SYNTHESIS: A suspension of 5.65 g 1,4-dimethoxybenzene in 100 mL petroleum ether containing 6.5 mL N,N,N′,N′-tetramethylethylenediamine was magnetically stirred, placed in an inert atmosphere, and cooled to 0 °C with an external ice bath. There was then added 27 mL of 1.6 M butyllithium in hexane. The solids present went into solution, and after a few min continued stirring, a fine precipitate appeared. The reaction was allowed to stir while coming up to room temperature. There was then added 4.8 g dimethyl diselenide which led to an exothermic reaction, bringing the petroleum ether up to a reflux and showing a color change from white to yellow, to light green, to an eventual brown, all over the course of 30 min. After 2 h additional stirring, the reaction was quenched by pouring into dilute NaOH. The organic phase was separated, and the aqueous phase extracted with 2×75 mL Et2O. The pooled organics were washed first with dilute NaOH, then with dilute HCl, and then the solvent was removed under vacuum. Distillation of the residue at 0.4 mm/Hg gave an early fraction (75–100 °C) that solidified in the receiver and was largely unreacted dimethoxybenzene. A pale yellow oil distilled from 100 to 120 °C which proved to be largely 2,5-dimethoxyphenyl methyl selenide. Microanalysis gave C = 49.86, 49.69; H = 5.32, 5.47. As C9H12SeO2 requires C = 46.76, H = 5.23, there is approximately 13% dimethoxybenzene present (C8H10O2 requires C = 69.54, H = 7.29). This mixture was used as such, without further purification.
A mixture of 1.25 g POCl3 and 1.1 g N-methylformanilide was warmed on the steam bath for several min until the color had become a deep claret. There was then added 1.5 g of the 87% pure 2,5-dimethoxyphenyl methyl selenide and the steam bath heating continued for an additional 25 min. The very tarry reaction mixture was poured into 100 mL H2O, producing fine yellow solids almost immediately. These were removed by filtration and distilled at 0.2 mm/Hg. A first fraction distilling up to 100 °C was a mixture of unreacted ethers and what appeared to be 2,5-dimethoxybenzaldehyde. A second cut distilled at 140–150 °C, solidified to a yellow solid in the receiver, and weighed 1.2 g. A small amount of this product (with mp 91–96 °C) was recrystallized from MeOH to give an analytic sample of 2,5-dimethoxy-4-(methylseleneo)benzaldehyde with a mp 88–92 °C. All efforts to achieve a tighter melting range were unsuccessful. Anal. (C10H12O3 Se) C,H. Although this benzaldehyde migrates normally on a silica gel TLC plate (Rf of 0.4 employing CH2Cl2 as a solvent) when it is once completely dried on the plate, there seems to be some irreversible reaction with the silica, and the spot will no longer move at all.
To a solution of 0.85 g 2,5-dimethoxy-4-(methylseleneo)benzaldehyde in 10 mL nitromethane there was added 150 mg anhydrous ammonium acetate, and the solution was heated for 35 min on the steam bath. Removal of the volatiles under vacuum yielded brick-red solids (1.1 g) which were ground under a small amount of MeOH, filtered, and air dried. This yielded 0.88 g of solid 2,5-dimethoxy-4-methylseleneo-β-nitrostyrene with a mp of 170.5–171.5 °C. Recrystallization from IPA or from toluene gave no improvement of mp. Anal. (C11H13NO4Se) C,H.
A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under He, to 0 °C with an external ice bath. With good stirring there was added 0.53 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 0.85 g 2,5-dimethoxy-4-methylseleneo-β-nitrostyrene in 20 mL hot anhydrous THF. There was an immediate discoloring. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for 0.5 h, then all was cooled again to 0 °C. The excess hydride was destroyed by the cautious addition of IPA and, when there was no further activity, the reaction mixture was poured into 500 mL dilute H2SO4. This was washed with 2×100 mL CH2Cl2, and then made basic with 5% NaOH. The milky aqueous phase was extracted with 2×100 mL CH2Cl2, and extensive centrifuging was required to obtain a clear organic phase. Evaporation of the pooled extracts gave 1.6 g of an oil that crystallized. This was distilled at 130–140 °C at 0.15 mm/Hg providing 0.6 g of a white oil that set to a crystalline solid melting at 87–89 °C. This was dissolved in 4 mL boiling IPA, neutralized with 8 drops of concentrated HCl and the formed solids further diluted with IPA with a little anhydrous Et2O. This crystalline product was removed by filtration, washed with Et2O, and air dried to constant weight, yielding 2,5-dimethoxy-4-methylseleneophenethylamine hydrochloride (2C-SE) with a mp of 240–241 °C.
DOSAGE: perhaps 100 mg.
DURATION: 6–8 h.
QUALITATIVE COMMENTS: (with 50 mg) “My tongue feels as if I had eaten hot food. Overall I got up to a plus 1, and found the effects to be completely benign. I wandered about within the Graves exhibit at the Oakland Museum but there seemed to be only minor enhancement of the visual input.”
(with 70 mg) “The water solution of this material has an unspeakable smell. But there is no lasting taste, thank heaven. This is up to a 1.5+ and probably half again would be an effective dose. The first awareness was at 45 minutes, and the plateau lasted from 1.5 hours to about the fourth hour. I was at certain baseline at 8 hours.”
EXTENSIONS AND COMMENTARY: With an entirely new hetero atom in the molecule (the selenium), and with clear indications that large dosages would be needed (100 milligrams. or more), some discretion was felt desirable. There was certainly an odd taste and an odd smell. I remember some early biochemical work where selenium replaced sulfur in some amino acid chemistry, and things got pretty toxic. It might be appropriate to get some general animal toxicity data before exploring those dosages that might get to a +++.
What doors are opened by the observation that the selenium analog of 2C-T is an active compound? The potency appears to be in the same ball park, whether there is a sulfur atom or a selenium atom there.
From the point of view of the thing that is hung onto the hetero-atom, the selenium, the most active (and as first approximation the most safe) analogue would be the same ones that are the most potent with sulfur. These would probably be the Se-ethyl, the Se-propyl, or the Se-isopropyl, the analogs of S-ethyl, S-propyl, and S-isopropyl. If one were to be systematic, these would be called 2C-SE-2, 2C-SE-4, and 2C-SE-7. And a very special place might be held for 2C-SE-21, the analogue of 2C-T-21. Not only is this of high potential potency, but it would certainly be the first time that both fluorine and selenium are in the same centrally active drug. In fact, might not this compound, 2C-SE, be the first compound active within the human CNS with a selenium atom in it? It is certainly the first psychedelic with this atom in it!
From the point of view of the hetero-atom itself, there are two more known below selenium in the Periodic Table. Each deserves some special comment. The next atom, directly below selenium, is tellurium. It is more metallic, and its compounds have a worse smell yet. I heard a story about a German chemist, many years ago, who was carrying a vial of dibutyl telluride in his pocket in a passenger coach from here to there in Germany, back at about the turn of the century. It fell to the floor and broke. No one could remain in the car, and no amount of decontamination could effectively make the smell tolerable. Scratch one railway coach. But the compound, 2C-TE, would be readily makeable. Dimethyl ditelluride is a known thing.
However, the atom below tellurium (and at the bottom of that particular column of the Periodic Table) is the element polonium. Here one must deal in terms of theory, as far as human activity goes, since there are no non-radioactive isotopes of polonium. The only readily available isotope is that with mass 210, which is also called Radium F, and is an alpha-particle emitter. If this were ever to be put into a living organism, and if it were to seek out and hang around some particular site of action, that area would be thoroughly and completely cooked by alpha-particle emission. It would be a fun academic exercise to make 2C-PO (2,5-dimethoxy-4-methylpoloneophenethylamine), but in no way could it ever go into anyone. I knew an eminent physiologist named Dr. Hardin Jones (now dead) who always argued that the continuing use of drugs would burn out the pleasure center of the brain. It is a certainty that 2C-PO would, quite literally, do this. If I ever made it, I would call it HARDINAMINE in his honor.
There was an interesting observation associated with the making of 2C-SE. In the synthesis of many of the sulfur compounds (of the 2C-T family) is was quite common to find, when there was a quantity of some organic sulfide let go as a by-product of a reaction on a warm summer night, a number of flies coming into the lab to pay a visit. On the first synthesis of the starting material for 2C-SE, a quantity of CH3SeH was let go into the environment. Within minutes, there were two beautiful dragonflies in the lab. A coincidence certainly, but somehow, it was a nice message to receive.
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.
“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
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.
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.Transform Press,