Shi surprises some with contra-electronegative carbomagnesiation

Citation:

Ye, X.; Sun, B.; Shi, S.-L. Contra-electronegativity transmetallation unlocks alkene carbomagnesiation to access quaternary stereocenters. Nat. Chem. 2026, ASAP. https://doi.org/10.1038/s41557-026-02073-1

Summary Figure:

 

Background:

Transmetalation (spelled with one L, by the way) is one of the elementary steps of organometallic compounds. It is one of the least studied elementary steps due to the difficulty developing reliable mechanistic probes. Several mechanisms (with different stereochemical outcomes) are known:

 

(Taken from Liang, H.; Zhang, X.; Morken J. P. Stereospecific cross-coupling reactions: Programmed assembly of chiral molecules by reaction of chiral reagents. Sci. Adv. 2025, 11, eadz3901. https://www.science.org/doi/epdf/10.1126/sciadv.adz3901  James Morken has some great chemistry that will be highlighted in the next blog post!)

Additionally, it is known that transmetalation is thermodynamically favorable when moving the carbon fragment from a low-electronegativity metal to a high-electronegativity metal (e.g., Mg to Ni). This makes intuitive sense, as a more electronegative atom is going to better stabilize the negative charge on the carbon fragment. Additionally, this can be rationalized using hard-soft acid-base theory. Taking the example from the summary figure, the bond between the carbon atom and the more electronegative metal center (in this case, Ni) is going to be more covalent and "soft", compared to the bond in the Grignard reagent, Mg-C. At the same time, the new metal-halogen (or pseudohalogen) bond formed (Mg-X) is usually more ionic and "hard". Creating two bonds that have better hard/soft matching provides a thermodynamic driving force that forces transmetalation in the "right direction". 

The ability to put carbon fragments on transition metal centers via transmetalation with Grignard reagents is what originally allowed  Kumada to realize that nickel could do cross-coupling (see my post on the discovery of cross-coupling: https://alwaysbecoupling.blogspot.com/2025/05/looking-back-how-was-cross-coupling.html)

However, today's paper is doing cross-coupling in the opposite direction, moving carbon from nickel to magnesium. This contra-electronegativity transmetalation is unintuitive and usually thermodynamically unfavorable, so how did they do it?

How it works

What the authors were trying to do is a dicarbofunctionalization reaction:  

 

This can be looked at as an "interrupted" cross-coupling reaction. There is a nucleophilic reagent (ArMgX) and an electrophilic reagent (Ar-X), but rather than being cross-coupling with each other, migratory insertion into an alkene occurs first. 

 

In this excerpt of their catalytic cycles, I've highlighted the normal cross-coupling product in blue, which does not involve the alkene at all. Highlighted in red is the expected dicarbofunctionalization product. 

Part of their strategy for this reaction was to use bulky, chiral NHC-ligands, which would allow for the enantioselective construction of quaternary centers. This work was successfully accomplished and published previously (https://www.nature.com/articles/s41929-022-00854-8)

They had noticed some reactions had low yields, and they did some work to identify the deleterious side pathway. My guess is they saw "reduction"

 

And then tried quenching with D2O to see if it was being quenched by a hydrogen atom (one electron chemistry) or a proton (two electron chemistry) and saw that it was the proton) 

 

Which means that they were forming the organometallic intermediate in solution. The fact that they saw greater yield of the quenched product than the nickel loading is strong evidence that it was not merely getting trapped as the alkyl-nickel species, but forming the alkyl-magnesium species instead. 

A little bit of optimization (notably, changing the solvent to THF) allowed them to get the yield of the organomagnesium reagent up to 98%, likely by increasing the solubility of the organomagnesium intermediates. 

 So why does this work?

We have to look at the competing processes from the key intermediate:

 

First, there is no possibility of beta-hydride elimination from this intermediate, as there are no beta-hydrogens. My guess is that if there was any possibility of beta-hydride elimination, it would be extremely rapid, due to the ability to release the steric pressure of the system. 

Second,  there is the possibility of the original desired transmetalation to put form another nickel-carbon bond

 

However, that R group is almost certainly larger than the halogen or pseudohalogen attached to the nickel prior. Additionally, the authors generally draw this as a cationic nickel species, with a triflate counterion not attached to the nickel. 

 

The combination of the adjacent quaternary carbon with the extremely bulky NHC ligand makes the steric hindrance a major obstacle in this transmetalation, making it mostly unfeasible. Notably, it works enough under some conditions that they were able to previously turn it into a synthetic method, but it is still challenging. 

This opens up door #3, which is to do a contra-electronegativity transmetalation to move from nickel to magnesium. The relief from steric strain provides enough of a thermodynamic driving force to enable this process. 

 

 Overall, this process amounts to a way to make very complicated Grignard reagents, and the authors showed a ton of possible products that could be made from this, which I will not belabor here.

Conclusions:

One of the great jokes in organic chemistry is to say "oh, it's probably either a steric or an electronic effect." If it's not sterics, it's probably electronics (and vice versa). This is a great application of this idea. Transmetalation is usually thermodynamically driven due to an electronic effect, but that does not mean that it cannot be driven by a steric effect, and this can be used to overwrite the more common reactivity. 

Another good lesson from this paper is to understand why your byproducts are forming. Figuring out that the side product from the previous paper was the organomagnesium reagent enabled this entire second highly successful project. Understanding exactly what is going on in your flask is what enables good science.