#122 MEM SYNTHESIS: A solution of 83 g bourbonal (also called ethyl vanillin, or vanillal, or simply 3-ethoxy-4-hydroxybenzaldehyde) in 500 mL MeOH was treated with a solution of 31.5 g KOH pellets (85% material) dissolved in 250 mL H2O. There was then added 71 g methyl iodide, and the mixture was held under reflux conditions for 3 h. All was added to 3 volumes of H2O, and this was made basic with the addition of 25% NaOH. The aqueous phase was extracted with 5×200 mL CH2Cl2. The pooling of these extracts and removal of the solvent under vacuum gave a residue of 85.5 g of the product , with a mp of 52–53 °C. When this product was recrystallized from hexane, its mp was 49–50 °C. When the reaction was run with the same reactants in a reasonably anhydrous environment, with methanolic KOH, the major product was the acetal, 3-ethoxy-α,α,4-trimethoxytoluene. This was a white glistening product which crystallized readily from hexane, and had a mp of 44–45 °C. Acid hydrolysis converted it to the correct aldehyde above. The addition of sufficient H2O in the methylation completely circumvents this by-product. A solution of 1.0 g of this aldehyde and 0.7 g malononitrile in 20 mL warm absolute EtOH, when treated with a few drops of triethylamine, gave immediate yellow color followed, in a few min by the formation of crystals. Filtration, and washing with EtOH, gave bright yellow crystals of 3-ethoxy-4-methoxybenzalmalononitrile with a mp of 141–142 °C.
A well stirred solution of 125.4 g 3-ethoxy-4-methoxybenzaldehyde in 445 mL acetic acid was treated with 158 g 40% peracetic acid (in acetic acid) at a rate at which, with ice cooling, the internal temperature did not exceed 27 °C. The addition required about 45 min. The reaction mixture was then quenched in some 3 L H2O. There was the generation of some crystals which were removed by filtration. The mother liquor was saved. The solid material weighed, while still wet, 70 g and was crude formate ester. A small quantity was recrystallized from cyclohexane twice, to provide a reference sample of 3-ethoxy-4-methoxyphenyl formate with a mp of 63–64 °C. The bulk of this crude formate ester was dissolved in 200 mL concentrated HCl which gave a deep purple solution. This was quenched with water which precipitated a fluffy tan solid, which was hydrated phenolic product that weighed about 35 g, and melted in the 80–90 °C. range. The mother liquors of the above filtration were neutralized with Na2CO3, then extracted with 3×100 mL Et2O. Removal of the solvent gave a residue of about 80 g that was impure formate (containing some unoxidized aldehyde). To this there was added 500 mL 10% NaOH, and the dark mixture heated on the steam bath for several h. After cooling, the strongly basic solution was washed with CH2Cl2, and then treated with 200 mL Et2O, which knocked out a heavy semi-solid mass that was substantially insoluble in either phase. This was, again, the crude hydrated phenol. The Et2O phase, on evaporation, gave a third crop of solids. These could actually be recrystallized from MeOH/H2O, but the mp always remained broad. When subjected to distillation conditions, the H2O was finally driven out of the hydrate, and the product 3-ethoxy-4-methoxyphenol distilled as a clear oil at 180–190 °C at 0.8 mm/Hg. This product, 45.1 g, gave a fine NMR spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1, supporting the freedom of the OH group on the aromatic ring from adjacent oxygen. Efforts to obtain an NMR spectrum in D2O immediately formed an insoluble hydrate. This phenol can serve as the starting material for either MEM (see below) or (see separate recipe).
To a solution of 12.3 g 3-ethoxy-4-methoxyphenol in 20 mL MeOH, there was added a solution of 4.8 g flaked KOH in 100 mL heated MeOH. To this clear solution there was then added 10.7 g methyl iodide, and the mixture held at reflux on the steam bath for 2 h. This was then quenched in 3 volumes H2O, made strongly basic with 10% NaOH, and extracted with 3×100 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 9.4 g of an amber oil which spontaneously crystallized. The mp of 1,4-dimethoxy-2-ethoxybenzene was 42–43.5 °C, and was used, with no further purification, in the following step.
A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed to stand for 0.5 h, producing a deep claret color. To this there was added 9.2 g 1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on the steam bath for 2 h. It was then poured into chipped ice and, with mechanical stirring, the dark oily phase slowly became increasingly crystalline. This was finally removed by filtration, providing a brown solid mat which showed a mp of 103.5–106.5 °C. All was dissolved in 75 mL boiling MeOH which, on cooling, deposited fine crystals of that were colored a light tan and which, after air drying to constant weight, weighed 8.5 g and had a mp of 108–109.5 °C. Search was made by gas chromatography for evidence of the other two theoretically possible positional isomers, but none could be found. The NMR spectrum showed the two para-protons as clean singlets, with no noise suggesting other isomers. There was a single peak by GC (for the recrystallized product) but the mother liquors showed a contamination that proved to be N-methylformanilide. A 0.3 g sample, along with 0.3 g malononitrile, was dissolved in 10 mL warm absolute EtOH, and treated with a drop of triethylamine. There was the immediate formation of a yellow color followed, in 1 min, by the deposition of fine yellow needles. Filtering and air drying gave 0.25 g of 2,5-dimethoxy-4-ethoxybenzalmalononitrile, with a mp of 171–172 °C.
A solution of 7.3 g 2,5-dimethoxy-4-ethoxybenzaldehyde in 25 g glacial acetic acid was treated with 3.6 g nitroethane and 2.25 g anhydrous ammonium acetate, and heated on the steam bath. After two h, the clear solution was diluted with an equal volume of H2O, and cooled in an ice bucket. There was the formation of a heavy crop of orange crystals which were removed by filtration. The dry weight of 1-(2,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene was 4.8 g and the mp was 120–124 °C. Recrystallization of an analytical sample from MeOH gave a mp of 128–129 °C. Anal. (C13H17NO5) C,H.
To a gently refluxing suspension of 3.3 g LAH in 400 mL anhydrous Et2O under a He atmosphere, there was added 4.3 g 1-(2,5-dimethoxy-4-ethoxy)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble apparatus containing the nitrostyrene, thus effectively adding a warm saturated ether solution of it to the hydride mixture. The addition took 2 h. Refluxing was maintained for 5 h, and then the reaction mixture was cooled to 0 °C with an external ice bath. The excess hydride was destroyed by the cautious addition of 300 mL of 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 100 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3×100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts produced an almost white oil that was dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was deposited a white crystalline solid of 2,5-dimethoxy-4-ethoxyamphetamine hydrochloride (MEM) which weighed 3.1 g and had a mp of 171–172.5 °C. Anal. (C13H22ClNO3) C,H,N.
DOSAGE: 20–50 mg.
DURATION: 10–14 h.
QUALITATIVE COMMENTS: (with 20 mg) “I experienced some physical discomfort, but doesn’t that tell us about the work to be done, rather than the property of the material? The breakthrough I had was the following day (and this seems to be the way MEM operates, i.e., first the energy and expansion, next day insight) was of the highest value and importance for me. I was given a methodology for dealing with my shadow parts. No small gift. And I did it all alone and the results were immediate. I am so grateful.”
(with 20 mg, at 1.5 h following 120 mg ) “The transition was very smooth, with no obvious loss of the MDMA experience. I felt less of a need to talk, but the intimate closeness with the others was maintained. The experience continues to grow more profound and euphoric and I prayed, in the latter part of the afternoon, that it wouldn’t stop. It continued until midnight with marvelous feelings, good energy, and much hilarity. And it abated very little over the next several days leaving me with the feeling of lasting change with important insights still coming to mind one week later.”
(with 25 mg, at 2 h following 120 mg ) “I found that sounds in general were distracting. No, they were out-and-out annoying. I may have been in an introspective mood, but I really wanted to be alone. No body problems at all. Felt good. I developed some color changes and some pattern movement. Not much, but then I didn’t explore it much. The wine party afterwards was certainly most pleasant. The soup was a great pleasure. And that hard bread was good. The material was clearly not anorexic, or at least I overcame whatever anorexia there might have been.”
(with 30 mg) “I was aware of this in thirty minutes and it slowly developed from there to an almost +++ in the following hour. There were visual phenomena, with some color enhancement and especially a considerable enhancement of brights and darks. The first signs of decline were at about six hours, but there was something still working there after another six hours had passed. A slow decline, certainly.”
(with 50 mg) “I came into the experience knowing that yesterday had been a very fatiguing and tense day. I felt this material within the first ten minutes which is the fastest that I have ever felt anything. The ascent was rapid and for the first hour I tended to an inward fantasying with a distinct sensual tinge. There was a persistent queasiness that never left me, and it contrasted oddly with a good feeling of outward articulation and lucidity which succeeded in coming to the fore after the introverted first hour. Sleep was difficult, but the next day was calm and clear.”
(with 50 mg) “Lots of energy, best directed into activity. Clear imaging, thinking. Intense yet serene. Good feeling of pleasantness and some euphoria. I felt the need to keep moving. Hard to stay still.”
(with 70 mg, in two parts) “The effects of the 40 milligrams were muted by another drug experiment yesterday morning, and I never got much over a plus 1. There is an erotic nature, tactile sensitivity perhaps not as delicate as with , but it is there. At the 2 hour point, an additional 30 milligrams increased the body impact (a distinct tremor and sensitivity) but somehow not a lot more mental. I have been compromised by yesterday.”
EXTENSIONS AND COMMENTARY: MEM was both a valuable and dramatic compound, as well as a drug that played a watershed role. The completion of all the possible trimethoxyamphetamines (the TMA’s) showed that only two of them combined the values of dependability of positive psychedelic effects with a reasonably high potency. Both and are treasures, both active in similar dosages, and both offer methoxyl groups that are begging to be replaced by other things. The first focus was on TMA-2, partly because the needed synthetic chemistry was better known, and partly because I had discovered its activity earlier. But there were three entirely different and distinct methoxyl groups to work on, in TMA-2. There is one at the 2-position, one at the 4-position, and one at the 5-position. The most obvious thing to do, it seemed, was to make each of them one carbon longer. Replace a methoxy with an ethoxy. And a logical naming pattern could follow the use of M for methoxy, and E for ethoxy, in sequence right around the ring from the 2- to the 4- to the 5-positions. The first group to be compared, then, would be , MEM, and . And of these three, it was only MEM that was right up there in drama and in potency. But, by the time that became apparent, I had already completed the diethoxy possibilities (, , and ) as well as the triethoxy homologue, . With the discovery that the 4-position was the magic leverage point, and that the homologues at positions 2- and 5- were clearly less interesting, all emphasis was directed at this target, and this has led to the many 4-substituted families that are now known to be highly potent and felt by many to be personally valuable.
Why put such emphasis on potency, I am frequently asked? Why should it matter how much of a compound you take, as long as the effective level is much lower than its toxic level? Well, in a sense, that is the very reason. There are no guides as to what the toxic levels of any of these many compounds might really be in man. There is simply no way of determining this. Only a few have been explored in animals in the pursuit of an LD50 level. Most of them are similar to one-another, in that they are, in mice, of relatively low toxicity and, in rat, of relatively high toxicity. But this toxicity appears not to be related to potency in man. So, if one might extrapolate that they are of more or less the same risk to man (from the toxic point of view) then the lower the dosage, the greater the safety. Maybe. In the absence of anything factual, it makes a reasonable operating hypothesis.
Many of the reports of MEM effects have been with experiments in which an effective dose of had been taken shortly earlier. There has developed a concept, embraced by a number of researchers, that the ease and quietness usually seen with the development of the MDMA experience can mitigate some of the physically disturbing symptoms sometimes seen with other psychedelics. This may be partly due to a familiar entry into a altered place, and partly due to a lessening of dosage usually required for full effects. MEM seems to have had more trials using this combination than many of the other psychedelic drugs.
1 Nov 2018 · ·

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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