Hartwig hunts haloarene oxidative addition with Ni(0) phosphines
Citation:
Pierson, C.N.; Hartwig, J.F. Mapping the mechanisms of oxidative addition in cross-coupling reactions catalysed by phosphine-ligated Ni(0). Nat. Chem. 2024, 16, 930-937.
https://www.nature.com/articles/s41557-024-01451-x
Old paper today as I go through papers I missed from 2024. This one is too good not to do!
Summary Figure:
Background:
Oxidative addition of low-valent nickel species into aryl halides works. We know it works, because there are tens of thousands of papers that rely on this elementary step as the backbone of their catalytic cycles. However, just because we know that it works, doesn't mean that exactly how it works is known. The difficult question to answer is: how do the electrons move? There are four reasonable pathways for oxidative addition:
In order:
(Top left) Nickel can attack the π* orbital of the aromatic system in an addition-elimination sequence common in SnAr reactions.
(Top right) Nickel can conduct halogen atom abstraction, attacking the C-X σ* orbital on only the halogen and producing an aryl radical, which quickly recombines to form the final Ni(II) complex
(Bottom left) Nickel can approach the C-X bond and form a sigma complex, attacking the C-X σ* orbital on both atoms.
(Bottom right) Nickel can donate an electron to the aryl halide in a single electron transfer, forming a radical anion and eventually leading to fragmentation of the C-X bond to form a halide anion and an aryl radical.
How they did it:
There are really 2 types of experiments performed in this paper: competition experiments, and radical clocks.
Competition experiments are where you add 2 possible reactive partners and one catalyst, and see which partner reacts first.
In experiment A, they reacted a nickel(0) catalyst with 1 equivalent of a very electron deficient aryl chloride and also 1 equivalent of an electron rich aryl bromide in the same pot. Their hypothesis is that the SET mechanism (from the bottom right in the background figure) involves formation of an electron rich radical anion. If this is the mechanism, the electron poor aryl chloride should react first, because it can tolerate the extra electron density. (Note that it would also react first in the SNAr mechanism for a similar reason). Their results, which showed the aryl bromide reacted first, are consistent with the mechanism not being SET.
In experiment B, they reacted a nickel (0) catalyst with 1 equivalent of an easy to reduce aryl bromide and a more difficult to reduce aryl iodide. Their hypothesis is that the concerted oxidative addition mechanism (from the bottom left in the background figure) should favor the reactivity of the aryl iodide, as the bond strength of the C-I bond is lower than that of the C-Br bond. If concerted oxidative addition ins the mechanism, the aryl iodide should react first. Their results, which showed the aryl bromide reacting first (although the aryl iodide is close behind), are consistent with the mechanism is SET.
This is why studying elementary steps is hard!
To solve this out, they use a very nice radical clock. Radical clocks are functional groups that can be added to molecules that will undergo some intermolecular reaction with radicals. If your molecule forms a radical, and then that radical sits around for some amount of time, it will react with the functional group. The amount of time is dependent on the functional group, and the rate of that intermolecular reaction can be known beforehand, so you know (roughly) how long that radical remained without reacting. One of the most common kind of radical clocks is a tethered alkene, which will cyclize to form X-membered rings and another radical (which can be quenched in a number of ways). The rate depends on the size of the ring, so you can hone in on the lifetime of the radical.
If they run the reaction with the radical clock attached, and they get one of these cyclized products, then an aryl radical must have formed (probably via the SET mechanism). If they don't get the cyclized products, then either (a) the reaction did not proceed via an aryl radical or (b) the recombination of the aryl radical with the nickel complex is faster than the rate of cyclization. This is one of the problems with radical clocks- they cannot confirm that you didn't have a radical, only that the radical must not have existed for very long. This is the classic scientific case of being unable to prove a negative, you cannot say with certainty the radical did not exist. Fortunately for the researchers, they got some positive results.
The first thing they tested was what happened if they changed the halide. The figure somewhat speaks for itself:
Wow. Complete reversal of products going from the chloride to the iodide, and the bromide is perfectly stuck in the middle. They did a similar test with substituents on the aryl ring in like a Hammett plot, to similarly incredible results:
Complete reversal of selectivity going from electron-rich to electron poor. Again, wow.
They also tested how the identity of the ligand affects the catalyst's preference for concerted oxidative addition versus the SET pathway, and found that the aryl radical pathway was more common with more electron donating ligands, which makes sense. The SET mechanism makes the aryl halide into a radical halide, but it also requires making the nickel into the positively charged radical cation. A more electron rich nickel complex will be able to better tolerate that positive charge.
Finally, they also showed that the SET mechanism preferred polar solvents (again, because it makes charged radical anions and cations) while the concerted mechanism preferred nonpolar solvents.
That's a lot of mileage out of this one radical clock.
Finally, the researchers did some additional competition experiments to show all these aryl radicals form via SET to the aryl halide and not via the halogen atom abstraction mechanism (from the background figure, top right). That mechanism would also involve the formation of the aryl radical, so they did need to rule it out, mostly by showing that the key factor determining the rate of reaction was the reduction potential of the aryl halide, not the strength of the C-I bond. If halogen atom abstraction was the mechanism, then the weaker C-I bond would react first. If SET was the mechanism, the more reducible aryl halide would react first.
Initial Questions and Key Findings:
1. What is the predominant mechanistic pathway for the oxidative addition of Ni(0) phosphine complexes into aryl halides?
A: Both concerted oxidative addition and SET are feasible and operative mechanistic pathways.
2. What factors control which mechanism is most likely to be operating in a given system?
A: The reduction potential of the aryl halide and the electron richness of the nickel catalyst. Aryl halides that are easier to reduce (like aryl iodides or electron poor aryl bromides) proceed via SET. Electron rich catalysts (with trialkyl phosphines) enable SET, while less electron rich catalysts (like triaryl phosphines) prefer concerted OA.
Takeaways:
Absolutely wonderful mechanistic work. When radical clocks work, they are incredibly effective at describing the presence and reactivity of radicals in a system.
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