Sciencemadness Discussion Board

Several questions regarding Eugenol

Intergalactic_Captain - 21-12-2006 at 21:08

I'm going to take it on good faith that those with the knowledge to answer these questions know what the end product is, and will not mention it by name.

1. Cleavage of the methoxy group to yield the phenol:
After looking at this for quite some time, it finally hit me that it should be a simple acid-catalyzed ether cleavage. My copy of Solomons Organic Chemistry (2nd ed.) states that it can be done concentrated HI or HBr. It's an older book, and quite vague at that, and offers no indication as to the efficacy of HBr on an aryl ether. The question is, could it be done in a low-temp (somewhere between 0-20C) DMSO solution of H2SO4 and NaBr with the HBr formed in situ?

2. Markovnikov HBr addition to the allyl group:
http://www.erowid.org/archive/rhodium/chemistry/halosafrole....
The above link offers a lengthy discussion of the process in a DMSO/H2SO4/NaBr solution. It is unclear, though, whether a PTC is necessary to facilitate the reaction. Might anyone with first-hand experience know whether it is necessary? If it is, could it be as simple as adding a bit of hair conditioner to the reaction vessel?

3. Combining 1 and 2:
It would appear that it is quite possible to accomplish both of the above reactions at the same time with 2x the HBr necessary to accomplish either of them. I plan to test this myself, but if anyone would care to tell me why it is impossible I would love to know why. Also, would the CH3Br react with the newly-formed B-bromo-propylcatechol in any adverse way?

4. I'm guessing it wouldn't be a problem, but I'll ask anyway - The next step in the process is a base catalyzed methylenation w/ DCM in DMSO to the methylenedioxy compound. The reaction it is based on utilizes 4-allylcatechol, not the B-bromo species. I'm guessing the reaction will proceed somewhat differently, but will the difference in precursors be enough to stop it from happening?

5. Finally, the Delepine reaction to yield the end product. I have not been able to find anything regarding the reason that EtOH is necessary as the solvent. Though I could easily enough prepare anhydrous EtOH, it would be much easier for me to obtain MeOH. I only ask because EtOH is the only thing that is technically illegal for me to obtain, at least for the next two years (Land of the free my ass!). Would MeOH simply lower the yield or completely inhibit the reaction?



Hopefully, I can successfully prepare a 3-step process with eugenol and DMSO being the only precursors that one could not obtain in a trip to the hardware store. The main goal is to find a one-pot process from eugenol to the brominated propylcatechol that doesn't require anything remotely exotic. The only problem, though, is that in being so simple I have serious doubts as to whether it would work. Hopefully you guys could shed some light on it beforehand, though I'll be sure to post my results either way.

Nicodem - 22-12-2006 at 00:43

1.) Generally, the methoxyaryl ether cleavage with HBr requires heating.
2.) In DMSO the reaction would be in a monophasic media so why would one want to use a phase transfer catalyst?
3.) The methyl bromide side product does no harm, however you need way more than an equivalent of HBr for the demethylation.
4.) The methylenation of 1-(3,4-dihydroxyphenyl)-2-bromopropane would yield tar. Utmost, if you would be lucky, there would be some isosafrole formed (but certainly no 1-(3,4-methylenedioxyphenyl)-2-bromopropane).
5.) The Delepine reaction does not work on secondary halides.
Quote:
I'm going to take it on good faith that those with the knowledge to answer these questions know what the end product is, and will not mention it by name.

What a stupid assumption! I know several organic chemists who would be perfectly able to answer these questions and know shit about what the "end product" is supposed to be. And I know many, many people who know what this "end product" is and still have no clue about chemistry and would not be able to answer your questions.

nightflight - 22-12-2006 at 03:28

Sometimes, it´s all seems so narrowminded, as the narrow-minded force us to see it all as they do.

There´s a neat littlte chapter on this issue in Vogel´s Textbook of Practical Organic Chemistry, S.988f., plus a way for protecting th eoh-groups via the methylenedioxy:

"deprortection of allyl aryl ethers is accomplished by protonolysis with palladium on activated charcoal in methanol solution in the presence of toluene-p-sulfonic acid,
or by reduction with sodium bis(2-methoxyethoxy)aluminum hydride in touene solution.(Aldrich): th latter also cleaves aryl benzyl ethers."

[Edited on 22-12-2006 by nightflight]

Intergalactic_Captain - 22-12-2006 at 06:31

Thanks, I guess...But for some reason it seems like Nicodem only wants me to fail. If he's right he's right, but still...

First, regarding the delepine, what little I've found on it does state that it is for primary amines. But, all of the clandestine literature out there states that it will work on a secondary halide to give the desired amine. Granted, druggies may not be the best chemists, but I have not found anything that is obviously wrong in the rhodium archives...yet... Neither of my organic texts even mention the reaction, and I'm on break right now, so all I've got's the internet for further information.

Second, I realize that the DMSO HBr addition mix is a monophasic "aqueous" mixture. But, eugenol seems like it would act as an oil. The link I gave makes note of the bromination with and without the PTC, and these two facts combined are why I was wondering if it was necessary.

Third, would anyone know why the methylenation of the bromo compound wouldn't work? I know that it will work for the allylcatechol, so what's so different with the bromopropylcatechol? (I'm not calling you out, I sincerely am interested in how the mechanism changes)


Finally, the assumption was not necessarily that only those who know the chemistry would know the product. Rather, regarding the recent influx of people straight-up asking how to make drugs, I didn't want to just hand out a potentially viable synthesis. I guess it's different if it's not viable, but if I were to demethylate, methylenate, and brominate in that order then it's a different story.


Oh, and nightflight, I would kill for Vogel's...I actually have an edition of it as a pdf, but I can't stand trying to navigate through it. I do, though, have full ACS journal access, if anyone would happen to have any references I could check out.

That, and regarding the demethylation, I realize that there are many more ways to do it...The only thing, though, is that I do not intend to use anything precious or exotic in the process. None of the good chem suppliers sell to individuals anymore, and I'd rather not do anything that shady. So far, all my reagents can be acquired from the home depot and any horse supply website.

Nicodem - 23-12-2006 at 03:21

Quote:
First, regarding the delepine, what little I've found on it does state that it is for primary amines. But, all of the clandestine literature out there states that it will work on a secondary halide to give the desired amine.

I can also state all kind of assumptions and bullshit and you still don't have to believe me. However this still does not change the fact that the experimental data demonstrates the Delepine reaction only works on primary halides which is also expected given the several magnitudes lower reactivity of secondary alkyl halides in SN2 substitutions. Check Beilstein yourself if you don't trust me. Or if you prefer, trust some impulsive assumptions from some clandestine chemists. It's up to you.
Quote:
Granted, druggies may not be the best chemists, but I have not found anything that is obviously wrong in the rhodium archives...yet...

I can only assume this is some kind of a joke I failed to understand.
Quote:
Third, would anyone know why the methylenation of the bromo compound wouldn't work? I know that it will work for the allylcatechol, so what's so different with the bromopropylcatechol? (I'm not calling you out, I sincerely am interested in how the mechanism changes)

Well, think a little about it. What happens when you have a molecule that has both, a nucleophilic and electrophilic site on it that can interact irreversibly? The conditions needed for the methylenation require deprotonation of the phenolic groups yielding just such species. And these conditions are harsh more than enough to cause the bromide elimination from the isopropyl bromide side chain yielding 1-(3,4-dihidroxyphenyl)propene. This would not be so bad after all if it was not characteristic for such compounds to be quite prone to polymerize.

PS: Nightflight, do you mind explaining what the deprotection of benzyl/allyl protected phenols by hydrogenation has to do with the topic of eugenol demethylation?

nightflight - 24-12-2006 at 06:36

You could get away with boiling,resp. refluxing the phenyl ether with a conc. halide acid, which is not HCL, for 2-3hours to yield a phenol and an alkylhalide in molar ratio 1:1 acid:ether(Tiecco 1988).

the ether to be cleaved has a alkyl group (methyl) on it, right?

Intergalactic_Captain - 1-1-2007 at 12:13

I'm thinking 48% HBr reflux for a few hours. I believe I have successfully brominated the eugenol, and have moved the cleavage to the third step. A couple more questions though:

Would the straight alpha-methyl phenethylamine hold up in the reflux without being destroyed? It seems like the n-methyl version would be fine (HI/RP reduction of pseudoephedrine doesn't hurt the amine as reference), but I cannot find anything regarding 3-methoxy,p-hydroxy analogs.

The next question regards the formation of the amine. The reaction with MeNH2 is only ever noted as being performed in a bomb-type setup. Is this due to the reaction only taking place at a high temp, or could a reflux setup perform the rxn over a signifigantly longer period of time? Also, can the HCl salt be used, or is it the straight amine only?

Sauron - 2-1-2007 at 11:40

Vogel's in DejaVu format is easier to navigate around in than a pdf. Use the GoToPage function to see a particular page number.

You will need LizardTech's free DejaVu reader.

This book is in this site's library downloadable freely.

jon - 2-1-2007 at 12:08

refluxing in HBr should accomplish both Bromination, and demethylation, maybee more free radical addition in the case of HBr and heat, as U.V. light will generate free radicals, a reasonable extrapolation would infer heat could do the same. from anectdotal reports in C.A. you can react the alkyl bromide with methylamine (has to be dry mind you, that seems to be key in this reaction) dissolved in alcohol for four days at STP. and get the same result or better (due to less tar formation) as with heat. I'll get back with the abstract.
Now the last question is just plain dumb about using an HCl amine salt for this SN2. Methylamine is not a good nucleophile when it's protonated.
some alkylations use potassium carbonate to nuetralize the acid generated but in those cases the intended result is a tertiary amine, I think a more basic enviroment encourages sucessive alkylations to tertiary amines.

[Edited on 2-1-2007 by jon]

[Edited on 2-1-2007 by jon]

Ullmann - 3-1-2007 at 11:10

Quote:
Originally posted by jon
refluxing in HBr should accomplish both Bromination, and demethylation, maybee more free radical addition in the case of HBr and heat, as U.V. light will generate free radicals, a reasonable extrapolation would infer heat could do the same.


No, heat will not generate free radicals with HBr, only light will do so without adding any other chemical species. Beware of oxygen tough.
Quote:
Now the last question is just plain dumb about using an HCl amine salt for this SN2. Methylamine is not a good nucleophile when it's protonated.
some alkylations use potassium carbonate to nuetralize the acid generated but in those cases the intended result is a tertiary amine, I think a more basic enviroment encourages sucessive alkylations to tertiary amines.


No, successive alkylation to the tertiary amine will take place as long as there is excess electrophile present and no steric effect. In this case if an excess amine is used there should not be too much of the bis-alkylated compound. The amine must of course be freebase form, not the salt!

Elimination is the most notable side reaction with this SN2 swap of bromide by methylamine. Better to use NaN3 followed by Mg/formate reduction of the azide to the amino IMHO. Azide ion is a much better nucleophile than it is basic ; in contrary, methylamine, altough still a good nucleophile, is too much basic and leads to elimination as well.
Quote:
Originally posted by Intergalactic_Captain
I'm thinking 48% HBr reflux for a few hours. I believe I have successfully brominated the eugenol, and have moved the cleavage to the third step.


Aha! and did you thought about the protection of your amine toward your methylenating agent??? If not protected it will fail!


BTW nicodem is right about the delepine : it doesn't work for secondary amines... An alternative (beside the two steps azide swap/reduction) is through the use of 2-nitropropane on the halide, it is somewhere in hive archive or rhodium.

[Edited on 3-1-2007 by Ullmann]

Vogel's as PDF?

chemrox - 19-1-2007 at 09:36

Oh, and nightflight, I would kill for Vogel's...I actually have an edition of it as a pdf, but I can't stand trying to navigate through it. I do, though, have full ACS journal access, if anyone would happen to have any references I could check out.

You have Vogels as a PDF file? How would you like to post that?!!