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Diethyl malonate (1.55g, 9.69mmol, 1.1 equiv.) is added, the threads of the cap are wrapped tightly with Teflon tape for a tight seal, and the reaction is capped with a Green Open Top SURE-Link™ Polypropylene Cap. From: Methods in Enzymology, 2020
By James Ashenhurst Last updated: September 24th, 2022 | The Malonic Ester Synthesis And Its Cousin, The Acetoacetic Ester Synthesis
Table of Contents 1. The Common Pattern In The Malonic Ester SynthesisBefore 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). The Malonic Ester Synthesis Is Comprised Of Five Separate ReactionsThese processes are built out of five reactions in total: Step 1: Deprotonation To Give An EnolateIn 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 an enolate. The resulting enolate can be drawn as one of two resonance forms. Step 2: SN2 Reaction Of The Enolate Nucleophile With An Alkyl Halide ElectrophileEnolates are great nucleophiles. In the second step, the enolate acts as a nucleophile in an SN2 reaction to form a new C-C bond: Step 3: Acidic Ester HydrolysisNext (step 3), acid and water are added to perform the aqueous hydrolysis of the ester to a carboxylic acid. Step 4: Decarboxylation To Give An EnolNow 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”. [See article – Decarboxylation] Step 5: Tautomerization Of The Enol Back To The Carboxylic AcidFinally, 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“. [See article: Keto-enol 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!] Notes(Advanced) References and Further Reading
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