Choose the most appropriate reagent(s) for the alkylation of diethyl malonate with benzyl bromide.

By James Ashenhurst

Last updated: September 24th, 2022 |

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

• In the malonic ester synthesis, a di-ester of malonic acid is deprotonated with a weak base, and then undergoes C–C bond formation at the alpha position with an alkyl halide (enolate alkylation)
• Treatment with aqueous acid results in hydrolysis of the ester. Upon heating, decarboxylation spontaneously occurs to give a chain-extended carboxylic acid.
• A related process, the acetoacetic ester synthesis, results in alkylated ketones.
• The reaction has the advantage that only an alkoxide base is required and there are none of the problems with regioselectivity that sometimes occur in the alkylation of substituted ketones with alkoxides.
• If desired, two alkylations can be carried out before the decarboxylation step.

Table of Contents

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?

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:

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.

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:

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.

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”. [See article – 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“. [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

1. THE ADDITION OF MALONIC ESTERS TO BENZOYL-PHENYL-ACETYLENE.
   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.
2. THE CLEAVAGE OF DISUBSTITUTED MALONIC ESTERS BY SODIUM ETHOXIDE
   Arthur C. Cope and S. M. McElvain
   Journal of the American Chemical Society 1932, 54 (11), 4319-4325
   DOI: 1021/ja01350a026
   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

   
   DOI:1021/ja01174a080
   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.
5. DIETHYL 1,1-CYCLOBUTANEDICARBOXYLATE
   Raymond P. Mariella and Richard Raube
   Org 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.