Tuesday, August 22, 2017

ELECTRA-chemical amination, behind-the-SYN Stories

Following Phil’s Keynote lecture at the 254th ACS meeting, we are delighted to announce that our latest publication titled “Electrochemically Enabled, Ni-Catalyzed Amination” is available on the website of Angewandte Chemie International Edition. As usual, you will be able to find the details of our amination reaction in the manuscript and the SI. As the development of this reaction is closely intertwined with that of ElectraSyn, we would like to share some behind-the-(Eletra)Syn stories of this reaction.

  Let’s start with a bit of history first. Since San Diego no longer “charges,” we’ve elected to electrify our own lives with electrochemistry in the laboratory setting. Our last publication in this area on “Scalable, Electrochemical Oxidation of Unactivated C–H Bonds” came out in May. As we pointed out in the accompanying blogpost, developing the reaction wasn’t a smooth journey. However, “designing and crafting a homemade electrochemical apparatus, though laborious at times, kept my spirit up during the dark days…” Sadly, this infatuation with arts and crafts wasn’t shared by many. Throughout my time doing electrochemistry, many students/postdocs were turned away by the tedious setup. We even concealed the Rube-Goldberg-esque machines during recruiting weekends, lest they deter all interested prospectives from joining Scripps. I sometimes felt like a master of a lost art, wondering if anyone can repeat my reactions after my departure from the laboratory.


  Thus, I was truly elated to participate in the collaboration with IKA, hoping to develop an electrochemical device for and by organic chemists alongside some of the world’s leading engineers. Now the culmination of over 30,000 man hours of efforts, Electrasyn2.0 has been proudly unveiled by Phil today. It is as small as a stir plate; however, it integrates all the requisite functions—potentiostat, stirring and cyclic voltammetry. If you compare it with our homemade electrochemical apparatus, the difference is astonishing. Reactions can be set up by simply “plugging” in a standardized cell. Compared to the home-made devices, the ElectraSyn2.0 can just do it better and faster.  

IKA provided us a few testing units in June. Eager to try out these devices, we wondered if we could use them to conduct some of the most widely utilized reactions. To this end, Phil’s words resonate loudly in our minds—“For medicinal chemists, Suzuki coupling and Buchwald-Hartwig amination are an integral part of their jobs. These are some of the staple reactions of their lives at the moment.” Perhaps because they are used so often, new limitations are constantly emerging. In addition, exotic nitrogen-rich substrates push the limits of what these reactions can accomplish. Thus, we wondered if they could be facilitated or improved with electrochemistry…

After a brief exploration of various coupling reactions under electrochemical conditions,  Chao and I found a promising hit for C–N bond formation using aryl bromide as a coupling partner on June 14th. The reaction proceeded at room temperature and required only an inexpensive nickel catalyst. Phil was thrilled about this result—we agreed it would be fantastic if we could unveil ElectraSyn and this reaction on the very same day. After pondering for a few seconds, he said “Can you guys make a new paper with this amination reaction? Submission day is going to be …hmmm…August 3rd.

What!? August 3rd!? …It was not very difficult for me to imagine that the next month was going to be the busiest month in my life.

On July 5th, a very talented postdoc Hugh, who had just arrived at Scripps, joined the team and the amination project was officially started by three of us. As we only had less than a month left before submission, we had no time to waste. All ElectraSyn2.0 were running all day and you cannot imagine how this device helped our productivity—the plug and play features freed us from all the onerous steps below:  


Instead, all we need to do to assemble the setup was to slot in the electrodes:

Thanks to this, by the middle of July, we almost finished the optimization. Due to the efforts of Chao and Hugh, we successfully demonstrated the coupling on over a dozen  substrates. But there’s no time for complacency. At this point, Julien, a French visiting student, joined the project with an incredible work ethic—his enthusiasm was truly contagious. As such, we encouraged each other to “Keep up and just do it”. Finally, we managed to put everything together by August 1st.  

We had a lot of fun doing this project and using the ElectraSyn2.0 device. We are now focusing on expanding the scope of these electrochemical reactions and inventing new ones. The thrill of running electrochemistry using ElectraSyn is actually contagious so expect a lot more of this from our lab in the future (including some interesting total synthesis applications!). 

Finally, we would like to thank all people involved in this research, including our great collaborators Jeremy and Jinshan at Pfizer, and the very talented folks at Asymchem for the large-scale reaction.

Please let us know if you have any comments and questions!

Kawa and the electrochemistry team

10 comments:

  1. I really like this. If there is going to be a renaissance of electrochemistry in organic synthesis labs, an affordable sleek looking instrument from IKA that can run broad-scope arylations at room temperature is the way to go, to get everyone started

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  2. Thanks Milkshake! IKA deserves all the credit for investing in this and making it happen. They are a family owned business with great integrity and have a strong desire to do something good for chemistry.

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    1. and now the last thing remaining is for you to find the way to make your Ni-catalyzed system work with amalgamated aluminum foil instead of electricity :)

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    2. LOL we'll get to work on that!

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  3. Nice work guys. I just realized, I read a paper by Julien few weeks ago (the one about chan-lam coupling with H3BO3 additive) conditions didnt realy improve anything for me but thats the life :D

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  4. I know this is obvious: please have you tried to electrochemically pre-generate the catalytically-active Ni species first, then turn off the power to your cell and inject the aryl bromide last to the reaction mix?

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    1. We have tried the following experiment before. I hope it answers your question.
      First electrolysis was carried out for a short period with Zn sacrificial anode (to avoid anodic oxidation of the intermediate) and Ni foam cathode in the absence of aryl bromide and amine. The solution turned dark blue, which we think indicates the formation of low valent Ni species. Then, Zn anode was replaced with RVC anode and aryl bromide was added. The solution color changed from dark blue to blown orange without electrolysis. Finally, amine was added and electricity was passed to this solution. The formation of amination product was observed at this step. From this experiment, we clearly observed the formation of low valent Ni, oxidative addition of this low valent Ni to aryl bromide and formation of amination product under oxidative conditions. More detailed mechanistic studies are currently ongoing.

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  5. Now I think I understand - so the electrocatalytic cycle actually does not close by itself without anodic oxidation of the ArNiBr(L)(amine)x intermediate at the end

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  6. Have you attempted the dixiamycin B synthesis using the device, assuming you guys still have some xiamycin A in a fridge? I am curious about it's application in N-N bond synthesis.

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  7. No but the Waldvogel lab has been using ElectraSyn for their chemistry (see their recent JACS paper on N-N bond formation).

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