Tuesday, May 16, 2017

Practical Oxidation of Strong C–H Bonds using Electrochemistry

We are excited that our latest paper “Scalable, Electrochemical Oxidation of Unactivated C–H Bonds” was published in JACS earlier today! This reaction enables the oxidation of a simple unactivated methylene to a ketone. Although one may think that this reaction is similar to methylene oxidation by TFDO, a great advantage is its scalability as exemplified by a 50 gram scale oxidation of sclareolide. In addition, due to the different oxidation mechanism, this protocol tolerates alkenes and azines, in contrast to TFDO. Details on reaction setup, optimization, and scope can be found in either the paper itself or the accompanying SI. Therefore, in this blog, I’m going to tell you the behind-the-scene stories for this reaction instead. All right—let’s C-Harge up and scroll down.
Our last paper in this field was the oxidation of allylic C–H bonds (E. J. Horn et al, Nature, 2016, 533, 77–81)—oxidizing unactivated C–H bonds, especially the methylene units, was therefore our next logical goal. But, of course, it wouldn’t be easy considering that there are only a handful of chemical methods for methylene functionalization. Since the TCNHPI mediator did not work for these strong bonds, Phil suggested that we look for a "super mediator", which overcomes the huge reactivity difference between allylic (BDE = ca. 83 kcal/mol) and methylene C-H bonds (BDE = ca. 95 kcal/mol). Is there a limit to what can be used as mediators? The answer was a big resounding NO—anything under the sun (as well as in the darkness) could be examined. To us, this is the beauty of electrochemistry, it allows one to oxidize/reduce numerous reagents to access high-energy radical species potentially of unique reactivity in a simple and sustainable way.
Not surprisingly, my first three months had gone by without any progress. I tried all species that could conceivably generate a reactive radical species, including various amides and alcohols (assuming starting materials may be coaxed into electrocution in a non-sober state). I started rummaging through our inventory to identify next candidates. As I was involved in the Palau’chlor project years ago as a visiting student, my guanidine samples from earlier years caught my eyes immediately. I tried all of them in our electrochemical setup: All mediators I examined in that series were dead. For a long time, I thought I was looking for a needle in the haystack but Phil was always encouraging. After a prolonged period of condition searching, I finally found that 3-aceclidine, as a mediator, promoted C-H oxidation of adamantane in the presence of HFIP with ammonium electrolyte. Later, both HFIP and the choice of electrolyte were found to be crucial.
Designing and crafting a home-made electrochemical apparatus, though laborious at times, kept my spirit up during the dark days. Below is my latest collection. Undoubtedly, the electrodes played an important role in the reaction development. We always avoided expensive elements (e.g., platinum) at the outset of the project—therefore, I doubt I will ever amass a complete collection of the periodic table; nevertheless, the future may take me to some less well-studied elements.  
With a “home-made” electrochemical setup, I naturally wanted to oxidize compounds accessible to the common household. For example, the precursor of one of our oxidation substrates was readily (and inexpensively) obtained from Whole Foods Market.
To properly put this method in context, we compared it extensively to the TFDO oxidation, hitherto the “go to method” for methylene oxidation in our lab. I prepared TFDO myself and tried to oxidize some of the substrates in the paper. This was one of my more dreaded times during the project. I have always heard terror stories from colleagues on TFDO—how everything must be pre-cooled to cryogenic temperature with extra precaution. I followed the prep on Openflask but soon found out that an open flask does not suffice for this process. Rather, one needs a sophisticated setup. In my own experience, the preparation of TFDO itself was not that cumbersome on a small scale, but the yield was very low (around 2%). In addition, this was totally unexpected—due to its low boiling point, taking this reagent with a syringe was a great challenge. Maintaining cryogenic temperature was absolutely critical as the TFDO will be evaporated or decomposed. I can’t imagine using TFDO on a really large scale. Meanwhile, our collaborators from Asymchem found that our electrochemical method was very amenable for scale up.

Perhaps we could do another race to justify the comparison. However, I have yet to convince a volunteer (myself included) to prepare TFDO again.

Finally, I would like to thank all people involved in this research, including our great collaborators Mike and Jeremy at Pfizer, and the very talented folks at Asymchem for the large scale reaction. Please let me know if you have any comments and questions!



  1. This is really practical and may finally help to overcome the activation barrier of synthetic chemists against electrochemistry. My only complaint is that Me4N(+) is quite toxic (it is comparable to cyanide) so if 10 equivs of it goes to aq. phase, it would have to be waste treated of on process scale.

    I have 2 questions: 1) have you tried to sparge the electrolyzed mixture with oxygen, if O2 is the terminal oxidant?, to improve the rection time/conversion?

    2) Have you looked at mono-quaternized DABCO? It could serve as less electron rich version of quinuclidine. DABCO is very cheap (whereas quinuclidine is pricey), and mono-quaternized DABCO-derived cation radical is pretty reactive, judging by the success of Selectfluor reagent. In fact, I would like to convince you to consider trying DABCO-CH2Cl(+) BF4(-) as both reagent and electrolyte. It is intermediate of Selectfluor manufacture, made by refluxing DABCO in DCM and treating the product with NaBF4

    1. Hi milkshake,

      Thank you for your useful advices! Other ammonium salts such as Bu4NBF4 and Et4NClO4 (and I guess many other tetraalkylammonium salts too) can also be used without diminishing the efficiency of this reaction.

      1) The reaction works under oxygen atmosphere, but yelds are generally very similar to the reactions under air. Oxygen certainly improves conversion a little bit, but at the same time, more overoxidation also occures.

      2) Yes, I have tried monomethylated DABCO TfO(-) for this reaction. Unfortunately the reaction did not work possibly due to the significantly higher oxidation potential of monoalkylated DABCO compared to quinuclidine. I also tried selectfluor as a mediator, but the reaction was not efficient in this case either.

    2. Yu, hi, thank you for the explanation, it is very helpful.

      I have one more question, since the supplementary is not yet available. Please have you considered the possibility of the unique role of HFIP, that it serves more than just a mild source of protons - that the anion of HFIP is maybe participating in the catalytic cycle? Forgive me being naive but I remember HFIP is quite hard to oxidize to hexafluoroacetone - do you think it is possible that anodic oxidation of HFIP anion generates a HFIP radical that instantly abstracts electron from quinuclidine? Also, have you tried to use commercial hexafluoroacetone trihydrate? It forms stable gem diol (CF3)2C(OH)2. Thank you.

    3. Thank you for your insightful question.

      Regarding to this question, I have run the oxidation of sclareolide with Et4NOCH(CF3)2 (salt of ammonium cation and HFIP anion) as an electrolyte in the absence of quinuclidine. The product yield was very low, which means that no reactive radical species is formed from HFIP anion. Besides, the reaction still works when acetic acid was used insted of HFIP, although the yield was lower. I cannot completely rule out the possibility that HFIP is mediating the formation of quinuclidine radical cation by electron transfer, but it is less likely considering the results of these experiments. I also took cyclic voltammetry of Et4NOCH(CF3)2, but no clear oxidation peak was observed from 0 to 2V.

      Yes, I have tried hexafluoroacetone trihydrate. But unfortunately, no C-H oxidation was observed. It seems like generation of oxygen-centered radical is more difficult than nitrogen-centered radical possibly due to higher oxidation potential. I also tried other compounds such as various guanidines, benzoic acids, sulfonamides, sulfonimides, pentafluorophenol and nonafluoro-t-butanol, but none of them was effective. I recognised that quinuclidine is not the cheapest solution, so I continue to search "second generation super mediator".

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  3. "…due to [TFDO]'s low boiling point, taking this reagent with a syringe was a great challenge."

    You can use a mantle cooled syringe like that: http://imgur.com/a/tQ8kR (made from standard lab consumables). Especially on smaller scale, this is quite helpful.

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