Enamine Alkylation and Acylation

Concept: General Reaction

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Video Transcript

On this page, we're going to talk about a reaction called enamine alkylation and acylation. Just to catch you up, in the ketones and aldehydes section of your textbook, there's a reaction that ketones and aldehydes can undergo with amines that forms imines and enamines. These are functional groups that form from the addition of neutral amines to a ketone or aldehyde. Specifically, the one that we care about for this page is secondary amines because as you might remember or maybe you haven't gotten there yet and it’s fine, or you just forgot. Secondary amines are going to react with ketones to specifically give enamines. An enamine has a part amine at the top and an alkene at the bottom, hence the name.
Enamines are really important for one reason alone, which is that enamines have a nucleophilic alpha-carbon. If you think about it, this was the alpha-carbon to begin with. This is still the alpha-carbon. Enamines are able to use that alpha-carbon to do nucleophilic attacks. Enamines have the ability to alkylate or acylate via the formation of an iminium salt. What essentially happens guys is that you have your enamines and you have an electrophile. Let’s just say that it’s an alkyl halide to keep it easy. What happens is that the lone pair for the nitrogen can come down to make a double bond. You make that bond. You break a bond. You take this double bond and you attack the alkyl group with it because it’s electrophilic. What you wind up getting is the formation of an imunium salt, really important, because now that nitrogen has a positive charge. But more importantly, we just alkylated the alpha carbon.
Then we can use dilute acid to hydrolyze the iminium salt all the way to a ketone. If you’re wondering how that happens, this happens through what we call an acid work up. This is a very important reaction in Organic Chemistry 2. We need to know how to hydrolyze nitrogen compounds into oxygen-containing compounds. This is a multiple-step reaction but if you're interested in looking it up, you can look it up basically in the imine topic. When we discuss imines in the carbonyls section, ketones, and aldehydes, we’re going to talk about the forward reaction of this, how to go from a ketone to an imine. The reverse of that imine reaction is what we call an imine hydrolysis to get back to the ketone.
I’m not going to go through that whole mechanism now because I already have in prior videos. But just letting you know that we basically use acid to turn an imine derivative into a carbonyl. But now, it's not just a carbonyl, it’s alpha-substituted. What I want you guys to do is go through these two examples. Try to solve them yourself. Do the first one first, obviously. Then I’ll solve the first one and then we’ll do the second one together. Go ahead and do the first one. 

Example: Predict the Products

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Video Transcript

Alright guys. So, as you'll notice in this question it's not asking for a full mechanism, it would take over a page to draw this whole mechanism from scratch, okay? So, we're just going to predict the products like it says, the first thing, the first two reagents work together, these are going to be an acid catalyzed enamine reaction. Now, if you're wondering how to draw the parts of enamine, I don't really like to rely on the general formula. So, what I would do is I would draw that an, enamine is an N with two bonds at the top, a bond coming down and then a double bond coming out from one of its sides, okay? Then I just have to determine, what are the R groups that i substitute for everything, so the N is actually supposed to be attached to a square. So, I'm going to go ahead and complete the square at the top, okay? Now, the bottom was actually coming from the carbonyl, which was acetone. So, it's already drawn perfectly, okay? Now, it's time for the reaction for the actual nucleophilic attack. So, I'm going to draw my alkyl halide, I've got a phenyl group with a CH2 and a Br, okay? So, this is going to be an SN2 reaction where I'm going to take my electrons move them down kick out the Br and what I'm going to get is now an enamine that looks like this, drawing a little bit smaller since I don't want to run out of room. Now, I'm going to get a carbon, that's attached to, what will is attached to now a carbon with a benzene on it, okay? And a positive charge on that nitrogen, okay?

My last step looked like, just dilute acid in water, this is the hydrolysis step. So, after I hydrolyze with my H3O plus, which is what that is, I'm going to get my ketone, looks like this, interesting right? So, I was able through this reaction, look what I just did, I started off with acetone and I added this whole group through my alkylation because I went through an enamine, isn't that so cool? So, now we know that we can use enamines to add alkyl groups and acyl groups to the Alpha position, okay? Awesome. So, now, that being said, this is supposed to be question 2, I don't know why the number isn't there, go ahead and do question 2, see if you can get it right, and then I'll show you guys the answer, again, don't draw a mechanism I just want a product.

Example: Predict the Products

4m
Video Transcript

Alright, so for this one I'm definitely going to draw smaller from the beginning so that we have enough space. So, we know that the first two reagents have to do with making my N-amine, once again, we'll go back to that general structure of an N-amine, the general structure is right, It's a nitrogen with a bond, bond, bond, double bond, right? I have to plug stuff in. So, once I plug stuff in, what that's going to become is, I'm really running out of room here, I'll just use the one that I have, okay? So, what I'm going to get is a methyl on one side the N and ethyl on the other side of the N and then at the bottom it's going to be a cyclohexane but now the cyclohexene because it's an N-amine perfect, okay? So, now I'm going to introduce that to my alkyl halide, which in this case is a really easy one. So, methyl iodide. So, this one is going to do an awesome SN2 reaction, awesome backside attack, and I'm going to attack and what I'm going to get is now a new N-amine watching the minium salt, right? That looks like this, positive with a methyl group there, okay? Now, I'm going to hydrolyze an acid, okay? An acid is going to take me back to my carbonyl. So, now I'm just going to end up with a cyclohexanone that has a methyl group on it. So, I was able to alkylate the Alpha position, isn't that so cool? I keep saying, you're just like sure Johnny? Well guys, let me show you something that is cool, that you're going to like.

Now, that I've showed you guys two different reactions and maybe you think about it there's a really easy way to predict these reactions, did you figure it out yet? all it is guys is that you just look at your alkyl halide and whatever you're ordered your electrophile, whatever that electrophile is you just place it on the Alpha position, okay? I told you from the beginning, this is just an alpha substitution. So, just take whatever electrophile you're given and place it there, in the case of the top one it was a benzyl group. So, that's what I added here, this is benzyl, right? Has an extra CH2 and in the case of the bottom one it was a methyl group, okay? Now obviously, if your professor wants to see like all of steps involved for all draw all of them but if they just say predict the products of these four reactions, you honestly don't even need to draw the N-amine, right? Because you already know in your head, I'm going to make the N-amine, I'm going to put the thing on the Alpha, I'm going to hydrolyze it. So, what's the point of even drawing it? you could just draw the product. Notice that this product is just a ketone like it started, okay? So, that I know you like, because that's like a cheat, okay? Don't use it too much but just letting you know that's as easy as this is. So, now you know pretty much another way to add alkylations to alpha positions, okay? Awesome guys. So, let's move on to the next video.

Problem: Provide the major product after each step for the following reaction.

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Problem: Which of the following can NOT be formed through the stork enamine reaction with 2-butanone? 

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Enamine Alkylation and Acylation Additional Practice Problems

Draw the structure of the product that is formed when the compound shown below is treated with the following reagents: 

1) pyrrolidine, heat; 2) EtBr; 3) H+, H2O. Pyrrolidine is a cyclic secondary amine with a five-membered heterocycle, (CH2)4NH.

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Provide the missing product. Show only one most preferred product. Consider only monosubstitution for EAS where appropriate.

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Propose a step-by-step MECHANISM to explainn the reaction below. Show all intermediates, charges, and use curved arrows to indicate the flow of electrons.

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Provide an electron push mechanism using the curved arrow formalism to explain the formation of the product from the following transformation. Include all nonzero formal charges.

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Show how you could go from a cyclohexanone to 2-acetylcylohexanone by filling in the boxes along the way with the correct compounds and reagent(s). 

 

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Draw the mechanism for the following reaction. 

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For the following reactions, draw the predominant product or products. When a new chiral center is created, mark it with an asterisk (*) and if a racemic mixture is produced, you must write "racemic" under your structure. If an E,Z mixture is produced as the result of a dehydration step, write "E,Z mixture", but you only have to draw one isomer, not both.

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Predict the product(s) below:

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Propose a mechanism for the following reaction.

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The final product of the following synthesis is:

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