Enols and Enolates
The Malonic Ester and Acetoacetic Ester Synthesis
Last updated: February 1st, 2023 |
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
- 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
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:
- 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
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?
(Advanced) References and Further Reading
- 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
Org 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.
22 thoughts on “The Malonic Ester and Acetoacetic Ester Synthesis”
How can we synthesize the 2-ethylpentanoic acid from malonic ester?
The longest carbon chain needs to be 5 carbons, and the “core” of malonic acid will only have 2 after decarboxylation, so you need to add 3 carbons (propyl) and also an ethyl group (2-ethyl) to complete the molecule.
Starting with malonic ester, first, alkylate with propyl bromide, then ethyl bromide, then hydrolyze and decarboxylate. The result is 2-ethylpentanoic acid.
My teacher has us use saponification instead of acidic hydroloysis of the ester (I believe because it is more efficient). If I use saponification, do I need to add a separate acid workup since it makes a carbolylate or can the decarboxylation occur directly after this step?
Why is this reaction called a Malonic ester “synthesis”? We’re starting with a malonic ester and ending up with a carboxylic acid, we aren’t creating a malonic ester in the end.
Is a protonated carbonyl group a strong enough electrophilic center to accept the lone pair from the malonic enolate?
The malonate enolate is a much stronger base than the carbonyl carbon. Adding acid will just irreversibly protonate the enolate.
Can you do a michael addition to a beta keto ester?
If it’s an alpha, beta unsaturated beta-keto ester, yes. of course, they are great substrates.
If you’re talking about just a beta keto ester… then perhaps you are aware that they exist in the enol form. It’s possible to do addition-elimination reactions if you convert the OH to O-Tf for example and add a good nucleophile (e.g. a dialkylcuprate) but now we are getting far beyond the scope of what’s generally covered in introductory organic chem.
I’m trying to find a more simplified explanation of the Gabriel (malonic-ester) synthesis, specifically when potassium phthalimide reacts with diethyl bromomalonate to generate an amino acid. Is it ester —> carboxylic acid, and then —> amino acid, following certain additions? I’m by no means a chemist; I’m just studying for the MCAT, and I’m having a conceptual issue with this problem.
Right. So the Gabriel would form a C-N bond, and then hydrolysis would lead to decarboxylation.
So ester –> carboxylic acid, and depending on choice of conditions (usually hydrazine) phthalimide —> amine.
Could you please explain why the base(hydroxide here) prefers to deprotonate the alpha carbon instead of attacking the carbonyl carbon Is this a general rule? Would deprotonation, even a second time be preferred to a 1,2 addition??
Thank you for you work the website is very helpful and I am here constantly! Thanks for the time and effort you put into it, definitely HUGE HELP!
Pretty sweet article, and thanks for the answer upload james. I worked them out right, but it’s nice to have something to check against to boost the confidence.
Check it out here: http://imgur.com/NZJth
Hi is there a mechanism for the end step, where the malonic ester is converted to a carboxylic acid in the presence of acid?
Yes, it’s the acidic hydrolysis of esters. Covered in more detail here:
Can you please talk about the stereochemistry of the disubstituted malonic ester synthesis? Is the product racemic? Thanks!
Thanks for the comment. Yes, the product of the malonic ester will be a mixture of stereoisomers – it goes through a flat (planar) enol (after decarboxylation) and then protonation of the enol can occur from either face.
If that’s the only stereoisomer present, then yes, the product will be racemic.
If there’s already a chiral center in there somewhere, then you’ll get a mixture of stereoisomers.
Hope this helps? James
Why is the reaction product of diethyl malonate with ethyl bromide in the presence of sodium ethoxide(absolute alcohol medium) is called a monosubstituted ester? and the reaction product of the above monosubstituted malonic ester with 2-bromopentane in the presence of sodium ethoxide(absolute alcohol medium) is called a disustituted malonic ester?
It has to do with how many C-H bonds on the central carbon of diethyl malonate have been replaced by C-C bonds. If one C-H has been replaced (e.g. with ethyl) that’s monosubstituted. If two have been replaced (e.g. with ethyl and 2-pentyl) that’s disubstituted ethyl.
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