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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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In the Pipeline

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October 28, 2010

Shine A Light

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Posted by Derek

I'm enjoying myself very much in the lab today, doing something I haven't done in 20 years: photochemistry. I did some during my post-doc (with Bernd Giese, which is also the last time I've done free radical chemistry, at least on purpose). Since then, though, it's one of those things that's never come up. We had a mercury lamp apparatus in my grad school group, which I saw used a few times - one of which resulted in one of those nose-wrinkling "What's that funny smell?" moments, when the person running it forgot to turn on the cooling water. Don't do that. Medium-pressure mercury lamps can get pretty toasty. (They'll also permanently tan your eyeballs if you're so foolish as to look at them, I should also note, so don't do that, either!)

Most synthetic chemists will have had a brief experience with the technique - it's very appealing to think of doing chemistry just by shining a light on the reaction. But there can be a lot of variables - the sort of lamp you use (and thus the wavelengths and energy flux), various filters, sensitizing additives, hardware setups. Many people find that they use it for one reaction at some point, to make a specific compound, and never quite find a use for it again. In my experience, every decent-sized chemistry department has a photochemical rig of some sort, and no one quite knows where all its parts are.

That's probably a shame. There are a lot of unusual and interesting reactions that can be done photochemically - if you like 3- and 4-membered rings, this is certainly a field you should look into. I can recommend this recent bookas a general review of the field, for anyone who's thinking about it. We'll see how much use I get out of my current setup, but for now, I'm happily blasting away with the ultraviolet. . .

Update: blasting away is right! My cooling water dribbled down and then cut out on me after I tried to turn it down a bit, and, well. . . now I'm cleaning melted goo off of the quartz. A razor blade is working pretty well, but that's no way to treat a working piece of equipment.

Comments (31) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Hap on October 28, 2010 10:08 AM writes...

Stephenson (BC) and Yoon (Wisconsin?) are trying to bring photochem back, though I think they're trying to use visible light and metal complexes. It still seems interesting - light is cheap.

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2. processchemist on October 28, 2010 11:18 AM writes...

Ah, photochemistry! Lumilysergol synthesis (nicergoline intermediate), some fancy oxidations on corticoids...

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3. John Spevacek on October 28, 2010 12:02 PM writes...

But for us polymer chemists, UV is a godsend - fast, solvent free, easy to scale up to production.

I always thought Norrish got it wrong when a Type I photoninitiator breaks into 2 parts, while the Type II stays together as 1. But hey, he did win a Nobel Prize, while I can spell Nobel Prize.

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4. Brian on October 28, 2010 12:12 PM writes...

I wonder how easy it is to scale up a photochemical reaction. If I had to give a number, I couldn't even give you an educated guess. Is there any ? Anyone know ?

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5. processchemist on October 28, 2010 12:41 PM writes...

@4
Not so simple. I've seen some attempts to scale up photochemical reactions in 10 l flask, with the light source immersed (lamps enclosed in borosilicate glass pockets), ending in total messes, with the product sticked to the lamp surface, no matter how heavy was the stirring.
Industrial reactors with a glass cover and lamps over the cover can be used (mediocre efficiency).
Personally I planned from time to time to set up a continuous system, but I never worked up this idea.

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6. barry on October 28, 2010 12:45 PM writes...

The key step in my dissertation work was photochemical. Alas, it was a very dirty step if run to completion, as the product has a significant chromophore of its own. The great step forward was using a solution of Bismuth chloride as a filter for the light. That proved to be as clean as driving the reaction with a UV laser. When it was run right, the arene-olefin-metaphotcycloadduct crystallized out from the cyclohexane solvent.
I'm indebted to friends in the department both for the Bismuth idea and for the use of the laser.

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7. p on October 28, 2010 1:18 PM writes...

On scale up: light is a reagent in these reactions, so you can't just put the same lamp in a bigger flask. You'd need to scale the lamps as well.

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8. noname on October 28, 2010 1:42 PM writes...

I did alot of optimization of a photochemical reaction for my dissertation using an old Rayonet photoreactor. I had to use quartz glassware but we only had medium to large scale quartz vessels. I found someone in one of the P-chem groups who for some reason had lots of quartz tubing, about 1 cm ID, lying around. He agreed to make about 10 mini-reactors for me, about 1.5 mL each, for exploratory work. So I was able to do condition batteries on small scale in the Rayonet, just like we did for thermal reactions. Nothing speeds up development work faster than testing 10 conditions at once (or more of course).

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9. Brian on October 28, 2010 2:15 PM writes...

@5 and others, so what sort of residency time does it usually take for a photochemical reaction, i.e. how long do you have to leave it in contact with the lamp ?

@5 A continuous process ? Using a microreactor ? I would imagine depending on how long it would take for the reaction occur, you might not need a big light.

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10. Derek Lowe on October 28, 2010 4:02 PM writes...

Several people have mentioned continuous flow and scale-up. I'd recommend these papers; it looks like a good idea to me:

http://pubs.acs.org/doi/abs/10.1021/jo050705p

http://linkinghub.elsevier.com/retrieve/pii/S0040403910009366

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11. Nick K on October 28, 2010 4:16 PM writes...

Photochemistry is beautiful and elegant, but I've never seen it performed on more than about a gram. Has anyone tried running photochemical reactions in a recirculating flow system? With short residence times it might be a way round the problems of scale and over-reaction.

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12. p on October 28, 2010 4:25 PM writes...

You should look at Garcia-Garibay's stuff. He's done a lot of photochemistry on suspended crystals on a fairly large scale.

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13. J-bone on October 28, 2010 4:53 PM writes...

I'm certainly no expert, but I've been impressed by MacMillan's recent papers using standard watt light bulbs in his reactions (trifluromethylations I think?)

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14. Nick K on October 28, 2010 4:56 PM writes...

Thanks, Derek. Your post has answered my question in the affirmative.

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15. Handles on October 28, 2010 5:25 PM writes...

The most success Ive ever had with photochemistry was in undergrad, photoisomerisation of a double bond. I tried a Barton reaction in the real world but couldnt get it to work.

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16. Brian on October 28, 2010 6:12 PM writes...

Thanks Derek. When I am back for some more reading, I will pick that paper up.

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17. Brian on October 28, 2010 6:15 PM writes...

Thanks Derek. I will pick that one up when I go to get some new papers.

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18. anon the II on October 28, 2010 8:01 PM writes...

I used photochemistry to make a neat little amino acid natural product when I was in graduate school. It worked quite well. When I scaled up to about 20 g, it was evident that light had become the rate limiting "reagent". Formation of a thin dark laquer on the inner wall also slowed the reaction down.

Later, on one occasion after I had matriculated to industry and nothing was working well, I whipped out the photo apparatus and made a new batch of the natural product, just to convince myself that I could still do chemistry (Thanks Wyeth).

When the JOC photoflow paper showed up, I wanted to try it out with my reaction, but I haven't had photo equipment around for a few years.

Photochemistry is neat stuff but you do need to be aware of how all those variables that Derek mentioned actually impact what you're trying. It helps if you have a nice reactor setup with the Hanovia lamp and a few filters like Ace glass sells. Also, don't bother buying one on those little pen UV lights to do reactions on a small scale. They don't put out enough oomph to do anything useful.

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19. processchemist on October 29, 2010 5:39 AM writes...

@ 9

No microreactors: a cell, a pump with high flow rate, a cooled jacketed reactor, continually recycling to the reactor the output of the cell and feeding the content of the reactor to the cell. More "flow" than "continuous".

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20. Kevin Booker-Milburn on October 29, 2010 6:46 AM writes...

Hi Derek

Enjoyable blog and interesting entry on photochemistry. Please persevere - it is a very powerful technique as many have demonstrated over the last 50 years.
We are the group responsible for developing the first continuous photochemistry flow reactor in the JOC 2005 paper a few users have referred to. We have made a few more developments since but the basic design still holds. It is capable of producing over 600g per 24h of 2+2 adducts - how many academic methodologies can do that I wonder?
Also has proved useful in avoiding the secondary photoadduct problem that dogs batch irradiation.

The biggest barrier to using photochemistry is the fear of photochemistry itself! This means that synthetic chemists avoid it and therefore do not have 'photo-disconnections' as part of their retrosynthesis toolkit.

Keep up the good work.

Best

KIBM

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21. Thomas McEntee on October 29, 2010 6:55 AM writes...

In the 1970s during my time with Syntex, as we were getting ready to produce naproxen, we bought a plant in Verona, MO previously owned by Northeastern Pharmaceutical and Chemical Company (NEPACCO) that had manufactured hexachlorophene. We discovered that we had inherited a dioxin problem. Incineration options were blocked by legal issues. A photochemical loop reaction system was developed and TCDD levels were reduced from 343 ppm to 0.2 ppm. About 7 Kg of TCDD were destroyed photochemically. Our joy with this success was shattered when it was discovered that the previous owner had disposed on far greater quantities of TCDD-laden oily waste by selling it to a company that sprayed oil on roads for dust control. This was the infamous Times Beach, MO hazardous waste problem. Syntex was tarred incorrectly with the brush of "the parent company of NEPACCO." US EPA purchased the entire town and in the 1990s, using new and improved technology, using a Syntex-funded incinerator, destroyed more than 250,000 tons of PCB-contaminated soil and debris.

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22. lbf on October 29, 2010 9:22 AM writes...

Photochem can be scaled up. I worked for a company that specialized in manufacturing benzotrifluorides, made from benzotrichlorides w. HF. They had 2000 gallon photochlorinators, with 5-6 foot tall immersion lamps (a few per reactor), so it can be done.

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23. Petros on October 29, 2010 9:39 AM writes...

One of the few times I used photochemistry, to try and isomerize a double bond we lacked a suitable lamp.

On looking for the supplier's address I found that their premises were 2 miles away!

The reaction worked well the first time but never again!

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24. Jose on October 29, 2010 10:22 AM writes...

barry- bismuth chloride??!!?? How by the moons of Jupiter did you come up with that little trick?

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25. Michael Lainchbury on October 29, 2010 11:57 AM writes...

I carried out my PhD under the supervision of Kevin (see point 20). I used the continuous photochemistry flow reactor and can therefore vouch for its ease of use. An HPLC pump is used to flow your solution through FEP tubing, which itself is wrapped around a UV lamp. It is as simple as that! The pump and lamp hardly even take up the corner of your fumehood. Give it a go, it will probably be the easiest scale up you will ever do!

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26. Michael Lainchbury on October 29, 2010 11:58 AM writes...

I carried out my PhD under the supervision of Kevin (see point 20). I used the continuous photochemistry flow reactor and can therefore vouch for its ease of use. An HPLC pump is used to flow your solution through FEP tubing, which itself is wrapped around a UV lamp. It is as simple as that! The pump and lamp hardly even take up the corner of your fumehood. Give it a go, it will probably be the easiest scale up you will ever do!

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27. medicnman on October 29, 2010 12:47 PM writes...

I remember a presentation I attended by a top tier pharma scientist. I am not too certain how public this info is, so I will keep it vague...

Production required a sterospecific cyclic coupling for scale up. The easiest way to perform the reaction was (unfortunately) also a very "cute" method. Using a flow process with tuned hv; IIRC, the process made it all the way to mid-scale production ( X-million dollar reactor, blah blah blah) and was then killed due to the technology being "unproven"... even though the process was better than any in traditional manufacturing...

It's really too bad that these things/ideas get shoved into a large broom closet before they can be implemented... then again... most novel things in industry die for the same reasons.

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28. newnickname on November 1, 2010 6:22 AM writes...

Anyone ever done bromination with NBS in CCl4 using a "sunlamp"? Some people think it's photochemical initiation (even though usually done in Pyrex, hence UV cutoff around 270 nm). Some say it's just thermal, from the hot lamp, which can reflux the CCl4. Others point out that unlike the good old sunlamps (the conical shaped ones, like patio lamps), new sunlamps have little or no UV at all due to regulations. (They produce UV but are required to have filtered lenses so very little gets out.)

I've got one of those old sunlamps around here someplace. A valuable relic!

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29. newnickname on November 1, 2010 11:15 AM writes...

Re: goo on your quartz. If you have access to an annealing oven (better: a glassblower with an annealing oven), a really high temp cycle can bake off almost anything without harming the quartz. I've had brownish, light amber, stained quartz cleaned up that way. (But not complete goo; I clean off the goo first.)

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30. Paul on December 19, 2011 11:27 AM writes...

The largest scale application of photochemistry (in terms of quantity of photons consumed) I've heard of is the Toray PNC process for caprolactam. Is that still used, and is there any other process that even approaches it in throughput?

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31. Mamie Nolder on August 18, 2012 9:48 AM writes...

I savor, result in I found just what I was having a look for. You've ended my 4 day long hunt! God Bless you man. Have a great day. Bye

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