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
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Category Archives
August 25, 2008
Posted by Derek
You need access to vacuum if you’re going to work at the bench in chemistry. In fact, you need more than one kind. Reasonably hard vacuum (well, by our standards, which is laughable by the standards of the physicists) is down in the single Torr or below – that is, less than about 1% of normal air pressure. We use that for pulling out residues of water or organic solvents from our compounds. You can’t usually see it happening from the solid ones, but the syrupy liquids will foam up or blow a long series of thick bubbles when the vacuum is applied. The foam can be an irritating problem at times; some things will fill your flask with sticky bubbles and go right on up into the vacuum line if you’re not watching them.
The lesser vacuum lines are used for bulk evaporation of solvent (on your rotavap) and for filtering things off. We do an awful lot of both of those, too, and a full vacuum-pump pull is too vigorous for them in most cases. Evaporating down reactions is a constant task in an organic chemistry lab; I’d rather not think about how much of it I’ve done over the years. As for filtration, there are many cases where a solid product can be filtered out of the bulk liquid (which is good) or where some undesired solid by-product has to be filtered out before you can go on (not as good).
The low-tech way to get the sort of pull-it-though vacuum you need for these things is a water aspirator. You don’t see these as much any more, and you don’t see them at all in industry, since they necessarily pull solvent vapors into the water stream. But they work. An aspirator is basically a narrowing tube that hooks up to a hard-spraying water tap and has a sidearm fitting. The accelerating blast of water pulls the air in the tube along with it as it goes, creating a useful vacuum. If you wanted to make one rather more environmentally friendly, you’d keep a well-stocked dry ice condenser in line with it to trap out the solvent vapors before they go down the drain (which is what your rota-vap should have on it, anyway), but even with that, you’re always going to be turning the water flow into a waste stream. As I say, you don’t see them as much these days.
But we used them back when I was in grad school, that’s for sure, mostly for the rotavaps. If you wanted to keep things from splashing around back in your hood, you attached some rubber tubing to the other end of the thing and ran it further down the drain a bit.
Well, one day, one of the guys in the lab next door to me was shocked to see water blasting around in his hood. It was a real fountain, just geysering out full blast from what must have been a cracked water line or something in the back. He ran over and immediately shut off every tap – but to no avail. Roaring, showering water everywhere. Getting a look at the source, he realized, to his consternation, that the water was coming up out of the drain in the back of his hood. I remember standing there with him, staring at this in disbelief. It looked like a special effect. How on earth could you get water blasting up out of a drain pipe?
Suddenly it hit me. I ran around to the other side of the lab, where a new Japanese post-doc had taken up residence. “Masa”, I asked him, “Did you just put that rota-vap in your hood today?” “Yes, yes, just started it today”. There was a water aspirator flooshing away back in the back of his hood. “Did you put some rubber tubing on that thing?” “Tubing? Oh, yes” “How much?!” “Whoaaa. . .” He spread his arms to indicate the mighty extent of the rubber tubing he’d added.
Mighty, indeed. He’d run the stuff down his drain, through a horizontal pipe and right through a T joint, and back up out of the drain of the other guy’s hood, which backed on to his. So when he turned his water on full throttle, he immediately started irrigating his labmate’s space. We finally go thing turned off, and trimmed back the rubber tubing to a more reasonable length (like, not seven feet), and order was restored. For a while.
Note: if you want to see How Not To Do It to a really expensive vacuum rig, try here.
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August 19, 2008
Posted by Derek
I wanted to recommend this post by Milkshake over at Org Prep Daily (and not just because he liked the recent column I wrote for Chemistry World). I was writing about the limited number of reactions that some med-chem labs get locked into, and the effect of this both on the compounds that get made, and on the motivation of the chemists. Milkshake has a good set of recommendations on how to avoid the boredom trap, and I recommend checking them out. He ends with the following:
You should care about the chemistry methodology and do things not just to crank out the final compounds to fill up the testing queue. Your boss (has) perhaps lost all his chemistry interest already and maybe he is unnerved about the project progress and pushes people hard - but while you try not to get fired you don’t necessarily want to think like your boss (and end up wretched). If you continue to look at your research project with curiosity and do things also for the sake of your chemistry interest you are likely to be more original because thinking about the methodology will suggest new directions in your medchem project. You may get accused of playing with chemistry and going off-tangent but you will likely remain more content and productive. . .
And this is all true. Most projects need some oddball compounds thrown into them, to keep things interesting (and honest), and it’s the people who are keeping up with the literature who will probably make them. I went through a period some years ago when I didn’t stay current with the journals very well, and if I’d let that continue to slide, it would have had a bad effect. (RSS was one of the things that saved me!)
But there’s another very good reason to stay sharp and run the unusual reactions, though: the boring reactions are increasingly going to be shipped to someone else, someone who probably works in a very different time zone. Yep, this is my “give ‘em something they can’t get in Shanghai” talk again. The outsourcing shops are there to pound out molecules as quickly as possible, and they’re going to use well-established chemistry as much as they can. Now, that’s the same pressure that operates in most med-chem projects, but I strongly recommend differentiating yourself if possible.
Be the person who runs the new stuff, who reads the literature and adopts things quickly, and who makes compounds that aren’t like all the stuff that’s already in the screening deck. You don’t have to go completely crazy, you know. There are plenty of good, reasonable structures that no one else is making at your company – have no doubt – and if you’re the person who makes them and who introduces new chemistry into the department, you have something with which to justify your salary (or a higher one!) On the other hand, if you’re the person who cranks out the sulfonamide libraries, well. . .they can get that cheaper somewhere else, you know.
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July 28, 2008
Posted by Derek
1. “Hey, who dropped that condenser out on the floor in front of my hood? That looks just like the one I had on my reaction flask. . .”
2. “How come the toxicology people haven’t called me about our lead compound yet? Two-week tox finished a while ago, and usually they’re a lot faster than this. . . “
3. “Is there any active aluminum compound left in this reaction or what? I keep dripping methanol into it to quench it, and nothing’s going on at all so far. . .”
4. “Who’s going to scale up our candidate compound, anyway? We need 300 grams of the stuff, and the scale-up group is booked solid. . .”
5. “So, is this the high-pressure hydrogen line or the low-pressure one that I’m opening?”
6. “I wonder what the error bars are on that behavioral assay. . .”
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July 21, 2008
Posted by Derek
One of the things that no one realizes about research (until they’ve done some) is how much time can be spent going back over things. Right now I’m fighting some experiments that should be working, have worked in the past, but have (for some reason) decided not to work at the moment. Irritating stuff. There’s a reason buried in there somewhere, and when I find it things will be that much more robust in the future, but I’d hoped that they were that solid already.
And across the hall, a check is going on of some screening hits. When you get a pile of fresh high-throughput screening data, including some fine-looking starting compounds for a new project, what do you do with it? Well, if you have some experience, the first thing you do is order up fresh samples of all the things you could possibly be interested in, and check every single one of them to make sure that they actually are what they say on the label. Don’t start any major efforts until this is finished.
In fact, you should order up solid samples from the archives along with some of the DMSO stock solution that they used in the screening assay. They might not be the same, not any more. False negatives and false positives are waiting in your data set, depend on it: compounds that should have hit, but didn’t because they decomposed in solution, and compounds that (sad to say) did hit only because they decomposed in solution. You’ll probably never know about the first group, and you can waste large amounts of time on the second unless you check them now.
Getting a project going, then, can seem like trying to get a dozen nine-year-olds into a van for a long trip. Someone’s always popping out again, having forgotten something, which reminds someone else, and your scheduled departure time arrives with everyone running in circles around the driveway.
But nine-year olds can eventually be corralled, as can the variables in most scientific projects. But not always. Where you don’t want to be is the situation people had with the early vacuum-tube computers. Vacuum tubes have not-insignificant failure rates. So if you have, say, twenty thousand of the little gizmos in your ENIAC or whatever, doing the math on mean-time-between-failures shows you that the thing can run for maybe forty-five minutes before blowing a tube (unless you take heroic measures). And the more vacuum tubes you have, the worse the problem gets: make your computer big enough, and it’ll blow right after you throw the switch, every time.
So that’s the other thing you have to watch when troubleshooting: try to make sure that your problems aren’t built into the very structure of what you’re trying to do. In med-chem projects, look out for statements like “we have all the activity we need, now we just need to get past the blood-brain barrier”. Sometimes there’s a way out of those tight spots, but too often the properties that (for example) could get your compound into the brain are just flat incompatible with the ones that gave you that activity in your assay. You’d have been better off approaching that combination the other way around, and better off realizing that months ago. . .
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July 18, 2008
Posted by Derek
Here’s an appropriate topic for a Friday, although at first many of you may think I’ve lost my mind. What would happen if you combed the full text of the experimental sections of the chemistry journals, looking for how long people ran their reactions?
I’m pretty sure that I know what you’d see: there would be a lot of scatter in the short time periods, with some peaks at the various half-hour and hour marks just for convenience. But as you went out into the multiple-hour procedures, I feel sure that you’d see pronounced spikes in the data at around sixteen to twenty hours and again at around 72 hours.
Some readers have doubtless started nodding their heads, having done the math. Those times correspond to "overnight" and "over the weekend", and I'm willing to bet that they're over-represented (and how) in the data set. I'll go on to predict scarce examples in, say, the 14-hour or 38-hour ranges - there's not much way to run a reaction for those intervals and not be in the lab too early in the morning or too late at night.
A second-order prediction is that when such reactions are found, that their origins will skew heavily toward academia rather than industry. And I'm also willing to bet that patent procedures will tend to follow the working-day timelines more than the general literature, for the same reasons. My last higher-order prediction is that the reaction times would not, in fact, obey Benford's Law, as many other data sets of this kind do.
As far as I know, no one's ever done this sort of analysis, but I suppose it would be possible, especially for someone at Chemical Abstracts or at one of the scientific publishers. If someone wants to try it, please let me know what comes out. And if the results follow my predictions, please feel free to refer to the title of this post or something similar. I won't object.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | The Scientific Literature
July 9, 2008
Posted by Derek
Here’s a question that came up in a discussion at work the other day: when a new head of research comes in, how long should you give them before judging how they’re doing?
That’s a tough one to answer, I think, because there are a lot of variables. First is the size of the outfit, coupled with the scope of the position. A really big organization is a very, very hard thing to change, no matter how powerful the new person might be. I’m not at all sure how possible it is to change a company’s culture, but I’m pretty sure that it requires major shock therapy to do it. (If any of you have read C. N. Parkinson on what he calls “injelititis”, you’ll know the sort of thing I have in mind).
And different levels of authority affect processes with different timelines. A head of chemistry will be able to show results in less time than a head of research, who will need less time than a head of total R&D, because that person has to wait for the clinical results. As I’ve mentioned before, that seems to me to be one of the biggest challenges in this industry – the way that big changes can take years to work their way through to the results stage. It’s hard to steer intelligently if the front tires respond ten miles after you cut the wheel over hard.
You also have to ask what the new person is being asked to do. Steer the course on something that already seems to be working? Or shake the place up and make things happen (for once)? Expand the workforce, contract it, spend money or save it, stick with the existing therapeutic areas or branch into new ones? The job descriptions on these things are pretty wide-ranging, so the evaluations have to be, too. Without a clear idea of what the new boss is trying to do, it’s impossible to say how well it’s being done. You could wind up giving bozos credit for something that had nothing to do with them, or blame excellent managers for things that were completely out of their abilities to control. (I know, I know, that kind of thing happens all the time, but you don’t have to add to it if you can help it).
So, how long for an evaluation, then? One to three years for head of chemistry, five or six for head of research, up to ten for head of R&D (if they last that long?) I'd be interested in hearing other estimates. . .
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July 3, 2008
Posted by Derek
A colleague and I were talking the other day about some of the molecules that turn up when you dig through a company's internal database. This was a favorite sport of mine during slow afternoons at the Wonder Drug Factory - I would put in a query for bizarre or unlikely chemical groups and see what fell out. I was rarely disappointed - eventually I assembled a folder of the most hideous examples, which never failed to astound.
The compound collection at my current employer isn't nearly so weird, fortunately. But every drug company has large lists of compounds that aren't so attractive as leads, because they were made in the last stages of previous projects. This is a well-known problem, often referred to as a gap between "drug-likeness" and "lead-likeness". For the most part, the compounds you start a project with don't get smaller - they get bigger, as people hang more things off of them to get more potency, selectivity, or what have you. So you're better off starting as small as you feasibly can, giving you room for this to occur without taking you off into the territory of too-huge-to-ever-work. (That's one of the fundamental ideas behind the vogue for fragment-based drug discovery, for example).
"Too-huge-to-work" is a real category, as my industry readers will gladly verify. I think that the "Rule of Five" cutoffs have been sometimes applied a little too mindlessly, but there's no getting around the fact that if your latest molecule weighs 750 and has thirteen nitrogen atoms in it, the odds of it being a drug are rather slim. As my colleague put it, when you make something like that and send it in for testing, what you're saying is "I know that almost every molecule that looks like this fails. But I'm different. I feel lucky". And that's no way to run a research program. Given finite time and finite money, you're better off prospecting in chemical areas with better chances.
So what to do? We kicked around the idea of setting up some filters in the compound registration system itself - if someone tries to send in some horrible battle cruiser of a molecule, the system would make a puking noise or something and refuse to register the compound at all. There would have to be be some sort of override (perhaps for a higher-level manager to authorize) for those times when you actually have evidence that the ugly molecule works, but maybe the "You Lose: Make Something Else" screen would focus attention on the properties of what's being made. Of course, if anyone ever implemented this, the arguing would begin about where to draw the line (maybe there'd be a yellow "warning zone" in between), but I think that everyone agrees that at some point a line should be drawn.
So, for my readers around the industry - do you have such a cutoff? Can you register any crazy compound that crosses your bench, or does your company's software fight back? If so, what's the feedback - beep, e-mail warning, electric shock? Inquiring minds want to know.
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June 4, 2008
Posted by Derek
I was talking with a colleague recently about the different cultures that have grown up in different drug companies where lab associates are concerned. For those outside the industry, those are non-PhD-holding scientists, who (for the most part) do not move into managerial positions. There's room for a whole separate blog post on the people who (for one reason or another) never got the PhD degree but are the equal or superior of anyone who has, but for now I'm talking about the rest of the associate population.
As people get more experienced, they become more valuable, or at least they should. An experienced chemistry lab associate is one of the most readily employable people in the industry, under normal conditions. A company may or may not feel a need for another twenty-year middle manager type, but there's always a need for hands at the bench to make compounds, and good associates are the people who make the most. And with some time in the industry, they have a far better understanding of the real world of drug discovery than any PhD coming in fresh out of their post-doc.
Or at least they should. There are, though, some companies that treat their associates more like draft animals, putting them in the position I held in the summer of 1979 when I worked for in a greeting card factory before going to college. I was a "materials transport handler", which meant "See that big pile of stuff here? Haul it over there." It's the only time I've done manual labor for money for more than an afternoon, when I think about it. But I'm told that there are shops in this industry that tell their associates exactly what to do at every turn, up to the point (so I hear) of having them take spectral data and turn it over to their supervisors rather than interpret it themselves.
That's something you associate with the old-style German and Swiss labs, where there's a clear heirarchic division between the PhD holders in their offices and the "laboranten" out in front of the hood. Even there, I don't think this is quite as rigid as it used to be, so the thought of this here in the US is quite odd. But it does seem to go on, so I'm asking the readership: what's the status of the usual lab associate where you work?
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June 3, 2008
Posted by Derek
We recently encountered a problem that’s (unfortunately) a rather common one. An enzyme assay turned up an interesting hit compound, with some characteristics that we were hoping to see for leads against our target. A re-test showed that yes, the activity appeared to be real, which was interesting, since this hit was a welcome surprise from a class of compounds that we weren’t expecting much from.
It was a comparatively old compound in the files, and all we could find out was that it had been purchased rather than made in house. Looking around, it seemed that there were very few literature references to things of this type, and only one commercial source: the Sigma-Aldrich Library of Rare chemicals, known as SALOR. That, though, was a potential warning flag.
Those compounds come from an effort started by Aldrich’s Alfred Bader many years ago, who started trolling around various academic labs looking for unusual compounds that no one wanted to keep around any more. Over time the company has accumulated a horde of oddities that are often found nowhere else, but there are several catches. For one, these things are usually available only in small quantities, tens of milligrams for the most part. That’s plenty for the screening files, but you’re not going to make a bunch of analogs starting from what comes out of a SALOR vial. Another catch is that the compounds are sold, very explicitly, as is: the university sources tell Aldrich what’s on the label, so that’s what they sell you and caveat emptor all the way, dude.
So often as not, you get what we got, a nice-looking white powder which, on closer analysis, turned out to only have a vague relationship to the structure on its label. We knew that we were in trouble as soon as the first NMR came out: way too much stuff in one region, nowhere near enough in some others. Mass spec confirmed that this thing weighed more than twice as much as what it was supposed to. We’ve since pretty much nailed down what the stuff really is, and our interest in it has decreased as each of the veils has been removed from the real structure.
We’re correcting the data in our own screening files, of course. And yes, we’re going to tell the folks at Aldrich to change their label, too, assuming they have any of this stuff left. At least the next person will know what they’re getting. For once. But there are more of these things waiting out there – in every large compound collection, in every catalog, in every collection of data are mistakes. Watch for them.
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May 30, 2008
Posted by Derek
Well, while the mail continues to come in about my post yesterday, I’m going to pull back from the global perspective and zoom back into the glassware drawers of my lab bench today. A while back I wrote about the different sizes of ground glass joints that organic chemists typically use. People from outside the field are sometimes struck by the fact that we don’t have to do as much glassblowing and the like as they might have thought. Decades ago there was a lot more, but for a long time now we’ve been able to build up all sorts of apparatus (apparati?) by connecting standardized glass fittings together.
This has all sorts of advantages, letting us assemble odd custom configurations pretty easily, and change them without too much work. The downside is that the ground glass joints aren’t by themselves vacuum tight – not by the standards of inorganic chemists, for sure – and need to be anointed with thick, nasty vacuum grease before they can be trusted to that level. And if you don’t grease them for normal work, which we tend not to because the grease gets into your compounds, then the joints tend to freeze if left too long or too tight.
There are all sorts of voodoo tricks for unsticking them. I pride myself on being able to do it, but (objectively) I don’t think my success rate is all that greater than the norm. For the record, my technique is to put a few drops of silicon bath oil up around the edge of the stuck connection and let it soak in for a few hours. Then I rapidly heat the outside joint, grab it with a towel, and do the usual pulling and tapping while hoping for the best. There are better ways, but they're typically found only in a glassblowing shop.
When I last wrote about this fascinating subject (hey, chemists like their glassware), I mentioned that I’d gotten in the habit of using 29/42 size joints. (That’s a measure of size: the first number is a diameter, and the second is the length or taper). That’s a larger one than is common in American labs; you see it more in Germany, among other places. I’m so used to it now that the standard 24/40 glass joints you see all over the place look narrow and shrunken to me – will I really be able to get my product out of that?
The standard small size these days is 14/20 – that’s the size of all our 5, 10, and 25 milliter flasks. (You can get 100 mL flasks (or larger) with that size joint, too, but they start to look disproportionate and weird, and there’s no real reason for large flasks to have such a small neck). In between that and good ol’ 24/40, though is the 19/22 size, which I really should look at again. It would be the wide-mouth counterpart to 14/20, in the same way that 29/42 is to 24/40. I’d probably like it.
But I’ve hardly seen a flask of that size since I was an undergraduate, and that whole range of glassware immediately recalls sophomore organic chemistry labs. I wondered why that was, but now I have the story thanks to reader Norm Neill of glassmaker NDS Technologies, who saw its birth at Kontes:
"The 19/22 Glassware kit was developed jointly by Eric Nyberg from Kontes Glass and Dr Howard Martin from Lake Forest College in the late 1950's. . .they wanted to scale down the size of the glassware from the traditional 24/40 glassware to something smaller so it could be issued as a complete kit to a student and locked in his lab drawer. . .The next size down from 24/40 is 19/38 but the joint length was too long to allow us to scale down the kit (and) fit into a standard lab bench drawer. The 19/22 medium length joint was the best trade off at the time. . .The packaging of the kit was so popular that during the early 1960's production had to be allocated. The overwhelming success of the 19/22 glassware started the development of an extensive line of 14/20 glassware under the Bantamware® brand."
It's my impression that the 14/20 glassware has been taking over the student market in recent years as well, what with the move to smaller and smaller amounts of solvents and reagents. That makes me wonder if 19/22 glass has a future, which means that I'll probably find some lunatic reason to switch my small-scale stuff to it really soon, giving me the most oddball glass collection in the place. . .
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May 20, 2008
Posted by Derek
For those who were wondering, my copper reactions the other day worked out just fine. They started out a beautiful blue (copper iodide and an amino acid in straight DMSO – if that’s not blue it’s maybe going to be green, and if it’s not either one you’ve done something wrong). Of course, the color doesn’t stay. The copper ends up as part of a purple-brown sludge that has to be filtered out of the mix, which is the main downside of those Ullman reactions, no matter how people try to scrub them up for polite company.
And DMSO is the other downside, because you have to wash that stuff out with a lot of water. That’s one of the lab solvents that everyone has heard of, even if they slept through high school chemistry. But it’s not one that we use for reactions very much, because it’s something of a pain. It dissolves most everything, which is a good quality, but along with that one comes the ability to contaminate most everything. If your product is pretty greasy and nonpolar, you can partition the reaction between water and some more organic solvent (ether’s what I used this time), and wash it around a lot. But if your product is really polar, you could be in for a long afternoon.
That mighty solvation is something you need to look out for if you spill the stuff on yourself, of course. DMSO is famous for skin penetration (no, I have no idea if it does anything for arthritis). And while many of my compounds are not very physiologically active, I’d rather not dose myself with them to check those numbers. At the extreme end of the scale, a solution of cyanide in DMSO is potentially very dangerous stuff indeed. I’ve done cyanide reactions like that, many times, but always while paying attention to the task at hand.
Where DMSO really gets used is in the compound repository. That dissolves-everything property is handy when you have a few hundred thousand compounds to handle. The standard method for some years has been to keep compounds in the freezer in some defined concentration in DMSO – the solvent freezes easily, down around where water does (Not so! Actually, I've seen in freeze in a chilly lab a couple of times, now that I'm reminded of that in the comments to this post. Pure DMSO solidifies around 17 to 19 C, which is about 64 F C - a bit lower with those screening compounds dissolved in it, though).
But there are problems. For one thing, DMSO isn’t inert. That’s another reason it doesn’t get as much use as a lab solvent; there are many reaction conditions during which it wouldn’t be able to resist joining the party. You can oxidize things by leaving them in DMSO open to air, which isn’t what you want to do to the compound screening collection, so the folks there do as much handling under nitrogen as they can. Compounds sitting carelessly in DMSO tend to turn yellow, which is on the way to red, which is on the way to brown, and there are no pure brown wonder drugs.
Another difficulty is that love for water. Open DMSO containers will pull water in right out of the air, and a few careless freeze/thaw cycles with a screening plate will not only blow your carefully worked out concentrations, it may well also start crashing your compounds out of solution. The less polar ones will start decided that pure DMSO is one thing, but 50/50 DMSO/water is quite another. So not only do you want to work under nitrogen, if you can, but dry nitrogen, and you want to make sure that those plates are sealed up well while they’re in the freezer. (As an alternative, you can go ahead and put water in from the start, taking the consequences). All of these concerns begin to wear down the advantages of DMSO as a universal solvent, but not quite enough to keep people from using it.
And what about the compounds that don’t dissolve in the stuff? Well, it’s a pretty safe bet that a small molecule that can’t go into DMSO is going to have a mighty hard time becoming a drug, and it’s a very unattractive lead to start from, too. That’s the sort of molecule that would tend to just go right through the digestive tract without even noticing that there are things trying to get it into solution. And as for something given i.v., well, if you can’t get it to go into straight DMSO, what are the chances you’re going to get it into some kind of saline injection solution? Or the chances that it won’t crash out in the vein for an instant embolism? No, the zone of non-DMSO-soluble small organics is not a good place to hunt. We’ll leave proteins out of it, but if anyone knows of a small molecule drug that can’t go into DMSO, I’d like to hear about it. Taxol, maybe?
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May 15, 2008
Posted by Derek
I was running a copper-catalyzed coupling reaction the other day when my summer intern asked me how it worked. I showed her the mechanism that the authors of the paper had proposed, but pointed out that it was mostly hand-waving. The general features are probably more or less right: the copper iodide presumably does form some kind of soluble complex with the amino acid that’s needed in the reaction mix, and that may well form some sort of complex with the aryl halide, which opens up the ring to nucleophilic substitution, etc. If this were an exam, I’d give full points for that one.
But a lot of these couplings are, as I pointed out to her, very hazily worked out. The Ullman reaction, in various forms, has been with us for many decades, and there are more variations on it than you can count. If it always worked reasonably well, or if people had any strong ideas about how it did so, the literature on it wouldn’t be in the shaggy shape it is. Copper chemistry in particular has been (simultaneously) a very useful area for people to discover new reactions, and a horrible trackless swamp for people trying to explain how they work.
All you have to do is look at the vicious exchanges between Bruce Lipschutz and Steve Bertz during the 1990s about whether such as thing as a “higher-order cuprate” exists. I have absolutely no intention of reconstructing this argument; I would have to be paid at a spectacular hourly rate to even attempt it. It's enough to say that the arguments raged, in an increasingly personal manner, about what state the copper metal was in, what ligands coordinated to it, and what the active form of these reagents might be (as opposed to what the bulk of the mixture was at any given time). It culminated in what must be one of the most direct titles for a scientific paper I've ever seen: It's on lithium! An answer to the recent communication which asked the question: 'if the cyano ligand is not on copper, then where is it?'. That's in Chemical Communications 7, 815 (1996), if you're interested (here's the PDF for subscribers). Bertz continued to shell Lipshutz's position past the time when any fire was being returned, as far as I can tell, and continues to work in the area. Lipshutz, for his part, hasn't published on the higher-order cuprates in some time (being no doubt heartily sick of the whole topic), but has kept up a steady stream of work on new reactions involving copper, nickel, and other metals.
So if well-qualified researchers, brimming with grad students, postdocs, and grant money, can argue for years about copper mechanisms, I'm going to stay out of it. As time goes on, I'm increasingly indifferent to reaction mechanisms, anyway. I want to get product out the other end of the reaction. And while there are times when knowing the mechanism can help reach that goal, those times do not occur as frequently as you might hope.
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May 14, 2008
Posted by Derek
I have a summer intern this year, and she has (so far) not caused anything to burst into flames. That’s the first thing you ask of a summer student, and the fact that she’s gotten several reactions to work is just a welcome extra. A summer with no laboratory bonfires will be a successful summer, as far as I’m concerned.
That’s because I’ve experienced the alternative, as I’ve detailed here before. If most of the lab fire stories you hear start out with the phrase “We had this solvent still. . .”, the rest of them all seem to begin with “We had this summer undergrad student. . .” (You can imagine the flame-filled end to any story that starts out with a summer student distilling some solvent – that Venn diagram leaves you with no way out at all).
No, after watching an undergrad next door to me kick a four-liter jug of pyridine all over the floor, causing a shimmering wave of unspeakable pyridine vapors to almost knock me off my feet. . .and after watching another one walk away for two hours after setting up a reduced-pressure DMSO still, which inadvertently turned into a high-pressure apparatus and blew DMSO and calcium hydride all over the inside of a hood. . .and after watching them charcoal reactions by plugging heating apparatus straight into the wall outlet instead of into the Variac. . .and, well, you get the idea.
I should add that I was no great shakes as a summer undergrad myself. I did a summer after my sophomore year with Tom Goodwin, but didn't get a great deal accomplished (through no fault of his!) Then after my junior year, I worked with Dale Boger, back when he was at the University of Kansas, but I mostly (and rather slowly) found a list of conditions that don't work for inverse electron demand Diels-Alder reactions. But although I spilled some generous amounts of solvent, I didn't set anything on fire.
No, we're going to have a calmer and more productive summer around here. I have my student working on a problem I've had a longstanding interest in, one that needs some variables chased down and figured out. With any luck, enough data will be generated to make for an interesting publication late in the year, and everyone will come out ahead.
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May 12, 2008
Posted by Derek
One of the reasons I starting this blog was that many people I met were interested in my job. Very few of them had ever talked to someone who discovered new medicines for a living, and a surprising number of them (well, surprising to me) had no idea of where medicines came from in the first place.
Talking to such folks (interested, but with no particular training in science) gave me some good practice in explaining the work. It helps that the kind of work I do is actually fairly easy to explain. There are a lot of details – as with any branch of science, the closer you look, the more you see – but I haven’t run across any key concepts that can’t be communicated in plain language. (It also helps that medicinal chemistry, as it’s actually practiced, uses an embarrassingly small amount of actual mathematics).
The toughest things to deal with are the parts of the field that actually touch on physics and math. My vote for the hardest everyday phenomenon to explain at anything past a superficial level is magnetism. So that means that explaining how an NMR machine works is not trivial. At least, explaining it in a way that a listener has a chance of understanding you isn’t – a while ago, I took up the challenge to try to explain it here in lay terms, and I haven’t done it yet, for good reason.
Explaining statistical significance is doable, but going much past that (principal components, the difference between Bayesian and frequentist approaches) takes some real care. And, of course, when you open the hood on chemical reactivity, the mechanisms of bond-forming and bond-breaking, you quickly find yourself in physics up to your armpits. It’s easier to stipulate, openly or by assumption, that there are such thing as chemical bonds, and that some of them are stronger than others. You don’t want to start answering a question about why one group falls off your drug molecule easier than another one does, only to find yourself fifteen minutes later trying to explain the Pauli exclusion principle. Counterproductive.
But the basics of medicinal chemistry can be sketched out pretty quickly, which makes some of the more curious listeners wonder, after a while, why we aren’t better at it. The best example I can give them is to advance a quick, hand-waving explanation of, for example, how compounds get into cells. Then I point out that that explanation is unnervingly close to the best understanding we have of how compounds get into cells. The same holds for a number of other important processes, way too many of them.
And that's why drug discovery is simultaneously frustrating and fascinating. We know huge numbers of things, great masses of detail that can take years to piece together. And it's not enough. Some of the most important puzzle pieces are still weirdly ill-defined, and there are probably others whose existence we haven't even realized yet. I'd be willing to bet that if you scanned the whole history of pharmaceutical discovery, you'd find people at every point thinking "You know, in any thirty years they should have all this figured out". But the years go by, and they - we - don't. Give it another thirty years, you think?
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May 5, 2008
Posted by Derek
We order chemicals from all sorts of suppliers – big, reputable outfits like Sigma-Aldrich-Fluka all the way down to places that none of us even have heard of before. In those latter cases, the primary question is always whether or not the reagent will actually show up, and the secondary one is how long it’ll take. There are some of those small suppliers who pad their catalog with things that aren’t exactly available, not yet – but hey, they will be if someone orders them. They’ll just tell you it’s back-ordered, and tell someone in the lab to get cracking.
And when you get your compound in, they arrive in various forms. Glass or plastic bottles are the norm, naturally, with the occasional irritating (but presumably necessary) sealed-glass ampoule. But after some time in the lab, you can tell some of the suppliers from across the room. For example, the Japanese company TCI sends a lot of its compounds in normal-looking glass bottles, but these are first put inside capped plastic containers, like larger translucent versions of the ones that 35mm film probably still comes in. And once you taken them out, their glass bottles have these odd plastic labels on them which come up around the screw cap and are perforated around the cap’s border. On the labels, they also have that same thin, fussy, serif font that the Japanese have been using for Roman-style letters for decades (since the war?) and is only in recent years disappearing from their world.
Maybridge, British vendor of all kinds of odd stuff, often sends its compounds in these weird little squat brown-glass bottles with small black caps on them. They must have the world supply of that particular bottle shape tied up, since I’ve never seen one anywhere else. It most resembles the small bottles that solutions for injection are packaged in. So many of the company’s catalog items are in such bottles (or even smaller ones) that it seems wrong somehow when you come across a huge (huge for Maybridge) hundred-gram bottle with their label on it.
Most of the suppliers have neutral-sounding names like those above. They could be chemical companies, vendors of kitchen cabinets, real estate trusts, who knows: Maybridge, Oakwood, Lancaster (now gone, and their blue labels with them). And some of them are unmistakably in the chemical supply business, but rather blandly named (Pharmacore, for example, or Chembridge). Some names are, perhaps, mistakes: the namers of Asinex, for example, seem to have been unaware that the closest Engish word is “asinine”, which means that they have to hope for people to pronounce that “s” as if it were a “z”. (I should mention that both Asinex and Chembridge indulge in one widely hated practice: putting no useful information on their tiny vials other than a catalog number or bar code – Bionet (Key) is a similar offender).
In this dull company, I’m always glad to see the weirdos. I miss the now-purchased-away British supplier called Avocado – green labels, naturally – and always wondered who named them and why. Tyger Scientific makes me wonder if there’s an English major in somewhere at their founding, fond of William Blake. And there’s one company that came into the industry under the glorious name of, I am not making this up, “Butt Park”, and many are the chemists they’ve made stand puzzled in front of the supply cabinet. (I'd provide a link, but I can't find a direct one, and Googling it can be a real minefield).
I refuse to consider that name a mistake. That's a feature, not a bug, and I wish that there were more competition in the category. I would proudly and purposely send business to, say, Batshit Chemical Supply, Inc., even if they back-ordered me every single time.
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April 15, 2008
Posted by Derek
Not many chemists come into the drug industry knowing very much about biology. I certainly didn’t, not on the level that was needed. It’s not surprising, but it’s also not as much of a handicap as you’d think, at least not at first.
That’s because the first job of a new hire in the med-chem department is to crank out compounds, and that goes for both the PhD and Master’s levels. (Those roles diverge as time goes on, though). But with a few obvious rules in hand (no hot reactive functional groups, no huge greasy monster molecules, etc.), a person can contribute reasonable-looking compounds pretty quickly. No biological knowledge needed.
But if you’re going to be more valuable than a new hire (and as time goes on, you’d better be), then you have to start picking up some more of the broader science of drug discovery. That turns out to involve a lot more than chemistry, which is one of the things that chemists have to get adjusted to. If you’re going to move up to the point of being considered to lead a new project, you’re going to have to show that you can converse with the folks who know protein expression, assay development, molecular biology, PK, toxicology, and so on. You’re not going to be expected to come in and solve their problems (although if you do manage to solve one once in a while, it’ll do both you and them some good). But you are expected to understand what they’re talking about.
So that’s a piece of advice I can give to new chemistry hires in this business: get ready to learn everyone else’s business, too. Listen up when the people from the other departments talk about what they’re up to, and especially when they complain about their problems. Try to understand why they’re complaining, and ask them (especially one on one) about what they usually try when this sort of thing happens. The occasional paranoid might think at first that you’re compiling info in order to mess with them later, but you shouldn’t be the sort of person around whom that suspicion credibly lingers. In general, if the people in those other groups are any good at all, they’ll be glad to tell you what’s going on, and you’ll pick up a lot of practical knowledge.
The consequences of not doing this sort of thing become more severe as time goes on. At one of my former companies, we once brought in a job candidate from BNP (Big Name Pharmaceuticals). He’d been around seven or eight years, enough time to be considered fairly experienced. But people at that level vary a lot, and he was (as it turned out) on the low end. When we’d ask him about, for example, any formulation problems he’d had to deal with on his project compounds, he told us that well, he didn’t usually go to those meetings, his boss did. And when we asked him about how he got along with the PK group – well, they were over in another building, and he hardly ever saw them. And so on, and so on.
He was well along to being crippled by the way things were done at BNP. Actually, it may have been more the way he was doing things. From talking with other people from that shop over the years, it’s clear that it didn’t have to be that way – if you made the effort, you could go to those meetings, and if you took the time, you could go over to those other buildings and show your face. But you didn’t have to, and this guy (since he didn’t have to) didn’t bother to. And by keeping to his burrow, he hadn’t learned nearly as much as he could have. We didn’t make him an offer. So talk to people, talk to people outside your field. If you’re any good at all, they’ll learn something from you, too.
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April 14, 2008
Posted by Derek
Hexane (or its cheaper, less well-defined cousin, petroleum ether) is the proto-solvent. Light and thin, it’s the weakest at actually dissolving anything, so it’s the background to most stronger mixtures in a purification. Like most other solvents, though, it’ll strip the oils right off your skin, leaving you spiderwebbed with white lines across your fingers and in need of some lotion. Its smell isn’t pleasant, but it doesn’t really stink, either. A nonchemist would easily place it in the oil / kerosene / gasoline end of things, which is exactly where it belongs.
When I first encountered ethyl acetate back in college, little did I realize that I was picking up the scent of the rest of my life. I've been in the lab ever since, and so has it. Pleasant, unspecifically fruity, vaguely bubblegum-like, the smell of that solvent is a daily companion to almost every synthetic organic chemist in the world. Mixed with hexane in different proportions according to your needs, it runs the majority of chromatographies in the world. Squirt bottles of it sit around on benches. By now, it’s an old, old friend, and the smell of it says that I’m actually getting something done.
Ether (the real ether, diethyl ether) seems like it’s close to not being there at all. No long for this world, it’s supremely light, and evaporates so quickly, that it just barely holds on to the liquid state. It has a slightly dangerous overtone to it, since it can ignite so easily and forms explosive peroxides if it’s left sitting around. The somewhat smothering smell can’t quite be described, but is instantly recognizable. Its oxygen atom gives it more dissolving power, so ether/hexane mixtures are good for delicate separations, although often impractical on a larger scale. To me, ether is sort of a lighter, stronger hexane, in the relationship that titanium has to steel.
Methanol, on the other hand, has no smell – no smell whatsoever to me, at any rate, despite what that Wikipedia link says, although I think I can tell it from air. Pure lab ethanol smells great, but methanol is a blank to me. It’s the most watery of the common solvents – it’s lighter, but that OH group gives it some surface tension, which (along with its bizarre weight) is one of water’s defining characteristics. You notice the difference, compared to thin, slippery hexane or ether – methanol is a solvent with some body to it. It’s powerful stuff in chromatography, too – one per cent added to a weaker solvent will totally change things.
Do you call it dichloromethane or methylene chloride? The latter probably gets more use, and rolls off the tongue a bit more easily. This stuff is like the demon form of hexane – it has no oxygen atoms like ether or ethyl acetate, but is a pretty strong solvent, in what always seems a mysterious way. With another immediately recognizable but hard to describe smell, its odor is the prototype of “chlorinated”. But the thing that stands out the most is its weight. This is the only common solvent that’s heavier than water, and you can build up your arms doing curls with jugs of the stuff. We don’t use its even denser cousin chloroform all that much; it would be even better bodybuilding material.
Acetone is one of the solvents familiar both in and out of the lab: nail polish remover, without the added scents. You hardly ever run an actual reaction in the stuff, though, and when you do it feels a bit odd. That’s because acetone has become the default flask-rinsing solvent of the chemistry world. I’m not sure when that was settled, but it was decades ago: a perfectly respectable solvent, stuck in the role of janitor to all that brown, red, and yellow stuff stuck to the inside of a million round-bottom flasks.
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April 9, 2008
Posted by Derek
Time for another quick quiz on whether you have what it takes to be a big-time medicinal chemist. Prepare for some not-so-welcome old friends to visit you yet again:
1. Your two main assays refuse to act as if they’re part of the same project. Most of your potent compounds in the first enzyme assay don’t do much against the cells, and the best cellular compounds are no great shakes in the enzyme assay. There’s a narrow zone of overlap, but it doesn’t look big or robust enough to base the whole project on. Do you pursue the cellular activity, on the theory that that’s the effect you’re looking for, or pursue the enzyme activity (on the grounds that it’s the right target, and you just have to get the things into the cells), or consider revamping the assays completely, or what?
2. In the next case, your disconnect doesn’t occur until you get to metabolism and PK. When you run your compound across liver enzymes, they grind it into dust. But you did that after you dosed the animals, you buckaroo, and not only did the compound seem to work OK, but its blood levels weren’t bad, either. So how come it looks as if it should be disappearing? The most destructive of the enzymes, by the way, was the human one. Are you worried about that, or not?
3. The project you’re on has a compound profile as a goal – so much potency, at least so much selectivity, and the like. As time goes on, there’s one selectivity assay in particular that you just can’t seem to shake. The only time you see a decent separation between your activity and the one you don’t want is in a compound series that you don’t like – they’re big and greasy, and although they look very active in the enzyme assay, they never perform as well as they should in the animals. But it’s starting to seem as if you have a choice: good properties or selectivity, but not both at the same time. What to do?
4. OK, let’s back up some. You’re working on a project that hasn’t really made it to the medicinal chemistry stage. The screening folks have run the target, and forwarded you their data. Nothing shows up really potent, but there are some 500-nanomolar things scattered around. And “scattered” is the word, all right. You probably have two dozen near-singletons in that range – nothing seems to show much of a robust effect across a given class of compounds. But this is a target that everyone wants to start a program on - it's hot, it's happening. How do you proceed?
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March 26, 2008
Posted by Derek
I ran a reaction the other day which gave me two very similar products. That's not so uncommon, but this one really shouldn't have been able to do that. (For the chemists in the audience, these two so similar, in fact, that the usual LC/MS conditions only showed one peak. NMR tells you different, though, and a painstaking multiple-elution TLC in some nonstandard solvent mixtures resolves the two spots).
I thought about the problem a bit, and decided that the first thing to do was to check my starting material. And there they were: two very similar starting materials, together in the same jar. Mind you, there's only one structure on the label. No wonder the stuff was so sticky. I'd received the Special Extended Edition without knowing it - odds are, the supply company sent it to me without knowing it, either, although that'll change when they get my e-mail. One of the components, anyway, seems to be the right stuff, so I suppose it could be worse.
This happens more often than it should, often enough that every working chemist has a similar story or two. And it doesn't correlate that well with the size or renown of the company you're ordering from, since everyone sources material from all over the place. Little mom-and-pop operations have sent me plenty of fluffy, flawless stuff, while Aldrich has on occasion mailed me goo. (On another occasion they mailed me a perfectly empty sealed ampoule with a label on it, but since the label didn't read "Air", I thought I had reason to complain). That doesn't mean that reputations don't vary. Even though they're now part of the same company as Aldrich and Sigma, those Swiss fanatics at Fluka do this sort of thing to you comparatively less often than their cohorts.
Not all the unopened slime you encounter is necessarily the fault of the company that shipped it. Some things just aren't stable, or at least aren't so stable in the back of an unventilated truck or sitting out in the sun on a loading dock. And the longer it is after an order's been received, the more the problem is likely to be with the receiver. A look at the condition of the vials in a drug company's compound repository will convince anyone that the kinds of molecules we like may not have indefinite shelf lives.
In this case, it's going to be easier to clean up the starting material and run the reaction again than it would be to clean up my dueling products. Easier yet would be to get a bottle of the right stuff from the supplier, but this one isn't exactly a high-volume compound, and I suspect that it's all the same nasty batch on their shelves. Worth a try, though. And thus does science stagger on.
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February 15, 2008
Posted by Derek
Lab fires don’t happen as often as you might think, at least to hear the way organic chemists talk. We all have alarming stories of alarming reactions (often set up by some rather alarming labmates), but these things are harvested over a fairly broad range of experience. It’s a familiar enough topic that I can remember someone sitting down at lunch while we were swapping lab stories and saying “Oh, this conversation. . .”
But happen they do, and it’s always worth taking a couple of minutes to think about what you do in such a situation. That depends on the fire, of course. For starters, a small one burning out of the neck of a flask can be put out quickly just by slapping a beaker over the top of it. Never neglect that possibility, because it’s fast, effective, and (truth be told) if no one saw you do it, no one necessarily has to know that your (minor!) fire even happened.
Larger ones aren’t going to be so easy, but there are some potential ways out of those, too. My wife had a labmate in her molecular biology department who was always setting off blazes with the ethanol she used to wipe things down with. (This person neglected to turn off the Fisher burner used for sterilizing wire loops, etc., before she started sloshing the alcohol around). A fire like that will just burn itself out if you close the hood sash and let it rip for a few seconds, as long as you’re sure that there’s no fuel source (like the wash bottle of ethanol you might have chucked in there in a moment of panic, for example).
Most chemistry hoods, though, have all too many sources of fuel in them, so you probably won’t be able to put out a blaze through benign neglect. If it comes to a fire extinguisher, make sure you already know where the nearest one is, for starters. You'd be surprised how hard it is to find one of the darn things when you really need it. And once you've found it, make sure that you know which kind you’re using. The carbon dioxide ones don’t make the horrible mess that the dry-chem ones do, which is one thing in their favor, although I think in general they’re a bit less effective. You can tell the difference immediately – the carbon dioxide ones have the big nozzle on them, while dry-chem is a short, plain hose. My lab is outfitted with the latter, which makes me wish more than ever that we never have to use them.
And if you happen to have halon extinguishers (are those still around?), make a note of that, because the technique you may have learned for using the other ones won’t work. Instead of coming in and aiming at the base of the fire, with halon you have to stand further back and let the stuff shower down on it. A colleague of mine once blew the contents of a flaming oil bath all over the lab because he hadn’t been trained in that distinction.
The safety people always tell you that if you’ve used up one extinguisher and the fire still isn’t out, to head for the door rather than reach for a second one. That’s probably good advice (although I’ve seen it disregarded), and I’d advise you to take it. Actually, I’d advise you never to have that decision to make at all, but that’s not always up to you. You may be doing nothing but adding sodium sulfate to a bunch of dichloromethane today, but who knows? The guys next door might be gearing up for Trimethylaluminum Fiesta Days. You never can tell.
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February 13, 2008
Posted by Derek
I’m going to be working up an Arbuzov reaction this morning, which is an odd thing for me to say. That’s because to the best of my recollection, which is pretty good, I’ve only run any of those during one period in my lab career. That was back in grad school, along about 1985, I’d say. I hope this one proves more useful than that one did – I was trying to make some dimethyl diazomethylphosphonate, and the prep was a relentless barrage of No Fun. (The first part of the sequence was identical to this).
I keep a list in my head of songs that I’ve only heard one time (no, I don’t appear to be normal, thanks for asking), and perhaps it’s time for me to assemble a list of reactions that I’ve only run once. That’s a tougher one, because if a reaction fails, you may well run the thing again. Still, I’ve only done one hydrogenation at 2000 psi with rhodium on alumina (July 3, 1984, and it looked like used lawnmower oil afterwards, I should add), and I’ve only used samarium iodide one time (and it didn’t work). But for a longer list I might have to settle for some things that I ran for a brief period and never have since.
The Claisen rearrangement would fall into that class, for sure. A feature of my early grad school work, I’ve never had the need to run one since. I can't think of the reaction without smelling ethyl vinyl ether in my memory, which is not a feature, in case you're wondering. I did a lot of carbohydrate reactions back then that I haven’t had the need to return to, either – Ferrier rearrangements being just one of them. And, like many other chemists, I had a brief photochemistry period, in my case during my post-doc, and have never run one of those again, either. Others that enjoyed their day in the sun and have never been seen again in my hood are the Prins reaction, nitrone cycloaddition (not since I was an undergrad in 1983), Lindlar hydrogenation, and the Henry reaction.
The thing is, any of these could make a comeback at any time. They’re still all perfectly reasonable reactions, and depending on what comes out of the next high-throughput screen or literature search, I might be setting one up next week. You never know. But there are some reactions that I think I’ve said goodbye to forever. In some cases, that’s because better alternatives are now available - I mentioned here that I haven’t used PCC for oxidations in years, and I think that one’s been pretty much superseded.
Others are history because I either very much doubt I’ll have the need for them, or because I just flat out Don’ Wanna. For example, I made Dess-Martin periodinane three times on a hundred-gram scale, during a period in the early 1990s when it wasn’t commercially available, and I plan, with any luck, never to do that again. The prep has been improved since those days, but that explosive intermediate was never something I enjoyed seeing. I don’t think I’ll be synthesizing fluorosulfonic acid starting from hydrofluoric acid any time soon, either. I did that one as an undergrad, too, if you can believe that – this guy must have had confidence in me, which I’m not at all sure was warranted by the evidence at hand. Nor do I foresee any need to make Fremy’s Salt from scratch again. (You can see someone else do it here, though - the internet amazes me sometimes). And if I never do another reaction that requires half a mole of phosgene, that’ll be fine with me, too.
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February 7, 2008
Posted by Derek
A couple of years ago, I wrote about electronic lab notebooks, and pointed out how much better they've made my record-keeping. My new job also uses an electronic platform, to my relief, and if anything it's better implemented than the one I was using before. It's clear to me, that software lab notebooks are the only way to go. Drawing the structures, setting up duplicate or related experiments, attaching all the data files from LC/MS and NMR, the ease of retrieval for patent filing purposes, the ability to search structures across a whole organization's experience - there's no substitute. (One thing they don't handle well, though is TLC data, which I was just talking about - anyone have a solution for that?) But that aside, going back to paper would be agonizing; a directive to use hardbound notebooks would induce terror and dismay.
Still, both of the electronic notebooks I've used are in-house jobs. I've had some mail wondering if I have any recommendations among the commercially available software, and that's a question I can't help out with at all. So I thought I'd throw this one out to the readership: what's worked for you? And how much did it cost? Is there anything open-source that'll do the job? (I've heard of Wetlab and OS-ELN, but know nothing more about them).
And here's another question, which is more of a poll. Are you using paper or pixels for your notebook? If you answer in the comments, which I'm glad to report seem to be working again, mention what kind of work you do and if it's in an academic or industrial setting. I'm curious to see if the expected correlations show up. . .
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February 6, 2008
Posted by Derek
You know you’re getting older when techniques that you used to use constantly are in danger of becoming lost arts. The one that I’m thinking about today is thin-layer chromatography, or TLC. This is a classic lab method, taught to generations of undergraduates and used by untold hordes of working organic chemists. And it’s slowly on the way out.
Before we go into what’s killing it, a brief bit of background for the non-chemists in the crowd. To do a TLC, you take a plate of glass (or something else stiff, like thick aluminum foil) that’s been coated with a thin layer of some finely ground solid. The usual choice is silica gel, which is basically very pure, very finely ground sand. In its powdered state, it resembles a slightly grittier form of corn starch. In the old days, you’d spread this stuff out on the plates yourself, but it’s been twenty years since I saw anyone do that. During my whole career, you’ve been able to buy them premade, in all sorts of variations.
Then you take a drop of your mixture and put it on the silica layer, down near the bottom of the plate. Once it dries, you stand the thing up in a beaker or jar that has some solvent in the bottom - the idea is to wet the plate at the bottom, but not so far up that it rinses off your spot. As the silica gel layer wets, the solvent creeps up the plate. And (as in all the other forms of chromatography), the various compounds in your mixture will travel faster or slower, depending on their interactions with the silica versus with the solvent. A strong polar solvent (methanol) will tend to whip everything up with the solvent front, and a wimpy one (hexane) will tend to leave everything back at the start. Adjusting the solvent mixture can give you a spread of spots up and down the plate once you've let it run for a bit, and you can see those with a UV lamp, or by dipping the plate in some reagent that will generate colored material from your compounds. Excellent pictures of the process can be found here.
TLC is cheap, fast, convenient, and can be run in untold different variations. So what's killing it? Something even faster, more convenient, and more powerful: liquid chromatography/mass spectrometry. That was just barely possible when I was in grad school, and was expensive and tricky when I was in my early years in the industry. But now the machines, while still not cheap, are everywhere, and they're used in walkup mode. Just enter your data - or link it over from your electronic lab notebook - put your sample vial in the rack, and go away. What you get back is a better separation than TLC can give you, and every peak/spot now can be checked for the masses of the compounds in it. You can ask all the possible questions, such as "which peak has the mass I'm looking for?", or "What the heck is the main mass in that peak, anyway?". The mass spec gives you more information than you can deal with, and it's all stored digitally for your later perusal and second thoughts.
This trend has been coming on for years now, but it's reached a very noticeable point. Even a comparatively old-school guy like me hardly runs TLC plates any more. Once in a while, I'll need to, but mostly, it's just "throw it on the LC/MS". And I get the impression that people coming through grad school now are losing the finer points of TLC completely. And why not? They've never had to worry about them at all. . .
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February 1, 2008
Posted by Derek
1. You’ve got a compound repository, right? Lots of vials, robot retrieval systems if you’ve got the cash, all that stuff? What fraction of those vials are full of sticky stuff that are colored warning shades of dark orange, red, or soy-sauce brown? And of those, what fraction has had colorfulness overtake it while in your repository racks, as opposed to the stuff that arrived looking that way? Bonus question: are you aware of any cranberry-red wonder drugs, and have you ever heard of anyone formulating a big manufacturing batch for Phase III while checking to make sure it’s the right shade of brown?
2. You’ve got some molecular modelers, right? And you ask them to try to dock some of your compound ideas into your favorite binding sites? OK, first question: how many times have any of them come back to you saying that they can’t fit something in? If the answer is “never”, you have a problem with your modelers. Second question: if you do get told that your compound doesn’t seem to dock, do you keep going down the hall until you find someone who can jam your idea into the model? In that case, the problem is closer to home.
3. You’ve got biologists on your project, right? In vitro assay people, then the in vivo group, ready to test whatever makes it that far? So, how much compound do they ask for? And how much of that do they plan to actually use? When they ask, how much compound do you tell them you have on hand (or can make)? And what fraction of what you really have or can make is that, exactly? Depending on the ratio between these various answers, you can either have no problems or you can be living with quite a few different ones simultaneously.
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January 25, 2008
Posted by Derek
Over at Org Prep Daily, Milkshake did an excellent post earlier this month on extraction techniques. It’s well worth looking over, even for experienced lab crew. Solvent extractions are a way of life for organic chemists, a fact that has not changed since the beginning days of the science, because (for one) we still do the bulk of our reactions in one sort of solvent or another, and (two) because the bulk of our reactions need to have garbage removed from them, and this is the first line of cleanup. (Here it is in real life - scroll down).
For those readers who aren’t chemists, three paragraphs of explanation: extraction works on the “like dissolves like” principle. A look at a bottle of oil-and-vinegar based salad dressing that’s been sitting for a while will show the familiar layers, with the oil on top and the aqueous layer below. If you were to take samples out of each and analyze them, you’d find that they contain rather different parts of the dressing mixture. The oil layer will have the compounds that can’t dissolve in water very well – organic pigments like carotenes or lycopenes, for example. They’re better off in with the oil molecules; they don’t have any polar molecular features strong enough to horn in on the hydrogen bonds that water uses to stick to itself.
Down in the water layer, on the other hand, is all the stuff that has such polarity. All the amino acids and most proteins will be there, as will the sugars and other soluble carbohydrates. These compounds have a lot of groups (hydroxyls, amines, carboxylic acids) that can interact strongly with the small, polar water molecules. Since there’s a lot of vinegar in there, too, acid-base chemistry will be a factor. The compounds with strongly basic groups (fishy amines and the like) will be protonated by that acetic acid, and the resulting salt is a natural for the water layer. A few base-containing things that might otherwise be just as happy in the oil layer will be pulled in by this effect.
So if you have a messy mixture of stuff, you can separate the greasy components from the polar ones by shaking up the lot in a mixture of water and some solvent that’ll form a separate layer. Sometimes you’ll want one layer, sometimes the other, depending on what your product is like, but most of the time organic chemists are throwing out the water layer and keeping the other one. There are other tricks – for example, if your compound’s acidic or basic, you can adjust the aqueous layer the other way to hold it as a salt, wash out all the other goo with solvent, and then change the acidity so that your compound will now go into a fresh solvent wash. In all these cases, you drain off the appropriate layers with one of these.
I would not like to hazard a guess at how many extractions I’ve done. Shaking a sep funnel is such a basic act of organic chemistry – every time you mix something up and wait for the layers to separate, you’re participating in a rite that goes back to the days when labs were only illuminated by sunlight or fire. It’s one of the few things that a scientist from the 1850s would immediately recognize if teleported in front of my fume hood, that’s for sure (the fume hood itself would be a revelation, for starters).
I have to say, though, that Milkshake’s nom de blog is an unfortunate one for the topic, since one of the worst things that can happen to you during an extraction is a thick emulsion. That’s when the layers don’t want to separate – millions of tiny droplets of each component decide, for various irritating reasons, that they’re happy where they are, thanks, and don’t pair off with their former comrades. The result is a thick, opaque mess, so the name for the most intractable emulsions is, naturally, “milkshake”.
One of the things he mentions as seldom seen these days is actually one of my favorite pieces of lab apparatus: the liquid-liquid continuous extractor. Sad to say, I don’t have one these days, but I could find or buy one if the need arose. There’s something appealing about setting up a continuous, automatic purification. Being able to see the results over time (the solvent pot in these things gets uglier) makes you feel as if you’re getting something done even if all you’re doing is standing there watching the extractor. A fine apparatus it is, and worth a post of its own some day. . .
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January 24, 2008
Posted by Derek
There are some well-known expensive ways to make scientists happy: buy them lots of equipment and put it in fancy new buildings, pay them lots of money to work there. Come to think of it, that works on just about anyone. But there are some cheap ways to make them happy, too, and companies are really hurting themselves if they don’t pick up on them.
Recognizing what the people in the lab do doesn’t cost very much. Odds are excellent (odds are downright overwhelming) that the people downstream in regulatory affairs and marketing have no idea of who the people were that came up with the latest drug they’re trying to get over the top. Some of them, in a large company, may have only a rough idea of where it came from at all.
Let ‘em know, but do it the right way. Company newsletters get thrown away, mass e-mail get deleted. No, next time there’s a department-wide meeting over there, give ten minutes or so to bring up some of the people who discovered and worked on the current hot compound. If one of them is up for it, have them say a few words. Seeing the hordes of people working on their compound will cheer up the scientists, and seeing where the compounds came from will be a new experience for marketing. Human contact is good; it’s harder to let people down after you’ve met them and seen them.
You can run this in a negative sense, too, naturally, if you’re so inclined. Get one of the higher-ups in the company to mispronounce the name of a discovery project or two during a big speech, and watch what happens. I’ve seen it myself – it works like bug spray on morale, and one of the reasons is that everyone knows that it’s such an easy mistake to avoid.
Not being a hard case about time is another one. You’d think that this would cost money, as people abuse your generous spirit, but for the most part, it’s the opposite. I knew a lab at a former company where the lab head immediately swiveled to look at the wall clock whenever an associate arrived in the morning, or left in the afternoon. This person couldn’t seem to help it. They had to check to make sure they were getting their full day’s work out of the underlings. Morning, evening, check that clock. What did this buy them? A lab full of people who made sure to never set anything up that would take them one minute past Official Quitting Time, and who made the absolute most out of any sanctioned opportunity to not be in the lab with their boss. Not the outcome you want. The same goes, on a larger scale, for vacation days. Slip people a day here and there when they need it, and they’ll work when they’re there.
Keeping people informed isn’t that expensive either. I’ve worked in places where, once a compound went off to the clinic, it vanished off the edge of the earth as far as the people in the discovery labs could see. There was one time when a drug that had been years in development was canned, and chemists who had spent many of those years only heard about it by third-hand rumor. That’s just not right, and it sure didn’t improve anyone’s mood. Losing a drug from the clinic is never a happy occasion, for sure, but you don’t want to add to the pain. . .
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December 21, 2007
Posted by Derek
It’s time, across most of the drug industry, for people to prepare their labs for a few days off. Some companies officially close between Christmas and New Year’s. At the others, you’ll find about 20% occupancy, and those people will likely as not be taking advantage of the time to shovel stuff out of their offices. Not much drug discovery lab work gets done in the last week of December, I can tell you.
I’ve written before about how I used to leave my lab space in what I thought was good shape, only to come back after the break and find that I’d labeled flasks with helpful legends such as “Large Batch” or “2nd Run”. And every January, there I’d be, looking at some tan-colored stuff and thinking “Hmm. Second run of what, exactly?” I could usually work it out, but a couple of times over the years I’ve had to run NMR or mass spectra just to figure out what I was getting at.
So, make sure your stuff is labeled with something more intelligent, is my advice. And even more importantly, make notes to remember lines of research, and plans of what to do. It’s easy to lost the thread after being off for a while. This isn’t always bad – one of the good things about a break is that you lose the threads of a few things that are well lost. But it’s a good idea to write down what’s in progress, what you plan to do about it, and what you’re going to try to do next.
I’m convinced that a lot of good ideas get lost. They're not followed up on, they're forgotten, or they're buried under later duties. I've been trying to keep that from happening, which is one reason I was asking about literature and note-organizing software a while ago (more on that in January). One of my tasks today is making sure that all the current thoughts I have are battened down for the season. As usual, it'll probably turn out that some of the things I'm doing now would be well replaced by some of the things I've just been thinking about.
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December 19, 2007
Posted by Derek
There is a pecking order in chemistry. That’s because there’s one everywhere. If it’s a human endeavor, staffed by humans, you’re going to have hierarchies, real and perceived - who you did a post-doc with, what huge company you're a big wheel in. But that doesn’t mean that we have to bow down to them, and it doesn’t excuse this sort of thing, from The Chem Blog:
” Waaaaaayyy back at the ACS in San Fran at the poster session, we were walking around and introduced ourselves to this guy standing in front of his poster. Now… old boy (a graduate student) engaged us in some dialog about his poster and we were getting along famously, my friend asking most of the intelligent questions (I was still recovering from giving blood a few hours before and drinking multiple beers immediately after.) As conversations normally flow, he asked us where we were from. I told him my fine institution and my buddy told him his. I assume he wasn’t put |
