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#68 DOM
STP; 2,5-DIMETHOXY-4-METHYLAMPHETAMINE
SYNTHESIS: To a
solution of 54.9 g
2,5-dimethoxy-4-methylbenzaldehyde
(see the recipe for
2C-D for its preparation) in 215 g glacial acetic
acid there was added 19.5 g
anhydrous ammonium acetate and 30.6 g
nitroethane. This mixture was heated for 3 h on the steam bath, the
reaction mixture was cooled in a wet ice bath, allowing the
spontaneous formation of yellow
crystals. As much H2O as possible was
added (just short of a persistant cloudy oily character) and after a
few additional h standing, the
crystalline
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene was removed by
filtration and re
crystallized from boiling acetic acid. The yield,
after drying to constant weight, was 28.3 g and the mp was 87-88 °C.
Anal. (
C12H15NO4) C,H,N.
A suspension of 9.5 g LAH in 750 mL well stirred
anhydrous Et2O was
held at reflux under an inert
atmosphere, with the return of the
condensed
solvent passing through a Soxhlet thimble containing 9.5 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene. After the addition
of the
nitrostyrene was complete, the stirred suspension was
maintained at reflux for an additional 4 h, then cooled to room
tem
perature and allowed to continue stirring overnight. The excess
hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously,
until the hydrogen evolution ceased, then at a speed that allowed the
formed solids to disperse. The
phases were separated, the aqueous
phase washed once with
Et2O, treated with 225 g
potassium sodium
tartrate, and finally made basic (
pH >9) with 5%
NaOH. This was
extracted with 3x150 mL
CH2Cl2, the extracts pooled, and the
solvent
removed under vacuum. The residue was 9.6 g of a clear oil which
spontaneously formed
crystals with a mp of 60.5-61 °C from hexane.
These solids were
dissolved in 150 mL
anhydrous Et2O, and saturated
with
anhydrous HCl gas. After standing at room tem
perature for 2 h,
the
crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM)
was removed by filtration, washed with
Et2O, and air dried to constant
weight. There was obtained 8.25 g of glistening white
crystals that
had a mp of 190.5-191.5 °C. The
sulfate had a mp of 131 °C. Anal.
(
C12H20ClNO2) C,H,N.
The above
nitrostyrene may also be converted to the final
amine
product through the intermediary of the corresponding
phenylacetone.
To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial
acetic acid held at reflux tem
perature, there was added 4.9 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene as a solid.
Refluxing
was continued for 2 h and then all was filtered through wet Celite.
After washing with 300 mL H2O followed by 300 mL
Et2O, the combined
filtrate and washes were separated, and the aqueous
phase extracted
with 2x100 mL
Et2O. The organic
phase and extracts were combined and
washed with 2x100 mL saturated
K2CO3 and the
solvent was removed under
vacuum yielding a reddish oil weighing 3.3 g. This was
distilled at
111-115 °C at 0.5 mm/
Hg to give a pale green solid. After
re
crystallization from
benzene, there was obtained 2.8 g
1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white
crystals with a
mp of 57-59 °C. This
ketone has also been described as a pale-yellow
oil with a bp of 115-118 °C at 0.4 mm/
Hg. A
solution of 0.7 g
1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated
with 6.0 g
ammonium acetate, 0.3 g
sodium cyanoborohydride, and 3 g
Linde 3 A
molecular sieves. The mixture was stirred overnight, the
solids removed by filtration, and the filtrate
dissolved in 100 mL
H2O. The
solution was acidified with dilute H2SO4, and washed with
2x25 mL
CH2Cl2. The aqueous
phase was made basic with aqueous
NaOH,
and the product extracted with 2x25 mL
CH2Cl2. The
solvent was
removed under vacuum, and the residue
distilled (at 160 °C at 0.2
mm/
Hg) to give colorless product which was
dissolved in 3 mL IPA,
neutralized with concentrated HCl, and diluted with 50 mL
anhydrous
Et2O. There was obtained 0.18 g of
2,5-dimethoxy-4-methylamphetamine
hydrochloride (DOM) as a white solid with a mp of 187-188 °C.
The optical
isomers of DOM have been prepared in two ways. The
racemic base has been resolved as the ortho-
nitrotartranilic acid salt
by re
crystallization from
EtOH. The (+) acid provides the (+) or "S"
isomer of DOM preferentially. Also, the above-mentioned
1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively
aminated with optically active
alpha-methyl benzylamine with Raney
Nickel. This
amine is isolated and purified by re
crystallization of
the
hydrochloride salt. When optically pure, the
benzyl group was
removed by hydrogenolysis with palladium on
carbon. The mp of either
of the optical
isomers, as the
hydrochloride salts, was 204-205 °C.
DOSAGE: 3 - 10 mg.
DURATION: 14 - 20 h.
QUALITATIVE COMMENTS: (with 1.0 mg) There is almost certainly an
effect. Physically there is a slight dryness in the mouth, and my
eyes are noticeably dilated. There is an eerie feeling overall.
(with 2.3 mg) Mood elevation at 2-3 hrs. After 3 hours, emotional
effects become more pronounced, enhancement of color also. Very
little distortion of perception, no disorientation, no creeping or
flowing, but color enhancement considerable. The emotional content
and empathy for others was closer to mescaline than to
amphetamine, a
welcome change. No suggestion of nausea at any time. Unable to sleep
at ten hours, so I took 3/4 grain Seconal. Headache and listlessness
next morning, probably due to the Seconal.
(with 3 mg) In the middle of the experience I found that I was able
to separate components of complex things so as to evaluate them
separately. There is no need to respect their normal purpose. The
sharpness of observation is enhanced, but one can focus at every
different depth of a thing or a concept. Colors are not just
brighter; there are more of them. There is a profoundness of meaning
inherent in anything that moves. A line of thought or a bit of
personal history ties the thinker to the objects that had been thought
of, or once experienced. It is this relationship that will prove
productive. Not like in a movie which is circular in its totalness,
but as in true life where the future is the result of your own
involvement with everything about you.
(with 4 mg) The first four hours were largely directed to the body.
There was a shuddering, and a tight jaw, and I am not particularly
motivated to talk to anyone. It is more arousing (like
amphetamine)
than depressing (like
phenobarb). I am feeling just a little sick at
the three hour point, but a bit of
regurgitation clears this up. Then
at the fourth hour, it went totally outside of me. I saw the clouds
towards the west. THE CLOUDS!!! No visual experience has ever been
like this. The meaning of color has just changed completely, there
are pulsations, and pastels are extremely pastel. And now the oranges
are coming into play. It is a beautiful experience. Of all past joys,
LSD, mescaline, cannabis,
peyote, this ranks number one. Normally I
have no color effects with mescaline. A dynamic experience. Feels
good, too.
(with 5 mg) There was the magnification of light, color and odors.
It was all very pleasant and beautiful, except that I had an
overwhelmingly negative feeling. This at times grew to considerable
intensity, and I feel it was clearly due to anger. At times the
negativity disappeared completely, and I broke into the most
enjoyable, even hilarious experiences. I alternated about 50-50
between joy and discomfort. As the evening drew on, I became
withdrawn and pensive. It seemed clear that I had made all the wrong
decisions--choice of partner, place to live, isolation, no meaningful
activity. The greatest shocker was that my practice of meditation,
which is one of my central focuses, and which I thought had brought me
much peace and understanding, seemed to be a delusional
solution to my
unhappiness and isolation. The experience continued unabated
throughout the night with much tension and discomfort. I was unable
to get any sleep. I hallucinated quite freely during the night, but
could stop them at will. While I never felt
threatened, I felt I knew
what it was like to look across the brink to insanity.
(with 8 mg) The very quiet development picks up speed betweeen the
first and second hour. There is a rich curly-imaged eyes-closed show
that interlocks closely with music. It is occasionally an off-beat
fantasy and not directly knit tog
ether, and even occasionally
unenjoyable. But always intense and completely appropriate to the
music. There is a continuous thirst, and little urine. Napping seems
OK at 16 hours, but real sleep must wait until the 20 hour point.
Overall a rolling +++, and I am looking forward to a repeat some day.
(with 10 mg) If on this page I shall have expressed it to you then it
is true that DOM has the glory and the doom sealed up in it. All
that's needed to unseal it is to surround it with a warm living human
for a few hours. For that human for those hours all the dark things
are made clear.
(with 12 mg) The first awareness was at 30 minutes and it was in the
tummy. The development was extremely rapid, something more like LSD
than previously remembered. The body tremor feels like poisoning,
there is no escaping the feeling of being disabilitated, but at least
there is no nausea. This transition ended and the trauma cleared
completely at about the second hour. The music was exceptional, the
erotic was exceptional, the fantasy was exceptional. Listz's "A
Christmas
Cantata #1," part 1, with eyes closed was an experience
without precedent. There were some
residual effects still noted the
next day. This may be a bit much for me.
(with 0.3 mg of the "R"
isomer) Maybe slightly wiry? No effects.
(with 0.5 mg of the "R"
isomer) There is a real effect, and it is
significant that the first effects of the racemate were noted at 1.0
milligram. There is a trace of time slowing and in general a pretty
full manic state. There is some mydriasis. Everything had pretty
much cleared up by evening.
(with 2.0 mg of the "S"
isomer) No effects. There was an unexpected
slight
tachycardia at the two hour point, but nothing suggesting
psychotropic action.
(with 2.6 mg of the "S"
isomer) There are signs of both pulse
increase and blood pressure increase. There is some teeth-rubbiness,
but still no
psychological turn on at all.
EXTENSIONS AND COMMENTARY: The rationale for the design and making of
DOM has already been discussed. One could predict that it could have
been, theoretically, a totally inactive compound and maybe an
effective blocker for whatever receptor sites are being occupied by
other
psychoactive drugs and even for strange things that some
unbalanced people might actually make within their bodies, using their
own personal chemistry. On the other hand, it could have been a
potent
psychedelic in its own rights, and if so, probably long lived.
The latter "could have been" proved to be so.
The very modest amount of study of the individual optical
isomers
clearly indicates that the "R"
isomer is the more active. The sparse
comments suggest that some of the heavier physical aspects of the
racemate might be due to contri
butions from the "inactive" "S"
isomer.
It is, after all, the "S"
isomer of
amphetamine that carries the major
punch of that stimulant. Maybe if that
isomer were removed, and one
were to explore the pure "R"
isomer of DOM, the dramatic visual
aspects of the larger dosages might not be complicated with a
troublesome physical component.
This compound, unbeknownst to me, was scattered widely and plentifully
in the heyday of the Haight-Ashbury in San Francisco, in mid-1967. It
was distributed under the name STP, which was said to stand for
Serenity, Tranquility, and Peace. It was also claimed to represent
Super Terrific
Psychedelic, or Stop The Police. The police called it:
Too Stupid to Puke. Actually, the name was taken from the initials of
a motor additive which was completely unrelated chemically.
Incredibly, and sadly, one of the avowed experts in the area of the
"sensuous drugs" actually stated that STP, the motor oil additive, was
really one and the same as STP, the highly dangerous
psychedelic. The
motor oil additive, he wrote in a book of his, had properties somewhat
related to those of LSD, mescaline, and the
amphetamines. How
fortunate that the love children of the time didn't do much reading,
for they might have gotten into yet deeper
pharmacological troubles
with drug raids on the local gasoline stations.
Two complications became apparent during this first appearance and
they led to serious difficulties. One, there was no equation made
between STP and DOM. No one knew what this drug was which had been
distributed in a cavalier way throughout the city. There could be no
educated guess as to the best treatment of overdose emergencies. And
secondly, the initial tablets that had been distributed apparently
contained 20 milligrams of DOM per tablet; later, it was dropped to 10
milligrams. Either of these, in retrospect, is now known to be a
thoroughly whopping dose. The overdose situation was aggravated by
the slow onset of DOM. The user may be aware of some initial effects
at the half-hour point, there will be what might be called a + or ++
at the end of the first hour, and the full impact of the drug is not
appreciated until some two hours have elapsed. But many of the
recipients of the free handouts of DOM were familiar with LSD which
can show its alert in 15 to 20 minutes, or even sooner with a large
dose, and there is already a deep and compelling intoxication felt at
the half-hour point. They, quite reasonably, expected this familiar
activity pattern with STP and assumed, when there was little if any
activity noted at the half-hour point, that the potency was less than
expected. They took one or even two additional dosage units. Thus,
some of the overdose victims of that period may well have taken as
much as 30 mg of DOM. The slow onset of action, coupled with the
remarkably long duration, caught many innocent users unprepared.
Clinical studies have documented the rapid tolerance development from
repeated exposures to DOM. Five volunteers were given 6 milligrams
daily for three days. Objectively,
psychological tests showed a
decrease in responses. Subjectively, all found extremely intense
effects on the first day, and all but one found it unpleasant. By the
third exposure on the third day, all had diminished responses, ranging
from only "moderately strong" to "felt absolutely nothing." One
actually slept during the experience on the third day.
The
hexadeutero-
analogue (
deuterium atoms on the two
methoxyl groups)
has been prepared as an internal standard for
analytical work, but
there are no reports of its human
pharmacology. A study with this
sort of derivative would be a fine companion to the studies already
underway with the mescaline
analogues that are similarly
substituted.
A difference exists, however. With mescaline, it is believed that the
loss of a
methoxyl group is a step towards the inactivation of the
compound, whereas with DOM this loss may be associated with the
formation of an active
metabolite. The several fascinating questions
raised by possible differences in both the rates and the degree of
demethylation of these two compounds are well worth trying to answer.
A number of compounds related to DOM had been
synthesized and studied
at the University of
California at San Francisco, at about this time.
Two of these were simply the juggling of the two
methoxyl groups and
the
methyl group on the ring, still maintaining the
2,4,5-ness
relative to the
amphetamine chain. These are
2,4-dimethoxy-5-methylamphetamine and
4,5-dimethoxy-2-methylamphetamine. Since the slang name for DOM in
and about the medical center was STP, and since STP was the name of a
motor oil additive, it is not unreasonable that the first of these to
be
synthesized, the
2,4-dimethoxy-5-methyl isomer, was referred to by
the name of another motor oil additive popular at that time, F-310.
The Vilsmeier reaction between
2,4-dimethoxytoluene and the Vilsmeier
complex of POCl3 and N-
methylformanilide gave the
benzaldehyde (mp
117-118 °C) with a yellow
malononitrile derivative from
EtOH with a mp
of 193-194 °C. The
nitrostyrene from this and
nitroethane formed
yellow
crystals from
CH3CN, with a mp 138-139 °C. The
amine formed
easily with LAH in
ether, and the product F-310 (or 5-DOM) gave white
crystals from
CH3CN with a mp of 182-183 °C.
And the other
isomer, the
4,5-dimethoxy-2-methyl counterpart, became
known familiarly as F-320, or sometimes simply 2-DOM. Its preparation
followed an identical procedure, starting from
3,4-dimethoxytoluene.
I have been told that F-310 is not active even at 20 milligrams in
man, which would make it several times less potent than DOM (STP). I
know of no trials with F-320. The use of the letter RFS does not
imply any relationship between these two compounds and the series
described elsewhere with the RFS code followed by other numbers, such
as F-2 and F-22. These latter are F's because they are furans, not
motor oil additives. And yet another oil additive, well known at the
time as Z-7, became associated with the synthesis of the DOM (STP)
isomer with its groups in the
2,4,6-positions. This is entered
separately under gamma-DOM.
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