Lactones, Lactams and Cyclization Reactions: Videos & Practice Problems

Lactones and lactams are cyclic esters and amides formed through cyclization reactions of hydroxycarboxylic and amino carboxylic acids, respectively. Stable 5- and 6-membered rings are favored, while smaller rings like 4-membered lactams are less stable and may require additional reagents. Naming involves Greek letters indicating the position of the original substituent, such as delta lactone or beta lactam. Beta lactams, found in antibiotics like penicillin, disrupt bacterial cell membranes, highlighting their significance in pharmaceuticals.

Lactones and Lactams

Now I want to discuss lactones, lactams, and cyclization reactions. It turns out that esters and amides can be made to form rings. When you have a cyclic ester or a cyclic amide, these molecules have their own names that are very prevalent in organic chemistry and that you should be aware of. A cyclic ester is called a lactone. A cyclic amide is called a lactam. The way that you get these is through the cyclization of either hydroxycarboxylic acids. Here I have an example here. A hydroxy group on a carboxylic acid or amino carboxylic acids as I have here. These molecules are going to form rings spontaneously when the rings can be 5 and 6 membered. Why? Because these are very stable rings. For example, here I have delta hydroxyvaleric acid. Notice that when delta hydroxyvaleric acid cyclizes, what happens is that this O comes in, attacks the carbonyl, you get a tetrahedral intermediate, but eventually, you kick out this OH. This will just be basically an esterification reaction. Notice that the size of your ring is going to be 1, 2, 3, 4, 5, 6. That's exactly what we would expect. We get a 6-membered ring. These equilibrium arrows that I drew are purposeful. I show that they're pretty much in perfect equilibrium because if you can make a 5 or 6 membered lactone, that's definitely going to form an equilibrium. In fact, that actually happens in our bodies. In our bodies, sugars are forming lactones all the time. Sugars can form 6-member rings and they form lactones all the time in your body. Now let's go on to lactams. Lactams, same idea. Nitrogen could come in, do a nucleophilic acyl substitution. Eventually, you kick out the OH and you can make a form of a ring. Now this one, this equilibrium arrow is also purposeful because notice that I'm making a ring smaller than 5 members. In this case, I'm making a 4-member ring, that is much, much less stable. In fact, there's a possibility that this doesn't happen on its own at all because of the fact that it's just so strained that it would prefer to exist as a chain. It might take some extra help, some extra reagents to make it into a 4-membered ring. Makes sense so far? 5 or 6 is good. Anything less than that is bad. Also, anything bigger than that, also not very favored. Now we get into naming. How do we name these guys? It turns out that the functional group of a lactone or a lactam can also be specifically named by the size of the ring. But instead of saying it's a 6 carbon lactone or whatever, what we do is we use the Greek symbols from where the original substituent would have been. To make this lactone here a 6-membered ring, that means that my alcohol would have had to be on the alpha, beta, gamma, and delta carbon. Since my alcohol was originally on the delta carbon, this would be called a delta lactone. If you're ever confused about what type of lactone or lactam you have, you could always just start counting from scratch. You could just say the carbon next to the carbonyl is my alpha and then you could just go from there. Just remember that you only count carbons. It's alpha, beta, gamma, delta. We're done. This is a delta lactone. Same thing with lactams, exactly the same except that now since this one's smaller, this is what we would call a beta lactam. Now not to bore you but beta lactams are really important guys because beta lactams are found in pharmaceuticals all the time, in antibiotics. Beta lactams are extremely good at disrupting the cell membranes of bacteria. That's why they work really well in your body. That's what penicillin is. It's a beta lactam. That is really all you need to know in terms of the general features of lactones and lactams. Why don't you guys go ahead and try to cyclize this molecule, see what you get, and see if you can generalize what the functional group is. I don't need you to name it because that's way beyond the scope of this course. You don't need to name the exact molecule. But tell me what type of functional group it is and the Greek letter in front of it. Do that now.

Cyclization Reaction

Just following the general mechanism of nucleophilic acyl substitution, my nitrogen could attack. I would eventually get a tetrahedral intermediate which would then kick out the OH. In terms of the size of the ring, the size of the ring would be 1, 2, 3, 4, 5. There's a chance that this could form spontaneously. What I would get is a 5-membered ring with a nitrogen on one side and I just have to add the leftover groups. I know that I would now have a methyl group on that nitrogen and I would have a double bond between the 2 and the 3 that looks like it's right there, we're done. Oh wait. No, I messed up because it was 23. It was between 34. So it would actually be right here. You might be wondering what happened to this H. Don't worry about it. It got lost in the mechanism. If we had to categorize this functional group in general, what would we call it? I don't want the name. The name is very complicated. We would call it an alpha, beta, gamma. This is going to be a gamma lactam. Not quite as cool as beta lactam. Sorry. Cool. Awesome, guys. Now I just want to talk about one more reaction then we'll be done with this page.

Cyclic Anhydrides and Imides

The whole point of the sequence of reactions behind me isn't for you to memorize this exact sequence. That's not what I'm interested in. I'm just trying to give you an overview of different cyclizations that we might have missed to this point. The first one is really important which says that you can use a diacid. Ten points for whoever can remember what's the name of that diacid. Remember, oh my science. This would be the 4-carbon diacids. This would be succinic acid. Succinic acid in the presence of heat can self cyclize and make a cyclic anhydride. Remember I was telling you guys that anhydrides could be made by the combination of 2 carboxylic acids coming together. That's what would happen with a diacid except it would be a ring. That's the first part.

It turns out that anhydrides, if you use a combination of amine with water, you could make a compound that has both the combination of amide on one side and carboxylic acid on the other. How does that work exactly? Think about it like imagine that you have 2 equivalents of your ammonia. By the way, this is supposed to be NH3. Wow, my apologies guys. This is supposed to be NH3 not NH₂. Say you have 2 equivalents of NH3. You act on both sides and you get 2 amides. You get like a diamide. Then you could use water to replace only one of them. You'd get an amide on one side and a carboxylic acid on the other. What's interesting about that is that if you have a situation where you have an amide and a carboxylic acid on the same chain, you can then use heat to bring those together and make what's called an imide. An imide is a new functional group that we haven't talked about. Think of it almost like an anhydride but with a nitrogen in the middle. It's like an anhydride with nitrogen. Makes sense?

Now guys, it turns out that this amide is actually kind of important because this amide is made out of succinic acid. That means that this is actually called succinamide. Has anyone heard of that's right where I am. Has anyone heard of succinamide before? Does that name sound familiar? It turns out that a reagent that we've used a lot in organic chemistry so far was succinamide. Do you guys remember NBS? NBS. What did NBS stand for? NBS was n-bromo succinamide. It's literally this compound but instead of having an H there, having a Br there. Isn't that cool? Now you guys know how to make a succinamide by using a diacid. I'm not asking you to memorize this whole sequence, just to be familiar with the parts of it. Awesome. Let's move on to the next video.

Here’s what students ask on this topic:

What are lactones and how are they formed?

Lactones are cyclic esters formed through the cyclization of hydroxycarboxylic acids. When a hydroxy group (-OH) on a carboxylic acid (R-COOH) reacts with the carbonyl group (C=O) of the same molecule, it forms a ring structure. This reaction is favored when the resulting ring is 5 or 6 members, as these sizes are more stable. For example, delta-hydroxyvaleric acid can cyclize to form a 6-membered lactone. The process involves the nucleophilic attack of the hydroxyl oxygen on the carbonyl carbon, forming a tetrahedral intermediate, which then eliminates water to form the lactone.

What are lactams and why are beta lactams important in pharmaceuticals?

Lactams are cyclic amides formed through the cyclization of amino carboxylic acids. In this process, the amino group (-NH2) attacks the carbonyl group (C=O) of the same molecule, forming a ring. Beta lactams, which are 4-membered rings, are particularly important in pharmaceuticals because they are found in many antibiotics, such as penicillin. Beta lactams disrupt the cell membranes of bacteria, making them effective in treating bacterial infections. Despite their small ring size and inherent strain, beta lactams are crucial in medical applications due to their antibacterial properties.

How do you name lactones and lactams based on ring size?

Lactones and lactams are named using Greek letters to indicate the position of the original substituent relative to the carbonyl group. For lactones, the carbon next to the carbonyl is the alpha (α) carbon, followed by beta (β), gamma (γ), and delta (δ). For example, a 6-membered lactone formed from a hydroxy group on the delta carbon is called a delta lactone. Similarly, lactams are named in the same way. A 4-membered lactam, where the amino group was originally on the beta carbon, is called a beta lactam. This naming convention helps in identifying the structure and size of the ring.

What is the significance of cyclization reactions in organic chemistry?

Cyclization reactions are significant in organic chemistry because they allow the formation of cyclic compounds, which are often more stable and have unique chemical properties compared to their linear counterparts. These reactions are crucial in the synthesis of various natural products, pharmaceuticals, and polymers. For example, the formation of lactones and lactams through cyclization of hydroxycarboxylic and amino carboxylic acids, respectively, is a key step in producing many biologically active compounds. Cyclization can also lead to the formation of anhydrides and imides, expanding the diversity of functional groups available for chemical synthesis.

What are the stability factors for lactones and lactams?

The stability of lactones and lactams depends on the ring size. 5- and 6-membered rings are generally more stable due to minimal ring strain and favorable bond angles. Smaller rings, such as 4-membered lactams, are less stable because of increased ring strain and angle strain. Larger rings can also be less stable due to entropic factors and the difficulty in maintaining a planar structure. The stability of these cyclic compounds is crucial in determining their formation and reactivity in chemical and biological systems.