Overview of Alpha-Alkylations and Acylations - Online Tutor, Practice Problems & Exam Prep

Three key reactions alkylate the alpha carbon of carbonyl compounds: enolate alkylation, enamine alkylation, and dicarbonyl ester alkylation. Enolate alkylation involves forming an enolate with a base, which then attacks an alkyl halide. Enamine alkylation requires creating an enamine from a carbonyl and a secondary amine, followed by a similar attack. Dicarbonyl ester alkylation forms an enolate between carbonyls, leading to an SN2 attack. Each method ultimately yields an alpha-alkylated carbonyl, showcasing diverse synthetic pathways for adding R groups to alpha carbons.

Overview

In this video, I want to give you guys an overview of 3 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 are 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 are actually 3 different things, 3 different reactions that all do this. I'll just write down the number 3. I'm going to go through these 3 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 you 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 and that enolate is then going to attack an alkyl halide. Then I would do like a backside attack and I'm going to get an R group on that enolate. Of course, we'll talk more about this in the actual page about 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'd 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'd 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 straightforward of the 3.

The second one is called enamine alkylation or enamine alkylation. You guys should be approaching the point where you learn 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 we're going to go through this, of course, separately but it makes a molecule that looks like this. We have a double bond, an N with 2 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. You might be wondering what happens to the nitrogen. It gets hydrolyzed. Don't worry. There's a whole acid workup 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 3 steps. But the reason that it's so many steps is because the first step is to make the enamine. 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 alkylations, what we do is we end up forming an enolate between the carbonyls because we know 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 4 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 like pros at this. Again, these three reactions, I might not teach them to you in perfect order from here on out. That's going to be because I'm going to try to follow your textbook as closely as I can. Sometimes, your textbook will split this up between 2 different chapters and that means that I'm going to have to split up the explanations in 2 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. That being said, let's move on to the first reaction.

Here’s what students ask on this topic:

What is enolate alkylation and how does it work?

Enolate alkylation is a reaction where an enolate ion, formed by deprotonating the alpha carbon of a carbonyl compound using a base, attacks an alkyl halide. The enolate acts as a nucleophile and performs a backside attack on the alkyl halide, resulting in the substitution of the halide with an alkyl group. The general mechanism involves the following steps:

1. Formation of the enolate ion: $R_{-}+H_{-}\to R_{-}+H_{+}$

2. Nucleophilic attack on the alkyl halide: $R_{-}+R_{-}\to R_{-}+R_{+}$

This method is straightforward and widely used in organic synthesis to introduce alkyl groups at the alpha position of carbonyl compounds.

What is enamine alkylation and what are its steps?

Enamine alkylation involves the formation of an enamine from a carbonyl compound and a secondary amine, followed by nucleophilic attack on an alkyl halide. The steps are:

1. Formation of the enamine: A carbonyl compound reacts with a secondary amine in an acid-catalyzed environment to form an enamine.

2. Nucleophilic attack: The enamine, acting as a nucleophile, attacks the alkyl halide, resulting in the addition of an alkyl group at the alpha position.

3. Hydrolysis: The enamine is hydrolyzed back to the carbonyl compound, completing the reaction.

The overall process can be summarized as:

$R_{-}+R_{-}\to R_{-}+R_{+}$

This method is useful for introducing alkyl groups at the alpha position of carbonyl compounds, especially when direct enolate alkylation is not feasible.

What is dicarbonyl ester alkylation and how is it performed?

Dicarbonyl ester alkylation involves forming an enolate ion between two carbonyl groups, which then undergoes an SN2 attack on an alkyl halide. The steps are:

1. Formation of the enolate: A base deprotonates the alpha carbon between the two carbonyl groups, forming an enolate ion.

2. Nucleophilic attack: The enolate ion performs an SN2 attack on the alkyl halide, adding an alkyl group at the alpha position.

3. Hydrolysis and decarboxylation: The ester is hydrolyzed, and the resulting carboxylic acid undergoes decarboxylation to remove the carboxyl group, yielding the final alpha-alkylated carbonyl compound.

The overall process can be summarized as:

$R_{-}+R_{-}\to R_{-}+R_{+}$

This method is particularly useful for introducing alkyl groups at the alpha position of carbonyl compounds with high selectivity and efficiency.

What are the differences between enolate alkylation and enamine alkylation?

Enolate alkylation and enamine alkylation are both methods for introducing alkyl groups at the alpha position of carbonyl compounds, but they differ in their mechanisms and steps:

1. Enolate Alkylation:

- Involves forming an enolate ion by deprotonating the alpha carbon with a base.

- The enolate ion directly attacks the alkyl halide in a single step.

2. Enamine Alkylation:

- Involves forming an enamine by reacting a carbonyl compound with a secondary amine in an acid-catalyzed environment.

- The enamine then attacks the alkyl halide, followed by hydrolysis to regenerate the carbonyl compound.

While enolate alkylation is more straightforward, enamine alkylation can be advantageous when direct enolate formation is challenging or when specific selectivity is required.

How does the stability of the enolate ion affect the outcome of alpha-alkylation reactions?

The stability of the enolate ion significantly affects the outcome of alpha-alkylation reactions. More stable enolate ions are formed from carbonyl compounds with more acidic alpha protons. Stability is influenced by resonance and inductive effects:

1. Resonance: Enolate ions stabilized by resonance structures are more reactive and selective in alkylation reactions.

2. Inductive Effects: Electron-withdrawing groups near the alpha carbon increase the acidity of the alpha protons, stabilizing the enolate ion.

Stable enolate ions lead to more efficient and selective alkylation reactions, reducing side reactions and increasing yields. Understanding enolate stability helps in choosing the appropriate conditions and reagents for successful alpha-alkylation.