Palladium Chloride Cuprous Chloride DMF
Distilled H2O 1 cylinder of pure 02
500 grams 53 grams 300 grams 2187.5 mLs 312.5 mLs
The above reagents (ok the safrole and H20 aren't reagent) are weighed or measured accordingly. The flask is securely clamped into place on the magnetic stirrer. Add the DMF and H20. Start stirring, and then slowly add the palladium chloride and cuprous chloride. If you add the powders first then the liquids you'll have problems with the stir bar finding a place to spin.
Now you have the DMF and H20 stirring away with the PdCI2 and -66-
CuCI added. Insert the claisen head adapter into the flask. Be sure to apply some vac-grease to the joints. Place the addition funnel in the center hole. Add the 500 grams of safrole to the funnel, but don't start adding it to the stirring solution. Next fill the balloon up with 02. She said that she filled it up pretty tight, but don't blow it up. Carefully attach the balloon to the remaining open hole on the claisen adapter and then TAPE or wire it to prevent any leakage. For those of you that don't have access to various pieces of glassware, placing the balloon on the addition funnel will work as well. This was described in the book, Total Synthesis, pages 52 to 55.
You let the solution stir for 1-1/2 hours so it absorbs as much 02 as possible before you start adding the safrole. Everything is kept at room temperature for this procedure. The stirring solution looks very dark, almost black in color. Now slowly add the safrole from the addition funnel so that it takes about 60 minutes for the 500 grams to drip in. There is no noticeable reaction as the safrole is dripped into the stirring solution. Once this is completed let it stir away for the next 24 hours. Note: In her dream, she checks the balloon at the 12-hour mark. It has gone down in size as 02 is being absorbed by the stirring solution. She inflated another balloon, removed the one that had been on there for the past 12 hours and placed the new, full balloon on the open hole. Tape or wire it so there's no leakage. This ensures an adequate 02 atmosphere while the process finishes (excessive, yes, but cheap and simply). She noted that after 3-4 hours of stirring the solution changes from a dark almost black color to a dark sea green or dark olive green in color.
After 24 hours, the stirring is stopped. Now it's time to filter out the Cuprous Chloride, which is one of the two slight nuisances regarding this procedure. Note: forget about Palladium Chloride recovery. It's too complex for the simplicity of this procedure and purchased from a photo supplier it shouldn't cost more than $6.50 per gram. We'll call this next process Phase Two.
Phase Two - Equipment (Vac filtering) Vacuum pump
Whatman filter paper
1 4-liter filtering flask (Heavy Walled)
Support stands and clamps
Phase Two - Chems
3N HCI Book calls for 1500 mLs, on the 5x scale up she used 3000mLs
Silica sand (white, sterilized and washed) or Celite
There are two ways one can try to filter this solution before acidification. First, set-up your vac-filter flask with vac-trap, Buchner funnel & vac source and start the filtering process. A 5x scale up will take about 6-8 hours to Alter. The cuprous chloride is in suspension and it almost completely clogs the filter paper making the process painfully slow. She found a method that works fairly well and reduces the filter time to about an hour. Set-up your vac-filtering as usual, moisten the filter paper with a little H2Q, then pour a 1A inch thick layer of sterilized and washed white silica sand on the filter paper. Moisten the sand with a small amount of H?0. Apply the vacuum to the set-up and then start pouring the solution right into the sand. The sand will keep the cuprous chloride from totally clogging the paper up. Celite can be used in place of the sand. Celite is a 'filter aid' is available wherever fine chemicals are sold. It's a standard and unwatched laboratory item. Celite works in a similar fashion as the sand. White silica sand is readily available without having to deal with a chem/lab supplier. Place the filtered liquid into a PP container and add the appropriate amount of 3N HCI. She stirred it with a wooden paddle for a few minutes.
The solution is ready for extraction. In her first dream she used DCM and broke it into 4 extractions of about 1500 mLs each (she had a 2-liter separatory funnel). Since DCM goes to the bottom, a separatory funnel is a must. Buy or make one. The extractions should go without any problems, as there isn't any emulsions to contend with. She used 100 mLs of DCM for each extraction.
The extracts are pooled. Wash once with a saturated solution of sodium bicarbonate. This washing is absolutely necessary (the book says it can be skipped - DON'T!). The problem with it (and this is the other nuisance of this process) is that a scum and emulsion develop from the wash neutralizing the acidic nature of the extraction. The easiest way to deal with is to vac-filter the mess. Your rid yourself of the scum and breakup the emulsion into a fairly easy to separate liquid. One washing with sodium bicarbonate is sufficient, then wash once with a saturated solution of sodium chloride, then once with fresh H20. Now the extract is dried with sodium sulfate. Your are ready for vacuum distillation. The DCM extraction should be golden to dark brown in color.
Phase Three - Equipment (Vac distillation)
Heat Mantle with heat controller
Or hot plate with oil bath
1 3-liter boiling flask (round or flat bottom)
3-way adapter (still head) 24/40
1 West condenser
Vacuum adapter; condenser to receiving flask (24/40)
1 1-liter round or flat flask (used for receiving ketone)
1 thermometer adapter (24/40)
1 thermometer -10 to 400 C
Tubing for water in/out
Mise fittings to hook water lines up
Aluminum foil (to wrap flask & still head-insulation)
Support stands & clamps
Phase Two - Chems Washed & dried DCM extractions
Set-up for vac-distillation. She wraps the flask and still head with aluminum foil to act as an insulator. Speeds up the distillation process. Begin to heat the DCM extraction slowly under maximum
vacuum. Her vac-pump would only pull 100mm Hg, so the temp at which product first started coming over was 198-200 C (approx 60 grams of isosafrole - 12%), then again at 204 C. (*yield of ketone was 308 grams 61.6% + ). The plus being residue that could not be distilled as there was not a small enough flask to finish the distillation. DO NOT run the larger flask close to dry. If you do, upon cooling the residue will carbonize and push black crap through the condenser and into your clean, yellow ketone. Or worst yet, it will-expand so rapidly that the carbonized mass will cause the flask to push away from the condenser and possibly break a valuable piece of glassware. When you get to 1/4" of material to be distilled, it's time to stop. Either save to pool with other similar materials for future distillations or use the bisulfite procedure to separate and purify. This was explained from experience; she ran it close to dry and had the worse happen. Black crap shooting through the condenser into 330 grams of clean ketone. Two distillations did completely rid it of the discoloration or smell.
*Yield; isosafrole, 60 grams (12%) TOTAL-MDP2P, 338 grams (57.6%) The smaller portion was distilled in a 500 mL flask and yielded another 30 grams. Total yield 79.6% / 67.6% (MDP2P) + 12% (ISOSAFROLE).
The above dream was scaled up in exact portions, as it was her first. Her next dream had some variations to weights and measures, plus a longer reaction time...
Noted are the changes to the above dream: Phase One - Chems Safro/e: 500 grams (same)
Palladium Chloride: 26.5 grams (50% less & big saving in $$) Cuprous Chloride: 300 grams (could have cut this to 200 g) DMF (n,n-dimethylformamide): 1500mLs (31% reduction) Distilled H20: 300 mLs 1 cylinder of pure 02
Do everything else the same except; let the solution stir in the 02 atmosphere for 72 hours. You'll need to check the balloon every 12 hours or so. Replace as needed (when it starts to sag). The color of the reaction after 72 hours was a richer, darker green and the final yield was 362 grams ketone 72.4%, 51 grams isosafrole 10.2%). Not bad for very little work and it is very difficult to screw this up! Once the safrole is added, you can forget about it until it's time to check the balloon."
Note TDK's appalling pronoun use. Actually, niether TDK nor Strike can be held accountable because this was written by someone else who addresses the audience in a normal way. That aside, look what happened in that account. Seems like the traditional reagent proportions of PdCI2 and others may have been overkill. Given enough time to react, very small amounts of PdCl2 can do the job just fine. That certainly makes a difference in one's wallet!
The next example was a post on the Hive by a bee named TaRa (Could be an alias of TDK. Strike ain't sure.). It is essentially the same old song except this girl proved that CuCI2 (cupric chloride) can indeed be used in place of CuCI (cuprous chloride). It also gives you more examples of technique. The more of this one has the more confident they will be in their 'understanding' of the method.
"Interesting results for something that was thought to be a lost cause [Lost Cause?!]. Dreamt about using CuC/2 for process #3 as follows:
In this dream the book writer's chapter began like this - It took 800 g saf, 44 g PdCI2, 240 g CuCI2, 3500 mis DMF + 500 mis H20, stirred in 02 atmosphere with balloon for 96 hours in a 3-neck 12 liter flask; yield was 69-71%, (distilled, did bisulfite and then redistilled the oil from the bisulfite procedure).. Note better lab techniques would get better yield. Materials lost in washing and filtration, purification distilling, etc... This chapter followed the book's (TS) outline, but a few simple variations were applied. To eliminate the nasty emulsion from the sodium bicarbonate wash they washed the initial solvent extracts (right after acidification) 3x with H2OL Used DCM as extract solvent. Removed a good deal of CuCI2+ some PdCI2 with those H20 washes. Note, don't know if
this helped but they dissolved the catalysts in 400 mis of DMF + 100 mis of HzO before they were added to the vessel. The catalysts remained dissolved for the complete rxn' Maintained as much pressure as the balloon would hold as they feed the flask directly from the 02 cylinders putting the balloon on the top opening of the addition funnel. Used a ground glass 3-way joint with a hose from the regulator to feed 02 into the system. Was easily able to keep flask as full as possible with 02. BTW, balloons will burst when filled beyond capacity and it will give you a rush that's not forgotten easily', (makes you think you blew you rxn up)"
Interesting note, using CuCI2 for the first time.. NO OLIVE GREEN color appeared. Stayed slightly yellow -dark brown... All the way through the rxn. Never came close to Green (light, dark or olive). When rxn finished solution was very dark reddish-brown, even when acid washed it stayed dark reddish brown.
The reduction of catalysts warranted the additional stir time. 96 hours maybe excessive, I believe they were hoping it would turn green and the longerthey waited the more they thought it was a lost cause. Fortunately it worked out on the +++ side;)"
To read more about the use of CuCI2 read ref #15.
Now here is a post from a very influential chemist named Spice-boy who has contributed quite a bit to this science (hypothetically of course). She decided to go ahead and apply the idea of using benzoquinone as the oxygen source. If this works it would mean that one would not have to use a balloon of 02 at all, thus making the entire apparatus much more simpler and causing an increase in the efficiency of oxygen uptake and transfer by the system. So let's see what Spiceboy dreamt might happen if this were actually applied:
Holy Ketone! What a dream
Dream setup; 100 ml of DMF stirring in a flask equipped w/ a sidearm 34 g of safrole was added in 4 portions of about 8 g each. Mixed intimately. Next, 11g of p-benzoquinone was added. Stir rate was upped. Finally, 7 g of pdcl2 was added. A dry addition
funnel was coupled to the flask, and 5ml of dh2o was measured into it. Thermometer was attached to side tube. At midnite, one ml of h2o was added, temp went to 70c. Brisk stir rate. 15 min et and another ml of h2o added. External heat, if needed is used. At 1:00 another ml was added, and temp held at 70c. at 2:30 the final ml was added, and there should be a trace left, but ok if it aint held at 70 c for 30 more minutes, allowed to cool to room temp, flooded w/ chilled h2o, and extracted wl starting fluid(nod to Q) BOOOOOM! yield; over 70% "
That looks great, Spiceboy. Thanks, Bra'! And to show you that Spiceboy isn't making this up, the following experimental will prove it. This was taken from the review  written by the same doctor that authored the progenitor PdCI2 article that Strike drew from to formulate this recipe. And just as Spiceboy says above, there is no need for any copper compound or balloon. Also, the reaction time is seriously shorter and the amount of PdCI2 catalyst needed is drastically reduced:
" In a 100mL round-bottomed flask fitted with a magnetic stirrer is placed a mixture of palladium (II) chloride (89mg, 0.5mmol), p-benzoquinone (5.94g, 55mmol) and 7:1 dimethylformamide/water (20mL). To the solution, 1-decene [substitute safrole for this compound) (7.0g, 50mmol) is added in 10 min and the mixture is stirred at room temperature for 7h. The solution is poured into cold 3 normal hydrochloric acid (100mL) and extracted with 5 portions of ether. The extracts are combined and washed with three portions of 10% aqueous sodium hydroxide solution and a portion of brine, and then dried After removal of the solvent, the residue is distilled to give 2-decanone [P2PJ; yield 6.1g (78%).
The last variation we should discuss is about the use of solvent. Ever-bitching about the rarity and price of chemicals, the bees have thrust their anger at the DMF used in this method. TDK sent Strike an article that gives some credence to this , In it the alcohols methanol, ethanol, 1-propanol, ethanediol and others were used in place of DMF with beautifully high yields. Below is the sample experimental from the article (just picture using safrole or allylbenzene in place of the 1-hexene):
»2- and 3'Hexanone.—A 50-ml portion of 0.665 M 1-hexene, 0.020 M PdCI2 and 0.100 M CuCI2 2HzO in 1-propanol was shaken for 120 min at 50C under 3 atm oxygen. The reaction fnixture contained 2.0% water from all sources (salt hydration, impurity in the alcohol and water of oxidation). Of the hexene charged, 13% (by gc area) remained unreacted and 86% was converted into hexanone and 1% into side products. Resolution of the hexanone peak showed 75-76% 2-hexanone [or MD-P2P for the likes of us] and 24-25% 3-hexanone, both identified by means of residence times and infrared spectra in comparison with authentic samples."
Whaddya mean it won't work for things like safrole just because the substrate used was 1-hexene?! The only thing Strike had to go on years ago was one article  which had as its star 1-decene. And yet the method translates! This last contribution (by Spiceboy again), shows that using methanol as a solvent works just fine and, as has been suggested by others, can lead to a reduction in the amount catalyst needed. Strike doesn't know what the hell is up with the bicycle pump, but to each her own:
"Welcome back...now, before I give up dream details, I want to thank Osmium for his inspiration. You got me to thinkin' man. I want to say that this is another offshoot, I guess , of #3, but with some twists. Such as process ONE HUNDRED GRAMS of olefin With 2 g of pdcl2, and 8 g of cucl2. There will be no oxygen tank. FUCK THAT SHIT! The reference I based this on indicated that air will work, Whaddya know? Theyre right. The air comes from a 14.95 piece of shit tire pump from walmart. It will pressurize the SP.V in about 10-20 seconds. Here we go:
Dissolves g CuCI2 in 80 ml MeOH.Dissolve 2 g PdCI2 in40 ml MeoH. Dissolve 100g of safrole in 200 ml MeOH. Pour it all in and add MeOH to make 500 ml MeOH total. Swirl and gently shake. Pressures the SRV to 37 psi. A tire gauge works great. After one hour, release the pressure and immerse in warm water for 2-3 wins. Shake. Re-pressurize. Repeat process hourly. At night, be fore bed, pressurize again, allow to stand overnight My time elapsed; 13 hours at bedtime + 8 hr sleep = 21 hours reaction time. Hit it w/ 3N HCL and extract per usual. KA-FUCKIN' BOOMi 80% +1!!!!!!"
Whatever!!! This person needs some serious psychological help! But Strike would not dismiss the chemistry. No way!
Well, that should be enough examples to give you a good idea of how this Wacker oxidation method works. There are a lot more interesting variations that bees have been posting on the Hive if you wish to read more.
Finally, it must be restated that the biggest plus of this method is that it produces 70-80% MD-P2P or P2P, and 20-30% isosafrole or propenylbenzene as a side product. So if the chemist were to turn around and process that isosafrole using, say, the formic acid method #1, then the potential P2P production from this method could climb to well over 90%!
METHOD #3: As of the printing of this book, this method is still in the experimental stage. But it represents the next generation of the Wacker oxidation and should, if properly realized, scorch the old one in both yield, cost and time. This is entirely due to the work of Osmium, TDK and an aggressively active European chemist named Sunlight. They, and maybe others, found the journal reference, contemplated it and started dreaming about its application. All Strike is doing is filling you in on what Strike has seen and been told.
The method is basically an application of the Wacker oxidation except that the catalyst used is palladium acetate ( Pd(AcO)2 or Pd(02CCH3)2), the solvent is acetic acid or tert-butyl alcohol and the oxygen source is the previously suggested hydrogen peroxide (H202) .
This article was written by a French group. Strike has mixed feelings about French science. On the one hand they are usually quite correct in their chemistry. On the other hand they are always too lazy to write up the details in a comprehensive and detailed manner. It's like they want to tell you how great they are, but they don't want you to share in it. Strike can say this with confidence because Strike has yet to have anyone from France buy any of Strike's books, so Strike knows they won't see this one either (tee heel).
Anyway, the details are a little hard to process but the results are very clear:
" This paper describes a very efficient catalytic procedure for the oxidation of terminal olefins [ie safrole] to methyl ketones [ie MD-P2P] by hydrogen peroxide using a palladium catalyst and operating in the absence of halogens and co-metals [ie no CuCI or CuCI2 needed]... This reaction is carried out either in biphasic medium, using solvents such as ethyl acetate or dichloroethane, or in homogeneous solution, using iert-butyl alcohol or acetic acid...a quite complete conversion of 1-octene (90-95%) was obtained after ~3h or reaction time...Under these conditions, 1 mol of palladium was found to transform ~400 mol of 1-octene into 2-octanone per hour."
That, folks, is an incredible reaction rate! They are essentially saying that less than a gram of Pd catalyst will turn 100+g of safrole into MD-P2P in less than 3 hours! The cryptic optimal reaction conditions and procedures are as follows:
" temp = 80C; H202 (30%): 1-octene = 5; 1-octene:Pd = 1500; re action time = 6h. [or in other words] 0.5x10'3 M Pd(AcO)2; 0.75 M 1-octene; 3.75 M H202 (30%); solvent AcOH; temp 80C."
The experimental procedure:
"The olefins were oxidized in a three-necked 1L thermostated glass reactor equipped with a magnetic stirrer, a condenser, and a 100mL glass funnel (for introduction of H202) and connected through a gas counter (for the evaluation of 02 evolution) to the atmosphere. H202 solution was introduced dropwise into the mixture of olefin, solvent, and catalyst during 30 min at the reaction temperature. When the reaction was complete, the mixture was cooled and water was added. The yellow upper layer containing the catalyst was separated and passed through a column of alumina in order to eliminate the catalyst and reduced under reduced pressure."
Yeesh! What the hell did all that mean? Well, let's see what Sunlight's preliminary interpretations are as were secreted to Strike via encrypted messages. It is interestingly voyeuristic to see the first machinations of a recipe come to life:
"Well, I've started to work a few days ago with palladium acetate. Normally I start with quantities of 10- 20 cc of safrol, but this time, animated becuase you [not Strike!] said there's someone who said this way is good, I make a direct production test with 150 grams of safrol. Well, at 80 C, and after 1 hour or so, I go out from home 10 minutes, and when I came back, rxn was no controllable, a exho-termic rxn started with a lot of evaporation of acid, I did another mistake when trying to stop rxn and a lot of acid whas in the atmosphere. It was hard, near intoxication. Other test with small quantitie shows me 80 C it's too much. The product obtained was only a clear brown tar with no ketone. The problem was the temp, it's too high. I've started again with my classic tests. I put yesterday 10 cc of safrol with 50 mg of Pd(OAc)2 and 35 cc of H202 30 % and 70 cc of acetic acid at room temp (30 C). After 16 hours, this morning before go to work, rxn was not complete, (in the night temp goes down), and I think in 24 hours it will be done. I put a piece of glass in the flask and wait to acetic acid is evaporated,
then I smell, if there's safrol, I smell first safrol but like safrol is more volatile than ketone, after 5 minutes (or more depending ratio safrol:ketone) start the ketone smell. I can now smell the ketone in my fingers. I don't know how yield can be achieved. Other probelms are if temp is not used, it's necessary more solvent, may be 1 liter for 100 cc of safrol, what is too much, it will complicate extraction, although in my test there are 70 cc and it seems to work, but it is not an homogeneus solution. In JOC they say the reaction can be done in dual phase, this will be my next try, if it runs, it will be the best, just stir safrol with H202 and solvent (I'll try with toluene), when done, add some NaHC03 and stir, and then separate layers, distill. Perfect simplicity, will it work ? It seems best temp will be 40-50 C, it will increase reaction speed."
A few days later:
"I'm working now. Best results were obtained with dual phase with toluene at 50-60 C 24 hours stiring. The isolated oil smelled a lot to ketone, and when two drops were added to a saturated solution of sodium metabisulphite and stired, practically all reacted forming the addition product that precipited to the bottom. I think it's about 80 % yield, but it's only an impression, may be less. Now I'm repeating the experiment to determine conditions and then, I'll do a >100 grams batch, so I'll determine yield. The problem has been is needed a good stirer, and I was working with a motor cassette with two magnets, I realised only 300-400 rpm. Then I bought a more potent one, but now my problem is the noise of it, because it must run 24 hours...
The recipe will be something like :
100 grams of safrol
150 cc of toluene.
100 cc H202 30 % added dropwise
100 cc H202 30 % added dropwise at 6 hours
100 cc at 12 hours
100cc at 18 hours...
2.5 cc of acetic acid
0.5-1 gram of Pd(AcO)2 stirabout 24 hours thats all.
Then add a bit of NaHC03 (4 grams ) and salt to saturate solution. Stir a bit more. Separate layers, Extract one more time and distill. Time depends on reaction speed. Reaction speed depends on the amount of catalyst and temperature. 60 C seems to be good, more catalyst, less time. More temperature ? May be more byproducts, this is what happen when acetic acid is the solvent. Probably a good way will be also acetic acid and 40-50 C, but dual phase is easy to extract ans uses less chemicals.
I hope my reaction success and I can run the 100 grams batch tomorow. Another difficultie is now water tap is at about 29 C ( to distill), may be I'll use a refrigerator compressor, I think it will be enough to distill ketone at about 180 C.
Couple of questions forme:
?>Add the toluene + safrol into rxn vessel, then add acetic acid + >Pd(AcO)2, then start stirring, then start dripping in H202?
Well, I think it's better to add a bit of H202 to the toluene + safrol + catalyst to prevent catalyst decomposition, for example, with 100 cc of safrol, 10 cc of H202, and then add the rest dropwise.
?>Also, is the amount of acetic acid exact, for example would 5 cc hurt
>the rxn or help it (in your opinion) I don't think more >temperature would help, probably create more by-products! ?
Well, I thought previosly a bit of acetic acid can help reaction to prevent decomposition of catalyst. Now I'm thinking after re-read JOC article 1425 times, acetic acid is not needed at all, because if catalyst degrades to Pd metal, is not more dissolved, so why add acetic acid ? My last test with 10 cc of safrol had 0'4 cc of acetic acid, but I'll omit it in next rxn.
I've found that unfortunately, there is a hyper oxydation of oleofin as side reaction, and gives organic acids, probably MDPhenylace-tic acid and may be a bit of piperonylic acid. It's easy to realise it,
just measuring ph after reaction. I suppose this side reaction is more important when temperature is high. My last try was dual phase, 10 cc safrol, 0.7 PdfAcOs), 20 of toluene and about 45 cc H202 in three times and at 60 C, may it's too much high. So if we decrease temp reaction, we must increase time or catalyst. If we increase time, H202 degrades in time, so we must add more, and H202 concentration decrease, so reactivity decrease also a bit (I think ). Best solution will be increase a bit catalyst. BTW, in my next try I'll use PdCI2, as I said you in the first samples I saw PdCI2 yilds also ketone. So I'll do a sample with exact conditions to Pd(AcO)2, and I'll compare results. It' would be better to work with PdCI2. Now, when I come back to home, I'll extract my last 10 cc reaction, and I'll see the lose of material in carboxylic acids, because they will go out in basic wash. I'm afraid my last yield will be about 50-60 % only, far from desired 80 %, but not bad having the nature of chemicals (toluene and H202, OTC ) and the little effort that supposes. But I would prefer 70 +. So try to send me the information of your friend's friend, may be there is some key in it important for me. I'll hope improve this method to make a simple, elegant, cheap, OTC, high yielding procedure. I have only a bit more than 100 cc of safrol. I'll do one or two tests more and then I'll process the rest. And Ketone research will finish for me. May be I'll have your post tomorrow ? Thanks"
See how things happen when a competent, energized chemist gets ahold of a new recipe? Well as it so happened, Sunlight was getting a little uncomfortable with the results (as was communicated in later emails) and decided to contemplate the alternative use of tert-butyl alcohol and other solvents as was discussed in the French journal article. But just days before this book went to print came the news that will change the production of phen-ylacetones forever. TDK, bolstered by the reassurances from a secret group of chemists that have apparently been using this recipe for years but forgot to tell everyone else, came through again. The following is the proof positive definitive application of this recipe:
"200 g safrol + 1 g Pd(AcO)2 + 500 mis tert butyl alcohol + 400 mis 35% H202. Added everything but H202 to a 5 liter two neck flask equipped with a reflux condenser, thermometer, and dropping funnel, mounted in an oil bath on a good magnetic stirrer. Started stirring while bringing the temp to 80C. At 78-80C start to add the H202. It was added over a 30 minute time frame. As this was added, they noticed an evolution of bubbles coming from the rxn (02 from the H202). Monitored stirring and temp with no unusal occurrances until hour 4... Initially solution was a light orange brown, after 4 hours in started to turn a very deep orange, almost reddish color. Also the smell of safrol was completely gone and was replaced with a unique aroma of ketone. One that is attributable to this rxn as it differs from the smell of the wacker oxidation ketone. Continued rxn for a total of 6 hours, maintained temp at 79 to 82C. Color at the end of rxn was deep orange- reddish, pH of solution was 2.
To separate the oil added an equal volume of fresh cool water (note: waited until solution cooled before adding the water). The oil started to drop out perfectly, used DCM to extract all traces of the oil. This work up is by far the cleanest, easiest and simplest to date... (This dreamer was tried all method of ketone synthesis)... Once the oil was extracted, the extracts were pooled washed with sodium bicarbonate 1x, saturated solution of NaCI 1x, and two washes with fresh dH20... Some time was required for the work up as there was a little emulsion from the use of the base wash and then with the first water wash. The JOC ref suggested using an alumina column to remove the catalyst (could be a better way to go).
So now we have this solvent containing ketone, dried with MgS04... Not being able to vac-distill today, took about 50 mis of solvent/ketone and placed in beaker on stir plate and boiled off the solvent. The resulting oil was a nice reddish-orange color. Had a very unique smell too. Took about 2 grams worth of this oil, added to a test tube containing a saturated solution of sodium bisulfite... In less than 60 seconds the oil precipitated into a whitish yellow mass (very similar to what acetone would do if added to a bisulfite solution). Never had this quick of a crystallization. Not
having access to HPLC or other more accurate method of analysis, I would say the purity of this ketone is >90% and the yield will be minimum 78% and probably as high as 86%. No isosafrol either, as this rxn is highly selective.
This is the best method, easiest and most fool proof process to date!"
Strike wants to believe that, but right up til the last day this book had to go to press, the ball was still up in the air on this one. Conflicting, odd results have been seen from many different groups. This method has a lot of advocates and proof of its efficacy. But it seems to be a little fickle at times; the causes of which are still being debated to this day.
METHOD #4: This is a P2P recipe that Strike has no hand in. Strike never even knew about it until Strike saw everybody talking about it on the net. But it seems to be extremely popular. Shulgin has written about it. Uncle Fester, Strike understands, has written about it. And there seems to be a lot of posts regarding its high success rates. Most people get started from the method description in the patent literature where they were first published. The following are some representative examples from the U.S. Patent #4,638,094 "Process for Producing Phenylacetones":
"Example 24: Add .1 mole of 3-(3,4-methylenedioxyphenyl) propylene, .25 mole of methyl nitrite, .008 mole palladium bromide as a catalyst, ,5L of methanol and 36g of water to a flask. Stir magnetically for 2 hoursat 25C. Yield of 3,4-methylenedioxyphenylacetone (also known as 3,4-
methylenedioxyphenyl-2-propanone/MDP-2-P) is 95% with 100%of the reactants consumed.
Example 51: Add .1 mole of 3-(3,4-methylenedioxyphenyl) propylene, .25 mole of methyl nitrite, .5L of methanol, 36g of water, .00025 mole of trimethylamine, and .0005 mole of palladium chloride as a catalyst to a flask. Stir magnetically for 1.5 hours at 25C. The conversion of the starting material was 92%, the yield of MDP-2-P was 83% and the Pd Turnover Number was 166
Example 68: Add .1 mole of 3-(3,4-methylenedioxyphenyl) propylene, .25 mole of methyl nitrite, .5L of methanol, 36g of water, .006 mole of bis(benzonithle) palladium (II) chloride as a catalyst to a flask. Stir magnetically for 1.5 hours at 25C. The conversion of the starting material was 100%, the yield of MDP-2-P was 88%.
Example 86: A 0.10 mole amount of the starting 3-(4-hydroxyphenyl) propylene, 0.25 mole of methyl nitrite, 0.5 liter of methyl alcohol, and 0.006 mole of a palladium chloride catalyst were charged into a reaction vessel. Then, the reaction was carried out at a temperature of 20.degree. C. for 1.5hours."
Those 'propylene' species that the authors were using are no different than safrole or allylbenzene. In fact, safrole is a perfect substitute. Yowza! Those recipes look awesome! Now as Strike understands it, there has already been a detailed writeup of the by-the-numbers application of the above patent as written. This, Strike believes, can be found in Uncle Fester's "Secrets of LSD Manufacture" and/or "Secrets of Methamphetamine Manufacture'^ 8], But our adventurous chemist Sunlight came thru again and submitted a new, hybrid form of this method which she seems to have formulated after a lot of 'thought' on the matter. So here again is Sunlight:
" This is a new post in the Hive, I've performed a new reaction [she's just kidding folks!] with the new experience, with is much better than the other. Darkness part is extraction (yes, a lot of dark - 83 -
brown product), so may be it's better to do it as your procedure top #3 , sometimes is really hard to make the two layers different in colour. I hope we are in time to include in your bood, if you want.
The present post is an adaptation to kitchen chemistry of Japanese patent #4,638,094, process for producing phenylacetones, and is the result of a large battery of dreams. In SOMM (Uncle Fester), we have three versions of this patent, one uses PdBr2, other PdCI2 and the "prefered" uses PdCI2 and CuCI2. Last one doesn't run. Also SOMM version be dangerous because in the scheme of rxn, Fester lets 6 mols of NO and nitrites to go out free of rxn vessel (see Eleusis vs. Fester, Rhodium's page, eleusis it's right). Well, both gases are very toxic, good ventilation is not enough and these gases must by carried out of the window through a tube (use a two hole rubber stop or a two necked flask). Also in this sample a precipitate that is taken out, these are undesirable byproducts, also washes must be done when rxn is done to liberate as Pd as possible. Two explosions have been reported when distilling, may be because this reason. Also in this procedure we spend much less solvent, minimizing evaporation time, less catalyst and less NaN02. Otherwise, I agree Uncle Fester his work because he have shown me a lot of things, I recognize also the good part of his work.
Interest of this reaction is that uses OTC chemicals or non suspicious, as NaN02 (it's used in food industry as a conserver) , and it's really easy. Methanol used is drugstore methanol, PdCI2 is from photografy supplier in the net or elsewhere...
Procedure is as follow:
A solution of chilled dilute H2S04 (C) is dropped in a solution af methanol, water and NaN02 (B), then methyl nitrite is generated,
and bubbled in a solution of safrol in methanol containing PdCI2 catalyst (A).
This example has been done with good yields :
A. 50 cc of safrol, 300 cc of methanol, 2,5 grams of PdCl2
B. 100 grams of NaN02, 60 cc of methanol and 200 cc of H20
C. Chilled solution of 38 cc of H2S04 and 85 cc of H20
C or a part of C is put in a sep. funnel wich is connected to flask containing B ( wich can be a bottle), and a tube connect this flask to the bubbler into flask containing A, wich have other tube to redirect No and nitrite gases. Flask A is in water bath to keep rxn temp between 20 - 30 C /reaction is slightly exothermic) and stired magnetically. MeONO is bubbled in A with a bubbler that provides little bubbles (not necessary a gas difusor, but a single tube is not enough, you must increase then B and C). Bubbler is all deep as it is possible.
We start rxn, one drop /second or so C in B. Sometimes we close sep funnel and shake flask B to ensure a constant rate of MeONO generation. Addition speed is limited by equilibrium of pressure between flasks. If it is too much quick, then MeONO gas go through sep. funnel, then we close the sep funnel and wait a bit till generation is low. The addition of C in B takes 1 hour, we close sep funnel and shake a bit B to finish reaction. If rxn (A) climbs temp too much, we can add ice in the water bath. I've monitorized temp touching a part of solution that was out of water bath. At the final part may be water is to much cool, so we can take it out. After the addition of C in B we wait one more hour.
Now we open flask A. We can put a piece of glass and smell it once methanol is evaporated. There is no safrol smell, It's different, it's the dialkoxy derivative of safrol, rxn is completed perfectly. We add now 75 cc of water and stir 45 minutes more. There's a precipitate. We filter the reaction. I don't know what is this, may be also black tar, I thought this may be palladium complexes, this is a - 85 -
organic compound that burns easily and may be contains Pd. This will forme tar later, now we don't have it. We can now smell another time rxn. This smell is ketone, we have more than 80 % of MDP2P (patent says 91 %). Good extraction procedures will give better yields.
This is my version, but may be better done. First one, evaporate methanol, better with vacuum. Then we have two layers similar in volume, we add 100 of solvent and 50 cc of basic solution (sodium carbonate, bicarbonate or 10 % NaOH). We shake it and may be we will have little more precipitate or tar. Also may be we can't see separation, then we add a bit more solvent without shaking to see separation. We make two more extractions with 50 cc of solvent. Even if we can't see separation, we can add enough HCI and shake, this will forme some tar and layers will be distincts, so we can separate and make a basic wash. Sometimes I've done first an acid wash, but I can't sure it's better. I'm thinking now may be is better to do all extraction as Strike's top #3. Add acid solution, like 250 cc (less PdCI2 and no CuCI) 15% HCI, extract and make a basic wash.
This procedure has been tested for a lot of bees and conditions are similar. Distill solvent and distill ketone with a water pump. My yield, 41 grams, about 75 %. Scaling. Of course. This procedure have been done with 150 cc of safrol, but with 1'75 I of methanol with simialr yields, so I've prefered to present this version wich is better (less solvent, less time) Addition of nitrite was done in 2,5 hours. When scaling, water in B can be decreased if we have problems with our volume flasks, but this means a lot of NaN02 is not dissolved, so each 15 minutes, we close sep. funnel, and shake B a bit, and when there is no foam, we can open sep. funnel again (1 drop or abit more /second). My opinion is 150 is ok, but theorically you can scale more. More time rxn is not a problem for product.
Bubbler. I've done it widening the end of a glass tube, then puting in the hole with pression a piece of glass sponge ( for feet) and welding it with a flame (Bunsen). When done, you can blow through it in water to see there are many bubbles. It's enough.
Flasks. Flask containing B can be a bottle. A is a round bottom flask, it's better because in a bottle or a fíat bottom flask, PdCI2, wich is not dissolved in methanol until it reacts, could be in thé corner of flask without reacting.
Hazards. If you add two much quickly C in B, MeONO goes through sep. funnel. So close the key, but if there was too much addition or you shake immediatly then generation is higher than the possibilities of bubbler, and rubber on flask B can jump with a lot of foam and solution. For this reason it's better to have NaN02 dissolved , to prevent surprises, but it's not necessary. Be patient and shake. Don't forget redirect NO and MeONO fumes out to the window.
Cleaning flasks. Flasks, specially distilling flask are really dirty, with a brown black semisolid tar. It's easy to clean them. Make a 25 % or stronger NaOH solution (from drugstore, of course), put it in the flask and heat, till boiling if necessary, all tar go out easy. Use gloves, please.
Bisulphite. My personal nightmare. I use metabisulphite, what I think it's the same. Sometimes product is unfilterable, other one couldn't be recovered with NaOH solution. Investigate, I'm not a great chemist. Solvent, NaN02 or PdCl2 may be can be reduced, but I think the quantities in this sample are really good. Solvent is easily evaporated, NaN02 could be only slightly reduced and PdClz is about 4,5 % versus 6 % in patent, but it's enough because all safrol reacts. Well, I think it's all..."
METHOD #5: Could something this easy really work? Actually, yes! Well, ya wanna know something? Actually Strike doesn't know if this really works or not (We'll discuss this in a bit. But first read the following which was what Strike wrote in the first edition of TS). Safrole is converted to MD-P-2-P in about 8 hours with no watched chemicals and a yield of 70%-80% . The reaction is shown in the accompanying diagram.
This will work for conversion of allylbenzene to P2P. And the bonus is that the major side product is isosafrole. The mercury (II) salts that one can use are mercuric acetate (HgOAc), which can be made quantitatively (100% bubba) from mercuric oxide (HgO) and acetic acid (why anyone would do that is beyond Strike since the stuff is easily purchased), or mercuric propionate made from HgO and propionic acid. The oxidation of the intermediate alcohol is achieved by using Jones reagent , An 8M solution of Jones reagent is made mixing 267g of cold chromic acid (Cr03) 230ml_ cold H2S04 and 400mL cold dHzO then the solution is brought up to a final volume of 1L with dH20 (or can be purchased). The working concentration that one wants is 2M, so the chemist mixes 125mL 8M stock with 375mL dH20.
The chemist now gives her knuckles a crack and begins. An appropriate sized flask or PP container is placed in a tray of water on the stirplate. Into the flask is dumped 800mL acetone, 25mL
dH20 and 32g HgOAc. This is stirred a little, then 82g of safrole is slowly poured in. The solution should be bright yellow. Now, 375mL of 2M Jones reagent is added drop by excruciating drop over a period of 4hrs. The chemist will keep chunking pieces of ice in the tray to keep the temperature at 25°C +/- 5°C, and the solution will turn dark greenish brown. After addition is complete the solution stirs for 4hrs more.
When completed, the solution is merely dumped into 1L of dH20 and extracted 3 x 100mL Et20 or DCM or benzene. BUT when that solution hits the solvent, the biggest, ugliest emulsion Strike has ever hypothesized occurs. It is wicked! The chemists can try all the usual tricks to get rid of that bitch, but when it comes down to it, there is only one way that works. The chemist is going to have to extract with hundreds upon hundreds of ml_s of solvent. The idea here is to saturate both the aqueous and emulsion layer with so much solvent that a separate solvent layer can form. Once saturated, the entire mix can then be properly extracted.
The solvent is then washed 3 x 50mL dH20 and, if desired, can be washed once with 100mL saturated NaCI solution. Finally, the solvent is dried through Na2S04, removed by vacuum distillation, and the first 5 to 10mL of oil that distills over is saved because it is isomerized safrole (iososafrole), which is suitable for reuse. The rest of the oil that comes over will be the ever lovely MD-P2P, which is perfectly suitable for amination by any method given in this book.
What you have just read is what Strike wrote in the first edition. Strike laid down one day just before publishing and had this bad ass premonition regarding the recipe. But most people since then have not. Let's see what the problem is.
Strike got the journal article for this recipe as literature citation used in the original Wacker oxidation Strike used for Method #2. In it both mercuric acetate, and to an extent, lead acetate produced ketones as described. Someone-Who-ls-Not-Strike also got a certain ketone. But maybe they were lucky or just plain wrong. Most people on Strike's site say this mercuric acetate thing
just ain't happening. But some say that it does. Funny how Strike only happened to save those positive posts...
"Posted by Dr. Quack on March 08, 1998 at 16:53:53:
So there's this little duck and round and round she struggled with this method. But here is the report for all to benefit from, Quack, Quack...
So for all you book owners out there, boy did you get your money's worth. Check this out (btw, Dr. Quack has NO idea how this came about, but Quack!, Quack! it what the pigeons told Dr. Quack - promise):
For top ten #2 (Mercuric Acetate method) use the following in place of reagent grade materials:
1. Ether - Starting fluid (works great - Quaaaaack!) 2. Home made mercuric acetate (Now this stuff can be special ordered from ones chem supplier but there's a delay, may look funny - Quaaaaack!, and is more expensive. So what is the solution to this? Make it yourself!!! Its easy, quantitative, and cheaper. Strike mentions this in the book and points ducks to a reference. Follow the EXACT same procedure for Mercuric Propionate except use glacial acetic acid...quackl). You'll need to use 20 to 25% more of the home brew mercuric acetate since it is a little contaminated with acetic (ducks can't get it totally dry without a vacuum oven). 3. NaOH washed Brazillian is fine!!! Quack!!!! No need to purify further for starting material!
Now here is the secret(s):
A. Ducke/Bees/ Whatever MUST keep the temperature in the range of 20 to 30 C during the dripping of the Jones Reagent. Either add tepid OR cool ice to the water bath to keep it in this range. Maintain drip at 1 large drop every 4 to 5 seconds...Quack!!! This is imperative since the mecanism of chromic oxidation requires NO excess to be present during the oxidation. That's why one has to drip in over a four hour period. Also, after the drip, the full 4 hours following of stirring IS required but the temp should remain stable...QuaaaaaacK.
B. Big secret...Quack!!!!!!, Use approximately a total of 600 ml (twice the amount prescribed) for the three extractions. Don't quack at me...its starting fluid. It's cheap!!!! Quack! Here it is: Let the first extraction sit for several hours (or overnight) and the seperation will be VERY clean. However, there will still be an emulsion present in the ether layer. Now, the Quackload of product will be in the first extraction, so the emulsion and settling of the following two will be much quacker (faster). Combine ALL three ether extracts and note that there will be a little water that will separate out from them.
C. Big secret #2...Quack!!!l!...One MUST filter this 600+ ml of ether...but a duck cant do this all at once...so one must filter in vacuum filter in 200 ml portions...changing the duck paper every time and wash the filter cake with ether...Dr. Quack thinks a vacuum filter (apirator) at this stage is a must..Quack!!!!!!!
D. Now the ether will be a deep reddish yellow. Distill off the ether...quack...and take the temp up to 170 C to drive off any other volatiles. Should recover 90%+ of the original weight of oil. Now add 500 ml of saturated bisulfite and stir for 1.5 hours...Quack!!!!!!! Vacuum Filter, the duck fat crystals!!! Wash with water and ether, yield dull fine ppt in the filter cake...stable bisulfite addition product...can be stored forever...Quack!!! Yield -50 to 80% depending on a ducks technique!!!!
Dr. Quack thought ole Strike had a screw loose at first, but after continual quacking and persistence, Dr. Quack is convinced...this method is great as well!!!! Quaaaaaaaaaaaaaaack!!!!!!!!!!!!!!!! Hope the pigeons cleared some things up for some of you bees and ducks. Quack, Quack."
Now as you can see, Dr. Quack is half nuts! And his description of things and outcomes are right in line with what Someone-Who-ls-
Not-Strike may have seen. But what Dr. Quack did that SWINS did not was use the bisulfite test with positive results. What does that mean? It means that some doublebonded oxygen was formed, unless Dr. Quack was fibbing to us. It cannot have been a propiophenone (don't ask) because propiophenones cannot form the bisulfite addition product. Could an aldehyde have formed (don't ask)? Maybe. But highly unlikely considering the mechanism of the reaction.
Later on Strike noticed a few posts from Dr. Quack grumbling about how things did not, in the end, work out with the products of this procedure. Is Dr. Quack cwazy? Yes! Is she a bad chemist? NO! So what gives? Well, the following is a personal communique from Merlin: a chemist that all of you will thank when you see the stuff she wrote later on in this book...
"#2 without water - proceed as follows. After the 4 hours stirring is complete extract direct with Ether. A normal amount of Ether will do nothing so add more till a layer forms. This is due to the need to drag the acetone out from the water. Water and Acetone mix, the Ether needs a hell of a pull to drag it out. The layer will be huge as it includes the Acetone. This will leave the mush which wants to form an emulsion in the water layer which can now be discarded. The ether/acetone layer is now washed with water which will extract the acetone from the ether, leaving a small ether layer which contains the product. This layer will be deep red in colour. After three washings (leaving the boogers in the lower water layer each time) dry with sodium sulfate. Only a tiny amount of isosaffy will come over beforehand (a couple of mils) which will float on top of the product (which I hope is MDP2P as this method is so fucking quick and easy compared to Isosaffy bastards and that palladium chloride method). This extraction method would take 3 hours in total including purification, no need to fuck about with nasty emulsions, and the yield seemed to be nearer 60% (rather than 50%) giving just less than 60g product from 82g of saffy."
And a later email said this:
"Well the gospel according to Sodium Bisulfate confirms it is a ketone. Whether that's all it is I'll know tomorrow."
See?! There it is again! But even when this person sat down and contemplated the use of the P2P nothing but misery followed. This method has to work because its potential is massive. But it needs further study! Yeesh!!!
METHOD #6: This one is for meth cooks only as it is only practical for making P2P, not MD-P2P because Strike don't know where one can get 'piperonylic acid'. It has been around awhile and works really well . Therefore the chemicals needed have been restricted for quite some time. But if one can get them then what the hell.
This is a way to do this procedure without having to use one of those crazy tube furnaces stuffed with thorium oxide or manga-nous oxide catalyst . The key here is to use an excess of acetic anhydride. Using even more than the amount specified will insure that the reaction proceeds in the right direction and the bad side reaction formation of dibenzylketone will be minimalized (don't ask). 18g piperonylic acid or 13.6g phenylacetic acid, 50mL acetic anhydride and 50mL pyridine are refluxed for 6 hours and the solvent removed by vacuum distillation. The remaining residue is taken up in benzene or ether, washed with 10% NaOH solution (discard the water layer), and vacuum distilled to get ~ 8g P2P (56%).
METHOD #7: Another piperonylic acid method for your perusal [22, 23], 70g piperonylic acid or 65g phenylacetic acid in 250mL DCM is stirred in a flask and 64g SOCI2 is added dropwise. The solution is heated to reflux until no more HCI gas is released from the solution. The chemist should have a tube leading from the top of the reflux condenser to a glass of water to catch all that HCI
gas. What the chemist now has is a chloro-intermediate oil that is fractionally distilled to purify. 65g of this oil is added to 100mL toluene and then this toluene mixture is added dropwise to a solution of toluene containing 210g of methyl zinc iodide (MeZnl). The solution is stirred overnight at room temperature, poured into ice water, acidified with H2S04 and the toluene layer distilled to give P2P in yields of about 40-50%.
METHOD #8: Check this out! This uses benzene or 1,3-benzodioxole (forX) as the starting material . This method is better suited for speed makers because the AICI3 catalyst can tear up that methylenedioxy ring structure of the X molecule precursor. Chloroacetone can be easily purchased.
41.3g AICI3 and 100mL anhydrous benzene are stirred in a 500mL flask fitted with an addition funnel and reflux condenser. A tube is attached from the drying tube atop the reflux condenser to a water trap to catch the noxious HCI gas that is going to be evolved. The solution is heated to reflux and 14g of chloroacetone is added dropwise from the addition funnel over a period of 30 minutes. After addition the solution is continued to reflux for 5 hours to give a black solution. While everything is in the same position, water is added from the addition funnel to destroy any remaining AICI3. This will cause more HCI gas to be evolved until all the catalyst is gone. After such a time 20mL dH20 and 20mL concentrated HCI are added, the benzene layer separated and the aqueous layer is extracted once with benzene. Both benzene portions are combined, vacuum filtered, dried through Na2S04 and vacuum distilled. The first thing to distill over is benzene, then about 9g of a low boiling oil which will be the P2P and then 10g or so of black, high boiling crap that the chemist leaves behind in the reaction flask. The P2P can also be purified by making a sodium bisulfite addition product out of it which is outlined in this reference and
also discussed in this book. This procedure can be scaled up to massive proportions.
METHOD #9: -This is a little, oddball method that will transforms piperonal or benzaldehyde into a quasi-cyclic intermediate that will lead directly to MD-P2P or P2P ,
Over a 4 hour period 23g of powdered sodium ethoxide is added to a stirred solution of 50g piperonal (40g benzaldehyde) and 61 g bromoproprionate which is being chilled to below 0°C with a bath of ice and rock salt. After addition the solution is stirred for 12 hours at room temperature, then for an additional 6 hours at reflux. Ice water is added and the solution acidified with dilute acetic acid. The solution is extracted with ether, the ether washed with dilute sodium carbonate solution and dried through Na2S04. Distillation affords about 50% glycide ester intermediate (don't ask). 35g of this intermediate is refiuxed for 5 hours in 150mL 10% NaOH in ethanol. The ethanol is then removed by distillation, 500mL dH20 is added to the residue and acidified with HCI. This acidified solution is extracted with ether and the ether layer separated. Remember, this is not an MDA or amphetamine we are talking about so acidifying is not going to bring this into the water. The ether is removed by simple distillation to give a residual oil. This oil remains alone in its flask and about 0.2g of copper powder is added. A condenser is placed on the flask and the oil is heated to 180°C for 18 hours. The procedure claims reflux occurs but Strike is doubtful that reflux as we know it will happen. After 18 hours the MD-P2P or P2P is vacuum distilled directly from the flask it just spent the last 18 hours in to give ~ 45% yield from the intermediate.
Well that's the end of Strike's section on MD-P2P/P2P synthesis. But that's not all this book has on the subject. For the goods on advanced, cutting-edge recipes, including more P2P synths, just go and check out Rhodium's Chapter. You won't regret it!
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