate to form Hemiacetal
- 2 Acetal Can Be Synthesized from Hemiacetal
- 3 Use of Acetal as a Protective Group
- 4 Learn the Properties of Acetal, an Important Protecting Group
Ketones and Aldehydes Hydrate to form Hemiacetal
Some compounds have a different shape when they exist on their own and when they are dissolved in solution. A typical example of this is a compound with a carbonyl or formyl group.
Compounds with ketone or aldehyde functional groups have a different form when dissolved in a water or alcohol solvent. This is called hydration. In the case of aldehydes, in particular, most compounds change their shape through hydration reactions.
Ketones and aldehydes hydrate, and the resulting compound is hemiacetal. The reaction mechanism of hemiacetal is as follows.
The above figure shows the reaction mechanism in acidic conditions. Not only acidic, but also basic conditions can produce hemiacetals. With ketones and aldehydes, hemiacetals are formed in many cases.
Hemiacetal Is Unstable; Hydrates Are Reversible Reactions
However, it is not possible to isolate hemiacetals when doing experiments in organic chemistry. There is no doubt that it will hydrate and react when compounds with carbonyl and formyl groups are dissolved. However, since hemiacetals are unstable, they return to their original ketone or aldehyde compounds when water or alcohol is removed.
This is because the hydrate is a reversible reaction. Even though hemiacetal is formed by the hydration reaction, when water or alcohol is no longer present, the reverse reaction occurs.
The reaction mechanism by which the hydrate returns to the original carbonyl compound is as follows.
Even if the compound is hemiacetal in an aqueous solution, these reversible reactions will restore it to its original state, which is why you can’t get a hemiacetal compound when the solvent is removed.
Acetal Can Be Synthesized from Hemiacetal
In addition, if the reaction is carried out under acidic conditions, the reaction proceeds further from hemiacetal and yields acetal. Neutral and basic conditions do not yield acetal. Only under acidic conditions can acetal be obtained.
When reacted under acidic conditions, hemiacetal is transformed into acetal by the following reaction mechanism.
An important part of this reaction is that the reaction produces water (H2O). Initially, the H2O is released when an oxygen atom combines with a proton. This results in the formation of an oxonium ion.
Without the presence of a proton (H+) in the solution, the synthesis of acetal will not proceed. This is the reason why acetal cannot be obtained in neutral or basic conditions.
Oxonium ions are unstable intermediates. Therefore, the reaction proceeds further when the alcohol attacks them, resulting in the formation of acetal. Unlike hemiacetal, acetal is a stable substance and can be isolated.
The Synthesis Reaction Proceeds While Removing Water
Just as hemiacetal is a reversible reaction, acetal is also reversible. When water is added to the acetal synthesized in the hydration reaction, it returns to ketones and aldehydes.
However, as mentioned earlier in the reaction mechanism, water is produced when acetal is synthesized from hemiacetal. When water is present, a reversible reaction takes place and the acetal is hydrolyzed to its original state. Therefore, when synthesizing acetal, the synthesis must proceed with the removal of the water produced.
-Hydrolysis Under Acidic Conditions; Acetal is Stable Under Basic Conditions
The reaction conditions for the hydrolysis of acetal to return to the original carbonyl compound are acidic. If the reaction conditions are not acidic, acetal hydrolysis will not occur.
Under basic conditions, acetal is stable. It is important to understand that although acetal is hydrolyzed by the acid, it is stable to the base.
Use of Acetal as a Protective Group
So why is acetalization so important in organic chemistry? It’s because acetal is frequently used as a protecting group for ketones and aldehydes.
Carbonyl and formyl groups are highly reactive. Nucleophilic addition reactions can easily take place when the carbonyl carbon is attacked by nucleophiles. For example, a basic compound is the Grignard reagent, which is very strongly basic. However, if there are ketones in the molecule, they will react within the molecule as follows.
So, we will protect the acetal in advance. If you convert the ketone to acetal, you can add magnesium (Mg) to make the Grignard reagent and it will not cause an intramolecular reaction.
As mentioned above, acetals are basic and stable. The Grignard reagent is a strong base and therefore will not react with acetal. These protective groups allow for regioselective organic synthesis.
-Cyclic Acetal Is More Stable and Frequently Used Than Chain Acetal
For reference, cyclic acetals are more stable than chain acetals. For this reason, acetal protecting is often provided by ethylene glycol.
When ethylene glycol is used, a five-membered cyclic acetal is formed. This compound is called dioxolane.
Ethylene glycol is one of the cheapest organic compounds you can get. So acetal protecting of carbonyl compounds can protect them from nucleophilic attack by basic substances.
Deprotection by Hydrolysis to Obtain Target Compounds
Naturally, the protecting group from acetal will be removed at some point. The removal of the protective group is called deprotection.
The method for deprotection is simple. All you have to do is mix it with an acidic solution such as hydrochloric acid or sulfuric acid. The addition of these acid catalysts is enough to cause hydrolysis, which can be easily converted back to ketone or aldehyde.
The reaction mechanism of hydrolysis of acetal-protecting compounds to carbonyl compounds has already been explained, so we will skip the details. The reaction mechanism by which hemiacetal is hydrolyzed to ketone or aldehyde has been described previously, and the carbonyl compounds can be obtained in the same way.
Acetal protecting is frequently used in organic chemistry because it can easily protect carbonyl and formyl groups, and the deprotection method is simple.
There Are Many Applications of Acetal Protecting Groups, Such as Alcohol Protecting
These protecting groups are frequently used in many situations. Protecting groups using acetal protecting are used not only for carbonyl compounds, but also for the protecting of hydroxy groups (-OH).
For example, suppose you have a compound of 1,3 diols; by reacting the 1,3 diols with a carbonyl compound, you can synthesize a cyclic acetal. This will result in a protective group for the 1,3 diols.
-Alcohol Protecting by THP and MOM Groups
On the other hand, it is possible to protect not only 1,3 diols, but also a single hydroxy group. Examples of such protective groups are as follows.
- THP (tetrahydropyranyl)
- MOM (Monomethoxymethyl)
When making THP, DHP (dihydropyran) is used as a reagent. MOM, on the other hand, utilizes chloromethyl methyl ether as a reagent. It is as follows.
It is important to note that both THP and MOM are acetal. We have discussed acetal protecting with carbonyl compounds, and you can also use the THP and MOM to protect alcohol with acetal protecting.
Since acetal is stable in basic conditions, no side reactions will occur if the alcohol is protected and then reacted under basic conditions. Acetal protecting is not only widely used with carbonyl and formyl groups, but also with hydroxy groups.
Learn the Properties of Acetal, an Important Protecting Group
Carbonyl compounds undergo many types of synthetic reactions. One of the most important reactions is hydration. Carbonyl compounds react with water or alcohol to produce hemiacetal. Acetal can also be obtained under acidic conditions.
The reason why acetal synthesis is so important is because it is a protective group. Protecting groups are very useful when you want to react in a regioselective manner only at specific locations.
In addition to carbonyl and formyl groups, acetals are also useful as protecting groups for alcohols. Acetal protecting is beneficial in many situations.
Acetals are frequently used as protective groups because they can easily be deprotected under acidic conditions. So, let’s make sure you understand the properties of acetals.