Wednesday, April 20, 2016

C–H Oxidation Meets Electrochemistry


When we look back at some of our lab’s terpene syntheses using a “two-phase” approach, it becomes abundantly clear that one oxidation reaction is used more than anything else: the allylic C–H oxidation. What isn’t obvious just by reading, though, is how unappealing these reactions actually are to perform. In the case of taxayunnanine D, our synthesis required 30 equivalents of our unique chromium (V) reagent, while a challenging oxidation en route to phorbol required 100 equivalents of CrO3! While these reagents served their purpose, we knew that the cost and toxicity associated with them would unquestionably preclude scaling up of these syntheses.
Terpene synthesis in the lab has relied on allylic oxidation for many many years.


This challenge presented us a unique opportunity to design a new system for allylic oxidation with the goal of a scalable and sustainable solution as reported today in Nature. Having explored some anodic oxidations a couple of years ago in both methodology and synthesis, the idea of allylic oxidation using electrochemistry was pretty appealing. As is almost always the case, someone had a similar idea during the Cold War – unfortunately, conditions developed back then were not general and led to poor conversions and yields in the reactions. We theorized that developing a variant of N-hydroxyphthalimide bearing electron-withdrawing groups would improve the reaction, and we found that using tetrachloro N-hydroxyphthalimide (Cl4NHPI) as a catalyst in the presence of a co-oxidant such at tBuOOH led to dramatically improved yields in these reactions.
Lots of optimization summarized here

One thing that we don’t really go into in the paper, is what it took to get these reactions to work from an engineering perspective. Initially we used graphite rod electrodes, these are pretty much big things of pencil lead that we purchase from Mcmaster-Carr (an online supplier of hardware stuff). At some point during the optimization process, we realized that while we were able to get beautiful conversion by crude NMR, the mass recovery for the reactions was often extremely low. After a ton of frustration, we reasoned that the lost mass was being absorbed into the graphite electrodes! We tried extensive washing of the electrodes, even resorting to soxhlet extraction for days, but these procedures were cumbersome and even with the extractions, we never were able to account for all of the material. After some more experimentation, we began to look at alternative electrode materials. While there are many examples of preparative organic electrochemistry using gold or platinum electrodes, these are quite expensive and we reasoned that even if Phil would let us buy them (he probably wouldn’t) their high cost would discourage any other labs or process groups from using our methodology. Glassy carbon, which is also often used as an electrode material, was also cost prohibitive. After searching through the chemical literature as well as scouring through random materials suppliers on the internet, we discovered RVC foam.
RVC electrodes, simple and cheap.
This stuff is pretty much an inexpensive source of glassy carbon, and is sold in sheets of various “pores per inch”. Since glassy carbon is impermeable to gasses and liquids, we figured that this should improve the yield of our oxidation and not suck up material into the electrodes. It took us quite some time from getting our first order of RVC foam delivered, to having our optimized electrochemical setup. The key thing we found was that for the reaction to proceed efficiently, we needed to maximize electrode surface area. Eventually we came to the setup we describe in the paper (and have laid out in detail in the Supporting Information). In summary, to put together the cell, we take a brick of RVC foam (100 ppi, costs ~$20 for a sheet from K.R. Reynolds co. which can make >10 electrodes) carve out two half-cylinder electrodes using a razor blade, and then solder connections to the top using stainless steel wire. The electrodes are placed in the cell (a test tube) and to keep the electrodes from touching we put a glass slide between them.



Admittedly, this setup is a little crude, and we are sure that a group with more engineering resources at their disposal could fabricate a prettier and perhaps more efficient device to carry out this reaction However, we are not an engineering group, and really wanted to develop a way to run this reaction using stuff that was inexpensive, and for the most part can be found in any synthetic organic chemistry lab. With optimized conditions in hand, we went on to explore the substrate scope. Methodologists like simple substrates, so we did those to make them happy. One thing we want to highlight is that the reaction tolerates tertiary allylic alcohols, and gives none of the allylic transposition product that is usually observed when oxidizing these substrates using traditional (chromium) methods.
Some selected simple compounds

What we were really interested in, however, were natural products. We bought, isolated, and synthesized as many terpenes as we could in as short a time as we could, hoping to oxidize them to enone containing terpenoids. We were able to oxidize several different terpene skeletons bearing a variety of olefin substitution patterns, electronic characteristics, and oxidation barcodes. We even found that the conditions were mild and selective enough for a fully deprotected glycosylated steroid (try that with chromium!). One of our favorite substrates was the oxidation of valencene to nootkatone (compound number 5) that had been previously reported using 15 equivalents of chromium! For those of you who have never been exposed to nootkatone, it is the primary fragrance component of grapefruit aroma, so anytime we would make it the smell of delicious grapefruit would permeate throughout the lab. We were also excited by this substrate since recently nootkatone has recently been show to be quite an effective mosquito repellant and a San Diego based company that produces nootkatone and valencene via fermentation had recently been purchased for $ 59 million!

Lots of natural products were prepared in this paper.
At some point during this project, we were approached by one of our collaborators, Asymchem (a CMO in Tianjin, China) who are interested in developing a platform to conduct reactions using electrochemical methods in order to decrease cost and environmental footprint. We gave them our procedures and some instruction of how they might carry out this transformation on a larger scale. In a few weeks time they were able to get this reaction to work 100 g scale! Perhaps equally cool was their crazy simple reaction setup, which consisted of two graphite plates submerged in an eight-liter beaker, contained in a bucket filled with ice! At the time we were trying to put the paper together Phil wanted to up the scale even more (can we do a mole?!?!), but the only limit (at the time) was the fact that the potentiostat asymchem had only went up to 1 A. In theory if a process group wanted to there is no limit to the scale of this reaction. 
This IS bucket chemistry...
It is easy to say that a reaction is “green” but we wanted to really show how much of an improvement our allylic oxidation was compared to the current methods that are used to run allylic oxidations on scale. Since we had been working with BMS process chem to use this reaction for some of their early-stage intermediates (Thanks Martin and Ke!), they provided some interesting metrics comparing our method for the oxidation of dehydroepiandrosterone acetate to two other literature examples that used chromium and ruthenium. The Process greenness score (PGS) is a rating used by BMS (other process companies use similar metrics) to evaluate the environmental impact of a reaction, taking into account the amount of waste the reaction generates (including workup) and the overall efficiency of the reaction. A higher % PGS indicates a “greener” reaction. The electrochemical reaction scores 56% vs. 32 and 37% for the chromium and ruthenium-based oxidations. As stated in the paper the PGS associated with our oxidation is in the range of standard amide bond forming reactions, as well as palladium-catalyzed coupling reactions. It is also worth noting that the PGS does not take into account the cost of disposal or the toxicity of the reagents, which means that compared to the chromium and ruthenium oxidations, our electrochemical reaction is even more of an improvement.
Metrics support the obvious conclusion: Electrons are better than chromium.
Overall this was a really exciting project to work on. Neither of us thought we would end up doing electrochemistry in the Baran lab, and although at the beginning it felt way outside of our comfort zone and chemical expertise, it is an interesting experience to do something completely different. One of the coolest parts of the whole thing was actually developing something that is scalable and sustainable that people actually might use. Phil had been alluding to this project during some of his recent ACS talks, and we have already been contacted by a number of process groups in the fragrance industry wanting to apply this chemistry to the manufacturing of a few chemicals. While electrochemistry might seem daunting, once you get over the initial learning curve there are a lot of really cool and practical applications, and hopefully you will see some more out of our lab in the future. We hope that other groups (academic or industrial) will begin to embrace this methodology, and electrochemistry in general, as an enabling tool for sustainably carrying out redox reactions in the lab, especially on scale. 


-Evan and Brandon

14 comments:

  1. This is really nice, for too long electrochemistry was the last method a natural product synthetic chemist would use - Your group has been leading the renaissance. But as a chemist who never used any electrochemistry, I wanted to ask you - how difficult is to purify the reaction mix from the perchlorate electrolyte and other additives (compared to traditional reaction mix)? Also, I noticed the reaction mix looks dark - do you get any carbon colloids from the electrodes? Also, for releasing any product stuck on graphite electrodes - please have you tried addition of a greasy solvent like toluene or xylenes? Also, is the absorption on carbon electrode surface important to the anodic oxidation (i.e. does the reaction work better in highly polar solvents rather than in more lipophilic ones)? Does the cathode have to be from RVC carbon foam, or would some common metal (i.e. titanium) also work for the purpose?

    ReplyDelete
  2. Thanks! In general this reaction is no more different to purify than a non-electrochemical reaction, the lithium perchlorate is simply removed in the aqueous wash. The reaction is not completely homogeneous since the Cl4-NHPI•pyridinium salt is not completely soluble so that accounts for the dark color of the solution. As far as carbon colloids, glassy carbon/RVC is extremely inert so I do not believe that the electrolysis decomposes the electrodes at all. However, the RVC foam is fairly brittle so sometimes the stir bar can grind away some of the electrode and you get bits of it in the reaction, but this doesn't seem to be a problem.

    When we were using graphite electrodes, we did use toluene to extract the starting material/product from the electrodes, this worked better than more polar solvents and better than hexane, but we still were unable to recover all the material. For some of the more volatile substrates this is an issue since you loose a lot of the product removing the toluene.

    The solvents that we found to work for the reaction were acetone, MeCN, DCM and pyridine. Other less polar solvents like toluene and hexane didn't work since we could not get enough of the LiClO4 or LiBF4 electrolyte dissolved so the reaction is unable to pass current. Etherial solvents also didn’t work, and we suspect this is because they undergo competing C–H abstraction from the pthalimide radical.

    In theory we could use a number of other materials for the cathode in this reaction; however, one thing that we did not go into detail in the paper is the fact that there is salt buildup on the cathode that increases the resistance of the cell and eventually insulates it to the point that current is unable to pass. We get around this issue by alternating direction of the current every 15 minutes (so that the anode becomes the cathode and vis versa). This causes the salts to slough off and the current to remain more stable.

    Thanks for the questions!

    ReplyDelete
  3. sorry bothering you one more time: please have you tried some more electron deficient analogs of HOBt, namely HOAt with pyridine ring? It is more acidic and has very good solubility, its anion is yellow... The material is explosive on large scale but as very fluffy cotton-like solid it does not pose much hazard. Advanced Chemtech has it for a good price (CAS# 39968-33-7) and unlike tetrachloro-NHPI it is a very polar compound with a small molecular weight.

    ReplyDelete
    Replies
    1. Thanks for the suggestion, we will look into that!

      Delete
  4. last thing: the salt buildup on cathode. One possible candidate is lithium carbonate - it has low solubility. (The carbonate would come from oxidative degradation of anode but Li2CO3 would precipitate on cathode because of high local concentration of Li+).
    If it is Li2CO3 that precipitates on cathode, maybe switching from LiClO4 to NaClO4 would solve this problem, sodium perchlorate solubility in acetone is less than of Li-perchlorate (0.52g dissolves in 1mL of acetone, vs. 1.37g/mL for Li perchlorate) but it might be still good enough for your purposes.

    ReplyDelete
  5. I see what you are thinking, but we are pretty sure that the ppt is some sort of pyridinium or NHPI salt. We had tried NaClO4 but due to the lower solubility it did not work as well. We also don't think that the electrodes are being oxidized to carbonate, since glassy carbon is extremely resistant to oxidation and the potential is not high enough. Thanks for the ideas though!

    ReplyDelete
  6. How much time did the reactions take to go to completion (a range of values is fine)? Thanks!

    ReplyDelete
    Replies
    1. The reactions can take anywhere from 8 to over 24 hours to go to completion.

      Delete
  7. Do you have any tips for soldering the RVC electrodes? My solder keeps balling up and falling off. Also- what gauge SS wire did you use? Thanks!

    ReplyDelete
  8. Yeah, soldering the wire can be a little tricky, as the solder does not stick to the carbon well. The trick is that you do not want to melt the solder by directly putting the solder to the tip of the soldering iron, but rather use the soldering iron to heat up the wire/RVC until the wire is hot enough that it melts the solder. This way both interfaces are hot and the solder can flow into the cracks and pores of the electrode/wire. After a small amount of solder has melted, I jiggle the wire a little bit until the ball of solder drops into the hole that the wire is in, and then I keep the soldering iron on the wire for a little bit longer to make sure the solder really flows into the pores. If you just have the drop of solder on the top of the electrode, it will not hold, it needs to really be inside that hole where the wire is (the hols goes in ~3-4 mm). This takes a little bit of practice but once you get it down it is quite easy.

    For wire, make sure you are using some sort of wire that is braided or spun so that there is more cracks and surface area for the solder to stick to. If you just use straight gauge wire it will be difficult to get the solder to make a solid mechanical connection that will not easily pull out. Picture hanging wire works well for this, and can easily be purchased at any hardware/framing/craft store. Just make sure it is stainless steel so that it is a little more resistant to corrosion. Hope this helps! If you still have trouble please contact me directly and we can try to work something out.

    Evan

    ReplyDelete
  9. This comment has been removed by the author.

    ReplyDelete
  10. Nice job ! :) Please can I have the reference of your potentiostat asymchem? Thanks !

    ReplyDelete