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#24 2C-E
2,5-DIMETHOXY-4-ETHYLPHENETHYLAMINE
SYNTHESIS: A suspension of 140 g
anhydrous AlCl3 in 400 mL
CH2Cl2 was
treated with 100 g
acetyl chloride. This slurry was added to a
vigorously stirred
solution of 110 g
p-dimethoxybenzene in 300 mL
CH2Cl2. Stirring was continued at ambient tem
perature for an
additional 40 min, then all was poured into 1 L water and the
phases
separated. The aqueous
phase was extracted with 2x100 mL
CH2Cl2 and
the combined organic
phases washed with 3x150 mL 5%
NaOH. These
washes, after combination and acidification, were extracted with 3x75
mL
CH2Cl2 and the extracts washed once with saturated
NaHCO3.
Re-moval of the
solvent under vacuum provided 28.3 g of
2-hydroxy-5-methoxyaceto-phenone as yellow
crystals which, on
re
crystallization from 2 volumes of boiling MeOH and air drying,
provided 21.3 g of product with a mp of 49-49.5 °C. Ethyl-ation of
this material serves as the starting point for the synthesis of
2CE-
5ETO. The
CH2Cl2 fraction from the base wash, above, was stripped
of
solvent on the rotary
evaporator to give a
residual oil that, on
distillation at 147-150 °C at the water pump, provided 111.6 g of
2,5-dimethoxyacetophenone as an almost white oil.
In a round bottom flask equipped with a reflux
condenser, a take-off
adapter, an immersion thermometer, and a
magnetic stirrer, there was
placed 100 g
2,5-dimethoxyacetophenone, 71 g 85% KOH pellets, 500 mL
of
triethylene glycol, and 125 mL 65%
hydrazine. The mixture was
brought up to a boil by heating with an electric mantle, and the
distillate was removed, allowing the tem
perature of the pot contents
to continuously increase. When the pot tem
perature had reached 210
°C, reflux was established and maintained for an additional 3 h.
After cooling, the reaction mixture and the
distillate were combined,
poured into 3 L water, and extracted with 3x100 mL hexane. After
washing the pooled extracts with water, the
solvent was removed
yielding 22.0 g of a pale straw-colored liquid that was free of both
hydroxy and
carbonyl groups by infrared. This was
distilled at
120-140 °C at the water pump to give
2,5-dimethoxy-1-ethylbenzene as a
white fluid product.
Acidification of the spent aqueous
phase with
concentrated HCl produced a heavy black oil which was extracted with
3x100 mL
CH2Cl2. Removal of the
solvent on the rotary
evaporator
yielded 78 g.of a black residue that was
distilled at 90-105 °C at 0.5
mm/
Hg to provide 67.4 g of an orange-amber oil that was largely
2-ethyl-4-methoxyphenol. This material could eventually be used as a
starting material for ethoxy
homologues. However,
remethylation (with
CH3I and KOH in
methanol) provided some 28 g additional
2,5-dimethoxyethylbenzene.
A
solution of 8.16 g of
2,5-dimethoxy-1-ethylbenzene in 30 mL
CH2Cl2
was cooled to 0 °C with good stirring and under an inert
atmosphere of
He. There was then added 11.7 mL
anhydrous stannic
chloride, followed
by 3.95 mL
dichloromethyl methyl
ether dropwise over the course of 0.5
h. The stirred reaction mixture was allowed to come up to room
tem
perature, then held on the steam bath for 1 h. The reaction
mixture was poured into 1 L water, extracted with 3x75 mL
CH2Cl2, and
the pooled extracts washed with dilute HCl. The organic
phase was
stripped under vacuum yielding 10.8 g of a dark viscous oil. This was
distilled at 90-110 °C at 0.2 mm/
Hg to yield a colorless oil that, on
cooling, set to white
crystals. The yield of
2,5-dimethoxy-4-ethylbenzaldehyde was 5.9 g of material that had a mp
of 46-47 °C. After purification through the
bisulfite complex, the mp
increased to 47-48 °C. The use of the Vilsmeier
aldehyde synthesis
(with POCl3 and N-
methylformanilide) gave results that were totally
unpredictable. The
malononitrile derivative (from 0.3 g of this
aldehyde and 0.3 g
malononitrile in 5 mL
EtOH and a drop of
triethylamine) formed red
crystals which, on recrystallization from
toluene, had a mp of 123-124 °C.
A
solution of 21.0 g of the unre
crystallized
2,5-dimethoxy-4-ethylbenzaldehyde in 75 g
nitromethane was treated
with 4 g of
anhydrous ammonium acetate and heated on the steam bath
for about 2 h. The progress of the reaction was best followed by TLC
analysis of the crude reaction mixture on
silica gel plates with
CH2Cl2 as the developing
solvent. The excess solvent/reagent was
removed under vacuum yielding granular orange solids that were
re
crystallized from seven volumes of boiling MeOH. After cooling in
external ice-water for 1 h, the yellow
crystalline product was removed
by filtration, washed with cold MeOH and air dried to give 13.4 g of
2,5-dimethoxy-4-ethyl-beta-nitrostyrene. The mp was 96-98 °C which
improved to 99-100 °C after a second re
crystallization from MeOH.
A total of 120 mL of 1.0 M
solution of LAH in THF (120 mL of 1.0 M)
was transferred to a 3 neck 500 mL flask, under an inert
atmosphere
with good
magnetic stirring. This
solution was cooled to °C with an
external ice-water bath, and there was then added 3.0 mL of 100% H2SO4
over the course of 0.5 h. This was followed by a
solution of 5.85 g
of
2,5-dimethoxy-4-ethyl-beta-nitrostyrene, in 40 mL of warm THF. The
reaction mixture was stirred for 0.5 h, brought to room tem
perature,
heated on the steam bath for 0.5 h, and then returned to room
tem
perature. The addition of IPA dropwise destroyed the excess
hydride, and some 4.5 mL of 5%
NaOH produce a white cottage cheese, in
a basic organic medium. This mixture was filtered, washed with THF,
and the filtrate
evaporated to produce 2.8 g of an almost white oil.
The filter cake was resuspended in THF, made more basic with
additional 15 mL of 5%
NaOH, again filtered, and the filtrate removed
to provide an additional 2.8 g of crude product. These residues were
combined and
distilled at 90-100 °C at 0.25 mm/
Hg to give a colorless
oil. This was
dissolved in 30 mL IPA, neutralized with concentrated
HCl, and diluted with 50 mL
anhydrous Et2O to provide, after
spontaneous
crystallization, filtration, washing with
Et2O, and air
drying, 3.87 g of
2,5-dimethoxy-4-ethylphenethylamine hydrochloride
(2C-E) as magnificent white
crystals. A similar yield can be obtained
from the reduction of the
nitrostyrene in a suspension of LAH in THF,
without the use of H2SO4. With 11.3 g of LAH in 300 mL dry THF, there
was added, dropwise, a
solution of 13.4 g of
2,5-dimethoxy-4-ethyl-beta-nitrostyrene in 75 mL THF over the course of 2
h. The mixture was kept at reflux for an additional 8 h, and killed
by the careful addition of 11 mL H2O, followed with 11 mL 15%
NaOH,
and finally another 33 mL of H2O. This mass was filtered, washed with
THF, and the combined filtrates and washes
evaporated to a residue
under vacuum The approximately 15 mL of residue was
dissolved in 300
mL
CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated
HCl. On shaking the mixture, there was
deposited a mass of the
hydrochloride salt which was diluted with a quantity of additional
H2O. The organic
phase was extracted with additional dilute HCL, and
these aqueous
phases were combined. After being made basic with 25%
NaOH, this
phase was again extracted with 3x75 mL
CH2Cl2 and after the
removal of the
solvent, yielded 12.6 g of a colorless oil. This was
dissolved in 75 mL of IPA and neutralized with concentrated HCl. The
solidified mass that formed was loosened with another 50 mL IPA, and
then filtered. After
Et2O washing and air drying there was obtained
7.7 g of
2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) as
lustrous white
crystals. Anal. (
C12H20ClNO2) C,H.
DOSAGE: 10 - 25 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 16 mg) There was a strange devil-angel
pairing. As I was being told of the ecstatic white-light ascent of my
partner into the God-space of an out-of-body experience, I was
fighting my way out of a brown ooze. She saw the young Jesus at the
bottom of a ladder drifting upwards step by step to some taking-off
place, and I saw all the funny gargoyles around the base of the ladder
surrounded by picnic bunting. For me it was the 4th of July, rather
than Easter!S
(with 20 mg) The view out of the window was unreal. The garden was
painted on the window, and every petal of flower and tuft of grass and
leaf of tree was carefully sculptured in fine strokes of oil paint on
the surface of the glass. It was not out there; it was right here in
front of me. The woman who was watering the plants was completely
frozen, immobilized by Vermeer. And when I looked again, she was in a
different place, but again frozen. I was destined to become the
eternal museum viewer.
(with 25 mg) I have a picture in my living room that is a stylized
German scene with a man on horseback riding through the woods, and a
young girl coming out to meet him from the nearby trees. But she was
not just 'coming out.' He was not just riding through the woods. The
wind was blowing, and his horse was at full gallop, and his cape was
flapping in the storm, and she was bearing down upon him at full bore.
The action never ceased. I became exhausted.
(with 25 mg) Within minutes I was anxious and sweaty. Each person
has his own brand of toxic
psychosis--mine always starts with the
voices in my head talking to me, about all my worst fears, a jumble of
warnings and deep fears spinning faster. Twenty minutes later this
complex chaos passed as quickly as it had come. At lower dosages 2C-E
has been a truly enjoyable esthetic enhancer. But it really has a
steep dose/response curve.
EXTENSIONS AND COMMENTARY: Here is another of the magical half-dozen.
The range is purposefully broad. At 10 milligrams there have been
some pretty rich +++ experiences, and yet I have had the report from
one young lady of a 30 milligram trial that was very frightening. My
first experience with 2C-E was really profound, and it is the
substance of a chapter within the story. The amphet-
amine homologue
is DOET, which is not only much longer in action, but considerably
more potent. Several people have said, about 2C-E, "I don't think I
like it, since it isn't that much fun. But I intend to explore it
again." There is something here that will reward the experimenter.
Someday, the full character of 2C-E will be understood, but for the
moment, let it rest as being a difficult and worth-while material. A
very much worth-while material. One Tweetio of 2C-E is known. The
5-
EtO-
homologue of 2C-E is
5-ethoxy-4-ethyl-2-methoxyphenethylamine,
or 2CE-
5ETO. The
nitrostyrene intermediate had a melting point of
110-110.5 °C, and the final
hydrochloride a melting point of 184-185
°C. The effective level of 2CE-
5ETO is in the 10 to 15 milligram
range. It is gentle, forgiving, and extremely long lived. Some 3 to
4 hours were needed to achieve plateau, and on occasion experi-ments
were interrupted with
Valium or
Halcion at the 16 hour point. After a
night's sleep, there were still some effects evident the next day.
Thus, the dose is comparable to the parent compound 2C-E, but the
duration is 2 to 3 times longer. It was given the nickname "Eternity"
by one subject.
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