Enols and Enolates
By James Ashenhurst
The Malonic Ester Synthesis
Last updated: March 26th, 2019
Apropos of nothing, here’s a post about a series of reactions that is a common source of student difficulties. It’s called the malonic ester synthesis, and it’s an interesting way of making substituted carboxylic acids. There’s an essentially identical process called the acetoacetic ester synthesis and it makes substituted ketones; the only difference between the two processes is the choice of starting material.
Here’s an example of both processes. Pay attention to the bonds that form and the bonds that break.
Before going into the mechanism, see if you can identify the common pattern for each of these malonic ester syntheses. Follow the different colors of atoms. Where does each come from? Where do each of them go?
The cool thing about this process is how it’s built from a series of simple reactions. Again, mechanisms in organic chemistry are a lot like music – from a small number of parts, we can build up something complex.
Let’s walk through the mechanism (focusing on the malonic ester synthesis for brevity – the acetoacetic ester synthesis mechanism is identical except we’re starting with a different compound).
These processes are built out of four reactions in total:
- deprotonation of the ester to form an enolate
- SN2 of the enolate upon an alkyl halide, forming a new C-C bond
- acidic hydrolysis of the ester to give a carboxylic acid
- decarboxylation of the carboxylic acid
In the first step, a base (CH3O– in this case) removes the most acidic proton from the ester (on C2 here, with a pKa of about 13) to give anenolate. The resulting enolate can be drawn as one of two resonance forms.
Enolates are great nucleophiles. In the second step, the enolate acts as a nucleophile in an SN2 reaction to form a new C-C bond:
Next (step 3), acid and water are added to perform the aqueous hydrolysis of the ester to a carboxylic acid.(the full mechanism is here)
Now comes the part which often gives students trouble. When carboxylic acids have a carbonyl group (C=O) two bonds away, they can readily lose carbon dioxide. Why? Because the carbonyl can act as an electron “sink” for the pair of electrons coming from the breaking C–C bond, forming an enol. This is called “decarboxylation”. Note how this is also the case for carboxylic acids with a ketone two bonds away, so-called “β-keto acids”.
Finally, the enol that is formed is not a stable species. It can undergo transformation into its constitutional isomer: in this case, a carboxylic acid. These two constitutional isomers are in equilibrium with each other, although the “keto” form (with the carbonyl group) is greatly favored. This process is called “tautomerism“.
Again, the key point to make about the malonic ester synthesis is to observe the pattern of bonds formed and bonds broken. As with any reaction in organic chemistry, if you can see the pattern going forward, you should be able to apply it going backward as well. See if you can figure out how to make compound A from a malonic ester synthesis.
Secondly, it’s also possible to do two alkylations before doing the aqueous hydrolysis step. Can you figure out how to make B from a malonic ester synthesis?
[If you’ve read this far, worked on these problems, and would like an answer, leave a comment!]