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Author: Subject: Synthesis N,N-Dimethyl tryptamine
GreenD
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[*] posted on 26-5-2011 at 14:34
Synthesis N,N-Dimethyl tryptamine


Shulgin makes DMT in a very odd manner, with extensive washes, drying, concentrating, and the use of reagents one isn't going to be able to come up with if one doesn't work in a lab.

However, in his synthesis of DET (diethyltryptamine) the synthesis is straight forward;
tryptamine is combined with ethyl bromide and hunig's base in a solvent and the majority of the product is the favored DET.

So, I was wondering why could not one synthesize DMT from methyl bromide? I see that it's boiling point is 3.9°C which most certainly may be the reason why it is not preferred - however, this does not mean it is impossible...

Methyl bromide is also easily (err... well obtained) from the elementary substitution reaction of methanol and HBr. The product could be isolated in an acetone/dry ice bath or with liq. nitrogen, or with great loss - ice water. The following reaction would have to be done as fast as possible with the tryptamine.

So, am I correct in thinking this is possible, but really messy? Especially since bromomethane is highly toxic and very volatile. But in a fume hood or with extremely proper care, this is viable, right?

My first assumption after seeing the extreme difference in the synthesis of DMT to DET was that methyl bromide is
1. either much more stable than ethyl bromide, and will not react favorably.
OR
2. Is extremely reactive, and will methylate the indolic nitrogen.

I believe 1 is closer to the truth, yes?
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[*] posted on 26-5-2011 at 19:23


You are certainly right that methyl bromide will not react "favorably." Alkylating tryptamine with a methyl halide will produce a tetraalkylammonium product if special conditions are not employed.

[Edited on 27-5-2011 by Bolt]
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[*] posted on 27-5-2011 at 12:58


So, i'm assuming since the leaving group does not change in the SN2 reaction, the reason a tetra-substituted ammonium is formed is due to the slight change in the bulk - otherwise I don't see why methyl bromide would be much more reactive than the ethyl bromide?

Either way - understood. I know that methyl iodide makes the ammonium salt, but I was wondering if lowering the efficacy of the leaving group (I -> Br) allows for the equilibrium to stay at the tertiary amine.
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[*] posted on 4-6-2011 at 05:57


Quote: Originally posted by GreenD  
So, i'm assuming since the leaving group does not change in the SN2 reaction, the reason a tetra-substituted ammonium is formed is due to the slight change in the bulk - otherwise I don't see why methyl bromide would be much more reactive than the ethyl bromide?

It has to do with the nucleophilicity of the involved amines. N-Methylalkylamines and N,N-dimethylalkylamines are more nucleophilic than the original alkylamine so the methylation goes all the way to the quaternary ammonium salt. The trend changes with ethylation where steric hindrance gets to play a role. Ethylations of primary amines can generally be stopped at the tertiary amine stage with surprisingly good selectivity, even making them the main product (dipropylations and homologous N,N-dialkylations with primary alkyl halides or sulfonates are even more selective). For the same reason it is possible to obtain N-isopropylalkylamines by monoisopropylation (diisopropylation of aliphatic amines is essentially impossible as far as literature goes, so the reaction stops at the secondary amine stage). Anilines and other aromatic amines are an exception and can be efficiently N,N-dimethylated under properly harsh conditions due to the thermodinamic equilibrium favouring tertiary amines under proper stoichiometry (the quaternization of anilines is much more reversible than it is with aliphatic amines).
Quote:
Either way - understood. I know that methyl iodide makes the ammonium salt, but I was wondering if lowering the efficacy of the leaving group (I -> Br) allows for the equilibrium to stay at the tertiary amine.

It does not have much to do with the leaving groups and the electrophilicity of the methylating reagent. The low electrophilicity of the methylating reagent could only prevent quaternization once it would be comparatively as low as it is the electrophilicity of the end quaternary ammonium salt. For example, if the N,N-dimethylation would be performed with a quaternary methylammonium salt, then the reaction would stop at the thermodynamic equilibrium, meaning the end product could be set to mainly the tertiary amine. Obviously, methylating an amine with a quaternary methylammonium salt requires conditions probably too harsh for such substrates as discussed here (though there is a post at Hyperlab claiming success). You can always try and tell us how it went. You can also try to use other onium salts of intermediate electrophilicity, like the easily made trimethylsulfonium bromide.




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[*] posted on 4-6-2011 at 11:39


Isn't the goal of this thread to make a psychedelic drug? Don't we frown upon that? Even though the discussion here is really interesting and higher level.



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[*] posted on 5-6-2011 at 02:41


Quote: Originally posted by hkparker  
Isn't the goal of this thread to make a psychedelic drug? Don't we frown upon that? Even though the discussion here is really interesting and higher level.

No we do not frown upon that. That is not the forum policy, as far as I know. What we frown upon are kewls, greed and malice.
"We" as the forum collective are supposed to be (amateur) scientists, so we are supposed to behave scientificaly as long as the discourse is kept on a scientific level without the annoying tweaker's delirium, expressions of greed, kewlishness, SWIMing, street slang, pretending idiotism, spoonfeed requests or recipe questions. If you see any post that does not conform, please use the report button.
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[*] posted on 5-6-2011 at 12:05


Quote: Originally posted by Nicodem  

No we do not frown upon that. That is not the forum policy, as far as I know. What we frown upon are kewls, greed and malice.
"We" as the forum collective are supposed to be (amateur) scientists, so we are supposed to behave scientificaly as long as the discourse is kept on a scientific level without the annoying tweaker's delirium, expressions of greed, kewlishness, SWIMing, street slang, pretending idiotism, spoonfeed requests or recipe questions. If you see any post that does not conform, please use the report button.


Ok, thank you.




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[*] posted on 5-6-2011 at 12:50


You can cure a drug problem but ya can't fix stupid!




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[*] posted on 12-6-2011 at 11:41


I think you can fix some stupid with a bit of a certain drug :).

Thanks Nicodem - I think I am understanding, but I'll have to re-read that again. You are saying that the governing factor here is not the leaving group (the R->I or the R->Br) but rather the nucleophilicity of the amine. The nucleophilicity of a tertiary amine is by far the governing factor for methylations with methyl-halogens. [ correct ? ]

Changing to the a methyl salt may create a better equilibrium for the product to be less substituted. I think I am seeing it.

I don't know the trends of nucleophilicty and electrophilicity, and feel I am in a deep rut without such understandings, while sitting on a chemistry degree - i feel a bit foolish.

So in order of nucleophilicity it would go like;
Primary amine, sec. amine, tertiary amine quaternary methylammonium salt, quaternary amine, halomethane?

Is this what I am to be understanding? At any rate I will be researching the diethyl first, then looking into dimethyl. But it does make sense now that sterics begin to play the biggest role once larger alkylating agents come into play - however, I was sure I saw Diisopropyl tryptamines before, or perhaps it was n-isopropyl-n-ethyl[tryptamine] or something of the like...

PS - researching drugs is not the same as selling drugs, buying drugs, or even using drugs. And that is not even to speak of the different social and psychological groundings at play when one speaks about tryptamines while another speaks of amphetamines...

The search for understanding and learning should never be frowned upon.

[Edited on 12-6-2011 by GreenD]
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[*] posted on 18-6-2011 at 17:11


Quote: Originally posted by GreenD  
I was sure I saw Diisopropyl tryptamines before, or perhaps it was n-isopropyl-n-ethyl[tryptamine] or something of the like...
[Edited on 12-6-2011 by GreenD]

Yes, there are quite a few diisopropyl tryptamines, as well as n-methyl-, and n-ethyl-n-isopropyl tryptamines that have been synthesized.
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[*] posted on 18-6-2011 at 21:33


Unlike DMT and DET, the di-isopropyl tryptamine was administered orally in the trials in the 60's by Shulgin, Weingartner, Soskin, et.al.

The classical synthesis of di-alkyl tryptamines was by direct alkylamination of indol-3-yl-glyoxyl acid chloride followed by a hydride reduction.



[Edited on 19-6-2011 by arsphenamine]
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[*] posted on 18-6-2011 at 23:07


Quote: Originally posted by GreenD  
however, I was sure I saw Diisopropyl tryptamines before, or perhaps it was n-isopropyl-n-ethyl[tryptamine] or something of the like...

DiPT was specifically mentioned in the thread Nicodem dug out for you. :(
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[*] posted on 19-6-2011 at 05:30
Yup...


Quote: Originally posted by ssitch  
Quote: Originally posted by GreenD  
I was sure I saw Diisopropyl tryptamines before, or perhaps it was n-isopropyl-n-ethyl[tryptamine] or something of the like...
[Edited on 12-6-2011 by GreenD]

Yes, there are quite a few diisopropyl tryptamines, as well as n-methyl-, and n-ethyl-n-isopropyl tryptamines that have been synthesized.



A few years back a whole bunch of "Shulgin's Specialties" showed up for sale as Research Chemicals. They had quite a run in the 1999 to 2003 period until the DEA emergency scheduled most of them into Schedule 1 drugs (like LSD, heroin, marijuana) thus ending their common sales on the internet.

One very popular one was 5-MeO DIPT: N,N Diisoproyl-5-Methoxy Tryptamine. There were all sorts of weird combos, some having Bromine on the ring, others Sulfur. One of the latter resulted in three deaths. It was 2-CT-7: 4-(n)-Propylthio-2,5-Dimethoxy Phenylethylamine. This one was most likely the cause of three deaths; all via sorting a good sized dose (about 50mg)!! The main trouble is this chem has a really sharp dose/response curve and needs a scale accurate at the mg level. I doubt that kind of scale was available to most users. A threshold dose is in the 4mg to 8mg range. 20mg to 30mg is considered a full dose. So it's not hard to see how this chemical was pretty easy to OD on.

A flashback on Shulgin. Back in my last year at college (1978 to 79) I needed to do a presentation on structure/activity relationships. During my research I came upon Shulgin's work on Phenylethylamines. It was great; I couldn't believe the large number of weird PEAs he had dose/response data on. But one thing really puzzled me. Some of the results were way out of line with your basic predicted values. I wondered how the heck he knew they had that response. Then 20 years later I read PHIKAL (Phenylethylamines I Have Known and Loved) and found my answer. He got those values empirically! He and his friends had those drugs multiple times and rated their effects :o Now there's a host with the most :D


So yes, sticking on a longer carbon chain is no big deal. Not surprisingly, this type of modification tends to increase the duration of the drug's effect.
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[*] posted on 21-6-2011 at 14:48


The name escapes me, I believe it to be Chris Douglas, but there is a researcher who is in the somewhat more modern version of Shulgin - and has been the "reason" for the rise in new research chemicals, especially in Europe.

I read one of his papers from a long while back and was extremely interesting in the pharamacology of some substances. They really don't know why some exhibit activity, while others don't. At one point, due to his literature papers ending up in the households of many research chemical cookers/suppliers - he decided to completely discontinue any research on *one* certain chemical. Some may have found it, but I don't know what it is - but he quotes

"This one would have been just too powerful, and I didn't want it to get into the wrong hands"

I also don't know if it was a tryptamine or a phenethylamine... Intriguing none the less.
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[*] posted on 14-7-2011 at 20:28


Shulgin's entry on DMT in TiHKAL mentions a few ways of reducing the product of alkylation with methyl iodide to the tertiary amine.

Quote:

The demethylation of the thiophenolate salt: A suspension of 2.5 g N,N,N-trimethyltryptammonium iodide in 25 mL MeOH was brought into solution by heating, and treated with 1.0 g Ag2O. The mixture was heated for 10 min on the steam bath, the solids removed by filtration and washed with an additional 20 mL MeOH. The methanol solutions were treated with 1.0 g thiophenol and the solvent was removed under vacuum. The resulting viscous oil (2.12 g) was heated with a flame to the reflux point and there was extensive bubbling. After 5 min, the light colored reaction mixture was cooled to room temperature, dissolved in 50 mL CH2Cl2, and extracted with two 25 mL portions of dilute HCl. These were pooled (pale yellow color), made basic with 5% aqueous NaOH and extracted with 3x25 mL CH2Cl2. After removal of the solvent from the pooled extracts, the residue (an amber oil, 1.04 g) was distilled at the KugelRohr. A white oil distilled over at 130-140 °C at 0.1 mm/Hg, and crystallized spontaneously. This distillate weighed 0.77 g, and was recrystallized from boiling hexane after decanting the solution from a small amount of insolubles. There was thus obtained 0.40 g of dimethyltryptamine (DMT) with a mp 67-68 °C. The distillate contained about 3% of 2-Methyl-1,2,3,4-tetrahydro-b-carboline (parent peak mass 186, major peak mass 186) as an impurity which was lost upon recrystallization.


What I'd like to know is what the underlying chemical reactions taking place are, and how this relates to the general dealkylation of quaternary ammonium salts.

[Edited on 15-7-2011 by sentinel097]
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[*] posted on 15-7-2011 at 07:46


Quote: Originally posted by sentinel097  
What I'd like to know is what the underlying chemical reactions taking place are, and how this relates to the general dealkylation of quaternary ammonium salts.

It is called bimolecular nucleophilic substitution (SN2 by using mechanistic shorthands). It is one of the most common mechanisms in organic chemistry, being one of the most common way the nucleophiles react with the electrophiles. It has no intermediate, meaning that it does not proceed stepwise, so there are no other chemical reactions taking place for you to comprehend. In this particular case you quote, the nucleophile is the benzenethiolate anion and the electrophile is the ammonium cation.

The SN2 is usually the first polar mechanism thought to students. So, if you are interested you can undoubtedly find lots of pedagogic material about it. Otherwise, I already provided an answer to this topic in another thread.




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[*] posted on 15-7-2011 at 08:15


I don't think he's talking about the methylation reactions, Nicodem - the starting material in the sequence he posted is the quaternary ammonium salt.

I don't know a lot about this mechanism, but I understood that it was a free radical transfer of an alkyl group from the nitrogen to the sulfur of the thiophenol. I've also seen homocysteine used instead of thiophenol. I don't know what the Ag2O is for.
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[*] posted on 15-7-2011 at 08:54


Quote: Originally posted by fledarmus  
I don't think he's talking about the methylation reactions, Nicodem - the starting material in the sequence he posted is the quaternary ammonium salt.

I was not talking about the N-methylation reaction, but about the N-demethylation reaction described in the quote from TiHKAL. That is a normal SN2 reaction with thiophenol as commonly used for N-demethylation or debenzylation of quaternary ammonium salts. It is not a SET type of reaction as it works with nucleophiles other than thiolates as well. Also, there is a mechanistic study that confirms that the reaction of ammoniums with benzenethiolate anion is indeed a SN2 [2]. Ironically, some N-demethylations of more electrophilic ammonium salts work even with amines as nucleophiles (e.g., with DABCO [3] or in ethanolamine reflux [4]).

The Ag2O is only used as an insoluble base to form the corresponding ammonium hydroxide that is then neutralized with thiophenol. Evaporation of the solvent then leaves the ammonium benzenethiolate. Personally I prefer the general methods as described elsewhere, but Shulgin is a meticulous analytical chemist and this often shows up in his experimental work. His unortodox approaches are often quite interesting. If he was an organic synthetic chemist by profession, he would often chose less creative approaches.

[1] Tetrahedron Lett. 1966, 7, 1375–1379. & Tetrahedron Lett. 1969, 10, 635–638.
[2] Can. J. Chem. 1975, 53, 3216–3226. & Can. J. Chem. 1979, 57, 1089-1097.
[3] Synthesis 1972, 702.
[4] http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p1018




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[*] posted on 15-7-2011 at 09:29


Thank you for the references Nicodem - I don't have time to do a full comparison now, but I will get to them this evening when I get off work.

In return, I'd like to point you to some work by Hillhorst. She studied the mechanism of especially biological dealkylations, but her model system was similar to the thiophenol reaction described. She does refer to the 1966 Tet Lett paper you mentioned as claiming an Sn2 mechanism, but her own research using substituent effects, competitive dealkylation between benzyl and methyl groups, and C13 labeled methyl groups led her to the conclusion that this was a radical mechanism.

I don't see a base in the procedure described by Sentinel097, which may make the difference. More research for me...

Hillhorst et al, Tetrahedron 50(26), 7837-7848 (1994)

Available at http://dare.uva.nl/document/34201
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[*] posted on 15-7-2011 at 15:18


That is an interesting article that I already encoutered in a different context, but forgot about the hypothesis given about the alkylation of thiolates with ammonium salts. It is true that their results are anomalous in regard to the SN2 hypothesis, but there are several things they did not consider:

a) A switch of mechanism for p-nitrobenzyl and benzhydryl groups transfer is likely. Both these groups are ideal for the proposed SRN1 mechanism. It might just be that ammonium salts for some reason enhance the SRN1 pathway in some benzylic substrates that otherwise would not be expected as suitable (e.g., it is expected for p-nitrobenzyl, but not so obvious for benzhydryl). It appears to me that pyridinium salts have such an ability, though for some reason nobody ever realized this.

b) Even though possible in debenzylations, I don't think an SRN1 mechanism is possible for demethylations. A methyl radical would almost certainly abstract the hydrogen from acetonitrile before reacting with the thiolate. This is further support for the switch of mechanism on specific substrates (kind of like is known in the reactions of benzyl vs. p-nitrobenzyl halides with nitroalkanes). Also, it should be easily verified if the N-demethylations of ammonium salts with PhSK involves a methyl radical. If so, then the demethylation would be inhibited by the presence of PhSH due to ease of hydrogen abstraction, giving PhSSPh instead of PhSMe.

c) The authors did not cite the Can. J. Chem. 1975 and 1979 articles, which indicates they were unaware of these studies on the SN2 transition state in the benzylation of benzenethiolates with benzylammonium salts.

d) I learned the lesson that whenever sulfur is around, single electron transfer (SET) mechanisms, like the SNR1 is, are always a likely possibility. The alkylations with sulfonium salts are also known to have non-SN2-like selectivity in alkyls reactivity (Bull. Chem. Soc. Jpn. 1990, 63, 2593–2600). I think this anomaly is not yet satisfactorily explained, but at least it is not present in the same form in ammonium salts, where reactivity of most alkyl groups still follows the SN2 criteria for "normal" nucleophiles (other than thiolates).

Edit: I just realized that the mechanism in the article implies the alkyl radical couples with a thiophenol radical, which is not the case for a SNR1 pathways where the radical would be attacked by the benzenethiolate forming an anion radical which then donates the electron to another ammonium ion, thus restarting the cycle. Radicals can only couple in solvent cages else the chance of encounter is near to nonexistent due to negligible concentrations. However, a radical coupling pathway would also be possible if the electron transfer and radical coupling occur sequentially inside the initial ion pair complex faster than it decomposes due to vanishing electrostatic interaction. Such a SET mechanism would also explain the above mentioned anomalies observed in the alkylations with sulfonium salts.

[Edited on 16/7/2011 by Nicodem]




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[*] posted on 29-7-2011 at 18:05


The TiHKAL entry also details a total synthesis from indole, which I assume is what GreenD was originally referring to. I think the same process could be applied to indole-3-carbinol with some adjustments like first converting it to the chloride ester for preparation of the corresponding organolithium compound, and replacing oxalyl chloride with phosgene, but other than that I see no reason why it wouldn't work, theoretically speaking.
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