10-09-00 03:01
No 58487
Has psychokitty won the OTC safrole contest? I think so, my fellow bees.
It's been almost two years since this problem first reared it's ugly head. Many suggestions were made but none seemed to offer any hope of going directly from eugenol to safrole in at least two easy steps. Some of the more notable methods offered can be found on Rhodium's page (most of them from psychokitty and Rev. Drone).
At first, it seemed like eugenol or isoeugenol would offer the best starting point to get to safrole via MVK (MethylVanillylKetone) by way of the wacker on eugenol or the performic on isoeugenol. SWIMM managed to isomerize eugenol to isoeugenol in a novel efficient way utilizing KOH and a PTC (details also on Rhodiums page) but found that application of the modified performic on isoeugenol only served to waste alot of chemicals (SWIMM got back practically all of his starting isoeugenol from the mix). At first, SWIMM assumed the hydrogen peroxide to be at fault but when it was used in another performic reaction using isos_frole as the starting material, all went well. So regarding this problem, SWIMM is still swimming in the theoretical pool looking for answers. Any suggestions, fellow bees?
Anyway, although there are patented proceedures for carrying out the performic on isoeugenol, the yields and excessive mess factor really discourage SWIMM from pursuing them as possible ways to MVK. As for the wacker, a CA reference which kitty has indicates that low yields (30%) were obtained when eugenol was reacted with O2 and PdCl2-CuCl2 under various conditions. The nitrite wacker DOES work on eugenol to get MVK (80%) as indicated in the original US patent, but neither kitty nor SWIMM has never tried it and to his knowledge no one else has either. Either way, the problem of ether cleavage was still present whether one used eugenol, isoeugenol, or MVK as a starting point to get to the 3,4-dihydroxyphenyl compound.
Sooooooo, when the OTC safrole contest was in effect, LOTS of us (LOTS!!)contributed many interesting and potentially useful articles detailing many interesting and potentially useful ways to cleave that methoxyl group on the three position of eugenol. Pyridine hydrochloride, HCl, HBr, HI (alone or with a PTC), KOH, NaOH, alkaline earth metals in either alcohol or polar-aprotic solvents, AlCl3, AlBr3, AlI3, iodotrimethylsilane, chlorotrimethylsilane and NaI, boron tribromide, boron tricholide, and even boron tiflouride etherate were suggested as potential cleaving agents. Yet none of the articles ever used eugenol, isoeugenol, or MVK as the subject of their proceedures. Way back when, Drone used his Crossfire account to search for possible leads. Even so, to this cat's knowledge, no one has found a published proceedure detailing the synthesis of allylpyrocatechol from eugenol, or even propenylpyrocatechol from isoeugenol, or 3,4-dihydroxyphenylacetone from MVK . . . until now.
Before the OTC safrole synthesis contest, our beloved Rhodium had created a thread detailing the synthesis of protocatechualdehyde from vanillin using AlCl3, pyridine and DCM as solvent. He claimed that from what he had read of the article, he could see no reason why the same reaction couldn't be applied to eugenol. Well, browsing through kitty's stack of papers the other day, kitty came across a copy of Rhodium's thread. Only two bees had responded to it, and then, not suprisingly, the subject was quietly forgotten and the thread closed.
Wanting to know what Rhodium meant by "from what I have read of the article" kitty decided to hop over to the local library where they keep copies of JOC, and take a look at the article itself.
Here is the important stuff, basically what Rhodium reported about two years ago:
Protocatechualdehyde. -- Anhydrous aluminum chloride (9.7 g., 0.0724 mole) was suspended in a solution of 10 g. (0.0658 mole of vanillin in 100 ml of methylene chloride in an apparatus protected from atmospheric moisture. While stirring briskly and cooling to maintain the temperature at 30-35 deg C, 22.9 g (0.290 mole) of pyridine was added slowly. The reaction was vigorous; the resulting clear, light orange solution of the reaction complex was heated to reflux (45 deg C) and maintained at that temperature while stirring for 24 hrs. The solution, which had darkened only slightly during the reflux period, was cooled to 25 deg C and the product hydrolyzed, while stirring and maintaining the temperature at 25-30 deg C, by the addition of dilute (15-20%) hydrochloric acid until the mixture was definitely acidic to Congo Red indicator. Of the two phases present at this time, the lower methylene chloride layer contained most of the unchanged vanillin and essentially no protocatechualdehye; the latter was dissolved in the aqueous phase. Evaporation of the methylene dichloride solution yielded 0.8 g of vanillin. Extraction of the aqueous phase with ether followed by evaporation of the ehter left 7.9 g (87%) of pale yellow crystals of protocatechualdehyde melting at 153-154 deg C.
Not bad considering that the reaction is mild, the reagents are cheap, readily available, unwatched (except maybe pyridine), and recyclable. No harmful byproducts (such as MeBr) are formed and the proceedure is simple enough for even the most pathetic of bees. And, of course, it's always good that the yields are high.
Buuuut, the article didn't mention the use of any alkenyl precursors (i.e., eugenol) but did offer hope for MVK since 3-methoxy-4-hydroxy-acetophenone was used in the reaction yielding 3,4-dihydroxyacetophenone in 70% yield.
So, your favorite kitty went looking for other hopeful cleaving agents. Some of the more notable are the boron trihalide-dimethylsulfide complexes which are stable and can be safely handled at room temperature. This might give some hope to Drone's initial plan to apply boron tribromide as an efficient reagent for ether cleavage of eugenol. Anyway, here's the reference: Tetrahedron Letters 1980, 21, 3731.
Feeling a little discouraged, kitty decided to search the CA volumes. This had been done over two years ago (quite thoroughly) using numerous keywords too numerous to mention here. None, however, yielded any terribly useful proceedures. This time, following Rhodium's lead, kitty searched the index of each year after 1962 using the keyword "protocatechualdehyde" . . . and in volume 60 was found something interesting:
CA vol. 60 2847f
3-Alkylpyrocatechols. Monsanto Chemical Co (by Robert G. Lange). Fr. 1,330,382 (Cl. C 07c), June 21, 1963; U.S. Appl. June 21, 1961; 23 pp. o-Hydroxyphenyl alkyl ethers, which can contain a halogen, a C1-4 alkyl, ALKENYL, or alkoxy group, NO2, SO3H or SH on the ring are hydrolyzed with acids in the presence of a tertiary amine and AlCl3 in an inert org. solvent to give the title compds. Anhyd. AlCl3 (146.8 g) is added to a mixt. of 152 vanillin and 1500 ml of CH2Cl2 under anhydrous conditions, 348.0 g of pyridine added at 30-5 deg C, the mixt. heated 24 hrs. at 44 deg C, cooled to 20 deg C, and hydrolyzed with 15-20% HCl (acid to Congo red), the aq. phase sepd, the aq. mixt. extd. with ether, and the ext. evapd. the give protocatechualdehyde (I), m. 153-4 deg C, 87% yield.
Many other compounds were made, but to kitty, the most interesting one of them all is "3,4-(HO)2C6H3CH2CH:CH2"; namely, allylpyrocatechol from eugenol.
Hah!!! Kitty's won the contest!!! Yip-yip-yippie for the kitty!!!
Actually, Rhodium won, but didn't know it as he never proved his method. Kitty guesses they can both share the $1000 that Strike now owes them ($500 for Rhodium, and from kitty's half, $250 going to Drone as they agreed that through their collaboration, they would split the money; good luck to you Drone, wherever you are).
Honorable mention should go to Cherrie Baby, as she (he?) once offered an article which used AlI3 made in situ from Al and I2 to hydrolyze the methoxyl group of vanillin to protocatechualdehyde in high yield. More than likely, based on the information found in this post, that reaction will probably work on eugenol as well.
NOW, although this method looks ridiculously promising, there is still the issue about yields. Somebee will have to get ahold of the original french patent (or the corresponding U.S. Patent, if there is one) in order to find out just how much allylpyrocatechol one gets from using this oh-so-wonderful-looking reaction.
Comments?
--PK
(Hive Elder/ Old Fart)
10-09-00 04:01
No 58501
Your like one of the James Brown(Hardest working man in showbiz) of the hive. Good work...
(Stonium's / Changer)
10-09-00 11:04
No 58562
My comment to all that is still the same: H2SO4.
Fuck the yield, eugenol is cheap and most bees would prefer a lower yielding OTC procedure over anhydrous compounds which can only be had from chemical suppliers. When you consider the amount of chems needed I'm even sure that the H2SO4 procedure will be much cheaper, even if it produced only 30% or so yields.
(Chief Bee)
10-09-00 16:34
No 58592
In the article I found, they stated that triethylamine worked fine as a substitute for pyridine, with just a slight reduction in yield. Triethylamine is MUCH cheaper than pyridine.
We just need someone who is willing to try this reaction out on eugenol (dirt cheap).
Osmium: H2SO4? For hydration of safrole to methylvanillyl ketone? But how do you plan to demethylate the aromatic ether?
http://rhodium.lycaeum.org
(Stonium's / Changer)
10-09-00 16:36
No 58594
No, for demethylation.
(Chief Bee)
10-09-00 16:43
No 58599
I have never seen H2SO4 being used for demethylations. Do you have any references on this subject? A trial run would be very easy if one had something to go on.
http://rhodium.lycaeum.org
(Stonium's / Changer)
10-10-00 15:12
No 58912
Yes I have seen it somewhere, but don't remember exactly where it was. Don't blame me, that was about five years ago
.I think it was in one of those Willgerodt refs where PAA was prepared from styrenes/acetophenones (seem to remember it was in JACS or JOC 1947or 48? maybe, can't search it myself right now). During the final acid reflux (50% H2SO4?) of the phenylthioacetomorpholide intermediaries those researchers encountered demethylation of methoxies, p-MeO being cleaved the easiest and m-MeO was hardest to hydrolyse.
Somebody dump some eugenol or vanillin into 50-70% H2SO4, reflux the shit out of it for 12-24 hours and test the resulting tar with TLC/IR/GC or whatever is available.
(Moderator)
10-10-00 19:32
No 58954
Dr. Beilstein says:
6-MeO-2-acetyl-naphtaline to 6-OH-Naphtyl-2-acetic acid:
Bull.Soc.Chim.Fr. 962, 963 1955 (Ormancey, Horeau)
J.Amer.Chem.Soc. 70, 2843, 2845, 2846 1948 (Jones et al)
Reagents: sulfur, morpholine, 140°C, heating the product mixture with acetic acid / dil. HCl.
(Stranger)
10-10-00 22:54
No 59039
Sorry, bubba, but I have a JACS article that specifically lists safrole, isosafrole, eugenol, isoeugenol and a few others as being energetically polymerized by concentrated H2SO4 at 0 deg C. As for 50% H2SO4, I really doubt it will work. You would be dealing with problems of hydrolysis at the allyl side chain, which although might be somewhat good, doesn't allow much room for the average bee to figure out what they've got in their mix that's good apart from that which is bad.
Besides, that JOC article I mentioned above talks about the degree to which 3-methoxy-4-hydroxy compounds are resistant to hydrolysis. Boiling HBr, HCl, HI, AlCl3 in benzene, ad nauseum, had no effect on vanillin whatsoever, which leads me to believe that MVK never had a chance in hell of being hydrolyzed by these routes. The AlCl3, pyridine (or triethylamine), DCM route is very specific for vanillyl-compounds. m-methoxy-this, dimethoxy-that, and methylenedioxy-blah, blah, blah, were unaffected by the reaction.
Anyway, I don't know what everyone is complaining about. To get from just about anything to honey, you have to pretty much at least have some contact with a supply company. This OTC problem is not as big an obstacle as you all think. Clove oil is OTC enough.
Rest assurred, this method is going to get tried. I've waited too long for this.
Eugenol is the future, my friends, in a world deprived of sassafras oil. Remember that.
--PK
(Stonium's / Changer)
10-10-00 23:31
No 59056
You are right that probably no useful precursor can be isolated from a boiled eugenol or vanillin and H2SO4 solution, but my whole point is trying to find a way to make this demethylation easier. I have worked with vanillin before and most of you wouldn't believe how easily it is oxidised in solution. MVK is a whole different story though! All I want is a proof that the demethylation with H2SO4 works.
Lili: thanks, but I'm pretty sure that the procedure from the ref. used H2SO4. Can you look up some refs in Beilstein from around those years detailing acetophenone ---> PAA? And a synth for 4-MeO-PAA? I think both were in that ref.
(Moderator)
10-11-00 14:29
No 59276
I did that, but that was the only source I found.
(I searched for all reactions of ring methoxy substituted acetophenones to phenylacetic acids)
(Stranger)
10-13-00 05:52
No 59686
Could somebody please get the original article from which I think Cherrie Baby got her method of vanillin ether cleavage? The reference is Synthesis 1985, (4) 437-9 wherein is detailed the AlI3 (made in situ, I think) ether cleavage of many phenyl ether compounds with alkyl side chains. I would like a little more information about the mechanism to see whether it can be applied to eugenol or isoeugenol ether cleavage.
I still don't even know if the article Cherrie Baby posted is the same one listed in the reference above (found in CA, BTW). I tried to get to Cherrie Baby's original post in the "OTC Safrole contest, Part II" thread located somewhere in the original Hive database, but for some reason it just doesn't seem to exist anymore.
A quick response would be appreciated.
Thanks.
--PK
(Moderator)
10-17-00 12:04
No 60836
S. Andersson, Synthesis 437, 1985:
Reflux aluminium powder with iodine in benzene or cyclohexane for 90 min to produce AlI3. Add equimolar amounts of phenolether, 0.25 equivalents of the phase transfer catalyst tetrabutylammonium iodide (chloride may also work), reflux for 20 min, and isolate the (poly-)phenol.
Representative substrates and yields from 13 examples given: 4-OH-3-MeO-toluene (98%), 4-OH-3-MeO-benzaldehyde (88%), 3,4-methylendioxy-benzaldehyde (84%), MeO-benzene (100%).
Has Lilienthal won the OTC safrole contest? I think so, my fellow bees.
(Stranger)
10-19-00 14:34
No 61450
speculation speculation speculation
One needs to do the reactions to see how difficult they are. I have performed most of them often and as yet have had no success. The unsaturated sidechain seems to be the problem. In analgous reactions (i have several refences of no interest really) these types of compounds are always difficult to demethylate, producing low yeilds and/or very difficult to extract from the mess products. The py/alcl3 method produces tar when used on eugenol, of course I am sure there is something useful in the tar but not much fun when you want to do 100g+. The vacuum distil on the tar resulted ina slow climb in temp over the course of the distil-conclusion-many compounds present. Also most of these references are performed on quanities that frankly would be quite useless for the type of industries authors on this site are engaged in. Have you ever tried to suspend 100+g of AlCl3(anhydrous) in anything, not much fun.
I am working on the AlI3 method currently and if this proves useful I will let all know when i have it nutted out (give me a couple of weeks). Importantly you have to use a catalytic amount of PTC with the reaction, the reference specifies an iodine based quat but i will try with some Cl based ones also, shouldn't really matter as it is only in catalytic amounts. The whole process will hopefully be very very OTC, ie aluminum foil, iodine (extract from kelp if you are really paranoid), PTC, aromatic solvent blah blah vlah la blah blah.
Now a question as i am rather new at the whole cladestine speak thing, what is this TS II everyone keeps referring to, and is there a TS I.
Final question, does anyone have any material data on allylpyrocatechol so i can confirm my observations, ie mp, bp, azeotropes, does it sublime, IR data, coupling constants, your help would be appreciated.
blue always
except for at the start
(Moderator)
10-19-00 18:51
No 61486
TS 1 + TS 2: Total Synthesis (of MDMA) by Strike
3,4-dihydroxy-allyl-benzene:
mp: 46 ... 48.5°C, cryst. solvents: benzene / petroleum, ether, light petroleum
bp: 123 - 124 (1 torr), 123 - 125 (1 - 2 torr), 156 - 158 (16 torr), 155 - 157 (13 torr), 147 - 149 (10 torr), 141 - 144 (7 torr), 98 - 102 (5 torr), 139 (4 torr), 120 - 123 (2 torr)
solubility: 25 g/l in H2O at 26°C
(Moderator)
10-19-00 19:49
No 61500
Never attribute to malice that which can be adequately explained by stupidity.
(Stranger / Eraser)
10-20-00 05:49
No 61688
SWIM is also interested in performing the Al, I2, PTC reaction as SWIM has all of the materials needed to get it done. However, Lil has not indicated how much solvent to use in the reaction. Also, what is the mechanism at work here? Is an intermediate complex formed between the phenolether and the AlI2? Is this then hydrolyzed in some manner? What SPECIFIC role does the PTC play in this reaction, in terms of it's contribution?
A quick response would be greatly appreciated.
--PK
(Stranger)
10-20-00 07:20
No 61703
the solvent the article used was mainly cyclohexane but some trials used benzene. I have a completed trial at present that just requires working-up, it seems alright though, no tar at least. i will post the results in 12 or so hours. if i recall they used 120ml of solvent for what was equivalent to 8.5g of eugenol. I used toluene.
Now mechanisically, the paper mentioned better access to the al-ether complex for the Iodide ions through use of the phase transfer catalyst.
From what i can gather the AlI3 complexes with the methyl ether, this is a very extothermic reaction. This in theory with time liberates the less stable carbocation (the methyl (CH3-), ie the complex want to hold onto the stronger one) the trick is in all of this is always breaking this Al-goodbit complex. None of the papers ever really speak about but the hydrolysis of the complex but it usually requires at least 2M HCl warmed on a steam bath for at least an hour, otherwise you get some purply very crystalline salt when losing all solvent. Anyway I will read the paper again when i get back to the lab, post a more comprehensible explanation and let you know how my trial went. if you are desperate to start, the production of the suspension of AlI3 takes a few hours so you can do that bit, ie mix the iodine, al powder/finelycut foil in the cyclohexane and/or beneze and/or equivalent and let it stir until the red iodine tinge has gone, i don't know how long it takes because I let mine stir overnight, he paper claims 2hr but you know what papers are like.
.............................Anyway more later
ps i understand urgency
blue always
except for at the start
(Stranger)
10-22-00 17:46
No 62408
I'm with Semtex on that call "Go Kitty Go!"
(Stranger)
10-23-00 15:03
No 62628
It seemed to all go very well, I didn't take too much care with it and i have a more precise trial running at present. A big problem was filtering out the Al-sludge at the end, it just seemed to reside in everything and would immediately clog up any filtering system, I even tried running a vac pump through the side arm flask at 29in/hg and this didn't pull through. the NMR on the product is being run currently, i will let you know when i can confirm success with a complete write up for your barn. A problem with the technique is definitely the amount of iodine required. To demethylate 500g of eugenol requires 1kg of Iodine, so i guess we need to order a 10kg bag from somewhere, any ideas???, maybe i should move to the dead sea.
A further note, has anyone perfomed the methylene bridging reaction on 4-allyl catechol, any pointers? It reads quite straight forward, but then they all do don't they, especialy this girl i was seing once, i thought she really loved me.......................
blue always
except for at the start
(Newbee)
10-25-00 02:09
No 63055
You can make your own I2 from VERY OTC chemicals (sulfuric acid, NaI, and potassium permanganate are heated together, diluted with water and the I2 extracted with solvent; haven't tried it though).
Still don't understand what you are saying about the hydrolysis. Are you adding dilute HCl or does the use of a PTC eliminate the need for this? And at what point does the aluminum precipitate? After the reflux step using the PTC?
Anyway, to get around the aluminum filtration problem, all you have to do is add dilute HCl whenever it's convenient. This forms aluminum chloride which will fall into the lower aqueous layer. The goods will be in the top solvent layer (toluene was a very good choice, BTW). Dry, evaporate, and see what you get. If the stuff is crystalline, it's a good bet that it's what we want. If it's an oil, just wait. It will probably crystallize soon. If you have ferric chloride, add some to the suspected allypyrocatechol in alcoholic solution. This should form a green color reaction. Otherwise, check the melting point. You don't have to use a small itty-bitty sample to do this (which would be hasslesome). Put some (or all of it, if you wish) in a glass container heated slowly in an oil bath. If the stuff all starts to melt somewhere in the 48-50 deg C area, you might be good to go.
Keep up the good work. SWIM will start up his trials soon.
--PK
(Stranger)
10-27-00 07:24
No 63799
After adding the combination of eugenol/PTC/bitofsolvent dropwise to the stirring but cold AlI3 suspension the mixture was refluxed for about 30minutes, then cooled to about 5C with lots of stirring to stop the suspension settling, then the entire mix was poured into 2M HCl (i was doing a 19.2g eugenol trial and dumped the whole thing into 200ml acid), vigorous stirring was applied for a five minutes then the mixture left for the layers to seperate, three layers formed, a bubbling water/grey suspension layer on the bottom, the bubbles were dragging some of the suspension to the top were they would promtly fall back down. The top layer was the cyclohexane (oh i changed solvents for this trial) and inbetween the two layers was a black crystalline mass with specks of red in it. The bubbling continued for some thirty minutes (it was not solvent boiling off as the mix was only warm to touch and anyway it was generated in the lower water layer not the solvent layer), i don't think it was Me-I (bp?) so what was the mystery gas???
Anyway after the gas had stopped i filtered off the mass in the interface, separated the layers and removed the solvent, the cyclohexane had a small mass(~2g) of black gooey tar dissolved in it, the water when evporated on a water bath (my rot evap is fucked) produced a white crystalline mass on top of the water as the water evaporated (ie allylpyrocatechol is sparingly sol?, the water/air interface is cold enough for it to crystallise, i am clutching at straws?), I then went home because it was late and i was tired and had an exhibition to go to, then i went to this bar and meet this girl that i had spoken to a few times, she was nice, we chatted, she bought me a drink, we went to another bar, we played with each others hands, we kissed, we went back to her house, oh yes the workup, when I got back in in the morning the white crystalline mass had turned black and tarry and the whole thing looked shot. Whilst doing a vacuum distil I got hungup on the IR and forgot about it, it was rather a sorry mess when i got back there, but i could see the presence of some of those purpley crystals which i think are the Al-goodbit complex. Anyway will start again tommorrow after that fuckup.
Also though, i ran a trial using iodine and aluminium foil (cut in thin slivers) instead of the 5micron aluminum powder i was using. the foil worked fine.
Has anyone tried using HI to cleave this bastard, you could form it insitu from the insitu created AlI3 by keeping the mix cool (ie don't go to reflux) and dropping water in.
Anyway will try again another day, i need to do some legit work next week, don't have any safrole at present so I have to wait for the RuCl3 and catalyic converter trial on the benzo wacker, good luck mr/mrs/miss/ms/dr/prof/rev/mc/mp kitty-man, crack it next week so i can move on to the methylene bridge reaction, i am bored of the cleavage shit.
Sorry just re-read your post there are some problems with the ease in which you describe the workup, firstly the organic layer also has residual iodine in it, secondly the allypyrocatechol has some solubility in water.
Basically what happens when you make the AlI3 is that you mix the iodine/al/solvent at room temp the whole thing goes bright purple, you then reflux and stir for a couple of hours, the solution goes clear with a finely dispersed grey suspension wizzing around, next you need to cool it in order to add the eugenol, cooling seems to decompose some of Ali3 and the solution turns reddy again, then when you begin to add the eugenol the whole things turns dirty orange but for some reasom the iodine after hydrolysis wants to stay in the organic layer (is this normal?), giving it a red colour.
A further point, sorry this is a very long post, someone gave me a demethylation method where the aryl ether is dropped into a ALCl3/NaCl (5:) melt at about 150C, left for about three minutes then dumped into icewater, its all done under N2, anyone had any experience with this reaction, it sure sounds quick and easy. Yeah you say a quick and easy way to make tar.
OK I am going now
blue always
except for at the start
(Stonium's / Changer)
10-27-00 15:15
No 63907
I wouldn't expect the phenol to be very soluble in cyclohexane. That black shit layer could be your product.
(Moderator)
10-27-00 18:36
No 63969
The mystery gas is H2 from the reaction of excess Al with HCl. I also think that the product is unsoluble in cyclohexane. I would extract the product from an aqueous phase 3 - 4 x with ethyl acetate. Additionally I would use Al foil instead of powder and no HCl. The product is possibly very sensitive to strong bases and metal ions / H+.
> the iodine after hydrolysis wants to stay in the organic layer (is this normal?)
Yes
(Stranger)
10-28-00 05:38
No 64193
Thanks for the input people, i will do the reaction again, hydrolyse half with water, see what products i get, if they are similar i will extract the black crud with 4x Ethyl acetate and see what i get, if they are not similar i will hydrolyse the remainder with the normal 2M HCl and still do the extractions.
Does anyone know what color the pyrocatechol is supposed to be?
Also i have in my possesion 15kg of anhydrous AlCl3, can anyone suggest something to do with it???It was free so i don't mind wasting it.
blue always
except for at the start
(Hive Addict)
10-29-00 02:11
No 64472
What about this, looks easy enough to try :
"Eugenol and vanillin were both demethylated by cooking with either 5% NaOH or 5% Na2SO4, 1% NaHCO3 and H2O. The degree of demethylation is not given in the abstract but it is in the paper which luckily is in English if one cares to look it up. The reaction does proceed slowly"
Hayashi and Namura, Nippon Mokuzai Gakkaishi 13, 24-27 (1967)
Chemical Abstracts 67, 4500z (1967)
--psyloxy--
(Hive Bee)
10-29-00 04:21
No 64525
"Eugenol and vanillin were both demethylated by cooking with either 5% NaOH or 5%
There are lots of ways to perform the demethylation. The problem is that most of them will also either isomerize the double bond to form the isosafrole precursor or add halogen to the double bond. Cooking with NaOH for long enough to demethylate should also isomerize the double bond.
(Hive Addict)
10-29-00 09:45
No 64633
>Cooking with NaOH for long enough to demethylate should also isomerize the double bond.
Nothing bad with that IMO. Performic rulez!
--psyloxy--
(Stranger)
10-30-00 13:55
No 64934
Yields for demethylation via a caustic route have always been ordinary, which in this case would be tolerable as eugenol is cheap and in plentiful supply. the real problem is that via the caustic route you end up with re-arrangements. Any trained chemist writing the mechanism on paper can see the potential for nucleophillic attack by not only the hydroxyl but by the liberated methoxyl groups. The resultant re-arranged products are very difficult to separate from the product you want as they are often isomers or chemically similar.
Face it, if it was as easy as boiling up some eugenol with NaOH to faciliate a servicable demethylation reaction then why would their be so many more exotic patented methods published. Why would industry waste money on anhydrous AlCl3 methods. The reality is this is not an easy reaction and no method currently seems to be fool proof enough for scaling, that is why there is so much discussion regarding this issue
Has anyone read the demethylation route via AlCl3 and pyridine. The problem with this method is the workup needs to be adjusted. I have tried it a couple of times and always gotten muck, probably because of the Al/H+ issue in the workup. Are their any organometallic/inorganic chemists out there who could enlighten us on the nature of olefin-Al complexes, how strong are they, how do they decompose etc. i know I could look it up but at present I simply don't have the time as my mom is quite ill. Any help would be appreciated.
One more thing does anyone have any material data on the demethylated/isomerised eugenol product.
Thanking you all in advance for your help
bye bye buy buy
blue always
except for at the start
(Stranger)
11-04-00 07:22
No 66534
The product from the fabled demethylation of eugenol seems not to have too much attention in the literature. Some time ago someone posted some data on this compound, the mp, bp and some solubilities, thanks very much for this data. Now what i really want to know about is it's stability, in air and light. Seems to me that whenever I leave the unworked-up product for any period of time the whole sheebang goes from looking rather clean and discrete to looking shitty, any ideas(?), maybe I should be less lazy and do the reaction through to completion.
Anyway lets not drop the ball on this method, eventually a servicable method will appear, so keep vomiting up your ideas one and all.
blue always
except for at the start
(Stonium's / Changer)
11-04-00 21:54
No 66639
Most phenols are easily discolored by oxidation. Just because it changed appearance doesn't mean it's unusable. Store dark and air tight.
(Hive Bee)
11-05-00 05:27
No 66707
1,4 and 1,2-diphenols are readily oxidized to the corresponding quinones. Keep it away from air.
(Stranger)
11-05-00 08:47
No 66753
OK so it's easily oxidised, any idea how easily. benzoquinone hangs around for a while in light and air, but that is a 1,4, would a 1,2 oxidise far more readily?
Pyrex is opaque to UV so if we were to work under N2 in pyrex we shouldn't have any problems should we (unless of course visible light is a problem??)
I will now retry the pyridine/AlCl3 method under n2 to see if the results improve, will keep posted.
Thanks for the advice
blue always
except for at the start
(Newbee)
11-10-00 23:58
No 68536
Well I have a solution of 4-allyl catechol in ethyl acetate, great huh.
How it was done, i will give proportions
1mol Al turnings (or foil or powder all work well, powder is the quickest closely followed by foil then turnings a distant third) is combind with 1.5mol (note the excess of Al) of Iodine in 1000mL of cyclohexane (exchange solvent as needed but not ether!!!!!). This mix is stirred under reflux until the red colour has turned to a grey (about 1.5hrs with powder, 2-3 with foil, 4+ with turnngs). At this point the heat is turned off and the AlI3 in solvent allowed to cool to room tempeature with stirring. in a dropping funnel, eugenol (1mol), tetra n-butyl ammonium iodide(1/360 mol) and a little cyclohexane are combined. This is slowly dripped into the AlI3/cyclohexane with vigourous stirring and inert gas sheilding. After all the eugenol has been added the solutiuon is brought to reflux (it is a tan coloured slurry at this point, but upon refluxing turns less viscous) for 1 hour. The solution is then cooled in an ice bath and hydrolysed with ~600mL of water, slowly.
The resultant mix is filtered under nitrogen and the solid collected immersed in ethyl acetate, this is swirled for a couple of minutes, then filtered. The ethyl aceate is seperated from the water (collected through the filtration) and removed and what you have left is a tan coloured solid with a charactistic 'smoke' smell and a melting point 45-51, althought this range could be tightened by recrystalisation or vac distillation with hot water in the condenser.
A few notes
-If you are quick then maybe you can not bother with the inert atmoshpere in the workup, however the filtering takes a long time (don't even consider using gravity) beacause the Al is very finely divided and clogs up the filter paper.
-it seems the reactant ratios are critical so get them right.
-The workup is a shit for large quantities, any suggested impovements would be appreciated. Note particularily that the next step (adding the methylene bridge) requires the catechol to be dissolved in DMF, so we need to figure out a way to end up with the 4-allyl catechol in DMF.
looking forward to your suggestions.
blue always
except for at the start
(Chief Bee)
11-13-00 15:32
No 69032
What kind of yield did you get?
http://rhodium.lycaeum.org
(Newbee)
11-14-00 12:45
No 69244
The stuff was black and hard when i got to it the next morning, this reaction is really iritating me, the workup is simply not scaleable. have an idea though for using some hydroquinone in the AlCl3 demethylation to try to halt the black tar factor from fucking everything up, will post results. but for the record don't bother as yet with the previously mentioned AlI3 method, unless you are of course trying to help me develop it.
But some good news, well i think it is good news, let me know what you think, vanillin is demethylated by the AlCl3/Ch2Cl2/pyridine method set out by Lange in 1962 (can't remember the journal but the reference is mentioned earlier in this string, 87% yield). Good thing is the method is set out for vanillin and we are not making assumptions by adjusting the method for eugenol.
The demethylated protocatechualdehyde is then methylated to piperonal using the reported (yes they did it on actual protochatualdehyde, 90% yield) method of Cark et al, the reaction takes 1hr, no inert atmoshpere, just mix your protocatecualdhyde with KF add DCM, reflux at 115 for 1hr and extract.
Now the thing question is---- is piperonal a known, ie a known, ie ie ie a fucking known, as has anyone actually performed the reaction type known (sorry for the dissenting attitude but there is far too much speculation masked as reality around), precursor to MDP2P via the knovenagel reaction with nitroethane and reduction with Fe and HCl or Al etc, if so please post the entire method somebody or some weblink to it (I have used the search engine here and looked on Rhodium if it is there i am blind).
Once I am convinced that piperonal is a useful precursor to aspire to instead of safrol from eugenol then I will go ahead and try the above mentioned synth as I have all the neccessary bits and post my results. Again apologies for the threatening tone, not meaning to get aggressive, it is just late and the batteries on my blow up wife are spent, sick of this oppresive governmental regime I live under and woe-est-me-to-the-enth-degree
Anyway hopefully someone/anyone/please someone/please anyone/ hey you over there yes you please post, will post
But for now good night
blue always
except for at the start
(Chief Bee)
11-14-00 21:28
No 69305
Look in Pihkal #100. Shulgin condenses piperonal with nitroethane and reduces the nitropropene with Fe/AcOH to MDP2P. It works.
If you use CH2Cl2 and K2CO3 in DMSO as in TSII for your methylenation of protocatechualdehyde, it will be a lot cheaper and less toxic than using KF et al.
http://rhodium.lycaeum.org
(Newbee)
11-15-00 00:28
No 69337
thank-you for your reply Mr/Ms Rhodium,
In my country it is very difficult to obtain TSII, I brought back shulgins book when i went to the US on a conference so i can access them, if it is not too much trouble could you please post or email me the DMSO/K2CO3 method, just the basics. i am beginning the vanillin route today now that i know the piperonal method will be effective, the demethylation takes 24hrs, will post results as per usual.
just a note do you think polar aprotic solvents would interact with AlCl3 more stongly than the aryl ether (ie would they complex preferrentially over the ether). if not then the demethylation can be performed in DMSO/DMF and then the demethylated product can be rrun straight into the methylene bridging reation without having to strip off solvent under n2/out of light etc. Just a thought, would appreciate input, will look in Feiser. But i will do the method straight out of the paper first but our goal is to design a synth that can be easily perfomed at home with OTC chemicals, then i get the $1000, right, I think it will end up being split eighteen ways perhaps.
Back to the lab
Bliss is a disinterested supervisor
blue always
except for at the start
(Newbee)
11-16-00 16:49
No 69608
The double bond in eugenol (the one on the side chain) is electron rich, much more so than the oxygen on the arlly methoxy ether. hence any electrophile one sends to establish contact with the methoxy/ether oxygem will invariably get side tracked to the side chain olefin. Thus unless one converts/deprotects the methoxy ether it will be difficult to cleave it.
it is amazing to see how simple it is suspend AlCl3 in vanillin compared to how difficult it is to suspend it in eugenol.
Let us focus our attentions on the deprotection of the methoxy, any ideas?????????
Again, in the words of Madonna, let's not drop the ball.
blue always
except for at the start
(Kitty-KrZ)
11-17-00 05:34
No 69757
Do you mean to imply that the allylpyrocatechol which you have isolated about twice wasn't allylpyrocatechol to begin with? Or does it simply decompose readily before you have a chance to use it?
Why don't you simply go the route of biphasic DCM/PTC/catechol compound/NaOH/dH20 to effect the required methyleneation? It would be easier, less hasslesome than the DMF/KF/DCM reaction which requires anhydrous conditions. Information on how to conduct this reaction under pressure are detailed on Rhodium's page. But I do have a reference to a Tettrahedron Letters article wherein the reaction is performed at room temperature. SWIM has performed the DMSO methyleneation on catechol to get benzodioxole in about 60-65% yields -- being sloppy, that is. Although it was very VERY easy, I doubt this method is suitable for allylpyrocatechol or protocatechualdehyde.
I recently saw a chemistry paper online detailing the cleavage of aryl methyl ethers using only pyridine hydrochloride and the ether nuked at low temperatures in the microwave (conventional) for about 16 minutes. Yields were high and this was performed in a solvent-free environment. Might be worth a try.
Another suggestion is to find a way to form MVK first, and then go on to the cleaved product. This might avoid the decomposition product that you seem to be getting over a short period of time. Any nitrite wacker fans out there willing to try eugenol in your reactions?
I'll get you that reference soon.
--PK
(Kitty-KrZ)
11-17-00 06:23
No 69763
Here is that online reference to that microwave demethylation proceedure that I referred to earlier:
http://www.rsc.org/CFmuscat/intermediate
--PK
(Newbee)
11-20-00 11:27
No 69918
Thanks for the comments wack-cat/nutter-pussy/schitz-mog, they are appreciated, I have just converted vanillin in piperonal and you would not believe how easy it went, for the safrolly-challenged like myself i think this makes a more realistic route than from eugenol, vanillin is also much cheaper than eugenol (~$555.00 for a 25kg bag of food grade) and you can get it pure so no need to distil. i used the alcl3/pyridine method. I had tried this method on eugenol often and always had difficulty (difficulty as in abject failures)with it, however with vanillin it is a beautiful, simple, extremely scalable process. i even got back the pyridine in the end so you don't need to find buckets of this chemical. My yield was 70% but the paper i followed claims 87% so i might get better at it) A side note does anyone know why pyridine is watched?
Anyhow the KF/DCM(and/or DBrM)/DMF method for the methylation is simple, quick (a 1hr reflux) and scalable.
Anyway I have not taken the piperonal through to the amine yet so this might still be my undoing, although all reports lead me to believe mr shulgin can be trusted, so i am not too concerned. I am doing a 1000g run of the vanillin later next week, i will post my successes/lack of successes up.
And lastly in relation to the demethylation product from eugenol, the difficulty is it is soluble in everything, this combined with the fact that you have all the Alsalt fine powder around makes for any scaling quite difficult. I am however going to try to hydrolyse it next time using 50ª, it might be more soluble in this phase, but who knows.
Anyway the snows falling and I am up for a board, the lab can wait for a few days.
blue always
except for at the start
(Kitty-KrZ)
11-21-00 05:39
No 70022
This is good news and congratulations!!!
As for the issue of going from piperonal to either the safrole or isosafrole or the ketone, there are numerous ways to do it. You could use a grignard reaction of Mg-ethylbromide in THF to get the 1-3,4-MD-phenylpropanol and then dehydrate it with potassium bisulfate to get isosafrole. Or you can condense piperonal with nitroethane to get the intermediate nitroalkene, which can be reduced to the ketone any number of ways (dissolving Fe supposedly being the best and cheapest of the lot).
There are a few untested but very compelling ways to get from the aldehyde to the 1-alkene and, get this, to the epoxide (go figure) that are published in several references that I have. If someone is willing to get the articles, these may in fact be quite promising. One article that I have FOR SURE lists piperonal as the starting material, which is then reacted to form a silyl intermediate, which upon hydrolysis, forms safrole. It looks easy enough, although the yields were somewhere around 48%. But this is a problem at the hydrolysis phase as the intermediate silyl compound is formed in about 88%yield. I've never bothered to mention these articles before as I never believed vanillin would be the way to go, but after your last few posts, I've begun to rethink the possibilities.
As for the AlI3 method, isn't this easier than AlCl3/pyridine? More OTC, I mean? The reason that I ask is because of it's applicability to vanillin ether hydrolysis, which I believe, yields protocatechualdehyde in about 90% or above.
More later.
BTW, pyridine was once heavily watched because of it's use in converting phenylacetic acid into phenylacetone. Phenylacetic acid reacted with acetic anhydride catalyzed by pyridine yields P2P. However, this reaction scheme hasn't been popular since the late 80's. I doubt pyridine is still much of a hot item.
For those interested, I finally got the French Patent. Details saved for later.
--PK
(Moderator)
11-21-00 12:53
No 70113
Some thoughts on the AlI3 method:
- Excess I2 should possibly be avoided if you have olefinic double bonds in your molecule.
- Al salts / excess Al can be brought into aqueous solution with a small amount of HCl or H2SO4.
- The polyphenolic compounds can be extracted from this solution with three to four ethyl acetate extractions.
- Why not try to substitute I2 with Br2, which is much cheaper on a molar base.
(Newbee)
11-22-00 00:32
No 70182
Thanks l-man, good info, I am on the pyridine HCl/microwave trail at present but will come back to the AlI3 method if this also proves frustrating (am worried about adding Cl across the olefin as well as demethylating with the pyridineHCl/microwave method) any thoughts anyone?
Also piperonal steam distills doesn't it???
How many vietnam vets does it take to change a light bulb
you wouldn't know you weren't there
disclaimer-that joke was not intended to offend any former vietnam veterans, if any were perhaps offended i am very sorry
blue always
except for at the start
(Newbee)
11-22-00 02:08
No 70196
Does anyone have any great ideas about how to extract piperonal from DMF without the obv. vac. distill and/or steam distill, the next step would be the knove. condensation with nitroethane if that helps.
tanks guys, you guys rock(et), get it, no, oh well
the punmaster
blue always
except for at the start
(Hive Bee)
11-22-00 03:18
No 70213
Extraction of piperonal (my guess): Dilute DMF solution with water, extract with suitable solvent, separate, wash, then distill off solvent to get the goods. If the piperonal needs cleaning, then stir solvent layer with saturated bisulfite solution, filter crystals, wash, dry, break up salt with dilute HCl, extract with solvent, and then distill off solvent to get goods.
According to the french patent, there is no stated yields for the eugenol >> allylpyrocatechol conversion. Only in example 27 "avec un bon rendement". "Rendement" seems to mean "yields". Anyone know what "bon" means? Good? Either way, pretty vague.
As for that Tetrahedron Letters article detailing the PTC Williamson Synthesis, here's the reference: 1975, v.40, pp.3489.
As for that synthesis of safrole from piperonal:
JOC 1982, 47, 1983-1984. "[B-(Trimethylsilyl)ethyl]lithium:
--PK
(Stranger)
11-23-00 07:05
No 70421
Here's another angle on the Eugenol swing donated by the Wizard.
This is a bit of cool cat chemistry if I do say so. May you notice pretty much all of the chems can be easily obtained. Hydriodic acid can be made, check Rhod's site plus old message board for some kick ass OTC methods.
Also the lustful lack of any serious work up until the very end (nice huh).
DISCLAIMER : THE FOLLOWING INFORMATION IS FOR INFORMATIONAL PURPOSES OR ACADEMIC STUDY ONLY. CHECK YOUR LOCAL, STATE AND FEDERAL LAWS, AND PROCURE THE NECESSARY PERMITS BEFORE UNDERTAKING ANY OF THE REACTIONS DESCRIBED BELOW. WIZARD X SHALL NOT BE HELD LIABLE AND INDEMNIFIED FROM IMPEACHMENT FOR THE USE, MISUSE, INJURY, DEATH, IMPRISIONMENT OR FELLATION DUE TO THE APPLICATION OF THIS INFORMATION.
SYNTHESIS OF ISOSAFROLE FROM EUGENOL
Eugenol, M.W = 164.20 gr/mol; density @ 20 degC = 1.067 gr/cm3
PROCEDURE
Obtain pure eugenol from clove oil which has a boiling point of 255 degC at 760mmHg. With vacuum distillation the boiling point is 123 degC at 12-13mmHg, and 110-111 degC at 5mmHg.
In a 500 ml round bottom flask, cool in ice to 0-2 degC, 100 mls of 57% HI SOLUTION (HYDRIODIC ACID, M.W = 127.93) = 99 grams of HI = 0.774 moles of HI. (B.p 125.5-126.5 deg C/760mm Hg ; Density 1.70 gr/ml ; 55-57% w/w HI is 0.936 to 0.99 grams of HI per ml).
Add 32.8 grams, ~ 35.0 mls (0.2 moles) of Eugenol to the 100 mls of 57% HI, while the flask is still in the ice. Swirl gently, stopper, place back in the ice and insulate the container holding the ice and place in the fridge compartment for a period of 12 hours. Every 2 hours swirl gently again.
After the 12 hours period, add 1.0 grams of hydroquinone (a polyerisation inhibitor)[NOTE1] and swirl, stopper, remove from the ice to allow it to obtain room temperature. Attach a long reflux condenser and reflux for 2½ hours between 120-130 degC, perfect temperature is 128 degC. After refluxing for the time period allow to cool to room temperature. Dilute with 1 liter of ice cold distilled water and solvent extract with 3 x 100 mls of diethyl ether or petroleum ether and wash once with minimum distilled water 50 mls. Distill the solvent off and the methyl iodide, CH3I, Bp 42.4 degC.[NOTE2] Crystals will form, however some oily residue may or will persist.
In a 1 liter round bottom, reflux reaction flask, add the following.
A volume of 300 mls of ethanol is added to the crystal residue of 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and the 3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 and hydroquinone. Another 1.0 grams of hydroquinone is added and mixed together.[NOTE1] A solution of 22.44 grams (0.4 moles) of potassium hydroxide, KOH, in 200 mls of 50/50 distilled water/ethanol is made. The potassium hydroxide solution is then added with stirring to the above 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and the 3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 residue-ethanol solution. The combined mixture is then gently refluxed with stirring on a hot-water bath or steam bath for 1 hour.[NOTE3]
Add a solution of 53.58 grams (0.2 moles) of diiodomethane, ICH2I (M.W = 267.9 gr/mol), in 150 mls of ethanol and continue refluxing for 2 hours.[NOTE4] Strip all ethanol solvent under vacuum distillation, and add 400 mls of distilled water. Solvent extract with ether 2 x 100 mls. Keep the water layer as it contains unreacted 3,4-dipotassiumoxy-1-propenylbenzene, 3,4(KO-)C6H3-CH=CH-CH3.[NOTE5] The ether/isosafrole solution mixture is washed once with distilled water, and under careful vacuum distillation the isosafrole is distilled at 179.5 degC at 100 mmHg or 135.6 degC at 20 mmHg.
[NOTE6]
[NOTE1] hydroquinone oxidizes in air and in solutions exposed to air rapidly. Keep the flask well closed and protected from light.
[NOTE2] the solution contains a mixture of methyl iodide, CH3I ;
3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and the
3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 and hydroquinone.
[NOTE3] at this stage the 3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 will be converted to 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and 3,4-dipotassiumoxy-1-propenylbenzene, 3,4(KO-)C6H3-CH=CH-CH3.
[NOTE4] methanol can be used in all cases, instead of ethanol. At this stage the main product is isosafrole. Dibromomethane, BrCH2Br can also be used.
[NOTE5] add dilute HCl until slightly acidic and solvent extract to obtain the 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3.
[NOTE6] propenylbenzene, C6H5-CH=CH-CH3, are susceptible to polyerisation, influenced by acids. Both isosafrole and safrole can be steam distilled.
TESTS
3,4-dihydroxy-1-propenylbenzene; 3,4(HO-)C6H3-CH=CH-CH3, in an alcoholic solution develops a deep green-blue colour on treatment with 2 % alcoholic ferric chloride solution.
Eugenol : In a cold saturated aqueous solution of ferric chloride, gives a turbid grayish-yellow colour. With 2 % alcoholic ferric chloride solution, a blue colour, which fades to grey-yellow colour in 15 minutes. An intense purple-black colour develops when reacted with 48 % hydrobromic acid at 2 degC.
Safrole and Isosafrole : an intense red to scarlet red colour develops when dissolved in concentrated sulphuric acid.
(Newbee)
11-24-00 03:54
No 70575
the method has a crap yield (I performed it last week), i think the problem is with the methylation reaction, it only goes well with polar aprotic solvents (DMF/DMSO/ethacet if you are desperate).
I will try a revised method next week which still utlilses the first step but after the ether removal i will use KF/DMF/DIM instead of the etOH/KOH, then after recovery will boil up the mix with KOH ala elusis style to transform all to isosafrole, will post results, my yield from that method was about 7% (crude prod) and removing the ethanol took far too long for that measely quantity. Not to be discouraging just warning others off, also HI is not fun to work with, either to buy (expensive!!!!!), to make (nasty!!!!!!!!!) or to have split all over your gentitals (ouch that burns).
Anyway may have some good news for all soon after a little vac distill this afternoon.
caio
blue always
except for at the start
(Newbee)
11-27-00 06:34
No 71081
Hhmm that looks like a whole lot of pain. 7% that's really shit. Well hopfully the methylation is the fuck up. Which isn't too much to ask considering every methylation I ran into either used polar-aprotic or autoclaves and years to get it to run.