#55 3,4-DMA SYNTHESIS: A solution of 33.2 g of veratraldehyde in 15.0 g nitroethane was treated with 0.9 g of n-amylamine and placed in a dark place at room temperature. In a day or so, separated H2O was apparent and, after a couple of weeks, the mixture completely solidified. The addition of 50 mL EtOH and heating effected complete solution and, on cooling, this provided 1-(3,4-dimethoxyphenyl)-2-nitropropene as yellow crystals, 29.0 g, with mp of 70–71 °C. The more conventional reaction scheme, 6 h heating of a solution of the aldehyde and nitroethane in acetic acid with ammonium acetate as catalyst, gave a much inferior yield of product (33.2 g gave 14.8 g) of the same purity. Recrystallization from MeOH increased the mp to 72–73 °C.
To a refluxing suspension of 7 g LAH in 600 mL anhydrous Et2O, stirred and under an inert atmosphere, there was added 7.5 g 1-(3,4-dimethoxyphenyl)-2-nitropropene by allowing the returning condensed ether to leach out the material as a warm solution from a Soxhlet thimble. Following the completion of the addition of the nitrostyrene, refluxing was maintained for 24 h, and the reaction mixture allowed to stand several days at room temperature. The excess hydride was destroyed by the cautious addition of 500 mL H2O containing 40 g H2SO4, and the phases were separated. The aqueous phase was washed with both Et2O and CH2Cl2. There was then added 200 g potassium sodium tartrate, and the pH brought above 9 by the addition of aqueous NaOH. This clear solution was extracted with 3×150 mL CH2Cl2, the extracts were pooled, and the solvent removed under vacuum to give a residual oil. This was dissolved in Et2O, saturated with anhydrous HCl gas, and the resulting solids removed by filtration. Recrystallization from 10 mL acetone gave 1.35 g 3,4-dimethoxyamphetamine hydrochloride (3,4-DMA) as beautiful white crystals with a mp of 144–145 °C.
DOSAGE: a few hundred milligrams.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 70 mg i.v.) [One patient received 0.004 mM/kg of the hydrochloride salt intravenously and exhibited only slight increase in psychiatric symptoms; a comparable dosage in a second individual also elicited only insignificant changes.]
(with 700 mg i.v.) [When one of these patients was reinjected at a later date with approximately 0.04 mM/kg of 3,4-DMA a definite ‘mescaline-like’ state was induced. The symptoms included colored hallucinations of geometric figures and occasional structured forms. The other individual experienced visual distortions, notable after-imagery, feelings of unreality, and paranoid ideas. Marked mydriasis and gross body tremors also occurred but apparently no hallucinations were experienced.]
EXTENSIONS AND COMMENTARY: These “Qualitative Comments” are not explicit quotations from people who had taken 3,4-DMA. They are written descriptions by the observers who had given 3,4-DMA to psychiatric patients. This is one of the most outrageous chapters in the books on military medicine. The chemical warfare group within the U.S. Army explored many potential psychedelics by administering them to innocent patients with not even a thought of obtaining informed consent. These experiments took place at the New York State Psychiatric Institute (amongst other places) in the early 1960’s. The Edgewood Arsenal code name for 3,4-DMA was EA-1316. A few non-military studies have indicated that 3,4-DMA is orally active at 160 milligrams, and so probably its potency by this more conventional route would fall midway between that of and of . The 3-methoxy-4-other-than-methoxy things (such as hydroxy, ethoxy, allyloxy and methyl) are mentioned in the recipe for . The alpha-ethyl homologue of 3,4-DMA, 2-amino-1-(3,4-dimethoxyphenyl)butane, and of other DMA’s are discussed under the recipe for .
There are a total of six possible amphetamine molecules with two methoxyl groups attached. The 3,4-orientation has always been the most appealing to the life scientists as this is the positional substitution pattern found in the natural neurochemicals , and . These latter two are called noradrenalin and adrenalin in England. Two adjacent hydroxy groups represent the catechol in the well known word catecholamines. You might read in a textbook, “This is where nature placed the groups when she put the compounds in our brains. So that is where the groups might be the most interesting in a psychedelic.” Why? I have never understood this kind of reasoning. If a possible psychedelic has just the exact oxygen positioning of a neurotransmitter, then, voila, that’s why it is active. And if a possible psychedelic has some positioning of these oxygen atoms that is different than that of a neurotransmitter? Then voila again. That’s why it is active. Both sound equally reasonable to me, and neither one even begins to address the fundamental question, how do the psychedelic drugs do what they do? A study in the human animal of the intimate effects of one of these neurotransmitter analogues might bring us a little bit closer to answering this fundamental question. But maybe it wouldn’t, after all. Nothing has made much sense so far! Anyway, 3,4-DMA is one of the ten essential amphetamines that can, in theory, arise from the ten essential oils of the spice and herb trade. In this case, the origins are methyl and methyl .
Two of these “different” isomers, and , have already been discussed in their own separate recipes. And the remaining three of the six possible DMA’s that are “different” have been made and studied pharmacologically in animals but not in man. These are the , and the isomers. The products of their reaction with elemental bromine are discussed under .
Both the 2,6- and the 3,5-isomers, as the N,N-dimethyl homologues, have been looked at as potential radio-halogen recipients in the search for positron-emitting brain blood-flow indicators, as discussed in the recipe for . Both were made from the appropriate nitrostyrene via the corresponding phenylacetone.
The 2,6-isomer was derived from 2,6-dimethoxybenzaldehyde. This, in nitroethane and ammonium acetate, gave the nitrostyrene as canary-yellow crystals from MeOH that melted at 101.5–102.5 °C. Elemental iron in acetic acid converted this nitrostyrene to 2,6-dimethoxyphenylacetone (a water-white oil with boiling point of 95–105 °C at 0.4 mm/Hg. Anal. (C11H14O3) C,H) and reductive amination with dimethylamine and sodium cyanoborohydride gave 2,6-dimethoxy-N,N-dimethylamphetamine perchlorate () with a melting point of 109–110 °C. This base was readily fluorinated with 18F acetylhypofluorite and iodinated with chloramine-T-oxidized 122I iodide ion. It was also halogenated with (non-radioactive) bromine and iodine monochloride to give the corresponding (and ) but these, in turn, did not react with radioactive acetyl hypofluorite.
The 3,5-isomer followed precisely the same flow sheet. 3,5-Dimethoxybenzaldehyde gave the nitrostyrene (with a melting point of 87–88 °C), the phenylacetone (with a boiling point of 110–130 °C at 0.3 mm/Hg) and the product 3,5-dimethoxy-N,N-dimethylamphetamine perchlorate () with a melting point of 100–101 °C. This also reacted readily with 18F acetylhypofluorite () and 122I-hypoiodite (). Several alpha-ethyl homologues of these compounds have also been discussed in the recipe for .
13 August 2017 · Creative Commons BY-NC-SA ·

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 history 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.
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.
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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