Author Topic: Monomethylation of Amphetamines  (Read 1292 times)

dingbow

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Monomethylation of Amphetamines
« on: August 23, 2011, 01:11:41 PM »
Alright so the old man down the road finally decided to give this a go, heres what I witnessed:

-1.1g MDA.HCl basified, extracted twice with DCM
-DCM stripped off, the remaining base then taken up in MeOH
-To this was added 0.38ml formalin (though I screwed up the pipetting of such a small amount, inevitably this caused an excess)
-The solution of MDA formaldehyde imine was then left in a dropping funnel for ~1hr.
-in an RB, 120mg of HgCl2 (originally started with 20mg, then kept adding more to get a decent reaction rate)  and ~0.2g aluminium were amalgamated in a solution of MeOH.
-The amalgam mixture was brought to ~50°c and the MDA formaldehyde imine solution then dripped in.
-Reaction ran for ~2hrs, when most of the aluminium was used up, keeping in mind I used a decent excess of aluminium.
-Reaction volume was doubled using a solution of NaOH, then filtered to remove solids.
-The remaining liquid was extracted twice with xylene.

Yet to do the final work up to get the final result and yield (if any), will post when this is done. This is my first time witih Al/Hg and I must say I already dislike working with HgCl2, its a pain in the ass because of the precautions needed with cleaning etc. Seems like Al/Ga could be used, though im yet to find any good posts regarding its use (if anyone has any, please share).

Reference: http://www.erowid.org/archive/rhodium/chemistry/amphetamine.methylation.html

joejack

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Re: Monomethylation of Amphetamines
« Reply #1 on: August 23, 2011, 03:45:03 PM »
Perfect thread to ask this question, i have that link in my bookmarks, it has been for few months.I was intrested in the part 'Paraformaldehyde, Platinum Oxide and Hydrogen' part in monomethylation of phenethylamine.

The question, the resulting N-methyl 2-phenethylamine, how would i put this to words, is it like amphetamine that it stimulates mind and body or is it like phenethylamine so it gets destroyed by monoamine oxidase and does nothing?

letters

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Re: Monomethylation of Amphetamines
« Reply #2 on: August 23, 2011, 04:42:55 PM »
Klute of SM showed (with pictures) the succesful monomethylation of phenethylamines byfirst  using benzaldehyde to form a protective imine, then methylation with home-made (also pictorial by Klute is available) methyl tosylate, followed by hydrolysis to give a methylated amine. it is easy and simple. methyl tosylate is far less nasty then the usual methylating agents (DMS, MeI) but still will methylate your dna if given a chance, so use normal precautions.

dingbow

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Re: Monomethylation of Amphetamines
« Reply #3 on: August 24, 2011, 09:21:56 AM »
Klute of SM showed (with pictures) the succesful monomethylation of phenethylamines byfirst  using benzaldehyde to form a protective imine, then...
Yeah I saw you pointed this out in another thread, I dont have benzaldehyde though and tosyl chloride isnt available OTC from here.

Just test the presence of Hg2+ with NaI and wash your product with acetone till red color disappears.
Also see this http://127.0.0.1/talk/index.php/topic,938.msg25101.html#msg25101
Thanks will check out that thread, NaI isnt available OTC here either and I dont have any. Could probably make it with iodine I suppose. When you basify the whole thing though, does it not convert the Hg ion to elemental mercury?

dingbow

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Re: Monomethylation of Amphetamines
« Reply #4 on: August 25, 2011, 01:26:11 PM »
Final workup has just been completed and yielded absolutely nothing. Pretty disappointing.

Guess I might try again when I have more starting reagents to play with and up the scale a bit.

Not really sure what went wrong either, I was expecting something, even if it was a poor yield.

Enkidu

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Re: Monomethylation of Amphetamines
« Reply #5 on: August 25, 2011, 05:54:44 PM »
Guess I might try again when I have more starting reagents to play with and up the scale a bit.

No, you want to decrease the scale until you get it working.

dingbow

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Re: Monomethylation of Amphetamines
« Reply #6 on: August 27, 2011, 09:36:11 AM »
I know what your saying and thats generally what you would do, small scale until you have the reaction working.

But it was hard working with such small amounts (im no seasoned chemist by any means), my pipetting screw up wasnt the only one and I think I had a fair bit of mechanical losses. Might scale up to 2g amine.HCl next time and see how I go.

My assumption is that the reduction failed, given that you cant really go wrong forming the imine. Do you guys think I should dump the the whole imine solution into the Al/Hg or drip it in again like I first did?

jon

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Re: Monomethylation of Amphetamines
« Reply #7 on: August 30, 2011, 09:49:23 AM »
you are forgetting methyloxalate

dingbow

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Re: Monomethylation of Amphetamines
« Reply #8 on: August 30, 2011, 01:47:27 PM »
Not sure I follow.

Is it used in another monomethylation method?

Enkidu

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Re: Monomethylation of Amphetamines
« Reply #9 on: August 30, 2011, 06:21:11 PM »
Methyl oxalate won't work to methylate amines..

POSEIDON

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Re: Monomethylation of Amphetamines
« Reply #10 on: August 30, 2011, 11:52:47 PM »
Look this pdf
The chemists are a strange class of mortals, impelled by an almost insane impulse to seek their pleasures amid smoke and vapour, soot and flame, poisons and poverty; yet among all these evils I seem to live so sweetly that may I die if I were to change places with the Persian king.
— Johann Joachim

fries

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Re: Monomethylation of Amphetamines
« Reply #11 on: August 31, 2011, 12:55:10 PM »
I seem to remember someone saying that Hg/Al amalgam reduction on this imine might not produce what you expect it to...

Sedit

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Re: Monomethylation of Amphetamines
« Reply #12 on: August 31, 2011, 11:49:17 PM »
I expect it to produce Isoquinoline if acidic conditions are used.
There once were some bees and you took all there stuff!
You pissed off the wasp now enough is enough!!!

letters

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Re: Monomethylation of Amphetamines
« Reply #13 on: September 01, 2011, 04:31:48 PM »
if your mind is set on using formalin then you should use adam's catalyst under an H2 atmosphere. this works very well.

fries

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Re: Monomethylation of Amphetamines
« Reply #14 on: September 02, 2011, 08:28:28 AM »
That's the route that I was planing on... But I've not managed to find any OTC platinum compounds to substitute.

dingbow

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Re: Monomethylation of Amphetamines
« Reply #15 on: September 03, 2011, 02:54:50 AM »
if your mind is set on using formalin then you should use adam's catalyst under an H2 atmosphere. this works very well.
This would imply the imine formation is not the issue but rather the reduction.

Though im confused, Al/Hg reduction seems to be a simple reaction?!

Im going to give it another go when there is more amine available to experiment with. Im going to try Al/Ga.

Fancy catalysts are out of reach in this part of the world, for the OTC bee's
« Last Edit: September 03, 2011, 02:56:21 AM by dingbow »

letters

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Re: Monomethylation of Amphetamines
« Reply #16 on: September 03, 2011, 10:21:19 AM »
the imine formation will happen given the right conditions. aqueous conditions obviously retard its progress due to equilibrium, but it doesn happen non the less. an efficient reducing agent, which will attack the aldehyde much slower then it would the imine is whats called for. another thing to consider is that methylated amines, like the ones discussed in this forum, are more prone to further reaction then the primary amine, so it is easy to get double alkylated amine.
I have only tried al/hg with an aliphatic ketone and a short chain amine, and it works ok. workup is a bitch, but thats life... Adams catalyst is consistently reported in the old school literature as a suitable reduction catalyst.
You can also rely on thousands and thousands of posts and topics on the various drug forums, and even some literature articles, which consistently shows that with the common reducing agents (nabh4, al/hg etc) this type of reaction is usually unsuccessful due to both reasons ive listed above.

java

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Re: Monomethylation of Amphetamines
« Reply #17 on: September 03, 2011, 11:27:22 AM »
Reference Information

.....interesting 30 minute lecture on imines...

http://www.softconference.com/ACSchem/player.asp?PVQ=HGFE&fVQ=FHMGKM
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dingbow

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Re: Monomethylation of Amphetamines
« Reply #18 on: September 05, 2011, 12:20:55 PM »
the imine formation will happen given the right conditions. aqueous conditions obviously retard its progress due to equilibrium, but it doesn happen non the less. an efficient reducing agent, which will attack the aldehyde much slower then it would the imine is whats called for. another thing to consider is that methylated amines, like the ones discussed in this forum, are more prone to further reaction then the primary amine, so it is easy to get double alkylated amine.
I have only tried al/hg with an aliphatic ketone and a short chain amine, and it works ok. workup is a bitch, but thats life... Adams catalyst is consistently reported in the old school literature as a suitable reduction catalyst.
You can also rely on thousands and thousands of posts and topics on the various drug forums, and even some literature articles, which consistently shows that with the common reducing agents (nabh4, al/hg etc) this type of reaction is usually unsuccessful due to both reasons ive listed above.

I thought the whole purpose of forming the imine was to prevent overalkylation, which is the issue if you try to directly methylate the primary amine to secondary?

Interestingly, I only just noticed this bit of text from the erowid reference, under the platinum section:
"Originally about 20 ml of 37% formaldehyde solution was added (0.25 mole). In view of the reported danger of dimethylation of primary amines when formaldehyde is used, it appeared safer to use paraformaldehyde, since an exact amount could be weighed."

So it seems that having too much aldehyde can be an issue, which I did have. Using paraformaldehyde also removes any water from the reaction which is a plus.

Reference Information

.....interesting 30 minute lecture on imines...

http://www.softconference.com/ACSchem/player.asp?PVQ=HGFE&fVQ=FHMGKM

Thanks for the link Java, it again mentioned how water needed to be removed from the reaction. Using paraformaldehyde should get around this issue (though later in the presentation with the 'green' solvent they use, it says that more water speeds up the reaction! though I dont think its relevant here).

So I guess maybe I should form some paraformaldehyde from my formalin solution, dump the imine solution in wholesale rather then drip it in and see how it goes.

Interestingly the non polar solvent that was supposed to contain the secondary amine, which i gassed, I kept and now has a dark red tar like substance at the bottom. Seems like I extracted something from the reaction, just dont know what.
« Last Edit: September 05, 2011, 12:44:31 PM by dingbow »

dingbow

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Re: Monomethylation of Amphetamines
« Reply #19 on: September 05, 2011, 12:55:33 PM »
Look this pdf
Thanks for this! it discusses the issue of overalkylation, but reference 98 in the document also pointed me to:
hp://library.sciencemadness.org/library/books/organic_reactions_v4.pdf (page 174)

i'll have a read and see what I can dig up.