Book II of PiHKAL: A Chemical Love Story. Alexander & Ann Shulgin #161: TMA-5
SYNTHESIS: A solution of 100 g 1,2,4-trimethoxybenzene in 1 L hexane was cooled to 15 °C and treated with 400 mL of a 15% solution of n-butyllithium in hexane. A white precipitate formed immediately, and stirring was continued for an additional 2 h while the reaction returned to room temperature. There was then added a solution of 40 g freshly distilled propionaldehyde in 100 mL hexane. The reaction was exothermic and, as the stirring was continued, the precipitate gradually dissolved. Stirring was continued overnight at room temperature. There was then added 1 L H2O, and the reaction was acidified with HCl. The hexane phase was separated, and the remaining aqueous phase was extracted with hexane, then with Et2O. The pooled organic extracts were stripped of solvent under vacuum, and the residue distilled to give 60 g ethyl 2,3,6-trimethoxyphenyl carbinol, with an index of refraction nD20 = 1.5192. Anal. (C12H18O4) C,H. From the Et2O extracts above, additional carbinol was obtained, containing a small amount of the starting 1,2,4-trimethoxybenzene. The two materials were readily separated by vacuum distillation, providing an additional 21 g of carbinol.
The above alcohol, 60 g of ethyl 2,3,6-trimethoxyphenyl carbinol, was stirred without solvent and cooled to 0 °C with an external ice bath. There was then added 80 g PBr3 at a rate that maintained the temperature below 60 °C. At the end of the addition, there were added quantities of chipped ice, followed by H2O. The reaction mixture was extracted with 3×100 mL Et2O, and removal of the solvent provided 60 g of 1-bromo-1-(2,3,6-trimethoxyphenyl)propane which was used in the following dehydrobromination step without further purification.
A solution of the above 60 g of 1-bromo-1-(2,3,6-trimethoxyphenyl)propane in an equal weight of EtOH was treated with 120 g of flaked KOH. The exothermic reaction was allowed to run its course with stirring continued overnight. The mixture was then quenched in H2O and extracted with 3×200 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a crude product which contained no starting bromo material, but which was contaminated with an appreciable quantity of the ethoxy analogue, 1-ethoxy-1-(2,3,6-trimethoxyphenyl)propane. This impure product was heated briefly to 80 °C with 50% H2SO4. Cooling, dilution with water, and re-extraction with 3×100 mL CH2Cl2 gave, after removal of the volatiles under vacuum, 1-(2,3,6-trimethoxyphenyl)propene. This was distilled to provide 7.0 g of a clear oil that was a 12:1 ratio of the trans- and cis-isomers.
A well-stirred solution of 6.8 g of the mixed isomers of 1-(2,3,6-trimethoxyphenyl)propene in 40 g of dry acetone was treated with 3.2 g pyridine and cooled to 0 °C with an external ice bath. There was then added 6.5 g tetranitromethane over the course of 1 min, the stirring was continued for an additional 2 min, and then the reaction mixture was quenched by the addition of 2.2 g KOH in 40 mL H2O. There was additional H2O added, and the organics were extracted with 3×75 mL CH2Cl2. The solvent from the pooled extracts was removed under vacuum, and the 5.3 g residue distilled at 0.2 mm/Hg. A fraction boiling at 150–170 °C proved to be largely 2,3,6-trimethoxybenzaldehyde. A second fraction (170–200 °C at 0.2 mm/Hg) also spontaneously crystallized to a yellow solid. This was recrystallized from MeOH to provide, after drying to constant weight, 2.8 g of 2-nitro-1-(2,3,6-trimethoxyphenyl)propene with a mp of 73–74 °C. Anal. (C12H15NO5) C,H.
To a refluxing and stirred suspension of 2.4 g LAH in 300 mL anhydrous Et2O and under an inert atmosphere, there was added a solution of 2.4 g 2-nitro-1-(2,3,6-trimethoxyphenyl)propene in 100 mL anhydrous Et2O. The mixture was held at reflux for 4 h, cooled, and then the excess hydride cautiously destroyed by the addition of 1.5 N H2SO4. There was then added 40 g potassium sodium tartrate followed by sufficient aqueous NaOH to raise the pH to >9. The Et2O phase was separated, and the remaining aqueous phase extracted with 3×100 mL CH2Cl2. The organic phase and extracts were combined, and the solvent removed under vacuum yielding 1.8 g of a colorless oil. This was dissolved in 200 mL anhydrous Et2O which was saturated with anhydrous HCl gas. There was generated a thick oil that slowly crystallized. The resulting white crystalline solid was removed by filtration, providing 2.2 g 2,3,6-trimethoxyamphetamine hydrochloride (TMA-5). The mp was 124–125 °C. Anal. (C12H20ClNO3) C,H.
DOSAGE: 30 mg or more.
DURATION: 8–10 h.
QUALITATIVE COMMENTS: (with 20 mg) “There appeared to be a slight stimulation. Modest eye dilation, but normal pulse. If this is the marginal edge of intoxication, then it is not a psychotomimetic, but a stimulant. Go up with care.”
(with 30 mg) “Intense introspection. Comparable to about 75 micrograms of
EXTENSIONS AND COMMENTARY: TMA-5, as was the case with
Pharmacologists have developed quite an art in the design and evaluation of animal behavior models for the study of psychedelic drugs. They have always faced two formidable tasks, however. There is the qualitative question: is the drug a psychedelic? And there is the quantitative question: how potent is it?
The first question is addressed by taking a number of known psychedelic drugs, and searching for some animal responses that are common to all. Since there is little logic in the argument that animals can experience, let alone reveal, altered states of consciousness or fantasy fugues or colored imagery, the investigator must look for objective signs such as conditioned responses to stimuli, or unusual behavior. If one explores ten drugs that are known psychedelics, and all ten produce, say, bizarre nest-building behavior in mice, and an eleventh drug of unknown pharmacology does exactly the same thing, then the eleventh drug can be suspected of being a psychedelic drug.
And the second question, how potent, is answered by seeing how much of the drug is required to evoke this standardized behavior. This is called the dose-response curve, in which the more drug you give, the more response you get. This curve gives confidence that the drug is indeed responsible for the activity that is seen, as well as giving a quantitative measure of that activity.
But this entire discipline depends on the acceptance of the fact that the first ten drugs are indeed psychedelic materials. And these inputs can only come from human trials. What is the validity of these assumptions with TMA-5? Not very good. The statement that it is psychedelic has actually been published in reviews solely on the basis of the above two studies; the potency has been put at some ten times that of
The two-carbon analogue of TMA-5 is 2,3,6-trimethoxyphenethylamine (or
About PiHKAL • info
This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The errata and changes page has further details.
“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
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PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
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