Org Prep Daily

November 25, 2008

More lab disasters 2

Filed under: lab destruction — milkshake @ 6:06 pm

When I was in high school, I got free run in a chemistry lab that belonged to a youth center. I was trying to synthesize papaverine, and this was completely above my ability (and the lab resources) but I was very persistent. The key building blocks for papaverine are homoveratric acid and homoveratryl amine, and I set out to make them by myself: I had several bottles of catechol to start from – my problem was how to methylate it, I could not just buy stuff – I had to go by with what was in the stockroom.

First I made lots of methyl iodide, from red P + iodine and methanol – refluxing and distilling it on the bench so I know how methyl iodide smells – but the methylation was messy. Next I tried to make dimethyl sulfate from sulfuryl chloride and methoxide in situ, and it worked to some degree – the vanilla smell of guaiacol was everywhere – but again I could not isolate anything from the mess. So my next idea was to use diazomethane made from nitrosomethyl urea.

So I was cooking and then distilling AcNH2 on a grand scale, from AcOH and urea – and this went quite well (apart from the all-pervasive mice urine-like smell of acetamide) and then I was to carry out the Hoffman degradation.  When one uses concentrated aq KOH and bromine, the in-situ generated MeNCO reacts with a second molecule of acetamide to produce MeNHCONHAc, an intermediate for preparing nitroso methylurea; I needed it for a large-scale diazomethane reaction so I did it on a mol scale on the first run.

The procedure called for Br2 to be added into AcNH2 + 30% aq KOH mix in a 1L flask, then gently heating the mix until a rapid gas evolution commenced. Since I scaled up the preparation by a factor of twenty on the first run, and I did not have a 20L flask, I used the biggest flask I could find, a 4L Erlenmeyer, and loaded the stuff up; it all fit in there. But then, the mix did not wait to be gently heated and instead jumped out at me all at once.

I usually did my work without glasses, on the bench – but this one time I put goggles on and it was well worth it. The hot KOH + KOBr solution rained all over the place and bleached my hair blond; also my T-shirt and jeans ended up with white vertical stripes. A colleague stood nearby and saw the whole thing and dragged me into shower.

Eventually I did make some nitrosomethyl urea and diazomethane but never finished the papaverine project. No explosion, poisoning or other injuriy happened during all these crazy experiments. But there was another like-minded highschool kid, repeatedly working on some chemistry involving acetone cyanohydrine, and he was making it from acetone and NaCN, in our little fume hood with a lousy fan-driven exhaust. I think he never finished his project either but I remember once we were going down the stairway and he was saying “I don’t know if this exhaust really works ’cause I was smelling hydrogen cyanide this time a lot” and then we got outside there were two dead pigeons on the grass and we looked up and the exhaust from our fume hood was looming right above us…

50 Comments »

  1. There must be an enormous number of dead versions of you in parallel universes. I am amazed you havent run out of stories yet, but Im so glad you havent.

    Comment by Handles — November 25, 2008 @ 7:08 pm

  2. seriously, even the most dangerous undergrad is supervised to some extent. these stories make it sound as if you were some wandering gypsy that destroyed, to some extent, each lab that you stop to rest in. weren’t there any people ‘taking responsibility’ of you? hah! always entertaining…and very surprising that you were never seriously hurt (maybe we haven’t heard about that yet) or discouraged to follow up this ‘chemistry thing’

    Comment by fng — November 25, 2008 @ 9:01 pm

  3. As much as I love your stories, I’m always glad these things happen to you and not to me. ;)

    Seriously, though, what’s your secret for lab invincibility?

    Comment by Ψ*Ψ — November 25, 2008 @ 9:21 pm

  4. Someone should write a graphic novel about Milkshake’s adventures. He is awesome.

    Comment by Klug — November 25, 2008 @ 9:39 pm

  5. Luck. The dead, the blind, the crippled ones are not posting their stories online.

    Or maybe the Creator has some weird plan. You know, a classmate gave me these goggles just one day before the mishap. She has been pestering me for some time and I could hardly stand her – there were few girls at our highschool that I had crush on but Rosalie definitely wasn’t one of them. She always wanted to talk to me about something or other and she was pretty persistant about it. And this time again, she came and said that her mom was employed in an enthomology lab and they just got these fancy goggles at work, and her mom brought an extra pair from work, and she (Rosalie) immediately thought of me. I remember suffering through these explanations and I didn’t want anything from her but I took the goddamned goggles so that she would leave me alone. The next day I found them in my jacket and thought, with bromine and all, maybe I should give that a try.

    Comment by milkshake — November 25, 2008 @ 10:54 pm

  6. do you ever find that in your work, your “unconventional” chemistry education from tinkering around give you an edge over unless adventurous colleagues? it would be interesting to see whether your experiences would make for a better model for teaching kids.

    well kids who have more curiosity than sense anyways…

    Comment by Justin — November 25, 2008 @ 11:41 pm

  7. I don’t think so – had I worked under direction of a real chemist early enough, on some interesting synthetic project, I would do much better. I grew up in Prague, in 80s – there were only few good research labs/PIs doing synthetic chemistry. And I managed to infuriate them all.

    Comment by milkshake — November 25, 2008 @ 11:56 pm

  8. Tried to synthesize dimethyl sulfate? Ugh. I never liked using that stuff, much less synthesize it.

    Then again, people have synthesized methyl triflate and methyl fluorosulfonate. That is a bit spicy for my tastes……

    Comment by T — November 26, 2008 @ 12:15 am

  9. I know these youth centre labs, although from the 90-ies. I was supervising children between 14 and 17, who wanted to attend chemistry olympiade. They were very smart, but half of them wanted to synthetise drugs, the other ones explosives. One of them had only one finger on one hand, because he had lab at home and not so much luck as you.
    Unfortunately, it was impossible to give them good synthetic projects, because of equipment.

    Comment by IF — November 26, 2008 @ 4:15 am

  10. It was the centre at Havlickovy Sady in Prague. We even had a rotovap there (that did not work so great). The biggest problem was the product analysis – TLC and a melting point was the only option. Also we had no real lab solvent supply, and a lack of time was also a problem – it is hard to do any meaningful work if one could spend there only one or two afternoons a week. Later in the highschol, a junior faculty guy at university let me on evenings into his lab which was much better. But then we decided to work on phosphines – a serious miscalculation.

    Comment by milkshake — November 26, 2008 @ 5:10 am

  11. “My” centre was in Bratislava (iuventa). I think, the equipment in the 90-ies was even worse then before revolution, because all projects were stopped. I was the last assistent there.

    Comment by IF — November 26, 2008 @ 7:01 am

  12. Respect…with an appropriate incredulous shaking of head, naturally.

    Comment by DrSnowboard — November 26, 2008 @ 8:36 am

  13. If you search Wikipedia for “quantum suicide” there is a derivation of the “many-worlds” hypothesis that suggests that one can become “immortal” just by avoiding death in a very large number of alternate universes.

    I think Milkshake might be potential proof in support of this hypothesis.

    Comment by Rhenium — November 26, 2008 @ 3:50 pm

  14. Sorry for the non-sequitor, but does anyone know what Hyflo is? I was reading a JACS article from 1948 and it is used in the workup. Thanks in advance for the help!

    Comment by Old School — November 26, 2008 @ 4:22 pm

  15. I too agree with the SciFi slant that if parallel universes exist your alter-ego’s may not have survived as well as you have. I can only appreciate that you are around this one to tell such stories.

    In terms of learning I think (based on observing many people from diverse backgrounds) a lot can be said for those who do experience limited resources since often means they must come up with more inventive or at least alternate ways to address standard thing plus especially problems. In the main most US chemists, even and a small Uni/company, are spoiled with access to equipment/chemicals and such that they tend to not think about different approaches. I remember once when the NMR was down (we won’t point any fingers on who accidently quenched the magnet) the Med Chemists pretty much all stopped making things because they “didn’t know what they had” even in cases where they were pretty much repeated preps on same or related analogs. A few learned to use HPLC for first time on their own so could at least get more than TLCs

    Comment by CMC Guy — November 26, 2008 @ 4:41 pm

  16. Old School,
    In my experience, “Hyflo” refers to a specific type of Celite, which is simply a filter aid. Hopefully that makes sense in the context of your 1948 procedure!

    Comment by anniechem — November 26, 2008 @ 9:46 pm

  17. Could you enlighten those of us who have never experienced the scent of methyl iodide… how does it actually smell like?

    Comment by pretty casual — November 28, 2008 @ 5:34 am

  18. “In terms of learning I think (based on observing many people from diverse backgrounds) a lot can be said for those who do experience limited resources since often means they must come up with more inventive or at least alternate ways to address standard thing plus especially problems.”
    Yes but it can go a little far….
    http://en.wikipedia.org/wiki/David_Hahn

    Comment by DrSnowboard — November 28, 2008 @ 10:26 am

  19. So, how did you come to pick papaverine? I’m glad I don’t know what MeI smells like. I see that it is being iused as a fumigant in agriculture.

    Comment by gaussling — November 30, 2008 @ 6:56 pm

  20. Papaverine is opium alkaloid that is fairly easy to synthesize. I found “Alkaloids” compendium in the library and it was like a revelation for me. I would work on morphine if I could but even then I realized how hopeless that would be.

    Methyl iodide has a sweetish smell like DCM but with an unpleasant finish, as if there was some thiol in it. I think it is possible that my product contained some smelly phosphorus impurity from red P.

    Comment by milkshake — December 1, 2008 @ 6:47 am

  21. hey milkshake, i’m studying for an undergrad synthesis exam and i’m going through tonnes of reactions and for most of them we are not given a reason why a particular solvent is used. i understand the reason behind certain solvent use like claisen cond or grinard but are the other solvent used just from experience of better rate? how do you determine how much solvation occurs with each solvent and reagent? and more importantly how do you keep track of them in lieu of rote memorization?

    sorry for the annoying question

    Comment by Justin — December 7, 2008 @ 3:06 am

  22. Most of time it is really just a matter of convenience, chemical compatibility, solubility etc. For example you don’t want to use a solvent that has a high boiling point unnecesserily – because then it takes often more work to get rid of it during workup. You don’t want to use a solvent with a high freezing point if you are going to run your reaction at low temperature. You don’t want your solvent to react with the material or reagents, etc.

    The properties and chemical compatibility of the common solvents are quite easy to remember, once you start planning your own experiments. The first order of selection is that the solvent should dissolve your stuff and not interfere with your chemistry. Then you can start thinking about more subtle effects – some reactions proceed better in protic media or in more polar solvents, coordinating solvents can attenuate the reactivity etc.

    You will notice that people tend to do most of their chemistry in DCM, THF, toluene or acetonitrile, because these solvents are quite pleasant to work with and are compatible with lots of chemistry.

    Comment by milkshake — December 7, 2008 @ 1:03 pm

  23. milkshake although good general answer to solvent selection I think other considerations also come into play when advance to larger scale: typically grade, cost and availability must be factors in as well as safety and environmental aspects. Of solvents mentioned Toluene is a favorite for scale-up and THF can be applied in some circumstances whereas ACN more rarely with DCM mostly avoided.

    Comment by CMC Guy — December 7, 2008 @ 11:33 pm

  24. thanks cmc guy but it’s just for an exam and mr. milkshake’s answer is sufficient for me for now

    Comment by Justin — December 8, 2008 @ 1:36 am

  25. Is anyone experienced with work with TETRANITROMETHANE? Is it really dangerous? Supposes to be nitrating reagent and also useful for detection of double bonds.

    Comment by Dany — December 12, 2008 @ 8:20 am

  26. I only heard of the stuff, and it is something that I would be reluctant to work with. It is a corrosive liquid that exists in equilibrium with NO2+ and (NO2)3C(-), and its solutions in organics behave like high explosive. It does not get used for nitrations by anybody because many much better alternatives exist. The sideproduct, trinitromethane, is extremely shock sensitive. (Garage chemistry enthusiasts of course want the explosions to happen, and would attempt the preparation involving a moody witch-brew. If you want hot fuming nitric acid in your face please go right ahead and try)

    In old times chemists did all kinds of horrible things, like studying reactions of NCl3 or doing large-scale preparations with thalium(III) salts.

    Comment by milkshake — December 12, 2008 @ 10:28 am

  27. Question: I am planning to make an orthoester using the classic Pinner-reaction with a nitrile, methanol and HCl gas, isolating the imino ether salt and reacting it with methanol in hexane. I thought I’d make the HCl gas simply by reacting NaCl with concentrated H2SO4. Does this sound viable? I mean, will the gas be pure and dry enough?

    Comment by Rennip — December 14, 2008 @ 1:11 pm

  28. That sounds fine. You can also generate dry HCl by adding conc. hydrochloric acid to conc. H2SO4. The generated HCl gas should be dry enough for your purpose but you can pass it through a bubbler with conc H2SO4 or through an empty dry ice-cooled trap, if you want to be absolutely sure.

    For smaller quatities of HCl in methanol, it is often more convenient to use TMS-Cl as a HCl equivalent; TMS-OMe is volatile.

    Comment by milkshake — December 14, 2008 @ 1:54 pm

  29. Thank you for your answer, milkshake. Here is one more question, if I could: Recently I was asked by someone who is working in the same lab as me for a definition of a transition metal and I mumbled something to the effect of the IUPAC-definition, that a transition metal has one or more unfilled d-orbitals or readily give rise to cations with unfilled d-orbitals.

    This definition, however, got me thinking as the group 3 metals Sc, Y, La and Ac thus can be classified as transition metals, but many people, including myself, don’t tend to view them as such. Why is that, really? And finally, Cu, for example, is a metal which is considered a transition metal, but Cu+ has the electron configuration [Ar]3d10, right? So is it because it also forms cations Cu2+, Cu3+ (and sometimes even Cu4+), that it is considered to be a transition metal?

    Comment by Rennip — December 15, 2008 @ 1:15 pm

  30. I am sorry but I don’t know, I think there must be the correct explanation in a book somewhere.
    Here is an idea: Your professor probably has visiting hours – and unless he is a pompous ass you can go and ask him. He might be even delighted to discuss the subject with you and remember you for it (which can come helpful later when you ask him for recommendation letters).

    You will notice that lots of what goes into chemical theory is a mess. Explanation with varying degree of applicability, often just little better than mnemonics. Sometimes one just accepts the jargon so that he can talk to other chemists – even if the underlying concept is shaky. For example you can go very deep into the nature of a chemical bond and argue over definitions (is the C-Li bond in butyl lithium ionic or covalent in nature, what is the oxidation state of carbon in organic molecules, what exactly is this “orbital hybridization” business, etc) but in the end it is more helpful to learn about chemicals empirically and then derive analogies and notice patterns rather than trying to figure out chemistry from first principles.

    Comment by milkshake — December 15, 2008 @ 2:10 pm

  31. Question, Milkshake. I am trying to find a good condition for a peptide coupling. What makes it hard is the steric hinderance – there is a gem-dimethyl subsitution next to a 2nd amine. The reaction is fine w/o the gem-dimethyl. HATU in DMF does not work. Some people suggested EDCI but my feeling is that HATU is actually an enhanced version of EDCI. Will it help? Can I rise the temperature for the HATU/DMF reaction? Any other suggestions? The amine is precious, so I can not try too many conditions.

    Comment by diketene — December 19, 2008 @ 12:33 pm

  32. By the way, activating the acid to the acid chloride does not seem to be good as this is an alpha hydroxyl carboxylic acid.

    Comment by diketene — December 19, 2008 @ 12:47 pm

  33. Diketene: I had also to prepare a hindered amide some time ago. After searching the literature, it became clear that acid chloride was the choice.
    After using HATU, EDCI and other classical peptide coupling agents I had to prepare the acid chloride. The problem was that I had some BOCs in the molecule and some of them did cleave with the HCl which is generated.

    There are also some neutral methods to prepare acid chlorides in the literature like using cyanuric chloride, check that out.

    I’m afraid, in your case you’ll have to protect that OH to get good yields.

    Comment by vasili — December 19, 2008 @ 4:09 pm

  34. I have done something similar, coupling of lithium salts of acrylic acids that had unprotected alpha-hydroxybenzyl substituent in the 2 position, (these allylic alcohol-acids came from Baylis-Hillman reaction) and the only way I found to couple them was to use HATU in DMAc or DMF, and make the pre-activation time very short (1 min) and then throw in the primary amine without delay. It was a race against time – so I couldn’t really do any hindered cases.

    What I would do in this case is to make a protected acyl chloride or fluoride. Or make a protected symmetric anhydride if your hydroxy acid is cheap. The other possibility is a self-protected cyclic carbonate anhydride (with triphosgene, cyclized on the hydroxy) but I like the protected version better.

    There is one very easy protocol: You silylate the alpha hydroxy acid with TBS-Cl 2.2 equivs and imidazole in a small volumeof DMF for few hours, then quickly work up the reaction under neutral conditions (so that the OTBS ester does not fall off) and then you treat the crude double silylated material with oxalyl chloride 1.2 eqiv and 2 drops of DMF in DCM,at RT, to get the crude protected acyl chloride (only the OTBS ester falls off) which you can then dry and use for coupling right away.

    Please be sure to use some very mild base with the acyl chloride, such as pyridine or 2,6-lutidine for the coupling, acyl chlorides are very base sensitive, and can racemize or turn into dark muck. If everything fails you can use AgCN as a base with your acyl chloride (four equivs, in benzene or anh HMPA or 1,3-dimethyl-2-imidazolinone, RT to 50C) – it is stoechiometric silver and heterogennous, and has to be protected from light, but AgCN does not ruin the acyl chloride and does not cause much racemistaion – it is the prefered most powerful combo when everything else fails. I used dimethylimidazolinone (aka DMEU) as solvent (instead of HMPA in the orig reference) and it worked very well – better than benzene.

    The lit references are: JOC vol 43(20) 3972-4 (1978 ) and Bull Chem Soc Jpn vol 49 (8), 2335-6 (1976)

    Comment by milkshake — December 19, 2008 @ 4:19 pm

  35. Thanks for the suggestions, vasili and milkshake. Seems that I need to try to form acid chloride in neutral and mild condictions. I will try what you suggested with a model base first.

    Vasili, can you give me more detailed condition on using cyanuric chloride to activate acids? SciFinder only gives a 1978 paper on the Indian Journal of Chemistry. I could not get the oringinal paper.

    Comment by diketene — December 19, 2008 @ 8:37 pm

  36. Diketene, here is a detailed protocol thanks to google:

    http://www.erowid.org/archive/rhodium/chemistry/cyanuric.chloride.carboxylic.acids.html

    Good luck

    Comment by vasili — December 20, 2008 @ 5:00 am

  37. Funny question for you all: What’s olive oil’s core molecule?

    Wikipedia seems to think that it’s mostly oleic and palmitic acids; my sense is that olive oil’s core constituent is probably a triglyceride of the oleic and palmitic. “Triolein” seems to be its name, but a lot of websites seem to think that oleic acid is the primary constituent.

    Seems to me that if the core constituent of olive oil was a fatty acid, there wouldn’t be a downgrade in quality for olive oil having a high free acid content AND the test for olive oil quality wouldn’t be a titration. If the core constituent was an ester, that would make more sense.

    What say you all?

    Comment by Chemjobber — January 3, 2009 @ 8:19 pm

  38. sorry I am not a food chemist. Olive oil is a glyceride triester of course. My understanding is that olive oil has some acidity that develops naturally due to the enzymatic processes in crushed olives. The resulting acidity level depends on the processing/extraction method; extra virgin oil of good quality should have low acidity. Cheapo refined olive oils are washed with diluted alkali to improve their free acid analysis result.

    Wikipedia is the analog of Hitchhikers’ guide to galaxy.

    Comment by milkshake — January 3, 2009 @ 9:32 pm

  39. Thanks, Milkshake!

    Comment by Chemjobber — January 4, 2009 @ 4:53 pm

  40. Sorry off-topic question, I need a phenol protecting group that is bulky (to control stereochemistry); however unfortunately my compounds are sensitive to acid and hydrogenation, which rules out most OH protecting groups. Any ideas? Thanks in advance!

    Comment by Daniel — January 5, 2009 @ 4:11 am

  41. sorry I don’t know what’s in you molecule and what kind of Ar substitution reaction are you running but for example
    triisopropylsilyl is perfectly suitable for protecting phenols.

    Comment by milkshake — January 6, 2009 @ 12:34 pm

  42. just for the record, “triolein” is a name for the triclyceride of oleic acid…

    Comment by Kai — January 12, 2009 @ 6:15 pm

  43. So Kai — continuing my question, is triolein or oleic acid the main constituent of olive oil? I would imagine (and milkshake seems to confirm) that it is the triglyceride, triolein. Online, though, the vast majority of sites seem to think that it is oleic acid.

    Comment by Chemjobber — January 16, 2009 @ 11:58 pm

  44. “25% aqueous MeOH”

    Is that 25 mL MeOH and dilute to 100 mL with water, or is it 25 mL water and dilute to 100 mL with MeOH?

    Comment by Rennip — January 31, 2009 @ 6:19 pm

  45. Aqueous means a solution of something in water. So, 25% aqueous MeOH means 25% MeOH in H2O.
    Your first option is correct.

    Comment by vasili — February 1, 2009 @ 1:35 pm

  46. How do you store trimethyloxonium tetrafluoroborate? I’ve read different things about its storage (dessicator at -20 C, glove box either at rt or in the freezer). Also, I’m using it to derivatize a product so I can track the reaction kinetics by GC – how fast does it alkylate an alcohol at room temperature? I remember reading that you have experience handling this salt, so I thought I’d ask. Thanks for any comments you can provide!

    Comment by Ron — February 3, 2009 @ 9:21 pm

  47. Hello!!!

    1)ease, i m seeking for process/procedure to generate HCl gas.

    2)used BF3. Et2O/ Ac2O/ toluene/ reflux/ 2 hrs to generate 2′,4′-dihyroxy-3′,6′-dimethoxy acetophenone (acylation) from 2′,4′-dihydroxy-3′,6′-dimethoxybenzene. Unfortunately i could not get the acylated product. Please, i seek ur favor and suggestion for any other suitable methods.

    Comment by Santosh Kumar Gurung — February 4, 2009 @ 1:25 am

  48. I worked mostly with triethyl oxonium BF4 , about 20 years ago, and it is not very stable – I made it myself using the OrgSyn procedure and stored it as a stock solution in DCM – and the solution titer decreased over few months in the fridge. I think it is better to store the solid reagent. Also if you can buy the hexafluorophosphate or hexafluoroantimonate salt, these should be slightly less hygroscopic than the tetrafluoroborate salt. I have seen people storing these things in common fridge but I suppose freezer is just as good. The main killer is moisture, so it is important to let the bottle to warm up in a dry place like desicator (to prevent condensation) before opening it. Since you are going to use it frequently I suppose you can divide a big bottle of the reagent into several smaller ones, so that they get open fewer times.

    But I don’t have any experience with alkylating alcohols with it – I suppose it very much depends on what kind of alcohol you have.

    Comment by milkshake — February 4, 2009 @ 1:46 pm

  49. Thanks, milkshake – I appreciate your comments :)

    Comment by Ron — February 4, 2009 @ 2:46 pm

  50. Ah, youth. When I started working in an organic lab ca. 1981, my boss first off taught me proper drying and distillation of ethereal solvents. He showed me how to prepare Na-K alloy from the solid metals and put it into the THF still. I was fascinated with how two solids became, after melting together, a room temperature liquid like mercury. Then I attempted to transfer the liquid alloy from the melt to the still with a large pipette, and the rubber bulb popped off, releasing about 10 mL (yep!) liquid NaK into the hood and all over the lab floor. The little beads in the hood rolled all over of course, then burst spontaneously into blue flame as they picked up moisture. The larger beads of metal rolling on the lab floor hit a puddle next to the sink and went off like a meteorite. I stomped on the fire and dispersed it into a thousand little blue flames from wall to wall. My boss ran in and covered everything in celite.

    That was my first full day on the job, as I recall. Almost 30 years later I am still making a living in the lab. Amazingly.

    Comment by easong — March 13, 2009 @ 12:27 am


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