Amine Alkylation - Online Tutor, Practice Problems & Exam Prep

Amine alkylation involves the reaction of amines with alkyl halides, typically through an SN2 mechanism. This process can synthesize primary amines, but challenges arise due to the nucleophilicity of the product, leading to polyalkylation. Using excess amine can mitigate this, but the reaction often results in secondary or tertiary amines instead. Understanding these limitations is crucial for developing more controlled synthetic methods for primary amines, emphasizing the need for alternative strategies in organic synthesis.

General Reaction

Hey guys, in these next few videos, I'm going to be discussing amine alkylation. And by the word amine, I'm not talking about an angry alkylation. Obviously, I'm talking about the functional group amines. So now that we've settled that one, let's go ahead and get into the reaction.

So guys, a huge part of this section of your text, the amines portion of your text is going to be trying to figure out how to synthesize primary amines. Primary amines are useful for lots of different applications and we're always trying to figure out what's the best way to make a primary amine of my choice. The go-to reaction that we would possibly think of is why don't we use an alkyl halide because if you look at an amine, it's got a very nucleophilic lone pair. Now there isn't a full formal charge on this molecule at all. I'm just using the N_u^- as my symbol for nucleophile. I've got an electrophile which is the carbon that is attached to my halide. This opens up for a reaction that we learned a long time ago and it's one of those mechanisms you're never allowed to forget, backside attack or SN2. Theoretically, we can make primary amines through the reaction of an amine and an alkyl halide.

Let's go ahead and just talk about this for a second. I'm not going to draw the whole mechanism but we're just going to draw like an abridged one here. You would have the lone pair doing a backside attack because, on my electrophilic carbon, I would kick out my leaving group. What you would wind up getting just from this very first reaction is you'd have an NH₃ that's now attached to a 3 carbon chain. I'm just going to write 1, 2, 3. Now one of the problems with that is that you're going to have a positive charge because now you have an extra bond to deprotonate the product. Then hopefully, by the end, we're actually getting our primary amines. I'll just draw that one more time, NH₂ with our 3 carbon chain. Everything seems pretty straightforward. It seems like this should be our go-to reaction for making primary amines because it's so easy to use. I could just literally throw any alkyl halide in there as long as it was primary, secondary, or methyl and I could get an SN2.

Remember that SN2s are tricky. They don't work on tertiary alkyl halides because the leaving group is kind of too backed up. It's too difficult to access. But we've got another problem on top of that, guys. It's not just that SN2 has its limitations. One of the biggest problems of this reaction is that we still have a nucleophilic lone pair at the end of the reaction. Notice that your product is just as nucleophilic as it was at the beginning. What we get is a possibility of multiple alkylations. We're going to find is that the predominant product in these reactions is going to be a polyalkylated amine which kind of sucks if you're trying to make a primary amine. There is a way to counteract that which is to use excessive amounts of amine. So if you can drown the solution with tons of your amine and then have very little of your alkyl halide, that reduces the chances of getting multiple R groups on the same nitrogen. But it's still quite a limiting reaction and one that we're not going to find very synthetically useful. We're going to rely on other methods of making primary amines for this reason.

Let's go ahead and look at the next video. In the next video, I'm going to be explaining the entire polyalkylation mechanism of an amine.

Propose a Synthesis

We've got 2 transformations that we need to keep track of here. First, I need to turn my tertiary amine, which would be referred to as an aniline derivative because this is an aniline with 2 R groups, so it's an aniline derivative. Somehow I need to turn my tertiary amine into a quaternary amine. You might have a better idea of how to do that now that we just went through this reaction. We'll be giving you some ideas. Have you seen a quaternary amine being made before? Another transformation that I need to make is I need to add chlorine to the meta position of the benzene because it's meta to the original group that was there. We've got basically 2 reactions that need to happen. One of them is going to have to be an amine alkylation because amine alkylations are a really surefire way to get quaternary amines. Once you have a quaternary, you can't keep alkylating, so that's the endpoint. That's actually going to be the perfect reaction for this.

Now over here, to add the chlorine, that's going to be an EAS halogenation or an EAS chlorination. Now the question is, does it matter which order these are in, or can I just put them in any order? The order matters, guys, because right now, this is an ortho/para director. Aniline derivatives are ortho/para directors. They're one of the strongest ones there is. Whereas notice my quaternary amine has what kind of charge? Positive. Do you guys remember what a positively charged substituent is going to do? It's going to be a deactivator. It's going to be a withdrawing group. This is now an electron-withdrawing group. It's actually one of the strongest electron-withdrawing groups because it has a full positive charge right there and it's going to be a meta director. What that shows you guys is that amine alkylation is actually a sequence group. Again, this is all drawing from your aromaticity section. But just letting you guys know, it is a sequence group because this group can alter the sequence of the reagents for synthesis. In this case, since I want meta activity, I want a meta-directed product, I'm going to go ahead and do my alkylation first. The specific R group I'm adding is just the CH3, so I could just use a methyl alkyl halide. I'm going to use CH3Cl. Normally, we would run an amine alkylation in base, so I would say CH3Cl and NaOH. But there's not going to be anything to deprotonate here because I'm literally just adding the 4th R group on. That's all I need. I don't need a base here. In fact, if I put in a base, it's not going to do anything. There's nothing to deprotonate. You would only use a base if you were starting from a primary or secondary or ammonia. If you're starting from a tertiary like this, then there's really going to be nothing to deprotonate.

Now the second reaction is going to be the EAS halogenation. You guys remember the reagents for that? You got this. Cl2 and FeCl3 as my Lewis acid catalyst. That is going to make my chlorine atom in the meta position because now I have a strong meta director and we're good. I hope that made sense, guys. This is really the only synthetically useful application of amine alkylation. We're not going to use it a lot for synthesis because of the complications that we just discussed with polyalkylation. Let's move on to the next reaction.

Here’s what students ask on this topic:

What is amine alkylation and how does it work?

Amine alkylation is a chemical reaction where an amine reacts with an alkyl halide to form a more complex amine. This typically occurs through an SN2 mechanism, where the nucleophilic lone pair on the nitrogen attacks the electrophilic carbon attached to the halide, displacing the halide ion. The reaction can be used to synthesize primary amines, but it often leads to polyalkylation, resulting in secondary or tertiary amines. This is because the product amine remains nucleophilic and can further react with additional alkyl halide molecules.

Why is polyalkylation a problem in amine alkylation?

Polyalkylation is a problem in amine alkylation because the product amine remains nucleophilic and can continue to react with additional alkyl halide molecules. This leads to the formation of secondary, tertiary, and even quaternary ammonium salts instead of the desired primary amine. This uncontrolled multiple alkylation makes it difficult to obtain pure primary amines, which are often the target products in synthetic organic chemistry.

How can the issue of polyalkylation be mitigated in amine alkylation reactions?

The issue of polyalkylation in amine alkylation reactions can be mitigated by using an excess of the amine reactant. By flooding the reaction mixture with a large amount of amine, the likelihood of multiple alkylation events on the same nitrogen atom is reduced. This approach increases the chances of forming the desired primary amine. However, this method is not always practical or efficient, and alternative synthetic strategies are often preferred for controlled amine synthesis.

What are some alternative methods for synthesizing primary amines?

Alternative methods for synthesizing primary amines include the Gabriel synthesis, reductive amination, and the use of azides followed by reduction. The Gabriel synthesis involves the reaction of phthalimide with an alkyl halide, followed by hydrolysis to yield a primary amine. Reductive amination involves the reaction of an aldehyde or ketone with ammonia or a primary amine, followed by reduction. Azides can be synthesized from alkyl halides and then reduced to primary amines using hydrogenation or other reducing agents. These methods offer more control and specificity compared to direct amine alkylation.

What is the SN2 mechanism in the context of amine alkylation?

The SN2 mechanism in the context of amine alkylation involves a bimolecular nucleophilic substitution reaction. The nucleophilic lone pair on the nitrogen of the amine attacks the electrophilic carbon attached to the halide, resulting in the displacement of the halide ion. This occurs in a single, concerted step with a backside attack, leading to the inversion of configuration at the carbon center. The SN2 mechanism is favored for primary and secondary alkyl halides but is hindered for tertiary alkyl halides due to steric hindrance.