SYNTHESIS: Into 1 L H2O that was being stirred magnetically, there was
added, in sequence, 62 g toluhydroquinone, 160 mL 25% NaOH, and 126 g
dimethyl sulfate. After about 2 h, the reaction mixture was no longer
basic, and another 40 mL of the 25% NaOH was added. Even with
stirring for a few additional days, the reaction mixture remained
basic. It was quenched in 2.5 L H2O, extracted with 3x100 mL CH2Cl2
and the pooled extracts stripped of solvent under vacuum. The
remaining 56.4 g of amber oil was distilled at about 70 °C at 0.5
mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The
aqueous residues, on acidification, provided a phenolic fraction that
distilled at 75-100 °C at 0.4 mm/Hg to give 5.8 g of a pale yellow
distillate that partially crystallized. These solids (with mp of
54-62 °C) were removed by filtration, and yielded 3.1 g of a solid
which was recrystallized from 50 mL hexane containing 5 mL toluene.
This gave 2.53 g of a white crystalline product with a mp of 66-68 °C.
A second recrystallization (from hexane) raised this mp to 71-72 °C.
The literature value given for the mp of 2-methyl-4-methoxyphenol is
70-71 °C. The literature value given for the mp of the isomeric
3-methyl-4-methoxyphenol is 44-46 °C. This phenol, on ethylation,
gives 2-ethoxy-5-methoxytoluene, which leads directly to the 2-carbon
2CD-5ETO (one of the Tweetios) and the 3-carbon Classic Lady IRIS.
A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide was heated
for 10 min on the steam bath, and then there was added 30.4 g of
2,5-dimethoxytoluene. Heating was continued for 2.5 h, and the
viscous, black, ugly mess was poured into 600 mL of warm H2O and
stirred overnight. The resulting rubbery miniature-rabbit-droppings
product was removed by filtration and sucked as free of H2O as
possible. The 37.2 g of wet product was extracted on the steam-bath
with 4x100 mL portions of boiling hexane which, after decantation and
cooling, yielded a total of 15.3 g of yellow crystalline product.
This, upon recrystallization from 150 mL boiling hexane, gave pale
yellow crystals which, when air dried to constant weight, represented
8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde, and had a mp of 83-84 °C.
Anal. (C8H12O3) C,H,N. The Gattermann aldehyde synthesis gave a
better yield (60% of theory) but required the use of hydrogen cyanide
gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3
g malononitrile in absolute EtOH, treated with a drop of
triethylamine, was an orange crystalline product. A sample
recrystallized from EtOH gave a mp of 138.5-139 °C.
A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde in 30 g
nitromethane was treated with 1.1 g anhydrous ammonium acetate and
heated for 50 min on the steam bath. Stripping off the excess
nitromethane under vacuum yielded orange crystals which weighed 12.2
g. These were recrystallized from 100 mL IPA providing yellow
crystals of 2,5-dimethoxy-4-methyl-beta-nitrostyrene which weighed, when
dry, 7.70 g. The mp was 117-118 °C, and this was increased to 118-119
°C upon recrystallization from benzene/heptane 1:2.
To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under
an inert atmosphere, there was added 7.7 g
2,5-dimethoxy-4-methyl-beta-nitrostyrene in 35 mL THF over the course of
0.5 h. This reaction mixture was held at reflux for 24 h, cooled to
room temperature, and the excess hydride destroyed with 25 mL IPA.
There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The
granular gray mass was filtered, and the filter cake washed with 2x50
mL THF. The combined filtrate and washes were stripped of their
volatiles under vacuum to give a residue weighing 7.7 g which was
distilled at 90-115 °C at 0.3 mm/Hg to provide 4.90 g of a clear,
white oil, which crystallized in the receiver. This was dissolved in
25 mL IPA, and neutralized with concentrated HCl which produced
immediate crystals of the salt. These were dispersed with 80 mL
anhydrous Et2O, filtered, and washed with Et2O to give, after air
drying to constant weight, 4.9 g of fluffy white crystals of
2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D). The mp was
213-214 °C which was not improved by recrystallization from CH3CN/IPA
mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 °C.
The acetamide, from the free base in pyridine treated with acetic
anhydride, was a white crystalline solid which, when recrystallized
from aqueous MeOH, had a mp of 116-117 °C.
DOSAGE: 20 - 60 mg.
DURATION: 4 - 6 h.
QUALITATIVE COMMENTS: (with 10 mg) There is something going on, but
it is subtle. I find that I can just slightly redirect my attention
so that it applies more exactly to what I am doing. I feel that I can
learn faster. This is a `smart' pill!
(with 20 mg) Butterflies in stomach whole time. OK. This is about
the right level. In retrospect, not too interesting. Primarily a
stimulant, not entirely physically pleasant. The visual is not too
exciting. I am easily distracted. One line of thought to another. I
feel that more would be too stimulating.
(with 30 mg) I was into it quite quickly (not much over
three-quarters of an hour) and got up to a ++ by the end of an hour.
There is something unsatisfactory about trying to classify this level.
I had said that I was willing to increase the dose to a higher level,
to break out of this not-quite-defined level into something
psychedelic. But I may not want to go higher. Under different
circumstances I would not mind trying it at a considerably lower
dosage, perhaps at the 10 or 15 milligrams. I do not have a
comfortable label on this material, yet.
(with 45 mg) There was a rocket from the half-hour to the one and a
half hour, from nothing up to a +++. Somehow the intimacy and the
erotic never quite knit, and I feel that I am always waiting for the
experience to come home. Talking is extremely easy, but something is
missing. Appetite is good. I am down by the fifth hour, and sleep is
comfortable. This compound will take some learning.
(with 75 mg) This is a +++, but the emphasis is on talking, not on
personal interacting. I am putting out, but my boundaries are intact.
I was able to sleep at the sixth hour. Communication was excellent.
This is fast on, but not too long lived. Maybe a therapy tool?
(with 150 mg) A truly remarkable psychedelic, one which could compare
favorably with 2C-B. There are intense colors, and I feel that more
would be too much.
EXTENSIONS AND COMMENTARY: Wow! This particular compound is what I
call a pharmacological tofu. It doesn't seem to do too much by
itself, always teasing, until you get to heroic levels. But a goodly
number of experimental therapists have said that it is excellent in
extending the action of some other materials. It seems to boost the
waning action of another drug, without adding its own color to the
experience. Yet, the comment above, on the high level of 150
milligrams, is a direct quote from the use of this compound in Germany
(where it is called LE-25) in therapeutic research.
This is probably the most dramatic example of the loss of potency from
an amphetamine (DOM, active at maybe 3 milligrams) to a phenethylamine
(only one tenth as active). It is so often the case that the first of
a series is not the most interesting nor the most potent member. As
intriguing and as difficult-to-define as the 2C-D story might be, the
next higher homologue of this set, 2C-E, is maximally active at the 15
to 20 milligram level, and is, without any question, a complete
psychedelic.
The N-monomethyl and the N,N-dimethyl homologues of 2C-D have been
synthesized from 2C-D. The N-monomethyl compound was obtained by the
quaternization of the Schiff's base formed between 2C-D and
benzaldehyde with methyl sulfate, followed by hydrolysis; the
hydrochloride salt had a melting point of 150-151 °C, from EtOH. The
N,N-dimethyl compound resulted from the action of formaldehyde-formic
acid on 2C-D; the hydrochloride salt had a melting point of 168-169 °C
from EtOH/ether. These two compounds were some ten times less
effective in interfering with conditioned responses in experimental
rats. There is no report of their having been explored in man.
I have learned of an extensive study of ethoxy homologues of a number
of the phenethylamines in the 2C-X series; they have been collectively
called the "Tweetios." This Sylvester and Tweety-bird allusion came
directly from the compulsive habit of trying to alleviate the boredom
of driving long distances (not under the influence of anything) by the
attempt to pronounce the license plates of cars as they passed. The
first of this series of compounds had a name that indicated that there
was an ethoxy group at the 2-position, or 2-EtO, or Tweetio, and the
rest is history. In every compound to be found in the 2C-X family,
there are two methoxy groups, one at the 2-position and one at the
5-position. There are thus three possible tweetio compounds, a
2-EtO-, a 5-EtO- and a 2,5-di-EtO-. Those that have been evaluated in
man are included after each of the 2C-X's that has served as the
prototype. In general, the 2-EtO- compounds have a shorter duration
and a lower potency, the 5-EtO- compounds have a relatively unchanged
potency and a longer time duration; the 2,5-di-EtO- homologues are
very weak, if active at all.
The 2-EtO-homologue of 2C-D is
2-ethoxy-5-methoxy-4-methylphenethylamine, or 2CD-2ETO. The
benzaldehyde (2-ethoxy-5-methoxy-4-tolualdehyde) had a melting point
of 60.5-61 °C, the nitrostyrene intermediate a melting point of
110.5-111.5 °C, and the final hydrochloride a melting point of 207-208
°C. The hydrobromide salt had a melting point of 171-173 °C. At
levels of 60 milli-grams, there was the feeling of closeness between
couples, without an appreciable state of intoxication. The duration
was about 4 hours.
The 5-EtO- homologue of 2C-D is
5-ethoxy-2-methoxy-4-methylphenethylamine, or 2CD-5ETO. The
benzaldehyde (5-ethoxy-2-ethoxy-4-tolualdehyde) had a melting point of
81-82 °C, and the details of this synthesis are given in the recipe
for IRIS. The nitrostyrene intermediate had a melting point of
112.5-113.5 °C and the final hydrochloride salt had a melting point of
197-198 °C. The hydro-bromide salt had a melting point of 158-159 °C.
At dosage levels of 40 to 50 milli-grams, there was a slow, gradual
climb to the full effects that were noted in about 2 hours. The
experience was largely free from excitement, but with a friendly
openness and outgoingness that allowed easy talk, interaction, humor,
and a healthy appetite. The duration of effects was 12 hours.
The 2,5-di-EtO- homologue of 2C-D is
2,5-diethoxy-4-methylphenethylamine, or 2CD-2,5-DIETO. The
benzaldehyde (2,5-diethoxy-4-tolualdehyde) had a melting point of
102-103 °C, the nitrostyrene intermediate a melting point of 108-109
°C, and the final hydrochloride salt a melting point of 251-252 °C.
At a level of 55 milligrams, a plus one was reached, and what effects
there were, were gone after four hours.
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