What’s another (kilo)gram?

Prior to my current post, I’d not given too much thought to scale up.  I suspect to the majority of early career synthetic chemists, “large-scale” is synonymous with breaking out the one-liter round bottom flask.  That’s pretty much the comfortable upper bound of what you can work with 1) on a benchtop; 2) with magnetic stirring; and 3) with a oil bath heat source.

Your efforts on this scale will yield somewhere in the ballpark of 100 grams of product, depending on formula weight and a slew of other variables.  And what’s more, purification and workup has now ventured into the realm of things that are no longer routine.  A one-liter reaction volume is going to require a rather large separatory funnel (as a side note, Chemglass sells them up to 22-L — good luck with that).  And unless your starting materials and product have wildly different silica affinities, you’re going to have quite a bit of fun trying to run a 100-gram flash column, so you’ll likely have to break it into a couple runs.

And that’s all great until you need to crank out a kilogram of material.  You can now forget about running things in round bottomed flasks (Chemglass also sells a 22-L round bottomed flask, a testament to the age-old adage “just because you can does not mean you should“).  You’re also not going to have much luck trying to fit a vessel that size onto a hot plate, so that rules out both magnetic stirring (which would be ineffective anyway) and conventional heating baths or mantles.

Things like efficient mixing and heat transfer — which we hand wave away at the gram-scale — start to matter quite a bit once you cross the kilogram threshold.  So you’re going to need a specialized, jacketed reactor, through which you can recirculate a heated (or cooled) thermal transfer media.  And because surface area to volume ratios are the way they are, the temperature gradient between the outside of the reactor and the inside can be pretty dramatic.  So you’ve really got to get things mixed well, which means you need motorized stirring and a decent sized impeller.

Next on your synthetic checklist is workup, which now takes an entire day in and of itself.  Pray you don’t need to purify anything chromatographically.  Your precipitation that required 10 ml of solvent X per ml solvent Y suddenly won’t fit in any container in the lab, save the 55-gallon waste drum.  I’m not ashamed to admit I’ve MacGyvered a workup involving a 5-gallon orange Home Depot paint bucket at a previous position.

All this, and I haven’t even touched on time yet.  Everything at the kilo-scale takes longer.  A reaction which you could comfortably set up in 20 minutes at the gram scale will take you all morning to get going.  And you’d best triple check your work here, as mistakes on this scale are costly.

Of course, the proper process chemists will scoff at the struggles of the kilo-scale.  Steel reactors replace glass, drum evaporators replace rotavaps, and somehow I doubt the tried and true paint bucket workup would pass cGMP muster.

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