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 2x75
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-beta-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-beta-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 2x100 mL CH2Cl2, and then made
basic with 5% NaOH. The milky aqueous phase was extracted with 2x100
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 com-pounds 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.
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