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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

« Into The Trackless Wilderness | Main | Beta-Secretase: Not So Fast? »

May 16, 2007

Sunbeams, Single Electrons, and You

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Posted by Derek

A comment on the most recent post got me thinking about photochemistry. I've done that, but just for one project, and I'll bet that many other chemists have had the same pattern.

A lot of people who've never done light-powered chemistry find the idea neat - no nasty reagents, no masses of inorganic salts to remove, just shine a light on the flask and you're done. It seems like Chemistry Of The Future - you feel as if you should be wearing some sort of white jumpsuit with padded shoulders if you ever get around to setting some up.

The idea is appealing, but the reality is less so. Photochemistry often isn't as clean as you picture it being - a look at your clear starting solution gradually turning orange and brown under the punishing glare of the UV lamp tips you off about that. Things get hot in those setups, too, which also doesn't fit the sleek, cool, futuristic template. When you take a hot flask of darkened gunk off the lamp, it's hard not to wonder what would have happened if you'd just cooked it in the oil bath the old-fashioned way.

Probably not what happened under illumination, though. Light does do some odd stuff, and there are some neat-looking reactions that can be run that way. The problem is, many of those neat reactions are free-radical mechanisms, and that's what leads to a lot of that colorful crud. There are a lot of concerted mechanisms that can be driven photochemically, and those should (in theory) be cleaner, but in my experience, it can be hard to keep a lot of radical chemistry from going on, and it can swamp the cleaner stuff right out.

Radical reactions were all the trend back when I was in grad school (get off my lawn!), but while they've never disappeared, they've never caught on to become an essential part of every organic chemist's toolkit. There are several well-used reactions that run (or can run) by single-electron processes, but as a class, free radicals still have an exotic, slightly disreputable look to them. People will look at a potential transformation on the board, and say "Hmm, I bet I could do that by a dipolar cycloaddition", or "I'll bet that I'll able to do an olefin metathesis to get that". There are dozens of reaction classes that you reach for without thinking twice: metal-catalyzed coupling, epoxide opening, reductive amination, electrophilic ring substitution. But do you reach for a free-radical closure to a five-membered ring, a well-trodden radical process if ever there was one? Well, I don't, anyway - and I've done the things. Do you?

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Zany on May 16, 2007 9:36 AM writes...

Radical Reactions in Organic Synthesis by Zard - outstanding book covering the area. I used to believe radical reactions only worked well on "tailor-made" substrates. Reading this book changed that opinion. Compared with some of the in-style transition metal catalyzed cyclization chemistry coming out daily (which in most cases ALWAYS requires tailor-made substrates), radical reactions hold up remarkably well. A very underappreciated field, IMHO.

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2. milkshake on May 16, 2007 9:44 AM writes...

I am all in favor for visible light photochemistry that is catalytical in photons - you just need some common floodlight next to the flask, to get the process (usualy it is a radical chain) going.

Reactions that are stoechiometric in photons are inherently going to suck on scaleup; one mol of photons is hell lot of light and the typical quantum yields are below 10% and lots of photons won't make it through the glass (especially in the UV range) and then there is the problem with the meager electricity-to-light conversion efficiency of the the UV lamp; so you end-up with generating a huge amount of waste heat that has to be removed. Wrapping your hood around into Al foil and trying not to ruin your eyes by accident is also not fun./

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3. Hap on May 16, 2007 12:30 PM writes...

Our research group used radical addition of thioacetic acid to terminal olefins followed by hydrolysis as the standard method to make thiols; it worked pretty well but stank.

A lot of radical closures, etc. seem to require large amounts of tin - there are alternatives (catalytic tin, (TMS)3SiH, etc.) but the reliance on tin probably inhibits their use.

Permalink to Comment

4. Fred on May 16, 2007 2:37 PM writes...

Thanks for the image of you in a white jumpsuit with padded shoulders.

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5. Wavefunction on May 16, 2007 2:52 PM writes...

I guess the 5-exo-trig ring closing radical addition is still pretty commonly used?
I always remember those radical syntheses that Paul Wender did.

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6. Anonymous on May 16, 2007 6:34 PM writes...

Derek,

Where is the love for photons? One of your fellow travelers from Hendrix to Dook was quite successful in employing photochemistry for total synthesis. This was at much higher quality university though. :)

Permalink to Comment

7. azmanam on May 17, 2007 3:36 PM writes...

Anon-

If he's the guy I think you're thinking of, then I'm from that group ... and I'm doing photochemistry in my total synthesis. Right now, the hardest part is making the photochemistry precursor.

I have used the lamp to make singlet oxygen for a 4+2 reaction. Rose Bengal was the sensitizer. I used water to cool the jacket around the lamp to help with that heat problem. Except one time the line got kinked... and I started boiling the methanol solvent. Next thing I knew my hood was a lovely shade of pink. Man that stuff was a pain to remove.

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8. walkerma on May 18, 2007 8:08 PM writes...

The funny thing is that radical reactions were the first type of organic reaction I learned as an undergrad uisng Morrison and Boyd.

...recall too that there was a time when hv initiated radical reactions were the rage (much like organic catalysts of today)...simply dial in choose a wave length to effect a reaction of one's choosing...

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9. radical chemist on May 21, 2007 2:18 PM writes...

Radicals have come a long way in the last few years. In particular, the yields and stereoselectivities of conjugate radical additions are pretty much even with those achieved by cuprates. Yes, there is indeed still the Tin-issue, but as mentioned before, there are alternative H atom donors out there. I'm not familiar with any attempts to scale these reactions up, however.

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