Enols and Enolates
The Malonic Ester Synthesis
Last updated: February 27th, 2020 |
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.
Table of Contents
- The Common Pattern In The Malonic Ester Synthesis
- The Malonic Ester Synthesis Is Comprised Of Five Separate Reactions
- Step 1: Deprotonation To Give An Enolate
- Step 2: SN2 Reaction Of The Enolate Nucleophile With An Alkyl Halide Electrophile
- Step 3: Acidic Ester Hydrolysis
- Step 4: Decarboxylation To Give An Enol
- Step 5: Tautomerization Of The Enol Back To The Carboxylic Acid
- (Advanced) References and Further Reading
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 five 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 to give an enol
- tautomerization of the resulting enol to a 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 an enolate. 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!]
- THE ADDITION OF MALONIC ESTERS TO BENZOYL-PHENYL-ACETYLENE.
Elmer P. Kohler
Journal of the American Chemical Society 1922, 44 (2), 379-385
One of the earliest instances in the literature of the use of malonic esters in organic synthesis.
- 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
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.
- 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.
- 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
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.
- DIETHYL 1,1-CYCLOBUTANEDICARBOXYLATE
Raymond P. Mariella and Richard Raube
Synth. 1953, 33, 23
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.