Org Prep Daily

December 17, 2011

Fighting Pd colloids with salt

Filed under: procedures — milkshake @ 12:54 am

I have been running some debenzylations of a macromolecule with the Pearlman catalyst  in water. The hydrogenation often results in reaction mixtures with persistant dark colloids. I have seen this kind of problem before, with small molecule-hydrogenations on Pd/C though it was never quite as bad. I suppose this polymer loves to stabilize Pd nanoparticles in water.  Pre-activating the Pearlman catalyst with hydrogen prior the substrate addition does not help much.

I noticed that in this case 1) Celite and other brands of diatom-based filtration materials are ineffective for removing the dark colloids but filtration through a thick pad of charcoal actually works, to a degree, especially when combined with disposable plastic submicron Millipore filtration setup (pilfered from biologists);  filtration through charcoal tends to be slow and in some cases charcoal alone does not remove the colloids completely. 2) Saturating the hydrogenation reaction mix with salt before the filtration breaks the Pd colloids – they actually coalesce into a perfectly filterable precipitate and are removed  with the Pd-C catalyst.

I wonder if this high-salinity trick (in a polar solvent) could be employed in workup of other reactions suffering from product discoloration by colloids, i.e.  Ru-catalyzed periodate oxidations or olefin metathesis.

9 Comments »

  1. Hi milkshake, have a completely off-topic and random question if you don’t mind.

    I need to make 5-(hydroxymethyl)furfural (HMF) from fructose on a fairly large scale (10-20g). The prep I have calls for heating in DMSO with 10% sulfuric acid for 2 days. At the scale I’m planning on doing, this amounts to 50-100 mL of DMSO. The workup (according to the papers) involves either diluting with 10X DCM and washing with water until neutrality, or diluting with 4X EtOAc, filtering over Celite, then pumping off solvents on high vac.

    Somehow I don’t find either of the workup methods to be particularly attractive, especially the first one with DCM, since ChemDraw tells me the product has a logP of -0.21, which means every aqueous wash I’m just going to lost product. Do you have any good suggestions? Thanks a lot and Happy New Year!

    Comment by student — December 30, 2011 @ 9:32 pm

    • I think you are right about aq. wash losses. Wikipedia says that in this process 2-butanol can be used in place of DMSO as a reaction solvent and that methylethylketone can be used for the product extraction. Maybe you can sacrifice yield for the sake of convenience of workup on scale because fructose is so cheap. I would include a wash with a small volume of half-saturated NaCl to get rid of unreacted sugars and Celite filtration of the EtOAc extract is probably a good idea (there will be gummy polymers).

      Here is a paper that claims very good yields and conversion with 5% HCl in isopropyl alcohol (but I don’t have the journal access): http://onlinelibrary.wiley.com/doi/10.1002/cssc.201100489/abstract.
      In this paper they used a biphasic mix of saturated NaCl with THF as a reaction media, at 150C: http://www.springerlink.com/content/a242560768450726/

      And there is a two-step process from US patent application #20080200698

      107 g (0.6 mol) of D-fructose and 122 g (0.6 mol) of MgCl2.6H2O were introduced into a 2 l three-neck flask with stirring and heated to 75° C. for 30 min. The reaction mixture was admixed with 420 ml of anhydrous acetic acid (glacial acetic acid) and heated to 90-95° C. for 4 h. Thereafter, approx. 80% of the acetic acid was distilled off, the mixture was cooled to room temperature and 5 g (0.04 mol) of 4-(N,N-dimethylamino)pyridine were added. With stirring, 616 ml (6.5 mol) of acetic anhydride were added drop wise to the reaction mixture at 30-40° C., and the 600-700 ml of acetic acid were distilled off. At approx. 80° C., the reaction mixture was admixed slowly with 500 ml of water, 500 ml of MIBK and 50 g of activated carbon. After filtration through a pressure filter, the organic phase and aqueous phase were separated. The organic phase was freed of the solvent on a rotary evaporator and the residue was distilled under reduced pressure at 117-125° C./7 mbar. Yield= 45.9 g (0.27 mol, 45%) of 5-acetoxymethylfurfural.

      Hydrolysis of 5-acetoxymethylfurfural: 179.1 g (1.07 mol) of the 5-acetoxymethylfurfural prepared in Example 1A were dissolved in 1.1 1 of methanol and admixed at 20-25° C. with 140 g (1.01 mol) of potassium carbonate with stirring. After 1 h, the reaction mixture was admixed with 10 g of activated carbon and stirred for 20 min, and the solid constituents were filtered off and washed with 100 ml of MeOH. The clear methanolic solution was concentrated under reduced pressure on a rotary evaporator. The residue was admixed with 300 ml of MtBE. The precipitated salts were filtered off and washed with 20 ml of MtBE. The solution was concentrated on a rotary evaporator and the residue was distilled in a short-path evaporator at 90° C./0.03 mbar. Yield: 85.2 g (0.68 mol, 63% based on 5-acetoxymethylfurfural, 29% based on D-fructose). Alternatively, the residue can also be admixed with MtBE, and the product crystallized at 0° C. (yield: 98.4 g) (0.78 mol, 73% based on 5-acetoxymethylfurfural, 33% based on D-fructose)).

      P.S. If you get a reasonable method for scale-up I will be happy to post it here. Happy New Year to you too.

      Comment by milkshake — December 31, 2011 @ 2:49 am

      • Hi Milkshake, thanks a lot for your help, just wanted to give you an update.

        So I did the reaction on 13.5g (75 mmol) scale according to that ChemSusChem paper (4h reflux in iPrOH). I only got 42% yield of HMF, and the product seems to be 90% pure at best (NMR doesn’t look too bad, but you can definitely see extra peaks). I may have overloaded the column, so separation was not optimal. After the 1st column I still have 4 spots including the product spot. Of course the other 3 spots are quite weak, but still visible. After running some quick TLCs I found that the “standard” column conditions (Hex/EtOAc 1:1) is NOT optimal — the 4 spots are all quite close to each other (Rf < 0.1).

        Turns out that DCM/EtOAc 8:2 is a much better system — 2 spots separate quite nicely, there's 1 more spot behind the product but with some tweaking I think I could get that to separate (at least partially anyway). Will have to run another column, but I guess some things you learn the hard way.

        Comment by student — January 7, 2012 @ 7:36 pm

  2. Would you be removing water by saturating the reaction mixture with salt? The amout of charcoal on the filtercake might pose a fire hazard if you are working on scale.

    Comment by jasonF — January 6, 2012 @ 3:28 pm

    • the salt is there to push the polymer into organic phase (as it is pretty water soluble) and to supres emulsion formation during the extraction.
      Activated charcoal is not a fire hazard, especially when wet with brine in it, and the cake goes to Pd waste (as a water slurry) anyway – we can’t dispose heavy-metal contaminated material in common solid waste

      Comment by milkshake — January 6, 2012 @ 4:48 pm

  3. Question for everyone. We have an ISCO Combiflash system and really love it. The one annoying thing with the system is that if you don’t use the ISCO columns, the system shuts itself off above 50 psi. I’ve heard that there may be a way to turn off this function. Does anyone know anything about this? Many thanks.

    Comment by PotStirrer — January 12, 2012 @ 11:28 am

  4. Most likely all that you are doing is screening the electrostatic repulsion of the charged colloids by adding salt. They then get close enough that van der Waals forces lead to coagulation. Works for emulsions, too, which is why it’s often better to use brine than plain water for aqueous workup…

    Comment by Kai — January 17, 2012 @ 7:44 pm

    • It could be. Another possibility is that high salinity disrupts micelles; by having a small greasy and a large hydrophilic portion the polymer perhaps acts like a detergent.

      Comment by milkshake — January 17, 2012 @ 8:02 pm


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