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!