Author Topic: future of safrole  (Read 25325 times)

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starlight

  • Guest
solvent volumes
« Reply #40 on: April 21, 2004, 11:54:00 AM »
The original procedure using SIBX (

Post 451672

(Rhodium: "Novel Oxidative Demethylation of Eugenol", Novel Discourse)
) uses a high solvent volume for a small amount of eugenol. Scaling this up proportionally would require 20 litres of solvent per mole of eugenol. Hopefully this could be avoided.

psychokitty

  • Guest
But not for identification purposes
« Reply #41 on: April 22, 2004, 07:40:00 AM »
The SIBX reaction is valuable particularly because it can yield allylpyrocatechol without complication.  Like I posted before, for identification purposes.

As for the solvent issue, so what?  I'm sure the experimental reaction scheme has not been optimized.  And besides, who knows what a little experimentation can accomplish?  Just look at how the other popular syntheses that were once thought to be immutable have now changed.  The Al-Hg reaction has been altered in regards to its ratios of solvent to reagents to substrate.  One now knows that the use of methanol is paramount to success whereas the use of other solvents is now discouraged.  Where once dimethylformamide was the only solvent thought to be applicable to the wacker, now virtually any educated bee knows that methanol will suffice.  But as for the demethylation of eugenol, there has to be a beginning somewhere . . .

PK

psychokitty

  • Guest
What about this method?
« Reply #42 on: April 22, 2004, 08:10:00 AM »
Maybe this reaction scheme is more desirable.  It uses less solvent, is relatively non-toxic, facile, quick, high-yielding, forms no dangerous byproducts and tolerates many functional groups, including double bonds.  Also, the reagents required are just as commonly available as those used in the SIBX reaction.

Tetrahedron Letters Volume 38, Issue 50, 15 December 1997, Pages 8749-8752
 
Chemoselective Aryl Alkyl Ether Cleavage by Thiophenolate Anion Through its In Situ Generation in Catalytic Amount

Abstract:  Catalytically  generated alkali metal thiophenoxide in NMP (1-methyl-2-pyrrolidinone) chemoselectively cleaves aryl alkyl ethers in high yields.

Rhodium

  • Guest
Aryl Alkyl Ether Cleavage by Thiophenolate
« Reply #43 on: April 22, 2004, 06:23:00 PM »
As mentioned in

Post 502219

(psychokitty: "What about this method?", Methods Discourse)


Chemoselective Aryl Alkyl Ether Cleavage by Thiophenolate Anion Through its In Situ Generation in Catalytic Amount
Mrinal K. Nayak and Asit K. Chakraborti

Tetrahedron Letters 38(50), 8749-8752 (1997)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/ether.cleavage.cat-phsh.pdf)
DOI:

10.1016/S0040-4039(97)10342-2



Abstract
Catalytically in situ generated alkali metal thiophenoxide in NMP (1-methyl-2-pyrrolidinone) chemoselectively cleaves aryl alkyl ethers in high yields.


starlight

  • Guest
sounds stinky!
« Reply #44 on: April 22, 2004, 11:56:00 PM »
Thiophenol smells pretty bad and its odor threshold is 0.6 ppb so maybe this isn't one to try in your kitchen.

psychokitty

  • Guest
Whoa! Whoa! WHOA!!!
« Reply #45 on: April 23, 2004, 08:39:00 AM »
I may have jumped the gun.

I looked up the citation to the LiCl demethylation of eugenol listed on Rhodium's page and it really looks like a winner.  Dimethylformamide and LiCl are about as easy to get as anything is.  Not exactly OTC, but who cares.  Certainly, the reaction is just as operationally simple as the SIBX reaction; however, it's a bit better when it comes the the volume of solvent required (but it's still pretty way up there; not as good as the Thiophenol method, but at least it's been proven to work in the literature).

Buuuut, there are a few typos that deserve mention. 

For one, eugenol has a molecular weight of 164.20.  So, as the patent describes, 354 ml could NOT possibly be 2.30 mmol!  It more likely has to be 2.30 mol, as this would equal 377.66 g, which, in turn, would likely equal 354 ml due to the density of eugenol.  Besides, 2.30 mmol of eugenol would be .377 g or .354 mL.  I zoomed in on the relevant text in the patent and there are no decimal points whatsoever to be seen.  So, basically, the patent should read 354 ml (2.30 mol) and NOT 354 ml (2.30 mmol).

Also, the time increments in regards to the additions of 292 g of LiCl should read 4, 22, and 29 hours, NOT 4, 18, and 7 hours.

What gives?

Cadenza

  • Guest
Demethylating Eugenol: Some Experiences
« Reply #46 on: April 24, 2004, 01:29:00 AM »
Hello all,

First of all, I would like to take a moment to say that Rhodium's chemistry page is one of the most comprehensive archives that I have ever seen on any subject.  I have always been staunchly anti-drug, but I admit that I have begun rethinking my stance after carefully reviewing current medical literature pertaining to entactogens, hallucinogens, etc.

I have attempted the demethylation of eugenol many times, although not for the purpose of MDP2P synthesis.  (My purpose is to obtain the anti-oxidant 4-allylcatechol, but one of the ways of proving it is to methylate the product to safrole).  This is not a straight-forward task; as Startinout/wacko-reaco stated earlier, the synthesis of 4-allylcatechol has not been well-studied in open literature.

I have a few comments regarding the properties of 4-allylcatechol and various methods that have been attempted:

1.  4-allylcatechol properties:

In response to Pyschokitty, 4-allylcatechol is indeed unstable under RT/exposure to light and air.  I have a dish of 4-allylcatechol sitting in the lab that has turned from a light clear-yellow color to a dark red over the course of three days.

However, it must be noted that 4-allylcatechol does not decompose very quickly, provided that Lewis acids are not used in the demethylation process.  Moreover, the "smokey" demethylated smell is due, in some part, to the interaction of AlCl3 with eugenol rather than some intrisinic property of 4-allylcatechol itself.  I believe this to be the case because the demethylated product from pyridine hydrochloride does not particularly smell like smoke.

2.  Pyridine hydrochloride

This method does work (I have never had problems obtaining 4-allylcatechol from pyridine hydrochloride) but the construction of a microwave reflux apparatus is probably necessary.  I believe that this method is the best way of obtaining a sample of 4-allylcatechol for analysis, since the catechol spontaneously recrystallizes in high purity in situ  following hydrolysis in an ice-bath.

3.  Triethylamine hydrochloride

Triethylamine hydrochloride, by itself, does not work as a demethylating agent under microwave radiation.  I suspect that the main reason is the high melting temperature (~260 C), but in the many trials that I have performed, the amine salt actually decomposes, leaving a polymerized tar substance.

4.  Triethylamine hydrochloride and aluminum chloride under microwave irradiation:

I actually succeeded in a one-pot synthesis of safrole from this combination, although the yield was so low that I didn't bother isolating the product (most likely < 5% yield of a clear oil with a candy-shop odour).

5.  Aluminum Chloride

Literature states that o-methoxy groups may be demethylated by the cleavage agent NaI/AlCl3, but I highly doubt that this will work, given the sensitivity of the double-bond to iodination.  Nevertheless I have not tried this, and experimentation is king.

I have attempted cleaving the ether using AlCl3 independently in both solvent and solvent-free conditions.  However, this does not seem to work, since product was not obtained after hydrolysis of the oxonium complex.

Thoughts:

Given that I have not tried SIBX, LiCl, AlI3, or other classical reagents such as BBr3, I cannot really say that (reasonable) demethylation of eugenol is impossible.  It is possible, but to obtain it in large quantities will require a lot more research.

If anyone has any suggestions (Psychokitty and wacko_reaco, you guys/gals seem to know quite a bit about o-ether cleavage, do you have any ideas?)


psychokitty

  • Guest
Perhaps an in situ demethylation/methyleneation?
« Reply #47 on: April 27, 2004, 08:09:00 AM »
If one demethylated using the LiCl method in refluxing DMF, one could then add the toluene as instructed to precipitate -- what? -- the suspected LiCl (complex?), filter, distill the toluene, which will take with it any water that may be found in the spent reaction matrix.  Then, assuming that tar is not the other 50% by-product of the demethylation reaction, DCM and NaI could be added, reacted to form DIM (diiodomethane) which would form NaCl as a by-product (no big deal).  Then, NaOH could be added all at once or incrementally so that a methyleneation reaction could take place.  Then, water could be added and -- viola! -- steam distillation should yield the desired alkene.  Hence, a straight-through reaction can take place without the need for isolation of the intermediate catechol nor purification of the final alkene through vac distillation. 

Again, assuming that the intermediate catechol is pure enough from the demethylation reaction, the above reaction scheme should work.

As far as other demethylation reactions, I have quite a few experimental ones listed in my arsenal.  Here are two really good ones:

SYNTHETIC COMMUNICATIONS,34(4), 641-649 (2002)
"IMPROVED METHOD FOR DEMETHYLATION OF NITRO-CATECHOL METHYL ETHERS"

Several nitro-catechol compounds,useful as inhibitors of COMT were obtained in excellent yield and purity via an improved proceedure for demethylation of the corresponding methyl ethers using aluminum chloride and pyridine in ethyl acetate.

AND

SYNTHETIC COMMUNICATIONS, 31(6), 869-875 (2001)
"NICKEL/ZINC-MEDIATED ALKYL CARBON-OXYGEN BOND CLEAVAGE OF ALKYL ARYL ETHERS"

Alkyl carbon oxygen bonds of alkyl aryl ethers bearing suitable coordination sites were efficiently cleaved by treatment with nickel(II)chloride and zince in p-xylene under neutral conditions.

Cadenza

  • Guest
in situ is ideal, but...
« Reply #48 on: April 27, 2004, 06:32:00 PM »
The difficulty lies not in the demethylation per se but rather the separation of the catechol and unreacted eugenol.  Solvent extraction does not work because eugenol and 4-allylcatechol are pretty similar in polarity.

I do not know the mechanism behind the LiCl demethylation-- the procedure looks simple, but it requires quite a large amount of solvent and a LOT of lithium salt.  Another potential problem with this scheme is the formation of polymerized catechol w/the addition of NaOH.

Now as to the first reference ("IMPROVED METHOD FOR DEMETHYLATION OF NITRO-CATECHOL METHYL ETHERS"), this works on vanillin, with a few caveats.  Both "startinout" and "bones" managed to get this working-- Startinout directly used Lange's method w/DCM as solvent, and bones used the optimized ethyl acetate.  I have performed this procedure and it is indeed very easy with vanillin (although correct pH and very vigorous stirring are required).

Incidentally, the procedure w/ethyl acetate does not work with triethylamine (Lange claims a 61.5% yield from triethylamine w/DCM as a solvent).

Startinout also performed this procedure with eugenol, with what he called "abject failures."  Having worked with eugenol and Lewis acids, I am inclined to agree- eugenol really should be kept away from AlCl3 and/or other Lewis acids if possible, to avoid vinyl polymerization and Friedel-Crafts interactions.

Another thing to keep in mind is that in these demethylation reactions involving eugenol, the side products will also end up as aromatic oils that steam-distill.  (For example, when I attempted a demethylation with conc. sulfuric acid w/subsequent PTC methylation, a clear oil smelling of fuel came over during steam distillation).

I really believe that the best way to demethylate eugenol is to use an amine-based hydrochloric salt (pyridine, etc).  In Lange's reference, a very interesting table was included:

(Robert Lange, 1962)
DEMETHYLATION OF VANILLIN WITH ANHYDROUS ALUMINUM CHLORIDE AND VARIOUS TERTIARY AMINES

Tertiary Amine         %Yield Protocatechualdehyde

2-methylpyridine              41.3
2-methyl-5-ethylpyridine   36.7
4-methylpyridine              72.7
Quinoline                         22.6
Dimethylaniline                33.1
Triethylamine                   61.5

The key factor in whether a given hydrochloride salt will produce yields under microwave demethylation is whether

a) it is sterically hindered
b) it has a appropriate melting point (~150 Celcius)
c) it will reflux to absorb excess heat

Based on these factors, I believe that 4-picoline hydrochloride (4-methylpyridine hydrochloride) and imidazole hydrochloride are worthy of investigation.


psychokitty

  • Guest
Some suggestions
« Reply #49 on: April 29, 2004, 04:34:00 AM »
Allylpyrocatechol can be separated from eugenol by several different ways:

1.) Steam distillation (eugenol should steam distill; allylpyrocatechol should not)
2.) Vac distillation
3.) Crystallization of allylpyrocatechol in either pentane or hexane.  Allylpyrocatechol is, at most, only sparingly soluble in these solvents; eugenol, I believe, is completely soluble in both.

To avoid polymerization of the allylpyrocatechol upon addition of sodium hydroxide, instead use either potassium carbonate, potassium flouride, or cesium carbonate for the methyleneation reaction.

Even if other aromatic oils are formed during the methyleneation reaction, separation of them from the desired alkene after steam distillation should be no problem as the bp of each is likely to be considerable.

Cadenza

  • Guest
allylcatechol purification / strong acid cleavage
« Reply #50 on: April 29, 2004, 07:00:00 AM »
Thank you for the advice, psychokitty.  Being a somewhat impatient person, I did not think about distillation as a means to separate eugenol/4-allylcatechol, but it sounds like a reasonable method to me.  The heat from a vac-distill should not affect the catechol in any significant way, as the demethylation takes place at 150 ¡ãC+.

Now I have an interesting demethylation question concerning acids.  In the past, HBr has been used to cleave ethers (notably vanillin w/poor yields).  I always assumed that HBr would add across the double-bond, so I did not think about pursuing this method.  In addition, I did not particularly wish to work with HBr.

However, the use of halo-acids is still appealing, since they are greener than most amine-bases (I am not fond of working with pyridine and triethylamine).  Also pyridine hydrochloride is ridiculously deliquesent-- generally a pain to use under atmospheric conditions.

Now, HCl is not generally an effective ether-cleaving agent, but I thought it might be interesting to conduct some microwave experiments with it.

Experimental:

10 mL of eugenol was placed in a 1000 mL roundbottom flask, and 20 mL of concentrated HCl was added slowly, causing the formation and subsequent separation of a green layer.  10 mL of water was added, and the flask was placed in a microwave reactor for 90 minutes under low-power.

Upon cooling and extraction with diethyl ether, a silver-green crystalline substance was obtained (2.5 grams).

I have not conducted any analysis on the product other than a very crude MP test (MP appears to be significantly higher than that of 4-allylcatechol), and I am curious if any properties of chloroeugenol are known (I assume that HCl will add across the double bond w/Markinokov addition)-- whether it cleaves the ether is very much in doubt.

Anyway, I will conduct a more precise MP test, etc. and get back to you on it.


psychokitty

  • Guest
You've probably got a sample of the eugenol dimer
« Reply #51 on: April 29, 2004, 10:58:00 AM »
I think I read somewhere sometime that both hydrochloric acid and/or hydrobromic acid cause both eugenol and isoeugenol to polymerize.

Here is an interesting reference to a patent I found online:

http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0106995&QPN=WO0106995



Unfortunately, the text is in German, so some German-fluent Hive bee will have to translate the relevant parts; namely, those areas which may (hopefully) describe the synthesis of hydroxychavicol (allylpyrocatechol), or, at the very least, list a few commercial sources and/or suppliers of it.

Organikum

  • Guest
The patent is based on the use of ...
« Reply #52 on: April 30, 2004, 12:00:00 PM »
The patent is based on the use of hydroxychavicol in plant extracts from piper betel - usual pepper leaf extraction with alcohol and ethylacetate is described (soxhlett). No synthesis. No suppliers.


CharlieBigpotato

  • Guest
a word on sassafras roots:
« Reply #53 on: April 30, 2004, 02:58:00 PM »
zib finds much irony in this post, as he lives in the southern appalachian mts. of the u.s.

these mountains are presently beeing raped and pillaged on a grand, heart-breaking scale.
in my zone (cumberland plateau) the hardwood forests are now beeing 'logged' for an ever smaller marketable commodity.
long gone are the big oaks and veneer quality black walnuts...now, its mostly down to trees large enough for pallet wood...or smaller...chips.

the massive chip mills on the tennesse river and navigable tributaries are buying trees that aren't big enough to make a 2x4  and shredding them up to make chip board and osb plywood, etc.

what am i getting at here?

that anyone willing to investigate this pillaging and 'follow' the bulldozers thru the once gorgeous hills will litterally trip over endless sassafrass roots that have been torn from the ground.

the smell alone will allow you to find them.
sassafrass is very common; very much not in demand; pretty much a weed tree.

a person could fill a pickup truck with root bark in a few hours without seeing another human beeing.

get it while it lasts?

(oddly enough, the adventure will also put you in touch with several of the substitute plants!)


hypo

  • Guest
great for you!
« Reply #54 on: April 30, 2004, 03:28:00 PM »
but it doesn't really help us people who don't live in the appalachians
or don't own pickpup trucks.

sad thing about your woods though. you should chase away the wood-killers  :P


Sredni_Vashtar

  • Guest
UK
« Reply #55 on: May 01, 2004, 01:43:00 AM »
There are a few sassafras trees growing in Hyde Park if you are interested.

...and there are quite a few juniper trees left, though they are in decline: no more gin - which is a good thing (Real Ale is much better for you.)

It would be great to have a natural UK source of safrole.

CharlieBigpotato

  • Guest
good for more than me, hypo
« Reply #56 on: May 01, 2004, 02:00:00 PM »
i wasn't trying to brag about my sassafras-rich enviorns, hypo...

just trying to pass on a tip to others who may bee able to locate such public logging operations and even rent or borrow a truck.

trying to actually dig up the roots would bee a tremendous chore, but the logging road construction efforts, which gwb has made easy, has also made collecting the root bark pretty damn easy.

might bee worth the trip for those who grok what is suggested.

ApprenticeCook

  • Guest
CharlieBigpotato, i have heaps of sassafras...
« Reply #57 on: May 01, 2004, 05:54:00 PM »
CharlieBigpotato, i have heaps of sassafras around here, but im talking oz... they are still Sassafras albidum but... heres the problem...

https://www.thevespiary.org/rhodium/Rhodium/chemistry/safrolefaq.html%5Bquote%5DJust

thought you might like to add some info onto your safrole FAQ sheet on your site. The Australian botanicals, southern sassafras and ziera smiithi have no safrole in their roots, bark, trunks or foliage. Southern sass has nothing worth mentioning whilst smiithi contains lots of methyl eugenol, which is where the confusion started I believe, the text 'poisionous plants of Australia' is fraught with errors and as much of the info in the current Safrole FAQ is lifted directly from this hence the errors. This will save readers much time I believe as I have wasted heaps of time collecting , seperating and steam distilling all the bits. The methyl eugenol's existence was confirmed through FTIR and NMR library matches so there is no doubt to the accuracy of this info. The only assumption I am making is that maybe safrole only seasonally appears in these species, as my samples were all collected in winter/spring.[/quote]"Southern sassafras"?? are they talking about Sassafras albidum in this description? or another type... same family lacking what we want...

-AC

demorol

  • Guest
Dealkylation with Niobium(V) Chloride
« Reply #58 on: July 10, 2004, 10:14:00 PM »
A Simple and Regioselective Carbon-Oxygen Bond Cleavage Using Niobium(V)
Shigeru Arai, Yukinori Sudo, Atsushi Nishida
Synlett 2004

DOI:

10.1055/s-2004-817766



Abstract
A simple and convenient method for the differentiation of alkoxy groups on aromatic rings is described. Niobium(V) is found to possess a strong Lewis acid property to transform alkyl arylethers smoothly to the corresponding phenols in high yields. The excellent regioselectivity was also observed in dialkoxy benzene derivatives under mild conditions.

Full text:


methymouse

  • Guest
Never going away
« Reply #59 on: July 12, 2004, 09:56:00 AM »
I'm with others on the forum that MDMA will never go away;  I suspect that four things will happen:
(1) Much more "fake" MDMA tablets will begin to appear on the streets, a perverse consequence of the government's policy.  MDMA is much safer than PMA, PMMA and the various cocktails consisting of mixtures cocaine, meth, ketamine, etc.
(2) More MDMA will be imported from the third world and former communist areas.  This will allow law enforcement to increase their budgets and power by earmarking money for MDMA border control operations.  The DEA seems to believe (erroneously) that they can much better control drugs being brought into the country than ones produced domestically, but the black markets on marijuana, cocaine and opium say otherwise.  Since MDMA sells at a higher per-gram cost than cocaine, the incentive to import it will be (and indeed is) very high.
(3)  Domestic MDMA manufacture will become a very specialized creed akin to LSD production involving either highly skilled chemists or chemists with the ability to obtain safrole or the like. 
(4) Clandestine chemists (or perhaps quasi-legitimate "legal drugs" chemical companies) will produce some of Nichols' MDMA analogues, which will then be marketed as MDMA.  Of course most of these are harder to make than MDMA, but if the various members of the hive put their minds together, some reasonable OTC syntheses would be produced.

Given enough time, skill and chemicals, one could make it from catechol, which can be made from aspirin (though at the moment there is not a substantial law-enforcement effort to control photochemicals).  Like the original poster, I haven't seen any reports of success with demethylating eugenol or vanillin in a clandestine setting, though clearly it can be done as there are numerous papers on this kind of ether cleavage.  The problems with this (and other direct syntheses) are the relatively low quality and variety of reagents available to the clandestine chemist, and the relatively low skill of most clandestine chemists (myself included).

Another possibility is the extraction of relevant chemicals from black pepper.  My roommate tried to do this, and ended up with a mess of gunk which refused to crystalize, but it's possible that a different extraction procedure could be found.  Pepper is, unfortunately, a much more complex mixture of chemicals than is sassafras oil, and the precursors are much larger molecules which makes them both more difficult to extract, and more fragile.

Based on what I've read and tried, small scale production is likely to be limited to people clever enough to get safrole, and people skilled enough to make MDMA directly.