Negishi Coupling Reaction - Video Tutorials & Practice Problems

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.