PiHKAL: The Chemical Story 6
This is part 3 of 6 of the second half of PiHKAL: A Chemical Love Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos or misprints in this file; further, because of ASCII limitations, many of the typographical symbols in the original book could not be properly represented in these files.
If you are seriously interested in the chemistry contained in these files, you should order a copy of the book PiHKAL. The book may be purchased for $22.95 ($18.95 + $4.00 postage and handling) from Transform Press, Box 13675, Berkeley, CA 94701. California residents please add $1.38 State sales tax.
At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.... No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herin, without being familiar with that drug's action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.
#60 DMPEA; 3,4-DIMETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 33 g 3,4-dimethoxybenzaldehyde in 140 mL acetic acid was treated with 23 mL nitromethane and 12.5 g anhydrous ammonium acetate, and heated on the steam bath for 45 min. To this there was slowly added, with good stirring, 300 mL H2O, and the resulting solids were removed by filtration. The product was finely ground under a small amount of MeOH, filtered again, and air dried to give 13.5 g 3,4-dimethoxy-'-nitrostyrene with a mp of 142-143 °C.
To a stirred suspension of 12.0 g LAH in 500 mL anhydrous Et2O that was at a gentle reflux and under an inert atmosphere, there was added 11.45 g 3,4-dimethoxy-'-nitrostyrene by leaching it from a thimble in a modified Soxhlet condenser. The addition took 2 h and the refluxing was maintained for another 16 h. After cool-ing to room temperature, the excess hydride was destroyed by the cautious addition of 500 mL 1.5 N H2SO4. The phases were separated, and to the aqueous phase there was added 250 g potassium sodium tartrate. The pH was brought to >9, and the clear solution was extracted with 3x100 mL CH2Cl2. Remo-val of the solvent from the combined extracts under vacuum gave 5.2 g of a pale yellow oil. This was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas, giving 5.0 g of a slightly sticky off-white solid. This was recrystallized from 75 mL of boiling CH3CN to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride (DMPEA) as beautiful white crystals.
DOSAGE: greater than 1000 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 500 mg) Nothing.
(with 1000 mg) Nothing.
(with 10 mg i.v.) RNothing.
(with 1000 mg of 3,4-dimethoxyphenylacetic acid, a major human metabolite of DMPEA) RNothing.
(with 500 mg of N-acetyl-3,4-dimethoxyphenethylamine, a major human metabolite of DMPEA) RNothing.
EXTENSIONS AND COMMENTARY: Why all the interest? Why keep pursuing a compound that is so obviously without activity? Or a metabolite that is also without activity? The answer is that these are totally fascinating compounds just because they have no activity° By the way, in this instance, I actually made up most of the quotations. I am not sure that the subjects actually said, "Nothing," but they did report that there were no effects. In my own experiments, my notes record the phrase, RNo effects whatsoever.
A little background: one of the transmitter heavyweights in the brain is dopamine. Dopamine is called dopamine because it is an amine that comes from an amino acid that is 3,4-dihydroxyphenylalanine and this, in German, is Di-Oxo-Phenyl-Alanine, or DOPA. The levo-optical (or L-) isomer of DOPA has rather cutely been called the punch-drunk Spanish matador, or El Dopa. But that is not part of the story.
The story is really about the "Pink Spot of Schizophrenia." Many years ago, an observation was made in a biochemical laboratory on the East Coast that stirred up a rolling controversy. It had been found that if the urines of schizophrenic patients (sloppily called "schizophrenic urines") were extracted in such and such a way, and the extracts chromatographed, a pink spot would develop at a particular place on the chromatogram. Well, if this proved to be true with urines of a sick population, and were this proved to be different from the urines of a healthy population, it would constitute an objective diagnosis of schizophrenia. A simple chemical test to confirm a pathology that had defied all efforts to achieve consensus amongst the psychiatrists of the world.
The literature was suddenly filled with dozens of papers. Researcher A confirmed that the pink spot was found with schizophrenics, and not with normal controls. Researcher B found the pink spot in all urines, regardless of pathology. Researcher C found it in no urines at all. Researcher D argued that it was a factor from the hospital diet. Researcher E found that the pink spot reflected the time of day that the urine sample was collected. Researcher F drew a conclusion about where truth might lie by tallying the number of papers that supported argument A, B, C, D, or E.
The only confirmable fact that endured was that the pink spot was due to DMPEA. So a bright spotlight was directed towards its possible role in mental illness. And this expressed itself in the simple question: would it produce schizophrenia in a normal subject? No. And in a way I am comforted that that did not evolve into a simple litmus test for a schizophrenic diagnosis. There are so many cultural, political, and social factors that come to bear on the assignment of a diagnosis of mental illness, that I would have been forever skeptical of a neat biochemical marker.
A chemical modification of DMPEA that has been explored in this question of pink spots, mental pathology, and diagnostic markers, is the corresponding acetamide. One of the metabolites of DMPEA was found to be the N-acetyl deriva-tive, N-acetyl-3,4- dimethoxyphenethylamine. It was found to be demethylated in man, and to have pharmacological activity in animals. Maybe this was the active compound that could be involved in the schizophrenic process. But human trials with it, as with the principal metabolite 3,4-dimethoxyphenylacetic acid, showed nothing at all in man.
Another chemical modification is the beta-hydroxy analogue of DMPEA. It has been explored separately, and is the subject of its own recipe, in its own rights. See DME.
Pink was not the only colorful spot associated with schizophrenia. Somewhere at about this same time, a research paper from Canada reported the observation of a mauve spot in the chromatographic analysis of urines of schizophrenic patients. This had nothing to do with DMPEA. I was working closely with a researcher at the psychiatric institute and we were fascinated by, again, a possible diagnostic marker. We assayed the urines of the next 10 patients being admitted as acute schizophrenics. No trace of mauve. We wrote to Canada, and verified the analytical procedure. We were told that the whatzis should have been added after, rather than before, the whosey, and that we should have heated for 30, not 10 minutes. Okay. We assayed the urines of the next 10 patients being admitted using these new directions. No trace of mauve. Another call to Canada, and we were informed that we still weren't doing it right. They were consistently batting a 100% positive correlation between mauve spots and schizophrenics, and 0% with healthy controls. In fact, they actually gave this positive test the name of a disease, Malvaria.
Then, that little burst of insight° Aha° What if, just what if, they had been seeing something given to their schizophrenics? Chlorpromazine was the popular treatment of the day. We took a whopping dose of chlorpromazine, and over the next couple of days did manage (barely) to collect our urine samples. Both of us were positive Malvarians° And three days later, we were again negative. We were most likely seeing a metabolite of chlorpromazine. One last call to Canada with the ultimate question Q had you given any medication to your schizophrenics before your urine analysis? Of course (came the answer) Q it would not be ethical to leave them untreated. Another color down the drain, and still no objective measure for mental illness.
By the way, I cannot say I like the chlorpromazine trip. There is no real communication either with others or with yourself, with that stuff. You are a zombie, but if you are both schizophrenic and a zombie, you cannot possibly be troublesome for anybody in the emergency room.
#61 DOAM; 2,5-DIMETHOXY-4-(n)-AMYLAMPHETAMINE
SYNTHESIS: A solution of 110 g p-dimethoxybenzene and 102 g valeric acid in 168 g polyphosphoric acid was heated on the steam bath for 3 h, giving a deep red homogeneous solution. This was poured into 1 L H2O with good stirring. The strongly acidic, cloudy suspension was extracted with 3x200 mL CH2Cl2, the extracts pooled, washed with 4x150 mL 5% NaOH, and finally once with dilute HCl. The solvent was removed under vacuum, and the residual amber oil cooled overnight at 0 °C. Some 30 g of crystalline, unreacted dimethoxybenzene were removed by filtration, and the 85 g of residual oil distilled at the water pump. Another 15 g of di-methoxybenzene came over as an early cut, but the fraction boil-ing at 184-192 °C (mostly 188-192 °C) weighed 53.0 g and was reasonably pure 2,5-dimethoxyamylophenone. The reaction of the acid chloride of valeric acid with p-dimethoxybenzene and anhydrous AlCl3 in CH2Cl2 (parallel to the preparation of the butyrophenone analog, see DOB') gave an inferior yield (23.2 g from 92 g dimethoxybenzene), but did provide a sizeable sample (12.2 g) of 2-hydroxy-5-methoxyamylophenone from the basic washes of the crude reaction mixture. This pale yellow solid, after recrystallization from MeOH, had a mp of 62-62.5 °C. Anal. (C12H16O3) C,H.
To 360 g mossy zinc there was added a solution of 7.2 g mercuric chloride in 200 mL warm H2O, and this was swirled periodically for 2 h. The H2O was drained off, and the amalgamated zinc added to a 2 L three-neck round-bottomed flask, treated with 200 mL concentrated HCl, and heated with an electric mantle. A solution of 53.0 g of 2,5-dimethoxyamylophenone in 107 mL EtOH containing 30 mL concentrated HCl was added drop-wise over the course of 4 h accompanied by 330 mL of concentrated HCl added batchwise over this same period. The mixture was held at reflux overnight and, after cooling, diluted with sufficient H2O to allowed CH2Cl2 to be the lower phase. The phases were separated, and the aqueous phase was extracted with 2x200 mL additional CH2Cl2. These organic phases were combined, washed first with 5% NaOH and then with H2O, and the solvent removed under vacuum. Distillation at the water pump yielded two fractions. The first distilled from about 100-130 °C, weighed 8.8 g, had a faint smell of apples and fennel, and was free of a carbonyl group in the infra-red. It proved to be only 50% pure by GC, however, and was discarded. The major fraction was a pale amber oil distilling between 152-170 °C and was substantially free of smell. It weighed 18.9 g, and was (by GC) 90% pure 2,5-dimethoxy-(n)-amylbenzene.
A mixture of 36.3 g POCl3 and 40.9 g N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 18.5 g of 2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath for 2 h. This mixture was poured into a large quantity of H2O and stirred overnight. The black oily product was extracted with 3x100 mL CH2Cl2, and the extracts combined and stripped of solvent under vacuum. The black residue was distilled at 180-205 °C at 20 mm/Hg to give 12.5 g of a pale amber oil that slowly set up to a crystalline mass. An analytical sample was recrystallized from MeOH to provide 2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 °C. Anal. (C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74.
A solution of 12.3 g 2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL acetic acid was treated with 4.0 g anhydrous ammonium acetate and 12 mL nitroethane. This mixture was heated on the steam bath for 4 h, then poured into a large quantity of H2O. This was extracted with 3x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give a deep red oil that, on standing in the refrigerator, slowly set to a crystalline mass weighing 13.5 g. An analytical sample was recrystallized from MeOH to provide 1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow microcrystals with a mp of 44 °C sharp. Anal. (C16H23NO4) C,H,N.
To a gently refluxing suspension of 10 g LAH in 500 mL anhydrous Et2O under a He atmosphere, there was added by 13.2 g 1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the condensing ether drip into a Soxhlet thimble containing the nitrostyrene which effectively added a warm saturated solution of it dropwise to the reaction mixture. Refluxing was maintained for 18 h, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 1 L 8% H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and the aqueous layer was washed with an additional 2x100 mL Et2O. Removal of the solvent from the organic phase and washings provided 4.7 g of a thick red oil that was discarded. The aqueous phase was then extracted with 2x200 mL CH2Cl2 which actually removed the product as the sulfate salt. This organic phase was washed with 2x100 mL 5% K2CO3 (removing the H2SO4) and with the evaporation of the solvent there was obtained 6.2 g of an oily amber residue. This was dissolved in 200 mL Et2O and saturated with anhydrous HCl gas. Fine white crystals of 2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride (DOAM) separated, were removed by filtration, Et2O-washed and air dried, and weighed 5.2 g. The mp of 136-139 °C was increased to 145-146 °C by recrystallization from CH3CN. Anal. (C16H28ClNO2) C,H,N.
DOSAGE: greater than 10 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that in no way interfered with my day's activities. I was quite gay and voluble at lunch and bubbled on into the afternoon with puns and high spirits. There may have been a little motor incoordination as noted in handwriting, and there was a strange tenseness during driving. There were no sequelae, there was no trouble sleeping, and with this potency way down from the lower homologues, I have no pressing desire to take this compound to a higher dose.
EXTENSIONS AND COMMENTARY: The actual procedure that was published for the isolation of this final amine was a different one, one that would certainly work, but which was based on the procedures tried and proven with the lower homologues. The process described above is just a bit bizarre (a sulfate salt extracting into methylene chloride) but it was the actual thing that was done. The work was started towards two additional compounds but these never got past the first "ketone and phenol" stage. p-Dimethoxybenzene was brought into reaction with n-caproic acid with polyphosphoric acid (aiming towards 2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when DOAM proved to be down in potency. And the reaction between p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ). A goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was obtained as fine yellow crystals, but this line of inquiry was also dropped.
The preparation of DOAM was, as a matter of fact, the last of the homol-ogous series of compounds actually completed, which stemmed from the original discovery of DOM. The "Ten Classic Ladies" concept was mentioned under ARIADNE, and the adding of a methyl group in the place of a hydrogen atom at the 4-position-methyl led to the synthesis of Ms. HECATE and gave rise to DOET. The whole series of methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that the potency seemed to increase initially as the chain got longer, and then it abruptly dropped off. Wouldn't it be nice, I thought, if I could interest some pharmacologist in looking at this tight set of drugs with some animal model, to see if there is some neurotransmitter activity that would show a parallel action.
I learned of a curious young researcher in Washington who had an elegant procedure for measuring serotonin agonist action using the (otherwise) discarded sheep umbilical artery strips. These become available each year at lambing time, do not cost the life of anything, and require very little compound. He assayed my compounds and, lo and behold, the serotonin activity also went through a maximum in the middle of this series. We published a short paper to this effect, which served as a excellent vehicle to get the cogent human data into the scientific literature.
I have never understood the reasons that there might be connection between the twitching of a umbilical artery in a sheep and the appearance of an insight in the mind of man. And, I have never personally met this pharmacologist. Some day, I hope to do both.
#62 DOB; 2,5-DIMETHOXY-4-BROMOAMPHETAMINE
SYNTHESIS: To a well-stirred solution of 1.95 g of the free base of 2,5-dimethoxyamphetamine (2,5-DMA) in 12 mL glacial acetic acid, there was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over the course of 5 min. The slightly exothermic reaction was allowed to stir for 3 h, and then added to about 200 mL H2O. The cloudy solution was washed with 2x100 Et2O, made basic with aqueous NaOH, and extracted with 3x100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave about 3 mL of a pale amber oil which was dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl gas. The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine hydrochloride, DOB, were removed by filtration, Et2O washed, and air dried. These weighed 1.7 g and had a mp of 195-196 °C. Recrystallization from IPA brought this up to 207-208 °C. Proton NMR spectroscopy of the hydrochloride salt in D2O gave confidence that the bromine atom had uniquely entered the 4-position, in that there were only two unsplit aromatic hydrogen atoms present, at 6.97 and at 7.20 ppm downfield from external TMS.
DOSAGE: 1.0 - 3.0 mg.
DURATION: 18 - 30 h.
QUALITATIVE COMMENTS: (with 0.4 mg) There was a distinct enhancement of visual perception, and some strengthening of colors. A clean, cold feeling of wind on the skin. I felt an enriched emotional affect, a comfortable and good feeling, and easy sleeping with colorful and important dreams.
(with 2.0 mg) There was a continuous tremor at the physical level, and an incredible Moebius strip representation of reality at the intellectual level. I was able to enter into personal problems easily, and get out again when I chose to. During the next day, there were brief lapses of attention, or little fugue states, and it was not until the following evening that I was completely myself again.
(with 2.8 mg) About three hours into this I had a severe cramp, and had a near fainting response to the pain, and yet there was no pain° I felt that I was very near a loss of consciousness, and this was most disturbing. There were flashes of depersonalization. I saw rings around the moon with prismatic colors, and there were long-lasting "after-images" following any viewings of points of light. I was still a good plus 1 at 14 hours, but did manage to sleep. It was the next day before I was again at baseline.
(with 3.0 mg) This was a complex, but a very good day. It involved making a large pot of chicken-vegetable soup, and listening to H.L., my favorite Saturday morning fundamentalist Christian radio preacher, bless Tim. The Democrats are not exactly all anti-American dupes of Moscow (or the Devil), but to H.L., they are practically, almost, next-door to it. The Rapture is supposed to happen tomorrow according to a certain book, newly published (just in time, looks like) and he is busy softening the possible disappointment of those who may find themselves unchanged Monday morning. Wunnerful. It's been one heck of a good experiment, and I can't understand why we waited nine years to try this gorgeous stuff. Without going into the cosmic and delicious details, let's just say it's a great material and a good level.
(with 0.5 mg of the RRS isomer) I am underway, and this is a smooth intoxication. I am completely functional, but still really a plus two. I would not choose to drive a car. Not very far. I felt a rather quick dropping to a plus-one at the fifth hour, but there is a residual stimulation still the following morning.
(with 1.0 mg of the RRS isomer) By the fourth hour I am absolutely a +++ and am searching the kitchen for food. But what I eat is only so-so. There is not the introspection or intensity of 2.0 milligrams of the racemate material, but this is a rewarding place nonethless. At the 18th hour, there was some fitful sleep, with bizarre dreams. The next day I was still hungry for altered spaces, and successfully challenged the residual plus one with LSD and, as is usually the case, acid cut right through the detritus and allowed a direct shot up to a +++ again.
(with 1.5 mg of the RRS isomer) This is a +++ but it is vaguely irrational. I feel a heavy body load, but then the temperature outside is over a hundred degrees and I may not be in the best of all physical environments. I would not wish any higher dosage. There were cat-naps at the twelth hour, but most symptoms were still there at the 18th hour. A good experience. It would be interesting to compare this, some day, with 3.0 milligrams of the racemate.
(with 0.5 mg of the RSS isomer) There are no effects at all.
(with 1.0 mg of the RSS isomer) There is something warm and nice at a couple of hours into this, but I am no more than threshold, and the effects are very slight. By the fifth hour there are no longer any effects.
EXTENSIONS AND COMMENTARY: The stars had clearly lined up in favor of making DOB and exploring its biological activity. This preparation had been completed in 1967 and the report of this compound and its unprecedently high potency published in 1971. And very shortly, two additional papers appeared completely independently. One described DOB made via a different route, and describing high activity in rats. The other described DOB and a couple of closely related brominated amphetamines and their action in man.
This is one of the last of the experimental compounds within the phenethylamine family on which any animal toxicity studies were performed by me prior to human studies. A mouse injected with 50 mg/Kg (ip) showed considerable twitching and was irritable. Another, at 100 mg/Kg (ip), had overt shaking at 20 minutes, which evolved into persistent hyperactivity that lasted several hours. Yet another, at 125 mg/Kg (ip), lost much of her righting reflex within 15 minutes, entered into convulsions at 50 minutes, and was dead a half hour later. A fourth mouse, at 150 mg/Kg (ip), entered into spontaneous convulsions within 10 minutes, and expired in what looked like an uncomfortable death at 22 minutes following injection. What was learned? That the LD/50 was somewhere between 100 and 125 mg/Kg for the mouse. And an effective dose in man of maybe 2 mg (for an 80 Kg man) is equivalent to 25 ug/Kg. Therefore the index of safety (the therapeutic index, the lethal dose divided by the effective dose) is well over a thousand. I feel that two mice were killed without anything of value having been received in return.
Actually, it is very likely that the damaging, if not lethal, level of DOB in man is a lot lower than this ratio would imply. There was a report of a death of a young lady following the snorting of an amount of DOB so massive, there was the actual recovery of over nine milligrams of the drug from her body tissues in the post-mortem examination. It was said that she and her companion had thought that the drug they were using was MDA and, taking a dosage appropriate for this, effectively overdosed themselves. He survived, following convulsions and an extended period (several weeks) of being in a comatose state. Tragic examples have been reported that involve arterial vascular spasm. But in most overdose cases ascribed to DOB, the identity of the drug has remained unestablished.
As with DOI, the presence of a heavy atom, the bromine atom, in DOB makes the radioactive isotope labelled material a powerful research tool. Studies with DOB labelled with either 82Br or 77Br have been used in human subjects to follow the distribution of the drug. The use of a whole body scanner permits the imaging of the intact body, with the travelings of the radioactivity easily followed from outside. A fascinating finding is that DOB goes first and foremost to the human lung where it accumulates for a couple of hours. It is only afterwards that the brain level builds up. There is a strong implication that some metabolic conversion occurs in the lung, and it is only after this that the truly active metabolite is available for central action. This is consistent with the relatively slow onset of effect, and the very long duration of action.
As with all the other psychedelics which can and have been studied as their optical isomers, it is the RRS isomer of DOB that is the more active than the racemic mixture, and the RSS is certainly much less active, but it has never been run up to fully active levels. The alpha-ethyl homologue of DOB is mentioned under ARIADNE. The positionally rearranged isomers of DOB are discussed under META-DOB.
#63 DOBU; 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE
SYNTHESIS: A well stirred suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 102 g butyryl chloride. This mixture was added in small portions, over the course of 20 min, to a well-stirred solution of 110.4 g p-dimethoxybenzene in 300 mL CH2Cl2. After an additional 1 h stirring, the mixture was poured into 1 L H2O, and the two phases separated. The aqueous phase was extracted with 2x100 mL CH2Cl2, and the organic fractions pooled. These were washed with 4x125 mL 5% NaOH which removed both unreacted butyric acid as well as a small amount of 2-hydroxy-4-methoxybutyrophenone. Removal of the CH2Cl2 under vacuum gave 156.7 g of a residue that was distilled at 170-178 °C at the water pump. The isolated 2,5-dimethoxybutyrophenone was a pale yellow oil that weighed 146 g and was about 85% pure by GC analysis. The principal impurity was unreacted dimethoxybenzene. The identical preparation with CS2 as a solvent, rather than CH2Cl2 gave a somewhat smaller yield of product.
To 150 g mossy zinc there was added a solution of 3 g mercuric chloride in 60 mL H2O, and this was swirled periodically for 2 h. The H2O was drained off, and the amalgamated zinc added to a 1 L three-neck round-bottomed flask, treated with 80 mL concentrated HCl, and heated on the steam bath. A solution of 20.8 g of 2,5-dimethoxybutyrophenone in 45 mL EtOH containing 10 mL concentrated HCl was added in increments over a 4 h period. During this period an additional 140 mL of concentrated HCl was added periodically to the ketone solution. Heating was maintained for an additional 4 h. After cooling, the aqueous filtrate was extracted with 3x100 mL CH2Cl2 and these pooled extracts washed with 2x200 mL 5% NaOH to remove a small amount of phenolic impurity. After removal of the solvent under vacuum, the residual 16.1 g of clear oil was distilled over the 100-160 °C range (largely at 141-145 °C) at the water pump to give 10 g of 2,5-dimethoxy-(n)-butylbenzene as a white oil. This was about 90% pure by GC analysis, and was used without further purification in the next step.
A mixture of 98 mL POCl3 and 108 mL N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 47.3 g of 2,5-dimethoxy-(n)-butylbenzene and the mixture heated on the steam bath for 1.5 h. This mixture was poured into 1 L H2O and stirred overnight. The H2O was drained from the extremely gooey black crystals that were formed, and extracted with 2x100 mL portions of hexane. The black residue was diluted with these extracts and, on slow evaporation there was deposited 26.4 g of oily amber crystals. Filtering these through a medium porous funnel and sucking the oily phase away from the solids yielded 14.8 g of yellow crystals that could be recrystallized from 50 mL MeOH to give, after filtration and air drying to constant weight, 6.4 g of 2,5-dimethoxy-4-(n)-butylbenzaldehyde as pale yellow crystals with a mp of 47-48 °C. The recovery of all organic soluble things from the above process gave, after removal of the extraction solvents and making boiling hexane extractions of the residues, a second crop of aldehyde of equal weight and of identical mp. An analytical sample, from hexane, had the same mp. Anal. (C13H18O3) C,H.
A solution of 13.2 g 2,5-dimethoxy-4-(n)-butylbenzaldehyde in 50 mL acetic acid was treated with 4.0 g anhydrous ammonium acetate and 10 mL nitroethane. This mixture was heated on the steam bath for 4 h, then poured into a large quantity of H2O. This was extracted with 2x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give 19 g of a deep red oil. This was dissolved in 35 mL hot MeOH and slowly cooled, depositing yellow-orange crystals. These were removed by filtration, washed with cold MeOH, and air-dried to constant weight. Thus there was obtained 11.8 g of 1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene with a mp of 54-56 °C. Recrystallization of an analytical sample from MeOH tightened the mp to 55-56 °C. Anal. (C15H21NO4) C,H,N.
To a gently refluxing suspension of 8.5 g LAH in 300 mL anhydrous Et2O under a He atmosphere, there was added 11.0 g 1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene by allowing the condensing ether to drip into a Soxhlet thimble containing the nitrostyrene, thus effectively adding a warm saturated solution of it dropwise. Refluxing was maintained overnight, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 600 mL H2O containing 55 g H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 250 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was then extracted with 3x200 mL CH2Cl2. Evaporation of the solvent produced 12 g of an amber oil that gelatinized to a waxy, amorphous mass. This was leached as thoroughly as possible with anhydrous Et2O which was clarified by filtration, then saturated with anhydrous HCl gas. After a few minutes delay, there commenced the separation of fine white crystals of 2,5-dimethoxy-4-(n)-butylamphetamine hydrochloride (DOBU). These weighed, after filtration, Et2O washing, and air drying to constant weight, 5.8 g. Recrystallization from boiling CH3CN (this is an unusually exothermic crystallization) yielded 5.4 g of a fluffy white product with mp 151-152 °C. Anal. (C15H26ClNO2) C,H,N.
DOSAGE: uncertain.
DURATION: very long.
QUALITATIVE COMMENTS: (with 2.2 mg) It was almost the fourth hour before I noticed something. Then I felt an increasing manic intoxication, winding up tighter and tighter. Sleep was impossible until some 18 hours after the start of the trial. There was some paresthesia, but no mydriasis. This might be a stimulant, but it is not a psychedelic, at least at this level. Go up slowly.
(with 2.8 mg) Nothing for over seven hours. Then there was what seemed to be an irritability and shortness of temper. Mentally I am completely clear, but no more alert than usual. There was no sleep that evening, and the next day there was a feeling of overall depression. Perhaps that was due to the lack of sleep, but there were no signs of residual sleepiness.
EXTENSIONS AND COMMENTARY: It is not possible to give a dosage range for DOBU. There is no question but that whatever is occurring is slow of onset, and very long lived. In general, the effects resemble stimulation more that anything else.
A butyl group has four carbons, and they can be interconnected in four ways (as long as you don't connect them in rings). If all four of them are in a straight chain, you have the so-called normal butyl (or n-butyl) group, and this is the exact arrangement that is found in the DOBU. The atoms can be numbered #1 through #4, going outwards from the point of attachment. The chain can, however, be only three carbons long, and the fourth or extra carbon attached on the #2 carbon atom; this is called the iso-butyl (or i-butyl) group. Or the extra left-over carbon can be attached to the #1 carbon atom; this is called the secondary butyl (or sec-butyl or s-butyl) group. Or lastly, the atoms can be all scrunched up, with the chain only two carbons long, and the other two left-over methyl carbons attached to the #1 carbon atom. This isomer is called the tertiary butyl (or tert-butyl or t-butyl) group. In animal studies, and in preliminary human studies, the activity of these compounds drops as the butyl group gets more and more scrunched.
The isomer with the iso-butyl group has been synthesized by the Friedel- Crafts reaction of isobutyryl chloride with p-dimethoxybenzene, followed by reduction of the ketone to an alcohol, dehydration to a dimethylstyrene, and final hydrogenation to a hydrocarbon. The formation of the benzaldehyde, reaction with nitroethane, and final lithium aluminum hydride reduction to 2,5-dimethoxy-4-(2-methylpropyl)-amphetamine hydrochloride (DOIB, mp 164-166 °C) were completely conventional. In drug discrimination studies in rats, DOIB was only a third as active as DOM, and in humans the activity falls in the 10 to 15 milligram area. The isomer with the sec-butyl group was made in a somewhat similar manner, from 2,5-dimeth-oxyacetophenone. The addition of ethyl magnesium bromide gave an alcohol which with dehydration yielded a pair of dimethylstyrenes isomeric to the compound mentioned above. From there an identical sequence of steps (hydrogenation, benzaldehyde synthesis, nitrostyrene, and lithium aluminum hydride reduction) produced 2,5-dimethoxy-4-(1-methylpropyl)amphetamine hydrochloride (DOSB, mp 168-170 °C.). In the rat studies it was only a twelfth the potency of DOM, and in man the active dose is in the 25 to 30 milligram area. As with the normal butyl compound, there is a strong stimulation factor, with real and long-lasting sleep disturbance.
The last of the butyl isomers, the tert-butyl compound, was made from a much more obvious starting material. This is the commercially available tert-butyl hydroquinone. It was methylated in sodium hydroxide with methyl iodide, and then carried through the above sequence (benzaldehyde. mp 124 °C from cyclohexane, nitrostyrene, yellow crystals from methanol, mp 95-96.5 °C, and lithium aluminum hydride reduction) to give 2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp 168 °C). Rats trained in a process called the Sidman Avoidance Schedule gave behavior that suggested that DOTB had no activity at all, and in human trials, doses of up to 25 milligrams were totally without effect.
An effort was made to prepare a butyl analogue containing a ring, but it was never completed. This was the cyclopropylmethyl isomer, 2,5-dimethoxy-4-cyclo-propylmethylamphetamine hydrochloride, DOCPM. Only the first step of its synthesis was complete (the reaction of cyclopropylcarboxylic acid chloride with p-dimethoxybenzene) and even it went badly. The desired ketone (2,5-dimethoxyphenyl cyclopropyl ketone) was most difficult to separate from the recovered starting ether. A promising approach would be the isolation of the phenol (2-hydroxy-5-methoxyphenyl cyclopropyl ketone) which is a beautiful yellow solid with a melting point of 99-100 °C from methanol. Anal. (C11H12O3) C,H. It then could be methylated to the wanted intermediate. It is the major product when the reaction is conducted with anhydrous aluminum chloride in methylene chloride.
The 2-carbon phenethylamine homologues of these compounds could all, in principle be easily made by using nitromethane instead of nitroethane with the intermediary benzaldehydes. But, as of the present time, none of them have been made, so their pharmacology remains completely unknown.
#64 DOC; 2,5-DIMETHOXY-4-CHLOROAMPHETAMINE
SYNTHESIS: A solution of 6.96 g 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) in 250 mL H2O was made basic with aqueous NaOH and extracted with 3x75 mL CH2Cl2. After removal of the solvent from the pooled extracts under vacuum, the residual free base was dissolved in 36 g glacial acetic acid and, with good stirring, cooled to 0 °C with an external ice bath. There was then added, with a Pasteur pipette, 3 mL of liquid chlorine. The generation of HCl was evident, and the reaction was allowed to stir for an additional 3 h. The mixture was then poured into 300 mL H2O and washed with 3x100 mL Et2O. The aqueous phase was made basic with NaOH and extracted with 3x150 mL CH2Cl2. After removal of the solvent from the pooled extracts, the residue was dissolved in Et2O and saturated with anhydrous HCl gas. There was the formation of a heavy oily precipitate. The ether supernatent was decanted, and the residue was intimately mixed with 200 mL of fresh anhydrous Et2O. Everything set up as an off-white crystalline mass weighing 2.3 g. This was dissolved in 12 mL of boiling MeOH and diluted with 230 mL boiling Et2O. The clear solution was quickly filtered to give a clear, pale amber mother liquor, which soon started depositing lustrous white crystals. After filtering, Et2O washing, and air drying to constant weight, there was obtained 1.4 g of 2,5-dimethoxy-4-chloroamphetamine hydrochloride (DOC) From the mother liquors (from the original HCl saturation) an equal amount of product could be obtained by exploiting the acetone insolubility of the hydrochloride salt of the product. The published mp of this salt, from acetone/EtOH, is 187-188 °C. A sample of this hydrochloride salt, prepared from the amino analogue via diazotization and eventual hydrolysis of an acetylated precursor, was recrystallized from EtOH/ether and had a mp of 193-194.5 °C.
DOSAGE: 1.5 - 3.0 mg.
DURATION: 12 - 24 h.
QUALITATIVE COMMENTS: (with 1.6 mg) I was hit with a slightly light head; the effects were quite real. I was disconnected, and somehow spacey, but this was a favorable spacey which was kind of fun. Somewhere at about the sixth hour I realized that I was beginning to drop off a bit, but six hours later yet, there was still a lot of memory. This is a long thing.
(with 2.4 mg) This is what I might call an archetypical psychedelic. Everything is there in spades, with few if any of the subtle graces, the Tgentle images' and Tgentle fantasies' of the 2-carbon phenethylamines. This is the works. There are visuals, and there are interpretive problems with knowing just where you really are. The place where nothing makes sense, and yet everything makes sense. I have just slept for a few hours, and now I am awake and it has been eighteen hours, and there is a lot still going on, although I have a relaxed, good feeling. Anyone who uses this had better have 24 hours at their disposal.
(with 2.4 mg) Here I am at the sixth hour, and I am still roaring along at a full plus three. I have established that this material is neither anti-erotic nor anorexic. The body is very comfortable, and so is the mind. There is an interesting aspect, perhaps peculiar only to this experiment and under these conditions. With my eyes closed the fantasy is a completely dark screen, lovely and seductive, subtle, and yet light must be deliberately brought in. This is not in any way negative for being in the dark, but is just unusual. I will have to try this in the daylight next time, to see what the eyes-closed brings to the mind-screen. At 24 hours, I have found that my sleep was not too great. My dreams were tight, and I kept defending against trouble; the nervous system was too alert. I was in a good humor, though, and I still am. This is excellent stuff, but start early in the day.
EXTENSIONS AND COMMENTARY: It is clear that the three halo-amphetamine derivatives, DOI, DOB and DOC, are all pretty much of the same potency. And all of them very long lived. The difference between the various halogen atoms was brought up under the 2C-C discussion. DOC is clearly a long-lasting, dyed-in-the-wool psychedelic.
In the making of this, by the procedures that have been followed in Canada, there are two chemical intermediates which might, some day, be looked at as potential psychedelics under their own colors. Reduction of the compound that is called DON in this Book II (2,5-dimethoxy-4-nitroamphetamine hydrochloride) with Pd/charcoal and hydrogen, gives the 4-amino derivative. This is 2,5-dimethoxy-4-aminoamphetamine dihydrochloride, DOA, which melts at 248-250 °C. And the reduction of an oxime intermediate gives rise to the acetamido analogue, 2,5-dimethoxy-4-acetamidoamphetamine hydrochloride, DOAA, with a mp of 249-250 °C. Neither compound has been tasted, but someday this omission will be corrected. DOA and DOAA have a sinister ring to them, however, and some changes of terminology might be needed. DOA, in the coroner's vocabulary, means Dead-On-Arrival. But then, AMA (the American Medical Association) just happens to also mean (in the jargon of emergency medicine) Against-Medical-Advice. Everything averages out, somehow. Remember that the amyl homolog (amyl at the 4-position) follows the 4-letter convention of all of the DOM homo-logues, and has the code name of DOAM. Thus, DOA, amino; DOAA, acetamido, and DOAM, amyl.
One must learn to keep one's sense of humor. The immortal humorist Wavy Gravy once said, "If you can't laugh at life, it just isn't funny anymore." The code name of this compound, 2,5-dimethoxy-4-chloroamphetamine is, after, all, DOC. This should certainly appeal to some physicians.
#65 DOEF; 2,5-DIMETHOXY-4-(2-FLUOROETHYL)-AMPHETAMINE
SYNTHESIS: A well-stirred solution of 0.45 g free base DOB in 2 mL CH2Cl2 was treated with 0.37 g triethylamine, cooled to 0 °C, and there was then added a solution of 0.39 g 1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene in 2 mL CH2Cl2. The reaction mixture was allowed to return to room temperature, with stirring continued for 2 h. The solvent was removed under vacuum, the residue suspended in hexane, and the insoluble by-products removed by filtration through celite. Removal of the solvent under vacuum gave 0.60 g 1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane as a gold-colored impure semi-solid mass which was used without further purification.
To a solution of 0.60 g 1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane in 10 mL anhydrous Et2O under an inert atmosphere and cooled to -78 °C there was added 1.8 mL of a 1.7 M solution of t-butyl lithium in hexane. The resulting yellow solution was stirred for 20 min, and then treated with 1.65 mL of a 1.4 M solution of ethylene oxide in Et2O, the stirring was continued for 40 min, then the reaction mixture allowed to come to room temperature over an additional 40 min. There was added 20 mL hexane, and the temperature increased to 50 °C for an additional 2 h. The reaction mixture was treated with 3 mL H2O and diluted with 60 mL Et2O. The organic phase was washed with saturated NH4Cl, dried over anhydrous MgSO4, and after filtering off the inorganic drying agent, the organic solvents were removed under vacuum. The gold-colored residual oil was dissolved in 10 mL MeOH and treated with a 10% KOH. This mixture was heated for 30 min on the steam bath, returned to room temperature, and the volatiles removed under vacuum. The residue was dissolved in 3% H2SO4, washed twice with CH2Cl2, brought to pH 12 with 25% NaOH, and extracted with 3x50 mL CH2Cl2. The pooled extracts were combined, dried with anhydrous Na2SO4, and the solvent removed under vacuum to give 0.24 g of 2,5-dimethoxy-4-(2-hydroxyethyl)amphetamine (DOEH) as a white solid with a mp of 102-104 °C.
To a suspension of 0.94 g DOEH in ice-cold anhydrous Et2O containing 1.4 g triethylamine, there was added 2.4 g trifluoroacetic anhydride dropwise over the course of 10 min. The reaction mixture was brought to reflux temperature, and held there with stirring for 1 h. After cooling, 60 mL of CH2Cl2 was added, and the organic phase washed with saturated NaHCO3. The solvent was removed under vacuum, providing a gold-colored solid as a residue. This was dissolved in 50 mL MeOH, diluted with 30 mL H2O and, following the addition of 0.76 g solid NaHCO3 the reaction mixture was stirred at room temperature for 3 h. The excess MeOH was removed under vacuum, and the remaining solids were suspended in CH2Cl2 and washed with H2O. After drying the organic phase with anhydrous Na2SO4 and removal of the solvent under vacuum, there was obtained 1.34 g 1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane as white solid with a mp of 129-131 °C. Anal. (C15H20F3NO4) C,H.
A well-stirred solution of 0.09 g 1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane in 15 mL CH2Cl2 was cooled to -78 °C and treated with 0.05 g diethylaminosulfur trifluoride (DAST) added dropwise. The pale yellow reaction solution was stirred an additional 5 min and then brought up to room temperature and stirred for 1 h. There was then added (cautiously) 3 mL H2O followed by additional CH2Cl2. The phases were separated, the organic phase washed with H2O, dried with anhydrous Na2SO4 and, after filtering off the drying agent, stripped of solvent under vacuum. There was thus obtained 0.088 g of 1-[2,5-dimethoxy-4-(2-fluoroethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane as a white solid with a mp of 102-104 °C.
A solution of 0.12 g 1-[2,5-dimethoxy-4-(2-hydroxyethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane in a mixture of 5 mL CH2Cl2 and 5 mL IPA was treated with 0.2 mL 2 N KOH, heated on the steam bath for 30 min, and then stripped of solvents under vacuum. The residue was suspended in CH2Cl2 and washed with 20% NaOH. The organic phase was dried with anhydrous Na2SO4 which was removed by filtration, and the combined filtrate and washings stripped of solvent under vacuum. The residual glass (0.08 g) was dissolved in IPA, neutralized with concentrated HCl and diluted with anhydrous Et2O to provide 2,5-dimethoxy-4-(2-fluoroethyl)amphetamine hydrochloride (DOEF) as a white crystalline solid with a mp of 205-208 °C. Anal. (C13H21ClFNO2) C,H.
DOSAGE: 2 - 3.5 mg.
DURATION: 12 - 16 h.
QUALITATIVE COMMENTS: (with 2.2 mg) Somewhere between the first and second hour, I grew into a world that was slightly unworldly. Why? That is hard to say, as there was no appreciable visual component. I just knew that the place I was in was not completely familiar, and it was not necessarily friendly. But it was fascinating, and the music around me was magical. Time was moving slowly. I had to drive across the bay at about ten hours into this, and I was comfortable. That evening I slept well, but my dreams were pointless.
(with 3.0 mg) It took almost three hours to full activity. The first signs of effects were felt within a half hour, but from then on the progress was slow and easy, without any discernible jumps. There was absolutely no body discomfort at all. Completely comfortable. There was a general humorousness about my state of mind which is always a good sign. We went to the bedroom at the two and a half hour point, and proceeded to establish that the material is far from anti-erotic. Beautiful response, without a mention of any feeling of risk at orgasm. I myself was not able to reach orgasm until about 5th to 6th hour, and then it was full and exceptionally delicious. So was the second one, a couple of hours later, if I remember correctly. All systems intact, body, mind and emotion. Gentle. Good for writing. No dark corners apparent at all. For me, not highly visual. Would take again, higher.
(with 3.0 mg) There was no body threat at any time Q very comfortable. Good eyes closed, with complex imagery to music, but not too much with eyes-open. My attention span is relatively short, and easily diverted into new directions Q all quite reminiscent of DOI both as to dosage and effect. At 13 hours, I am still too alert to sleep, but a couple of hours later, OK. In the morning there is still a trace of something going on. This was a valid +++.
EXTENSIONS AND COMMENTARY: I was asked by a student of mine a while ago, when I told him of this material, just why would anyone just happen to place a fluorine atom at the end of the 4-ethyl group of DOET? It wasn't the sort of thing that someone would just happen to do. If there were a rationale, then that's fine. But by capricious impulse, no. But there is a rationale of sorts, which I just hinted at in the discussion under 2C-T-21.
This argument of reason goes as follows. Assume that I would like to put a fluorine atom into a drug that does not normally have one. Why would I want to? Because I want to have the molecule carry a radioactive fluorine atom into some inner recess of the brain. Why? Because by using a positron-emitting fluorine I could possibly visualize the area of the brain that the drug went to. And if it went there in some abnormal way, the exact measure of that abnormality might give some clue as to potential brain misfunctioning.
But, if you put a fluorine atom on a drug, it becomes a totally new drug and, quite reasonably, a pharmacologically different drug. However, a body of evidence is being accumulated that if a halogen, such as a bromine or an iodine atom, is replaced by a beta-fluoroethyl group, the electronic and polar properties of the drug can be pretty much the same. So, what psychedelics have a bromo or an iodo group? Obviously, DOB and DOI. Thus, DOEF is a natural candidate for fluorine-18 positron emission tomography, and also a natural candidate for clinical trials. And, voila, it is an active material.
And I'll bet you dollars to doughnuts, that if one were to make the two-carbon analog 2,5-dimethoxy-4-(2-fluoroethyl)-phenethylamine, it would be every bit as much a treasure and ally as is 2C-B or 2C-I. In fact, I am sure enough about this prediction that I am willing to name the stuff 2C-EF. It will be easily made from 2C-B by the same reaction scheme that was used above for DOEF. And I will even guess that its activity level will be in the 20-30 milligram area.
#66 DOET; HECATE; 2,5-DIMETHOXY-4-ETHYLAMPHETAMINE
SYNTHESIS: To a solution of 19.7 g 2,5-dimethoxy-4-ethylbenzaldehyde (see the recipe for 2C-E for its preparation) in 72 g glacial acetic acid there was added 6.5 g anhydrous ammonium acetate and 10.2 g nitroethane. After heating for 1.75 h on the steam bath, the reaction mixture was cooled in a wet ice bath, diluted with 10 mL H2O, and seeded with a small crystal of product. The yellow crystals were removed by filtration (7.6 g wet with acetic acid) and another 2.25 g was obtained from the mother liquors with additional H2O. The combined fractions were recrystallized from 25 mL boiling MeOH, to give 6.5 g fine yellow crystals of 1-(2,5-dimethoxy-4-ethyl)-2-nitropropene, with a mp of 67.5-68.5 °C. Anal. (C13H17NO4) C,H,N.
A suspension of 6.5 g LAH in 500 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 6.5 g 1-(2,5-dimethoxy-4-ethylphenyl)-2-nitropropene. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 18 h, then cooled to room temperature. The excess hydride was destroyed with 500 mL 8% H2SO4, added cautiously until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 150 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue, 7.9 g of a clear oil, was dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-ethylamphetamine hydrochloride (DOET) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 5.9 g of lustrous white crystal with a mp of 190-191 °C. Recrystallization from CH3CN or EtOAc increased the mp to 194-195 °C. Anal. (C13H22ClNO2) C,H,N.
DOSAGE: 2 - 6 mg.
DURATION: 14 - 20 h.
QUALITATIVE COMMENTS: (with 1.0 mg) This was a very gentle, relaxing level, but there were no psychedelic effects that were apparent. Easy, and relaxed, and I am in no way intoxicated or turned on. But I was in the throes of my menstrual period, and the cramps (and the accompanying irritability) were completely knocked out. Perhaps this is why I felt so relaxed and at peace.
(with 2.5 mg) There is much, too much, movement with my eyes closed. And an awful lot there with my eyes open. The movement on the concrete floor in the basement when I went downstairs for wood for the fireplace, was too much. I felt almost sea-sick. And I am having reality problems Q I cannot seem to find my centering point of reference. There has to be a place to pin myself down to, and it is not findable anywhere I look. And my legs are twitching, and feeling as if they are falling asleep, and I had a crawling sensation on my body, so the body is not at peace either. In the morning I was still ++, but there is a clear indication that I am repairing. Anyway, I survived the experience. This is definitely not my thing.
(with 4 mg) Just after an hour into the experiment, I was surprised by the awareness of some effects Q I had forgotten that I had taken something. At the second hour, it was real, but subtle. As a psychotomimetic or STP-like thing, there is very little there. But as a mood energizer, it is really a ++ or more. The clinical literature is right Q none of the hallucinogenic effects, but one brings into play whatever one wants to. Worked at cleaning up the office until 11 PM. I slept well. This has none of the LSD or STP seriousness.
(with 6 mg) The onset was slow, and subtle. But the effects are fully there in about three or so hours. Everything I smelled was vivid, as are all the colors and shapes; they are clean, beautiful, serenely self-contained. No visual movement. The eyes-closed fantasy images tend to take off on their own, however, and they are extremely rich. I don't see any dark corners. I believe it might well be possible to be creative with this, and there is no suggestion of body depletion, of body load.
(with 7 mg) A hot day. 'nbelievably lovely erotic-to-divine, deep loving, open, not much visual, eyes-closed form-image-symbol. Sleep attempts very shallow, slight Tthinness', with an anticipation of darts. Intellect and feeling-emotion area intact and functioning at all times. Next morning still at a plus one. Incredible material. Perhaps best at 6 to 7 milligrams, no higher due to body load.
EXTENSIONS AND COMMENTARY: The original code for this compound was DOE, which was completely logical based on DOM being the methyl member of this series (DO for the removal of the oxygen, desoxy, and M for putting a methyl in its place). And the putting of the ethyl thence should be DOE. This was fine until it was pointed out to me by a close colleague that DOE was a classic abbreviation for desoxyephedrine, a synonym for methamphetamine. The pressure to add the RTS of the RETS of the ethyl was heightened by looking ahead to other members of the series. DOA became DOAM, DOE became DOET, but DOM was already too firmly set in popular usage. And, anyway, DOME really looked strange.
The original publications of the action of DOM clearly documented the compound as being a psychedelic and one with a sizeable measure of potential abuse. And, it is not a surprise that it was quickly shuffled into a legal classification that effectively precluded any further study of it. So, when this immediate homologue of DOM was studied and discussed in the literature, all reported dosages were those that were at the lowest levels, and no disturbing hints of abusability were mentioned. And this particular homologue has so far escaped the attention and restrictive action of the drug enforcement agencies, although the specific wording of the Controlled Substance Analogue Enforcement Act of 1986 might make this point moot, at least as far as human trials are concerned. At modest levels, DOET has the reputation of being a cognitive enhancer and is largely free of those sensory distortions that would catch the attention of the authorities who cannot tolerate drugs that distort the senses. The higher levels mentioned here have never been put into the published literature. It must be noted that there is a considerable variation of individual responses to this material. The effective dose range stated is quite broad. Some people are quite sensitive. This is, after all, one of the Classic Ladies, namely HECATE.
The young experimental subject who had the dramatic relief from menstrual cramps at the one milligram dose tried the compound again the following month, and again had complete relief. But another volunteer, also plagued with severe cramping at that particular time of month, found no relief at all. A 50% success rate. No one else has, to my knowledge, explored this particular property.
#67 DOI; 2,5-DIMETHOXY-4-IODOAMPHETAMINE
SYNTHESIS: A mixture of 14.8 g phthalic anhydride and 19.5 g of 2,5-dimethoxyamphetamine (2,5-DMA) as the free base was heated gradually to about 150 °C 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 allowed to cool to about 50 °C and then diluted with 100 mL of hot MeOH. The solution was stirred until homogenous, seeded with product, and then cooled in an ice bath to complete the crystallization. After removal of the product by filtration, washing sparingly with MeOH, and air drying, there was obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide as off-white crystals, with a mp of 105-106 °C. Anal. (C19H19NO4) C,H,N.
To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide in 15 mL warm acetic acid which was being vigorously stirred, there was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid. This was stirred for 2 h at about 40 °C during which time there was a definite lightening of color, but no solids formed. The reaction mixture was poured into 600 mL H2O which produced a reddish glob floating in a yellow-orange opaque aqueous phase. The glob was physically removed, dissolved in 30 mL boiling MeOH which, on cooling in an ice bath, deposited off-white crystals. These were removed by filtration, washed with MeOH, and air dried to give 1.5 g of N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide as fine white crystals with a slight purple cast. The mp was 103-105.5 °C and the mixed mp with the starting non-iodinated phthalimide (mp 105-106 °C) was depressed (85-98 °C). Extraction of the aqueous phase, after alkalinification, provided an additional 0.15 g product. Anal. (C19H18NO4) C,H,N.
A solution of 0.75 g N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide in 10 mL EtOH was treated with 0.3 mL of hydrazine hydrate, and the clear solution was held at reflux on the steam bath overnight. After cooling, there was a crystallization of 1,4-dihydroxyphthalizine that started as small beads but finally became extensive and quite curdy. These solids were removed by filtration and had a mp of about 340 °C (reference samples melted over a five to ten degree range in the area of 335-350 °C). The filtrate was dissolved in 100 mL CH2Cl2 and extracted with 2x150 mL 0.1 N HCl. The aqueous extracts were washed once with CH2Cl2, made basic with 5% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent under vacuum gave 0.5 g of a colorless oil which was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was obtained, after filtration, and air drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) as white crystals that melted at 200.5-201.5 °C. This value did not improved with recrystallization. Anal. (C11H17ClINO2) C,H,N.
DOSAGE: 1.5 - 3.0 mg.
DURATION: 16 - 30 h.
QUALITATIVE COMMENTS: (with 0.6 mg) There was a nice spacey light-headedness for a few hours, and time seemed to move quite slowly. Then a generic sadness came over me, as I reminisced about earlier days (recalling pleasures now gone) and wondered if I would be allowed to be here on the Farm when I am old and not important. There is so much to be done, and I cannot do it all, and no one else cares. My mood became present-day and healthy by about the seventh hour.
(with 1.6 mg) The general nature of the experience was depressing, with a sad view of life. There was no way I could connect with my emotions. Even my sadness was vague. At about the ninth hour I decided that enough was enough, and this strangely disappointing about-plus-two was aborted with 125 micrograms of LSD. The emotions became present and living within a half hour. I was greatly relieved. The erotic was not a mechanical attempt but a deeply involved feeling with an archetype of orgasm easily available. It was shaped like a flower, richly colored, with an unusual RSS shape to it. This was a lovely end to a difficult day.
(with 3.0 mg) This is a clear, clean psychedelic. The eyes-closed imagery is excellent, with clearly delineated patterns, pictures, and colors. Perfect for an artist, and next time I'll devote some time to painting. Total ease for the body, but no help for my smoking problem. I still want to smoke. And at sixteen hours into this I am still at 1.5+ but I'll try to go to bed anyway, and sleep.
(with 3.5 mg) I was at a full crashing +++ for about three or four hours. There was none of the LSD sparkle, but there were moments of Tlight-headedness' where one could move sideways with reality. I could leave where I was right over there, and come over here and get a strange but authentic view of where the Tthere' was that I had left. It would be out-of-body, except that the body came over here with me rather than staying there. This doesn't make sense now, but it sure did then. There was no trace of body impact, and I slept late that evening, but with some guardedness due to the intense imagery. This was no more intense than with 3.0 milligrams, but it was a little bit more to the unreal side.
(with 1.0 mg of the RRS isomer) There was a clear ++ from the second to the eighth hour, but somehow there was not quite the elegance or the push of the racemate. I was sensible, and managed to do several technical chores in a reasonable way. Easy sleep at 15 hours into it.
(with 2.3 mg of the RRS isomer) The water solution of the hydrochloride salt has a slightly sweetish taste° I was at a +++ without question, but there was a slight down mood towards the end. And it lasted a really long time; I was distinctly aware of residual stuff going on, well into the next day.
(with 6.3 mg of the RSS isomer) I was at a benign one-and-a-half plus at about two hours, and finally flattened out at a ++. Would I double this dose? Probably not, but half again (to 9 or 10 milligrams) would feel safe for a plus 3. By evening I was near enough baseline to drive into town for a social obligation, but even when trying to sleep later that night there was some residue of imagery; remarkably, it was all in slow motion. The fantasies were slow-paced and sluggish. It would have been interesting to have explored eyes-closed during the day.
EXTENSIONS AND COMMENTARY: Again, as with every other psychedelic amphetamine analogue which has a chiral center and has been explored as the individual optical isomers, it is the RRS isomer that is the more potent. And again, the other isomer, the RSS isomer, still shows some activity. The same was true with DOB, and DOM, and MDA. The only exception was MDMA, but then that is more of a stimulant, and there is virtually no psychedelic component to its action. Rat studies, where there is a measure of the discrimination of a test compound from saline, have shown the RRS isomer to have about twice the potency of the RSS isomer. That the RRS is more potent is certain, but the above reports would suggest that the factor would be closer to times-four rather than times-two.
A number of studies with DOI in animal models have shown it to have an extremely high binding capacity to what are called the 5-HT2 receptors. Serotonin is a vital neurotransmitter in the brain, and is strongly implicated in the action of all of the phenethylamine psychedelics. The place where it acts, at the molecular level, is called its receptor site. As an outgrowth of the cooperative studies of the medicinal chemists working closely with the neuropharmacologists, a number of compounds have emerged that interact with these sites. But this one interacts with these sites and not those, and that one interacts with those sites and not these. So, there has developed a collection of sub-divisions and sub-subdivisions of receptor sites, all related to serotonin, but each defined by the particular compound that interacts most tightly with it.
Thus, there were serotonin R1S receptors, and then there were R1S and R2S receptors, and then R1a and R1bS and R2aS and R2bS receptors, and on and on. These are called 5-HT receptors, since the chemical name for serotonin is 5-hydroxytryptamine, and the scientist would never want to let the layman know just what he is talking about. DOI has been synthesized with a variety of radioactive iodine isotopes in it, and these tools have been of considerable value in mapping out its brain distribution. And by extrapolation, the possible localization of other psychedelic compounds that cannot be so easily labelled. A small neurochemical research company on the East Coast picked up on these properties of DOI, and offered it as a commercial item for research experiments. But I doubt that they are completely innocent of the fact that DOI is an extremely potent psychedelic and that it is still unrecognized by the Federal drug laws since, in their most recent catalog, the price had almost doubled and a note had been added to the effect that telephone orders cannot be accepted for this compound.
The four-carbon butylamine homologue (the ARIADNE analogue) of DOI has been synthesized. A mixture of the free base of 1-(2,5-dimethoxyphenyl)-2-aminobutane (see preparation under DOB) and phthalic anhydride was fused, cooled, and recrystallized from either methanol or cyclohexane to give crystals of N-[1-(2,5-dimethoxyphenyl)-2-butyl]phthalimide with a melting point of 76-77 °C and an analysis (C20H21NO4) C,H,N. This was iodinated with iodine monochloride in acetic acid to give N-[1-(2,5-dimethoxy-4-iodophenyl)-2-butyl]phthalimide which was chromatographically distinct from the uniodinated starting material (silica gel, CH2Cl2 ), but which did not crystallize. This was treated with hydrazine hydrate in ethanol to provide 1-(2,5-dimethoxy-4-iodophenyl)-2-aminobutane hydrochloride which was crystallized from CH3CN/EtOH to give white crystals with a mp of 217-218.5 °C and an analysis (C12H19CINO2) C,H,N. This butyl homolog of DOI has been assayed at up to four milligrams, and is without any central effects whatsoever. An experiment with 12.4 microcuries of 131I labelled material with the whole body scanner showed most of it accumulating in the gut and liver, with almost none to the brain.
For those who find such statistics interesting, the parent compound DOI vies with DOB as probably the most potent of the phenethylamine psychedelics as of the moment, and certainly one of the most long lived.
A very important, centrally pivotal, and completely paradoxical compound in this area, is the N,N-dimethyl homologue of DOI, or 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA). This compound was the starting point of the study of a large number of homologues and it deserves, and has received, a separate recipe.
#68 DOM; STP; 2,5-DIMETHOXY-4-METHYLAMPHETAMINE
SYNTHESIS: To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for its preparation) in 215 g glacial acetic acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g nitroethane. This mixture was heated for 3 h on the steam bath, the reaction mixture was cooled in a wet ice bath, allowing the spontaneous formation of yellow crystals. As much H2O as possible was added (just short of a persistant cloudy oily character) and after a few additional h standing, the crystalline 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene was removed by filtration and recrystallized from boiling acetic acid. The yield, after drying to constant weight, was 28.3 g and the mp was 87-88 °C. Anal. (C12H15NO4) C,H,N.
A suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 9.5 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 4 h, then cooled to room temperature and allowed to continue stirring overnight. The excess hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously, until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 225 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x150 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 9.6 g of a clear oil which spontaneously formed crystals with a mp of 60.5-61 °C from hexane. These solids were dissolved in 150 mL anhydrous Et2O, and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 8.25 g of glistening white crystals that had a mp of 190.5-191.5 °C. The sulfate had a mp of 131 °C. Anal. (C12H20ClNO2) C,H,N.
The above nitrostyrene may also be converted to the final amine product through the intermediary of the corresponding phenylacetone. To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial acetic acid held at reflux temperature, there was added 4.9 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene as a solid. Refluxing was continued for 2 h and then all was filtered through wet Celite. After washing with 300 mL H2O followed by 300 mL Et2O, the combined filtrate and washes were separated, and the aqueous phase extracted with 2x100 mL Et2O. The organic phase and extracts were combined and washed with 2x100 mL saturated K2CO3 and the solvent was removed under vacuum yielding a reddish oil weighing 3.3 g. This was distilled at 111-115 °C at 0.5 mm/Hg to give a pale green solid. After recrystallization from benzene, there was obtained 2.8 g 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white crystals with a mp of 57-59 °C. This ketone has also been described as a pale-yellow oil with a bp of 115-118 °C at 0.4 mm/Hg. A solution of 0.7 g 1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated with 6.0 g ammonium acetate, 0.3 g sodium cyanoborohydride, and 3 g Linde 3 A molecular sieves. The mixture was stirred overnight, the solids removed by filtration, and the filtrate dissolved in 100 mL H2O. The solution was acidified with dilute H2SO4, and washed with 2x25 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 2x25 mL CH2Cl2. The solvent was removed under vacuum, and the residue distilled (at 160 °C at 0.2 mm/Hg) to give colorless product which was dissolved in 3 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O. There was obtained 0.18 g of 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) as a white solid with a mp of 187-188 °C.
The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or RSS isomer of DOM preferentially. Also, the above-mentioned 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alpha-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The mp of either of the optical isomers, as the hydrochloride salts, was 204-205 °C.
DOSAGE: 3 - 10 mg.
DURATION: 14 - 20 h.
QUALITATIVE COMMENTS: (with 1.0 mg) There is almost certainly an effect. Physically there is a slight dryness in the mouth, and my eyes are noticeably dilated. There is an eerie feeling overall.
(with 2.3 mg) Mood elevation at 2-3 hrs. After 3 hours, emotional effects become more pronounced, enhancement of color also. Very little distortion of perception, no disorientation, no creeping or flowing, but color enhancement considerable. The emotional content and empathy for others was closer to mescaline than to amphetamine, a welcome change. No suggestion of nausea at any time. Unable to sleep at ten hours, so I took 3/4 grain Seconal. Headache and listlessness next morning, probably due to the Seconal.
(with 3 mg) In the middle of the experience I found that I was able to separate components of complex things so as to evaluate them separately. There is no need to respect their normal purpose. The sharpness of observation is enhanced, but one can focus at every different depth of a thing or a concept. Colors are not just brighter; there are more of them. There is a profoundness of meaning inherent in anything that moves. A line of thought or a bit of personal history ties the thinker to the objects that had been thought of, or once experienced. It is this relationship that will prove productive. Not like in a movie which is circular in its totalness, but as in true life where the future is the result of your own involvement with everything about you.
(with 4 mg) The first four hours were largely directed to the body. There was a shuddering, and a tight jaw, and I am not particularly motivated to talk to anyone. It is more arousing (like amphetamine) than depressing (like phenobarb). I am feeling just a little sick at the three hour point, but a bit of regurgitation clears this up. Then at the fourth hour, it went totally outside of me. I saw the clouds towards the west. THE CLOUDS°°° No visual experience has ever been like this. The meaning of color has just changed completely, there are pulsations, and pastels are extremely pastel. And now the oranges are coming into play. It is a beautiful experience. Of all past joys, LSD, mescaline, cannabis, peyote, this ranks number one. Normally I have no color effects with mescaline. A dynamic experience. Feels good, too.
(with 5 mg) There was the magnification of light, color and odors. It was all very pleasant and beautiful, except that I had an overwhelmingly negative feeling. This at times grew to considerable intensity, and I feel it was clearly due to anger. At times the negativity disappeared completely, and I broke into the most enjoyable, even hilarious experiences. I alternated about 50-50 between joy and discomfort. As the evening drew on, I became withdrawn and pensive. It seemed clear that I had made all the wrong decisions Q choice of partner, place to live, isolation, no meaningful activity. The greatest shocker was that my practice of meditation, which is one of my central focuses, and which I thought had brought me much peace and understanding, seemed to be a delusional solution to my unhappiness and isolation. The experience continued unabated throughout the night with much tension and discomfort. I was unable to get any sleep. I hallucinated quite freely during the night, but could stop them at will. While I never felt threatened, I felt I knew what it was like to look across the brink to insanity.
(with 8 mg) The very quiet development picks up speed betweeen the first and second hour. There is a rich curly-imaged eyes-closed show that interlocks closely with music. It is occasionally an off-beat fantasy and not directly knit together, and even occasionally unenjoyable. But always intense and completely appropriate to the music. There is a continuous thirst, and little urine. Napping seems OK at 16 hours, but real sleep must wait until the 20 hour point. Overall a rolling +++, and I am looking forward to a repeat some day.
(with 10 mg) If on this page I shall have expressed it to you then it is true that DOM has the glory and the doom sealed up in it. All that's needed to unseal it is to surround it with a warm living human for a few hours. For that human for those hours all the dark things are made clear.
(with 12 mg) The first awareness was at 30 minutes and it was in the tummy. The development was extremely rapid, something more like LSD than previously remembered. The body tremor feels like poisoning, there is no escaping the feeling of being disabilitated, but at least there is no nausea. This transition ended and the trauma cleared completely at about the second hour. The music was exceptional, the erotic was exceptional, the fantasy was exceptional. Listz's RA Christmas Cantata #1,S part 1, with eyes closed was an experience without precedent. There were some residual effects still noted the next day. This may be a bit much for me.
(with 0.3 mg of the RRS isomer) Maybe slightly wiry? No effects.
(with 0.5 mg of the RRS isomer) There is a real effect, and it is significant that the first effects of the racemate were noted at 1.0 milligram. There is a trace of time slowing and in general a pretty full manic state. There is some mydriasis. Everything had pretty much cleared up by evening.
(with 2.0 mg of theSSS isomer) No effects. There was an unexpected slight tachycardia at the two hour point, but nothing suggesting psychotropic action.
(with 2.6 mg of the RSS isomer) There are signs of both pulse increase and blood pressure increase. There is some teeth-rubbiness, but still no psychological turn on at all.
EXTENSIONS AND COMMENTARY: The rationale for the design and making of DOM has already been discussed. One could predict that it could have been, theoretically, a totally inactive compound and maybe an effective blocker for whatever receptor sites are being occupied by other psychoactive drugs and even for strange things that some unbalanced people might actually make within their bodies, using their own personal chemistry. On the other hand, it could have been a potent psychedelic in its own rights, and if so, probably long lived. The latter Rcould have beenS proved to be so.
The very modest amount of study of the individual optical isomers clearly indicates that the RRS isomer is the more active. The sparse comments suggest that some of the heavier physical aspects of the racemate might be due to contributions from the RinactiveS RSS isomer. It is, after all, the RSS isomer of amphetamine that carries the major punch of that stimulant. Maybe if that isomer were removed, and one were to explore the pure RRS isomer of DOM, the dramatic visual aspects of the larger dosages might not be complicated with a troublesome physical component.
This compound, unbeknownst to me, was scattered widely and plentifully in the heyday of the Haight-Ashbury in San Francisco, in mid-1967. It was distributed under the name STP, which was said to stand for Serenity, Tranquility, and Peace. It was also claimed to represent Super Terrific Psychedelic, or Stop The Police. The police called it: Too Stupid to Puke. Actually, the name was taken from the initials of a motor additive which was completely unrelated chemically. Incredibly, and sadly, one of the avowed experts in the area of the "sensuous drugs" actually stated that STP, the motor oil additive, was really one and the same as STP, the highly dangerous psychedelic. The motor oil additive, he wrote in a book of his, had properties somewhat related to those of LSD, mescaline, and the amphetamines. How fortunate that the love children of the time didn't do much reading, for they might have gotten into yet deeper pharmacological troubles with drug raids on the local gasoline stations.
Two complications became apparent during this first appearance and they led to serious difficulties. One, there was no equation made between STP and DOM. No one knew what this drug was which had been distributed in a cavalier way throughout the city. There could be no educated guess as to the best treatment of overdose emergencies. And secondly, the initial tablets that had been distributed apparently contained 20 milligrams of DOM per tablet; later, it was dropped to 10 milligrams. Either of these, in retrospect, is now known to be a thoroughly whopping dose. The overdose situation was aggravated by the slow onset of DOM. The user may be aware of some initial effects at the half-hour point, there will be what might be called a + or ++ at the end of the first hour, and the full impact of the drug is not appreciated until some two hours have elapsed. But many of the recipients of the free handouts of DOM were familiar with LSD which can show its alert in 15 to 20 minutes, or even sooner with a large dose, and there is already a deep and compelling intoxication felt at the half-hour point. They, quite reasonably, expected this familiar activity pattern with STP and assumed, when there was little if any activity noted at the half-hour point, that the potency was less than expected. They took one or even two additional dosage units. Thus, some of the overdose victims of that period may well have taken as much as 30 mg of DOM. The slow onset of action, coupled with the remarkably long duration, caught many innocent users unprepared.
Clinical studies have documented the rapid tolerance development from repeated exposures to DOM. Five volunteers were given 6 milligrams daily for three days. Objectively, psychological tests showed a decrease in responses. Subjectively, all found extremely intense effects on the first day, and all but one found it unpleasant. By the third exposure on the third day, all had diminished responses, ranging from only Rmoderately strongS to Rfelt absolutely nothing.S One actually slept during the experience on the third day.
The hexadeutero-analogue (deuterium atoms on the two methoxyl groups) has been prepared as an internal standard for analytical work, but there are no reports of its human pharmacology. A study with this sort of derivative would be a fine companion to the studies already underway with the mescaline analogues that are similarly substituted. A difference exists, however. With mescaline, it is believed that the loss of a methoxyl group is a step towards the inactivation of the compound, whereas with DOM this loss may be associated with the formation of an active metabolite. The several fascinating questions raised by possible differences in both the rates and the degree of demethylation of these two compounds are well worth trying to answer.
A number of compounds related to DOM had been synthesized and studied at the University of California at San Francisco, at about this time. Two of these were simply the juggling of the two methoxyl groups and the methyl group on the ring, still maintaining the 2,4,5-ness relative to the amphetamine chain. These are 2,4-dimethoxy-5-methylamphetamine and 4,5-dimethoxy-2-methylamphetamine. Since the slang name for DOM in and about the medical center was STP, and since STP was the name of a motor oil additive, it is not unreasonable that the first of these to be synthesized, the 2,4-dimethoxy-5-methyl isomer, was referred to by the name of another motor oil additive popular at that time, F-310. The Vilsmeier reaction between 2,4-dimethoxytoluene and the Vilsmeier complex of POCl3 and N-methylformanilide gave the benzaldehyde (mp 117-118 °C) with a yellow malononitrile derivative from EtOH with a mp of 193-194 °C. The nitrostyrene from this and nitroethane formed yellow crystals from CH3CN, with a mp 138-139 °C. The amine formed easily with LAH in ether, and the product F-310 (or 5-DOM) gave white crystals from CH3CN with a mp of 182-183 °C.
And the other isomer, the 4,5-dimethoxy-2-methyl counterpart, became known familiarly as F-320, or sometimes simply 2-DOM. Its preparation followed an identical procedure, starting from 3,4-dimethoxytoluene. I have been told that F-310 is not active even at 20 milligrams in man, which would make it several times less potent than DOM (STP). I know of no trials with F-320. The use of the letter RFS does not imply any relationship between these two compounds and the series described elsewhere with the RFS code followed by other numbers, such as F-2 and F-22. These latter are F's because they are furans, not motor oil additives. And yet another oil additive, well known at the time as Z-7, became associated with the synthesis of the DOM (STP) isomer with its groups in the 2,4,6-positions. This is entered separately under y-DOM.
#69 Y-DOM; Z-7; 2,6-DIMETHOXY-4-METHYLAMPHETAMINE
SYNTHESIS: To a solution of 2,6-dimethoxy-4-methylbenzaldehyde (mp 92-93 °C from the lithiation of 3,5-dimethoxytoluene followed by reaction with N-methylformanilide) in 10 mL nitroethane, there was added 0.1 g anhydrous am-monium acetate and the mixture was heated on the steam bath for 16 h. Removal of the solvent under vacuum gave a slightly oily red-orange crystalline mass which was finely ground under 1 mL of MeOH. Filtration and a sparing wash with MeOH gave, after air drying, 0.8 g of a light yellow crystalline solid with a mp of 121-122.5 °C. Recrystallization from 4 mL boiling absolute EtOH gave 0.6 g of 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very light yellow platelets, which melted at 123-124 °C.
To a solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and under He, there was added a solution of 0.3 g 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF. Upon the completion of the addition, the reaction mixture was held at reflux for 48 h. After cooling with an external ice bath there was added, in sequence, 0.5 mL H2O, 0.5 mL 15% NaOH, and finally 1.5 mL H2O. The inorganic solids were removed by filtration, and the filter cake washed with THF. The solvent from the combined filtrate and washings was removed under vacuum, and the residue (0.3 g) was a crystal clear colorless oil with a high refractive index. This was dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted with 35 mL of anhydrous Et2O. After a minute's standing, the solution became turbid, followed by the slow deposition of very fine white crystals. After standing 1 h at room temperature, these were removed by filtration, Et2O washed, and air dried to constant weight. There was thus obtained 0.3 g 2,6-dimethoxy-4-methylamphetamine hydrochloride (y-DOM) with a mp of 203 °C. sharp.
DOSAGE: 15 - 25 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 14 mg) I am really quite spacey. I can go from a train of thought straight up into thin air. Then, to get to another one there must be a careful choice of words. Logic has nothing to do with any of it. There is no trace of the MDMA-like magic. This is an interpretive drug, not simply an ASC [altered state of consciousness] opening.
(with 18 mg) There is a light-headedness, and a somewhat starry-eyed stoned state. Nothing visual, and no body concern except for what seems to be a very fine inner tremor. I think that with a little more, things might very well begin to move in the visual field. But I have no feeling of great concern about taking a somewhat higher dosage.
(with 25 mg) I was at a +++ for about three hours, and it was a very weird place. There were some visuals, but they were not at all commensurate with the degree to which I was simply stoned. The erotic does not knit, and it's hard to get involved with music. It is as if you were going down some totally unknown street in a completely familiar city. You know the territory, but yet it is strangely all new. Eyes closed fantasy and shaped imagery was quite remarkable. But some heart arrhythmias and a pretty constant diarrhea made the experience less than totally ideal. My sleep was good and with good dreams.
EXTENSIONS AND COMMENTARY: I can't remember the exact names of the companies that went with the oil additives. STP was, I believe, it's own thing, and originally stood for Scientifically Treated Petroleum. And F-310 was, I believe, a Chevron Oil product. F-320 was, of course, the product of the wild and happy chemists at the Pharmaceutical Chemistry Department at the University of California in San Francisco, playing with what they fondly called Rfunny drugs.S And when the 2,4,6-orientation became an obvious positional isomer, the Pennzoil Oil Company's additive, Z-7, was a natural to have its name volunteered to the cause. There was one additional isomer possible, with the methyl in the 2-position and the methoxyl groups at the 4- and 6-positions. This followed the more conventional aldehyde made from 3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and N-methylformanilide. This material (2,4-dimethoxy-6-methylbenzaldehyde with mp 64-65 °C from cyclohexane or from MeOH) is completely distinct from the isomer used above (2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92-93 °C from MeOH). The amphetamine from this isomer is 2,4-dimethoxy-6-methylamphetamine, and had been christened by the chemistry crowd as Z-7.1.
Much effort had been put forth in research by this medical school group of graduate students and graduate advisors, to try to explain the biological activity of the 2,4,5-things such as TMA-2 and DOM (STP). And a considerable investment had been made in the attempt to tie together the amphetamine world of psychedelics with the indole world of psychedelics. The convenience of having two methoxy groups para to one another was a clear invitation to speculate upon the formation of a benzoquinone intermediate of some kind, and this would require the loss of the methyl groups which were already known to be metabolically labile. This "quinone-like" intermediate was the cornerstone of a "hydroquinone hypothesis," as it allowed further condensation within the molecule itself involving the primary amine group, to form something called an indolene which, with some arcane electron pushing and removal, could eventually become an indole. There. We now have a tie-in to the tryptamine world, and to serotonin, and that entire neurotransmitter magic.
There was only one small fly in the ointment. No matter how the 2,4,5-things were explained, none of the proposed mechanisms could allow for the 2,4,6-things to also be active.
How can one accommodate such blasphemy? The first and obvious approach was the simplest. Denial. The 2,4,6-things aren't really active at all. Placebo stuff. There is a commonly used phrase, "bad science" which is an in-famous term used to belittle findings that do not fit with one's theories or purposes. But that simply didn't wash, because I knew, as did a few others who chose not to identify themselves too publicly, that TMA-2 and TMA-6 were both fully active in the 40 to 50 milligram area. And although not as potent as DOM, the compound of this recipe, y-DOM or Z-7, was certainly an active one. So, since approach number one didn't work, try approach number two. Make the shoe fit the wearer, without respect to the size of his foot. One single size shoe fits all. One single mechanistic hypothesis explains all. It was obvious that for the "hydroquinone" hypothesis to survive, Z-7 would have to undergo some metabolic oxidation Q phenol formation Q in the 3-position.
And guess who was actually euchred into embarking onto the synthesis of this hypothetical metabolic Lucy [that's the anthropological-type, not the LSD-type Lucy]? Moi° On to a new methoxylated amphetamine which would be called Z-7.2. Oxidation of the above 2,4-dimethoxy-6-methylbenzaldehyde with metachloroperoxybenzoic acid gave 2,4-dimethoxy-6-methylphenol which smoothly methylated (KOH, CH3I) to give 2,3,5-trimethoxytoluene as a white oil, bp 59-62 °C at 0.1 mm/Hg. This formed the anion between the meta-methoxy groups with butyllithium, and N-methylformanilide gave the new compound 2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130-140 °C at 0.7 mm/Hg) with an excellent NMR spectrum. This formed the 3-carbon nitrostyrene with nitroethane, as bright yellow crystals from methanol with a mp 67-68.5 °C (and excellent NMR and microanalysis, C,H,N). Lithium aluminum hydride reduction gave rise to what I was assuming would be the target amphetamine, 4-methyl-2,3,6-trimethoxyamphetamine or Z-7.2. This formed a hydrochloride salt which, although analytically excellent, insisted in remaining as an ether and chloroform-soluble oil which had an excellent NMR spectrum. This was certainly MY target compound, but it was not THEIR target compound. The upper echelons who were running the show were serious about this hydroquinone thing. Therefore, this product Z-7.2, that should have been entered into human evaluation, was instead processed further by the substitution of a t-BOC on the amine group, oxidation to the quinone with ceric ammonium nitrate, reduction to the hydroquinone with dithionite, and finally deprotection of the blocking t-BOC group by hydrochloric acid. The final product, 2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an extremely light-sensitive solid which was looked at by NMR (excellent spectrum in D2O) and by cyclic voltimetry (destructive and uninformative) but which would have been totally worthless to have tasted.
In fact, the whole 2,4,6 substitution concept is just now beginning to explode. Fully half of the drugs described in this Book II are of the classical 2,4,5-trisubstitution pattern, and it is becoming evident that every one of them will have a 2,4,6-trisubstituted counterpart that bids fair to be an active psychedelic. Diligence could thus easily double the number of known psychedelics. The nickname "pseudo" is really the Greek letter "psi" which looks like a candelabrum standing on the table holding up three candles. If I can find the type in some font, I will simply precede each known drug with this letter, to indicate that the 2,4,5-ness has become a 2,4,6-ness. Therefore, Z-7 is also pseudo-DOM.
Z-7.2 might have been an interesting compound to taste. But the academic climate was not appropriate at that time (early 1977) for such honesty. The "hydro-quinone hypothesis" is now not much more than a minor bit of history. And anyhow, it was just about this time that I had uncovered a slick way of getting a sulfur atom into the amphetamine molecule. I quickly lost interest in the pursuit of other people's hypotheses that didn't seem to lead anywhere. Maybe, someday, some single earth-shaking mechanism will emerge to explain everything. But in the meantime, the best contribution I can make to this "grand unified theory of psychedelic activity" is to continue to make new and unexpected things which, if they are active, will effectively destroy any hypothesis that just happens to be popular at the moment. It is a lot more exciting, too.
#70 DON; 2,5-DIMETHOXY-4-NITROAMPHETAMINE
SYNTHESIS: A solution of 8.4 g 2,5-dimethoxyamphetamine base in 40 mL acetic acid was added dropwise over the course of 0.5 h to 43 mL of 50% nitric acid which was well stirred and cooled with an external ice bath. The resulting solution was quenched with ice water, made basic with aqueous NaOH, and extracted with a benzene-ether mixture. The residue that remained after the removal of the solvent was dissolved in dilute HCl which, upon evaporation of the H2O, yielded a nearly colorless residue. Recrystallization from an ethanol/ether mixture gave, after drying, 10.5 g of 2,5-dimethoxy-4-nitroamphetamine hydrochloride (DON) with a mp of 206-207 °C. The acetamide derivative melted at 166-168 °C. The formamide derivative was easily hydrolyzed with 3N HCl. And the R-isomer of DON hydrochloride had a mp of 231-232 °C.
DOSAGE: 3.0 - 4.5 mg.
DURATION: 8 - 15 h.
QUALITATIVE COMMENTS: (with 3.0 mg) There was an amphetamine-like stimulation that was apparent an hour into it, and considerable anxiety. I had stomach cramps, but there were indications that there might be something hallucinogenic at a higher dose.
(with 4.5 mg) An enhancement of color perception, and some auditory distortion, that was still noticeable some eight hours into the experience. The visual changes were intense. I felt I was running a slight fever, and was restless, but there was almost no physical malaise. I was still somewhat wound up even at the 14th hour.
EXTENSIONS AND COMMENTARY: These qualitative comments are not true quotations, but have been reconstructed from the published summaries of the human trials reported by several South American researchers. I have personally never tasted DON and have only these fragments from which to create a portrait of activity. A brief quotation, from a note published by these researchers in a bulletin that is restricted to forensic scientists serving law enforcement agencies, is certainly subject to a number of interpretations. It reads as follows: "This action [a strong stimulant action reminiscent of amphetamine] seems to reduce the incidence of insightful, and therefore potentially unpleasant experiences, and thus [DON seems likely] to appear on the market as an illicit recreational drug." I must admit that I have tried, and I am still not able, to interpret this quotation.
#71 DOPR; 2,5-DIMETHOXY-4-(n)-PROPYLAMPHETAMINE
SYNTHESIS: A suspension of 285 g mossy zinc in 285 mL H2O containing 5.7 g mercuric chloride was treated with 285 mL concentrated HCl and shaken as needed to effect amalgamation. The H2O was then drained off, the zinc washed with fresh water and drained again. There was added a solution of 74 g 2,5-dimethoxypropiophenone (from the reaction of propionic acid and p-dimethoxybenzene in the presence of polyphosphoric acid, see under DOAM for an effective general procedure) in 140 g EtOH. The reaction mixture was held at reflux for 24 h with the periodic addition of concentrated HCl. It was then cooled, diluted with H2O and CH2Cl2, and the organic phase separated. The aqueous phase was extracted with 2x100 mL additional CH2Cl2. The combined organic phases were washed with 5% NaOH until the washes remained basic, once with H2O, and then the solvent was removed under vacuum. The residue was distilled at the water pump, giving an early fraction quite rich in starting p-dimethoxybenzene, and a second fraction (61 g, bp 140-160 °C) which was free of carbonyl group by infra-red, and which was largely 2,5-dimethoxypropylbenzene. It was used without further purification in the following aldehyde synthetic step.
A mixture of 124 g N-methylformanilide and 140 g POCl3 was allowed to stand until there was the development of a strong red color. There was then added 60 g of the above 2,5-dimethoxypropylbenzene and the mixture was held on the steam bath for 2 h. The mixture was added to 2 L H2O and stirred until the excess acid chloride had completely decomposed. The mixture was extracted with 3x100 mL CH2Cl2 and, after the removal of the solvent from the combined extracts, the residue was extracted with 3x100 mL boiling hexane. Removal of the solvent gave the product 2,5-dimethoxy-4-propylbenzaldehyde as an oil, 23 g, which was characterized as its malononitrile derivative. Equal weights of the product and malononitrile in EtOH with a catalytic amount of triethylamine gave yellow crystals which, on recrystallization from toluene, had a mp of 113-114 °C.
A solution of 21.5 g of the above crude 2,5-dimethoxy-4-propylbenzaldehyde in 75 g acetic acid, was treated with 10.4 g nitroethane and 6.6 g anhydrous ammonium acetate. This was heated on the steam bath for 1.75 h, then cooled and diluted with H2O to the point of turbidity. With long standing and scratching, there finally was the deposition of crystals which were removed by filtration and sucked as dry as possible. This 23 g of crude product cake was triturated under MeOH, filtered again, and air dried to give 11 g of dull orange crystals. Recrystallization from boiling MeOH gave 1-(2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene as fine orange crystals which weighed, after filtering, washing, and drying, 7.4 g, and which had a mp of 94-96 °C.
To a suspension of 6.0 g LAH in 500 mL anhydrous Et2O, which was being stirred and also held as a gentle reflux, there was added a saturated solution of (2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene in warm THF. The reaction mixture was held at reflux for 24 h, then cooled to room temperature. The excess hydride was destroyed by the cautious addition of 500 mL dilute H2SO4. The phases were separated, and the aqueous phase washed with additional Et2O. There was then added 150 g potassium sodium tartrate, and the pH was brought to >9 with aqueous NaOH. The product was extracted with Et2O and, after removal of the solvent, the residue was dissolved in 200 mL anhydrous Et2O and saturated with anhydrous HCl gas. The solids that formed were removed by filtration, giving 6.15 g 2,5-dimethoxy-4-(n)-propylamphetamine hydrochloride (DOPR) as an electrostatic, white crystalline powder, with a mp of 182.5-183 °C. This was not improved by recrystallization from either IPA or CH3CN.
DOSAGE: 2.5 - 5.0 mg.
DURATION: 20 - 30 h.
QUALITATIVE COMMENTS: (with 2.0 mg) The onset is slower than any other thing I can think of. There was nothing at all at the end of an hour, and only a threshold a half hour later. By the middle of the third hour, I was up to 1+, and that seemed to be about as high as it intended to take me. Attempts to sleep at the ninth hour were not successful, as there were strange patterns of not-quite logical thinking going on. Stuff like: "The block events (like a baby's rectangular building blocks) that were gotten, along with other things, from the full octaves of the left hand in Listz's Hungarian Rhapsody, events that allowed an easy recognition of the odds of achieving successful re-entry from any of several erotic codes." Clearly this was not a baseline state. After six hours of successful sleep, I was still off-baseline , and on into the following day. Go on up with curiosity but with caution.
(with 3.6 mg) Imagery that was constructed in response to the music turned out to be necessary to organize and contain it. The trio is the nucleus that transforms the written to the heard, but it has created its own bubble without connections to the real world, and must play on and on and on to keep itself afloat and never touching the stage again.
(with 5.0 mg) I am now at midnight, and still strongly +++. This is certainly maximum dosage, at least for a long time. There are faint intimations of nervous system scrungies. You know, the kind of thing that makes you figure it's going to be a while before you'll try to relax into sleep. This material, like all the other DO's, is a heavy duty psychedelic, the kind that says to you, 'Forget all that stuff about screening out visuals,' and then proceeds to prove it. Sort of indole-like in that way. Your body as well as your mind tells you you're into it, baby, and better relax and enjoy the trip, because you've left the shore way behind. When it was time for bed, I got to sleep with surprising ease, and slept for only about six hours. My dreams were excellent, balancing, and good humored. But the next day I realized I was still carrying the DOPR in me, and that baseline was definitely not there. But it was OK. No problems except for sleepiness. The next evening I went to bed at unheard-of hour of 9 PM and slept for 13 hours, give or take. Fascinating compound, but I won't go out of my way to take it again soon.
EXTENSIONS AND COMMENTARY: There is a thread of disconnection and of inconsistent reference that pervades most of the reports that I have received concerning the use of DOPR. The word that comes to mind is hypnogogic. There is a drifting into that place that lies between a not-quite-awake and a not-quite-asleep state seems to characterize this compound. There is no question but that it is very potent, and that it is very long-lived. But there is a nagging suggestion of the out-of-body, out-of-center character that is the hallmark of the anesthetic and delusional drugs such as scopolamine or ketamine. With them, the psychedelic effects become clouded with touches of amnesia. If DOPR shows this with it's three carbon alkyl group, thereis every reason to pay close attention as the chain becomes longer.
There had been quite a bit of speculation in the literature that the metabolic attack on DOM was at the 4-position, and this was an oxidation process. In a moment of inspiration, I decided to explore a similar oxidation step in DOPR, since it is probably the most potent of the DO-series. Why not make the compound which would be the first step in this oxidation, the 1-hydroxypropyl analogue? This I did, by using the phthalimide derivative of 2,5-dimethoxyamphetamine (described in the synthesis of DOI) and making the propiophenone using propionic acid as both reagent and solvent, and polyphosphoric acid as the condensing agent. The ketone product (a white crystalline solid from methanol) was dissolved in warm methanol and reduced to the alcohol with sodium borohydride. This product, also a white crystalline solid, was stripped of the phthalimide blocking group with overnight refluxing with hydrazine in ethanol. The product, 2,5-dimethoxy-4-(1-hydroxypropyl)-amphetamine (hydroxy-DOPR) had a mp of 148-150 °C from IPA. Its activity is not yet known, but there were no effects at all at trials, orally, of up to 200 micrograms.
But this is all with the normal-propyl compound. There is a rich collection of misinformation and potential discovery that is associated with the isopropyl isomer. This structural isomer, 2,5-dimethoxyl-4-(i)-propylamphetamine is properly called DOIP for des-oxy-iso-propyl. It has been synthesized and explored in animals and, to a modest extent, in man. The synthesis has proceeded from 2,5-dimethoxyacetophenone by the addition of a methyl group to the carbonyl followed by reduction to the hydrocarbon. Aldehyde formation, nitropropene synthesis with nitroethane, and lithium aluminum hydride reduction are uneventful, providing the hydrochloride salt DOIP, which has a mp of 183-184 °C as an analytical sample. Animal tests (such as rabbit hyperthermia assays), have indicated that the isopropyl compound DOIP is less potent than the propyl prototype, DOPR, by between one and two orders of magnitude. In man, a dose of four milligrams, a rousing dose of DOPR, is without any effects. At 10 milligrams, there is some disturbance but substantially no effects. I have been told that with doses in the 20 to 30 milligram range there are valid changes in mental state, but I have not been told the nature of these changes.
A fascinating red herring had been drawn across all of these exacting lines by a strange visitor to this research project. An olive-faced M.D., Ph.D., passed through this confusing scene briefly, and when he left, a small supply of DOPR left with him. He promptly published in an obscure journal some animal behavioral responses which he ascribed to the isopropyl analogue, DOIP. But what he had studied could only have been DOPR since DOIP, at that time, had not yet been synthesized either by me, or by either of the other two active synthesists of that moment. It was not yet a known material. We all made it some time later, but by that time our olive-face had disappeared. There is a magnificent French phrase that applies here as nowhere else; Il a foutu le camp. Its idiomatic meaning is equivalent to our, "He took off," or "He split the scene," but the literal translation is, "He fucked the camp."
#72 E; ESCALINE; 3,5-DIMETHOXY-4-ETHOXYPHENETHYLAMINE
SYNTHESIS: To a solution of 72.3 g 2,6-dimethoxyphenol in 400 mL MeOH, there was added 53.3 g of a 40% solution of aqueous dimethylamine folowed by 40 g of a 40% aqueous solution of formaldehyde. The dark solution was heated under reflux for 1.5 h on a steambath. The volatiles were then removed under vacuum yielding a dark oily residue of 2,6-dimethoxy-4-dimethylaminomethylphenol. This residue was dissolved in 400 mL of IPA, to which there was added 50 mL of methyl iodide. The spontaneously exothermic reaction deposited crystals within 3 min, and was allowed to return to room temperature and occasionally stirred over the course of 4 h. The solids were removed by filtration, washed with cold IPA, and allowed to air dry yielding 160 g of the methiodide of 2,6-dimethoxy-4-dimethylaminomethylphenol as a cream-colored crystalline solid.
A suspension of 155 g of the above methiodide of 2,6-dimethoxy-4-dimethylaminophenol in 600 mL H2O was treated with a solution of 130 g KCN in 300 mL H2O. The reaction mixture was heated on a steam bath for 6 h during which time there was a complete dissolving, the development of a brownish color with a bright blue film on the surface and the walls of the flask, and the gentle evolution of fine gas bubbles. The hot reaction mixture was poured into 1.2 L H2O and acidified with concentrated HCl (careful, HCN evolution). The aqueous solution was extracted with 3x150 mL CH2Cl2, the extracts pooled, washed with saturated NaHCO3 which removed much of the color. The solvent was removed under vacuum yielding about 70 g of a viscous black oil. This was distilled at 0.4 mm/Hg at 150-160 °C to provide 52.4 g of homosyringonitrile (3,5-dimethoxy-4-hydroxyphenylacetonitrile) as a white oil that spontaneously crystallized to lustrous white crystals that melted at 57-58 °C.
A solution of 5.75 g of homosyringonitrile and 12.1 g ethyl iodide in 50 mL dry acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux for 18 h. The mixture was diluted with 100 mL Et2O, filtered, and the filtrate solvent removed under vacuum The residue was recrystallized from Et2O/hexane to yield 5.7 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile with a mp 57-58 °C. Anal. (C12H15NO3) C,H,N.
A solution of 2.21 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile in 25 mL EtOH containing 2.5 mL concentrated HCl and 400 mg 10% palladium on charcoal, was shaken in a 50 lb/sq.in. atmosphere of hydrogen for 24 h. Celite was added to the reaction suspension and, following filtration, the solvents were removed under vacuum. The residue was recrystallized from IPA/Et2O to yield 2.14 g 3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) with a mp of 166-167 °C.
Synthesis from syringaldehyde: A well-stirred suspension of 21.9 g syringaldehyde in 45 mL H2O was heated to reflux in a heating mantle. There was then added a solution of 15 g NaOH in 60 mL H2O. The heating and stirring was continued until the generated solids redissolved. Over a period of 10 min, there was added 23 g diethyl sulfate, then refluxing was continued for 1 h. Four additional portions each of 5 g diethyl sulfate and of 6 mL 20% NaOH were alternately added to the boiling solution over the course of 2 h. The cooled reaction mixture was extracted with Et2O, the extracts pooled and dried over anhydrous MgSO4, decolorized with Norite, and stripped of solvent. The crude 3,5-dimethoxy-4-ethoxy-benzaldehyde weighed 21.8 g and melted at 51-52 °C.
A solution of 14.7 g 3,5-dimethoxy-4-ethoxybenzaldehyde and 7.2 mL nitromethane in 50 mL glacial acetic acid was treated with 4.4 g anhydrous am-monium acetate and held at reflux for 30 min. Cooling the reaction allowed the formation of yellow crystals which were removed by filtration and washed sparingly with cold acetic acid. The dried 3,5-dimethoxy-4-ethoxy-'-nitrostyrene weighed 11.5 g and melted at 108-109 °C after recrystallization from EtOH Anal. (C12H15NO5) C,H. Alternately, this product may be prepared from 3.9 g. 3,5-dimethoxy-4-ethoxybenzaldehyde in 60 mL nitromethane containing 0.7 g ammonium acetate and heated on a steam bath for 1 h. The solvent was removed under vacuum, and the residue dissolved in a minimum of hot MeOH. Cooling provided, after filtration and air drying, 2.3 g of bright yellow crystals of 3,5-dimethoxy-4-ethoxy-'-nitrostyrene, with a mp of 105-107 °C.
A solution of 2.25 g LAH in 45 mL anhydrous THF was vigorously stirred and cooled to 0 °C under He. There was added 1.5 mL 100% H2SO4 dropwise, followed by 2.3 g 3,5-dimethoxy-4-ethoxy-'-nitrostyrene in anhydrous THF. After the addition was complete, the mixture was allowed to stir for 30 min, and then brought to room temperature. The unreacted hydride was decomposed with 2.3 mL H2O in THF, followed by the addition of 9.2 mL of 15% NaOH. The white suspension was filtered, the filter cake was washed with THF, the filtrate and washings combined, and the solvent removed under vacuum. The residue was dissolved in 300 mL dilute H2SO4, washed with 2x75 mL CH2Cl2, made basic with 25% NaOH, and the product extracted with 3x75 mL CH2Cl2. After removal of the solvent, the residue was distilled at 110-120 °C at 0.3 mm/Hg yielding 1.4 g of a colorless oil. A solution of this oil in 20 mL IPA was neutralized with 17 drops of concentrated HCl and diluted with 100 mL anhydrous Et2O. After a few minutes there was the spontaneous formation of white crystals of 3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) which was recrystallized from 40 mL boiling EtOAc containing 1 mL MeOH. The mp was 165-166 °C.
DOSAGE: 40 - 60 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 40 mg) This is a powerful and complex intoxicant Q I could not have coordinated any rational muscular activity. I could not walk; I could not tie my shoe-laces. There is analgesia and an incoordination that I cannot shake. My menstrual flow started a bit ahead of time, but it was light.
(with 50 mg) I felt that the body tensions outweighed the psychological and sensory rewards, in that I had a lot of dehydration and my sleep had a nightmare quality. This pretty much offset the few virtues that I felt I had obtained.
(with 60 mg) There is a quality of rational analysis and insight that is totally impressive. Many subtle factors in my life can be viewed with insight, and usefully dissected. I got into a deep discussion, but I was not argumentative or even defensive and I remained detached and kept a tone of cool impersonality. I had a good appetite. But I also had some tachycardia and muscular tension. There was unquestionable sensory enhancement, but without an intellectual component. Overall it was most pleasant.
EXTENSIONS AND COMMENTARY: In an isolated situation, there is easy fantasy, but little synthesis of external sensory inputs such as music or visual stimulae. A gradual decline brings the subject back to a restful baseline somewhere before the 12th hour. The following day is often seen as one of tiredness and low energy. An anonymous flyer appeared in the California drug community in 1984 stating an effective range to be 50 to 100 milligrams, but it described the drug as the sulfate. The above data all pertain to the hydrochloride salt.
The replacement of that one methyl group with an ethyl group leads to a nice jeu de mots. The play on words depends on a remarkable coincidence. The name of the alkaloid mescaline stems from an ancient Nahuatl word for a drink (Mexcalli) which also provided the source of the term Mescal (an Agave of entirely different pharmacology). The prefix for the simplest, the one carbon organic radical, is methyl. This is from the Greek word "methy" and represents wine from wood. Such is, indeed, methyl alcohol, or methanol, or wood alcohol, the simplest one-carbon drink and a rather dangerous one for the human animal. And this is the group that is on the central oxygen of mescaline.
It is customary to refer to homologs (bigger-by-one) of methanol by their classical chemical names, so the natural extension of methyl is ethyl, and that of mescaline would be escaline. One carbon-chain on the 4-position oxygen becoming a two-carbon chain. This is all entymologically appealing, but there is no botanical support for any of it. The ethyl group is much more rare in nature. It is just a happy coincidence that mescaline (the plant), and methyl (the alkyl group involved), and methoxy (the group on the 4-position of the aromatic ring) all happen to start with the letter RMS.
Very few of the homomescaline phenethylamines have been synthesized as their three-carbon chain counterparts, the corresponding analogues of amphetamine. And only three of them have been explored in man (four, if you count the amphetamine analogue of mescaline itself, TMA). The obvious names for these compounds have, unfortunately, already been used. It would be logical to use the letter M for a methoxy, and the letter E for ethoxy, etc. and simply read the groups from around the ring. But this is the naming system for the 2,4,5-trisubstituted amphetamines. MEM is, for example, 2,5-dimethoxy-4-ethoxyamphetamine (in sequence, methoxy, ethoxy, methoxy reading around the ring, and a fascinating compound talked about at length in this book), so this term cannot represent 3,5-dimethoxy-4-ethoxyamphetamine.
A truly simple code employs the length of the carbon chain. The phenethylamine chain is two carbons long, and the amphetamine chain is three carbons long.
If a drug has been initially developed (and initially named) as an amphetamine derivative (three carbon chain) then the two-carbon chain analogue will use the original name (or a symbolic part of it) with the term 2C ahead of it. The two-carbon analogue of DOB (a three-carbon chain compound) will become 2C-B. DOI becomes 2C-I, DON becomes 2C-N, and DOET becomes 2C-E. Each of these is a substituted amphetamine derivative lacking one carbon atom, thus becoming a phenethylamine derivative. Most of these have 2,4,5-substitution patterns.
And if a drug has been initially developed (and initially named) as a phenethylamine derivative (two carbon chain) then the three-carbon chain analogue will use the original name with the term 3C ahead of it. The three carbon analogue of E (escaline, a two-carbon chain compound) will become 3C-E. P becomes 3C-P and CPM becomes 3C-CPM. Most of these have 3,4,5-substitution patterns.
Thus, R2-CS implies that a known amphetamine drug has been shortened to a phenethylamine, and R3-CS inplies that a known phenethylamine has been lengthened to an amphetamine. A great number of the former have been made and have proven to be most rewarding. Only a few of the latter are known, but most of them will eventually prove to be potent psychedelics.
#73 EEE; 2,4,5-TRIETHOXYAMPHETAMINE
SYNTHESIS: A solution of 13.3 g 3,4-diethoxyphenol (see the recipe for MEE for its preparation) in 20 mL MeOH, and a solution of 4.8 g KOH in 100 mL hot MeOH were combined. There was added 8.2 g ethyl bromide and the mixture was held at reflux on the steam bath for 2 h. The reaction was quenched by the addition of three volumes H2O, made strongly basic by the addition of 10% NaOH, and extracted with 3x150 mL CH2Cl2. The solvent was removed from the pooled extracts under vacuum giving a residue of 9.1 g 1,2,4-triethoxybenzene that solidified to a crystalline mass. The mp was 28.5-29.5 °C, but the infra-red analysis showed the presence of unreacted phenol. The CH2Cl2 solution was again washed thoroughly with 10% NaOH and, after removal of the solvent, the solidified residue weighed 6.0 g and appeared free of impurities. The mp of this sample was 33-34 °C.
To a mixture of 10.5 g N-methyl formanilide and 11.9 g POCl3 that had incubated at room temperature for 0.5 h (it had become quite red in color) there was added 6.4 g of the solid ether, 1,2,4-triethoxybenzene. The mixture was heated on the steam bath for 2.5 h, then poured into 500 mL of shaved ice. After a few minutes stirring, crystals appeared. The reaction was allowed to stand for a few h, then filtered and sucked as dry as possible. The damp 14.4 g of slate-green crude solids were dissolved in 30 mL boiling MeOH, and allowed to cool to room temperature overnight. Filtration of the cream-colored product, and air drying, gave 6.1 g of 2,4,5-triethoxybenzaldehyde with a mp of 94-95 °C. A solution containing 0.5 g of this aldehyde and 0.4 g malononitrile in 7 mL absolute EtOH was treated with three drops of triethylamine. There was an immediate formation of granular yellow crystals of 2,4,5-triethoxybenzalmalononitrile which, on filtering and air drying, weighed 0.4 g and had a mp of 169-170 °C.
A solution of 5.0 g 2,4,5-triethoxybenzaldehyde and 2.6 g nitroethane in 14.8 g glacial acetic acid was treated with 1.6 g anhydrous ammonium acetate and heated on the steam bath for 2 h. The addition of an equal volume of H2O gave a slightly turbid solution which, upon the administration of a small amount of externally developed seed, smoothly set up as orange crystals as the reaction mix returned to room temperature. The product was removed by filtration, washed with a little 50% acetic acid, and allowed to air dry to constant weight. There was thus obtained 2.5 g of fluffy yellow-orange (almost yellow) crystals of 2-nitro-1-(2,4,5-triethoxyphenyl)propene with a mp of 91-92.5 °C. Anal. (C15H21NO5) C,H.
To a gently refluxing suspension of 1.7 g LAH in 200 mL anhydrous Et2O under a He atmosphere, there was added 2.5 g 2-nitro-1-(2,4,5-triethoxyphenyl)propene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble containing the nitrostyrene, thus effectively adding a warm saturated solution of the nitrostyrene dropwise. Refluxing was maintained for 5 h, and then the reaction mixture was cooled with an external ice bath. The excess hydride was destroyed by the cautious addition of 300 mL 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 50 g of potassium sodium tartrate were dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was extracted with 3x200 mL CH2Cl2. Removal of the solvent under vacuum produced an amber oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. After a few min delay, there com-menced the separation of fine white crystals of 2,4,5-triethoxyamphetamine hydro-chloride, (EEE). These weighed, after filtration, Et2O washing, and air drying to constant weight, 1.75 g and had a mp of 167-168 °C, with prior softening at 162 °C. Anal. (C15H26ClNO3) C,H,N.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This amphetamine, the final item on the ethoxy homologue of TMA-2 project, has never been tried in man. I do not know how it tastes, but I suspect that it is probably bitter. An interesting sidelight concerning this project, and one which can serve as a measure of the enthusiasm that went into it, is that (except for the 2-ethoxy homologue EMM) all of the possible ethoxy homologues of TMA-2, including MEM, MME, EEM, EME, MEE and EEE, their precursor nitrostyrenes, the precursor aldehydes (and their malononitrile derivatives), the precursor ethers, and the precursor phenols, for a total of 33 compounds, were all synthesized, purified, and characterized within a period of just over three weeks. Actually it was 23 days, and that was a magically exciting time.
And there were two true treasures that came out of it all. The compound MEM, and the knowledge that the 4-position was where the action is.
#74 EEM; 2,4-DIETHOXY-5-METHOXYAMPHETAMINE
SYNTHESIS: To a solution of 12.3 g 3-ethoxy-4-methoxyphenol (see recipe for MEM for the preparation of this phenol) in 20 mL MeOH, there was added a warm solution of 4.8 g KOH in 100 mL MeOH. There was then added 8.2 g ethyl bromide, and the mixture held at reflux on the steam bath. Within 0.5 h, severe bumping ensued. An additional 3 g ethyl bromide were added, refluxing continued for another 0.5 h, then the reaction mixture was allowed to come to room temperature and to stand overnight. It was poured into 3 volumes H2O which produced crystals spontaneously. There was added additional base, and the mixture was extracted with 3x150 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 6.4 g of 2,4-diethoxyanisole as tan crystals with a mp of 48-48.5 °C.
A mixture of 10.9 g N-methylformanilide and 12.3 g POCl3 was allowed to stand at room temperature for 0.5 h producing a deep red claret color. There was then added 6.2 g 2,4-diethoxyanisole and the mixture was heated on the steam bath for 2 h. All was poured into 200 g chipped ice, and stirred mechanically. The dark viscous gummy oil gradually became increasingly granular and finally appeared as jade-green solids. These were removed by filtration and washed with H2O, giving a wet cake weighing 18 g and having a mp (from a porous plate) of 95.5-96.5 °C. The entire crop was recrystallized from 75 mL boiling MeOH which gave, after filtering, washing lightly with cold MeOH, and air drying, 5.4 g of 2,4-diethoxy-5-methoxybenzaldehyde with a mp of 98-99 °C. A solution of 0.2 g of this aldehyde, and 0.3 g malononitrile in 2.0 mL warm EtOH was treated with a drop of triethyl-amine. There was an immediate generation of crystals which were removed by filtration, EtOH-washed, and dried to constant weight. The bright yellow needles of 2,4-diethoxy-5-methoxybenzalmalononitrile weighed 0.15 g and had a mp of 172-172.5 °C.
A solution of 5.0 g 2,4-diethoxy-5-methoxybenzaldehyde in 16 g glacial acetic acid was treated with 2.7 g nitroethane followed by 1.7 g anhydrous ammonium acetate. The mixture was heated for 2.5 h on the steam bath, then removed and diluted with a equal volume of H2O. With cooling there was the generation of a heavy crop of orange crystals which was removed, washed with 50% acetic acid, and sucked as dry as possible. The product had a mp of 97-104 °C, and there was spectrographic evidence of some unreacted starting aldehyde. A small sample was recrystallized from boiling MeOH, with considerable loss, to give an analytical sample of 1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene as orange-yellow crystals with a mp of 112-113 °C. Anal. (C14H19NO5) C,H. The unpurified first crop was employed in the following synthesis of the corresponding amphetamine.
To a gently refluxing suspension of 2.9 g LAH in 400 mL anhydrous Et2O under a He atmosphere, there was added 4.0 g of impure 1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene by allowing the condensing ether to drip into a shunted Soxhlet thimble apparatus containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise over the course of 1 h. Refluxing was maintained for 5 h and the reaction mixture was cooled with an external ice bath with the stirring continued. The excess hydride was destroyed by the cautious addition of 400 mL of 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 100 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was then extracted with 3x150 mL CH2Cl2. Removal of the solvent under vacuum produced 2.7 g of a pale amber oil that was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. After a few minutes delay, there commenced the separation of fine white crystals of 2,4-diethoxy-5-methoxyamphetamine hydrochloride (EEM). After the crystallization was complete, these were removed by filtration, washed with Et2O and air dried, providing 2.55 g of a fine white crystalline solid with mp 158-159 °C. Anal. (C14H24ClNO3) C,H,N.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This particular identity and arrangement of the alkoxy groups on the amphetamine molecule, EEM, is a totally unexplored molecule. It is reasonable to assume that it would be way down in potency, but there is no way of guessing what the nature of its activity might be at the dosage that would be active.
#75 EME; 2,5-DIETHOXY-4-METHOXYAMPHETAMINE
SYNTHESIS: To a solution of 14.0 g 4-ethoxy-3-methoxyphenol (see the recipe for MME for the preparation of this starting material) in an equal volume of EtOH, there was added a solution of 5.3 g KOH in 100 mL hot MeOH. This was followed with 9.1 g ethyl bromide, and the mixture was held at reflux for 2 h. The first deposition of KBr was apparent in 5 min, and there was rather severe bumping by the end of the reaction. The mixture was diluted with 3 volumes H2O and 1 volume 5% NaOH, and extracted with 2x200 mL Et2O. The extracts were pooled, and the solvent removed under vacuum, yielding 14.3 g of a pale amber oil that set to crystals of 2,5-diethoxyanisole with a mp of 44-45 °C. The compound had been reported in the literature from the action of diethyl sulfate on methoxyhydroquinone.
To a mixture of 24.1 g N-methylformanilide and 27.3 g POCl3 that had been allowed to stand at room temperature until strongly red-colored (about 0.5 h) there was added 13.8 g solid 2,5-diethoxyanisole and the mixture was heated on the steam bath for 2 h. The black, thick reaction product was poured over chipped ice and, with continuous stirring, the color lightened and there was the formation of a yellowish powder. After a few h standing, this was removed by filtration and sucked as dry as possible. The 32 g of damp product showed the presence of isomeric contaminatiion by GC, and the aqueous mother liquor, upon extraction with CH2Cl2 and concentration, showed yet more aldehyde-like impurities. The isolated solids were recrystallized from 125 mL boiling MeOH giving 15.8 g yellowish crystals (wet weight) that still showed detectable impurities by GC. A second recrystallization from 100 mL boiling MeOH gave off-white fluffy crystals of 2,5-diethoxy-4-methoxybenzaldehyde which weighed, after air drying, 8.5 g. The mp was 109-110 °C. The combined mother liquors from the two MeOH crystallizations were stripped of solvent, and the resulting solid mass crystallized again from MeOH to give a second crop of aldehyde, 5.7 g, with a mp of 110-111 °C. A solution of 1.0 g of this aldehyde and 0.7 g malononitrile in 40 mL warm absolute EtOH was treated with a few drops of triethylamine. In a minute or so, there was the formation of crystals. These were removed by filtration, washed with EtOH, and air dried, giving 0.6 g of 2,5-diethoxy-4-methoxybenzalmalononitrile as brilliant yellow crystals with a mp of 156.5-158 °C.
A solution of 6.7 g 2,5-diethoxy-4-methoxybenzaldehyde in 21 g glacial acetic acid was treated with 3.1 g nitroethane and 1.93 g anhydrous ammonium acetate, and heated on the steam bath for 2.5 h. The addition of a small amount of H2O to the hot reaction mixture instituted crystallization of an orange product which, after the mixture had come to room temperature and stood for several h, was removed by filtration, H2O washed, and air dried. The product, 1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene, was dull orange in color, weighed 3.0 g and had a mp of 84-86 °C. An analytical sample from toluene had a mp of 85-86 °C. Anal. (C14H19NO5) C,H.
To a gently refluxing suspension of 2.0 g LAH in 250 mL anhydrous Et2O under a He atmosphere, there was added 2.8 g 1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise. The addition took 1 h and the refluxing was continued for an additional 6 h. The reaction mixture was brought down to ice-bath temperature, and the excess hydride was destroyed by the cautious addition of 150 mL 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated and 50 g of potassium sodium tartrate were dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x150 mL CH2Cl2. Removal of the solvent under vacuum produced 2.3 g of a clear white oil that was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. At first the solution remained completely clear, and finally there was the start of the formation of fine white crystals. When the crystallization was complete, these solids were removed by filtration, Et2O washed, and air dried. There was thus obtained 2.2 g of 2,5-diethoxy-4-methoxyamphetamine hydrochloride (EME) with a mp of 162-164 °C with prior softening at 154 °C. Anal. (C14H24ClNO3) C,H,N.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This is another of the collection of all possible ethoxy homologues of TMA-2. The latter and heavier members of this series were synthesized and completed before the directions of biological activity had become evident from the earlier ones. This compound has never been assayed, and it is a reasonable guess that it will have a very low potency, with hints of toxicity at higher dose levels. I suspect that it will never be assayed, certainly not by me.
