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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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« Genius, Sheer Genius | Main | Jobs, He Says »

February 12, 2014

The Bread Rolls of Synthesis

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Posted by Derek

Over at Colorblind Chemistry, I came across a quote from Fritz Haber, writing about his thesis work:

The thesis is miserable. One and a half years of new substances prepared like baker’s bread rolls… and in addition, lots of negative results just where I was looking for significant results, and further, results that I cannot even publish because I fear that a competent chemist will find them and prove to me that the camel is missing its humps. One learns to be modest.

Now, Haber was definitely someone to take seriously. He's showing up in "The Chemistry Book", for sure, both for his historic ammonia process and his work in chemical warfare. He was a good enough chemist to know that his doctoral work was not all that great, although he seems to have followed my own recommended path to get that degree as soon as is consistent with honor and not making enemies.

The post's author, MB, wonders what this says about organic synthesis in general. How much of it is just baking bread rolls, and how bad is that? My own take is that the sort of think that Haber was regretting is the lowest form of synthesis. We've all seen the sorts of papers - here is a heterocyclic core, of no particular interest that anyone has ever been able to show. Here it has an amine. Here are twenty-five amides of that amine. Here is our paper telling you about them. Part fourteen in a series. In six months, the sulfonamides. This sort of things gets published, when it does, in the lowest tiers of the journals, and rightly so. There's nothing wrong with it (well, not usually, although this stuff isn't always the most careful work in the world). But there's nothing right with it either. It's reference data. Someone, someday, might stumble into this area of chemical space again, and when they do, they'll find a name scratched onto the wall and below it, a yellowing pile of old spectral data.

I've wondered before about what to do with those sorts of papers. There are so many compounds in the world of organic chemistry that the marginal utility of describing new random ones, while clearly not zero, is very, very close to it, especially if they're not directed towards any known use other than to make a manuscript. So if this is what's meant by baking rolls, then it's not too useful.

But I'm a medicinal chemist. When I start working on a new hit structure, I will most likely turn around and put the biggest pan of bread rolls into the biggest oven I can find. This, though, is chemistry with a purpose - there's some activity that I'm seeking, and if cranking out compounds is the best and/or fastest way to move in on it, then crank away. I'm not going to turn that blast of analogs into a paper; most (maybe all) of them will be tested, found wanting, and make their way into our compound archives. Their marginal utility is pretty low, too, given the numbers of compounds already in there, but it's still by far the best thing to do with them. Any that show activity, though, will get more attention.

I really don't mind that aspect of the synthesis I do. Setting up a row of easy reactions is actually kind of pleasant, because I know that (1) they're likely to work, and (2) they're going to tell me something I really want to know after I send them off for testing. Maybe they aren't bread rolls after all - they're bricks, and I can just possibly build something from them.

Comments (15) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs


COMMENTS

1. CMCguy on February 12, 2014 10:19 AM writes...

I would be more interested in a place that was willing to publish "negative results" as this could often dissuade people from spending too much effort on low probability application to their work or alternatively prompt other "competent chemists" into figuring out how to make something work in face of poor precedent.

Permalink to Comment

2. a. nonymaus on February 12, 2014 12:34 PM writes...

Re: 1
I get occasional spam from some "All Results Journal" that seems to be what you have in mind. I've not looked into how dodgy they may be, though.

Permalink to Comment

3. Anonymous on February 12, 2014 12:39 PM writes...

The version in Spanish: "Ladron que roba ladron tiene mil anyos de perdon" (poorly translated to "A thief who robs a thief gets a thousand years of pardon")

Permalink to Comment

4. Anonymous on February 12, 2014 12:42 PM writes...

#3: Wrong thread

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5. gippgig on February 12, 2014 2:37 PM writes...

Is there a (or several) central repositories for data on compounds? Combine all the data on all the compounds that have ever been made and you have an enormous data set that would be very useful for developing models, testing theories, etc.

Permalink to Comment

6. Sarkis Dallakian on February 12, 2014 5:07 PM writes...

Instead of publishing why not make a YouTube video or as #5 suggested some sort of central repositories for data on compounds.

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7. oldnuke on February 12, 2014 5:10 PM writes...

A new field -- Combinatorial Baking?

Permalink to Comment

8. Curt F. on February 12, 2014 5:21 PM writes...

@7. oldnuke.

Check out http://www.youtube.com/watch?v=8YEdHjGMeho ... not a new field at all.

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9. rhodium on February 12, 2014 5:28 PM writes...

It is not just organic chemists who are guilty of this. Look into the older organometallic literature, JCS A and the like. It seemed one had to make the triphenylphosphine and the diphenylmethylphosphine and the triphenylphosphite and so on and so on analog. I recall wondering if there was some requirement that british chemists had to make 100 new compounds to get a Ph.D.

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10. Morten G on February 13, 2014 6:52 AM writes...

You guys are talking about nanopublications. There's a website and everything.

Anyway, if Haber's PhD hadn't been so meh do you think he would have become such a great chemist? I mean, might he not have learnt from failure? I'm not advocating that academic supervisors should be as terrible as they often are but I don't think a mediocre PhD is predictive of what the person can achieve.

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11. anon on February 13, 2014 10:46 AM writes...

IMO publishing negative results would be futile anyways. I know plenty of chemists who would see the failures as an opportunity to make the reactions work.

Along those lines it would always be tough to tell if the work was just sloppy, adventitious water, oxygen, bad reagents etc. or if the reaction failed for theoretical reasons.

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12. MTK on February 13, 2014 11:09 AM writes...

For some reason I'm imagining Fritz Haber's standards to be higher than most.

His breads may have been just bread, but there's nothing wrong with that if they were damn good bread.

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13. Hap on February 13, 2014 12:22 PM writes...

"Bricks" might not be the best term for what you're trying to make - maybe biodegradable Legos?

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14. Anonymous BMS Researcher on February 14, 2014 12:23 AM writes...

@Sarkis: totally off topic, but I notice your blog mentions bee pollen on cars. Look up Meselson Yellow Rain online for a truly fascinating story about that!

Permalink to Comment

15. No Nobel Prize for Aldol Reactions, Hopefully on February 15, 2014 7:03 PM writes...

The only way to save organic synthesis is that governments stop funding professors.

It has to be corporate money that drives research. Corporations know exactly where the problems are, not governments.

This way, a lot of money would go toward the energy-related fields and not to pointless reaction methodologies development and/or useless total synthesis.

Repeat after me: No more money for total synthesis, please! X 100

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