Cross-Coupling of Chlorides with Rotating Metal Rods and Magnets

 Citation:

 Feng, X.; Li, X.; Zhang, N.; Zhang, L.; Sun, F.; Liu, H.; Zhao, Z.; Li, X. Cross-Electrophile Coupling of Aryl Chlorides with Alkyl Chlorides Using Rotating Magnetic Field and Metal Rods. J. Am. Chem. Soc. ASAP. https://doi.org/10.1021/jacs.5c00381

Summary Figure:

  

Background:

Cross-electrophile coupling (XEC) reactions require three components to work: (1) a catalyst (2) a source of electrons (3) a way to activate the reductant. The catalyst is fairly self explanatory. Because XEC reactions are overall reductive transformations, there must be some ultimate place to get the electrons from. This can be metal powders, electrochemical metal anodes, organic reductants like (Bpin)2 or TDAE, amines, silanes, organometallic reagents, or many other reagents. Finally, there must be a way to get the electrons from the reductant to the catalyst and therefore the substrates.

A lot of the divisions in the field are sorted based on the techniques used to activate the reductant. For example, the entire point of photochemical XEC reactions is to find a way to activate a reductant. Electrochemical XEC reactions have exploded in popularity because they offer a new method to transfer electrons to a catalyst.

Often, this process looks simple but has surprisingly complex. For example, the surface of heterogenous metal powders can directly transfer electrons to the nickel catalyst. However, theoretically you can throw in a bead of metal in the reaction and that can transfer the electrons over. However, this usually doesn't work- the surface of the metal must be reactive, which means you have to start looking at things like particle size and additives to scrub the surface, etc. Additionally, theoretically any metal or alloy should be able to be used, including super cheap ones like steel. The iron in the steel has electrons to give, so why not? 

What the Li lab has come up with is a way to use a rotating magnetic field to activate steel rods in a nickel-catalyzed cross-electrophile coupling reaction between aryl chlorides and alkyl chlorides. The electron source is the steel rods, and the way to activate them is to use a rotating magnetic field to polarize the electron distribution, enabling them to be used for electron transfer. 

How it works (I think):

Caveat: I am not a physicist. My description of how the magnets work is almost certainly inaccurate, but hopefully is close enough to be understandable. 

This is the author's description: "Specifically, we envisioned that the cutting of the magnetic induction line in the external magnetic field could generate a polarized distribution of the free electrons in metallic conductors" I'm going to break this down as much as I can.

This is the best simple video that I've found to explain the general idea: https://www.youtube.com/watch?v=FehUCQKKRwo

First, one of the basic rules of electricity and magnetism is that a moving magnetic field generates a current, and a moving current generates a magnetic field (Faraday's law). If you move a magnet next to a conductive material, it generates an electromagnetic force. If you have a closed circuit, this force moves the electrons and generates a current. Here is a quick diagram:

 

If you move a magnetic field, a current is generated that opposes the direction of the magnetic field. This is also the idea of "nature abhors a change in flux".

If we rearrange the system a little bit to use a rotating magnetic field:

 

Once again, it should generate a current in our loop. 

Theoretically, you can use this property to move electrons around in a closed system. If we then take away the connections between the ends of the conductive material, then the energy that would go into the current still has to go somewhere. My understanding is this energy is used to separate the positive and negative charges within the conductive material, somewhat like a capacitor:

 

Obviously, an actual capacitor requires an insulator to keep the charges separated, because they want to go right back together. Most of the time, the charges will snap back together and release the energy as heat. However, the general principle of the idea is that you can use a rotating magnetic field to generate a polarized metal rod that has one side with too many electrons. This should change the reduction potential of the surface, enabling it to do chemistry that normally the metal rod can't do. We've activated our reductant.

The authors originally applied this to a trifluoromethylation reaction (https://pubs.acs.org/doi/10.1021/jacs.4c05987), but they hypothesized it could be useful for XEC reactions:

 

Theoretically, this method can be used to activate an iron rod, which theoretically can be used as a reductant in an XEC reaction, but does not normally work.

Initial Questions and Key Findings:

1. Does this work? Can you use iron rods as reductants in an XEC reaction by putting them in a magnetic field?

A: Yes. The authors apply it to an XEC reaction with aryl chlorides and alkyl chlorides, a fairly useful synthetic transformation, but also one that has been established previously. The goal of this paper is not to make organic molecules that have never been made before, but to do it with a new technology. 

 

2. Is this reaction highly specific to one system, or can it be used for this general transformation?

A: First, the goal of the authors is to see what general types of organic transformations this reaction is good for. Their initial report on this was on a completely different type of reaction, and now they are trying to use it for an organometallic cross-coupling reaction. Because this is a JACS paper, they reported that the reaction works on ~50 different substrate combinations, including a few drug-like molecules. 

3. How does the reaction work (outside of the whole magnetic field/iron rod stuff)?

A: The authors don't go into huge detail, but they propose the reaction proceeds through the same common mechanisms for Csp2-Csp3 XEC reactions: either a radical chain mechanism or a sequential reduction mechanism. They also propose the alkyl chlorides are transformed into alkyl bromides in situ by the TBABr salt, which is also precedented for this type of this reaction. The difference between this reaction and previously established similar reactions is the identity of the reductant, not the role. The iron rod is still acting to reduce Ni(I) and Ni(II) species to lower valencies.

 

4. Are we absolutely, 100% positive that the magnetic field is necessary? What about [insert other explanation here]? 

As you might expect from a reaction demonstrating a new technology, there are are lot of control reactions and mechanistic studies. The figure listing their mechanistic studies goes up to P, and that's not including the optimization table. I'm going to list out the general questions and the experiments that try to answer them, in roughly the order I think is most pressing:

A) You have an iron rod in the reaction, what happens if you don't apply the magnetic field?

There is 0% yield with no magnetic field. 

B) You have a bunch of iron rods in the reaction rubbing up against each other, isn't that generating heat? What if you cool the reaction down? What if you heat the reaction up?

The rotating magnetic field forces the iron rods to jump around in the reaction tube, rubbing up against each other. The authors have a great video of it in their SI of their other paper: https://pubs.acs.org/doi/suppl/10.1021/jacs.4c05987/suppl_file/ja4c05987_si_002.mp4

The temperature inside the reaction tube is approximately 100 C, which is a lot. If they keep the reaction at 70 C, the reaction yield decreases from 85% to 51%, and if they keep it at 20 C the yield goes to 0%. 

C) How do you know heat doesn't cause the reaction to go, and all the magnetic field is doing is heating the system?

If you heat the system to 100 C and do not turn on the magnetic field, you get 0% yield

D) If the magnetic field is both heating the reaction and causing the rods to grind against each other, is it exposing a fresh surface or creating a heterogenous powder with higher surface area?

The authors identified that the reaction generates a powder caused by grinding off the surface of the rods, which based on energy-dispersive X-ray spectroscopy (EDS), has the same elemental composition as the steel rods. Adding this powder to the reaction, along with the steel rods, at 100C, led to 2% yield of the XEC product. This isn't nothing, but means that the magnetic field is still doing something to go from 2% to 85% yield.

Additionally, they tested a couple different kinds of metal powders and found that Zn and Mn are able to mediate the reaction, but Fe, Cr, or Ni dust are not. 

Finally, they ran the reaction while the rods were fixed in place with an inert polypropylene scaffold and still observed a 36% yield of the product. 

E) How do you know that the magnetic field is doing something after the first 5 minutes of the reaction? What if it serves to generate an active surface or something and then does not affect the reaction? According to the hypothesis, the rotating metal field should need to continuously polarize the metal rods to modify the reduction potential, so if product continues to be formed after the magnetic field is turned off, the polarization may not be occurring. 

The authors performed the reaction by turning the magnetic field on for an hour, then off for an hour, then on for an hour, then off for an hour, then on for one more hour. After each hour, they took an aliquot of the reaction and evaluated the yield by GCMS. The authors found that the yield did not increase in the time periods where the magnetic field was off.

To summarize these key experiments: The magnetic field is definitely doing something. At the very least, it causes the steel rods to grind against each other, heating the reaction and exposing fresh non-oxidized surfaces. However, it also is applying a further effect that requires the magnetic field to remain active to generate product. 

Takeaways:

This is a very weird but cool and innovative technology. I don't know how useful it will be in the future, nor do I think the authors know. When trying to brainstorm new ideas and particularly when stepping into new fields, it is a good idea to ask yourself, "What are the key requirements for this process to work?" While fields usually settle on a few tried and true methods, there are likely other things out there waiting to be discovered. Whatever you find may not end up being useful, but the way we move forward as a field is by coming up with new ideas and putting the to the test- you never know until you try.