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 TsmartU pill!S
(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?S
(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 doesnUt 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 RTweetios.S 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.
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 temperature 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 recrystallization 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 temperature of the pot contents to continuously increase. When the pot temperature 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 temperature, 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 unrecrystallized 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 recrystallized 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-'-nitrostyrene. The mp was 96-98 !C which improved to 99-100 !C after a second recrystallization 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-'-nitrostyrene, in 40 mL of warm THF. The reaction mixture was stirred for 0.5 h, brought to room temperature, heated on the steam bath for 0.5 h, and then returned to room temperature. 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-'-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 Q 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 sub
stance 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, RI donUt think I like it, since it isnUt that much fun. But I intend to explore it again.S 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 REternityS
by one subject.
25 3C-E; 3,5-DIMETHOXY-4-ETHOXYAMPHETAMINE
SYNTHESIS: A solution of 3.6 g syringaldehyde (3,5-dimethoxy-4-
hydroxybenzaldehyde) in 50 mL MeOH was combined with a solution of 3.7
g 85% KOH in 75 mL warm MeOH. This clear solution suddenly set up to crystals of the potassium salt, too thick to stir satisfactorily. To this suspension there was added 7.4 g ethyl iodide (a large excess) and the mixture was held at reflux temperature with a heating mantle.
The solids eventually loosened and redissolved, giving a clear amber-colored smooth-boiling solution. Refluxing was maintained for 2
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