About this Author
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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November 18, 2008
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.
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August 2, 2006
Posted by Derek
The "Law of the Lab" I alluded to the other day is:
Yields go down faster and more unexpectedly than they go up.
My synthetic organic readers will all know what I'm talking about here. We've all had the experience of running a reaction that we've done many times before, only to find it suddenly giving half the yield that it usually does. One of the most important jobs of a process chemist is to iron things like this out, making sure that they don't happen by either tracking down the variables responsible, or ditching the reaction entirely for something more reliable.
But med-chem types like me don't always have enough time to spend on that sort of thing, so we have a lot of reactions that are in a sort of unstable equilibrium with respect to reproducibility. As long as the different factors involved - purity of the starting material, rate of addition of reagents, efficiency of heating, cooling, and stirring, etc. - are within their (sometimes narrow) green zones, things are OK. But let one or more of them wander off, and the fuses start to blow. All reactions will go to pieces on you if you push such variables too much off their mark, but the difference is that a robust one will stand up to all the variations that you'd usually encounter. A wonky reaction is just one sensitive to something that can be over the line under normal conditions.
And there sure are a lot of them. And the different chemistry that starts happening when things cut loose has a far greater chance of messing things up than it has of improving them. Most organic chemistry reactions are very artificial systems - we're using energetic reagents and conditions to make molecules go down particular paths that they wouldn't do to any useful degree by themselves. There are so many other things they can find to do otherwise, and they'll explore those pathways if they get the chance.
So while it's not completely unknown for a random variation to improve a reaction, it sure is rare. Most of them lead to yet another synthesis of the sticky brown gunk which seems to be a universal thermodynamic sink of organic chemistry. You're threading your way through a swamp of that stuff when you do synthesis, and liable to sink down into it at any moment.
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May 7, 2006
Posted by Derek
It's been too long since I added another to my list of "Lowe's Laws of the Lab". They're something I came up with in graduate school, late one night in the lab. Looking back on them, I can tell I was in a bit of a bad mood when I put them together, but that doesn't narrow things down very much. I wasn't at my best for four or five years there, from what I can see.
Today's law is: You are in real trouble if someone knows more about your project than you do. That's a realization that hits people at some point in their graduate school career - preferably not much past the midpoint. It marks the transition from being a student to being a working scientist. After all, when you're still a student, other people are expected to know more about what you're doing than you do yourself; you're supposed to be learning from them.
But that has to change at some point. It's not that you suddenly get as smart or as experienced as the better grad students or post-docs in the group, let alone your PhD advisor. More talented people might be better at your project than you if they devoted all their time to it, but they're not doing that: you are. No, you get to where you know the ins and outs of your own project, your corner of the research world, better than anyone else. With that comes the realization that no one else is going to get your project done for you, and no one else is going to get you out of grad school. If you don't reach that level of involvement and expertise, something has gone wrong, and things will continue to go wrong for you.
That's because you need that experience if you go on to a further career in research. If you're going to be any good at your work, you have to be willing to become the expert on what you're doing, and not rely on others to have things figured out. Because what if they don't? This happens rather often, which is another valuable lesson that grad school is supposed to teach you. (Independent work isn't just for PhDs, either. Experienced Master's level employees at a drug company are expected to work more and more on their own as time goes on, too, and will be considered more valuable the more that they can do so).
I don't mean that it's a good thing to bull around the place, telling everyone that you know best what to do and to get out of the way. You never stop learning the research trade; anyone who thinks they've seen it all is mistaken. But I am saying that the opposite sort of behavior is a very bad sign. "What do you think about this?" is a fine question to ask people, but it should never shade over into "Tell me what to do". And "I don't know; that's his department" or "I never got around to understanding that part" are statements that should get any lab head or project leader removed from their position. If you don't know these things, who will?
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May 4, 2005
Posted by Derek
This time, it's the libelous assertion that:
You should only believe yields in Tetrahedron Letters papers if you also send off for everything you see advertised on late-night TV.
Well, that's a little unfair. Not completely unfair - just a little. There are papers in Tet Lett whose procedures are perfectly reproducible - I've used some of them. And on the other hand, there are impressive full papers in JACS that have steps whose efficiency could only be reproduced by angels or advanced space aliens. I shouldn't be so hard on one particular journal. But I'll stand by the principle behind this one, and extend it to include other brief communications in the journals that specialize in them. Chemical Communications is a worthy example from England, and Chemistry Letters gets the nod from Japan, and how.
Why the scepticism? I know that the editors of Tet Lett have been trying to remedy the situation, and things have certainly improved from the days when I wrote that law back in grad school. But people often use these journals as dumping grounds of one sort or another. When there's not enough room to write out full experimentals, who can say you're wrong? Three carbon-carbon bonds formed in the same reaction. . .hmmm. . .how about 85% yield? Do I hear 96%? Sold! If the scheme in the paper just has a lithium reagent drawn over an arrow, who's to say that they didn't optimize it out the wazoo with some esoteric blend of solvents and temperatures? Without a full experimental section, we'll never know.
There's always going to be a residue of doubt around a paper that lacks full details. With apologies to the non-chemists in the audience, it's time for some lingo: You say you took off a trityl group and your THP stayed on? Show me. Tell me just how you did that, so I can see if I believe it. You say you got a 94% conversion with that exotic chiral zinc reagent? Peachy! Tell me how you made it - and that includes what kind of zinc it was, and where you bought the darn stuff. I'd like to do that reaction, too, and seeing a bunch of arrows and yields isn't going to help me much.
The idea of the shorter-length journals (or should I say, the ideal) is that they'd be used for preliminary communications of work that would be reported in full later on. Sometimes they are, but I'd like for someone to go to the trouble of seeing just how often that really happens. No one, as far as I know, has ever done that (and I'm not holding my breath, because it'd be a bibliographic nightmare,) but it would be interesting.
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March 16, 2005
Posted by Derek
Time for another one of Lowe's Laws of the Lab. This time, it's some more advice for synthetic organic chemists, but it applies to many other situations as well: "Think Twice Before You Get Rid of the Old Route, or You Will Spend Months Saving Time."
It's an insidious trap, that one, because you stay busy the whole time (and staying busy in the lab is what it's all about, right?) I've spoken before about how almost any problem can be interesting, which means that you might as well work on ones that are both interesting and important. The same principle applies here: almost anything will fill your days doing research. You can come up with enough work to keep you going 20 hours a day - alternate reactions, different conditions, back-up plans. But to what avail? It can be hard to slow down enough to ask yourself.
I've fallen for this one more than once, of course. I'll hit some roadblock in the science, and think about how to get around it. I think up a plan, and it sounds good, so I'll start in on it - and run into another hitch just trying to get that to work. But there's a way around, that, too, of course - just try this other reaction over here, and if that doesn't work, well, there's a way around that one, too, and. . .
Notice that at some point in there, things go off the rails. If you don't watch out, you'll end up working on the third alternate route to the reaction that could make the second way around the problem in your possible backup route work. Busy? You bet, more work than you can handle! But productive? Well. . .depends on how you define productivity. If, like a fool, you measure it only by notebook pages consumed and flasks dirtied, everything looks fine.
I recall being impressed at one point in my career by a guy down the hall from me, who was working like a man possessed. Every time I went past his lab, he was in there cranking away, looking like a multi-armed Hindu deity with each hand holding an Erlenmeyer flask. Closer inspection revealed the truth. It turned out that he was working like this because he was doing almost everything in the longest, most wasteful way possible. No wonder it looked so much effort. Cutting your lawn with a bread knife is a lot of work, too, and will fill your day up like nothing you've ever seen.
This law of mine comes down to the old advice of "Measure Twice, Cut Once." It's a hard rule to remember, when you've got a box of saws and the wood is just sitting there, daring you to have at it. But it's worth looking through the clouds of sawdust to see if there's any real carpentry going on.
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February 27, 2005
Posted by Derek
Three years ago (the Silurian era in blog time) I starting a series on "Lowe's Laws of the Lab." Time to bring them back, because I'd like to have them all in their own category over there on the right. Long-time readers will get a couple of repeats here, but I'm redoing the old posts a bit. (And I owe copies of the list to several people who've written in - could y'all drop me another another line?)
First, some background: when I was in graduate school, I sat down one evening and made out a list of what seemed to be inescapable laws of organic chemistry. I circulated the list among my friends, and some copies made their way around to research groups at other schools - for all I know, there are yellowing copies of those early versions still taped to someone's hood, somewhere. Looking back at the list, it's clear that I was not in a good mood when I wrote it out - but I did say that I was in graduate school, didn't I? No need for redundancy, then.
None of the laws are particularly original. Most chemists will look at them and go "Yep!" For example, Law #1 is:
You can never have too much starting material.
I sure proved that one over and over during my graduate days, as readers will have heard me complain about. My project got so long and unwieldy that it sucked in every available gram of material. I'd start off again, on larger and larger scales, only to find myself back up at the frontier, holding this little flask with 10 milligrams or so of clear syrup: all that remained of all that time and effort. I went up to crazy, ridiculous scales - initial reactions that used the biggest round-bottom flasks buckets I could find. To no avail. It all led back to yet another little flask with a little oily stuff in it.
Nothing I've seen since has persuaded me that this law isn't universal. Oh, it's true that the occasional project will crash right after a big bucket of starting material has been made. Into storage it goes, until someone thinks up a use for it (at which time there won't be enough of it.) But those cases are far outnumbered by the ones where each lab hoards their precious material, and every new batch gets a parade of supplicants asking for - well, not all that much, really - just enough to do a couple of things we've been trying to get around to for a while - I think all we'd need is, oh, not even more than half of what's in your flask. . .
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