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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: Overview


In this video, I want to give you an overview of three separate reactions that all do the same thing. What they do is that they alkylate the alpha carbon of a carbonyl. Let's get started.
Adding R groups to alpha carbons turns out to be very important synthetically. There's a lot of reasons that we would want to add an R group to an alpha carbon. It turns out that if we want to do that, we're not limited by techniques. There’s actually three different things, three different reactions that all do this. I'm going to go through these three synthetic pathways now, all in order so that you guys can get an idea of how they all work together. But your textbook might not teach them all in this order. I personally think that's a mistake. I think your authors made a mistake if they didn’t teach them back to back because they all do the same thing. But for right now, I'm just going to give this overview and then we'll just take every reaction as it comes in your textbook, every chapter that it’s in then I'll do that reaction. But just keep this in mind that they're all really doing the same thing.
The first method is direct enolate alkylation. Enolate alkylation just says that I'm going to use a base to form an enolate. That enolate is then going to attack an alkyl halide. Then I would you a backside attack. I’m going to get an R group on that enolate. Of course we'll talk more about this in the actual page about you enolate alkylation. One thing to keep in mind is that pretty much anytime that I tell you that you can alkylate something, it means that you can also acylate something. To acylate something, that means that you would be using an acid chloride. The mechanism would be extremely similar. It would just be that your negative attacks the carbon and eventually you kick out the Cl. It means that you would get a carbonyl there instead of just an R group. But this is the first reaction that does alpha-carbon alkylations and it’s called enolate alkylation. It’s definitely the most straight forward of the three.
The second one is called enamine alkylation. You guys should be approaching the point where you learned about enamines and how to make enol enamines. Enamines are when we add a secondary amine to a carbonyl in an acid-catalyzed environment. What an enamine does is it makes, and we're going to go through this of course separately, but it makes a molecule that looks like this where you have a double bond, and N with two R groups. It turns out that enamines are also great nucleophiles at the alpha-carbon. Enamines can also do backside attacks on alkyl halides and they can also add R groups. Now, you might be wondering what happens to the nitrogen? It gets hydrolyzed. Don’t worry, there’s a whole acid work up and you get rid of it. But we’ll talk about it. But in the meantime, just know that it does the same thing. In the same way you could also react with an acid chloride. An acid chloride would just do an enamine acylation. That was the second way. Obviously, it's more steps. You can see it’s three steps. But the reason that there’s so many steps is because the first step is to make the enamine. Then the last step is to hydrolyze the enamine. The middle step is the actual electrophile that we react with. Really, this is very similar to enolate alkylation. It’s just that you have to do that first step and that second step.
Finally, we get to the last one which is acetoacetic ester and dicarbonyl ester alkylations. With dicarbonyl ester alkylation, what we do is we end up forming an enolate between the carbonyls because we know that that is the most stable place for an enolate to form because it has the most resonance structures, that's the most acidic proton. That negative charge ends up doing an SN2 attack and adding an R group in that location. We go through a complicated process where then we hydrolyze the ester and decarboxylate it to remove that entire species and then we're left with the same exact thing that we started off with the other two reactions, which is just an alpha-alkylated carbonyl. This one obviously looks like it's the most complicated because now we have four reagents. But really guys, it’s a synthetic pathway that once you learn it, you’re going to get so good at it. It’s not even going to matter. You’re going to be pros at this.
Again, these three reactions, I might not teach them to you in perfect order from here or now and that's going to be because I'm trying to follow your textbook as closely as I can. Sometimes your textbook will split this up between two different chapters. That means that I’m going to have to split up the explanations in two different chapters as well. But I want you to always refer back to this page so you can understand to yourself that these three reactions are related to each other very much so that they do the same exact thing just in different ways. Alright, so that being said, let's move on to the first reaction.