Ch. 21 - Enolate Chemistry: Reactions at the Alpha-Carbon WorksheetSee all chapters
All Chapters
Ch. 1 - A Review of General Chemistry
Ch. 2 - Molecular Representations
Ch. 3 - Acids and Bases
Ch. 4 - Alkanes and Cycloalkanes
Ch. 5 - Chirality
Ch. 6 - Thermodynamics and Kinetics
Ch. 7 - Substitution Reactions
Ch. 8 - Elimination Reactions
Ch. 9 - Alkenes and Alkynes
Ch. 10 - Addition Reactions
Ch. 11 - Radical Reactions
Ch. 12 - Alcohols, Ethers, Epoxides and Thiols
Ch. 13 - Alcohols and Carbonyl Compounds
Ch. 14 - Synthetic Techniques
Ch. 15 - Analytical Techniques: IR, NMR, Mass Spect
Ch. 16 - Conjugated Systems
Ch. 17 - Aromaticity
Ch. 18 - Reactions of Aromatics: EAS and Beyond
Ch. 19 - Aldehydes and Ketones: Nucleophilic Addition
Ch. 20 - Carboxylic Acid Derivatives: NAS
Ch. 21 - Enolate Chemistry: Reactions at the Alpha-Carbon
Ch. 22 - Condensation Chemistry
Ch. 23 - Amines
Ch. 24 - Carbohydrates
Ch. 25 - Phenols
Ch. 26 - Amino Acids, Peptides, and Proteins
Johnny Betancourt

Acetoacetic ester (ethyl acetoacetate) is an extremely useful molecule that can be used to make ketones and other molecules. You’ll even use this later on in amino acid synthesis, so let’s break down the way it reacts.  




 

From Beta-Ketoester to Ketone:

How do we accomplish this transformation?How do we accomplish this transformation?

Enolate Formation: 

Labeled-alpha-carbonsLabeled alpha-carbons

See those two carbonyls there? Each carbonyl has something called an alpha-carbon, and each alpha-carbon has hydrogens that are easily abstracted. The pKa of the green alpha-hydrogen is about 20, and the pKa of the blue alpha-hydrogen is actually about 10. Why? Because of the resonance structures the anions can form! 

green-enolate-resonance-structuresGreen Enolate Resonance Structures

blue enolate resonance structuresBlue Enolate Resonance Structures

Whenever you have a beta-dicarbonyl like this one, the enolate will preferentially form on the shared alpha-carbon. The anion on the blue alpha-carbon above can form more resonance structures than the anion on the green alpha-carbon can, so the blue hydrogen’s pKa will be lower (more acidic). 

That all sounds cool, but can we just use any ol’ base to form our enolate? Definitely not! Let’s say we were to try using NaOH. Instead of forming the enolate, we’d actually wind up with a competing reaction: saponification, a type of nucleophilic acyl substitution. Notice that the hydroxide replaces the ethoxy group.

abridged saponification mechanismAbridged Saponification Mechanism

So, how can we specifically avoid that type of acyl substitution? We can use a bulky base like LDA or the anionic version of our alkoxy group! See how we’ve got an ethoxy group (—OEt) in our starting material? In order to prevent any substitutions of that group, we can actually use NaOEt. Those ethoxy groups are totally exchanging, but the same molecule is produced. 

Fischer-esterification-with-sodium-ethoxideFischer Esterification with Sodium Ethoxide

Methylene-enolate-formationMethylene Enolate Formation


Enolate Alkylation:

Okay, cool! These enolates are pretty good at SN2 reactions. They can act as nucleophiles on alkyl halides, acyl (acid) chlorides, and more! Let’s try adding a propyl group. 


Enolate-alkylationEnolate Alkylation


Decarboxylation:

Once we’ve got our alkyl group on there, we can actually get rid of the ester entirely through a mechanism called decarboxylation if we want to. All it takes is some heat and a little bit of aqueous acid. It could be written a ton of different ways—H2SO4 (aq), HCl (aq), or even generically as H3O+.

Acid-catalyzed-ester-hydrolysisAcid-catalyzed ester hydrolysis

First we hydrolyze the ester to make a beta ketoacid, and then we heat things up to lose CO2. After acidic hydrolysis, the enol (vinyl alcohol) that results will tautomerize back into a substituted ketone. 

 Tautomerization-and-decarboxylationTautomerizaation and Decarboxylation

Boom! There’s our product, a substituted ketone, in the green box! Not so bad, right? Of course, there are tons of different ways to use this molecule. We’ve just walked through the steps for a single alkylation, but there’s nothing stopping us from adding different groups. 


Adding Two Alkyl Groups: 

We’ve added one alkyl group, but what if we want to add another one? Well, we just have to follow the same steps! So, let’s start from the beginning. Let’s first add a propyl group and then an ethyl group. Once we’ve added the propyl group, all we need to do is add another equivalent of base and then the ethyl group. Here’s what the order of reagents looks like: 

Double-alkylation-reagentsDouble Alkylation Reagents

And here’s what the mechanism would look like:

Double-alkylation-mechanismDouble Alkylation Mechanism                                 

Adding Cyclic Alkyl Groups: 

Okay, but what if we want to add a cyclic group to our molecule? Well, luckily that’s not so bad either. We just need a molecule that has two leaving groups at terminal positions. Basically, it’s going to be very similar to the double alkylation but with just one equivalent of our alkyl molecule being added. Here’s what the reagents look like: Cyclic-alkylation-reagentsCyclic Alkylation Reagents

And here’s what the mechanism looks like: 

Cyclic-alkylation-mechanismCyclic Alkylation Mechanism


Adding Acyl Groups: 

Let’s take a step back and use the same enolate we used in the alkylation, but let’s use an acyl chloride instead of an alkyl halide this time. This follows basically the same pattern as the alkylation, but I’m going to rotate the acetoacetic ester a little bit and highlight the acid chloride so that it’s easier to follow. 

Enolate-acylation-mechanismEnolate Acylation Mechanism

See how we just followed the same pattern? Form the enolate, provide an electrophile, and cleave off the ester by adding acid and heating it up! 

Not so bad, right? Now you’re ready t o take on a whole new world of synthesis problems! Good luck and remember that I’ve got tons of videos on this topic and everything else you need in Organic Chemistry :)




Johnny Betancourt

Johnny got his start tutoring Organic in 2006 when he was a Teaching Assistant. He graduated in Chemistry from FIU and finished up his UF Doctor of Pharmacy last year. He now enjoys helping thousands of students crush mechanisms, while moonlighting as a clinical pharmacist on weekends.