by Chromic
This method is 100% OTC. It is awesome for a first time chemist who is interested in good yields of their favorite amines and has patience waiting for the peracetic acid to form. It scales very nicely and runs without much hassle. Not one suspect chemical is used.
Make 59.8g of 15% peracetic acid in a clean plastic high-density polyethylene container:
Swirl the container and allow this to sit for 4-7 days at room temperature before using. Only after the peracetic has aged, continue on.
Set up a 250ml round bottom flask, sitting in cold-water (no ice) on top of a magnetic stirrer. Now:
This will form a swirling white brew of chemicals in your flask. Fit the flask with a condenser fed with cold water, and allow the reaction to stir for 5 hours.
Transfer the mixture to a 500ml sep funnel using a magnet to keep the stir bar in the flask. Add 100ml of 5% NaOH to the sep funnel, shake this vigorously, venting when necessary. Drain off the DCM layer and keep it. Throw out the aqueous layer. Add another 100ml of 5% NaOH. Shake, let settle, and keep the DCM layer. Ensure no aqueous base is in the DCM layer you drained off. Now, distill off the DCM on a water bath and rearrange the oil. The rearrangement is exactly the same as in the rearrangement used in the Oxone method. It is also scaled for 100mmol.
After rearrangement and distillation of the ketone, the typical yields are >60%. (these yields are comparable to the buffered performic in DCM).
Photography chemicals rock. The war is over.
For those not familiar with what 100mmol alkene is, it is 16.2g isosafrole, 14.8g anethole or 20.8g asarone. This method was tested out with anethole, isosafrole and asarone. The only rearrangement used on the glycol was a 15% H2SO4 rearrangement for just over 2 hours with the presence of methanol as in the Oxone document. All of the ketones were eventually aminated by using methylamine or hydroxylamine to give the intermediate imine or oxime and after Al/Hg reduction to form, respectively, PMA, PMMA, MDMA, MDA, TMMA-2 or TMA-2. Anethole was the easiest to use, isosafrole second and asarone was rather difficult and relatively low yielding. Asarone did produce an exceptional compound, TMA-2, that is highly recommended to those who are looking for something to do after making MDA and MDMA. PMA and PMMA were of some activity but not really worth it for the tasting of the compounds. TMMA-2 was of nearly no activity. I'm positive that isodillapiole and isoparsley apiole could also be used to form their respective amine salts but I haven't had the chance to attempt those reactions although have had the chance to enjoy the pleasurable high of DMMDA-2. I look forward to trying them in the future.
Where do we obtain the chemicals? Well, DCM can easily be acquired from a window shop or by distilling from paint strippers that contain methylene chloride (it helps to add an equal volume of water if you use the ones that contain polymer "goop"). No problem. NaHCO3 is simply baking soda. Easy. Hydrogen peroxide can be found in two-part wood bleaches, at some pool stores and also at hydroponics stores. No trouble. Acetic acid can be found at chemical suppliers, it's a very non-suspicious chemical, but it is also available from photography supply stores. If you don't see 100% glacial acetic acid on the shelves, ask for it. They likely can find it. Perfect for OTC acquisition. NaOH was available at the hardware store and also from soap making shops. Easy. Sulfuric acid was found in a professional drain cleaner available at a local hardware store. Methanol is easily found at hardware and automotive stores. Anethole and asarone were obtained from an aromatherapy dealer in their native essential oil and were refined by fractional vacuum distillation as in my safrole distillation faq (along the lines as what appears in my Oxone writeup). The safrole, however, was freezed crystallized from sassafras oil, then subject to a KOH isomerization a la RoundBottom. With everything in hand, the experimentation commenced.
After working for some time with the Oxone method it quickly became apparent to me that the solvent volumes were too large for my liking. Before attempting my first Oxone run, I had tried a peracetic in acetic acid oxidation on isosafrole a la Semtex. This method seemed ideal in that all of the chemicals are cheap, easy to obtain and over-the-counter. The solvent volume is smaller, but unfortunately I met failure with that method (where did this method come from anyways?). That started my search for a new peracetic acid oxidation based on academic references.
The first reference that I came across in my searching was on Organic Syntheses, CV 4, 860. This showed the epoxidation of stilbene by peracetic in DCM. A 1.42 molar ratio of 35% peracetic was used to perform the oxidation with 1.5L DCM / mol, the DCM volume sounded right. A good start to the write up. Further searching came up with an excellent reference of Patent EP 1140788. This showed trans-cinnamyl alcohol being epoxidized with a 1.18 molar ratio of 35% peracetic acid with 1.3L DCM / mol. After much experimentation, this is the ratio I finally decided on. For buffering, a ratio similar to what was used in Chemical Abstracts vol. 82, 72640z (1974) for the buffered performic oxidation was used instead of the 1.42 mol Na2CO3 /mol used in the earlier reference. This number was sort of pulled out of a hat. There's some information saying that epoxides can be produced without buffering, and there's some info saying that the glycol or acetate glycol is made instead (for sure at higher temperatures). Producing the epoxide from the peracetic was of no concern for me, as I realized I would choose 15% H2SO4 hydrolysis (or possibly tosic acid, if I ever could get that to work) over thermal rearrangement of the epoxide. So that's why I picked that amount of NaHCO3. There was still a stumbling block, we had to go about finding out how to prepare peracetic acid.
Unfortunately I could only find information on preparing 35% peracetic from 50% H2O2 and acetic anhydride, neither of which was easily accessible to me. Luckily I stumbled across some information showing the equilibrium data for 100g 15% peracetic acid on a web site. At equilibrium, ~15% peracetic acid consists of 16.5g peracetic acid (odd?), 10g hydrogen peroxide, 35.5g acetic acid, 1g sulphuric acid and 37g water. Turning those into molar ratios, and finding out how much water, hydrogen peroxide and acetic acid was there initially came up with the numbers 48.5g acetic acid, 17.4g hydrogen peroxide, 33.1g water and 1g sulphuric acid. Well, it just so happens that 17.4g hydrogen peroxide and 33.1g of water is 50.5g of 34.4% hydrogen peroxide. The numbers worked out so nicely!
More research was spent finding out how to prepare the 15% peracetic acid. It turns out that the sulfuric acid is required to catalyze the formation of peracetic acid from acetic acid and hydrogen peroxide. Upon a US patent search information was found that this mixture takes approximately 5-7 days to come to equilbrium. This reaction happens slowly. If you should happen to have some already made peracetic acid and plan to store it for more than 7 days, keep it refrigerated. Do not use it after it has aged more than 6 months as it will slowly decompose and lose strength.
Now armed with information on how to make 15% peracetic acid, the ratios of NaHCO3, peracetic acid and DCM… there was just the question of the work up. A number of write-ups that I've read encourage using sodium sulfite to quench the unused peracetic acid. I thought this was overly cautious, and since I hated the smell of sulfur dioxide, I opted to use a 10% sodium carbonate wash or a 5% sodium hydroxide wash on the DCM to remove any traces of the peracetic acid before distilling off the DCM. I'm not sure how necessary these are, but I always felt better safe than sorry.
Although I wanted to pursue using tosic acid in toluene to rearrange the glycol as the yields are substancially higher than other OTC ways, 15% aqueous sulfuric acid with methanol was used instead.
Everything had been decided on. (take note that I tell this story as if all the research happened before I started my experimentation... well, that's simply a convenient lie that's designed to make me look smarter than I actually am…)
These are a collection of some of my better runs that illustrate getting from the isoalkene to the final amine or methylamine salt via Al/Hg reductions. The aminations are not necessarily ideal routes, but they are the ones that were used.
52.7g of isosafrole is added to a 1L flask along with 485ml DCM, 24.8g NaHCO3and a 1" stir bar. The flask is set in a cold-water bath. Stirring is started and 194.4g of 15% peracetic acid is slowly poured in (98.2g 35% H2O2, 94.3g acetic acid, 1.9g H2SO4, aged 5 days). The flask bubbles with carbon dioxide as the peracetic acid is added. A condenser is fit on top, and the reaction runs for 5 hours. The flask heats up after about 15 minutes but never reaches reflux due to the cooling of the cold-water bath. If you decide to not use a cold-water bath, the flask will reach a reflux and the condenser becomes necessary. The color changes from a colorless biphasic solution to gain a very light yellow tinge. At the end of the reaction, the solution is dumped into a 1L sep funnel and 325ml of 5% NaOH is added. The funnel is shaken and let to settle. The DCM is kept and washed again with 5% NaOH. Then the DCM is distilled off and recovered for future use. 66.8g of glycol is recovered. (105% yield, this yield is likely a bit high as some of the glycol is likely the mono- or di- acetate ester)
81ml of MeOH and 390g 15% H2SO4 (58.5g H2SO4, 331.5g water) is added to the flask. With the aid of a condenser it is brought to a reflux, and held there for just over 2 hours. The flask is cooled, and extracted three times with 60ml of DCM. The DCM is washed 3x with 185ml 5% NaOH. The DCM is distilled off. 69.5g of crude ketone remains in the flask. (86% crude yield). The ketone is distilled to yield 36.1g of light yellow MDP2P (60% yield) that forms a fluffy white milkshake-like slurry when 0.2ml of MDP2P is shaken with 5ml of saturated aqueous potassium bisulfite solution.
Some of the ketone is used with a methylamine Al/Hg to form MDMA and some of the ketone is used to form the isosafrole ketoxime that was then reduced with an acidic Al/Hg to form MDA.
In this example anethole ketone was used to form anethole ketoxime, but the amount of MDP2P is the given and in the end it will give a similar yield. Detailed notes on using isosafrole ketone aren't in my lab book as the procedure is straight forward and I never thought it necessary to take notes.
Added a 1" magnetic stirbar, 14ml dH2O and 6.7g Na2CO3 (126mmol base, 1.35 equiv) to a 250ml round bottom flask. Start stirring and add 9.6g (NH2OH)2.H2SO4 (116mmol hydroxylamine in the salt, 1.25 eq). Allow this to stir until uniform and add 72ml MeOH and 15.3g PMP2P (93mmol phenylacetone, 1 eq - or 16.6g MDP2P). Refluxed for 60 mins then added 37ml cold water. A white sludge settles to the bottom of the flask. This is not the oxime. Move this to the freezer for one hour. Remove and shake. Crunchy crystals of ketoxime should form. Do not confuse this with a thick sludge that always forms. Suction filter the solution and wash the crystals with 186ml of cold water. If you go to filter before the crystals form, you will see an oil form in the filter flask, this is your oxime that failed to crystallize. The yield of white anethole ketoxime in this example was 14.6g (87% yield). Expect a higher yield! I accidentally spilled some oil in transferring it... Isosafrole ketoxime has always been prepared in just as good yields, but has always turned out an off-white color. No purification was ever used before proceeding to the reduction. Make sure the oxime is bone dry--this can take days--before you take the yield and progress to the reduction. Also note that other substitutions for the hydroxylamine source, other alcohol solvents and other bases (baking soda, sodium acetate, etc) have worked just as well when in equimolar amounts.
125ml MeOH, 25ml H2O, 50mg HgCl2, 8.9g Al, 6.4g yellow crunchy bone dry isosafrole ketoxime, added 25g acetic acid. Added 90g NaOH in 200mL ice-water. Extracted with 80ml toluene then 45ml toluene. Washed with 125ml 5% NaOH, filtered, 125ml 5% NaOH, 125ml brine. Added 100ml distilled water. Titrated with hydrochloric acid using magnetic stirring until pH 4 (used methyl orange as an indicator on aqueous layer until it turned red) 5.9g MDA.HCl.(83%). Broke up crystals, sat in acetone, filtered (5.0g).
Dissolved 29.8g MeAm.HCl (442mmol) and 30mL water in a flask. Prepared 25% NaOH by adding 53ml water and 17.7g NaOH (442mmol) to another flask. Chilled both flasks in the freezer, and then slowly added all of the NaOH solution to the methylamine solution.
Now, in a 500ml flask added 185ml methanol, 0.2g HgCl2, stir bar. Now allowed it to stir, then added 11.9g of small crumpled Al foil balls. Waited for faint bubbling to appear on the aluminum foil. Quickly added the neutralized MeAmCl then 23.6g of MDP2P. Now attached the condenser and let run 5hrs. The temperature rose to about 50°C.
Once everything has calmed down, basified with 89g NaOH dissolved in 209ml water. Extracted that mixture with toluene using 200ml the first time, then 100ml the next time. Worked up the same way as with MDA. The yield was a pleasant 23.6g of MDMA.HCl. (78% yield)
The methylamine was prepared from hexamine and hydrochloric acid, recrystallized from methanol, and washed with acetone as appears in other write-ups.
Last, but surely not least, come the thank yous! Thank you Rhodium for your hard-work and dedication to your site and the Hive in general. Thank you Roundbottom for your isosafrole technique and for your support. Thank you Antibody2 for inspiring me to go after tma-2 and for your lovely acidic Al/Hg. Thank you Dr_Sister for revealing a path towards tma-2. Thanx also go out to Osmium, Bright Star, Methyl Man for their work with the Al/Hg's. Also thank you Hypo, Ueruma, Ezekill, Terbium, Antoncho, Eleusis and Sasha Shulgin for raising my knowledge, awareness and inspiration. :)