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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
Ch. 26 - Transition Metals
Tautomers of Dicarbonyl Compounds
Acid-Catalyzed Alpha-Halogentation
Base-Catalyzed Alpha-Halogentation
Haloform Reaction
Hell-Volhard-Zelinski Reaction
Overview of Alpha-Alkylations and Acylations
Enolate Alkylation and Acylation
Enamine Alkylation and Acylation
Beta-Dicarbonyl Synthesis Pathway
Acetoacetic Ester Synthesis
Malonic Ester Synthesis

Concept #1: General Mechanism


In this video, I’m going to introduce another very creative way to add R group. To the alpha-carbons of your ketones and aldehydes, and that’s called the beta-dicarbonyl ester synthesis pathway. What does this mean? We've already been over this guys, how beta-dicarbonyls are unusually acidic due to the incredible stability of the enolate. We talked about how the pKa of a normal alpha-carbon is about 20. But that in a beta-dicarbonyl compound, it’s closer to 10. It’s very easy to deprotonate. That's good for us because if it’s easier to deprotonate, that means I have yields of the enolate I’m looking for. We're going to use this as an advantage to us. That central carbon, we’re going to use it through a multistep synthesis that will consistently add to that center carbon, we’ll add our R groups. This is what pathway the looks like. You start off with a beta-dicarbonyl ester. Just so you guys know, there's two of these that we're going to be learning about. There's acetoacetic ester. Acetoacetic ester looks like this. It’s basically the one that you have drawn here. It's the one that's already drawn in that box.
But then there's also malonic ester. Malonic is the name for three-carbon di acid. It’s a three-carbon chain with two carboxylic acids. Malonic ester is just two esters on both sides. Technically, these R groups are all ethyl groups. But that’s beside the point. That's not really what I care about. What I care about is the shape of these things. Notice that I have two different esters but they're both beta-dicarbonyl. Both of them have an ester with a beta-dicarbonyl.
Then what you get is that the first step is going to be an enolate formation. The base we’re going to use, we’re going to be careful about it. We want to make sure if we're using an oxide base, that we’re using a base that contains the same R group as the R group in my ester. Does anyone have an idea of why that's important? Your R groups must be the same to avoid transesterification. If you’re a little bit confused about what transesterification is or don't remember, just type it into the search bar, the Clutch search bar. Transesterification will pop up and then you can learn all about it. Just letting you know, your R group should be the same. Since R is equal to ethyl, usually the base that we're using is OEt negative. Since I told you that the R is usually an ethyl group, you should be using OEt negative. That's going to give us an enolate. That enolate can do something very familiar, which is that it can attack an electrophile through an SN2 reaction or any other mechanism that would contribute to the attack of an electrophile. Now I have my electrophile here.
But we’ve got a problem. Notice that this part of the compound actually is an alpha-substituted ketone. If I could find a way to just keep that part of the compound, this would be an alpha-substituted ketone. The problem is that I’ve got all of this crap. What do I do with this? I don't want that part of the molecule around, but it's there. If I could figure out a way to get rid of all of this, then I could use this reaction as a means of alpha-substitution. Correct? It turns out, that's what the pathway is all about. The pathway is about you use the beta-dicarbonyl, get the electrophile on there. And then the final two steps are ways to get the ester group off.
The first thing we do is what’s called an acid-catalyzed ester hydrolysis. In an acid-catalyzed ester hydrolysis, you're going to use acid and water to hydrolyze my ester to a carboxylic acid. If you haven't learned about your carboxylic acid derivatives yet, that's okay. But just know that the definition of a carboxylic acid derivative, which is what ester is, is that it can be hydrolyzed to a carboxylic acid using acid and water. This hydrolysis, you don’t need to draw the whole mechanism here. You just need to know that you’re hydrolyzing an ester to a carboxylic acid.
What's important about that? One you do that, then you're going to have what we call a beta-carbonyl carboxylic acid. What’s special about beta-carbonyl carboxylic acids is that in the presence of heat, they decarboxylate. If you don't know what decarboxylation is, type it into your Clutch search bar. I’m just going to keep saying that because I’ve got videos for all of this. It might not be exactly in this part of your textbook, and that's fine, but you can just search for it or you might have missed it or who knows. You decarboxylate. That would take this entire thing off and it's going to just leave what's left over. It’s going to leave your alpha-substituted carbonyl plus you're going to get CO2 gas. You have your alpha-substituted carbonyl, your CO2 gas, and lo and behold, I use this bizarre four-step pathway to produce the same thing that I could have just gotten from an enolate akylation that I could have just gotten by just putting an enolate on the alpha-carbon and attacking an electrophile. But this is a more elegant synthesis because I'm able to use, I’m probably going to be getting what I want in higher yield because it’s easier to make my enolate. Notice that I have a much more powerful enolate that I'm using because my pKa of this hydrogen is so much lower. It’s much more acidic.
What I want to do next is go through the specific reactions that acetoacetic ester and malonic ester can go through. Let's go ahead and start off with acetoacetic ester.