Claisen Condensation
(and Crossed Claisen)
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Claisen condensation
A Claisen Condensation is very similar to an aldol condensation except esters are used instead of aldehydes and ketones. Esters can also have acidic alpha hydrogen atoms. These hydrogen atoms are not acidic as ketones or aldehydes, but they are still pretty acidic. Let’s examine the Claisen Condensation using ethyl acetate as our example molecule with a base.
A base can deprotonate at the alpha spot of the ethyl acetate to make an enolate. The enolate can attack another molecule of ethyl acetate. The enolate attacks the carbonyl of ethyl acetate. The pi electrons of the carbonyl go up onto the oxygen atom, but they come back down because there is a good leaving group, the ethoxide, EtO-. The electrons come back down from the oxygen atom to reform the carbonyl pi bond and the ethoxide, EtO-, leaving group leaves. The final product of the Claisen Condensation is a β-dicarbonyl compound.
Pay special attention to the base used, NaOEt, sodium ethoxide. Sodium ethoxide was carefully chosen so that the base used, EtO-, is the same as the OEt that is on the ester of our final product. If this EtO- attacks the carbonyl of the product, the electrons would go up, come back down, and the EtO- leaving group would leave.
This would not be a problem for us, because we end up with the exact same product. But, if we used a different base, we could end up with an ester we didn’t want! This careful selection of a base that keeps our final ester the same is a common trick in reactions involving esters.
6. Draw the products of the following Claisen Condensations.
a)
b)
Dieckmann condensation
- a cyclic Claisen condensation
The Dieckmann Condensation is a cyclic Claisen condensation, meaning a ring is formed. For example, a chain with two esters attached can undergo a Dieckmann condensation.
7. Draw the product when the following ester undergoes a Dieckmann Condensation.
Crossed Claisen condensation
Much like an aldol condensation can undergo a crossed aldol with two different aldehydes or ketones, an crossed Claisen condensation is when two different esters are used. Again, it is useful if only one of the esters has alpha hydrogen atoms so only one enolate can be formed. In the following example, ethyl acetate and ethyl benzoate are mixed together with a base. Only the ethyl acetate has alpha hydrogen atoms, the ethyl benzoate does not. The ethyl acetate is the only one that can form an enolate.
How can we help ensure that the enolate will react with a molecule of ethyl benzoate instead of another molecule of ethyl acetate? We need to run the reaction with a large excess of ethyl benzoate so the enolate is much more likely to encounter a molecule of ethyl benzoate in the flask instead of a molecule of ethyl acetate.
Ketones or aldehydes could also be the molecules that form an enolate that would attack an ester in a Claisen Condensation.
It is helpful to pause and notice something. Imagine the back of your thumb has written on it part of an alcohol (HOR) molecule (either the hydrogen atom or the alkoxy (OR) group). Then, if you cover up half of the Claisen Condensation product with your thumb, you can see the starting materials used in the Claisen 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.
8.
a) Draw the product when the following compounds undergo a Crossed Claisen reaction.
b) What two reagents would undergo a Crossed Claisen reaction to make the following compound?
Answers
6.
a)
b)
7.
8.
a)
b)
