You know, people make sulfonamides all the time. . .we love sulfonamides in med-chem, right? So why can't I make a simple little sulfonamide off this heterocyclic system, eh? OK, right, there aren't any examples of these things in the literature - not last time I checked, anyway - so maybe there's a reason, but having no examples in the literature is the whole reason I'm trying to make 'em in the first place.
Right. . .send this one down for LC/MS anyway, maybe there's some of the right stuff in there and at least I'll know what it looks like. Yikes, that doesn't dissolve worth a hoot in straight methanol; if I send down a cloudy vial like that they're going to beat me with sticks. Maybe some acetonitrile. . .if this were really a sulfonamide, wouldn't it dissolve better in methanol, anyway? Ah, who am I kidding, these compounds do whatever they want to. If I ever write a book on heterocyclic chemistry, and God forbid, I'll divide them into two kinds of ring systems: friendly and hostile.
Yeah, that'll sell. I'd do better with that idea I had in grad school: "Quantum Mechanics: A Hand-Waving Approach". There's a real market for that one, and by now a hand-waving approach is exactly what I'd be capable of. Man, I remember that course - sitting there doing integrals for particle-in-a-box problems until midnight, and when I tried to go to sleep my brain was still integrating by parts. Couldn't turn it off. What a relief when I woke up and it had finally stopped - never had that happen again, and I've stayed away from quantum so as not to take any chances. What a mess that was - I'd forgotten so much calculus that I had to re-learn, and it had been what? Four years? It's only been twenty since then; I'm sure I'd be a real whiz.
Of course, it was while I was sitting there at my desk in that ancient lab, staring at those integrals that I looked up and saw a kilo jar of benzidine on the shelf right next to where I was sitting. Benzidine. . benzidine. . .that rang a bell, and then I realized, oh yeah, bladder cancer, benzidine's the one that gives you bladder cancer, and here I am camped next to a pony keg of the damn stuff. If I tried to order that through our system now a bunch of sirens would probably go off.
They should have gone off, anyway, when I ordered that new reagent from Big Jim's Discount Chemicals, or whoever it was, some outfit I've never heard of. Month and a half later, and it hasn't shown up. The inventory system keeps sending me e-mails, "Please Enter This Overdue Order". I should set up an auto-reply: "Please Put It In Your Ear". But if I did that, odds are that I'd end up sending it to everyone in the department somehow. . .hard to see the upside of that. And that reagent was going to be the thing to make these sulfonamides. . .aargh, sulfonamides. . . .
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
1. zak on February 6, 2006 12:35 AM writes...
Just out of curiosty, do you ever, ever need knowledge of quantum mechanics in your line of work?
Permalink to Comment2. daen on February 6, 2006 3:54 AM writes...
Is it more or less scary to think of chemistry as applied quantum mechanics?
Permalink to Comment3. Lou on February 6, 2006 5:06 AM writes...
My theory was that chemistry (the theoretical branch at least) was physics in disguise. Wolf in a sheep's clothing. Blah. Never liked 'em myself.
Permalink to Comment4. tom bartlett on February 6, 2006 9:22 AM writes...
Sadly, handwaving Quantum doesn't work. As you know, Derek, you need calculations to explain regiochem in the simple Diels Alder of pentadienoic acid and acrylic acid.
I wish Ian Fleming would finish his update of that Frontier Orbitals for Dummies book of his-- I loved version 1-- very helpful to me.
Permalink to Comment5. Derek Lowe on February 6, 2006 9:38 AM writes...
As far as needing quantum mechanics in doing drug discovery, well. . .if by that you mean what a physicist would call "needing quantum mechanics", the answer is no. I have never, in over sixteen years, deployed the tiniest hint of a wave function.
Someone who works under the hood of a molecular modeling package would have done so, though (I hope). But my copy of Levine's "Quantum Chemistry" sleeps undisturbed in a secondary bookshelf, edges slowly turning brown.
But the consequences of quantum mechanics - those get used every day, although we usually don't think of them as such. Electron-puahing reaction mechanisms, cycloaddition regioselectivity, counterion effects. . .all those are, in the end, quantum-mechanical phenomena. You just don't often need to consider the Hamiltonians in daily life, for which I'm grateful.
Permalink to Comment6. The Novice Chemist on February 6, 2006 9:43 AM writes...
What does quantum mechanics have to do with counterion effects? The other stuff, I get.
Permalink to Comment7. Derek Lowe on February 6, 2006 9:48 AM writes...
Well, counterion effects are due to the relative affinities of small ones like lithium versus larger ones like cesium for different anions. And those affinity differences come down to the behavior of the outermost electrons in each . . .and we're back into the quantum world. Or you could start from the fact that there are defined energy levels and such a thing as outermost electrons. . .
Permalink to Comment8. Timothy on February 6, 2006 10:34 AM writes...
Man, I remember that course - sitting there doing integrals for particle-in-a-box problems until midnight, and when I tried to go to sleep my brain was still integrating by parts. Couldn't turn it off.
I had this same nightmare when I took a class on Taxation & Inequality theory. The text book started with, "This text is designed for use at all levels of economic instruction, students will only need to be able to integrate by parts..."
Permalink to Comment9. tom bartlett on February 6, 2006 11:23 AM writes...
"What does quantum mechanics have to do with counterion effects? The other stuff, I get."
Check out Ian Fleming's Frontier MO book.
Permalink to Comment10. LNT on February 6, 2006 8:52 PM writes...
Derek, you have to "send a sample down" for LCMS? You guys don't have walk-on LCMSs? In spite of the fact that I love being in "big Pharma" (for the past 6 months), it bugs me to no end that we actually had far better analytical capabilities at the small biotech where I started. When will "walk-on PREParative HPLC-MS" make it into big pharma? At the small biotech, all the medicinal chemists routinely purified thier own samples by preparative HPLC-MS. Most of my new "big Pharma" collegues have never even heard of such a thing. Even more sadly, most chemists that have been there for more than 10 years don't even know how to use the analytical LCMS. It's a sad state of affairs....
Permalink to Comment11. Derek Lowe on February 6, 2006 8:57 PM writes...
Oh, we have walk-up instruments, but this one is a tricky thing to see. The standard conditions on the open instrument don't do a very good job on it, so I let the folks downstairs take a crack at it, to their delight.
Permalink to Comment12. HighlyReactive on February 6, 2006 11:04 PM writes...
What's so scary about integration by parts?
Permalink to Comment13. Derek Lowe on February 7, 2006 8:53 AM writes...
The only thing scary about it for me was when my brain wouldn't stop doing it that evening. . .
Permalink to Comment14. The Novice Chemist on February 7, 2006 1:58 PM writes...
Tom Bartlett:
Fleming's book is great! Thanks for pointing it out!
Permalink to Comment