Clutch Prep is now a part of Pearson
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 Reaction


In this video, I want to discuss enolate alkylations and acylations. There's really nothing tricky to this reaction. As long as you can draw an enolate, you can do an enolate alkylation because all it is is that you’re either exposing an enolate to an alkyl halide or you're exposing an enolate to an acid chloride. What happens is the base grabs one of the protons and the alpha-carbon. You make a negatively charged enolate. That does a nucleophilic attack on either alkyl halide or on the acid chloride. If you use an alkyl halide, then this would be my product, an alpha-alyklated carbon. If you use your acid chloride, then you're going to wind up getting an acylated carbon, so you’d get a beta-dicarbonyl with an R group.
That’s it guys. This is a very easy mechanism to understand, very easy reaction to understand. So, let’s move on to the next part of the page. 

Concept #2: Directed Reactions


This brings us to directed reactions guys because the mechanism that I showed you above even though it's you know great and very easy to use, it only works with symmetrical ketones, it only works when there's only one type of enolate possible but what happens if you have an asymmetrical ketone, okay? That means that you would theoretically have more than one enolate possible, for example, take this ketone into consideration, I could get the red enolate on the more substituted side or I could get the blue enolate on the less substituted side, would I get both? Would I get are groups forming on both sides? No, this is something that we have to answer using directed reactions. Well, it turns out guys that you can use different bases to direct the direction of the protonation, of the deprotonation to make the enolate, okay? And guys, this is a concept that should be familiar to you guys because we've used it before, this is simply a thermodynamic versus kinetic control reaction, okay? So, the thermodynamic product, let's just review, is going to be the one that's more stable, right? In this case, this is an enolate intermediated reaction, it's going to be the one that has the lowest overall energy or the most stable enolate, okay? I'll show you how to determine, which is more stable in a second, the kinetic product is the one with the lowest activation energy or that just means easiest to make, okay? So, how do we know which enolate is more stable? Well, remember that enolate goes through two resonance structures, right? One of the resonance structures is like this but another resonance structure looks like this, right? We'll look at that, one of the resonance structures has an alkene in it, so the way you determine which one is the most stable enolate is by the most substituted alpha-carbon, okay? Why? Because and really guys, I'm sorry, I'm drawing that on that side and I really should have drawn it on the side with the actual red one, that's going to be over here, okay? So, if you want, I know you hate me right now, but you can pause the video and redraw it on this side if you want or you can just draw it here, okay?

So, the one, the most substituted alpha carbon is going to be the most stable, okay? So, that means that the red one would be my thermodynamic control, okay? Because the one that is going to, it has the most R groups on the Alpha carbon, so that means it's going to have the most R groups on my double bond, and that's what makes the one stable. Remember, that double bonds are stabilized through R groups, okay? Now, what makes a kinetic enolate, is the easiest to make or that's going to be the least substituted because it's less sterically hindered, okay? So, these are the competing themes here, okay? So, specifically, how do we choose one or the other? Well, if you want the blue enolate you choose a bulky base like LDA, okay? So, LDA is the most popular one in this section, you could also use tert-butoxide, okay? So, a bulky base is going to favor the kinetic product because it's the easiest one to make whereas a small base, okay? So, for example, NaOH is going to favor the thermodynamic because it's not going to have trouble getting into that spot to deprotonate and it's going to make the most stable enolate overall, okay? So, you would determine which side you substitute by you get your base and then using that enolate to react with your lecture file whether it be an alkyl halide or an acid chloride, okay? Awesome guys. So, in the next video I want to talk about how this applies to esters.

Concept #3: Enolates of Esters


Guys. So, really quickly esters can also be alkylated and isolated the only catch is that you need to use LDA, you can't use any other base, you can't just use like hydroxide, why do you think it would be a mistake to use OH negative on an ester? can you think of a reason? So guys, if you use OH negative on an ester, what you're actually going to get is a hydrolysis, you're going to wind up getting a carboxylate, okay? And that would be like a NAS reaction, you don't want your base to react with the alkyl group, same as if I used, let's say OR1, right? If I used an alkoxide base with an R differ from the R in my alkyl group, I'm going to get a transesterification, I don't want that to happen. So, we do is we use a non nucleophilic, LDA is considered a non, let me draw for you really quick, LDA, in case you haven't seen it in a while, nitrogen isopropyl, isopropyl lithium, this is considered a non-nucleophilic base, okay? Why? Because it has a very hard time, can't donate its electrons, electrons, okay? Can you see that? perfect.

Okay, sorry, one handwriting sucks down there but LDA is a non-nucleophilic base, it can't delay its electrons. So, it's not going to be able to attack this carbon instead it just reacts as a base and pulls off an alpha hydrogen, see? So, by using LDA we strategically make the enolate and we don't have to worry about any types of carboxylic acids derivative reactions, oh by the way guys, if you haven't studied carboxylic acids yet or if that wasn't your forte, don't worry about that, I don't really care that you know all the details here, if this is the first time you're hearing about transesterification or NES or any of that, just focus on the point, the point being use LDA for reasons that you don't understand yet, use LDA and later on, when we get to carboxylic acid derivatives it will make more sense, okay? So, LDA makes an enolate and then you would then do your attack on the alkyl halide or the acid chloride and you would get your products, either OR with an R group or OR with an acyl group, makes sense? Awesome guys. So, pretty, pretty easy page, nothing too crazy here, let's move on to the next page.

Practice: Determine if the reaction is thermodynamically or kinetically controlled