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#156 TM
4-TM; 4-THIOMESCALINE; 3,5-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE
SYNTHESIS: A
solution of 24.2 g N,N,N',N'-
tetramethylethylenediamine
and 27.6 g of
1,3-dimethoxybenzene was
dissolved in 400 mL
anhydrous
hexane. This was stirred vigorously under a N2
atmosphere and cooled
to 0 °C with an external ice bath. There was added 125 mL of 2.0 M
butyllithium in hexane. The stirred reaction mixture became yellow
and sludgy, and was briefly warmed back to room tem
perature to allow
easy stirring. After cooling again to 0 °C, there was added 18.8 g of
dimethyl disulfide which converted the viscous yellow
phase to a loose
white solid. Stirring was continued while the reaction mixture was
brought up to room tem
perature, and then all was added to 2 L of
dilute H2SO4. There was the immediate formation of a white
cystalline
solid which was removed by filtration, sucked relatively free of
water, and re
crystallized from 50 mL of boiling MeOH. There was thus
obtained 18.9 g of
2,6-dimethoxythioanisole as white
crystals with a
mp of 81-82 °C. Extraction of the aqueous filtrate with 2x50 mL
CH2Cl2 and removal of the
solvent under vacuum gave a residue which,
when combined with the mother liquors from the MeOH
crystallization,
afforded an additional 3.3 g product with a mp 77-79 °C.
To a stirred
solution of 18.9 g of
2,6-dimethoxythioanisole in 200 mL
CH2Cl2 there was added 16 g elemental
bromine dissolved in 75 mL
CH2Cl2. The initial dark red color gradually faded to a pale yellow
color and there was a copious evolution of HBr. The
solvent was
removed under vacuum leaving 27.5 g of a pale yellow
residual oil.
This was
distilled at 118-121 °C at 0.25 mm/
Hg to yield
3-bromo-2,6-dimethoxythioanisole as a white oil weighing 25.3 g.
Crystallization from hexane provided white
crystals with a mp of
30-30.5 °C. Anal. (C9H11BrO2S) C,H.
To a
solution of 19.3 g
diisopropylamine in 150 mL
anhydrous THF that
was stirred under a N2
atmosphere and cooled to -10 °C with an
external ice/MeOH bath, there was added in sequence 83 mL of 1.6 M
butyllithium in hexane, 4.4 mL of dry
CH3CN, and 11.6 g of
3-bromo-2,6-dimethoxythioanisole (which had been
dissolved in a little
anhydrous THF). The turbid reaction mixture gradually developed
color, initially yellow and progressively becoming orange and finally
a deep red brown. Stirring was maintained for a total of 20 min, and
then the reaction mixture was poured into 1 L H2O that containing 10
mL concentrated H2SO4. This was extracted with 3x75 mL
CH2Cl2, these
extracts pooled, washed with dilute H2SO4 followed by saturated brine,
and the
solvent was removed under vacuum yielding 8.7 g of a viscous
oil as a residue. This was
distilled at 0.11 mm/
Hg yielded two
fractions. The first boiled at 115-125 °C and weighed 3.8 g. This
material set to an oily
crystalline mass which was filtered, washed
with cold MeOH and then re
crystallized from MeOH. The white solids
had a mp of 60-63 °C and were not the desired product. This material
has not yet been identified. The second fraction came over at 150-180
°C, weighed 1.8 g and spontaneously
crystallized. It was triturated
under cold MeOH and filtered yielding, after air drying, 1.1 g
3,5-dimethoxy-4-
methylthiophenylacetonitrile, which had a mp of
95-96.5 °C. Anal. (C11H13NO2S) C,H.
A suspension of 1.0 g LAH in 40 mL
anhydrous THF under N2 was cooled
to 0 °C and vigorously stirred. There was added, dropwise, 0.7 mL
100% H2SO4, followed by 1.2 g
3,5-dimethoxy-4-methylthiophenylacetonitrile in 10 mL
anhydrous THF.
The reaction mixture was stirred at 0 °C for a few min, then brought
to room tem
perature for 1 h, and finally to a reflux for 30 min on the
steam bath. After cooling to room tem
perature, there was added 1 mL
H2O in 5 mL THF to destroy the excess
hydride, followed by 3 mL of 15%
NaOH to bring the reaction to a basic
pH, and finally 2 mL H2O which
converted the
aluminum oxide to a loose, white, filterable
consistency. This was removed by filtration, and washed with THF.
The filtrate and washes were stripped of
solvent under vacuum, the
residue was
dissolved in 200 mL
CH2Cl2, and this was extracted with
3x100 mL diute H2SO4. These extracts were pooled, washed with
CH2Cl2,
made basic with 25%
NaOH, and extracted with 3x100 mL
CH2Cl2. After
combining, the
solvent was removed under vacuum providing 1.2 g of a
colorless oil as a residue. This was
distilled at 122-132 °C at 0.05
mm/
Hg to give a colorless oil. This was
dissolved in 8 mL of IPA,
neutralized with concentrated HCl and, with continuous stirring,
diluted with 100 mL
anhydrous Et2O. The product was removed by
filtration, washed with
Et2O, and air dried to give 0.95 g.
3,5-dimethoxy-4-methylthiophenethylamine hydrochloride (4-TM) as
spectacular white
crystals with a mp of 193-194 °C. Anal.
(C11H18ClNO2S) C,H.
DOSAGE: 20 - 40 mg.
DURATION: 10 - 15 h.
QUANTITATIVE COMMENTS: (with 25 mg) I was first aware of any effects
as I was sitting in back of the house on a big fluffy pillow. The sun
was warm and the grass tall and green, but I felt strange inside.
There was distinct uterine cramping, and I could not find a
comfortable position for sitting. The others had gone out to the
garden leaving me here. It seemed that walking might relieve the
physical discomfort, so I went to find them. Walking was easy, but I
was a little light-headed and I had to watch my steps with care. They
were not there (we had passed on opposite sides of the house) and I
returned in some haste to my warm nest behind the house to find my
pillow gone. A strange detail, but it perhaps gave me the flavor for
my day. The pillow was for me. It was gone. My place was gone.
Therefore I am gone. I am dead and yet I can see and think. The
small touch of panic at finding myself dead dispelled any internal
concerns and I ran inside to find the others; they had brought my
pillow in. I was alive again, but the entire day balanced between the
alive unreality and the illusion that I was something removed and
merely watching the surrounding alive unreality. Everything that
happened was completely unlikely.
Like the soup scene. We decided that some hot soup would be welcome,
and so R. brought out three cans of
Campbell soup for the three of us.
But one was cream mushroom, one asparagus, and one tomato. The
discussion as to how to use two cans only, which two, without mixing,
and even how to decide to decide was totally beyond any of us. The
situation was hopelessly unresolvable, hilariously funny, and
distinctly
schizophrenic.
Or like the kite scene. We were returning from a short walk to the
back of the property, and I spotted a red thing in the parking area.
It had not been there before. None of us could identify it from this
distance, and we speculated wildly as to what it was, as we came
closer. And at the last approach, we found that there was loose
string everywhere about the driveway, all part of a downed kite. The
red object had apparently fallen from the sky, right here in front of
the garage. There had been no sounds of voices of kite-flyers, and
there was no one to be seen in any direction. And then one of us
spotted a sheet of paper, torn to the center where there was a small
hole, and it was flattened up against the kite. There was a message.
Apparently whoever had been flying it had put a message on the string,
and let the wind take it up to the kite itself. I reached for the
sheet of paper, and removed it. Nothing on either side. The message
was that there was no message. Exactly out of Marshall McLuhan.
Completely appropriate for this particular day.
That evening we were to be picked up by my friends for dinner.
Choosing what to wear, how to dress myself, how to adjust my persona
to fit other people, all this was chaotic. Somehow the dinner
succeeded, but I was able to flip in and out of the immediate company
easily, but not completely voluntarily. Sleep was com-fortable that
night, and I feel that the entire day had been very intense, not too
much fun, but somehow quite rewarding.
(with 30 mg) At the one and a half hour point, I was reminded more
than anything of LSD, with a distinct feeling of standing just a few
feet to the right of ordinary reality. There has been a mild tremor
ever since the first effects were evident, but it doesn't bother me
except to make my handwriting uncertain. I would not want to double
this level. Suddenly the concept of my 5:30's swept over me. I had a
penetrating view of myself as a person who had become invested in a
pattern of behavior that I had succumbed to, to come home and complete
my day with a transition from the work-world to the home-world, by
changing the inside clock at 5:30. My wife had been my 5:30 for
nearly 30 years and this had been my tacit agreement with her. Never
questioned, never challenged, and certainly never violated. And with
her death, I have found myself imposing this same 5:30-ness on myself,
as some form of an emasculating pattern that is comfortable and
stable. No, it is not comfortable, it is simply the course of the
least thought and the least disruption. If I were to meet someone
else, would I have such a negative image of myself that I would expect
her to become my 5:30 so as not to have to disrupt these tired and
comfortable patterns? That would be completely unfair to this other
person. And I can see where it is completely destructive to me. No
new person should ever have to play my wife's old role. I need never
again play my old role. And I won't.
(with 30 mg) At 2:20 PM I ingested 30 mg of TM. It had a mildly
alkaloid taste. Since the afternoon was warm, I took a two mile walk
with the dog, and with my two companions K.T. and T.T., both also with
30 mg. We talked without any difficulty even after the onset of the
first signs of effect. The major emotional and physical effects came
on very gradually and quite pleasantly as we sat in the patio. But
soon we all grew chilled, and put on more clothing. Nothing really
helped the inward chill, and we were to discover that it stayed with
us throughout the ex-perience. At 3:30 we went inside where the room
tem
perature was set at 70 degrees, and we all lay down. I launched
into an engrossing, somewhat chaotic and erotic reverie, that followed
no linear progression, but which lasted perhaps an hour. The ease of
talking surprised me; the content was cogent and I felt myself to be
articulate. It dawned on me after about two hours had gone by, that
the height of the experiment had already passed without any real
exhilaration on my part. But my companions suggested that my
expectations from the past had been misleading me and, as time went
on, they proved to be correct. The clarity and the continued ability
to talk, especially with K.T. on a personally difficult topic, were
for me the particular genius of this material. When I went inward,
which I could do without effort, the sensations were neutral in affect
but restful in some way. But coming out was entirely lucid and
pleasant. I soon found that I preferred this. I enjoyed a light
supper at 8:30 and found the dropoff gentle, and the conversation most
amiable until we separated at 1:00 AM. Sleep did not come until 3:00
AM and then only after 10 mg
Librium to quell the active mental
processes. The next day I awoke around 8:30 AM feeling languid but
cheerful.
(with 40 mg) For quite a while there was some physical concern. Not
actual nausea but a generalized uneasiness, with a distinct body
tremor. There was little urine produced (500 mL in 18 hours), and I
felt the need to search out fluids. There was mild intestinal
cramping. I found that my thoughts were able to go in several
directions at once, but since they stayed nowhere long enough to
structure anything, this was more annoying than constructive. I saw
this as a reality shell about me like a Möbius strip, continuous, yet
with no consistent side being presented. I was reminded of a similar
place with DOB, some few years ago. While lying down with eyes
closed, I found the imagery to be very impressive, but my thought
processes were quite convoluted and disjointed. Some were most
interesting, and some were ugly. I cannot see this as a party drug.
EXTENSIONS AND COMMENTARY: The dosage range has been
broadened to
include the 20 milligram level, in that several subjects found that
even with that small amount there was difficulty in walking and in
keeping one's
equilibrium. Walking was described as a floating
procedure, and one could tilt to one side or the other if care was not
taken. Anorexia was occasionally noted, and most people commented on
some degree of
anesthesia to touch.
All in all, this drug evoked a mixed bag of responses. The most
startling and unexpected property was the dramatic increase in potency
over the parent prototype, mescaline. The
substitution of a
sulfur
atom for an oxygen atom increased the power of the drug some ten-fold,
without any apparent decrease in complexity of action. As there were
many materials that were outgrowths of mescaline with the studies of
ethyl this and
diethyl that, each and all of these would be
interesting candidates for synthesis with this or that oxygen atom
replaced with
sulfur. Most of these have been made, and many of them
have proven to be interesting.
What is meaning of the phrase, "
sulfur-for-oxygen replacement?" Let me
try to explain it for non-chemists.
One of the most exciting bits of architecture in science is the
Periodic Table. The principles of
electrons and orbitals and
different counts of protons in a nucleus gets to be a complex story to
try to explain the grid-like structure of the arrangements of atoms.
It is easier to simply give the music. And this melody goes: As you
look across a row, elements are simple in their binding arrangements
on the left, become more complex towards the center where they kind of
change polarity, and then get progressively simple again but with the
opposite charge as you approach the right-hand side.
And when you look at a column from top to bottom, the bonding
complexity stays pretty much the same but the atom gets more and more
massive as you go down the column.
The combinations of atoms from the Periodic Table, by and large, is
the province of the inorganic chemist. Take one of this, and two of
that, and the combination is called a salt, or a complex, or an
adduct, and probably has interesting colors, and may even be found in
nature as part of a rock somewhere, or coming out of the vent of a
volcano.
But if one were to look at just four elements, three in the middle
right of the first row, namely
carbon,
nitrogen and oxygen, and the
one up there at the top and the lightest of all, hydrogen, you would
find quite a different story. These can be combined in an infinity of
ways since there can be dozens of atoms hooked to one-another; this is
the territory of the organic chemist, and this is the chemistry of
life. With a few exceptions, every molecule within the body, and the
food that maintains the body, and the drugs that affect the body, are
made up of a bunch of
carbons, and an occasional oxygen or two,
usually a
nitrogen somewhere, and all the remaining loose ends
satisfied with hydrogen atoms.
Almost every drug that is to be found in this book is nothing more
than a different arrangement of atoms of these four elements.
This compound, thiomescaline, is a byway that takes advantage of one
of those vertical columns. Directly below the element oxygen, there
is found
sulfur, which has much the same binding complexity, but is
twice as massive. The prototype of all the
phenethylamine drugs being
discussed in this book is mescaline, a very simple compound containing
these basic four elements of life and
pharmacology; it contains eleven
carbon atoms, three oxygen atoms, one
nitrogen atom, and there are a
total of seventeen hydrogen atoms required to balance the books. One
of the oxygen atoms holds a central position, and the other two are
reflections of one another and cannot be distinguished chemically.
The structure of thiomescaline is generated by plucking out that
central oxygen atom of mescaline, and putting a
sulfur atom back in
its place. The definition of the term "thio" is quite simple--it
means a
sulfur-in-place-of-an-oxygen, with everything else left alone.
It is a little awe-inspiring to think that every oxy anything can have
a thio something as a spatially similar
analogue. And there are a lot
of oxy things in the body and in the medicine cabinet. A number of
them are discussed in this book.
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