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How Not to Do It

How Not to Do It: Distilling HMPA

Dylan Stiles has a post up on distilling HMPA, which will be familiar to anyone who’s worked with the solvent. The problem is, HMPA doesn’t come dry, and it has be be dry to be any good. You can take the wimpy way out and dump a load of dessicant into a fresh bottle, but the only way to be sure is to distill the stuff.
Well, that’s one of the problems with it. The other one, as Stiles mentions, is that it’s carcinogenic. His advice – not to soak your genitalia in it – is sound. And that prompts me to update an old post from a few years ago here, to get it into the “How Not to Do It” archives. Longtime readers may recall it, but it’s worth bringing back:
One fine afternoon in graduate school, I was peacefully advancing the cause of science when one of the guys from down the hall came into my lab. “What’s HMPA smell like?” he asked. “Holy (excreta)!” I answered, “You think I know? Probably like it tastes, I guess.” He told me that one of our recent postdocs was distilling it, and he was afraid that the smell in the lab was, well, HMPA, odd as that might sound.
I went down the hall to investigate, and came upon the single stupidest distillation rig I’ve ever encountered. There it was, a two-liter round-bottom flask with a heating mantle on it, boiling and bumping away on the high vacuum line. (OK, fair enough, if you’re going to distill the stuff, you might as well get it over with.) On top of this lunking load of toxic solvent was the smallest still head in the group, a tiny little 14/20 short-path job that looked, in that context, to be about the size of the cherry on top of a triple banana split. This thing wasn’t even slowing the hot HMPA vapors down much. My friend had a right to be suspicious, because yes, that smell probably was the springtime-fresh aroma of HMPA itself.
Unfortunately, I can’t say much about the bouquet of this caricinogenic substance. You’d have to track down our Spanish post-doc and ask him; he was basically showering in the stuff. I stayed out in the hall while I ranted at him, and as he informed me that this was how they did it in Barcelona. “Well, go to Barcelona and do it!” I shouted, looking around to see if there were drops of solvent starting to run down the walls yet.
I left him peacefully distilling away, confident in his technique. Sometimes I wonder what’s become of the guy. . .
(Note: no slur is intended on Spanish post-docs – I’ve worked with lunatics from all over the world, and as far as I can see, none of us are safe. Besides, if there were any country where people didn’t make idiotic mistakes, they’d have taken over the world long ago, you’d think. . .)
Update: I should add that I haven’t used HMPA myself in at least fifteen years. It’s a no-win solvent in drug research. For one thing, it can be quite difficult to remove from your samples, and you have to make sure that it’s all gone before you assay anything. If your reaction will only work with HMPA in it, it’s as good as dead, because no scale-up group will use it. And if it’ll work with something else besides HMPA, well, you should have just used that to start with and saved yourself the trouble.

27 comments on “How Not to Do It: Distilling HMPA”

  1. boiledonions says:

    “as he informed me that this was how they did it in Barcelona. “Well, go to Barcelona and do it!” I shouted”
    His name wasn’t Manuel, by any chance?

  2. Jim Hu says:

    I don’t remember who did it, but I recall someone while I was in grad school redistilling phenol. They did it in the hood, and had a reasonable still head over the round-bottom flask…which was heated over a Fischer burner.
    I only saw this after the fire in the hood was extinquished.

  3. MadChem says:

    I once heard that years ago, when smoking in the lab was still alowed, it was not uncommon to smoke while performing an extraction with for instance ether (the chemists just turned their head with – the burning cigarette – away from the ether vapour when releasing the over-pressure) …

  4. dylan says:

    wasn’t it also *recommended* to smoke when working with cyanides, because HCN changes the taste of the smoke? seem to remember hearing that somewhere.

  5. Derek Lowe says:

    He wasn’t named Manuel, but when I think of the mood I was in throughout much of my grad school career, I realize that I must have sounded disturbingly like Basil Fawlty a lot of the time.
    And I’ve never seen a phenol fire, fortunately, but that must be a foul and smoky blaze indeed.

  6. Milo says:

    I must have sounded disturbingly like Basil Fawlty
    But did you do the goose-step? While poorly imitating German soldiers?

  7. org-turned-medchemist says:

    There’re safer alternatives now like HMPU. They don’t work as well but sure beats getting cancer while trying to get one reaction to work.

  8. Mark says:

    HMPA, HMPT–yuck.
    been a little while, I think we used to “dry” it over CaO
    Have successfully distilled it numerous times in grad school.’
    always fond of TMEDA as a replacement–not quite the same but shouldnt make the process guys squeal

  9. skatesailor says:

    Madchem and dylan are both correct about smoking in the chemical laboratory, when that was commonplace. Indeed, I recall that in 1964 as a graduate student at Dartmouth, I was extracting one liter of some aqueous mixture with 300-ml portions of ether, standing at a hood by a laboratory door containing a window. A passing senior professor of organic chemistry saw me and thought my efforts were not sufficiently vigorous. Resolving to instruct me, he burst in smoking a Lucky Strike cigarette, which dangled from his lips, seized the separatory funnel, and shook it powerfully. Then, turning his head away, he released the built-up pressure through the stopcock. He repeated all this to be certain of his teaching and my learning. Of course, I was fixed like a frightened rabbit on the spot, fearing that he would unluckily strike up a fireball. However, both of us escaped a threat that I would not care to relive; chemistry can be dangerous even without challenging fate.
    Fireballs in organic laboratories were common enough when heedless smokers discarded lighted cigarette butts. They threw them into waste cans containing sodium or magnesium sulfate soaked with ether.

  10. Fred says:

    Momma, don’t let your children grow up to be chemists.

  11. Jason says:

    The MSDS for HMPA makes it sound like perfume. Fragrant and spicy.

  12. Process Chemist says:

    Derek, if the story about the fearless HMPA-distilling postdoc from Barcelona goes back to your grad school years, there is a pretty good chance that he is now a professor in Barcelona and it is likely that I was a student in his class back in college.
    I only had to distill the evil juice twice in my postdoc years. It would have been only once if it wasn’t for a Brazilian postdoc that asked to borrow a few mls. I didn’t trust her, she was much more interested in the club scene than she was in getting her project somewhere. But, how can you say no to a member of your research group?
    Anyhow, an hour later I was walking in front of her hood and noticed my HMPA Schlenk without a septa on it or any nitrogen lines, completely exposed to the air. She claimed she didn’t know it had to be kept under nitrogen. Come to think of it, she probably didn’t know how to keep it under nitrogen.
    Obviously, since I’m now a process guy, I had to erase the word from my dictionary.

  13. Harry says:

    Wow- HMPA brings back memories. The company I worked summers and spring and Christmas breaks at while going to college used to make HMPA in ton lots. I made many a batch as a night shift operator. I also made such things as Sodium Amide (Sodamide) and Ethyl Fluoroacetate and Sodium Fluoroacetate (AKA 1080).
    Those summers gave me an education and industrial persepctive I could not have gotten in 20 years of lab work.

  14. Derek Lowe says:

    Harry, if you survived summer work next to tons of HMPA and fluoroacetates, your lab technique clearly passed the test. Some of the summer undergrads I’ve seen wouldn’t have made it as far as lunch the first day without poisoning themselves.

  15. Ryan Knight says:

    Haha… you guys are funny. There was only one time that I can think of that HMPA was required. It was the N-alkylation of a hindered indole, and some inept postdoc had spent a couple months trying it with tons of different conditions. Once we started working on it, we found a ref that looked eerily similar, and we tried 20% HMPA/DMF and it worked perfect the first time.

  16. Harry says:

    LOL Derek,
    One of my jobs one summer was packaging Sodium Fluoroacetate in 1 lb paint cans for shipment to New Zealand for use in rabbit and opossum baits. If memory serves, we used to ship about 200 lb./year down there.
    Oh yeah- almost forgot, we also made anticoagulant rodenticides like Diphacinine (1,1-Diphenylacetyl Indanedione) and Chlorophacinone (1-Chlorophenyl, 1-Phenylacetyl Indanedione). Like I said, a most educational place to work.

  17. Lab Rat says:

    My “stupid distillation” for which I was guilty as an undergrad (working as an intern at a certain US govt. lab circa 1984) was vacuum distillation of ~100% nitric acid. The still was under the hood…but not the exhaust from the vacuum pump. I was coughing violently by the time I noticed the yellow haze in the room, and coughed up blood the next day.
    The researcher I worked for and I both smoked (and it was allowed in the labs!), but we were much more careful than those mentioned in previous posts. One day our waste can caught on fire, and we pointed fingers at each other, claiming carelessness with cigarette butts. Then it caught on fire a SECOND time that same day and we were baffled. Later that day, I went over to a buchner funnel where we were vacuum filtering out palladium-on-charcoal from a 95% ethanol solution; the filter had run dry, and I looked down in horror at a 4 inch diameter ember of glowing charcoal, blowing hot air into ~1 liter of ethanol. Needless to say, we had been tossing the moist filtrant into the waste can.

  18. LNT says:

    Is HMPA all that bad when you are using it in a stiocheometric amount? I’ve seen several nice reactions that require 1 or 2 equivalents of HMPA. It seems like it would be easy enough to extract it away with just a few aqueous washes. I don’t see any issue with using that type of reaction in a medchem setting. The process guys usually completely revamp a synthesis anyway, reguardless of whether or not HMPA is involved.

  19. Harry says:

    HMPA is bad enough in rat studies. Later on in my career at the same company I had some responsibility for safety and industrial hygiene. I had gotten some information on HMPA toxicity from (IIRC) Haskell Labs, which was the tox testing arm of Dupont, which used mass quantities of HMPA in aramid production.
    While reading the rat inhalation studies- I noted that rats given relatively high inhalation doses over (IIRC) 30 days showed tumor induction. Also that lower doses over 90 days also showed tumor induction. The studies noted that rats were also being tested at still lower doses for 6 month and 12 month periods, but those results did not appear in the information I had, which was at that time several years old.
    I was curious enough to track down the author of the study , who was still working at Haskell. When I asked him about the long-term studies, he basically told me that they didn’t bother to do much follow-through, because at all doses tested, they found tumor induction, given long enough exposure.
    Now, as we all know, rats aren’t people, but to me this was a good reason to mimimize exposure to HMPA. I doubt if acute episodic exposure to even fairly high doses produces a measurable increase in risk, and I also doubt if there is a cumulative risk given widely separate episodes, but I’d still be careful, particularly with skin exposure.
    Now I may be a little off on the details as I present them here, because this all happened about 25 years ago, but I believe they are correct in essence.

  20. Anonymous says:

    You dear bellend,
    HMPA is easy to remove, just H2O does the job, and the waste water can be treated with bleach.
    People makes column with geneous quantities of hexane (which is fucking toxic, take a look in the EPA).
    People does hydrocyanations, guess what is needed.
    Dihydroxylations with OsO4, Michael Additions tih MVK or acrolein which wonderful Michael acceptors for your DNA.
    What about iodines andother alkylating agents.
    But of course, blame on the spanish postdocs and the HMPA running on the walls!? fucking hell is viscous and non volatile as a motherfucker and still can run!!
    You must be a genious.

  21. Derek Lowe says:

    You’d figure that that last comment must have come from Spain, but the IP address show the University of Edinburgh LAN.
    For the record, hexane is indeed toxic, if compared to (for example) ethyl acetate. But it’s not as toxic as HMPA, that’s for sure. The other compounds mentioned are toxic as well, of course. And if I saw someone handling them in the same cavalier way as my old postdoctoral colleague, I’d gladly make fun of them, too.
    Note also that HMPA is known to be carcinogenic in animal models via inhalation. Do you really want to distill liters of it through an inadequate rig, outside the fume hood while you’re sitting right next to it? Feel free. As for me, I’ll feel free to ridicule anyone who does it.

  22. Harry says:

    I agree with you 100%. The conversation I had with the fellow doing the tox studies on HMPA was enough to convince me that this was nothing to treat casually.
    Mr Anon. can do as he pleases. I, on the other hand will continue to take appropriate precautions with toxics and enjoy ridiculing those who don’t.

  23. Anonymous says:

    Hi guys,
    I do apologies if I overreacted and offended you,
    as I feel offended when you mentioned the nationality of the postdoc who did that generalising and probably creating miserunderstood about the quality of spanish postdocs.
    But I still think you are magnifying things with HMPA, of course is very toxic (LD50 2500-2650 mg/kg), but what I meant is that there are hundreds of substances as harmful as HMPA without such a bad reputation and nobody says or mention anything about that and seems that HMPA has got the turkey of all of them.
    I assumed that you guys, are working in industry, by the way in which you face safety issues, and I think that sometimes is excessive all the protocols needed and all the care you need, but indeed better than working in a cowboy fashion, indeed.
    I just going to mention and incident I had with two colleagues who went to industry for an intership and now are back.
    Once I had to do a cyanohydrin (TMSCN, LA,etc), when one of them found that, she went nuts, and tried to stopped me, even speaking with my boss about my supposed lack of skills etc, (of course I knew that after doing the reaction all the glassware and wastes had to be treated with bleach and just in case, I opened a couple of bottles of ether and left them in my fumehood while I was cooking my bacon up, superticious you would called me). Result:Nothing happened.
    Three days later the industry girl, needed a huge electromantle in my fumehood on which I had a 3L ether over Na distilling thing, do you what she did?
    Took the electromantle, quit the ether/Na flask from the condenser/receiver and selled with a stopper without any N2, I was a week off the lab, and imagine 3L of ether, no exit whatsoever for a hypothetical created overpressure and a week of sun over the flask (wonderful to generate peroxides)
    That’s what I meant about HMPA and other risky chemicals. Risk and safety should be taken rigorously, equally and without interest and not in a depending who-you-are-whats-my-premade-idea-of-the-stuff-where-are-you-from-basis.
    Apologies anyway

  24. Derek Lowe says:

    No problem! I’ve added a couple of lines to the original post to make sure that people don’t think I’m singling out Spain or its post-docs.

  25. Qgob says:

    My Ph.D. supervisor used to distill liquefied HF during his PhD in plastic coca cola bottles, the quote that rings in my ears:
    “I used to get onto of the Dyson Perrins building in Oxford, and wait for a favorable breeze”
    Try telling him you were uncomfortable distilling anything, or in fact using any reagent at all ~ my pleasure was methyl triflate, others had the bonus of distilling primary phosphines!
    Anyway, your inappropriate distillation set-up reminds me of the time when I discovered a student in the teaching labs with a 25 ml flask (half full) on the still-end of the distillation apparatus, and a 1 liter flask on the receiving end of the apparatus, which was about three quarters full. This lop-sided arrangement, as you can imagine, attracted my attention.
    I asked about the set-up stating that I though it was quite impressive. He then produced another two full 1 liter flasks from below the fumehood, stating that he also was quite impressed.
    On closer examination it turned out that there was a small crack in his cooling-condenser, which meant that cooling-water had been running into the receiving flask, and that in fact he had been collecting the cooling water for the last hour or so, and not in fact creating new matter.
    I wonder how long he would have sat there if undisturbed?!

  26. Parker Utz says:

    Get a dog or cat that can sing opera. It’s always worked for me.

  27. TfOH says:

    Any advice on removing this solvent without distilling?

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