Conjugate Addition - Online Tutor, Practice Problems & Exam Prep

Enones, formed from aldol condensation, can undergo further reactions through conjugate addition, also known as 1,4-addition. This involves nucleophiles attacking the electrophilic carbon at the 4-position, while strong nucleophiles like Grignard reagents favor 1,2-addition. Common nucleophiles for conjugate addition include cyanide and lithium dialkylcuprate. Notably, Michael reactions and Stork enamine synthesis are specific cases of conjugate addition that yield 1,5-dicarbonyls, which can cyclize to form six-membered rings, showcasing the dynamic reactivity of enones in organic synthesis.

1,2 vs 1,4 Addition

All right guys. Now I want to take this concept one step further and talk about what happens to an enone after it's been reacted. Can it keep reacting? Turns out it can. Now we're going to talk about what's called conjugate addition of enones. Remember that enones are those alpha, beta, unsaturated products of Aldol reactions. Cool. Just before we even get started, I want to just give you a disclaimer that this topic is called a lot of different things. It's also called 1,2 versus 1,4 addition of enones. It's also called nucleophilic addition versus conjugate addition of carbonyls. Just letting you know that if you find it in your textbook or online, it's got a lot of different names but it's all the same concept. What the concept is that once an aldol condensation is completed and you make your enone, this is your enone, an electrophilic carbonyl still remains. You still have this very partial positive. Do you think that it has to stop reacting? No. This thing can react again. Not only that, not only is it susceptible to nucleophilic attack the way that a normal carbonyl would be. But now it actually has a second electrophilic region. How does that work? Because if you look at the resonance structure of this molecule, you could always push the electrons up to the O. That would give me a positive and a negative. That's just a resonance structure of a carbonyl. Another resonance structure would be now that we have this conjugated portion, we could move this double bond into here and then I could get the positive out here. That means that I have an electrophilic region at the 2 position. If you consider my oxygens to be 1, then at the 2 position, I have an electrophilic region. I have a 1, 2 electrophile. But I also have an electrophilic position at the 4 if you're going to consider my oxygen by 1. This would be a 1,4 electrophile. How do I know if I'm attacking with another nucleophile, how do I know if I'm going to attack the 1,2 or the 1,4? The 1,2 is what we call the nucleophilic addition. This is something you should be extremely familiar with because we've been doing this a lot. Nucleophilic addition. The 1,4 addition because it had to do with a conjugated compound that resonated, this is what we call conjugate addition. When I say 1,2 versus 1,4, that's the same thing as saying nucleophilic versus conjugate addition. The answer is it's complicated. It's going to depend on the nucleophiles. Specific nucleophiles are going to favor the nucleophilic addition, the 1,2. And specific nucleophiles, other nucleophiles are going to favor the 1,4. Let's just hash these out. Nucleophilic addition is actually going to be the minority of reactions because that conjugate position is very reactive. There are really only 2 reactions that I know of that are going to want to do this nucleophilic addition on an enone. That's going to be 1, Grignard's. Oh man. I'm forgetting, sorry guys. Grignards. Grignards. And 2 organolithiums. I'm going to put RLi. These are extremely strong nucleophiles that are going to go for this site just like always and we're going to wind up getting a substituted alcohol, except that the alcohol happens to have a double bond on it. Conjugate addition is going to be the majority of additions. Pretty much any other nucleophile besides a Grignard or an organometallic or an organolithium is going to attack here at the 4th spot. What I'm giving you here is specific versions of that. Let's just say you took a generic nucleophile. The product of a generic nucleophile attacking that 4th position would look like this. Notice that there's no more double bond. It's just going to be in that 4 position. Just so you know, some examples of general nucleophiles that could do this would be there are a lot of them. But specifically, CN negative is a very common example. Also a Gilman reagent, so it'll be R₂CuLi. That's also called lithium dialkylcuprate or Gilman reagent. Notice that it's easy to confuse this with these guys but it's different. The lithium dialkylcuprate we've mentioned before is weaker than a normal organometallic. I'm going to expect it to add with my conjugate addition, not with my nucleophilic addition. Honestly, just make something up. There are a lot of different nucleophiles that could react there. 2 specifically that I want to add to this list that are very important are the nucleophiles that are going to make a Michael reaction and a Stork enamine synthesis. Because it turns out that a Michael reaction is going to be a conjugated addition of an enone with an enolate. A Michael reaction specifically is when you use an enolate to attack that 4th position. Interesting. When you use an enolate to attack that 4th position, you're going to wind up getting even more carbons attached to each other. An enolate would be specifically a Michael reaction. A Michael reaction is a type of conjugate addition but it's only of enolates. Then we have Stork enamine synthesis. Stork enamine synthesis is when you use an enamine. Remember what an enamine looks like. Let's say a double bond, something like this. I'll make it a really flat cyclohexene there. When you use a Stork enamine synthesis, again, this can be a nucleophile. You can get electrons going down from the end. It can be a nucleophile and it can attack that 4th position. What's so cool about both of these reactions is that both the Michael reaction and the Stork and amine synthesis make the same exact thing. They make 1,5-dicarbonyls. Now 1,5-dicarbonyls might not sound like they're very special. It's like why is that so special? It's just random carbonyls in different places. But if you think about it, 1,5-dicarbonyls are special for one reason. They can cyclize. They can cyclize and self condense. Why? Because they like to form 6-membered rings. The rabbit hole is just getting deeper because now I'm telling you that the product of an aldol can react with stuff. Now I'm telling you that the product of an aldol can react with another aldol to make an aldol product that can cyclize through aldol. Obviously, there's a lot going on. These things can just keep on reacting and reacting. At some point, we've got to call it quits cause this could just go on forever. But there are a few more reactions that are specifically going to need 1,5-dicarbonyls that I want to teach you because most textbooks or professors don't really put it together, don't explain how the Michael reaction and the Stork enamine synthesis both really do the same exact thing to get to the 1,5-dicarbonyl. Other than that, you guys understand that your nucleophilic or your nucleophilic addition just happens with these 2 reagents. Everything else adds conjugate. Let's just add one more we forgot to put the enamine here. Enamine is another one we could use. Let's just put a random one, so just you guys can see that it's like everything. For example, N₃ negative. Any nucleophile, pretty much any nucleophile could react at that 4 position and cause that reaction to happen. That being said, let's move on to the next video.

Here’s what students ask on this topic:

What is conjugate addition in organic chemistry?

Conjugate addition, also known as 1,4-addition, is a reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound (enone). This process involves the nucleophile attacking the electrophilic carbon at the 4-position, resulting in the addition across the conjugated system. This type of addition is common with nucleophiles like cyanide (CN^-) and lithium dialkylcuprate (R₂CuLi). Conjugate addition is significant in organic synthesis as it allows for the formation of complex molecules, such as 1,5-dicarbonyls, which can further cyclize to form six-membered rings.

What is the difference between 1,2-addition and 1,4-addition in enones?

1,2-Addition and 1,4-addition refer to the positions where nucleophiles attack an enone. In 1,2-addition, the nucleophile attacks the carbonyl carbon (position 2), leading to the formation of a substituted alcohol. This type of addition is favored by strong nucleophiles like Grignard reagents (RMgX) and organolithiums (RLi). In contrast, 1,4-addition, or conjugate addition, involves the nucleophile attacking the β-carbon (position 4) of the enone. This is favored by weaker nucleophiles such as cyanide (CN^-) and lithium dialkylcuprate (R₂CuLi), resulting in the addition across the conjugated system.

What are some common nucleophiles used in conjugate addition reactions?

Common nucleophiles used in conjugate addition reactions include cyanide (CN^-), lithium dialkylcuprate (R₂CuLi), and enamines. These nucleophiles are less reactive compared to strong nucleophiles like Grignard reagents and organolithiums, making them suitable for attacking the β-carbon (position 4) of α,β-unsaturated carbonyl compounds (enones). Additionally, enolates and enamines are used in specific conjugate addition reactions such as the Michael reaction and Stork enamine synthesis, respectively, to form 1,5-dicarbonyl compounds.

What is a Michael reaction in organic chemistry?

A Michael reaction is a type of conjugate addition where an enolate ion acts as the nucleophile and adds to the β-carbon of an α,β-unsaturated carbonyl compound (enone). This reaction results in the formation of a 1,5-dicarbonyl compound. The Michael reaction is significant in organic synthesis because the 1,5-dicarbonyl products can undergo further reactions, such as cyclization, to form six-membered rings. This reaction is a key method for forming carbon-carbon bonds and constructing complex molecular architectures.

What is Stork enamine synthesis?

Stork enamine synthesis is a method in organic chemistry where an enamine acts as a nucleophile in a conjugate addition reaction. The enamine attacks the β-carbon of an α,β-unsaturated carbonyl compound (enone), resulting in the formation of a 1,5-dicarbonyl compound. This reaction is similar to the Michael reaction but uses an enamine instead of an enolate. The 1,5-dicarbonyl products formed can further cyclize to form six-membered rings, making Stork enamine synthesis a valuable tool for constructing complex molecules in organic synthesis.