Negishi Coupling Reaction - Online Tutor, Practice Problems & Exam Prep

The Negishi coupling reaction is a cross-coupling process involving a carbon halide and an organozinc halide, facilitated by a palladium or nickel catalyst. The reaction proceeds through three main steps: oxidative addition, transmetalation, and reductive elimination. In oxidative addition, the carbon halide forms a new transition metal complex. Transmetalation transfers the organozinc group to the metal, while reductive elimination generates the desired coupling product and regenerates the catalyst. This reaction is significant for synthesizing stable, conjugated products, adhering to the 18 or 16 electron rule for transition metals.

Negishi Coupling Reaction

In this video, we're going to take a look at the Negishi coupling reaction. Now, the Negishi reaction involves the coupling between a carbon halide and an organozinc halide with a palladium or nickel catalyst. Now the reaction uses a palladium or nickel catalyst in the formation of mainly biaryl or bivinyl products. Now we're going to say here that the Negishi coupling reaction can mirror the generic setup for a cross coupling reaction.

So in our generic cross coupling reaction, we have R₁X which represents our carbon halide. We have R₂ZnX which represents our coupling agent. Through the use of a transition metal catalyst, we have the combining of R₁ and R₂ to give us our coupling product. CX would just be our byproduct. Now if we take a look at the Negishi coupling reaction, we're going to say we still have R₁X, so we still have a carbon halide, and we're going to say here that the R₁ group of the carbon halide is represented by a vinyl, aryl, alkyl, benzyl, or an allyl group. R₂ represents my coupling agent, but more specifically in terms of the Negishi coupling reaction, it represents my organozinc halide. So here R₂ can represent an alkyl group, it could represent a benzyl group, or an alkynyl group.

Now, here we're going to say in terms of this coupling reaction, our C is represented by Zn and X where X is either a chlorine or a bromine. And we're going to say here that the X group of the carbon halide as usual is and together to give us our coupling product here, and then we have our byproduct being created. So, fundamentally, what's happening, looking at it in a simple way, we can say that we have the loss of this X from the carbon halide and the loss of ZnX from my organozinc halide and then what's left is R₁ and R₂ which couple together, combine together to give us our product.

So that's the simple way of looking at this reaction before we even talk about the mechanism. So based on this pattern, look and see if you can do the example that's below. Click on the next video and see how I answer that same example question.

Negishi Coupling Reaction Example 1

So here we need to determine the product from the following Negishi coupling reaction. So remember, what's the simplest way of looking at this? Well, we have our halogen here, so this must be our carbon halide. Here this whole, benzene ring with the 2 methyl groups must represent R₁. Here we have Zn connected to X, which in this case is bromine, so this must be our organozinc halide. So the alkene portion must be R₂. So remember, the X group of our carbon halide and the C group of our organozinc halide are lost in the process so that my R₁ and my R₂ groups can combine together. So we draw out our R₁ group. Then we have this R₂grouping attached. So that would represent the product that I've just formed. So basically the R₁ group is replacing wherever the Zn and X group was in order to maintain the same type of stereochemistry around the alkene double bond. And what we just made is a product that's more conjugated and therefore more stable. Okay. So now that we've gone over the simple way of looking at this coupling reaction, click on the next video and see how exactly does the mechanism work to give us our more conjugated product.

Negishi Coupling Reaction

So the Negishi coupling reaction follows the traditional steps in terms of a coupling reaction and a catalytic cycle. We have our oxidative addition step followed by our transmetalation step ending with our reductive elimination step. So in the oxidative addition step, we have the carbon halide basically, combining with the transition metal complex. Now remember the transition metal has a lone pair which gets from its d orbital electrons. It uses them to connect to the halogen, and then that causes this bond here to break and attach to that same palladium. So what we wind up getting is our palladium with its 2 ligands still attached, now being connected to R₁ and X. So that is our new transition metal complex. Now, we're going to say that the R₂ group of the organozinc compound or zinc halide, transfers from zinc to the palladium complex. Alright. So what's going to happen here is this bond here breaks so that R₂ can attach to the palladium, at the same time the X leaves and attaches to the zinc. So, we wind up getting our palladium still connected to the same 2 ligands, now connected to R₁ and R₂. And then as a byproduct, we have our Zinc connected to 2 halogens. Then finally we have reductive elimination. So this step helps to form the coupling product that we want at the end and it also helps to regenerate our transition metal catalyst to help the whole process begin again. So we're going to have this structure here. We're going to bring it down. So R₁ is going to attach to R₂ and then R₂ is going to let go of the electrons in the bond and give them to the palladium to help regenerate our catalyst. Right. Now, we're going to have R₁ connected to R₂ plus the regeneration of our catalyst. Remember, the 2 main driving forces in terms of these types of coupling reactions are to help make a more conjugated, more stable product, but also, we want the transition metal to follow the 18 or 16 electron rule. By reforming to its original state, it's no longer following the 18 or 16 electron rule so it'll want to begin the process again. And thereby, reattaining either 18 or 16 electrons and also helping to make more coupling product at the end. So remember when it comes to this Negishi type reaction, what's happening fundamentally is that we have a carbon halide, it loses its X group and then we have an organozinc halide which loses its Z and X group. R₁ and R₂ combine together to give us our coupling product at the end.

Determine the product from the following Negishi Coupling Reaction.

Here it says determine the product from the following Gishi coupling reaction. We have our halogen here, so this has to be our carbon halide. And so the ring portion is our R1. Then we have our zinc with bromine. So that is our organo zinc halide structure. So, the alkene portion must be R2. Remember, we're going to lose the X group of the carbon halide and the ZnX group of my organo halide portion and R1 and R2 combine together. Remember, when it comes to the alkene, we want to maintain the same type of E or Z stereochemistry or configuration. Here, we're going to say we have an E configuration, so we want to maintain that. And to be able to maintain that, basically the R1 group attaches in the same position where we had the ZnBr group. So, we're going to write our R2 group. And then we have our R1 group getting attached. So this would be our final product where we help to create a more conjugated product. Now, we also have as our byproduct, the Br connecting to the zinc, but that's not that important. This is what's important. This is our organic product that we made at the end. Alright. Now that we've seen this, attempt to do the next question. So, remember, what's the whole purpose of coupling reactions? What are one of the main driving forces? Here we have 2 halogens present, but only one of them will be involved in this coupling reaction. It's up to you to determine which one will undergo it and why. Once you figure it out, write your answer, come back and see does your answer match up with mine.

Determine the product from the following Negishi Coupling Reaction.

So here it says determine the product from the following Negishi coupling reaction. We have 2 halogens, 2 Brs, but only one of them will undergo the reaction. Remember, these coupling reactions, one of their main driving forces is to help make a more conjugated product. And it's easy to do that if you're using a vanillic halide, a benzylic halide, an aryl halide. If using those types of structures that have double bonds, you can make a more conjugated product. If you're using just a simple alkyl halide though, you're not going to be able to make a product that's more conjugated. So you're not going to fulfill one of your primary driving forces for a lot of these coupling reactions. As a result, we're going to ignore the alkyl bromide and we're going to focus on this bromide because it's connected to an alkene carbon. Therefore, it's a vanillic halide which is better because it can help make a more conjugated product at the end. Now, because they're both alkenes, we have to remember that our stereochemistry E or Z is going to be maintained. This alkene here has an E configuration and this alkene also has an E configuration. So they both need to maintain that E configuration in the product. Remember fundamentally what's happening is we're losing a Br from our carbon which is R1 and we're losing our zinc with halogen which is part of R2. So here I'm going to draw out R1 and it's going to connect to R2. Here, this alkene is still E so its still E like it is here. And, this alkene is still E just like it is right there. So this would be our final product and it's more conjugated. We have more conjugated than what we started with. Therefore, it's more stable. So remember, it's incredibly difficult to use alkyl halides for a lot of these coupling reactions because that doesn't help us make a more conjugated, more stable product. Now that we've seen this, take a look at the last practice question here. So I'm going to give you guys a hint. This step here is similar to a step needed to create Grignard. Remember, to make Grignard, you start out with some type of carbon halide, and what do you react it with to make Grignard? Very similar to what we see here. Once you figure out what A is, then react it with the next set of reagents to create product B. If you get stuck or finish quickly, come back and see, does your answer match up with mine?

Determine compounds A and B from the following reaction sequence.

So I gave you guys a big clue to help you figure out what a is going to be. So, remember to make a Grignard reagent, you have a carbon halide and you react it with magnesium over some type of ether, like maybe, diethyl ether, and that would help make Grignard. Z and X are similar to Grignard. And here what do we have? We have zinc over diethyl ether. So this is going to help make our organozinc halide. So for a, we're going to have this as our product. So zinc comes in and then we're going to have I here. Now you could have zinc with I, but zinc with Cl and zinc with Br are better. But zinc with I is possible as well. Now, this right here, since this is our organozinc halide, this would represent our R2 group. Here, this is our carbon halide so the alkene portion will represent our R1 group. And then we have our palladium catalyst being used in order to create a connection between R1 and R2. Now, remember both of these are alkenes, so you have to make sure that if they have E or Z configurations, they are followed, even in the product. So here, this is an E alkene. This alkene here is not E or Z because both of these carbons are the same. We can't determine which one has higher priority, so it's not E or Z. All we have to do is just make sure that, when we replace the halogen with this R2 group, just place it in the same location. Alright. So we have our R1. The Cl is gone, and now we're about to replace it with the R2 alkene portion. Okay. So there goes that bond. And then we have the alkene portion. And here it's still an E configuration. So this would be our final answer. So remember, the Negishi coupling reaction, all it does is utilize a carbon halide with an organozinc halide in order to create a coupling product. One of the driving forces in this coupling reaction, just like in others, is to help make a more conjugated, more stable product. And remember, another driving force is we use a transition metal catalyst. The transition metal gladly accepts groups so that it can get closer to the 18 or 16-electron rule. By the end of this process, though, it's regenerated in its original form. So to get back to 18 or 16, it'll go through another cycle, another catalytic cycle which will help to create more coupling product.

Here’s what students ask on this topic:

What is the Negishi coupling reaction?

The Negishi coupling reaction is a cross-coupling process that involves the reaction between a carbon halide (R₁X) and an organozinc halide (R₂ZnX) in the presence of a palladium or nickel catalyst. The reaction proceeds through three main steps: oxidative addition, transmetalation, and reductive elimination. In oxidative addition, the carbon halide forms a new transition metal complex. Transmetalation transfers the organozinc group to the metal, and reductive elimination generates the desired coupling product (R₁-R₂) and regenerates the catalyst. This reaction is significant for synthesizing stable, conjugated products and adheres to the 18 or 16 electron rule for transition metals.

What are the steps involved in the Negishi coupling reaction?

The Negishi coupling reaction involves three main steps: oxidative addition, transmetalation, and reductive elimination. In the oxidative addition step, the carbon halide (R₁X) forms a new transition metal complex with the catalyst. During transmetalation, the organozinc group (R₂ZnX) transfers to the metal complex, replacing the halide. Finally, in the reductive elimination step, the desired coupling product (R₁-R₂) is formed, and the catalyst is regenerated to start the cycle again. These steps ensure the formation of stable, conjugated products while maintaining the 18 or 16 electron rule for the transition metal catalyst.

What role does the palladium or nickel catalyst play in the Negishi coupling reaction?

The palladium or nickel catalyst plays a crucial role in the Negishi coupling reaction by facilitating the three main steps: oxidative addition, transmetalation, and reductive elimination. In oxidative addition, the catalyst forms a complex with the carbon halide (R₁X). During transmetalation, the organozinc group (R₂ZnX) transfers to the metal complex. Finally, in reductive elimination, the catalyst helps form the desired coupling product (R₁-R₂) and regenerates itself to continue the reaction cycle. The catalyst ensures the reaction proceeds efficiently and adheres to the 18 or 16 electron rule for transition metals.

What types of products can be synthesized using the Negishi coupling reaction?

The Negishi coupling reaction is versatile and can synthesize a variety of products, including biaryl, bialkyl, and vinyl-aryl compounds. The reaction involves the coupling of a carbon halide (R₁X) with an organozinc halide (R₂ZnX), where R₁ can be a vinyl, aryl, alkyl, benzyl, or allyl group, and R₂ can be an alkyl, benzyl, or alkenyl group. This flexibility allows for the creation of stable, conjugated products that are valuable in pharmaceuticals, agrochemicals, and materials science.

How does the Negishi coupling reaction adhere to the 18 or 16 electron rule?

The Negishi coupling reaction adheres to the 18 or 16 electron rule by ensuring that the transition metal catalyst maintains a stable electron configuration throughout the reaction cycle. During oxidative addition, the metal complex forms, increasing the electron count. In transmetalation, the organozinc group transfers to the metal, maintaining the electron count. Finally, in reductive elimination, the coupling product is formed, and the catalyst is regenerated, returning to its original electron count. This cycle ensures the catalyst remains stable and effective, adhering to the 18 or 16 electron rule.