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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: Twitter: Dereklowe

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« Instant Med-Chem Wisdom | Main | Word For Word - But Why? »

June 10, 2009

Random Questions, Answered Randomly

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Posted by Derek

I had some requests to answer my own "Random Questions" from the other day, so here goes:

1. Does it bother you, or by contrast make you a bit proud, when you tell someone that you're a chemist and (as happens in about seven out of ten cases) they say "Oh, that was my hardest/least favorite/most boring subject when I was in school"?

Well, whether it bothers me or not, this happens all the time. Like pretty much every chemist in the world, I get to hear all about how people couldn't stand my subject in school. I take the point that mathematicians have it even worse, but it's not like we miss many of them with chemistry, either.

When people ask me what I do, I tell them "drug discovery", and I mention the diseases that I'm working on. That never fails to get some interest, and only then I spring on my listener the (often unexpected) info that this involves chemistry. Coming at it from that angle almost always leads to a good conversation, while coming at it from the "I'm a chemist" angle often leads to "Hey, look at the time!" effects. It's worth doing it in the right order, though - I like the effect when of showing that this boring/hard/useless subject actually leads to what most people find is a really interesting job.

2. How many thousands (10s, 100s of thousands) of dollars of unused equipment is sitting in dusty, unused storerooms at your company, because someone ordered it years ago and either (1) never got it to work, (2) was the only person ever to get it to work, or (3) found that it worked, but what it did wasn't worth doing that way?

Disused equipment? What is this disused equipment you speak of? Never have I seen such a thing. Why, those elaborate combichem machines in the sub-basement, they're just down there because they're so valuable. That rotating split-and-mix thingamabob and the multichannel parallel doohickey, we guard those closely.

Hah! Actually, I remember a couple of labs where this stuff wasn't in the basement at all. No, it was out there in the hoods, taking up space and slowly gathering dust, a standing reproach to everyone who walked past it. It would have been better off out of sight, but no one quite had the heart. And besides, it would sometimes get turned on for visiting groups - there was that.

3. Have you ever set up a reaction and thought "Boy, I sure hope that this doesn't work"?

I suppose that this is somewhat shameful, but yes, I have set up reactions hoping that they would fail. Usually it's been when I've had to use a particularly distasteful reagent (sodium ethanethiolate, for example), and I don't want to end up using it on a larger scale. I remember a fellow grad student presenting his work while we were trying to get our PhDs, and he detailed a deoxygenation step which only worked when his intermediate was made using a hefty excess of thiophosgene. "As fate would have it", said his long-suffering labmate from the back of the room.

And I've had less honorable instances, dating back to grad school or early in my industry career, when I was more or less forced to run a reaction a particular way even though I felt there was no chance for it to work. So yeah, in those cases I did look forward to saying "Yes, I tried your idea. And no, it didn't work any better than mine."

4. For the drug discovery people out there, what per cent of compounds you've made over the years would you guess dissolve in plain water to any real extent? Is that figure going up, or down?

The figure is hard to estimate, but it sure isn't high. Things that dissolve in straight water are hard to work with, y'know - they tend not to extract so well into ethyl acetate or dichloromethane, and they don't run so great on silica when you try to clean them up. That's worth another blog post in itself - the way that our standard chemistry techniques tend to push us away from a lot of polar molecules that might be just what we need for med-chem.

5. What, off the top of your head, would you say in retrospect is the most time-wasting chemistry you've ever ended up doing?

Tough competition. I'm tempted to say vacuum pyrolysis of corn starch to make levoglucosan, but I needed that for my dissertation, so it can't be called useless.

The real winner, in retrospect, has to be a series of reactions I did in my first couple of months in my grad school group, when I was still taking classes and working in the lab part time. I was presented with a route to a tetrahydropyran compound that we needed, a four-or-five stepper that involved an aluminum alkyne opening an epoxide, a Lindlar hydrogenation, a ring closure. . .I can still draw the damn thing on the board, now that I think about it, and it's been twenty-five years ago this spring. Being a first-year grad student, I hopped to it - and hopped right into the mud, since the route bogged down (and how) at the ring closure stage). I kept at it for a while, and then one evening I decided to look up my target compound in Chemical Abstracts.

That wasn't so easy in those stone ax and bearskin days - command-line access to CAS via a rockin' 1200 baud modem and a terminal was still a few months away. I paged through the five-year indices, and found. . .my compound. In a Tetrahedron paper. Two steps, from stuff you could buy from Aldrich, and you form the ring in the first step through a Prins reaction. I was shocked. Surely this couldn't be a known compound. Surely someone must have looked the structure up before coming up with that route I'd been given.

Surely not. And thus did my lab education begin. So you know, when I think about it, even though those first couple of months were a waste of chemicals and effort, perhaps they weren't as much a waste of time as I thought. . .

Comments (20) + TrackBacks (0) | Category: Graduate School | Life in the Drug Labs


1. Tom Davies on June 10, 2009 8:44 AM writes...

Now rather than 7/10 people telling you that they didn't enjoy Chemistry in school, do they instead ask "Could you cook meth like that guy in 'Breaking Bad'?"

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2. Anonymous on June 10, 2009 8:44 AM writes...

5. That levoglucosan prep is totally cool - what's the problem?

Finding a better prep for your starting material in the literature is a time honored tradition. As I recall, Emil Fisher started his Nobel lecture with "Well, nobody told me Aldrich sells glucose ..."

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3. Stuart on June 10, 2009 9:33 AM writes...

As one of my PhD labmates was fond of saying: a week in the lab can save you a whole hour in the library...

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4. CMCguy on June 10, 2009 9:41 AM writes...

Thanks Derek for another entertaining post.

A5: I can't count the number of times I "rediscovered" chemistry or compounds in the lab because I did post-literature search instead of library effort upfront. It may be easier these days with online database systems but there still were (are?) gaps so if one thinks something "must have been done/made before" there is a chance it was, usually by Germans or British pre-WWII. Likewise many things get (got) buried in Patents so until you do diligence there may have incomplete knowledge.

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5. davesnyd on June 10, 2009 10:22 AM writes...

I'm a physicist, not a chemist. The variation I often hear on:

'Does it bother you, or by contrast make you a bit proud, when you tell someone that you're a chemist and (as happens in about seven out of ten cases) they say "Oh, that was my hardest/least favorite/most boring subject when I was in school"?'

Is from an MD I've just met who is treating me or a family member.

"Really-- it was freshman physics that almost kept me out of medical school."

I try to keep from explaining that telling me they found "F=ma" difficult does not engender a lot of confidence.

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6. Norepi on June 10, 2009 11:49 AM writes...

#1: I've gotten the Breaking Bad remarks too. They're especially bad when they become pseudo-ethical in nature, i.e., "Would you ever do what the guy in the show does? Because you're a chemist? Huh? HUH?!"

#3: Another favorite variant: an hour in the library can save you six days in the hospital.

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7. John Thacker on June 10, 2009 1:31 PM writes...

Strange, I'm a mathematician and no one ever says anything like that to me when I tell them my profession. Perhaps that goes without saying for math.

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8. retread on June 10, 2009 1:33 PM writes...

#5 Davesnyd:

Agree. If you don't have the mental horsepower to comprehend f=ma or get through organic chemistry, you should not be trusted with the lives of the sick.

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9. CMCguy on June 10, 2009 3:32 PM writes...

#8 retread: you mean you are not in favor of the movement to drop Org Chem for pre-Meds? (BTW- Did you have a Sceptical Chymist post on this a while back? I searched but did not find) My confidence in (potential)MDs was shaken long ago after TAing a fair number who were accepted to Med School but who could not even run a TLC would having their hand held (often pitied the Nurses and Lab Tech that would have to deal with them) much less answer a question that was not in the Textbook.

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10. milkshake on June 10, 2009 3:39 PM writes...

The Breaking Bad question is best answered "and how do you think I paid my way through the college?"

Thiophosgene does not smell bad: it has a very intense aroma thats almost pleasant (like 1,3-dithiane) and a beautiful brick-red color. Not fecal as ethyl mercaptan.

Levoglucosan: In Prague I worked right next door to a group that was making the levoglucosane-derived epoxides. You could tell by the smell when they were pyrolyzing a new batch. They had a giant thermostat-controlled vacuum retort and were doing up to two kilos at one go (the yield is atrocious, about 10% depending on how much you purify it in the end). Isolating levoglucosane from the obtained caramel was not the most popular group job. Even less popular was unscrewing the retort and cleaning the asphalt from the inside

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11. knowsomeofthechemist on June 10, 2009 6:45 PM writes...

medicinal chemistry......
at Vertex?

some would say that's kind of a stretch

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12. spsp on June 11, 2009 4:03 AM writes...

Time-wasting: In a total synthesis project for a marine toxin, there was this problem that methylation of a secondary ketone didn't give the right diastereomer. The researcher had tried MeLi, two other methyl anion equivalents and failed. So, I was conscripted to do it by a completely different route, where you alkylated a methyl ketone instead. Initially, the model compound liked to polymerize (9% yield! yay!) and the model reactions gave atrocious yields in general. The tests with the actual compound weren't an overwhelming success either, but I wasted two months on this, only to learn that the researched had tried a titanium-based methyl anion EQV that *had* worked as intended.

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13. cookingwithsolvents on June 11, 2009 12:56 PM writes...

1. It used to bother me a whole lot. It bothers me less now but I still don't like the response. I realize it is somewhat of a backhanded compliment along the lines of 'oh cool you are good at something I'm not' but I don't find that comforting. I also can report the same kind of effect as Derek when I tell people "I research ways to make solar cells" vs "I'm a chemist".

2. Our lab has a ton of fittings and valves around which no longer get used but have not been recycled or tossed. Other than that we just have one or two gizmos that collect dust. Even the syringe pumps get used with some frequency (unfortunately).

3. If you never set up a reaction w/o wanting it to fail YOU ARE DOING IT WRONG. (science, that is) A lot of synthetic groups don't report controls with their catalysts and one does wonder from time to time. Other things pop up, like the "Pd-free" cross coupling which wasn't (they had only claimed it was to xxx detection limit, though, so good for them to keep on it and find the answer). Another example: I always wonder how many metal triflate-catalyzed reactions would work with triflic acid. . .

5. I've got about 2.5 years of my grad career that isn't even a footnote in my thesis so a lot could fit here. One newer example, though, was a particular variation of the condensation with a pyridyl aldehyde. Worked with benzaldehyde, worked in the lit (86% ha!), never worked beyond ca. 10% for me, if that. And that's using like 10+ eq of the "anion" component. Still get pissed about that one...bah.

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14. milkshake on June 11, 2009 1:17 PM writes...

pyridyl aldehydes are super reactive, like 2 orders of magnitude over benzaldehyde. (The same holds true for nitrobenzaldehydes. See why they do organocatalysis aldols suspiciously often with nitrobenzaldehyde - it won't racemize because of the reverse-aldol...)

I don't see why they should fail in Knoevagel - my suspicion is that you got Michael addition onto your cinnamic acid product (that had the pyridine ring) with another equiv of the nucleophile.

Usually you need to change reaction conditions or even reagent when you have a huge change in the substrate.

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15. Process Chemist on June 11, 2009 2:56 PM writes...

I know that it would make drug discovery that much more complicated, but since ultimately (i.e. on scale) one shouldn't be using dichloromethane or silica gel anyway, there's much more to your point #4 than simply water solubility.

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16. Math/Chemistry on June 14, 2009 7:16 AM writes...

No one ever wants to talk about my major-- double major in chemistry and math. Every time I've said this I just get shudders and pained looks. An occasional groan.

(Actually that's how I weed out potential friends, the ones who look excited when I say that are a) probably insane and b) probably going to be good friends)

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17. ElPolloLoco on June 16, 2009 3:11 AM writes...

I'm a lowly software developer, and I get that all the time ("Wow, that's great, I have so much trouble with computers!")

I stole my rejoinder from Einstein: "Well, you can't imagine how much trouble *I* have with them."

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18. Bob Hawkins on June 18, 2009 10:03 AM writes...

"Thiophosgene." Just the name made me laugh. I can afford to laugh, I'm a physicist, so I won't ever have to work with it.

Physicists say that the most startling result of MRI technology was the discovery that MDs can be taught to transfer helium.

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19. Danu Bratakusuma on April 29, 2010 3:33 PM writes...

I want to ask about levoglucosan,,
Can you show me what is the reaction if I want to make a hydrocarbon compounds from levoglucosan with deoxygenation and catalyst zeolit,,
thank you very much

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20. Frank on May 6, 2015 7:24 AM writes...

I'm a software engineer now, but I majored in pure maths.

It is somewhat depressing - it's not that people say it's *hard*, it's that nearly everyone says how boring and unpleasant maths is.

I also get the oddest looks when I describe my interests, which tend to the arty, as well. 'You're a mathematician and you write fiction*?'

And then either they scoff or they look a bit scared, like a person would have to be some kind of abnormal super-genius to be good at (and interested in) both those things.

*as yet almost but not quite entirely unpublished

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