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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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November 18, 2008

Cheese Dip and Hydrochloric Acid

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Posted by Derek

One of the more wide-ranging on my “Lowe’s Laws of the Lab” list is this: The secret of success in synthetic chemistry is knowing what you can afford not to worry about.

That’s because you have to have a cutoff somewhere. There are so many potential things that can affect an experiment, and if you have to sweat every one of them out every time, you’re never going to get anything done. So you need to understand enough to know which parts are crucial and which parts aren’t. I think the beginnings of this law came from my days as a teaching assistant, watching undergraduates carefully weigh out a fivefold excess of reagent. Hmm. Did it matter if they were throwing in 4.75 equivalents or 5.25? Well, no, probably not. So why measure it out drop by drop?

Tom Goodwin, the professor responsible for teaching me inmy first organic chemistry course, once advanced his own solution to this problem. Growing weary of the seemingly endless stream of lab students asking him “Dr. Goodwin, I added X by mistake instead of Y. . .will that make a difference?”, he proposed creating “Goodwin’s Book of Tolerances.” I think he envisioned this as a thick volume like one of those old unabridged dictionaries, something that would live on its own special stand down the hall. “That way,” he told me, “when some student comes up and says ‘Dr. Goodwin, I added cheese dip instead of HCl – will that make a difference?’, I can walk over, flip to page thousand-and-whatever, and say ‘No. Cheese dip is fine.’”

According to him, a solid majority of these questions ended with the ritual phrase “Will that make a difference?” And that’s just what a working chemist needs to know: what will, and what won’t. The challenge comes when you’re not sure what the key features of your system are, which is the case in a lot of medicinal chemistry. Then you have to feel your way along, and be prepared to do some things (and make some compounds) that in retrospect will look ridiculous. (As I’ve said before, though, if you’re not willing to look like a fool, you’re probably never going to discover anything interesting at all).

Another challenge is when the parts of the system you thought were secure start to turn on you. We see that all the time in drug discovery projects – that methyl group is just what you need, until you make some change at the other end of the molecule. Suddenly its suboptimal – and you really should run some checks on these things as you go, rather than assuming that all your structure-activity relationships make sense. Most of them don’t, at some point. An extreme example of having a feature that should have been solid turn into a variable would be that business I wrote about the other week, where active substances turned out to be leaching out of plastic labware.

But if you spend all your time wondering if your vials are messing up your reactions, you'll freeze up completely. Everything could cause your reaction to go wrong, and your idea to keel over. Realize it, be ready for it - but find a way not to worry about it until you have to.

Comments (18) + TrackBacks (0) | Category: Lowe's Laws of the Lab | Who Discovers and Why


COMMENTS

1. john.spevacek@aspenresearch.com on November 18, 2008 9:00 AM writes...

I think you tied yourself in notes today with the logic - that's o.k., because I would have done it to you if you hadn't. You're basically saying that you should know ahead of time what will/won't make a difference, until you find out later that you were wrong about your assumptions.

"If we knew what we were doing, it wouldn't be called research."

I think a better way to summarize the lesson(s) here is to make some assumptions so that you don't lock up with analysis paralysis, but then when something goes wrong, be able to identify ALL of the assumptions you made, both explicit and implicit. It's a huge step towards critical analysis of one's own experiment's or anyone elses experiments.

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2. john.spevacek@aspenresearch.com on November 18, 2008 9:02 AM writes...

Better make that "knots", not "notes".

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3. HelicalZz on November 18, 2008 9:34 AM writes...

Every law has a corrollary.

So let me put 'pH' as an item that 'is almost always important and not worried about often enough'. Perhaps also 'there is no accrual proton accounting'.

Zz

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4. RB Woodweird on November 18, 2008 12:36 PM writes...

You said it, brother. I recently got a bunch of SOPs to follow. Everyone who wrote them or ever ran them is long gone. So I have to go through them, thinking: OK, here it says to dry the precursor. How long? How hot? Why didn't they flame the glassware, then? Why do they want argon instead of nitrogen? Why did they add this reagent - it seems redundant. Why did they use this type of analysis - it seems inadequate. Why didn't they, etc.

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5. Jose on November 18, 2008 12:50 PM writes...

My personal feeling is that molarity, internal temperature, and rate of addition are the true uncontrolled variables in most experiments.

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6. DavidInRichmond on November 18, 2008 1:11 PM writes...

This rule also applies to other sink holes of one's time, such as Blacklight Power.

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7. Sili on November 18, 2008 1:26 PM writes...

If it wasn't for the confounding factors of talent and luck, one could imagine that undergraduate courses like that would be a good way to test just how robust a reaction is (sez the guy who failed the Cannizzaro and everything more complicated than that ...).

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8. Anon on November 18, 2008 4:04 PM writes...

I have long suspected that a lot of the best chemistry is done by feel and not too much thought

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9. CMC guy on November 18, 2008 5:28 PM writes...

#8 Anon sure chemistry may often seem done without much thought at times, because as Derek points out there could be too many things to worry about one could get paralyzed by over analysis rather than just seeing what happens.

#5 Jose that is frequently correct in much lab work but when move to process realm such factors often are critical components to understanding and optimization.

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10. Morgan on November 18, 2008 5:57 PM writes...

Son of a gun! Derek is the author of the Laws of the Lab!! Nearly 20 years ago, I first saw the list when starting grad school at MIT. I believe that list came from Jeff Huff, who had been at Duke if my tired old brain remembers correctly. I've carried on and propagated that list for years. Very cool to finally learn the genius of those cynical, but more-often-true-than-not guidelines. Thank you!

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11. Anonymous on November 18, 2008 10:56 PM writes...

I dislike when I see something exotic in a methodology paper without any comment whatsoever explaining it. One paper I was looking at used N,N-dimethyl pyrazine as the amine base to soak up some acid that gets generated. Well, I'm sitting there thinking, hmm, is that really necesary? Why not hunigs or triethyl amine? You'd think it would have been easy to say, "With Hunigs base we got X% yield, with the exotic base we got (X+3)% yield".

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12. Eric on November 19, 2008 12:36 AM writes...

That principle seems more generally applicable than just in chemistry. I switched over to cell biology from organic chemistry, and half of the productivity of the older students, I think, has to do with figuring out what's dispensable or fudge-able.

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13. bcpmoon on November 19, 2008 1:34 AM writes...

From a process perspective just two words: Critical Parameters.

It makes life a lot easier in scale-up when the medicinal chemist has run some experiments pushing the envelope. Better, forgot some things or had some labware malfunction and still got the right stuff out. Properly documented, these runs are a gold mine.
On the other hand, when you are sailing uncharted waters, changing more than one parameter at a time makes it more difficult to nail down what went wrong or not or what? But that´s whats DOE was invented for.

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14. processchemist on November 19, 2008 4:13 AM writes...

bcpmoon

DOE in process chemistry can be a wonderful tool, or sophisticated way to demonstrate the obvious.
Almost never seen "properly documented runs" coming from medicinal chemistry, where more years passes, more the hurry to crunch out molecules some way rises...
The more classical example: stirring. Most of the times no specification if magnetical or mechanical, and in many reactions stirring can make THE difference. Also true that mechanical stirring working on 500 mg of starting material is nonsense...

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15. Anonymous BMS Researcher on November 19, 2008 6:52 AM writes...

"Eye of newt, and toe of frog,
Wool of bat, and tongue of dog,
Adder's fork, and blind-worm's sting,
Lizard's leg, and howlet's wing,--
For a charm of powerful trouble,
Like a hell-broth boil and bubble."

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16. Derek Lowe on November 19, 2008 9:22 AM writes...

Morgan, Jeff and I were in the same year at Duke, and he was right down the hall from me. I can well remember a noise he made down there late at night when he filtered a small sample through the Wrong Kind of Membrane Filter and watched it dissolve right in front of his eyes. . .I could hear that one in my lab, easily.

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17. Anonymous on November 19, 2008 9:29 AM writes...

So I think this has been asked before, but are the compleat Lowe's Laws of the Lab posted anywhere? They were a hoot, and sadly profound ...

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18. Kevin on November 19, 2008 11:07 AM writes...

One of our associate scientists was presenting some of his work. He got one reaction to work by adding "a pinch of sulfur." At first we though we had misunderstood him since there was no conceivable rationale for adding S8, and his English is not so good. Excuse me did you say sulfur? Really? Why on earth...

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