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.