Lactones, Lactams and Cyclization Reactions

Concept: Concept: Lactones and Lactams

6m
Video Transcript

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 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, a hydroxyl 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 five and six-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. It would just be basically an esterification reaction. Notice that the size of your ring is going to be six, and that's exactly what we would expect. We got a six-membered ring. These equilibrium arrows that I drew are purposeful. Actually, they're pretty much in perfect equilibrium because if you can make a five or six-membered lactone, that’s definitely going to form an equilibrium. In fact, that actually happens in our bodies. Our body’s sugars are forming lactones all the time. Sugars can form six-membered 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. You can make a four-membered ring. This equilibrium arrow is also purposeful because notice that I'm making a ring smaller than five members. In this case I’m making a four-membered 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 strain that it would prefer to exist as a chain. It might take some extra help, some extra reagents to make it into a four-membered ring. Makes sense so far? Five and six 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 the ring. But instead of saying it's a six-carbon lactone, what we do is we use the Greek symbols from where the original substituent would have been. For an alcohol, to make this lactone here a six-membered ring, that means that my alcohol would have had to be on the 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 can just go from there. Just remember that you only count carbon. This is a delta-carbon. Same thing with lactams, exactly the same except that now since this one is smaller, this is what we would call a beta-lactam.
Not bore you, but beta-lactams are really important because beta-lactams are found in pharmaceuticals all the time, in antibiotics. Beta-lactam 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 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.  

Lactones, Lactams and Cyclization Reactions Additional Practice Problems

Predict the organic product(s) of the following reaction. When appropriate, be sure to indicate stereochemistry. If more than one product is formed be sure to indicate the major product, if stereoisomers are produced in the reaction be sure to indicate the relationship between them. Draw the answer in skeletal form.

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For the reaction below, draw the structure of the appropriate compound in the box provided. Indicate stereochemistry where it is pertinent.

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Complete the following reaction supplying the missing product and showing correct regio- and stereochemistry where applicable. If a racemic or diastereomeric mixture forms show all stereoisomers; if no reaction takes place, write N.R.

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Complete the following reaction supplying the missing product and showing correct regio- and stereochemistry where applicable. If a racemic or diastereomeric mixture forms show all stereoisomers; if no reaction takes place, write N.R.

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Give a stepwise mechanism for the following lactone formation:

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Complete the following reaction supplying the missing product and showing correct regio- and stereochemistry where applicable. If a racemic or diastereomeric mixture forms show all stereoisomers; if no reaction takes place, write N.R.

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Provide the missing reagents to complete the following transformation.

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Provide the mechanism for the following reaction. 

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Provide a detailed mechanism for the following reaction. All arrows and structures of intermediates must be clearly indicated. 

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Draw a reasonable mechanism for the reaction below. 

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Choose the reaction coordinate that best describes the following reaction.

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Complete the following reaction with the correct structure of the product. Don’t forget to specify the stereochemistry.

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Propose two mechanisms for the following reaction. 

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Predict the major product(s) for the reaction below. 

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Predict the product for the following reaction

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Which is a γ lactam?

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Shown below is a penicillin derivative meticillin (formerly methicillin). Which of the shown regions of this molecule reacts with the bacterial enzyme transpeptidase, which in turn inhibits cell wall synthesis and kills the cell?

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