32 2C-H; 2,5-DIMETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 50 g 2,5-dimethoxybenzaldehyde in 100 g nitromethane was treated with 5 g of anhydrous ammonium acetate, and heated on the steam bath for 4 h. The solution was decanted from a little insoluble material, and the solvent removed under vacuum. The clear oily residue was dissolved in 100 mL boiling IPA which, after standing a moment, set up as dense crystals. After returning to room temperature, these were removed by filtration, the product was washed with IPA and air dried, yielding 56.9 g 2,5-dimethoxy-'-nitrostyrene as spectacular yum-yum orange crystals with a mp of 119-120 !C. An analytical sample, from ethyl acetate, melted at 120-121 !C.
A suspension of 60 g LAH in 500 mL anhydrous THF was placed under an inert atmosphere, stirred magnetically, and brought up to reflux temperature. There was added, dropwise, 56 g of 2,5-dimethoxy-'-nitrostyrene dissolved in THF, and the reaction mixture was maintained at reflux for 36 h. After being brought to room tem-perature, the excess hydride was destroyed with 40 mL IPA, followed by 50 mL of 15% NaOH. An additional 100 mL THF was required for easy stirring, and an additional 150 mL H2O was needed for complete conversion of the aluminum salts to a loose, white, filterable consistency. This solid was removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in dilute H2SO4. Washing with 3x75 mL CH2Cl2 removed most of the color, and the aqueous phase was made basic with aqueous NaOH
and reextracted with 3x100 mL CH2Cl2. Removal of the solvent yielded 39.2 g of a pale amber oil that was distilled. The fraction boiling at 80-100 !C at 0.4 mm/Hg weighed 24.8 g and was water-white product amine. As the free base, it was suitable for most of the further synthetic steps that might be wanted, but in this form it picked up carbon dioxide rapidly when exposed to the air. It was readily converted to the hydrochloride salt by dissolution in 6 volumes of IPA, neutralization with concentrated HCl, and addition of sufficient anhydrous Et2O to produce a permanent turbidity. Crystals of 2,5-dimethoxyphenethylamine hydrochloride (2C-H) spontaneously formed and were removed by filtration, washed with Et2O, and air dried. The mp was 138-139 !C.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: I know of no record of 2C-H ever having been tried by man. It has been assumed by everyone (and probably correctly so) that this amine, being an excellent substrate for the amino oxidase systems in man, will be completely destroyed by the body as soon as it gets into it, and thus be without action. In virtually all animal assays where it has been compared with known psychoactive drugs, it remains at the Rless-activeS end of the ranking.
It is, however, one of the most magnificent launching pads for a number of rather unusual and, in a couple of cases, extraordinary drugs. In the lingo of the chemist, it is amenable to Relectrophilic attack at the 4-position.S And, in the lingo of the psychopharmacologist, the R4-position is where the action is.S From this (presumably) inactive thing have evolved end products such as 2C-B, 2C-I, 2C-C, and 2C-N. And in the future, many possible things as might come from a carbinol group, an amine function, or anything that can stem from a lithium atom.
33 2C-I; 2,5-DIMETHOXY-4-IODOPHENETHYLAMINE
SYNTHESIS: A mixture of 7.4 g phthalic anhydride and 9.05 g of 2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its preparation) was heated with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was poured out into a crystallizing dish yielding 14.8
g of a crude solid product. This was recrystallized from 20 mL CH3CN, with care taken for an endothermic dissolution, and an exothermic crystallization. Both transitions must be done without haste. After filtration, the solids were washed with 2x20 mL hexane and air dried to constant weight. A yield of 12.93 g of N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide was obtained as electrostatic yellow crystals, with a mp of 109-111 !C. A sample recrystallized from IPA was white, with a mp of 110-111 !C. Anal.
(C18H17NO4) C,H,N.
To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide in 130 mL warm (35 !C) acetic acid which was being vigorously stirred, there was added a solution of 10 g iodine monochloride in 40 mL acetic acid. This was stirred for 1 h, while being held at about 30 !C. The reaction mixture was poured into 1500 mL H2O and extracted with 4x75
mL CH2Cl2. The extracts were pooled, washed once with 150 mL H2O
containing 2.0 g sodium dithionite, and the solvent removed under vacuum to give 16.2 g of
N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide as yellow amber solids with a mp of 133-141 !C. This mp was improved by recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow solid with mp 149-151 !C. A small sample from a large quantity of IPA gives a white product melting at 155.5-157 !C.
A solution of 12.2 g
N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide in 150 mL hot IPA was treated with 6.0 mL of hydrazine hydrate, and the clear solution was heated on the steam bath. After a few minutes there was the generation of a white cottage cheese-like solid (1,4-dihydroxyphthalizine). The heating was continued for several additional h, the reaction mixture cooled, and the solids removed by filtration. These were washed with 2x10 mL EtOH, and the pooled filtrate and washes stripped of solvent under vacuum giving a residue which, when treated with aqueous hydrochloric acid, gave 3.43 g of voluminous white crystals. This, after recrystallization from 2
weights of H2O, filtering, washing first with IPA and then with Et2O, and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) as a white microcrystalline solid, with a mp of 246-247 !C. Anal. (C10H15ClINO2) C,H,N.
DOSAGE: 14 - 22 mg.
DURATION: 6 - 10 h.
QUALITATIVE COMMENTS (with 0 mg) I was present at a group meeting, but was only an observer. With zero milligrams of 2C-I, I was able to get to a delightful plus 2.5 in about five minutes after I arrived at your place, and absorbed the ambience of the folks who had actually imbibed the material. My level lasted about four hours and came down at about the same time as did the others. There were no after-effects experienced except for a pleasant languor.
(with 15 mg) Comfortable onset. Most notable are the visuals, patterning like 2C-B (Persian carpet type), very colorful and active.
Much more balanced emotional character, but still no feeling of insight, revelation, or progress toward the true meaning of the universe. And at 5 1/2 hours drop-off very abrupt, then gentle decline. I would like to investigate museum levels.
(with 16 mg) There was an immediate alert within minutes. As usual, it was only an awareness, then nothing happened for a while. In retrospect, I see some type of activity or awareness within 40
minutes, which then builds up over time. The peak was at 2 hours and seemed to maintain itself for a while. Near the peak, there was some hallucinogenic activity, though not a lot. The pictures in the dining room had color and pattern movement that was fairly detailed.
Focusing on other areas, such as walls or the outside of the house, produced little activity, though I tried. There was certainly a lot of color enhancement. There was also that peculiar aspect of the visual field having darkened or shadowed areas. These darker areas seemed to shift around to some degree. That aspect seems to be similar to 2C-B. I donUt think I was more than +2.5 at the peak.
Coming down was uneventful. I was down within 6 hours. I had no problems driving home, nor were there any difficulties with sleep.
There were no body problems with this material. I ate like a horse.
(with 16 mg) The 16 was a bit much, I realized, because my body was not sure of what to do with all the energy. Next time IUll try 14 or 15. However, my conversations were extremely clear and insightful.
The degree of honesty was incredible. I was not afraid to say anything to anyone. Felt really good about myself. Very centered, in fact. A bit tired at day's end. Early bedtime.
(with 20 m
g) I think there is slightly less than full immersion in the sensual, with this material, compared with 2C-B, but I suspect it's more a matter of getting used to the language of 2C-I and the feelings Q getting tuned to a slightly different frequency, really Q
rather than that the material is less sensual or less easy to use sensually. Just different frequency, and we are very, very used to 2C-B. Good on the body. Transition, for me, not as strongly dark as 2C-B. But it could certainly take a lot more exploring, if we were able to give the time (about 9 hours) to it. Next day: sleep excellent. Energy next day unusually good. Quite tired by evening.
EXTENSIONS AND COMMENTARY: The frequent comparisons between 2C-I and 2C-B stem, without doubt, from a bit of chemical suggestion. The two compounds have structures that are truly analogous, in technical terms. In one, there is a strategically located iodine atom, and in the other, an identically placed bromine atom. These are directly above and below one-another in the periodic table. And what is particularly maddening to the synthetic diddler, is that they cannot be lengthened, or shortened, or squooshed around in any way. You canUt make a longer and narrower version of a bromine atom, as you can do with, say, a butyl group. YouUve got what youUve got, like it or not. No subtle variations.
But, on the brighter side of the picture, you have a heavy atom here, and this atom is intrinsic to the central activity of the compound.
So, these materials are naturals for radio-labelling experiments.
2C-I has been made radioactive with radio-iodine, but the most impressive findings have been made with the 3-carbon analog, DOI.
One quotation from an observer of a group experiment is enclosed; an experiment with zero milligrams being taken. This is a instructive observation of what has been called a Rcontact high.
There is one Iodotweetio known. In Scrabble, would you challenge a word that had seven of its eleven letters as vowels? Especially if the vowels were, specifically, iooeeio? It sounds just a little like the noise coming out of Old McDonald's farm. But a Tweetio there is, namely, the 2-EtO-homologue of 2C-I. This is 2-ethoxy-4-iodo-5-methoxyphenethylamine, or 2CI-2ETO. The hydrochloride salt was a white, crystalline product with a melting point of 175-175.5 !C. The threshold level of activity was seen at an oral dose of 5 milligrams, and the generated effects were completely dispersed in a couple of hours. Most interestingly, larger doses, of up to 50 milligrams orally, seem to produce no more intense an effect, but simply to stretch out this threshold for an additional couple of hours. At no level that has been tried, has 2CI-2EtO produced even a plus-two response.
Where else can one go, from 2C-I? The iodine is the fourth, and the last of the so-called halogens, at the bottom of the classical periodic table. But, thanks to the miracles that have accompanied us into the nuclear age, there is a fifth halide now known, Astatine.
All of its isotopes are radioactive, however, and it seems unlikely that there will ever be an entry (other than this one) for 2,5-dimethoxy-4-astatophenethylamine. What might be speculated as to its activity? Probably similar in potency to 2C-I, requiring maybe 10
or 20 milligrams. The duration would be dicey to measure, since the isotope with the longest known half-life is half decayed in about 8
hours, and the longest lived natural isotope (for those who insist on natural rather than man-made things) is half decayed in less than a minute. Two predictions would be pretty solid. You might have quite a job accumulating your 10 milligrams of Astatine, as the most that has so far been made at one time is only about 0.05 micrograms, approximately a millionth of the amount needed. And the second prediction? You would not survive the screaming radiation that would bombard you if you could get the needed 5 or 10 milligrams of radio-astatine onto that magic 4-position, and the resulting 2C-A into your tummy!
34 2C-N; 2,5-DIMETHOXY-4-NITROPHENETHYLAMINE
SYNTHESIS: A cooled, stirred solution of 1.0 g 2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its preparation) in 20 mL glacial acetic acid was treated with 3.3 mL 70%
HNO3 in small portions, with the reaction temperature kept down with periodic cooling. After the addition was completed, the stirring was continued until there was the spontaneous separation of a yellow solid. This was 2,5-dimethoxy-4-nitrophenethylamine nitrate (2C-N) which was obtained after removal by filtration, washing with Et2O and air drying, as a fluffy yellow solid. This weighed 1.04 g and melted, with decomposition, in the area of 170-180 !C, depending on the rate of heating. A solution of 0.8 g of this nitrate salt in 50 mL H2O was made basic with aqueous NaOH. Extraction with 3x50 mL CH2Cl2, and removal of the solvent under vacuum gave the free base as a residue.
This was distilled at 130-150 !C at 0.35 mm/Hg to give an orange-red oil that weighed 0.5 g and set up as crystals. This was dissolved in 3 mL IPA, neutralized with 7 drops of concentrated HCl (the color lightened considerably at the titration end point) and diluted with 5
mL anhydrous Et2O. There was the formation of the hydrochloride salt which was a pumpkin-colored crystalline mass. After removal by filtration, Et2O washing and air drying, these crystals weighed 0.44
g. The mp, 193-195 !C, was not improved by recrystallization from any of several solvents (MeOH, IPA, CH3CN). The perchlorate salt was a yellow solid from MeOH, with a mp of 211 !C, with decomposition.
Nitration of 2C-H in a mixture of acetic acid and acetic anhydride produced the acetamide derivative of 2C-N as yellow crystals with a mp 142.5-143 !C. For the nitrate salt: Anal. (C10H15N3O7) C,H. This was the form used for all human titrations.
DOSAGE: 100 - 150 mg.
DURATION: 4 - 6 h.
QUALITATIVE COMMENTS: (with 120 mg) This came on very fast Q I was aware of it within a half hour, and it got as far as it would go by an hour. There are similarities to MDMA, but missing is the benign anti-stress component. I am light-headed, and there just might be a little eye wiggling. And then it dropped right off to nothing within a couple of hours.
(with 150 mg) There may have been some visual changes, IUm not sure.
But the talking was extremely easy. If there were no other things to use, this would be excellent, but there are other compounds available.
This doesnUt have too high a priority.
(with 150 mg) Am I enjoying it? Not exactly, but I am in a good mood. There is not the light-filled energy that some other materials can provide. By six hours, pretty much baseline. Strange material, but okay. Final score: body +3, mind +2, barely.
EXTENSIONS AND COMMENTARY: A most consistent feature with 2C-N was the fact that in every report, somewhere, there is the note that it somehow came up just a little short of expectations. From the esthetic point of view, the pure salt is yellow rather than the usual white color, so the solutions that are to be consumed are by definition also yellow colored. From the structural point of view, the 4-nitro group, like the 4-bromo group of 2C-B, is a dead-end. It cannot be stretched or compressed or lengthened or shortened. This unique aspect demands that you have to live with what you have, as there are no subtle ways of modifying the molecule. With 2C-B, the end product was a total winner; there was no wish to modify it. With 2C-N the end product is something a little less, and there is no way to modify it.
35 2C-O-4; 2,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE
SYNTHESIS: To a solution of 3.10 g 85% KOH pellets in 30 mL warm MeOH
there was added 6.16 g 2,5-dimethoxyphenol (there was immediate darkening) followed by 8.5 g isopropyl iodide. The reaction mixture was heated on the steam bath for 3.5 h. White crystals of KI appeared at the end of the first h. The mixture was poured into 800 mL H2O (it was still basic) and acidified with HCl. This was extracted with 3x100 mL CH2Cl2, and the combined extracts washed with 2x100 mL 5%
NaOH. The organic phase was stripped of solvent under vacuum, and the residual dark amber oil (6.4 g) distilled at 110-130 !C at 0.7 mm/Hg.
There was obtained 5.7 g of 1,4-dimethoxy-2-(i)-propoxybenzene as a white oil.
A mixture of 10 g N-methylformanilide and 10 g POCl3 was heate
d on the steam bath for 10 min producing a deep claret color. To this there was added 5.1 g of 1,4-dimethoxy-2-(i)-propoxybenzene, and the immediately exothermic reaction mixture was heated on the steam bath for 45 min. It was then poured into 800 mL H2O which was stirred until the dark oil changed into loose, light-colored solids. These were removed by filtration giving 5.7 g of an amber crystalline product with a mp of 76-78 !C. This was dissolved in an equal weight of MeOH, and heated to a solution which was clear at the boiling point. This was brought to 0 !C and held there for several hours, yielding 2,5-dimethoxy-4-(i)-propoxybenzaldehyde as a fine, off-white crystalline product which, after filtering and air drying, weighed 4.03 g. The mp was 79-80 !C with prior shrinking at 71 !C. Anal.
(C12H16O4) C,H.
A solution of 3.9 g 2,5-dimethoxy-4-(i)-propoxybenzaldehyde in 20 g nitromethane was treated with 0.17 g anhydrous ammonium acetate and heated on the steam bath for 1.25 h. The progress of the condensation was readily followed by a TLC analysis of the reaction mixture. With silica gel plates, the starting aldehyde and the product nitrostyrene had Rf's of 0.16 and 0.50 resp., using CH2Cl2 as a developing solvent.
The excess solvent was removed under vacuum to give a red residue that was dissolved in 10 mL boiling MeOH. The solution spontaneously crystallized giving, after filteration and air drying, 4.1 g of orange crystals of 2,5-dimethoxy-'-nitro-4-(i)-propoxystyrene.
A solution of LAH (60 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 1.60 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 4.0 g
2,5-dimethoxy-'-nitro-4-(i)-propoxystyrene as a solid, perhaps 200 mg at a time. There was an immediate loss of color after each addition.
The final pale salmon-colored solution was stirred for 2 h as it returned to room temperature. The excess hydride was destroyed by the cautious addition of 8 mL IPA, which was followed by 5 mL 15% NaOH
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