Benzoquinone Wacker Oxidation of Safrole in Methanol

by Methyl Man

Materials

  • 400mL MeOH (methanol)
  • 50mL distilled H2O
  • 150g p-Benzoquinone
  • 2g palladium (II) chloride (PdCl2)
  • 178g safrole
  • DCM (methylene chloride; dichloromethane)
  • NaCl (non-iodized table salt)
  • Sodium bicarbonate (baking soda)
  • 5% NaOH
  • HCl (hydrochloric acid, from muriatic acid)
  • Magnesium sulfate drying agent (epsom salts baked in 400°F oven for 2 hours)

Method

  1. In a 2L flask fitted with a reflux condenser and addition funnel place 400ml MeOH, 50ml dH2O, 150g p-Benzoquinone and 2g PdCl2 and leave to stir for a minimum of 60 minutes. Note that a recent improvement has been discussed which involves stirring the PdCl2 in the solvent (MeOH in this case) for several hours before adding the water and benzoquinone. It is likely that this does enhance yields a bit by ensuring maximum efficiency of the PdCl2’s catalytic action. Either way will work well, however. If you let the PdCl2 stir alone for a while, when you then add the water and benzoquinone, let them stir for an hour as well before beginning the next step so as to ensure complete dissolution of the benzoquinone.
  2. Place 178g safrole mixed with a bit of MeOH in an addition funnel.
  3. Add safrole dropwise from the addition funnel over 60 minutes or more. However, when the addition is about 80% finished, apply low heat just sufficient to start a mild reflux (cold water through the condenser).
  4. After the safrole addition is complete, leave mixture stirring and refluxing for 8 hours. (If you must stop at this point and resume another day, be sure to put the mixture in the freezer, sealed well. The raw ketone decomposes unless stored at freezer temperatures.)
  5. Filter out the solids present in the mixture, which are hydroquinone (the degradation product of the benzoquinone) and PdCl2. This can be done by vacuum filtration or by simple gravity filtration with coffee filters. Many prefer gravity filtration with this synthesis because the solids produced in this reaction are very fine and are problematic to filter with vacuum. Don’t try to recycle the PdCl2, as it is too difficult to separate from the hydroquinone to be worthwhile.
  6. Flood mixture with 1.7L 3N (~10%) HCl. (Here's the quick math: add 500mL of 31% HCl [muriatic acid] to 1150mL H2O to get 1.65L ~10% HCl—close enough for this purpose.)
  7. Extract flooded mixture with 3 portions of DCM (1 x 500mL, 1 x 250mL, 1 x 100mL) in a large separatory funnel. The desired raw product, MDP-2-P (“ketone”), migrates into the DCM as an oil. Separate the DCM/ketone layers and combine them. (Note: when you first hit it with the DCM you will probably observe a bit of scum which will float on top of the water layer, which will work its way down during these three extractions to appear as a blob of spongy semi-solid interface. It’s actually very mobile and easy to work around; simply avoid allowing it into your DCM separations. The same thing will happen in your washes in steps 10, 11 and 12 below, but by then you will be quite the pro at working with it.)
  8. Extract water layer with a final small amount of DCM.
  9. Add this final small DCM extraction to the combined oil/DCM solution from step 8.
  10. Wash the ketone/DCM solution with saturated sodium bicarbonate in water twice (500mL each wash).
  11. Wash the ketone/DCM solution with saturated NaCl 3 times (400-500mL each wash). (Note: as you do these bicarb and salt water washes, you should be seeing the ketone/DCM solution getting progressively more greenish colored; this is visible in the film of solution that runs down the inner surface of the sep funnel).
  12. Wash the ketone/DCM solution 3 times with 500mL 5% NaOH (500mL each wash). If you did step 5, you will have a very easy separation. (Note: you should also see a very noticeable color change upon doing the first of these three washes wherein the ketone/DCM layer becomes a strange, thick reddish-brown with green overtones. This happens as the NaOH pulls the majority of the solvated hydroquinone into its layer, cleaning the ketone. The NaOH layer in the first wash will be very dark brown, almost black in fact. The next two will be a far lighter, watery, orangy color.)
  13. Dry the ketone/DCM solution with ~50g magnesium sulfate.
  14. Distill off the DCM using mild heat on a water bath and ice-cold water through the condenser. This will take several hours.
  15. Add 50mL of high-oleic safflower oil (no additives!!) to the ketone oil as a buffer to prevent the ketone from scorching in the distilling flask.
  16. Vacuum distill the ketone/buffer oil mixture. This also will take several hours (around 8 hours at this scale, in my experience).
  17. At 100 to 140°C (wherever your particular vacuum dictates), a minor amount of safrole should come over. If your safrole-to-ketone conversion was good, there should only be a very small amount. If it is only a few drops to a milliliter or two, you can leave it in, and not change/clean receiving flasks. If you are a stickler for purity, discard it. It will not harm anything later if you leave it in. But if it’s more than a couple of milliliters, get rid of it.
  18. At anywhere from 25 to 40°C above the temperature your safrole usually comes over with the same vacuum, the ketone should begin coming over. You should get about 100 to 120g ketone. The color of the ketone coming over should be a pale, fluorescent-looking greenish yellow. In fact it looks not unlike anti-freeze—a similar “neon green.” You can stop distilling when the rate of ketone coming over has slowed to an agonizing one drop per 90 seconds or so. At this point there is so little left that it is probably not worth your time to wait for a drop per 1.5 minutes (it’s not worth mine anyway).
  19. Immediately store your precious fluid in the freezer in a sealed flask or bottle. Happy cooking!