Mineral oil is intended to be a high boiling liquid reaction medium, not a solvent. The basic product is extracted out with white vinegar as the acetate salt.
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Mineral oil is intended to be a high boiling liquid reaction medium, not a solvent. The basic product is extracted out with white vinegar as the acetate salt.
Thanks for providing the page/reaction number references (which turns out to be pp. 412-415 (T#6)):
The operation that intrigued me is his use of freshly made AgCl to partially accomplish the demethylation of the quat salt by precipitating the iodide followed by pyrolysis & isolation via the picrate salt. It seems to me that there are too many steps/reagents involved here & that a good industrial or experimental chemist could simplify this scheme significantly. For example, picric acid is hard to come buy as it is classified as an explosive. Making fresh AgCl sounds tedious. And pyrolysis of indole compounds may produce byproducts.
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Hypaphorine
A Google search for the exhaustive methylation of Trp came up with this interesting alkaloid. Pharmacologically it is of interest for promoting sleep:
Lenticin or hypaphorine is a compound found in lentil extracts. It can also be detected in blood after an individual has consumed lentils and may therefore serve as a food biomarker. Lenticin is an indole alkaloid that is essentially an N-methylated form of tryptophan. It is known to be a sleep-inducing compound (PMID: 18571406). In plants it is an agonist of the plant hormone indole acetic acid.
https://pubchem.ncbi.nlm.nih.gov/compound/Hypaphorine#section=Pharmacology-and-Biochemistry
Ozawa M, Honda K, Nakai I, Kishida A, Ohsaki A:Hypaphorine, an indole alkaloid from Erythrina velutina, induced sleep on normal mice. Bioorg Med Chem Lett. 2008 Jul 15;18(14):3992-4. doi: 10.1016/j.bmcl.2008.06.002. Epub 2008 Jun 6.
A Google search for the exhaustive methylation of Trp came up with this interesting alkaloid. Pharmacologically it is of interest for promoting sleep:
Lenticin or hypaphorine is a compound found in lentil extracts. It can also be detected in blood after an individual has consumed lentils and may therefore serve as a food biomarker. Lenticin is an indole alkaloid that is essentially an N-methylated form of tryptophan. It is known to be a sleep-inducing compound (PMID: 18571406). In plants it is an agonist of the plant hormone indole acetic acid.
https://pubchem.ncbi.nlm.nih.gov/compound/Hypaphorine#section=Pharmacology-and-Biochemistry
Ozawa M, Honda K, Nakai I, Kishida A, Ohsaki A:Hypaphorine, an indole alkaloid from Erythrina velutina, induced sleep on normal mice. Bioorg Med Chem Lett. 2008 Jul 15;18(14):3992-4. doi: 10.1016/j.bmcl.2008.06.002. Epub 2008 Jun 6.
Wouldn't be my first choice as a reaction medium. At the very least you'd have to run the reaction under dry nitrogen or similar inert gas.
DMT from tryptophan - summary
Here is a general recap of my recent posts over months on converting store-bought L-tryptophan into DMT without the use of any hazardous or difficult-to-obtain reagents.
The classic approach to methylating that amine is to use methyl iodide. As a thought, methyl bromide is a commercial (and highly toxic) insecticide/fumigant & might be more readily available in cylinders from commercial sources that might not ask too many questions.
A gas at room temperature, methyl bromide readily penetrates skin, cloth, and other protective materials such as rubber and leather. It is nonflammable and toxic at low concentrations. Methyl bromide is odorless and odor provides no warning of hazardous concentrations.
Reference on the decarboxylation of Trp: The procedure involved the heating of tryptophan (1) in a relatively small amount of tetralin with catalytic amount of carbonyl compounds (2) as shown in the table until the evolution of carbon dioxide was ceased. Tryptamine (3) thus formed was cleanly distilled from the reaction mixture and a single crystallization yielded a pure product in good yield.
The highest yield for the most available carbonyl compounds (MEK) is about 85%. Note that the ketone is used in 'catalytic' amounts.
Purification of tryptamine via distillation involves very low pressure & possible kugelrohr-type short-path bulb-to-bulb distillation. B.p. :137 ?C (279 ?F) (0.15 mmHg)
https://erowid.org/archive/rhodium/chemistry/tryptamine.takano.html
An alternative purification method not involving high vacuum: 'A good way to purify tryptamine without having to resort to distillation under strong vacuum is to dissolve the crude tryptamine hydrochloride in water, adjust the pH to between 7.6 and 8.2 and extract the solution with chloroform. The pH is then adjusted to 14 with NaOH and the pure tryptamine is filtered off with suction and air dried. https://erowid.org/archive/rhodium/chemistry/tryptophan.html
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https://www.sciencedirect.com/science/article/pii/S0040402001852674
The reactions of thiolate ions derived from thiophenol and homocysteine with substituted quaternary ammonium salts result in alkyl transfer from nitrogen to sulfur.
Thiolate ions are known to scavenge alkyl groups from quaternary ammonium salts. Using cheap & readily available sodium mercaptobenzothiazole, I propose the following sequence:
A possible alternative thiolate is sodium thiophenoxide from a number of sources in the Orient, possibly obtainable as samples.
The reactions of thiolate ions derived from thiophenol and homocysteine with substituted quaternary ammonium salts result in alkyl transfer from nitrogen to sulfur.
Thiolate ions are known to scavenge alkyl groups from quaternary ammonium salts. Using cheap & readily available sodium mercaptobenzothiazole, I propose the following sequence:
A possible alternative thiolate is sodium thiophenoxide from a number of sources in the Orient, possibly obtainable as samples.
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S.J.B.
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It's likely that the oxygenated products being formed from turpentine in air at high temperature are (a) aiding in solubilizing the tryptophan and (b) acting as catalysts for the decarboxylation.
Could be but I'd have enough other things to concern myself with in this project without worrying turpentine-induced side products.
Check out my very recent post on using a commercially available thiolate to deiodomethylate the Trp derivative. I think it might work.
Check out my very recent post on using a commercially available thiolate to deiodomethylate the Trp derivative. I think it might work.
S.J.B.
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Yep, I imagine so.
A note about thiol compounds. One of the suggested thiolates is sodium thiophenoxide, which is converted to (methylthio)benzene in this reaction. These sulfur compounds are very smelly & are the same class of mercaptans used as odorants in natural gas, LNG & propane. Unless you live out in Kansas or Montana & the nearest neighbor is 15 miles away, expect a visit from the FD if someone nearby catches a whiff of this stuff. I'm not familiar with the sodium mercaptobenzothiazole or its ethyl ether derivative, but these are likely smelly also. Here is an MSDS for a 50% solution: https://www.columbuschemical.com/MSDS/SDS/Sodium Mercaptobenzothiazole 0032.pdf. Sounds like pretty nasty stuff requiring special handling, including adequate ventilation (fume hood), rubber gloves, full face mask respirator, etc.
The end product, 2-(methylthio)benzimidazole, is also hazardous: Contact with water liberates toxic, extremely flammable gas. Water-reactive. It us also likely to be very smelly, so disposal could be a problem. So this chemistry must be done in non-aqueous media.. Precipitation of the NaI should help drive the reaction toward completion.
How to separate the DMT base from the 2-(methylthio)benzimidazole while avoiding water is the current question. Passing the crude reaction mixture through a column bed of acidic ion exchange resin seems to be one approach, then washing the bed with a non-aqueous solvent before eluting the DMT. Care must be taken to make sure the solvent system used is compatible with the ion exchange resin.
The end product, 2-(methylthio)benzimidazole, is also hazardous: Contact with water liberates toxic, extremely flammable gas. Water-reactive. It us also likely to be very smelly, so disposal could be a problem. So this chemistry must be done in non-aqueous media.. Precipitation of the NaI should help drive the reaction toward completion.
How to separate the DMT base from the 2-(methylthio)benzimidazole while avoiding water is the current question. Passing the crude reaction mixture through a column bed of acidic ion exchange resin seems to be one approach, then washing the bed with a non-aqueous solvent before eluting the DMT. Care must be taken to make sure the solvent system used is compatible with the ion exchange resin.
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Metabolites from South Pacific sponge Hytrios sp.
Interesting paper on 5.6-dibrominated derivatives of DMT & hypaphorine. (https://pdfs.semanticscholar.org/1005/095fd9bfc7074ffe78dcff010b738e502b46.pdf). These are reported to exhibit antibacterial activity. In marine secondary metabolites, bromine addition to molecules is linked to increasing toxicity. It is therefore very doubtful that the native compounds would show any significant psychoactivity. Interestingly, it may be possible to convert 5,6-dibromo-N,N-dimethyltryptamine to DMT via catalytic hydrogenation to remove the bromine atoms.
Interesting paper on 5.6-dibrominated derivatives of DMT & hypaphorine. (https://pdfs.semanticscholar.org/1005/095fd9bfc7074ffe78dcff010b738e502b46.pdf). These are reported to exhibit antibacterial activity. In marine secondary metabolites, bromine addition to molecules is linked to increasing toxicity. It is therefore very doubtful that the native compounds would show any significant psychoactivity. Interestingly, it may be possible to convert 5,6-dibromo-N,N-dimethyltryptamine to DMT via catalytic hydrogenation to remove the bromine atoms.
Brominated secondary metabolites in marine invertebrates are toxic defensive compounds designed to deter predators & ward off diseases. They are too toxic to be psychoactive in humans, I believe. But they may have other activities, such as antidepressants & sedatives. See abstract below.
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https://www.ncbi.nlm.nih.gov/pubmed/18217716
J Nat Prod. 2008 Feb;71(2):186-9. doi: 10.1021/np070371u. Epub 2008 Jan 25.
Secondary metabolites from three Florida sponges with antidepressant activity.
Kochanowska AJ1, Rao KV, Childress S, El-Alfy A, Matsumoto RR, Kelly M, Stewart GS, Sufka KJ, Hamann MT.
Author information
Abstract
Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.
J Nat Prod. 2008 Feb;71(2):186-9. doi: 10.1021/np070371u. Epub 2008 Jan 25.
Secondary metabolites from three Florida sponges with antidepressant activity.
Kochanowska AJ1, Rao KV, Childress S, El-Alfy A, Matsumoto RR, Kelly M, Stewart GS, Sufka KJ, Hamann MT.
Author information
Abstract
Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.
[h=1]CONVENIENT DEALKYLATION OF QUATERNARY AMMONIUM SALTS[/h]
The New Journal for Organic Synthesis vol. 12 1980 no. 6
=================================================================
NaBH4 in polar solvents looks workable for dealkylating the quaternary ammonium salt.
Journal[h=1]Organic Preparations and Procedures International [/h][h=1]The New Journal for Organic Synthesis[/h]
[h=2]Volume 12, 1980 - Issue 6[/h]
The New Journal for Organic Synthesis vol. 12 1980 no. 6
=================================================================
NaBH4 in polar solvents looks workable for dealkylating the quaternary ammonium salt.
Journal[h=1]Organic Preparations and Procedures International [/h][h=1]The New Journal for Organic Synthesis[/h]
[h=2]Volume 12, 1980 - Issue 6[/h]
The active demethylating agent is a strong nucleophile thiolate anion. Any would do.
And to make it strong, use one that is primary thiol. Sodium hydroxide is strong enough to deprotonate it to active species.
Hate odour? Use larger nonvolatile one like a octadecanethiol or like.
And to make it strong, use one that is primary thiol. Sodium hydroxide is strong enough to deprotonate it to active species.
Hate odour? Use larger nonvolatile one like a octadecanethiol or like.
Thanks for the constructive input. The simplest is Sodium methanethiolate, which reacts to form methanethiol, which smells exactly like s**t. That may not be a negative as it does not resemble the higher MW gas odorants. It could be scrubbed with NaOH solution & sent to the sewer where it would be in good company. The gas could be fed to a drum of aqueous caustic & later pumped to the septic drain. This would avoid the troublesome end product you get using sodium mercaptobenzothiole. Not a bad idea.
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Still, once the pH decrease as when you drained it from your strongly basic trap into the sewer, the equation shifts back.
(Normal acid-base equation...) and it releases alot of volatile thiol, not good!
Imagine the odorants of these are nose-detectable in ppb range. Now you have moles of it....along sewage line.
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For more input, any demethylating agents you would find in literature works by SN2 mechanism, you will need a strong unhindered nucleophile for this, hydride is a good one as pee your above reference stated about LiAlH4 or selectride, however owing to the autoignition, flammability of these agent it is discourage to use in preparative scale, and limited to preparation for analysis, mostly.
On the second, primary thiol is very good nucleophile and will achieve similar dealkylation effect, so it gained more popularity of use despite the strong smell. The benzothiazole is one of the example to find a “less stench” thiol to perform such action, it is much better less smelly in comparison to like, methanethiol, but still.....bleh. That’s why i recommended the thiol that is large enough to be nonvolatile.
(Dont drain it tho, bacteria still able to digest them to H2S and lower stench thiol)
Another application of these demethylation thiol is, under stronger reaction, it is able to dealkylate aryl-alkyl-ether at >70% yield at correct conditions . (Say, codeine to morphine)
(Normal acid-base equation...) and it releases alot of volatile thiol, not good!
Imagine the odorants of these are nose-detectable in ppb range. Now you have moles of it....along sewage line.
Edit:
For more input, any demethylating agents you would find in literature works by SN2 mechanism, you will need a strong unhindered nucleophile for this, hydride is a good one as pee your above reference stated about LiAlH4 or selectride, however owing to the autoignition, flammability of these agent it is discourage to use in preparative scale, and limited to preparation for analysis, mostly.
On the second, primary thiol is very good nucleophile and will achieve similar dealkylation effect, so it gained more popularity of use despite the strong smell. The benzothiazole is one of the example to find a “less stench” thiol to perform such action, it is much better less smelly in comparison to like, methanethiol, but still.....bleh. That’s why i recommended the thiol that is large enough to be nonvolatile.
(Dont drain it tho, bacteria still able to digest them to H2S and lower stench thiol)
Another application of these demethylation thiol is, under stronger reaction, it is able to dealkylate aryl-alkyl-ether at >70% yield at correct conditions . (Say, codeine to morphine)
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Yes but it smells like normal sewage, not like a gas odorant which have higher MW. As it is a natural product, it could not be discriminated from the stuff normally in the sewer even with sophisticated test gear. And sodium methanethiolate is available as a convenient solid or solution
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