My friend phosphorus oxychloride

A recent blog post from Derek Lowe talked about the fun of quenching a reaction, thinking you are finished, only to find the chemical has its own agenda and that apparently involves climbing out of the flask and redecorating your hood. It is quite startling how using the reagent in the normal part of the reaction (when you are encouraging it to react) ends up going off without a hitch, but when you quench it to destroy the excess, well, that is when the fun really begins.

The poster child for this type of behavior is phosphorus oxychloride (POCl3). I have had the opportunity to see it in action several times and it is always surprising how suddenly it takes off.

The problem with this particular reagent is that, though it reacts violently with water, at low temperatures it is sluggish, at least partly due to not being soluble. The unsuspecting chemist sees no vigorous reaction, so adds more. What happens is you get a build-up of reagent, skulking in the bottom of the flask as far from the horrible water as it can get, but eventually, enough mixing occurs to initiate reaction, temperatures rise and suddenly you have all the reaction happening at once and giving the best impression of that fountain display in Las Vegas that it can.

It seems like the safest thing to do: default behavior when you are playing it safe is to cool the vessel and add it in slowly and for most quenches this works admirably. Certainly, you don’t want the heat in the system getting out of control. The issue is to make sure that each drop you add is reacted before you add the next one and, though it always feels strange, that is why you should add your phosphorus oxychloride quench into warm (i.e. room temperature) water with plenty of stirring and careful temperature monitoring.

It does not help, of course, that a lot of procedures call for use of POCl3 as solvent and thus in large excess, which in turn leads to there being a lot of it left at the end to dispose of. It would be preferable from a safety standpoint, not to mention environmentally, to use less in the first place. Using a cosolvent such as toluene reduces it some, though half of a large excess is still pretty much in the large excess category. Similar to the way that dimethylformamide (DMF) activates thionyl or oxalyl chloride in acid chloride formation, DMF can activate POCl3 as well. Another procedure that I have had a lot of success with is the procedure of Morris Robins [see Can. J. Chem. 1981, 59, 2601], which accelerates the reaction by addition of chloride ion, in the form of something like benzyltriethylammonium chloride. This reaction can be done in acetonitrile and takes you from refluxing in neat phosphorus oxychloride for several hours to 50 to 80 C with the reaction complete in a few hours at most (I had one that was done in 30 minutes and would start to decompose if it ran too long). A lot of the problems with this type of chlorination or dehydration procedure is that the initial reaction is fast but loss of the phosphorus intermediate (somewhere between phosphate and PO2Cl2) is slow. This is also why sometimes you can start this reaction and it seems to have done something, but when you stop it (prematurely), the intermediate just hydrolyzes back to the starting material and you have wasted your time. The chloride increases the rate of the slow step. And you can get away with uses several equivalents of POCl3 instead of the less than scientific ‘lots’.

What is interesting about the frequency of incidents with this is a thread with common accidents in chemistry. They happen when you think the danger is passed. With very dangerous and toxic chemicals like hydrogen cyanide, everyone is very careful and accidents are rare as a result. It is when you are underestimating what is in your flask that you can get into trouble.

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14 comments on “My friend phosphorus oxychloride

  1. very nice and enlightening article. I was involved with excess POCl3 cracking for quite a few years. 100% agree with the conclusions of the article.

  2. Very Good, interesting and enlightening article. I was involved with excess POCl3 for chlorination and 100% agree with the conclusions of the article.

  3. Andy Nation says:

    Is anyone aware of an org syn prep or some other respected documentation that gives safe guidance on the quench and workup of POCl3 reactions?

  4. [...] comment on my post on phosphorus oxychoride (which I still get hits on even now) from Andy Nation asked if there was any Org Syn prep or other [...]

  5. r.m.chaudhry says:

    100% correct. i’ve been using this reagent since May 2011, but two days before i spent the whole day in the lab inhaling the fumes. at night i was afraid that i might lose my eyes. its so irritating

  6. Prashant m says:

    Sir i am working with pocl3 for making oxadiazols from hydrazide but the problem is that when i reflux the comp getting color initially to pink then to voilet. And i lost my product so help me sir

    • David Perrey says:

      I’ve not done that reaction myself, but that sounds like formation of side-products. How clean is the starting material going in? From my quick search, it looks like you can do it either in neat POCl3 or as a acetonitrile solution – the latter procedure (using much less POCl3) might be less prone to side reactions. I found a Merck patent: WO2006/33848 A1, 2006 which gives some details, but basically you add 1 eq of POCl3 to a cooled solution of your hydrazide and then heat to 80C. Take care with the quench!

  7. aditya says:

    sir any idea about bishler naperialski reaction , in which the usage of pocl3 occurs…….?

    • David Perrey says:

      I have run the Bischler-Napieralski reaction in varying different ways, most usually with 5-6 eq of POCl3 in toluene at 90C, though you can use acetonitrile as solvent. I’ve also seen a microwave procedure, in which they don’t even form the amide first, just mix acid and phenethylamine and get the B-N product. Most of the trouble is in the work-up, but the reaction is much easier if you have the right groups in the right place – something pushing electrons to the place where you want cyclization to occur – most commonly a methoxy group at the 3-position (which becomes the 6 in the final product).

      Anything you particularly wanted to know?

  8. Ahmed El-Sayed says:

    Dear dr. Perrey
    I have a big problem with phosphorus oxychloride, I react it with acid hydrazide and benzoic acid derivatives to produce oxadiazole ring, the reaction is done in neat phosphorus oxychloride at the boiling point of POCl3 which is about 110 c, first the acid and the hydrazide dissolve then the solution turns to red then to dark black, there is a new product formed, I can detect it on TLC, but the product is charred (black) and I can’t separate the new product to be analysed, do u have any solution that I can do to prevent this problem???
    thank u

    • David Perrey says:

      I don’t know exactly what the problem is, but it sounds like extended heating time is causing side products and/or decomposition on the product. My first thought is to reduce the amount of POCl3, do the reaction in a solvent, maybe with BnEt3NCl to aid in the formation of the intermediate (the Morris Robins paper I mention in the paper. In this way, the reaction does not need to run so hot.
      Another option is microwave chemistry, to reduce the overall amount of heating time.

  9. Michael Patrick says:

    Dr. Perrey…do you have an idea of the heat of decomp for POCl3 in water? I have been searching the net for 30 minutes and can’t find this number.

    • David Perrey says:

      Sorry no idea, of where to look for it even. All I have is the shared wisdom that its rate of decomp at 0 C is very slow and it rapidly increases at RT and beyond.

  10. sandip kumar saha says:

    Dear dr. Perrey,from last few months i am trying to make 2,5 disubstituted oxadiazole by the cyclization of N,N’-diacyl hydrazides using POCl3.but im not able to dissolve N,N’-diacyl hydrazides in POCl3 even after heating for a long time. after that to dissolve that material i have added few ml of DMF in the reaction mixture ,then the solution turned into dark brown oily liquid and some of N,N’-diacyl hydrazides remain as un dissolved.I have seen that in most of the journals they used POCl3 for cyclization and the made dissolved the N,N’-diacyl hydrazides in it.please help me to overcome from such a big problem.

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