This is my latests write-up for the buffered Performic reaction, to produce MDP2P ketone starting from Sassafras oil:
To help everybody out in this somewhat chaotic 2 year long discussion on one of the most interesting subjects for most of the readers, I offer you the following effusion :
A correct timeline of the-Hive's development of the following high yielding procedure is as follows:
Ritter first posted on the young Hive, end of '98 a short, buffered Performic acid oxidation, and he used
Na2CO3, Sodiumcarbonate as the buffer, and DCM as the solvent, then Beagle posted a similar procedure, and LaBTop posted a short one using
NaHCO3, sodiumbicarbonate (a.k.a. baking soda or sodiumhydrogencarbonate) and DCE, where he mentioned that DCM could be used in practice with similar yield. Then Gyrogearloose reproduced that one in practice also, on medium scale, 500 g MDP2P, then LaBTop wrote in april 2000 a very extensive writeup from past practice in the sticky threads, where he advised to use a new find from Osmium to produce the precursing Isosafrole with Aliquat phase transfer catalyst in 5 minutes after the heating reached the boiling point of safrole.
Then Baalchemist got enthousiastic and reproduced in practice LaBTops extensive practical MDP2P write-up, and made a few small alterations during the following year.
Ritter as the last one posted again, from practice,
saying there is no real difference between the use of sodiumbicarbonate and sodiumcarbonate as the buffer salt, and proved it with hard facts, so feel free to use either of these salts.
Now Rhodium included this procedure in short form in his latest write-up at his page.
LaBTop build all the latest info into his latest extensive write-up, with some important new additions for large scale production of MDP2P, which is mainly different compared to small or medium scale in producing performic acid portions only 1 hour before needed during the proces of adding it to the isosafrole/DCM, thus providing a constant supply of FRESH performic acid, no use of cooling when dripping the performic, and preheating the intermediate and the 15% H2SO4 before adding them together, which seems rather unimportant, but will increase yield substantially, if also a good professional vacuum source is used, yield percentages between 80 and 90% can be reached! Thanks go to Baalchemist for the last two.
And now LaBTop provides you with the latest extensive write-up, because he knows that 90% of the members will manage to majestically misunderstand these ultrashort writeups, because of the nature of this board, 90% non chemists and 10% chemists.
* * * * * * * * * * * * * * * * * * * * * * * * *
For small, medium and large scale MDP2P ketone entrepeneurs, I would strongly advise to pay full attention to the following write-up.
See first
Post 23325
(LaBTop: "Detailed Methods for Non-chemists Edit: IT'sDONE!", Methods Discourse), and
Post 184407
(Ritter: "Re: Medium scale performic", Methods Discourse) to get a grip on the Hive's historic development leading to the following newest procedures to produce MDP2P ketone.
After that I advise instead of the messy and time consuming Aliquat procedure mentioned there, to follow the most simple, next procedure, to convert your safrole, vacuum distilled from minimal 85% Asian or Brazilian sassafras oil, to vacuum distilled Isosafrole, and then the LT buffered Performic acid oxidation procedure to produce MDP2P from it :
Here's first the conversion from Safrole to Isosafrole done by LaBTop, Osmiums simple route was followed, yields are ~95% without vacuum, ~99% with vacuum :
No vacuum:
Weight 130 kg distilled safrole and add 2% = 2.6 kg KOH grinded flakes or pellets >98%.
KOH flakes are in some countries 85%, the 15% rest is water, check it on the label.
Then heat up. At 100 C the eventual 15% water will start evaporating, or, when 98% KOH was used, only a small amount of water will come off.
This removal of water is critical to the reaction, water present when refluxing will totally stop all isomerization.
Add more heat until all water is evaporated. Then at last connect a reflux condenser vertical on your vessel and continue heating until the safrole starts boiling, without vacuum, reflux will be constant at circa 232 C until boiling stops, that means it has nearly all converted to higher boiling Iso.
Do NOT crank up the heat then, but disconnect heating and let cool to roomtemperature. Reaction takes roughly 3 hours for non vacuum. You now have ~95% Isosafrole which you use for the MDP2P conversion step. You could distillate it now, to get >99% Isosafrole, but that seems to be no option for the ones who choose for this approach, they probably have no vacuum source, and ~5% safrole will not really interfere with the MDP2P step.
Under vacuum :
Same as above, only boil off eventual water first with a normal condenser attached, so you can check for any water present, when eventual water stops condensing in the condenser, change horizontal condenser to a vertical reflux condenser, and keep heating (far under 200 C, boiling temperature depends on vacuum source.)
Vac reflux should be done overnight because of lower temp, reactions at lower temps take longer.
Start a vacuum reaction f.e. at 21:00 hr and next morning its done, all boiling has stopped and safrole is nearly quantitatively converted to isosafrole.
Then just distillate the now isosafrole out of reaction flask, dont distill it completely dry though, because you can add a next batch safrole to that little bit leftover {isosafrole/safrole + all the used KOH} again for a next run.
Just add at the next run 50 gram of new KOH to refresh a little.
Trying to wash reaction in a sep funnel for purifying is terrible: results in a terrible emulsion that's nearly impossible to break up and ends up in alot of LONG labor and endproduct loss.
Distilling is a must for best result. Don't worry about leftover safrole with O's Isosafrole vacuum route, usually all converts.
However, if a small amount leftover safrole is present, f.e. because you have no vacuum, it wont screw up the performic route.
Notes:
No CaO at all, 98-99% KOH only. Make sure the KOH are roughly grind-up solids, (not a liquid mix with water), where you sieved all powdered KOH out for an easier workup at the end, use a nylon insect-screen.
Add 1-2% of safrole weight KOH flakes and away you go. Make sure that there is no H2O present anymore when you start the actual reflux!. At atmospheric it runs quicker because of higher temp, ~3 hours.
Bring it to a reflux and hold it till refluxing stops. Then you know it has converted to the isosafrole which has a higher boiling point. Vac reflux is much longer, but if you're into yield maximalization, then thats the way you want to go. ~98-99% yield.
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
Here's first Baalchemist's write-up for LaBTops modified performic as he posted it lately, then the second part is scaled to what LT/ would do. This can be scaled up or down according to your wishes, may they always come true :
Baalchemist:
There is no need to pre-stir for more than 5-10 mins. In a nutshell; With stirring in 2L flask add in this order> 250g Iso, 76.9g Baking soda, 770ml DCM, let stir 5-10 mins. Begin dripping in performic solution (232.2g 35% H2O2, 384.5g 86% Formic acid) over a period of a couple hours. It should reflux slightly during addition,but not a hard reflux.Solution will turn from yellow to orange,keep stirring 24 hours,no less. Allow to sit and remove DCM layer,and extract top layer with a small amt. DCM. Evap DCM extracts, add orange syrup to 2768g 15% H2SO4 (preheated to 80c). Stir for 2 hours, no more. Let cool, 2 layers will form. Remove bottom layer, and extract top layer with some DCM, add this to bottom layer. Evap off DCM and proceed to vac distill ketone. Yield 190g+ Ketone ~76% w/w.
============================
LaBTop's ultimate procedure :
(
If you prefer a small scale procedure, just change ALL kg in grams, and liters in milliliters !! ) PERFORMIC ISOSAFROLE GLYCOLIZATION STEP:
In a 1600 liter vessel ( f.e. a second hand stainless steel milktank ), add,
in this order (while heavy stirring anti-clockwise, (a must-have is a stirringmotor which can turn clock- and anti-clock wise (
1), otherwise too much oxigen and other gasses from the air will be mixed in; you will notice no vortex, but a 1 cm high and quite wide bubble on top instead) :
first: 125 kg Isosafrole, distilled.
then: 38.45 kg Baking Soda, NaHCO3, SodiumHydrogenCarbonate 98%.
then: 385 liter DCM, CH2Cl2, DichloroMethane a.k.a. MethyleneChloride, 98%.
Totals to 681.28
kg (weight of 1 liter DCM is NOT 1 kg!).
The purpose of the baking soda is to buffer the pH of the reaction in such a way that it doesn't become too acidic, in which case the intermediate monoformyl glycol may undergo oxidative cleavage (and thus lessen the yield). Running the reaction at a higher pH than usual makes more of the epoxide (and thus risk of tar forming) and less of the actual glycol and will decrease yield quite notible. (both will of course form the ketone with 15% H2SO4).
Attach a reflux condenser & addition-funnel/container with a dripping valve to the 1600 L vessel. All other openings must be frantically closed with proper tape, or teflon seals, or the reflux will not work accordingly. Leaks will make bad smells.
Allow this to stir fast anti-clockwise while you prepare the first 25 liter portion of the total amount of performic mixture :
192.5 kg 86% Formic acid (preferably made by diluting 99% Formic acid)
118 kg 35% H2O2 (hydrogen peroxide), as
FRESH as possible, don't use month's old stock.
This makes a total of 310.5 liter performic mixture.
To prevent such a big amount of performic mixture to get exothermic and too hot, while waiting all these many, many hours necessairy for dripping all of it in the Iso/BakingSoda/DCM mix :
Before adding parts of it to the 25 liter dripping container+drip-valve, only 25 (or even 10) liter portions are prepared each time
with strong mixing while adding the two ingredients together, and kept in a freezer at around zero degrees Celsius, until needed. Don't cool too deep, it will slow the reaction rate when added to the dripping container and dripped in the vessel.
It means that you make during ~half a day, under strong stirring, twelve 25 liter portions and one 10.5 liter portion performic mix, one portion each time, when the dripping container is 4/5 empty.
Or even better thirty 10 liter portions and one 10.5 liter portion.
That way your performic mix is of a constant FRESH nature, which increases end-yield.The performic acid portions should be prepared in advance (one hour, at room temp: the last 1/5 of the dripping container takes around 15 minutes to empty) to make sure the formic acid has reacted with the hydrogen peroxide (but don't let it stand overnight, or decomposition will occur).
Using DCM as the solvent is advantageous, as the reaction temperature can never exceed 40°C (bp of DCM), and by keeping the reaction temperature that low minimizes side reactions.
When the 25 liter dripping container is 4/5 empty, refill it from a 25 or 10 liter portion from the freezer.
(If your Formic acid isnt 86%, then down to 77% will work, compensate with more H2O2, based on % of formic acid available.)
The Formic acid is only acting as a solvent in this reaction, it does not react.
Remember, the less performic in the dripping container, the slower the dripping goes, so adjust accordingly, watch the reflux rate AND the temperature, when one of these go too fast or high, close the drip-valve a little, until both reflux and temp are stable again.
The technically gifted can make a pressure-equalized dripping container.
Slowly, add the performic-mix drop/or smallstream-wise over a 6 to 12 hour period under constant fast mixer speeds.
If you add it too fast, the reaction will boil over, and contaminate everything.
Use a glass or SS pipe with wide internal diameter, attached to the drip-valve, properly sealed where it enters the top of the 1600 liter vessel, extended just under the fluidlevel, to drip the performic-mix directly into the mass of the fluid, and so prevent too much oxigen or other gasses to interfere with the reaction.
It will start to reflux a little, adjust addition rate so it doesnt reflux too hard.
Once all performic is added, it will have turned from a yellow to an orangejuice color.
Keep
strongly stirring for 24 hrs total, no more, no less. (included dripping time). If you stir longer, sidereactions will kick in, lowering the end yield.
Note:
Remember, do NOT cool the whole reaction mix at all, let the reaction temperature be controlled by the dripping rate!
A good double check is the reflux rate, at no times, uncondensed vapours should leave the top of the reflux column! A bad smell indicates this.
End note. Turn off the stirrer after these 24 hours, allow the two layers to settle.
Separate off the bottom layer (DCM), and extract the remaining top residue-layer 2 times with a small amount of DCM, and add these to the already separated main DCM body.
Take this combined portion to a 22 liter Rotavap or conventional distillation machine, distill off the DCM in 15 liter portions, and collect all the resulting orange syrup portions in a heating vessel and heat it up carefully, meaning don't overheat it, to 80 Celsius. All eventual residual DCM, (if any), will evap off (about 5-minutes).
You will be left with 183 kg monoformyl glycol, nearly quantitative, 100% yield.
Remove the residual fluids from the above procedure for eventual recovery of solvents and clean the 1600 liter vessel with hot, slightly soapy water and then cold water.
SULFURIC ACID HYDROLISIS STEP:
After the vessel cleaning, pre-heat (
2) the 1600 liter vessel filled with 1384 kg 15% H2SO4 to 80 degrees Celsius.
NOTE:
Dilute 209.7
kg 99% H2SO4 with 1174.3 kg=liter distilled water for this amount of 15 % H2SO4.
Calculation of this amount:
15% / 99% = 0.1515% x 1384 kg total = 209.7
kg 99% H2SO4.
1384 kg 15% H2SO4 - 209.7 kg (99% H2SO4 + 1% water etc) = 1174.3 kg(=also liter) water.
209.7 kg (99% H2SO4 + 1% water etc) x 0.99= 207,6 kg 100% pure H2SO4/13.84= 15.00 % , always double check calculations. NO
liters used in calculation here!
End NOTEThen add all of the 80 Celsius preheated, distilled orange syrupy monoformyl glycol to the 80 Celsius hot 15 % H2SO4 portion in the 1600 liter vessel.
Connect a reflux-condenser on top of the 1600 liter vessel, and be sure there are no other open pipes or joints.
Keep the mixture between 75-80 Celsius for 2 hours,
NO longer, or again sidereactions will kick in.
DISTILLATION STEP:
Switch off the heat, and allow to cool back to room temperature.
Flooding the reaction mix with some extra H2O prior to extraction helps improve yield because it facilitates separation and fastens cooling down.
It will seperate into 2 layers, the bottomlayer is raw MDP2P ketone, which you tap off through the bottom ballvalve.
Extract remaining top watery layer with small amounts of DCM (2x, a few liters), tap them off, then add all these DCM portions to already tapped off raw ketone bottom layer. When your last tapped DCM has the same color as when you poured it in, there is no more raw ketone to extract.
Then wash and separate this raw ketone 2x with sufficient 5% Sodiumbicarbonate/H2O mixture (a few to 10 liters at a time), to neutralize all residual acid. Check pH first with pH paper, then start adding bicarb until pH stays constant, or even goes up, when adding a bit 5% NaHCO3 again. Then all acid is neutralized.
Now place 15 liter portions in a 22 liter Rotavap or newest distillation machine, and vacuum distill the MDP2P ketone which comes over between 155 and 165 Celsius and lower with the newest vacuumpump, it will begin to come over at circa 20 mBar vacuum and end at circa 1 mbar. A golden, honey coloured ketone will be obtained.
Clean the leftover tarry residue in your destillation flasks with acetone, a bit warm acetone will work faster.
Yield 76 % w/w, with a Rotavap, about 95 kg clean and pure MDP2P, ready for prefered method of amination.
Yield 85-90% with special distillation techniques, about 106.5 to 112.5 kg pure MDP2P.
Clean the leftover tarry residue in your destillation flasks with acetone, a bit warm acetone will work faster.
AND I DO NOT TELL THE OPPONENTS HERE WHAT THAT TECHNIQUE IS, and will be strongly pissed off when someone else does it openly here, we made their oppressive life already too easy.
We have PM's for that. And don't start PM'ing me to ask, only the few I trust to be able to do this can do that, the rest gets no answer. Yes, I'm a prick!
******************************************************************
NOTES:
1: Easy to construct with a stirrer shaft with a pulley on top, and the shaft leading through two ballbearings, one on top of the vessel, with an extra seal under it to seal the vessel airtight, and one at the bottom of the vessel, to keep the shaft+stirrer rigid. The motor has a pulley attached also, and the belt can then be attached to both pulleys normally, to stir clockwise, or in the form of a folded 8 to stir anti-clockwise. Motor must be tilted a little, to prevent the belt from scratching, when used in an 8 form.
You will be surprised what a 2-way stirrer motor costs, this is definitely cheaper to make yourself.
A 350 or 500 RPM motor+pulley and a SS-shaft+pulley with an outboardmotor SS-propellor attached is sufficient for all purposes. Instead of this expensive propellor you can design any other SS-mixerblade made by a machinist shop which will do the same job just as good, but will be much cheaper.
2: Heating such a 1600 liter vessel can be done in various ways, but the best is some sort of coiled-up hard-chromed copper pipe ( do NOT forget to hard-chrome the copper coils at a chroming-shop before ever using them in this kind of reactions, pure copper will solute in 15% sulferic acid and turn your solution to a nasty darkgreen color).
Place the coil, or coils, if your man-hole is too small for one big coil, at the bottom of the vessel and connect the ends outside the vessel to a convenient gear-pump and heating vessel, silicone-oil filled, and electrically heated, with a connection to a thermostate, triggered by a thermometer at the bottom of the 1600 liter vessel. Make the passages through the vessel top airtight with silicone glue!
This way you are sure to not form hotspots.
Another easy method is to attach electrical heated car motor-oilpan heating pads to the outside of the bottom and eventually the sides of the 1600 liter vessel.
This method can be combined with the above one, to speed up heating, do not forget to stirr maximal when using heatpads.
30 August 2001 by LaBTop.
WISDOMwillWIN
WISDOMwillWIN