The Malonic Ester Synthesis And Its Cousin, The Acetoacetic Ester Synthesis

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.

malonic ester synthesis example and acetoacetic ester synthesis example

1. The Common Pattern In The Malonic Ester Synthesis

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?

key pattern in malonic ester synthesis where does each component come from and where does each 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 Reactions

These processes are built out of five reactions in total:

  1. deprotonation of the ester to form an enolate
  2. SNof the enolate upon an alkyl halide, forming a new C-C bond
  3. acidic hydrolysis of the ester to give a carboxylic acid
  4. decarboxylation of the carboxylic acid to give an enol
  5. tautomerization of the resulting enol to a carboxylic acid

Step 1: Deprotonation To Give An Enolate

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 an enolate. The resulting enolate can be drawn as one of two resonance forms.

malonic ester synthesis mechanism step 1 deprotonation of alpha carbon with base

Step 2: SN2 Reaction Of The Enolate Nucleophile With An Alkyl Halide Electrophile

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:

malonic ester synthesis mechanism step 2 sn2 of enolate an alkyl halide

Step 3: Acidic Ester Hydrolysis

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)

step 3 malonic ester synthesis acidic hydrolysis of ester with aqueous acid

Step 4: Decarboxylation To Give An Enol

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”.

malonic ester synthesis step 4 decarboxylation

Step 5: Tautomerization Of The Enol Back To The Carboxylic Acid

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“.

malonic ester synthesis mechanism tautomerization

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 from a malonic ester synthesis.

malonic ester synthesis problems

Secondly, it’s also possible to do two alkylations before doing the aqueous hydrolysis step. Can you figure out how to make from a malonic ester synthesis?

[If you’ve read this far, worked on these problems, and would like an answer, leave a comment!]

(Advanced) References and Further Reading

    Elmer P. Kohler
    Journal of the American Chemical Society 1922, 44 (2), 379-385
    DOI: 10.1021/ja01423a019
    One of the earliest instances in the literature of the use of malonic esters in organic synthesis.
    Arthur C. Cope and S. M. McElvain
    Journal of the American Chemical Society 1932, 54 (11), 4319-4325
    This paper by Prof. A. C. Cope (of the Cope Rearrangement) shows that malonic acid esters can be synthesized from aliphatic acid enolates with diethyl carbonate.
  3. The Alkylation of Malonic Ester
    Ralph G. Pearson
    Journal of the American Chemical Society 1949, 71 (6), 2212-2214
    This paper is a very rigorous physical-organic study of the malonic ester synthesis and shows that the rate of alkylation is related to the acidity of the a-proton in the malonic ester.
  4. The malonic ester synthesis in the undergraduate laboratory
    Bernard E. Hoogenboom, Phillip J. Ihrig, Arne N. Langsjoen, Carol J. Linn, and Stephen D. Mulder
    Journal of Chemical Education 1991, 68 (8), 689
    DOI: 1021/ed068p689
    This publication describes a prototypical but still simplified method for carrying out the malonic ester synthesis, making it amenable for undergraduate organic chemistry laboratory courses.
    Raymond P. Mariella and Richard Raube
    Synth. 1953, 33, 23
    DOI: 10.15227/orgsyn.033.0023
    This procedure uses a dihalide to effect an intramolecular cyclization, which is also known as the Perkin alicyclic synthesis. Organic Syntheses, which is published by the ACS’s Organic Chemistry division, is a reputable source of reliable and independently tested synthetic organic laboratory procedures.

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