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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 14, 2012

Synthetic Electrochemistry: Who's Done Any?

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Posted by Derek

Looking through the literature this morning, I thought about another technique that, although you see it published on, no organic chemist I know has ever actually used: electrochemistry. There are all sorts of odd reactions that can apparently be made to go at electrode surfaces, but what synthetic organic chemist has ever run one, besides someone in a group that concentrates on publishing papers on electrochemical reactions? Since a few inconclusive cyclic voltammetry scans in 1984, I sure haven't.

That's more harsh-sounding than I intended. I definitely don't think that the technique is useless, but it surely doesn't get used much. One problem is that there are so many different conditions - solvents, electrolytes, electrode materials, voltage/current regimens. If you've never done the stuff before, it's hard to know where to start. And that leads to the next problem, which is that so much of the equipment in the field has been home-made. That makes the activation barrier to trying it yourself that much higher: do you want to do this reaction enough to want to build your own apparatus and troubleshoot it? Or do you have something else to do? If someone sold a standard electrochemistry kit (controller box to run different conditions, set of different electrode materials, etc.), that would free some people up to find out what it could do for them, rather than wondering if they've built a decent setup.

Then there's the scale-up problem. When you're working at a surface to do your chemistry, that's always going to be a concern. What's the throughput? Enough to meet your needs? And if not, how exactly are you going to increase it, without having to rebuild the whole apparatus? There's probably a way to integrate flow chemistry with electrochemistry, which might solve that problem. But that mixture is, as yet, still in the realm of a few dedicated tinkerers - which is what one could say, sometimes, of the whole electrochemical field.

Comments (39) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. fuelcelldave on February 14, 2012 9:08 AM writes...

I once tried to reproduce a powerful one electron Re oxidant (J. Am. Chem. Soc., 2005, 127 (45), pp 15676–15677). Failed repeatedly despite equipment and experienced electrochemists being on hand. Far too many variables to troubleshoot even after talking to authors. Seems the kind of chemistry where you have to visit and see it being done to notice what may be important.

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2. Matt on February 14, 2012 9:16 AM writes...

There are people who are trying some bulk electrolysis with Pd-based chemistry (specifically Harry Gray's group), but this work isn't published yet. However, there are a host of groups who have done photo-induced electrochemical synthesis - I think that the firs was McMillan at Princeton. I know that Sanford at Michigan has also done some of this work. So, while not done at an electrode, per say, the synthesis is still run with electrochemical methods.

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3. Anonymous on February 14, 2012 9:20 AM writes...

Your comment about the myriad of conditions is the same sentiment I feel about microwave chemistry.

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4. Ralos on February 14, 2012 9:40 AM writes...

I removed a tosyl protecting group from an amine using electrolysis. The system worked yet I could only run it up to about 7.5g. Scaling further just didn't work for a number of reasons.

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5. David Formerly Known as a Chemist on February 14, 2012 9:56 AM writes...

Before it was commercially available, I used to use electrochemistry (via an Org Syn prep) to make Fremey's salt. My first batch "violently decomposed" in the fridge overnight. Word to the wise, keep that stuff damp!

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6. John on February 14, 2012 10:09 AM writes...

The Swenton group used electrochemistry (better than Thallium)to make quinone di-ketals which could be converted to quinone monoketals which were used in the total synthesis of (+)-daunomycinone: see Tetrahedron Symposium Issue, (1984), 40(22), 4625-33.

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7. anonymous on February 14, 2012 10:14 AM writes...

While it may not find much use in pharma R&D, commodity chemical producers have been using it for years... both in R&D and manufacturing.

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8. anonymous on February 14, 2012 10:19 AM writes...

#2. Harry's reactions are best run in 43% ethanol, perferably, Vat #5

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9. cynical1 on February 14, 2012 10:27 AM writes...

Actually Merck's process group had a patent (US5700364) for an electrochemical epoxidation used in the synthesis of indinavir. This was back in Merck's heyday filed in 1996. (The good old days.)

I don't know if they ever used it on large scale or not but I was impressed. On the other hand, I didn't try to reproduce it either.

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10. A Nonny Mouse on February 14, 2012 10:39 AM writes...

Used industrially for the synthesis of maltol from a furan derivative (derived from corn husks).

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11. electrochemist1 on February 14, 2012 11:07 AM writes...

There are several cases in the literature using continuous-flow electrochemical cells on a microliter scale - mostly touting electrolyte-free small molecule transformations using solid-polymer electrolytes or acidic membranes.

Yoshida, J. et. al. Chem. Commun., 2005, 1303.

Marken, F. et. al. J. Electroanal. Soc. 2006, 153, D143.

Putter, H. et. al. J. Electroanal. Chem. 2001, 507, 215.

I am currently involved in an academic/industrial relationship to bring this technology to the bench for those few chemists with "tech-savvy" genes in their blood. I feel this evolution of the bench chemist is inevitable as greener, more efficient methods are steadily on the rise.

It is our hope that electrochemical methods and equipment will be adopted as a useful, "out-of- the-box" set of tools for any organic or medicinal chemist willing to try "new" things.

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12. KC on February 14, 2012 11:22 AM writes...

Cant find the paper at the moment but KC Nicalou used a 6 Volt battery in a cyclisation reaction. Not very technical but it works. Check R.D Little in California

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13. dingo on February 14, 2012 11:24 AM writes...

Who ever has those expensive electrodes?

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14. milkshake on February 14, 2012 11:25 AM writes...

Fremy salt: A colleague of mine while at CRO did a scale-up oxidation he got procedure for, no warning about the funny self-accelerated decomposition properties of the reagent. Since the oxidation with Fremy salt was done in water, he thought nothing of lading all that stuff into a reactor that was still wet with water from cleaning. Suddenly it all went poof, USD 20k worth of reagent erupted in a column of red smoke...

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15. Darwinsdog on February 14, 2012 11:36 AM writes...

ah, fremy's salt - you poofed on me sometimes too.

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16. Andy on February 14, 2012 11:37 AM writes...

A fascinating link, especially commodity chemicals made through electrochemistry.

http://electrochem.cwru.edu/encycl/art-o01-org-ind.htm

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17. HC on February 14, 2012 11:38 AM writes...

Moeller at Wash U has done lots of organoelectrochemistry..

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18. electrochemist1 on February 14, 2012 11:44 AM writes...

Kevin Moeller's group at Wash U has the field in my book.

Dirk Trauner's group at UC Berkeley has a nice example of an electrochemical cyclization being utilized in a total synthesis.

JACS 2006, 128, 17057.

RVC electrodes, a 6V battery, or an old cell phone charger are all examples of cheap items to get started with.

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19. electrochemist1 on February 14, 2012 11:56 AM writes...

Andy - great link!!

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20. SG on February 14, 2012 11:57 AM writes...

Interesting question;
Would more people use electrochemistry if there was a $10K apparatus they could buy (a la H-Cube) rather than just use a lantern battery and a graphite stick.

See; Frey, Wu and Moeller Tet Lett. 1996, page 8317
also see

http://www.chem.wisc.edu/areas/organic/studsemin/brownj/brown-ref.pdf

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21. Morten G on February 14, 2012 11:58 AM writes...

Well taking a page from macromolecular crystallography, you can try many conditions in parallel that usually work and pick one that looks okay and then do the same again but varying the parameters of the variables instead of which variables. The problem with that approach for synthetic chemistry is in my eyes in the analysis step. A crystallographer can look for crystals or something close and then later test whether the parameter optimization needs more work at the beam but I don't really see anything as fast as a microscope check for chemists. Maybe mass spec?

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22. WR on February 14, 2012 12:01 PM writes...

Indeed, Moeller's group has been doing oxidative electrochemistry with synthetic applications for more than 20 years. Prior to Moeller, there is R.D. Little's group at UCSB who really indroduced electroreductive chemistry in organic synthesis. And, prior to Little, there was Manuel Baizer who pioneered the electroreductive process for adiponitrile while at Monsanto in the the 1960's.

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23. Honclbrif on February 14, 2012 12:15 PM writes...

I recall reading somewhere that one of the major 'victories' the US had during the cold war was convincing the Soviets (through exciting double-agent spy shenanigans) that some of our nerve agents were made with a substrate which at the time could only be produced through an electrolytic process. In order to keep up they built an expensive electrolysis plant when in reality we were using a less effective but much cheaper alternative.

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24. molcat on February 14, 2012 1:11 PM writes...

I used electrosynthesis to prepare 1,2-bis(tert-butoxy)-4,5-bis(trimethylsilyl)benzene (5 gm. 71% yield after workup and distillation). The electrolysis cell (300 mL) was made by our glass blower and the stainless steel mesh cathode and sacraficial Al anode by the machine shop. A current regulated bench supply costing $170 and two Radio Shack multimeters at $35 each completed the system. The system worked like a champ and could have easily been scaled up.

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25. gippgig on February 14, 2012 1:51 PM writes...

It isn't synthesis, but I've used electrochemistry to restore heavily rusted (i.e., left outside until they turned into a lump of rust) tools for years. Just scrape a spot to get bare metal, wrap a wire around it, connect to roughly -10V (MAKE SURE THE POLARITY IS CORRECT or you'll make things worse), immerse in water (use a nonconductive container) with a shake of NaCl, put a wire connected to the positive terminal about an inch from the tool (if you want to get fancy, use a graphite rod from a carbon-zinc (not alkaline) battery), and let it run for a day. For safety don't exceed 20V and don't run it in a confined area since small amounts of explosive hydrogen gas are given off. The rust will flake off and turn black (the black is Fe3O4). Rinse thoroughly, gradually loosen moving parts, and oil. It won't work on edged tools but it has always worked with pliers.

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26. Fabrice Pierre on February 14, 2012 1:53 PM writes...

My Ph.D. supervisor, Claude Moinet, developed large electrochemistry flow cells using graphite felt as a large surface/volume ratio material for porous electrodes. The conversion was quantitative after one passage through the electrodes by adjusting the flow and the current according to the electron stoechiometry of the redox reaction. The cool thing about the system was the possibility to alternate electrodes of different polarities in the flow, allowing sequences of reduction/oxidation in the process, and the possibility to perform chemistry on reactive intermediates at the exit of the cell. We had in the lab a pretty large custom made cell able to produce kilo-scale material.

A couple of references on his work, some of them in French:

Electrochmica Acta, 1986, 31(1), 1.
J. Appl. Electrochem. , 1986, 16, 819.
Bull. Soc. Chim. Fr. 1988, 59.
Tetrahedron, 1989, 11, 3436.

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27. TER on February 14, 2012 2:16 PM writes...

Actually, Manny Baizer, working in a beaker equipped with rudimentary electrodes, reproduced previous Russian work on electroreductive dimerization of acylonitrile to adiponitrile reported in Chem Abstracts. Don Danly, fellow chemists and chemical engineers at the (then) Monsanto Pensacola plant did the heavy lifting and worked through the 'engineering details' that resulted in a (beautiful) >100M PPY process. Baizer's Monsanto organic electrochemistry group(St. Louis)grew to about 15 shortly before his retirement in the late 70's and while we had many technical successes no further significant commercial processes emerged. Derek, as you noted very few organic chemists have actually carried out a synthesis using electrodes to add or subtract electrons from a molecule. I, like John (above) chose to become a medicinal chemist instead.

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28. Anonymous on February 14, 2012 2:55 PM writes...

I did my doctoral work with RD Little and there's a little bit of e-chem in my disseratation. You can actually do some cool stuff with electrochemistry, but as Derek points out the field is desperately in need of plug and play equipment that is easily accessable to your typical o chemist. I doubt it will ever become mainstream but i'm sure there are some industrial scale redox reactions (like Baizer's homodimerization) that could benefit from the application of echem in lieu of typical metal salt redox reagents.

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29. Anonymous on February 14, 2012 3:01 PM writes...

I tried my (Pharma) R&D group to investigate using metal catalyst coated magnetic particles to better control some "excitable" reactions. The idea was to adjust a magnetic field with varying frequency to control rates of reaction.

My firm did not know at that time (1970's) what to even do with suggestions out of the norm, let alone implement. Surely someone since has tried and proven this works or fails. Has anyone tried it or heard of such?

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30. DSUK on February 14, 2012 6:05 PM writes...

In the 1990's my former boss at merck successfuly used a small electrochemistry kit to generate samples oxidative metabolites. The pattern of products was remarkably similar to those seen in vivo (after cyp oxidation) and it was quicker than getting the same thing by biotransformations

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31. Anonymous on February 14, 2012 7:56 PM writes...

Ship that crap over to China in exchange for real synthetic chemistry jobs moving back to the US!!! We are witnessing the death of synthetic/medicinal/process chemistry in the US...let's see where we're at 5 years from now. Any guesses???

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32. Fabrice Pierre on February 15, 2012 12:06 AM writes...

@30 DSUK, I am interested by your comment. Do you have any literature references related to the generation of metabolites by electrochemical oxidations? Do you remember what kit did your boss used?

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33. newnickname on February 15, 2012 12:07 AM writes...

Doesn't anyone remember the Electrosynthesis Company? They were a small company that provided complete "out of the box" electrosynthesis systems (electrodes, power supply, etc.), consulting, probably custom electrosynthesis on your compounds, electro cetera. I can't remember the name of the owner / PhD Chemist / operator / bottle washer but I met him several times at meetings. According to google, they went out of business or were sold to "Innogy Regensysis" in 2001.

There is current company by the same name that seems to offer electrochem services in many fields, including organic electrochem.

I borrowed some equipment to try some electrochem on a very difficult transformation. It didn't work as hoped, but neither did any of the conventional reactions that drove me to desperation.

Make it easy (and cheap) for me to try and I'm in!

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34. Lars Ambach on February 15, 2012 5:42 AM writes...

I'm just getting started using a micropreparative EC flow cell system from Antec (www.myantec.com) coupled to MS for metabolomics of drugs of abuse to mimic CYP oxidation reactions. Similar to what DSUK mentioned above.

@ 32 Fabrice Pierre: Here are some papers that might get you started:

J Chromatogr A. 2009 Apr 10;1216(15):3192-8. Epub 2009 Feb 10.
Metabolic studies of tetrazepam based on electrochemical simulation in comparison to in vivo and in vitro methods.
Baumann A, Lohmann W, Schubert B, Oberacher H, Karst U.

Anal Bioanal Chem. 2011 Feb;399(5):1859-68. Epub 2010 Dec 19.
Electrochemistry-mass spectrometry for mechanistic studies and simulation of oxidation processes in the environment.
Hoffmann T, Hofmann D, Klumpp E, Küppers S.

Expert Opin Drug Metab Toxicol. 2010 Jun;6(6):715-31.
Online electrochemistry/mass spectrometry in drug metabolism studies: principles and applications.
Baumann A, Karst U.

Rapid Commun. Mass Spectrom. 2003; 17: 800–810
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/rcm.978
Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions
Ulrik Jurva, Hakan V. Wikström, Lars Weidolf and Andries P. Bruins

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35. Design Monkey on February 15, 2012 10:26 AM writes...

>If someone sold a standard electrochemistry kit

I faintly recall some startup named Ylectra, which promised convenient small lab scale tools and technologies for organic electrosynthesis or something like that.

Given that there's nothing on Google about them, I guess they are gone poof.

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36. PirrungLab on February 15, 2012 6:22 PM writes...

LIke the Swenton group, we were making quinone ketals by an electrochemical oxidation route. I opted for a car battery charger and some carbon fiber cloth electrodes. All worked quite well, actually.

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37. oldchemist on March 5, 2012 7:37 PM writes...

A bit late to the party - sorry.

Andrei Yudin, a Prof at U Toronto, worked (works?) in organic electrosynthesis, and was involved very early with Ylektra. Ylektra was a great idea, but not sure where it went. I was quite impressed by what could be done using electrosynthetic methods - and even more surprised that I had never had a moment of it during all of grad school. We turned over OsO4 for the Sharpless diOHation reaction at Sepracor back in the early 1990s using electrochemistry; search Zepp and Gao as authors.

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38. oldchemist on March 5, 2012 7:38 PM writes...

A bit late to the party - sorry.

Andrei Yudin, a Prof at U Toronto, worked (works?) in organic electrosynthesis, and was involved very early with Ylektra. Ylektra was a great idea, but not sure where it went. I was quite impressed by what could be done using electrosynthetic methods - and even more surprised that I had never had a moment of it during all of grad school. We turned over OsO4 for the Sharpless diOHation reaction at Sepracor back in the early 1990s using electrochemistry; search Zepp and Gao as authors.

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39. Sam Sadeghi on March 18, 2012 9:17 PM writes...

We are working on electrochemical fluorination of PET (positron emission tomography) tracers and are looking for a postdoc with experience in redox reaction kinetics and electrochemical synthesis (particularly fluorination)to join our group.

If you know anyone please refer them to me for a UCLA START fellowship. http://www.crump.ucla.edu/start

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