There is a darkly funny story behind this post, stay tuned.
I guess you have seen this one before: “Experienced MS level chemist with a track record of research accomplishment is looking for a process development or medicinal chemistry position in the industry…”
It lasted twelve months – longer than I could have hoped. I will always remember our time together: The stunning saffron, cinnamon and maroon colors of your intermediates, the lustrous shimmering of microcrystalline flakes when you precipitated; I held you in my hands so many times. Your central atom – a noble metal from the platinum group – will stay in my heart and bones forever.
I am proud when I see how far you have advanced, now that you are to become a project to someone else. I am happy for you. But who will appreciate your special properties like I do, my unstable little molecule?
I have been trying to optimize a difficult reaction; I thought a presence of zinc chloride might help so I gave this a try and there was an improvement: The results were getting better, week after week.
Some time later – by now with improved product purity and filtrability – I begun to wonder if the zinc chloride effect was real, or maybe something else was going on, so I finally got around to run a control. And sure enough, the reaction worked even better without zinc chloride. So, after many tries with quantities of reagents and additives, I arrived at optimized procedure which looked almost exactly like the one that I started with, except few minor details – the little changes that were incidentally co-introduced because of the ZnCl2 addition – few small changes that make a difference… I would have never tried these changes without it. And I would have given up if I had run the control experiments earlier and found out it does nothing.
It is delightful to read methodology papers, the observations and explanations arranged neatly, flowing like a good detective story, with a chain of clear logical reasoning based on the experimental evidence. But I suspect it is mostly fictional (There is no good place in a process paper to explain that after very slow reagent addition because of a clogged valve that no-one cared to inspect before the pilot run, the impurity profile improved and the troublesome sideproduct from the second step no longer buggers up the recrystallization). I worry that reading published accounts of process research can give the management a very unrealistic impression what a normal project should look like.
A reflux in 12 molar HCl
Carefully watched for a frothing,
Painstakingly drained from the reactor,
To strip down and scrub off that gross thing.
My bosses, I tried please believe me,
I’m doing my best as you insist,
I’m ashamed of the material I burned through,
I’m ashamed of the deadlines we missed.
But if you could just see the beauty,
These things I could never describe,
These pleasures of process perfection,
This is my one lucky prize.
refrain: Product isolation…
My apologies to Joy Division
I have been making water-soluble polymers with biomedical applications for the last 16 months and it is quite satisfying: Our macromolecules are usually well behaved – they extract into organic phase. They precipitate as a snow-white fluffy crystalline solid, on a kilo scale. They even have beautiful NMR spectra. Unfortunately, such was not the case with the frothy mixture in the picture. I had to isolate the material from a solution in concentrated HCl (0.3L), with extra sludge of inorganic salts and assorted gunk that included gram quantity of dimethyl sulfide.
The usual process would be: dilute, filtrer, dialyze. But dialysis is a slow and rather frustrating business and we don’t even have bags giant enough for removing few mols of salts and HCl. So I was delighted to learn that tangential flow filtration is a turbo-alternative to a dialysis – instead of steeping a swollen dialysis sausage bag (that can burst overnight) for days and waiting for the diffusion to run its course, the tangential flow filtration setup visibly labors for you: the pump pushes the mixture against a semi-permeable membrane, water and other small molecular weight material leak out, the macromolecular fraction stays in. The purification is done in few hours.
The peristaltic pump in the picture circulates the crude mixture at moderate pressure and high flow rate (20 psi, 1.7 L/min) from the beaker to bottom of the column; the stuff that flows out at the top is fed back into the beaker in a closed loop. The column consist of a bunch of spaghettini-like capillaries that are coated with a semipermeable membrane. The spaghettini are housed in a plastic pipe casing. It is inside these capillaries that the mixture rushes through at high speed over and over again – water and small molecule material that leaks out through the walls of the capillaries collect in the casing and flow into waste (the sidearm and the transparent bottle). One has to keep adding water into the beaker quite often because with a good column + pumping rate/pressure the mixture gets concentrated rather quickly.
The time to end the purification is when chromatography (GPC) can no longer detect small-molecular weight impurities. Of course with a whopping excess of HCl at the beginning, one doesn’t need to run GPC to confirm that all low-molecular weight material is gone – a pH paper will tell you that. (A sniff test for dimethylsulfide presence is also fast … and revolting…)
Five months on – and there is no looking back. With potassium metal freshly cut, with the glassware, solvent and monomer lines pumped down overnight to 20 mTorr, ready or not, macromolecules, here I come.