Org Prep Daily

June 11, 2009


Filed under: procedures — milkshake @ 10:13 pm

Evaporating aqueous reaction mixture is a lamentable job –  by weight water has one of the highest evaporation enthalpy values – but with a good rotovap and enough persistence one can even take care of several liters of aqueous mix (if there is no better alternative). The one thing that can turn this into the most frustrating experience is foaming.

I was struggling today; a published homotropanone prep calls for freezing + lyophilizing the entire reaction mix. I scaled that thing by a factor of four and since I did not want to lyophilize a half-liter of the reaction mix, I just put it on the rotavap and suddenly the reasons for the recommended lyophilization became painfully clear…

Desperate people would add n-octanol or even couple of drops of silicone oil to their mix but I did not want to introduce non-volatile impurities into the product. I was dreaming about silanizing the flask glass surface instead (a rinse with Me2SiCl2 and tributylamine in dichloroethane does it) but in the end I just poured 1mL of of hexamethyl disilazane (TMS)2NH straight into my aqueous mixture  – and the foaming ceased like a miracle. It must have been the silicone film on the glass that produced this remarkable effect because when I later transferred the solution into another flask it started foaming crazy anew; and a little more (TMS)2NH and it was calm like a lamb again.


  1. But why not just lyophilize the stuff? Put it on at the end of the day. Nice white fluffy crystals in the morning.

    Comment by Chemgeek — June 11, 2009 @ 11:30 pm

  2. Fascinating. More please.

    Comment by Chemjobber — June 11, 2009 @ 11:36 pm

  3. I have used amylalcohol as a foam-breaker a couple of times with good results.

    Comment by vasili — June 12, 2009 @ 2:13 am

  4. Great trick! I’ll will remember it when I encounter such a painful situation.

    Comment by Yogi — June 12, 2009 @ 3:51 am

  5. Freeze-drying 500-ml isn’t too bad. We do that routinely around here. You just need the right kind of bottles and (ideally) a shell freezer.

    Comment by Jordan — June 12, 2009 @ 9:40 am

  6. Is reaction of hexamethyldisilazane with Si-OH (glass bottle) faster than with water?

    Comment by Dany — June 15, 2009 @ 10:37 am

  7. I think hexamethydisilazane with water goes to TMS-O-TMS quite fast but the silane layer floats ontop of the organic phase and greases up the glass in the upper half of the fask, thats where the foaming happens. I did not have a bottle of TMS-O-TMS to try, if it worked the same way.

    Comment by milkshake — June 15, 2009 @ 11:57 am

  8. Hi

    Love the blog.

    Any ideas on reducing an alkene in the presence of an ArCl? Pd/C(10%) with 1 atm H2 seems to have resulted in almost complete dechlorination.


    Comment by z — June 15, 2009 @ 4:39 pm

  9. I would definitely try platinum. 5% Pt-C is quite affordable catalyst, and very active for alkene hydrogenation. I had a good luck with Pt-C in EtOAc under balloon of H2, for reducing nitro to amino without dehalogenating aryl halides in the molecule.

    If Pt-C fails, I guess you can try borane or diimine (HN=NH) reductions.

    Comment by milkshake — June 15, 2009 @ 5:19 pm

  10. I would recommend Cy2BH + Schwartz reagent (cat.), then AcOH – very mild method

    Comment by krest17 — June 16, 2009 @ 2:40 am

  11. I find a centrifugal concentrator (mivac/genevac) is great for removing solvents for mixtures that have tendency to foam. Not as fast as a rotovap though, so I might try some of the additives next time I have a large amount.

    Comment by Matt — June 16, 2009 @ 8:22 am

  12. For the dechlorination problem, if you use 5% palladium on carbon that is “sulfided” then you don’t get dechlorination. Aldrich sells this. The sulfur I guess partially poisons the surface to prevent the dehalogenation but not preventing the olefin reduction or benzyl hydrogenolysis. Olefin reduction might be a little slower, particularly if you are used to using fresh 10% Pd on C.

    Comment by chem dude — June 16, 2009 @ 9:02 am

  13. Hi MS,

    Off topic again..I am stuuggling to purify a pyridine methyl ketone derivative..Shows vety good LCMS/TLC but colimn purification leads to messy mixture..Suggest me any better method of purifying methyl ketone..we tried Prep HPLC also but the crude residue is insoluble in HPLC system (water/CH3CN/TFA)..



    Comment by marto — June 16, 2009 @ 11:09 am

  14. Marto, if the problem is tailing you can add some amine to the eluent for the column and sharpen it up greatly.

    What I find works best in a methanol-DCM column is 0.5% or so ammonium hydroxide. I have even added NH4OH to EtOAc-hexane mixtures (but over time you will see some acetamide forming). Some people use Et3N or diisopropyl amine for that. I never had as much luch with it personally.

    Try a few different solvent systems. Then there’s also ion exchange columns- a bound acid (like on sulfonate SCX columns) would nicely bind the amne and then it would wash off with methanol haveing a little NH4OH. saves a lot of work if the contaiminants are not also amines.

    Comment by chem dude — June 16, 2009 @ 1:41 pm

  15. the best way to inject a material on HPLC is to dissolve it in a small volume of DMF. DMF makes a solvent front peak but that is not a problem. Also check out the chloroform-MeOH-ammonia mixtures, such as 100:10:1, for straight silica chromatography

    Also if your molecule has a pyridine you should consider making a salt with HCl, TsOH or some other strong acid and re-crystallizing it

    Comment by milkshake — June 16, 2009 @ 1:50 pm

  16. I had this problem one for pyridine derivatives – we used columns with basic Al2O3 – worked very good – SiO2 columns did not.

    Comment by krest17 — June 17, 2009 @ 12:49 am

  17. hi MS,

    thanks very much for the help…


    Comment by marto — June 17, 2009 @ 12:54 am

  18. Sorry – Need help!
    I have to separate mixture of 4 unsaturated unfunctionalized aliphatic compounds Rf – 0.85-0.9 (all of them) in hexane. Nothing works.
    Any suggestions???

    Comment by krest17 — June 18, 2009 @ 2:17 pm

  19. If any of your compounds has C=C you can try silica impregnated with AgNO3 – compounds are reversibly retarded by Ag+ based on the number of C=C they have in the molecule. It has been used for separating things like methyl esters of natural fatty acids. Silica-AgNO3 is not too expensive (especially when you make your own impregnated silica) but the material is light sensitive so it needs to be stored in dark and used in a dimmed lab at night.

    Also you can try to take common silica gel and silica gel plates and activate them in a common glassware drying oven at 120C overnight – the silica then becomes much more absorbing and should give you a better separation for non-polar compounds. The problem is that you would have to keep the TLC plates in desiccator because silica soaks up ambient moisture and gradually equilibrates into the original state. The same applies to silica. But it is relatively easy thing to try first, on TLC, before messing with silver-impregnated silica

    Comment by milkshake — June 18, 2009 @ 2:26 pm

  20. MW ? If it not too high you could fractional distill them but it doesn’t seem an easy stuff.
    HPLC or GC may be the only choice then.

    Comment by vasili — June 18, 2009 @ 2:26 pm

  21. I should mention that very greasy compounds have the tendency to streak with the solvent front, and they take other stuff with them in one ugly blob on top of TLC. When I was working on phospholipid project we would first develop the TLCs with hexane or hexane-ether mix, just to move the nonpolar lipids up, so as to not mess up separation of phospholipids.

    Comment by milkshake — June 18, 2009 @ 2:37 pm

  22. Thanks a lot. BTW – do a need to deoxygenate silica after oven? I have heard that activated in oven silica is very active chemically as well – behaves as quite strong LA.
    I’ll take a look how to impregnate silica – never did it before .

    Comment by krest17 — June 18, 2009 @ 2:53 pm

  23. Sorry again me.
    Did anybody tried “Dry Column Vacuum Chromatography” Synthesis 2001,16,2431. Will it work better for me?

    Comment by krest17 — June 18, 2009 @ 2:55 pm

  24. I never tried it – but Daniel Sejer Pedersen (the first author on the paper) has a blog Curly Arrow so ask him. There is a link to Currly Arrow on the blog list here;I am sure he would be delighted to discuss it – he wrote a post there about it some time back.

    Reading the paper I noticed that they are using a high-quality Merck silica with very small and uniform particle size. Silica gels with finer particles (like those used for TLC) separate a lot better but they also flow a lot slower. So maybe this technique is good not only that it saves solvents but that it also allows for using finer silica grade stationary phase.

    Oven-activated silica is more acidic, so one has to avoid acid-sensitive compounds like acetals and silyls and vinyl ethers but its not that acidic – I don’t think you will have to worry about oxygen

    Comment by milkshake — June 18, 2009 @ 3:55 pm

  25. Thanks again. I’ll ask him.

    Comment by krest17 — June 18, 2009 @ 4:29 pm

  26. If I understand the antifoaming argument right, the hexamethyldisilazane is being hydrolysed to hexamethyldisiloxane and this is what ‘greases up’ the glass surface ? Does the hexamethyldisilazane/hexamethyldisiloxane evaporate off during the distillation, necessitating its periodic replacement or is this not necessary (as it irreversibly reacts with the glass )? If the hexamethyldisilazane/hexamethyldisiloxane does not distill off with the water, your gear will be contaminated with hexamethyldisilazane/hexamethyldisiloxane (if you use too much). Presumably this can be removed on a high vacuum static pump.

    Finally, vasili mentioned the use of amyl alcohol. I’m guessing he means 1-pentanol, rather than some other isomer?

    Comment by kjwx109 — June 20, 2009 @ 3:53 pm

  27. TMS-O-TMS boiling point is 101C, so I don’t think there is a difficulty with evaporating it, and whatever happens it seems that the flask glass does get silanised around its neck where it matters, at least temporarily, and this supresses the foaming. Hexamethyl disilazane actually generates one equiv of ammonia upon hydrolysis and this can be problem with some reaction mixtures but in my case there was ammonia already from the reaction and the mix was mildly basic so it was a non-issue

    Comment by milkshake — June 20, 2009 @ 5:37 pm

  28. Hi! Very nice and informative blog you have here, I bookmarked it so I can check it daily.

    Anyway have a question related to what you blogged about, whenever I try to rotavap aqueous mixtures. Water has this nasty tendency to bump violently with sufficient force into the rotavap trap. Is there anyway to prevent this bumping aside from adding a boiling chip?

    Oh btw, any suggestions for removing lutidine salts from the aqueous layer? I tried a column with 5% MeOH/DCM load and gradually ramped up to 10% MeOH but the damn salt just streaks all over my column and co-elutes with my product!! The worst thing is I can’t make the aqueous layer basic since I’m making thioester conjugates and these are really sensitive to base (case in point: ~ 30 mg of stuff dissolved in 20 mL methanol will hydrolyze in 3 hours when ONE drop of triethylamine is added). Thanks in advance for any help!

    Comment by Rich — June 21, 2009 @ 4:30 am

  29. If you can acidify your mix with diluted sulfuric acid (instead of HCl) and use ether or tBuOMe or toluene for the extraction and do a final re-wash of your org extracts with water, you should not have any lutidine salts in your organic extracts.

    Avoiding bumping on the rotovap – apart form the obvious (a good adjustment of the vacuum and the bath temperature) it is also necessary that you remove all solids by filtration. Of course you don’t add any boiling chips. And you pull out the stirbar. The whole idea of spinning rotovap is to disrupt boiling and instead to have controlled evaporation from the surface of liquid and the film on the flask walls. So as a rule heterogennous reaction mixtures are unpleasant to evaporate because they tend to bump.

    Comment by milkshake — June 21, 2009 @ 6:11 am

  30. Hey thanks a lot, but I realized my last comment was ambiguous so let me clarify.

    I’m working with carbohydrates, so unless it’s a per-acetylated or per-benzylated derivative it usually stays in the aqueous layer. The stuff I’m trying to make most definitely likes the aqueous layer more, so my question should’ve been if it’s possible to remove the lutidine salts from the aqueous layer (ie extract them into the organic layer) without making the aqueous layer basic. I know I’m probably just dreaming, but hey it’s worth asking.

    Comment by Rich — June 21, 2009 @ 2:04 pm

  31. You can pass the aqueous solution through some ion exchanger resin with sulfonyl groups (then evaporate the filtrates). It will surely bind lutidine. I like Dowex sulfonylated resins better than Amberlyst for the aqueous work because Dowex resins tend to have a lot less of dark soluble crap that washes off the resin, in both cases its best to give the dry resin a good boil with deionised water and then few washes with hot deionised water- in that way the dry resin swells up fast and you extract away the dark impurities (that tend to slowly develop in the dry resin upon storage).

    But you have to be careful with the quantity of ion exchanger resin used for the lutidine removal because some glycosides mildly bind on strongly acidic ion exchanger resins also, I faintly remember seeing a procedure for chromatographic separation of alpha and beta 1-OMe-glucose glycosides on SO3H Amberlyst column.

    Comment by milkshake — June 21, 2009 @ 11:30 pm

  32. how does an long chain alcohol acts as foam breaker.

    Comment by pashu — June 30, 2009 @ 4:10 am

  33. I think the greasy additive foam-breaking effect has do do with the surface tension – I am not sure – but its quite general.

    Comment by milkshake — June 30, 2009 @ 5:38 am

  34. Sorry – Need a help..I am struggling to remove imidiazole from imidazole substiuted pyrimidones..I tried washing with Cold water .. still i got mixture…Compound and Imidazole have very similar Rfs..Please help me..


    Comment by marto — July 7, 2009 @ 1:12 am

  35. I wonder if you can dissolve your crude mix in hot benzene, and let cool overnight – imidazole is poorly soluble in benzene at room temperature and should precipitate out, together with some other polar impurities. You can then directly apply the filtrates onto a silica column, benzene is a very good solvent for column-loading compounds that are poorly soluble in hexane-ethyl acetate mixtures

    Comment by milkshake — July 7, 2009 @ 11:05 am

  36. Thanks very much..Marto

    Comment by marto — July 7, 2009 @ 11:04 pm

  37. Hi MS,

    Need one more help. I need to do a workup which involves treatment with Norite, the reaction is bromination of an hetrocyclic ring using Bromine in DCM. i searched in Google about Norite. But I did not get any good hits..Please help me..

    Thanks marto

    Comment by marto — July 15, 2009 @ 1:23 am

  38. Norit is a brand of charcoal. Any other kind of activated carbon (charcoal) will do for your purpose

    Comment by milkshake — July 15, 2009 @ 12:39 pm

  39. Thanks for the help..

    Comment by marto — July 15, 2009 @ 11:14 pm

  40. Hi MS,

    Need help!!!
    I am struggling to reduce imidalzole substiuted ester to the corresponding alchol.I get low yield of the alcohol mainly due to purification problems. I used LAH in all cases, it was diificult to isolate the product. I am plannig to try DIBAL-H and modifed borohydrides..would be great if you have any experince with such problems..Thnks

    Comment by marto — August 9, 2009 @ 3:48 am

  41. I would use LiBH4 in THF, quench with MeOH and then saturate with anhydrous HCl (or us excess of TMSCl), evaporate react mix to dryness, make basic with a small volume of sat bicarbonate, extract repeatedly with EtOAc.

    Comment by milkshake — August 9, 2009 @ 5:06 am

  42. Thanks very much MS

    Comment by marto — August 9, 2009 @ 6:47 am

  43. hi i am trying to control foaming in evaporation of biomethanated spent wash. it constitutes ammonia and other gases in traces and around 40% solids with pH @ 4-5. I want to know reasons for intense foaming as well as measures to reduce the same.

    Comment by pk — September 10, 2009 @ 4:44 am

  44. silanizing your flask? With you product in it? What do you mean?

    Comment by OrgChemisty — September 21, 2009 @ 12:54 am

  45. Hi MS,

    I am unable to remove traces of ethyl acetate from my final compound. The compound is bicyclic amine with trifluro ethyl group in it. I tried evaporating the solution of compound in diffrent solvents and also dried the sticky compound overnight under vacuo. The compound is still sticky and ethyl acetate is trapped inside.

    Please help me.

    Comment by marto — December 4, 2009 @ 7:16 am

  46. This happens all the time. Get a good pump – the vacuum matters, should be below 0.3Torr at the end when all is finished . Re-evaporate it from some volatile solvent like ether or tBuOMe into a large flask, put on and leave it overnight under vacuum.

    Comment by milkshake — December 4, 2009 @ 4:11 pm

  47. Thanke very much…


    Comment by marto — December 7, 2009 @ 12:56 am

  48. Greetings MS,

    I am unable to remove grease from my final compound. My compound is alkylated pyrdine compound. Even after hexane wash/drying, it not going. Please suggest me.



    Comment by marto — December 17, 2009 @ 3:10 am

  49. marto, maybe your grease is not real grease but something else that does not dissolve in hexane that well. Or another possibility is that the grease impurity is trapped inside the solid. I think the best would be to reprecipitate your compound – dissolve it in some solvent with sufficiently low polarity, for example dichloromethane or benzene (if it dissolves there) and pour it into a large excess of an anti-solvent (where your product insoluble) such as tBuOMe or cyclohexane-benzene mix, with a vigorous stirring. You can try also hexane. you can do the precipitation on cooling bath to aid the solidification. The main thing in the choice of solvent for precipitation is to use something that crashes out your product as a filtrable solid (and not, for example, a sticky gum)

    Comment by milkshake — December 17, 2009 @ 3:59 pm

  50. Thanks very much for the suggestion.


    Comment by marto — December 23, 2009 @ 12:14 am

  51. [...]  So, I started searching the “literature.”  The best piece of advice I could find came from Org Prep Daily’s milkshake, who recommended silanizing the glassware to reduce seeding sites for the foam.  Unfortunately, [...]

    Pingback by Fighting the Foaming Giant « Organic Chemistry Tips and Techniques — May 4, 2012 @ 8:08 am

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