Org Prep Daily

August 2, 2008

This phosphine will get you fired

Filed under: lab destruction, lit highlights, mechanisms — milkshake @ 11:32 pm

Beautiful asymmetric transition metal-catalysed chemistry with phosphine ligands chiral on phosphorus dates back to Knowles and Mislow. But these P-stereogenic homochiral phosphines are usualy harder to make, so they were eventually supplanted by ligands with chirality on carbon. As a freshman I used to work for a young assistant prof in Prague - and since I was very interested in asymmetric synthesis, he suggested that I could do a thesis work with him on these ligands; We would put some chiral but racemic phosphine building block onto optically active binaphtyl piece derived from BINOL, and we would get BINAP-like ligands with both axial chirality and chirality on phosphorus. We would then try to separate the stereoisomers and see which one worked better in Rh and Ru-catalysed asym hydrogenations, and we would try to interconvert the stereoisomers to see how the kinetic vs thermodynamic induction control looks like, etc. (Chiral phosphines are conformationally labile on phosphorus above 100C whereas the 2,2′-disubst binaphtyl pieces are fairly stable and should not racemize).

This all happened more than 20 years ago and there is over-abundance of commercial chiral phosphines nowadays -  though as far as I know the doubly-chiral BINAP idea was never put into practice. The reason why we never managed to put it into practice was that we were inadequate - We did not realise that phosphines are so unstable. Unless in crystalline form or complexed to things like borane, alkyl phosphines oxidise rapidly in air (for example the used silica and eluent has to be deoxygenated)- and we had no glovebox; not even a vacuum/argon manifold line.

The other reason was that I got fired from that lab soon after I started working on this project. Here is the story how it happened:

My adviser was a junior faculty, at a poor university - he shared the workspace with two other faculty members. The actual boss of the lab was an old and rather sardonic man. The old man became  noticebly grouchier during the year when I was working in their lab, especially after I had couple of fires and broke every valuable piece of glassware they had there; and soon everybody was calling me the Disaster-Master and “Bořivoj” – It translates as “the one who tears down the places”. Me and my young adviser made quite an enthusiastic team - we tried to synthesize optically active binaphtyl compounds on a grand scale. And when a 4-liter flask full of xylene refluxing on your bench ruptures into the heating mantle, people start taking notice…

There is a lovely one-pot procedure for turning triphenyl phosphine into PhePHMe: Sodium metal in liquid ammonia cleaves off phenyls from the phosphines in a controllable fashion. It goes like titration - while you feed the reaction mix with chunks of Na metal, the red color of Phe2PNa develops which then suddenly turns inky blue by the dissolved metal once you reach the equivalence point with 2 equivs of Na. Then you add tBuCl to selectively quench the formed sodium amide followed by MeI, to methylate the diphenyl phosphide anion, and the red color vanishes. Then you add more sodium until inky blue again, quench with solid NH4Cl, evaporate, then distill. The literature procedure has no comments on the smell of these things; I guess a man skilled in art is supposed to know. (We did not).

An inorganic chemistry colleague actually warned us about the phosphine stink - he advised us to make these compounds at night (and preferably in a student lab), to use baths of acidified permanganate or bleach or peroxide and decontaminate everything afterwards. It seemed  excessive to me but my boss borrowed keys from the teaching lab located at the distant end of a very long hallway, and we went to work there one Spring Sunday afternoon.

The reaction behaved beautifully - exactly as in literature procedure – the color transitions and all, and even the product distilled pure in a good yield in the end as a highly refractive clear, thin liquid. But the smell - right at the moment when we quenched (in a hood of course) we were pushed back by the solidity of the reek. I got to know many evil chemical smells over the years but nothing comes anywhere close. With the other stinkers, at least one can imagine what sort of unwashed, putrid, fishy, skunky, human-waste object those smells are related to. But I never encountered anything as nauseating or alien like PhePHMe: The memory is stil with me - the most sickly and sweetish smell of rancid gasoline combined with rotten water melons, with undertones of stale sweat, pig carcass, a hint of garlic, moldy oranges, russian-made aftershave and a cheap household air freshener…  its a whole package, and rather sweet one – like isonitriles or cyclopentadiene but magnified thousand times. A whiff of that thing and you feel that your nose just suffered a stroke and will hopefully die and peal off so that you never smell that thing again. Inconceivable - and it does not get any better when wearing off; quite opposite in fact – just like with butyric or isovaleric acid, the reek is developing a more alarming depth and complexity with the dilution.

Phosphines like to oxidise on air (unless in crystalline form) and those with H or small alkyls on P tend to catch on fire when neat. There was a flame-up when I took an adapter off after the vacuum distillation from a still warm flask - a bright flame jumped through, with a high-pitched bark and yet another wave of nauseating reek crashed over us…

Finally, we sealed the product into ampules as to keep it from oxidizing. We washed all the used glassware in permanganate and then in bleach - twice – and we put it on a cart and brought it back to our lab, happily tired after a long and productive Sunday. I remeber that before heading home - as I was putting the glassware on the drying rack above the sink - I noticed a shred of glass from a broken adaptor that remained in a joint of the distillation flask. (I panicked when the thing flamed on me and I broke it). So I dislodged that piece from the joint with tweezers and thew the shred into a glass waste bin next to the sink. It was late night and I did not give it much thought; I did not realise that the broken piece was stuck in the joint and the surface between the two did not get in contact with the bleach bath.

The next day we were both late, I made it to the lab at around 10:30a before my adviser arrived – and I noticed that all windows in the lab and hallway were open. Nothing too unusual on a warm late-spring day – except that our grouchy old colleague’s face was somewhat sallow. He even seemed pleased to see me, and he welcomed me calmly: ” Please sit down, Mr. Bořivoj. It is with enormous satisfaction for me to inform you that your long tenure in this lab just came to its abrupt end. My patience has been worn thin and through. I have been doing chemistry for forty years now and I have no desire to ever puke my guts out again in my own lab on Monday morning.”

I forgot to mention - this old man spent his career on making vinyl sulfur-and-selenium compounds. Forty years - and even he was impressed with our phosphine.

28 Comments »

  1. I can smell it now through your description -_-

    Comment by c — August 3, 2008 @ 6:23 am

  2. Nice reading indeed.

    Many syntheses of such phosphines were carried out in the 1950/60/70s by Issleib in East Germany, I belive sometimes under rather primitive conditions. The air-sensitivity and smell must have been well-known to the specialist indeed.

    Your first sentence asks for a comment:
    From the Nobel Lecture of Knowles:

    “A second development in the mid-sixties was the development of methods for making chiral phosphines by Mislow AND ALSO BY HORNER.”
    “Earlier it was thought that phosphines might pyramidally invert like their nitrogen analogs but Mislow AND ALSO HORNER showed they were stable at room temperature”
    “HORNER, SHORTLY AFTER OUR PAPER, reported EVEN MORE MODEST RESULTS with the same methylpropylphenylphosphine on a substituted styrene. there were OTHERS using other phosphines with UNINTERESTING RESULTS”

    So who is this HORNER guy who apparently is a pain in the a__ of the american view on the history of chemistry?

    Such distorted views are not limited to Knowles, who may feel the need to justify his Nobel-prize.

    Read what Jay Siegel has to write about Mislow (Chirality, 10, 3-7):

    “Thus pioneering syntheses of chiral enantiomerically pure phosphines were carried out at Princeton, and a second class of important chiral compounds traced to Kurt’s efforts. (Can we imagine the field of asymmetric synthesis today without chiral phosphines and chiral biphenyls?)”

    Please not that the chirality/resolution of biaryls does not go back to Mislow, and he has not really invented asymmetric synthesis (as Siegels remark in brackets might imply to the non-specialist).

    Comment by pretty casual — August 3, 2008 @ 6:28 am

  3. I was not quite aware of the long literature – as you know I was on that project only briefly.

    It takes a phosphine to reek like phosphine. The interested volunteers that want to get an approximate impression can take a sniff at Phe2PH, a commercially available cheap stinko that is a wimpy cousin of PhePHMe. I think you will then wisely decide not to pursue the real thing.

    Comment by milkshake — August 3, 2008 @ 7:21 am

  4. Very beautiful preparation! Cool!!

    Comment by alessandro — August 3, 2008 @ 2:21 pm

  5. Phosphines are good. We make them all the time… under Argon. The worst though, I think, is Tristrimethylsilylphosphine. Eek.

    Comment by Paula Schramm — August 3, 2008 @ 4:24 pm

  6. I make it a point to not use phosphines that don’t burst into flames upon contact with air. Cause, uh, it’s a rather annoying property. I don’t use tri-tert-butylphosphine much for that reason. And its wonderful phosphonium salt is really expensive. How does the smell compare to PMe3?

    Comment by excimer — August 3, 2008 @ 4:48 pm

  7. Re: (tBu)3P – Aldrich sell a solution in toluene that’s reasonably affordable and retains its activity for quite a while if you avoid doing stupid things with it. Quite nice for modifying Karstedt’s catalyst if you have a burning need to hydrosilylate an alkyne with absurdly high regioselectivity.

    Comment by dtb — August 3, 2008 @ 8:30 pm

  8. One of the people I knew in Evans’ group worked with Ph2PH – it doesn’t have all the noxious features of PhPHMe, but it has a pretty special odor all its own. Sort of like mesityl oxide, but persistent…it gave one of the other grad students headaches even from the hood, and he said he could smell on his hands at night even wearing vinyl and disposable gloves at work.

    How does it compare to isoamyl nitrite?

    Comment by Hap — August 3, 2008 @ 11:59 pm

  9. PMe3 is unpleasant but I work with it here all the time without hesitation, as 1M solution in toluene – its great for reducing azides (instant reaction, good yields, easy workup as Me3PO extract into water). Somewhat garlicky but not too pungent.

    But volatile Aryl-PH-R phosphines are different – the smell is very sweet. The moment you sniff it you wish you never learned that such smell even existed.

    Isoamyl nitrite does not smell bad when free of isoamyl aldehyde and isovaleric acid – it is just little fruity – but it produces a rapid headchae, feeling of “head balooning” and facial flushing as your capilaries dilate. Its very different thing. (I was actually having few whifs of it once – not to improve my sex life but I worked with TMSCN carelessly and begun feeling unwell and lightheaded for a moment – so I reached for isoamylnitrite bottle just to be sure).

    Comment by milkshake — August 4, 2008 @ 12:00 am

  10. Phosphines are known neurotoxins – hence the headaches and nausea for some people. I used to work with Ph2PH and PhPH2 – not fun at all, though not pyrophoric like PH3 or other small alkyl ones. Any residual phosphine in the reaction flask can stink up an entire lab – I always bleached the flasks before I took the glassware out of the hood. Call me crazy but that smell – I think it’s the smell of death.

    BTW, phosphines with bulky substituents (e.g tBu and cy) are much less prone to oxidation even though the substituents are technically “alkyl” – it has to do with the size of the substituents. I think Buchwald’s group had a nice paper on the mechanism of phosphine oxidation in JACS not too long ago (as in maybe 2007?).

    Comment by SciChick — August 4, 2008 @ 9:28 pm

  11. Recent (awesome) paper from the Bergman/Toste group regarding synthesis of P-stereogenic phosphine:

    Chan, VS; Stewert IC; Bergman, RG and Toste, FDAsymmetric catalytic synthesis of P-stereogenic phosphines via a nucleophilic ruthenium phosphido complex. J. Am. Chem. Soc., 2006,128(9):2786-7.

    Comment by SciChick — August 4, 2008 @ 9:34 pm

  12. You know I never had the pleasure to meet PhPH2 but its gotta be very similar. I remeber smelling PH3, from LAH reduction of BINOL-phosphoric acid (the old BINOL resolution route) but it was only garlicky; I guess without a phenyl it is not the real thing. I worked with PhPCl2 and PhPClMe (we made it from PhPCl2 using dimethyl cadmium) but those are wimpy also.

    The paper from Toste is not forthcoming about how they made PhPHMe – I mean one can buy it but it is very dear, something like $100/g. Their catalytic method and the ligand they used is very nice though.

    Comment by milkshake — August 4, 2008 @ 10:41 pm

  13. We used isoamyl nitrite in the undergrad lab I TA’d to generate benzyne from anthranilic acid for cycloaddition with tetraphenylcyclopentadiene – it was old which may have been why), but it smelled like nasty amines soaked into dirty socks and allowed to fester for a month or so. It had been be one hell of an orgasm enhancer to tolerate that stink.

    Comment by Hap — August 4, 2008 @ 11:09 pm

  14. You were smelling isovaleric acid, which is the essence of old socks.

    With the exception of tBu-ONO (which is the most stable commercial nitrite), nitrite esters do not store well because of their autocatalytic decomposition problem – and they must be washed with bicarbonate before re-distillation or they would keep decomposing during distillation. But it is extremely easy to make them afresh – you just add NaNO2 solution to a mix of alcohol and diluted sulfuric acid at -20C, warm up to 0C, separate, wash and distill.

    Comment by milkshake — August 4, 2008 @ 11:41 pm

  15. I had the essence of essence of dirty socks on my face: isovaleryl chloride. Moreover, I happily shared it with the entire block en route to the bathroom. And then there was a subway ride.

    Comment by LiqC — August 5, 2008 @ 1:30 am

  16. Phosphines smell “wrong”. Arsines smell EVIL! Fortunately they are a little less volatile and not as persistent an odor so phosphines win by sheer annoying power. For a great description of some arsenic pioneers read the Organometallics history paper on Cadet, Bunsen, etc. and realize how TRULY badass he and his coworkers were. (I worked with the cyclic (RAs)N compounds. . .they are not pleasant)

    “The first liquid to distill reacts with caustic
    alkali with strong effervescence, generating at
    the same time a garlic odor so strong that it is
    impossible to breathe. Neither vinegar nor other
    compounds with very strong odors can destroy
    the odor that remains in vessels that have been
    impregnated with this liquid. It is dissipated
    only after several months of exposure to fresh
    air.”

    DOI: 10.1021/om0101947

    Comment by cookingwithsolvents — August 5, 2008 @ 10:45 am

  17. Heya Cook w/sol, thanks for the DOI, that article is simply stunning.
    Is it unnatural to really, really want to make PhMePH, just to experience how truly horrible it is?

    Years ago, a coworker and I both made a thiol that smelled like death incarnate- we nicknamed it “Satan’s Anus.” I wonder what possible moniker we could give to your phosphine, or if the “S.A.” name simple moves onto the newest superlative?

    Comment by Jose — August 5, 2008 @ 7:03 pm

  18. I have an entertaining story on smells…

    One friday afternoon I decided I was going to set up a tosylation reaction. I had my secondary alcohol dissolved up quite nicely in some fresh anhydrous THF, along with a new bottle of TsCl which I was rea’d’y to crack open. Only problem was, I could not find a goddamn bottle of triethylamine anywhere. So I started looking through the old chemicals to see if I could find some. I found a curious looking bottle, which appeared to be from the late 60′s. It looked like a normal 100 mL bottle except that the top looked like a sealed glass ampule. I immediately thought to myself “Score!” A perfectly dry unopened bottle of triethylamine. I checked the label and saw the words Anhydrous…

    So I happily marched over to my hood, placed on a pair of leather gloves and proceeded to crack open the ampule. I was greeted with an intense WHOOOSH, and a volcano like eruption into the hood. I immediately put the bottle down in the hood, ran to the sink and washed my arms and face thoroughly. I spent the next few moments thinking about how stupid it was to put triethylamine under such an intense amount pressure. Within a few minutes, some people came down the hall complaining of a fish like odor that was permeating the whole building(3 stories…). I decided to take a closer look, only to realize that the bottle I had opened was not triethylamine, but rather it was triMETHYLamine. The stink remained until the following monday, and for several weeks my hood stunk of rotting fish.

    Comment by Tom — August 8, 2008 @ 7:53 am

  19. Trimethyl amine smell is amazing – that’s what makes neglected public urinals smelling like neglected public urinals. In my previous company we used kilos of NMe3.HCl salt for making 2AlCl3.NMe3.HCl liquid complex; it works great for deprotection of aryl methyl ethers. The salt stinks exactly like the free amine (as it slowly hydrolyses on air) but the salt has a pretty low volatility so the odor is only faint but very persistant. The salt is hygroscopic – you spill a little around the balances or on the floor and it “disappears”, melting into a fishy dew. We were scaling up a preclinical compound on a hundred gram scale and had to work with the reagent repeatedly, eventually everything in that lab including us got saturated with this amine salt and we could no longer even discern the unwashed fishy smell anymore – but our families and loved ones could – on return from work. A major social impairment it was.

    Comment by milkshake — August 8, 2008 @ 1:19 pm

  20. I’m a chem amateur, i hope you don’t mind me asking. What does “P-stereogenic homochiral” means?

    Comment by curiouschemistrygrad — February 4, 2010 @ 2:56 am

    • homochiral = single enantiomer (optically pure). P-stereogenic = possessing chirality because of the phosphorus.

      P is pyramidal – the forth corner of tetrahedra is the lone pair – and unlike nitrogen P in phosphines holds its umbrella shape quite well so it is configurationally stable at room temp whereas nitrogen tetrahedras typically flip up and down fast so nitrogen centers are for this reason disregarded as a source of chirality. (There are some exceptions with aziridines).

      Comment by milkshake — February 4, 2010 @ 3:21 am

  21. Hey,
    Bit of a shot in the dark here but does anyone know much about Aminophosphines, that is phosphines or phosphine oxides with one or more R groups with P-N bonds. I’m doing my final year undergrad (4th year and to be honest it’s more like a one year phD) research project on them and am a little bit lost when it comes to researching this type of thing. I’m only now getting to grips with the (potential) application of the ligands I’m making (second semester course on Pd catalysts) and wondering if anyone else might know a thing or two?

    Any help would be most welcomed and appreciated.

    Oh, and yeah, the headaches, rancid smells all come with the territory. Not to mention the effects of all the exposure to DCM, and other such solvents in conjunction with the phosphines. Also the group who we share a lab with work with thiols…..needless to say if someone throws an un-quenched syringe or broken glassware into the sharp bin we all know about it for a while….still though, gotta love chemistry

    Comment by Dec — January 17, 2012 @ 3:23 pm

    • amino-dialkoxy phosphines aka phosphoramidites (RO)2P-NEt2 and (RO)2P-N(iPr)2 are used in combination with 1H-tetrazole for extremely mild high-yielding oxidative phosphorylation in the synthesis of oligonucleotides and phosphopeptides (a phosphorylation method that is tolerant to amide bonds).
      For example, if you have a peptide with free OH on threonine or tyrosine, you mix it with (tBuO)2PNEt2 and tetrazole (2 equivs) in DCM or MeCN, then after 30 min quench it with tBuOOH (or iodine/water) and you get (tBuO)2PO-OR’where the R’is the peptide (or nucleotide). In P(III) compounds the P-NR2 bond is very sensitive to nucleophilic displacement, especially upon protonation; the amino group gets protonated by tetrazole (tetrazole is quite acidic) and so it acts as a leaving group, getting displaced by a second tetrazole molecule, to produce (tBuO)2P-tetrazole, a highly reactive phosphitylation agent that readily reacts even with hindered hydroxy group to provide (tBuO)2P-OR. In situ oxidation of the P(III) triester with a peroxide provides a phosphate triester which is fairly stable (unlike P(III) phosphite triesters). Deprotection of the two tert-butyls with acid then reveals the phosphate-monoester

      Comment by milkshake — January 17, 2012 @ 3:46 pm

  22. Reblogged this on my blog and commented:
    quite an entertaining read, though nothing of this caliber has happened to me (yet). I’ve only worked with tosyl chloride (nauseatingly sweet wet popcorn stench) and pivaloyl chloride (a mix of vomit and week-old garbage). Even though tosyl chloride smells horrible, the alkyl tosylate I made smelled quite pleasant.

    Comment by deathbypuppy — August 15, 2012 @ 12:34 am

  23. Hey milkshake

    I recently nauseated everyone in my lab by barely cracking open an Aldrich bottle of PhPH2 on the bench. What I wanted to ask was this. A common method for synthesizing hydroxypyridinone ligands is to react a primary amine with maltol (2-methyl-3-hydroxy-4-pyrone), substituting the primary amine into the pyrone ring. Do you think the same would be possible when using phenylphosphine? I have a hunch this would be a stable P-containing heterocycle.

    Comment by NUchemist — December 23, 2012 @ 11:19 pm

    • My only exposure to maltol chemistry was a reaction of maltol with glycine, in water at 40C to make the corresponding 2-Me-3-hydroxy-4-pyridone-1-acetic acid. (We were also looking into using isomaltol because it is supposed to give better yields than maltol in these condensation reactions, but isomaltol is not commercial and has to be made in 2 steps from lactose so I gave up on it). I have run it on a 100g scale (with about 1L react mix, over one week period) and it was quite a dirty condensation with lots of unreacted starting material together with lots of dark crap – the isolation in this case only worked due to a low solubility of the desired product, a product which precipitated out of the reaction soup after pH adjustment.

      Also, I do not think phosphines are similar to amines – they are more analogous to thiols. P-acyl phosphines hydrolyze easily, and P loves to form bonds with oxygen. I think your idea would be very easy to try but would most likely result in a terrible mess

      Comment by milkshake — December 24, 2012 @ 1:10 am

  24. […] Glenn Reynolds solidified his nerd credentials by forwarding this oldie-but-goodie chem lab story. […]

    Pingback by Never Yet Melted » In the Chem Lab — June 2, 2013 @ 8:54 am

  25. worst smell I ever smelled was norbornanedithiol. I have smelled phosphines, I have smelled arsines, everyone has smelled varous amines; phosphines are bad, but pretty routine. I agree with the above poster that arsines smell ‘evil’ or at least like they will make your brain rot. But nothing compared to norornanedithiol: ransid baby diapers of the spawn of satan. The compound is extremely potent and detectable in your nose at trace levels, yet non-volatile enough that it sticks to anything it touches and never leaves. I tried using bleach to get rid of the smell and residues, to no avail. The only way I could get rid of the smell was by soaking the glassware in neat nitric acid.
    Keep in mind that this was my reaction to the smell, after spending a few years working in a thiol lab; the thiol cabinet wreaked of ethane and propanedithiol (to me smell like rotten hot dogs), and the entire lab was instantly permeated as soon as you opened the door. Nonetheless, this smell was NOTHING compared to norbornanedithiol.

    I will say though, that I have not worked with H2Te or H2Se, and I hear that those put H2S to shame.

    Comment by Matt — June 27, 2013 @ 10:29 am


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