Aldol Condensation
(and Crossed Aldol)
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Aldol condensation
The aldol condensation is an important reaction. It is a reaction that helps form carbon-carbon bonds, which is extremely important in organic chemistry. In the aldol condensation, an enolate attacks a ketone or an aldehyde. Let’s begin our study of the aldol condensation using acetone as our model molecule. Acetone is a dimethyl ketone that contains acidic, alpha hydrogen atoms.
What would happen if we take a beaker full of acetone and add a base like hydroxide to it? The alpha hydrogen atoms of acetone can be deprotonated with the hydroxide to make an enolate. When this happens, the reactive, acetone enolate would be surrounded by gazillions of other molecules of acetone. The negative charge of the enolate can attack the carbonyl of the acetone, and the pi bond electrons can go up onto the oxygen atom to make a negative charge. The electrons cannot come back down because there is no good leaving group. This negatively charged species can be protonated, quenched, by acid and water to give an alcohol. Since a hydrogen atom and the hydroxyl group are on neighboring carbon atoms, a dehydration elimination can occur where water is given off and a conjugated double bond is formed. This dehydration is often exothermic, because a more stable, conjugated system is formed. A conjugated molecule is one that contains two double bonds separated by a single bond
To dehydrate or not
Not every aldol reaction results in the dehydration elimination.
1. If hydroxide is used as the base, the dehydration usually occurs.
2. If LDA is used as the base, the dehydration does not normally occur.
3. Under acidic conditions, the dehydration usually occurs.
2. The following compounds undergo aldol condensation reactions when they react with base. Show the products of the aldol condensation following dehydration.
a) propionaldehyde (propanal)
b) acetophenone (methyl phenyl ketone)
c) cyclohexanone
Crossed aldol
Many aldol condensations involve a molecule transforming into an enolate and then reacting with itself like in the acetone example above. But, that is not necessarily the case. It is possible for an enolate to react with a carbonyl compound that is different. When this happens, it is called a Crossed Aldol condensation. Let’s begin our study of the crossed aldol condensation with an example. In this case, acetone is deprotonated to form an enolate followed by a reaction with benzaldehyde. The mechanism is pretty much the same as before. The negative lone pair of electrons attack the carbonyl of benzaldehyde. The electrons of the pi bond go up onto the oxygen atom to form a negative charge. The electrons cannot come back down because there is no good leaving group. The negative oxygen is protonated with acid and water followed by possible dehydration to form a conjugated compound.
Once the acetone is deprotonated to form an enolate, any ketone or aldehyde can be added to the reaction. Benzaldehyde was chosen with a purpose. The second carbonyl molecule added to the reaction works much better if it does not have any alpha hydrogens on the molecule. The reason it is helpful that the second molecule does not have alpha hydrogen atoms is that we do not want it deprotonated to form an enolate. We want to be able to control which molecule makes the enolate. Notice, benzaldehyde does not have any alpha hydrogen atoms.
A second consideration is that if we want the enolate to attack benzaldehyde, we do not want the enolate to attack another molecule of acetone. How can we help ensure that will happen? The best way is to run the reaction with a large excess of benzaldehyde. This way, the enolate will be much more likely to bump into a benzaldehyde molecule in the reaction flask instead of an acetone molecule. Run the reaction with an excess of the one that cannot form an enolate.
It is helpful to pause and notice something helpful. Imagine the back of your thumb has written on it part of a water molecule (either the two hydrogen atoms or the one oxygen atom). Then, if you cover up part of the aldol product with your thumb, you can see the starting materials used in the aldol reaction. You place your thumb over half of the molecule at the double bond formed in the dehydration step.
The blue square is your thumb.
3. Draw the product of the following crossed aldol condensations - followed by dehydration.
a) benzophenone (diphenyl ketone) and butyraldehyde (butanal)
b) 2,2-dimethylpropanal and acetophenone (methyl phenyl ketone)
4.
a) Jasmine aldehyde is a compound with a floral, jasmine scent used in the perfume industry. Draw the two compounds (both are carbonyl compounds) that would be used in a crossed aldol condensation to make jasmine aldehyde. (Hint: Use your thumb to cover up half of the molecule at a time at the C=C.)
jasmine aldehyde
b) When the two compounds in the solution for part a are used to make jasmine aldehyde, a second compound is also made. It is the product of an aldol condensation where one of the compounds reacts with itself. Draw this unwanted side-product of this reaction.
5. Show the mechanism for the following aldol condensation.
Answers
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a)
b)
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