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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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May 29, 2009

Wait For It. . .Wait For It. . .

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Posted by Derek

Here's something that I'll bet every bench chemist has experienced: thinking that you've quenched some nasty reagent (it has to be gone by now!) only to find that it's very much still with you. These guests that won't leave can be smelly, corrosive, or downright dangerous when they finally yawn, stretch, and decide that it's time to move off the couch.

Alkylaluminum species, in my experience, take their time for longer than you'd think possible, and then depart in a tearing hurry. I used to use several diethylaluminum-X things (cyanide, alkynes, and so on), and was taken by surprise early on by their lackadaisical response to methanol or water at the end of the reaction. "Surely there's some excess aluminum junk in there", I remember thinking the first time this happened, "but there's nothing happening. Maybe I should just squirt in some more." That last phrase has been the prelude to many exciting chemistry moments, and so it was here. Not long after I acted on that impulse, the reagent caught on the fact that it had lots of methanol surrounding it ("Hey, I react with this stuff, don't I?"), and another geyser was born.

Perhaps the king of the "I thought it was hydrolyzed" bunch is phosphorus oxychloride. That stuff takes forever to get around to reacting with water, although on the face of it, you'd imagine it fizzing and sputtering as soon as it got within range. But no, many chemists who've used this reagent have returned to their fume hoods to find the contents of their sep funnels or waste jars gradually coming back from the dead. Milkshake can tell you all about it at Org Prep Daily, and so can many others: never take this one for granted.

Comments (19) + TrackBacks (0) | Category: Life in the Drug Labs


1. CMCguy on May 29, 2009 9:52 AM writes...

What you write is probably quite familiar to most chemists as even after some lessons can find stuff thought a reaction was quenched will take off. Picking up thread from couple days ago sometimes containers of reagents get left around for god knows how long because they are known to be "no longer any good" so no ones uses (in uni labs can be years, industry typically has more regular purge cycles, don't want to think about high school labs although probably don't get to get any of the fun stuff much these days I think). However when try to take care of these for disposal by "controlled" quench (ignored legal implications) find that the dead stuff was only sleeping and did not want to be awakened.

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2. SR on May 29, 2009 10:22 AM writes...

This is something we always watch for when quenching solvent drying stills containing a lot of sodium metal. Too many times somebody inexperienced notices the isopropanol is reacting somewhat slowly and figures the still must be nearly quenched, thus they dump a load of methanol in to finish it. When the methanol dissolves the gunk around the sodium and exposes the fresh and shiny new surfaces, the real fun begins.

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3. syregnask on May 29, 2009 10:30 AM writes...

If my memory serves me well, the tricky bit about POCl3 is partly due to the curious fact that at room temperature water and POCl3 are immiscible. This naturally slows down the reaction quite a bit, but it does take place, and as it is exothermic it tends to heat things up to the point were water and POCl3 become miscible .. and then the party really gets going.

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4. DC on May 29, 2009 10:35 AM writes...

Pouring into a large beaker of ice-water and stirring for an hour has always worked for me.

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5. NH_chem on May 29, 2009 10:56 AM writes...

POCl3 is my favorite. Had a nice blow up of that on the 55 gallon drum scale when doing a never forget that rumble sound.

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6. Norepi on May 29, 2009 11:59 AM writes...

I used to know a post-doc who used to practically shower in POCl3 (dehydrating ugly amides to ugly nitriles and then cyclizing them to even uglier quinolines, iirc). He came over to the US from China, and had some problems with English, so I'm not sure if he knew how to follow the directions.

I came in one morning on a particularly humid day at around 8AM to find the whole lab reeking like the acrid depths of the underworld. Our friend the post-doc was shouting "I use too much!" and motioning to his hood, where drops of phosphoric acid were condensing and running down the walls and sash.

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7. processchemist on May 29, 2009 1:31 PM writes...

POCl3! wow, after years it still can have surprises for me, from time to time. Ice quenching in scaled up condition is not a so good idea: it's better to quench with water, keeping T no so low (about 5°C). But stirring during the quench is the most important thing, and when you have a progressive formation of solids ... if you're working with a 10-22 l flask you can have an hell of a time. Reactors usually are safer to manage this chemistry.

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8. Kimist on June 1, 2009 6:15 AM writes...

A lesser known problem with POCl3...Not only can water cause those "runaway reactions", but it also reacts with acetone. After removing POCl3 from a rxn mixture on the rotavap, a scientist in our lab cleaned the rotavap with acetone. These washes were combined with the POCl3 and poured into the original rxn vessel - a pressure flask. It was late and the scientist decided to just quench it the next day. The next morning, he came in to find a hole blown through the side of the hood, the hood glass cracked and the flask blown to smithereens. There's a paper in OPRD where they experienced the same thing. Lesson learned - always quench POCl3 ASAP and don't store it in a pressure flask with acetone.

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9. milkshake on June 1, 2009 6:31 AM writes...

I gassed a large lab with a POCl3 quench once. About 200 mL of waste POCl3 recovered from a mol-scale experiment (where it was used as a reagent and solvent) mixed with ice was siting quietly in a plastic bucket in he hood until the ice melted, and then the mix erupted. The sash was not down all the way so a significant portion splashed outside the hood. Fortunately no one was around. I was in the office and my colleagues were out for lunch. I got hold of a gas mask and cleaned up the mess with diluted ammonia. Our safety officer was extremely unhappy about it - I was not trained to be in rapid response team and not authorized to use the mask etc etc. (I cleaned up in 20 min what they would spend the whole afternoon on, followed by a huge paperwork-reporting burden).

The one nice thing about POCl3 is that one starts choking on it immediately - it does not seem to have the delayed action like hard alkylating agents.

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10. Nick K on June 1, 2009 8:55 AM writes...

As other contributors have noted, POCl3 is particularly difficult to quench because it's immiscible with water at low temperature, leading to runaway reactions as the mixture warms up. I was faced once with the task of quenching a large quantity (ca. 3L) of the stuff. The workup of a small-scale (500g!) run with ice-water led to an eruption and a big mess, despite the fact that I stirred the mixture vigorously, and added the POCl3 very slowly. Finally, the penny dropped, and I tried siphoning in the reaction mixture slowly onto WARM water. Success! The exotherm was instantaneous and easily controlled by regulating the rate of addition. The heat was absorbed by adding ice occasionally, or merely by letting the water reflux.

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11. milkshake on June 1, 2009 9:39 AM writes...

I wonder if the produced HCl has some accelerating effect - that would cause the POCl3+water mix behave like autocatalytic system.

I know that bromination of acetophenones with elementary bromine is catalyzed by the produced HBr, unpredictability of such a system (if no catalytic acid is added in the beginning) has led to extremely nasty runaway mishaps.

The same goes for AcOH+fuming nitric acid - a little NO2 and the nitration mix suddenly starts warming with lot more NO2 produced, until the whole thing goes poof

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12. David P on June 1, 2009 10:38 AM writes...

We have had our share of POCl3 incidents, it even got its own special section in the safety manual at my last employer.

As Nick K noted above, the secret is to use a controlled addition into warm water. Quenching it with ice water mixes is generally a bad idea - you feel like you have done the 'safe' thing, but you have managed to add a lot of water that can all react at once.

But really, the safest thing to do is not use neat POCl3 in the first place, there are very effective chlorination procedures that do not use it as a solvent. DMF as a co-reactant has been quite effective, another I liked was using a secondary source of chloride (e.g. benzyltriethylammonium chloride) in MeCN with some base. A lot faster reaction time and a lot safer to quench too.

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13. processchemist on June 1, 2009 12:02 PM writes...

Maybe you know that halogenated solvents are usually not welcome in modern process chemistry and production (in the western world, obviously), but where I work 1,2-dichloropropane is in most cases the solvent of choice for POCl3 chlorinations and dehydrations. It's partially miscible with water: a problem for water waste treatment, but a plus for quenching reactions.

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14. Hap on June 1, 2009 12:51 PM writes...

Acetophenone and bromine must be yummy - a runaway reaction where the products are lachrymators. Whee.

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15. Norepi on June 1, 2009 10:14 PM writes...

# 8: I seem to remember an old labmate of mine accomplished a similar trick with acetone + ethyl chloroformate, only he maced himself in the face and wasn't wearing goggles when he threw the mess into the sink. I hear SOCl2 will do something similar

# 14: I work with tons of phenacyl halides, all of which are ill-tempered molecules. Whilst I've never had a bromination or chlorination take off on me, some of the end products are really awful. My personal favorite was following an old JOC paper, where the authors noted that the product was "lachrymatory." I somehow became sensitized to it, and handling even small amounts, like, you know, 2 mg for an NMR sample, caused me to cry and sneeze until the capillaries in my eyeballs ruptured. And this was, of course, with goggles, gloves, and dust-mask! We called them "Sneezyl Bromides."

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16. Nick K on June 2, 2009 5:43 AM writes...

David P: Thanks for a most interesting post. I didn't know one could run POCl3 reactions like that. It sounds far easier and safer than using POCl3 as solvent. Do you have any references?

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17. David P on June 2, 2009 4:04 PM writes...

Nick K: I was trying to find the original article (Can. J. Chem. as I recall), which had a really nice discussion of the mechanism, but I can't seem to find it right now.

They do use the process in this paper: J. Med. Chem. 1995, 38(23), 4679-86.

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18. David P on June 2, 2009 5:04 PM writes...

I remembered the author of the original work: Morris J. Robins.

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19. Nick K on June 3, 2009 4:20 AM writes...

David P: Many thanks for the ref. I'll try it out next time I have to do a POCl3 reaction.

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