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Book II of PiHKAL: A Chemical Love Story, by Alexander & Ann Shulgin #162: TMA-6
#162 TMA-6: 2,4,6-Trimethoxyamphetamine

#162 TMA-6 SYNTHESIS: To a solution of 100 g phloroglucinol dihydrate in 320 mL MeOH there was added 55 mL of concentrated H2SO4, and the clear solution held under reflux conditions overnight. After cooling, there was added 500 mL H2O, and the bulk of the MeOH was removed under vacuum. The residual oil was extracted with Et2O, and the removal of this left 60 g of a red oil as residue. This was dissolved in 300 g methyl sulfate (caution, this is extremely toxic through skin contact, and any exposure must be flushed thoroughly with dilute ammonium hydroxide). With good stirring, this was cautiously treated with 500 g of 40% aqueous KOH, and the exothermic reaction allowed to run its course. Extraction with 3×100 mL Et2O gave, after evaporation of the solvent from the pooled extracts, an oil that became largely crystalline. This was suspended in 100 mL hexane, and filtered through a coarse fritted funnel. With evaporation there was obtained 57 g of 1,3,5-trimethoxybenzene as a pale amber solid that melted at 44–50 °C. A sample purified by recrystallization from EtOH had the proper mp of 54–55 °C.

A mixture of 62.9 g N-methylformanilide and 71.3 g of POCl3 was allowed to stand for 0.5 h producing a light claret color. There was then added 30.9 g of 1,3,5- trimethoxybenzene and the mixture heated on the steam bath for 2 h. The reaction mixture then was poured into chipped ice, and allowed to stir for several h. The dark gummy mess was extracted with 2×100 mL Et2O (this was discarded) and then with 4×200 mL CH2Cl2. The latter extracts were pooled, and stripped of solvent under vacuum yielding 14 g of an amber solid. This was recrystallized from 80 mL boiling MeOH (with decolorizing charcoal employed and filtration of the boiling solution through paper) to give 10.0 g of 2,4,6-trimethoxybenzaldehyde as a white crystalline solid with a mp of 115–116 °C. The literature values are generally one-degree ranges, and they are reported as high as 121 °C. The malononitrile adduct was prepared from a solution of 0.5 g aldehyde and 0.5 g malononitrile in 10 mL warm MeOH treated with a drop of triethylamine. There was an immediate formation of a yellow crystalline mass which was removed by filtration, washed with EtOH, and air dried. The yield of 2,4,6-trimethoxybenzalmalononitrile was 0.5 g and the mp was 174–175 °C. Anal. (C13H12N2O3) N.

A solution of 5 g 2,4,6-trimethoxybenzaldehyde in 20 g nitroethane was treated with 1.0 g of anhydrous ammonium acetate and held on the steam bath for 24 h. The excess solvent/reagent was stripped from the deep-red colored solution under vacuum yielding a residue that spontaneously set to a crystalline mass. This was well triturated under 5 mL MeOH, filtered, and washed with 3 mL additional MeOH to give 5.4 g of 2-nitro-1-(2,4,6-trimethoxyphenyl)propene as yellow crystals. The mp of the crude material was 135–142 °C which could be raised to 147–148 °C by recrystallization from EtOH. The use of an alternate procedure for the synthesis of this nitrostyrene, using acetic acid as solvent and a stoichiometric amount of nitroethane (and ammonium acetate as catalyst), gave very poor yields. The use of butylamine as catalyst gave considerably better results.

A suspension of 50 g LAH in 1 L anhydrous THF was placed under an inert atmosphere, stirred magnetically, and brought to a gentle reflux. There was added a total of 56.9 g 2-nitro-1-(2,4,6-trimethoxyphenyl)propene as a saturated solution in THF. This was achieved by letting the condensed THF drip through a Soxhlet thimble containing the nitrostyrene with direct addition to the reaction mixture. The solubility was extremely low. The stirred mixture was maintained at reflux for 36 h, generating a smooth creamy gray color. After being brought to room temperature, the excess hydride was destroyed by the patient addition of 50 mL H2O, followed with 50 mL 15% NaOH (still some heat evolved) and then 150 mL additional H2O. Stirring was continued until the insoluble salts were white and loose. These solids were removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the 73 g of pale amber residue dissolved in 200 mL IPA, neutralized with approximately 50 mL concentrated HCl, and diluted with 2 L anhydrous Et2O. A lower, oily phase separated slowly set up as a crystalline mass. This was removed by filtration, Et2O washed, and allowed to air dry to constant weight. The weight of 2,4,6-trimethoxyamphetamine hydrochloride was 41.3 g and the color was an off-white. There was a tendency to discolor upon air exposure. The mp was 204–205 °C which was increased to 207–208 °C upon recrystallization from IPA. The literature gives a mp of 214–215 °C for this salt after isolation and purification as the picrate salt (with a mp 212–213 °C from EtOH).

DOSAGE: 25–50 mg.

DURATION: 12–16 h.

QUALITATIVE COMMENTS: (with 25 mg) “I was outside at the California-Washington State football game, which was completely nutty. As was I. With the crowd activity, it was impossible to separate the drug’s action from the environment. Later I simply sat in the car, and tried to define what the effects really were. Things were completely benign, there was ease with concepts, and writing was good and smooth. At twelve hours, comfortably down. Maybe a plus two.”

(with 35 mg) “My body was tingling all over, and there were times when walking was unsteady. Thinking was a little difficult, as I was quite intoxicated most of the day (all of the day, now that I think that over). To accomplish anything, such as toasting the toast in the toaster, was difficult. And things were so funny most of the time. Setting the table for supper, six hours later, proved to be hilarious. I like to think of the day as a mixture of the mad hatter’s tea party, and a trip to the moon. We were all still intoxicated at bedtime, whatever time that was. Had difficult time sleeping. If I were to repeat, would go lighter in dosage, I feel.”

(with 40 mg) “This experiment was begun at noon of a cool rainy day. Almost all of the day had to be spent indoors, without benefit of sunshine, This is worth mentioning because there was, for the first eight hours of the experiment, a decided feeling of inner chill which might not have occurred so strongly had it been a warm day. Most, if not all, of the other eight subjects also reported the same chill. There was some visual sparkle which persisted throughout. At the two hour point a minor but persistent stomach queasiness came on, preceded by a diarrhea-like bowel movement. There was no impairment of speech, but there was some halting quality to all thought processes. It was easy to talk about personal matters, but there did not seem to be a significant insight increase. Appetite for food was lessened. Sleep was decidedly difficult after the effects of the material seemed otherwise gone.”

(with 40 mg) “As the experience grows in intensity for the first four hours, I feel a strange mixture of plateaus, exuberance, and strong negative feelings, all replacing each other. I found myself inside a stout, hemispherical shell, curled up in the solid part, thoroughly walled off but absolute master within the shell, calling all shots, making all decisions, in complete control. Moving beyond the half-shell meant becoming vulnerable, which I refused to do. Consequently my difficulty in hearing what other people say, becoming involved in their perceptions and lives. I keep relationships shallow, pull away inside my shell rather than become involved. I like to be by myself. This was a great revelation; I had never seen it before. This material had an enormous drive. I feel extremely grateful for exposing a very deep personal problem.”

(with 50 mg) “My previous try at this level produced a record that said, ‘alteration of consciousness, but no visual, no anything,’ and oh my, surprise! It was very, very active, visual, colorful, etc., etc. Good talking, clear and steady control of body, despite intense energy flow. Extremely funny—great humor, wonderful laughter.”

EXTENSIONS AND COMMENTARY: Here is a simple and easily made compound that might well bid fair to be one of the most rewarding and pleasurable of the methoxylated amphetamines. It is fully as potent as its counterpart, TMA-2. This latter compound, with its 2,4,5-trisubstitution pattern, has served as a template from which an immense family of very active and fascinating drugs have arisen. The 2,5-dimethoxy aspect has been kept intact, and modifications in the 4-position have given rise to treasures such as DOM, DOB, DOET, DOI, and the Aleph compounds. And, of course, the entire world of the 2C-X’s has exploited this same orientation.

Here, there is the blatant, parallel call from TMA-6. It can serve, as the 2,4,6-counterpart, as a similar template compound. And the first indicators are that, in keeping the 2,6-dimethoxy aspect intact, a completely analogous series could be made, again with modifications of the 4-position. These have been named the psu-series, or psi-series, as an abbreviation for the prefix, pseudo, and can be differentiated from the 2,4,5-things with the use of the Greek letter “Psi”. Thus there is the Ψ-DOM (called Z-7 in this book, and certainly an active compound), and Ψ-DOB, Ψ-DOET, Ψ-DOI, and the Ψ-ALEPH. And, of course, the Ψ-2C-X counterparts (Ψ-2C-D, Ψ-2C-B, Ψ-2C-E, Ψ-2C-I, Ψ-2C-T)). I would expect all of them to be active and, certainly, some of them interesting. They will be considerably more difficult to synthesize. However, some of them, specifically things such as Ψ-2C-T-4, have already been prepared, and are being evaluated.

([Erowid Note: Gamma vs Psi Greek letters : The original digital transcription of PiHKAL included an error throughout that the uppercase Greek letter Psi was transcribed as “Gamma”. Hopefully we have fixed these problems now.]

One of the guiding premises of this Book II was to make all recipes employ commercially available materials as starting materials. And in the case of TMA-6, the required benzaldehyde (2,4,6-trimethoxybenzaldehyde) is an easily obtained trade item from any of several supply houses. Why not start the recipe there? Why tell how to make it from 1,3,5-trimethoxybenzene (also presently available from commercial sources) and how to make the ether in turn, from phloroglucinol? This simply reflects a valid paranoia of our times. Today the aldehyde is available (at $2/g) and can be easily purchased. But tomorrow? What about in the year 2003? Who can tell what will, or will not, be easily available then? There might be a world-wide acknowledgment that the “war on drugs” is more destructive than any drug itself could ever be, and every law that had been written in the attempt to dictate human behavior will have been transformed into a force that truly educates and allows choice. This might really happen. But maybe, on the other hand, no fine chemicals may be permitted to be held in any hands, at any price, except for those of licensed chemists and in authorized laboratories. The black market price for the aldehyde might be $1000/g with another $1000 for protection.

But, it will be impossible to remove phloroglucinol from availability. It is available as a natural component in the free form, in sources as diverse as the cones of the Sequoia sempervirens (the coast redwood tree) and species of Camillia (that provides the leaves of our morning tea). And combined with a molecule of glucose in the form of its glucoside, it is called phlorin, and it is present in the discarded rinds of almost all citrus fruits as well as the resins from many of the Eucalyptus species. And one step yet further back into nature, there is a dihydrochalcone glucoside called phloridzin which practically drips out of all parts of the apple and pear trees except for the apple or pear itself. It, on base hydrolysis, gives phlorin, which on acid hydrolysis gives phloroglucinol, which when dissolved in methanol and sulfuric acid gives Q . Nature is indeed most bountiful.

The phenethylamine homologue of TMA-6 is well known, but is virtually unexplored pharmacologically. The above benzaldehyde with nitromethane in glacial acetic acid containing ammonium acetate gave the appropriate β-nitrostyrene as yellow crystals with a mp 177–177.5 °C. This, with LAH in ether, gave 2,4,6-trimethoxyphenethylamine (2,4,6-TMPEA, or 2C-TMA-6) as the picrate salt (mp 204–205 °C) or the hydrochloride salt (mp 234–235 °C). It has been shown not to be a substrate to the soluble amine oxidase from rabbit liver, a property it shares with mescaline, but whether it is or is not active in man is at present unknown.

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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. Still others remain to be added.

I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore most of the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes page has further details.

Cautionary Note

“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.”

Alexander T. Shulgin

Copyright Notice

The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.

Ordering Information

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.

Although 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.

PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.

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