I was talking about vacuum distillation and recrystallization the other day, and several people pointed out in the comments that large-scale chemistry still relies on these techniques. That’s absolutely right, especially recrystallization. It’s all a question of scale.
These two are bulk techniques – they work out fine on reasonable amounts, but they’re very difficult to run on a microscale with conventional techniques. Distilling a kilo of something is just about as much work as distilling ten grams of it – but distilling ten milligrams, now that’s something I wouldn’t want to be in charge of. Going the other way, distilling ten kilos starts to take you into a another different world, and one of the main reasons operates across the entire scale: surface to volume ratio.
In a distillation from a really large flask, you have to find efficient ways to heat the thing, because just sticking it into a really, really big heating mantle or oil bath gets to be problematic. The surface area of the flask is going up as a square, and that’s what you’re depending on to transfer to heat to the inner volume. But that volume’s going up as a cube. In a 100-mL flask, no part of the contents is more than two or three centimeters from the wall, whereas in a 100-liter system the commute from the edge has grown to something pretty substantial.
Your heating problem is also a mixing problem, since those technologies don’t scale smoothly, either. In a 100-mL flask you can drop a good-sized magnetic stir bar in and whip the solution around smartly with the spinning magnet of a regular stir plate. A proportional stir bar for a 100-liter flask would be a real brick, liable to crash right through the walls of the flask, and you’d need some sort of diesel-powered stirring plate to spin the thing. Needless to say, there are plenty of heating, mixing, jkl and distilling methods for the industrial scale – the existence of gas stations is a testimony to that – but they don’t look much like what people like me use to make twenty milligrams of a test compound.
So much for the big stuff, now take it down to the ten-mg scale. The area-to-volume problem is now reversed. You can’t buy a proportionally sized distillation head, because you’d need a deranged artist of a glassblower to make one. Your tiny volume of solution will just spread out and coat the insides of the smallest distillation rig available. You’re working far within the error and loss of a normal distillation, and your sample will disappear into this gap and never be seen again. I can imagine some sort of microscale rig made out of glass capillaries, although I’ve certainly never seen such a thing. (Surface tension would surely start to become an issue with its operation). Microfluidics is a hot research area, but as far as I know they’ve yet to move on to distillation. I hope someone gives it a shot.
Now consider chromatography. Ten milligrams is plenty of material to work with on an HPLC system. (And if you’re just interested in analysis, and not isolating preparative amounts at the end, ten milligrams becomes a mountainous heap). But running an HPLC on 100 grams is pretty much out of the question. Running even a normal column on that scale isn’t much fun, and when you head up to ten kilos it becomes a major undertaking that you’d do all kinds of things to avoid. (Like, say, spending a week or two trying out recrystallization conditions). The amount of solvent become really substantial, as does the expense and trouble of handling it. It’s not that chromatography doesn’t get done on large scale, it’s just that it gets done only after better alternatives have been completely ruled out.
Recrystallization goes up and down the scale a bit better than these other two techniques. It’s tricky to do on a small scale, but if you have a good solvent combination to form the right kind of crystals you can recrystallize a ten milligram sample if you absolutely have to. One problem with trying to use the technique on that scale is that it generally takes a lot of messing around with the conditions to get a good system, and if you only have ten mgs you probably can’t get away with that. I’d much rather run that sample down an HPLC, though, believe me.
Crystals are much more fun when you’re making a few grams, where you don’t have to worry about every single bit stuck to the sides of the glassware. And the folks working on larger scale just love recrystallization more than anything. It’s true that you have to heat things up at the start, but the heating doesn’t have to be done as critically as in an actual reaction, since you’re generally just trying to get things to dissolve. And once everything has cooled back down and the new crystals have fallen out of solution, it’s just a filtration and wash, and that’s something that can be done well even on a gigantic scale.