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Book II of PiHKAL: A Chemical Love Story, by Alexander & Ann Shulgin #69: Ψ-DOM
#69 Ψ-DOM: Z-7; 2,6-Dimethoxy-4-methylamphetamine

#69 Ψ-DOM SYNTHESIS: To a solution of 2,6-dimethoxy-4-methylbenzaldehyde (mp 92–93 °C from the lithiation of 3,5-dimethoxytoluene followed by reaction with N-methylformanilide) in 10 mL nitroethane, there was added 0.1 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 16 h. Removal of the solvent under vacuum gave a slightly oily red-orange crystalline mass which was finely ground under 1 mL of MeOH. Filtration and a sparing wash with MeOH gave, after air drying, 0.8 g of a light yellow crystalline solid with a mp of 121–122.5 °C. Recrystallization from 4 mL boiling absolute EtOH gave 0.6 g of 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very light yellow platelets, which melted at 123–124 °C.

To a solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and under He, there was added a solution of 0.3 g 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF. Upon the completion of the addition, the reaction mixture was held at reflux for 48 h. After cooling with an external ice bath there was added, in sequence, 0.5 mL H2O, 0.5 mL 15% NaOH, and finally 1.5 mL H2O. The inorganic solids were removed by filtration, and the filter cake washed with THF. The solvent from the combined filtrate and washings was removed under vacuum, and the residue (0.3 g) was a crystal clear colorless oil with a high refractive index. This was dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted with 35 mL of anhydrous Et2O. After a minute’s standing, the solution became turbid, followed by the slow deposition of very fine white crystals. After standing 1 h at room temperature, these were removed by filtration, Et2O washed, and air dried to constant weight. There was thus obtained 0.3 g 2,6-dimethoxy-4-methylamphetamine hydrochloride (Ψ-DOM) with a mp of 203 °C. sharp.

DOSAGE: 15–25 mg.

DURATION: 6–8 h.

QUALITATIVE COMMENTS: (with 14 mg) “I am really quite spacey. I can go from a train of thought straight up into thin air. Then, to get to another one there must be a careful choice of words. Logic has nothing to do with any of it. There is no trace of the MDMA-like magic. This is an interpretive drug, not simply an ASC [altered state of consciousness] opening.”

(with 18 mg) “There is a light-headedness, and a somewhat starry-eyed stoned state. Nothing visual, and no body concern except for what seems to be a very fine inner tremor. I think that with a little more, things might very well begin to move in the visual field. But I have no feeling of great concern about taking a somewhat higher dosage.”

(with 25 mg) “I was at a +++ for about three hours, and it was a very weird place. There were some visuals, but they were not at all commensurate with the degree to which I was simply stoned. The erotic does not knit, and it’s hard to get involved with music. It is as if you were going down some totally unknown street in a completely familiar city. You know the territory, but yet it is strangely all new. Eyes closed fantasy and shaped imagery was quite remarkable. But some heart arrhythmias and a pretty constant diarrhea made the experience less than totally ideal. My sleep was good and with good dreams.”

EXTENSIONS AND COMMENTARY: I can’t remember the exact names of the companies that went with the oil additives. STP was, I believe, it’s own thing, and originally stood for Scientifically Treated Petroleum. And F-310 was, I believe, a Chevron Oil product. F-320 was, of course, the product of the wild and happy chemists at the Pharmaceutical Chemistry Department at the University of California in San Francisco, playing with what they fondly called “funny drugs.” And when the 2,4,6-orientation became an obvious positional isomer, the Pennzoil Oil Company’s additive, Z-7, was a natural to have its name volunteered to the cause. There was one additional isomer possible, with the methyl in the 2-position and the methoxyl groups at the 4- and 6-positions. This followed the more conventional aldehyde made from 3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and N-methylformanilide. This material (2,4-dimethoxy-6-methylbenzaldehyde with mp 64–65 °C from cyclohexane or from MeOH) is completely distinct from the isomer used above (2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92–93 °C from MeOH). The amphetamine from this isomer is 2,4-dimethoxy-6-methylamphetamine, and had been christened by the chemistry crowd as Z-7.1.

Much effort had been put forth in research by this medical school group of graduate students and graduate advisors, to try to explain the biological activity of the 2,4,5-things such as TMA-2 and DOM (STP). And a considerable investment had been made in the attempt to tie together the amphetamine world of psychedelics with the indole world of psychedelics. The convenience of having two methoxy groups para to one another was a clear invitation to speculate upon the formation of a benzoquinone intermediate of some kind, and this would require the loss of the methyl groups which were already known to be metabolically labile. This “quinone-like” intermediate was the cornerstone of a “hydroquinone hypothesis,” as it allowed further condensation within the molecule itself involving the primary amine group, to form something called an indolene which, with some arcane electron pushing and removal, could eventually become an indole. There. We now have a tie-in to the tryptamine world, and to serotonin, and that entire neurotransmitter magic.

There was only one small fly in the ointment. No matter how the 2,4,5-things were explained, none of the proposed mechanisms could allow for the 2,4,6-things to also be active.

How can one accommodate such blasphemy? The first and obvious approach was the simplest. Denial. The 2,4,6-things aren’t really active at all. Placebo stuff. There is a commonly used phrase, “bad science” which is an infamous term used to belittle findings that do not fit with one’s theories or purposes. But that simply didn’t wash, because I knew, as did a few others who chose not to identify themselves too publicly, that TMA-2 and TMA-6 were both fully active in the 40 to 50 milligram area. And although not as potent as DOM, the compound of this recipe, Ψ-DOM or Z-7, was certainly an active one. So, since approach number one didn’t work, try approach number two. Make the shoe fit the wearer, without respect to the size of his foot. One single size shoe fits all. One single mechanistic hypothesis explains all. It was obvious that for the “hydroquinone” hypothesis to survive, Z-7 would have to undergo some metabolic oxidation—phenol formation—in the 3-position.

And guess who was actually euchred into embarking onto the synthesis of this hypothetical metabolic Lucy [that’s the anthropological-type, not the LSD-type Lucy]? Moi! On to a new methoxylated amphetamine which would be called Z-7.2. Oxidation of the above 2,4-dimethoxy-6-methylbenzaldehyde with metachloroperoxybenzoic acid gave 2,4-dimethoxy-6-methylphenol which smoothly methylated (KOH, CH3I) to give 2,3,5-trimethoxytoluene as a white oil, bp 59–62 °C at 0.1 mm/Hg. This formed the anion between the meta-methoxy groups with butyllithium, and N-methylformanilide gave the new compound 2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130–140 °C at 0.7 mm/Hg) with an excellent NMR spectrum. This formed the 3-carbon nitrostyrene with nitroethane, as bright yellow crystals from methanol with a mp 67–68.5 °C (and excellent NMR and microanalysis, C,H,N). Lithium aluminum hydride reduction gave rise to what I was assuming would be the target amphetamine, 4-methyl-2,3,6-trimethoxyamphetamine or Z-7.2. This formed a hydrochloride salt which, although analytically excellent, insisted in remaining as an ether and chloroform-soluble oil which had an excellent NMR spectrum. This was certainly my target compound, but it was not their target compound. The upper echelons who were running the show were serious about this hydroquinone thing. Therefore, this product Z-7.2, that should have been entered into human evaluation, was instead processed further by the substitution of a tert-BOC on the amine group, oxidation to the quinone with ceric ammonium nitrate, reduction to the hydroquinone with dithionite, and finally deprotection of the blocking tert-BOC group by hydrochloric acid. The final product, 2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an extremely light-sensitive solid which was looked at by NMR (excellent spectrum in D2O) and by cyclic voltimetry (destructive and uninformative) but which would have been totally worthless to have tasted.

In fact, the whole 2,4,6 substitution concept is just now beginning to explode. Fully half of the drugs described in this Book II are of the classical 2,4,5-trisubstitution pattern, and it is becoming evident that every one of them will have a 2,4,6-trisubstituted counterpart that bids fair to be an active psychedelic. Diligence could thus easily double the number of known psychedelics. The nickname “pseudo” is really the Greek letter “psi” which looks like a candelabrum standing on the table holding up three candles. If I can find the type in some font, I will simply precede each known drug with this letter, to indicate that the 2,4,5-ness has become a 2,4,6-ness. Therefore, Z-7 is also pseudo-DOM.

Z-7.2 might have been an interesting compound to taste. But the academic climate was not appropriate at that time (early 1977) for such honesty. The “hydroquinone hypothesis” is now not much more than a minor bit of history. And anyhow, it was just about this time that I had uncovered a slick way of getting a sulfur atom into the amphetamine molecule. I quickly lost interest in the pursuit of other people’s hypotheses that didn’t seem to lead anywhere. Maybe, someday, some single earth-shaking mechanism will emerge to explain everything. But in the meantime, the best contribution I can make to this “grand unified theory of psychedelic activity” is to continue to make new and unexpected things which, if they are active, will effectively destroy any hypothesis that just happens to be popular at the moment. It is a lot more exciting, too.

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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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