We try to be delicate when we synthesize our molecules – really, we do. Delicate reactions often have better yields and fewer side products. Exotic catalysts in perfectly tuned metal coupling reactions – these things are wonderful when they work, because you go from pure starting material to darn near pure product.
But life in the drug labs is not always thus. We also have to turn back the clock, and break out reactions that our grandfathers would have recognized – dark, fuming things that will eat a hole in your lab coat. Nitration is one of these – good old nitric acid is still very much around for that reaction, often in vile mixtures with sulfuric and the like. It’s cheap, and it often works, so you can’t get away from it. And if 1:1 nitric/sulfuric won’t perforate your clothing, you must have put on armor instead of Armani.
Chlorosulfonic acid is another such reagent. It’s nasty by anyone’s standards, but it’ll stick a chlorosulfonyl group onto an activated aromatic ring in one step, which is nothing to take lightly. You don’t want to pour that into water to work it up, not unless you want to see it splatter all over your hood. Nope, you’ll need a trip to the ice machine – slow drizzling over crushed ice is the traditional workup, for good reason.
That’s a good acid for another brute-force reaction that we still have with us: the Friedel-Crafts. Fancier ways exist to acylate an aromatic ring – those metal-catalyzed ones, for example, often in the presence of carbon monoxide. But who wants to use CO if you don’t have to? And you need a leaving group where the acyl group is going to go. The Friedel-Crafts will just come in and jam one in on an unsubstituted carbon, if the electronics of the ring are right. And all you need to do is treat your molecule with some hammer-of-the-gods reagent like chlorosulfonic acid, polyphosphoric acid (which looks and acts like honey from Hell), or straight aluminum chloride powder. That last one is at least a solid, albeit a corrosive one, but you pay the toll during the workup. That’s when it hydrolyzes to piles of white aluminum oxide junk, often turning your reaction into a thick mess.
So no, it’s not all twenty-first chemistry, all the time. World War I-era chemistry is still very much with us at times. Actually, I sort of like it that way. When I have to break out the polyphosphoric acid, the powdered iron, or the elemental bromine, I feel as if I’m keeping faith with my predecessors. They wouldn’t know what to make of the LC/mass spec machine, but they’d grin when they saw me trying to work up my aluminum chloride reactions.
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
1. NH_chem on October 13, 2008 9:31 AM writes...
Chlorosulfonic acid- here's a nice story for Columbus day. While TA'ing in grad school, an experiment used chlorosulfonic acid. Having detailed the dangers of this with water and pointing out the waste container, a pre-pharmacy student does the dump into the sink......
BOOM goes the sink and the drain trap.....Needless to say the student repeated O-chem several times before finally deciding that pharmacy school could never happen unless you pass o-chem.
Permalink to Comment2. Jose on October 13, 2008 9:31 AM writes...
"Honey from Hell" is a superb moniker- damn I hate PPA! Eaton's reagent is a very useful alternative, BTW.
Permalink to Comment3. Anonymous on October 13, 2008 10:24 AM writes...
A slightly less exciting chlorosulfonic acid story. I TA'd a lab where the students were making sulfanilamide via chlorosulfonylation of acetanilide. One of the students was working diligently to work up the reaction, with no apparent difficulty. I wandered by her bench to check up, she turned around, and the lower front half of here shirt, from breastbone to belt, was gone. No lab jackets had been required, and thankfully she wasn't burned. Use your PPE's, folks!
Permalink to Comment4. Milo on October 13, 2008 10:29 AM writes...
It is interesting to note that most “commodity” chemicals are made using chemistries that are usually quite old.
Permalink to Comment5. S on October 13, 2008 10:48 AM writes...
Anonymous,
Good advice indeed. Just 10 minutes back, I bleached a relatively decent blue t-shirt to, wait for it, "pink". This was thanks to the bleach I was using to clean some of my glassware that had been used for selenium chemistry recently.
S
Permalink to Comment6. milkshake on October 13, 2008 1:28 PM writes...
There is a lovely cyclization of o-toluidine amides to 2-substituted indoles, done in molten KOtBu at 340C. Brian Stoltz use it to make 2,2'-bisindolyl on giant scale, in his staurosporine sysnthesis
Permalink to Comment7. RB Woodweird on October 13, 2008 1:29 PM writes...
You young whippersnappers have it easy! Why in my day, when we wanted some benzene, we had to fill the retort with urea and pyrolize it in a coke oven. It would have been easier if we had known what the stucture of benzene was, that's for darn sure.
Permalink to Comment8. Petros on October 13, 2008 2:08 PM writes...
When I started in the industry the pharmacologists still had their recorders for smoked drums (smoked with bezene) in the cupboard.
And one eraly hands on experience at school was reducing nitrobenzene to aniline.
20 Students boiling HCl in an open lab- lovely aroma!
Permalink to Comment9. srp on October 13, 2008 3:08 PM writes...
Think of it as survivalist chemistry. The better you are at making stuff from widely available materials, the better able you will be to find a useful place after the collapse of civilization. See Lucifer's Hammer for an entertaining account.
Permalink to Comment10. ZAL on October 13, 2008 3:27 PM writes...
Hey, Milkshake, isn't it called a Madelung indole synthesis? I'm having an interview soon and I'm currently enhancing my heterocyclic powers...
Permalink to Comment11. psi*psi on October 13, 2008 3:37 PM writes...
YES!!! Old-school chemistry--especially the aromatic variety--is pretty much my favorite kind. Keeps you on your toes ;)
Permalink to Comment12. RTW on October 13, 2008 4:23 PM writes...
SRP - Very good point, those of us old purportedly obsolete synthetic chemists will be back in demand! After all how many remember how to use gelatin, or diatomous earth to separate things? Problem is if it all comes down around our ears as portrayed in Lucifer's Hammer, even the simplest stuff might be very hard to find. BTW that was a very good Niven novel, but my fav is Oath of Fealty. Just read the latest (to me) Fleet of Worlds
Permalink to Comment13. RTW on October 13, 2008 4:31 PM writes...
Oh and the worst reagent mix I ever used was a nasty mixture of Formic Acid and 50% Hydrogen Peroxide. I was trying to open a double bond if memory serves. That one ate through my rubber gloves and turned the skin on a couple of my fingers black. Burned pretty well too.... I was lucky, as I recall this was added via dropping funnel and the stopcock was leaky. It could have been worse had I not been wearing Rubber gloves. I don't think Latex would have provided any protection.
Permalink to Comment14. Don B. on October 13, 2008 4:34 PM writes...
The "Ring of Fire" series is even better than Lucifer's Hammer. They even make chloromycetin(TM)
Permalink to Comment15. Harry on October 13, 2008 6:38 PM writes...
Ahh yes, PPA- I had the "pleasure" of using this in a Fisher Indole synthesis in 5 liter quantities. I also worked in a plant that was making Indigo by the classical route using Na/K eutectic. Lovely stuff.
Refluxing Chlorine, Birch reductions, Friedel-Crafts, Nitrations using red fumimg Nitric acid and Oleum, Sulfonations with SO3. Old-line industrial chemistry at its finest!
Permalink to Comment16. bcpmoon on October 14, 2008 1:32 AM writes...
My thesis was all mmol scale, nice, clean, contemporary chemistry... But the starting materials - fun! Triiodobenzene from scratch, reactions in boiling bromine... Those were the days.
Permalink to CommentFact is, that a lot of nasty chemicals are simply much easier to handle on scale, so stuff that you don´t want in your lab is very convenient when it comes via street tanker. And if you can use starting materials for your API that are somewhere made/needed/discarded in the bulk industry, it gets cheap as dirt. Profit!
17. Handles on October 14, 2008 5:36 AM writes...
Boiling bromine is great, it looks like the fires of hell in your condenser.
Permalink to Comment18. Hap on October 14, 2008 10:27 AM writes...
Probably smells like them, too.
Na/K was the source of our one-night lab shutdown - Na/K (80g) + flaw in glassware = glowing hood. The person running the reaction was smart enough to have the department's alkali metal fire extinguisher, but it still left a week's mess in the hood. Ick.
Permalink to Comment19. realchemist on October 14, 2008 11:09 AM writes...
It takes a real chemist to get white crystals from black sludge
Permalink to Comment20. eugene on October 14, 2008 12:38 PM writes...
"Boiling bromine is great, it looks like the fires of hell in your condenser."
There is always a bit of the bromine cloud that escapes above the condenser for me no matter what condenser I use. I've never figured out how to stop it really. A good exhaust is essential for large scale bromine reactions. As a 1:1 neat reagent it's also a bit of a pain to measure out correctly and transfer due to it's density and low vapor pressure.
Permalink to Comment21. Jose on October 14, 2008 1:27 PM writes...
Eugene- bromine has some weird vapor phase solubility behaviour(an azeotrope?) in CCl4. It all stays in a decent condenser quite well, unlike benzene, toluene, or DCM.
Permalink to Comment22. eugene on October 15, 2008 9:21 AM writes...
Thanks for the advice Jose! Usually when I use bromine on a really large scale, the solvent has to be aqueous HBr (which is not as viscous when it's at 60C, but makes for an overall nasty experience together with the bromine), but there are some other reactions where I could try that CCl4 trick.
Permalink to Comment23. Anonymous on October 15, 2008 7:34 PM writes...
I read Lucifer's Hammer about the time I was prepping for my first semester sophomore organic final. talk about motivation.
Derek, how about a 'Favorite Chemistry in Non-fiction' thread? Mine - Harry Gray in a Joe Wambaugh police thriller about the Nobel prize ("The Orange COast"?)
Permalink to Comment24. milkshake on October 15, 2008 8:04 PM writes...
Beznene and toluene are poor solvent choices for brominations wit Br2. Chloroform and DCM and DCE can get brominated as well. Acetonitrile is problematic when you generate HBr. CCl4 is outrageously expensive because of the Freon tax.
My favorite solvent for Br2 brominations is acetic acid and/or TFA. Conc aqueous HBr is a very good choice because some brominations (of ketones, for example) are catalysed by acid and display auto-induction behaviour without HBr - a very dangerous thing on scale. (I heard of a guy who lost his eyes when brominating acetophenone).
The thing about Br2 is that it not only looks evil - it is. It eats through latex gloves alarmingly fast and causes excruciating yperite-like deep burns that are very slow to heal.
Permalink to Comment25. processchemist on October 16, 2008 2:40 AM writes...
milkshake
Brominations are every day routine for me. AcOH or AcOH/DCM mixtures best choice for both HBr and bromine. AcOH alone tends to give problems in many cases when work up the reactions (poorly stirrable or filtrable slurries etc). The standard kit to work on the Kg/multi Kg scale: teflon tubing, nitrile gloves, aqueous ammonia at hand (and obviously a gas mask). Many times papers or transmitted syntheses filter without an appropriate quench after an aqueous workup. A mess, also on the 10-50 g scale. Traces of bromine in presence of HBr disgregate not only paper filters: these mixtures can damage also PP after long conctat times (some people I know did not expect any problem working with a glass lined filter, forgetting the PP bag inside...)
Permalink to Comment26. Toluene on October 16, 2008 2:50 PM writes...
Ahhh.......Brings back memories of making aromatic acetylenes. Stew up a substituted acetophenone in POCl3 then pour onto ice and work-up. Add product to sodium in liquid ammonia--worked great every time!
Permalink to Comment27. Jose on October 16, 2008 3:08 PM writes...
Several years ago a coworker had a syringe of bromine bump, spraying droplets on his arm between gloves and lab coat. The resulting burns were truly horrific and took eons to heal. Since then, I have had a *very* healthy respect for the element.
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