Pihkal

by Alexander Shulgin

  (with 80 mg) It took about two hours for the body to settle down.

  Emotions were true and well felt, a fact that is an all-important thing to me as it probably is to everyone else I know in this kind of exploration. Any sense that there is a dulling of the feeling and emotional area of the self is a negative, to be watched and noted as are other things such as disturbed sleep, unpleasant dreams, or irritability or depression the next day. I was interacting with others with a great deal of intensity. People found themselves wandering inside and out, listening to music, stirring soup, eating a bit and enjoying eating, talking, laughing a great deal, and being silent in great contentment. It's not a very silent material, though.

  Talking is too enjoyable. There was a slight descent noted at 6-7

  hours, but very gentle and smooth. Slow and pleasant descent until about 12th hour, when sleep was attempted. Next day, everyone slightly irritable but good mood anyway. The next night I slept deeply and well, and awoke whole and in excellent mood.

  EXTENSIONS AND COMMENTARY: These two excerpts give the color and complexity of IP. It has proven to be a completely fascinating phenethylamine. And, as with all the phenethylamines, there is an amphetamine that corresponds to it. This would be 3,5-dimethoxy-4-isopropoxyamphetamine, or 3C-IP. The prepa-ration of it would require access through the O-isopropoxylation product with syringaldehyde, followed by nitrostyrene formation with nitroethane, followed by reduction probably with lithium aluminum hydride. It has not been synthesized, as far as I know, and so it has probably not been evaluated in man. What would be the active level? It would probably be more potent than IP, but I would guess not by much. Maybe in the 30 milligram area.

  A moment's aside for a couple of the words that are so much a part of the chemist's jargon. Room temperature, as used above, means the natural temperature that something comes to if it is put on the table and is neither heated nor cooled. The phrase, I discovered during my year at Gif, is completely un-understandable in French. A room has no temperature. Only things in rooms have temperatures. Their expression is more exact. The object achieves, in the French terminology, a temperature normale dUinterieur, or about 15 to 16 !C.

  But in common laboratory parlance it has become the temperature dUambiance.

  And one finds the prefix RisoS used everywhere. Considerable care should be taken in the two different uses of the prefix RisoS in the nomenclature with the mescaline analogues. In general, the term RisoS

  means the other one of two possibilities. If you are allowed to paint a house only with green paint or red paint, and green is the color you actually use, then red could be called iso-green. With isoproscaline (here) there is a rearranging of the propyl group on the 4-oxygen of mescaline. It has been replaced with its branched analogue, the other of two possibilities, the isopropyl group. Everything is still with the 3,4,5-orientation on the benzene ring. However, with IM

  (isomescaline) there is a rearrangement of substitution pattern on the benzene ring, with the repositioning of the trimethoxyl substitution pattern from the 3,4,5- arrangement to the 2,3,4- arrangement. It has been the side-chain that has taken the other of two possible positions. The term RisoS must always be interpreted in precise context.

  93 IRIS; 5-ETHOXY-2-METHOXY-4-METHYLAMPHETAMINE

  SYNTHESIS: To a solution of 9.5 g flaked KOH (10% excess) in 500 mL

  95% EtOH there was added 20.4 g 4-methoxy-2-methylphenol (see under 2C-D for its preparation). This was followed with 23.5 g ethyl iodide, and the mixture was held at reflux overnight. The solvent was removed under vacuum and the residue suspended in 250 mL H2O. This was made strongly basic with NaOH and extracted with 3x50 mL CH2Cl2.

  Removal of the solvent gave 15.75 g of 2-ethoxy-5-methoxytoluene as an amber oil, which was used in the following step without further purification. Acidification of the aqueous phase followed by CH2Cl2

  extraction gave, after removal of the solvent, crude recovered starting phenol as a dark brown crystalline solid. The reasonably pure phenol was best isolated by sequential extractions with portions of 80 !C H2O which, on cooling, deposited the phenol as white crystals.

  A mixture of 38 mL POCl3 and 43 mL N-methylformanilide was allowed to incubate for 1 h and then there was added to it 15.7 g 2-ethoxy-5-methoxytoluene. This was heated in the steam bath for 2 h, then poured into 1 L H2O and allowed to stir overnight. The solids that formed were removed by filtration and H2O washed, giving 20.7 g of a crude, amber product. This was extracted with 2x150 mL boiling hexane which gave crystals on cooling. These were filtered and hexane washed, giving 12.85 g of 5-ethoxy-2-methoxy-4-methylbenzaldehyde as pale cream-colored solids with a mp of 75-76 !C. Recrystallization of an analytical sample from EtOH two times gave a product with a white color, and a mp of 81-82 !C.

  To a solution of 11.35 g 5-ethoxy-2-methoxy-4-methylbenzaldehyde in 48

  mL glacial acetic acid containing 4 g anhydrous ammonium acetate there was added 10 mL nitroethane, and the mixture heated on the steam bath for 2 h. Standing at room temperature overnight allowed a heavy crop of brilliant crystals to deposit. These were removed by filtration, washed cautiously with acetic acid, and air dried to give 8.6 g 1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene with a mp of 118-120 !C. Recrystallization of all from 200 mL boiling MeOH gave 8.3 g of lustrous crystals with a mp of 121-122 !C.

  To a gently refluxing suspension of 6.4 g LAH in 500 mL anhydrous Et2O

  under a He atmosphere, there was added 8.1 g 1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene by allowing the condensing ether to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene 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 400 mL H2O

  containing 40 g H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 160 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x50 mL CH2Cl2.

  Evaporation of the solvent under vacuum produced an oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.

  There appeared 5-ethoxy-2-methoxy-4-methylamphetamine hydrochloride (IRIS) as fine white crystals. These weighed, after filtration, Et2O

  washing, and air drying to constant weight, 5.3 g and had a mp of 192-193 !C. Recrystallization of an analytical sample from boiling CH3CN gave lustrous crystals with a mp of 196-197 !C with decomposition.

  DOSAGE: greater than 9 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 7.5 mg) At about three hours I felt that I was at threshold, but an hour later there was nothing.

  (with 9 mg) Maybe a little light headed? Maybe not. Little effect if any.

  EXTENSIONS AND COMMENTARY: This is one of the ten Classic Ladies, the ten possible homologues of DOM, which I had discussed under ARIADNE

  (the first of the Ladies). The active level is unknown, but it is higher than 9 milligrams (the highest dose tried) and since DOM itself would have been smashingly active at this level, it is obvious that IRIS is a homologue with decreased potency.

  This lack of activity brings up a fascinating point. I have referred to a drug's action on the mind, quite frequently in these notes, with the phrase Rreasonably complex.S By that, I do not mean that a drugUs action simply shows many facets, and if these were to be tallied, the drug-mind interaction would become clear. There is quite a bit of importance intrinsically implied by the term, complex. Simple things, as we have come to appreciate and depend upon them in our day-to-day living, can have simple explanations. By this, I mean explanations that are both completely satisfactory and satisfactorily complete.

  Answers that have all the earmarks of being correct. What is the sum of two plus three, you ask? Let's try five. And for most of our needs, five is both factual and complete.

  But some yea
rs ago, a mathematician named Gdel devised a proof for a theorem that anything that is reasonably complex cannot enjoy this luxury (I believe he used the word RinterestingS rather than reasonably complex). If your collection of information is factual, it cannot be entirely complete. And if it is complete, it cannot be entirely factual. In short, we will never know, we cannot ever know, every fact that constitutes an explanation of something. A complete book of knowledge must contain errors, and an error-free book of knowledge must be incomplete.

  There is a small warning light deep inside me that starts flashing any time I hear someone begin to advance an explanation of some reasonably complex phenomenon with an air of confidence that implies, RHere is how it works.S What the speaker usually has is an intense familiarity with one particular discipline or specialty and the phenomenon is viewed through those eyes, often with the assurance that looking at it that way, intently enough and long enough, will reveal the complete explanation. And be attentive to the phrase, RWe are not yet com-pletely sure of exactly how it works.S What is really meant is, RWe havenUt the slightest idea of how it really works.

  I must admit to some guilt in this matter, certainly as much as the next person. I am a chemist and I suspect that the way that the psychedelic drugs do their thing can eventually be understood through a comparison of the structures of the molecules that are active and those that are inactive. I put those that have methoxyl groups in pigeon hole #1, and those that are bicyclic into pigeon hole #2. And then, if pigeon hole #2 becomes more and more cluttered, I will subdivide the contents into pigeon hole #2A for bicyclics with heteroatoms and pigeon hole #2B for bicyclics without heteroatoms.

  The more information I can accumulate, the more pigeon holes I need.

  But in the adjoining lab, there is a molecular biologist who feels that the eventual explanation for the action of the psychedelic drug will come from the analysis and understanding of the intimate geometry of the places in the brain where they act. These classification pigeon holes are called receptor sites. But they, too, can become more and more subdivided as they become cluttered. One reads of a new sub-sub type quite regularly in the literature. The favorite neurotransmitter of the moment, as far as the current thinking of how these marvelous drugs work, is serotonin, or 5-HT (for 5-hydroxytryptamine). There are 5-HT1 and 5-HT2A and 5-HT2B and (for all I know right now) 5-HT2C and 5-HT2D receptors, and I donUt really think that either he or I have come much closer to understanding the mechanism of action.

  And, since the mind is a reasonably complex system, Gdel has already informed us both that neither of us will be completely successful.

  Sometimes I feel that the pigeon hole approach to the classification of knowledge might actually limit our views of the problem. A Harvard Professor of Medicine recently noted: RWe must recognize for what it is, man's predilection for dividing things into tidy categories, irrespective of whether clarity is gained or lost thereby.

  No. No one will ever have it all together. It is like sitting down in front of a jigsaw with a zillion zillion pieces spread all over the kitchen table. With diligent searching you will occasionally find a piece that matches another, but it rarely provides any insight into the final picture. That will remain a mystery, unless you had the chance to see the cover of the box in some other incarnation. But Oh my, what fun it is, whenever you do happen to find a new piece that fits!

  This harangue is really a lengthy prelude to the story of putting an ethoxy group in place of a methoxy on the 2,5-dimethoxy skeleton of these psychedelic families. The making of IRIS was the first move in this direction, done back in 1976. One can have a pigeon hole that is named REthoxy In Place of MethoxyS and toss in there the names of perhaps twenty pairs of compounds, which differ from one another by just this feature. Yet when they are looked at from the potency point of view, there are some which show a decrease in potency (which is the case with IRIS and most of the Tweetios) and there are some which seem to maintain their potency (such as the TMA-2/MEM pair) and there are some where there is a distinct potency increase (the mescaline/escaline pair, for example).

  What does one do to clarify the contents of this particular pigeon hole? The current fad would be to subdivide it into three subdivisions, maybe something like REthoxy in Place of Methoxy if 2-

  or 5-locatedS and REthoxy in Place of Methoxy if 4-located and other things 2,5S and REthoxy in Place of Methoxy if 4-located, and other things 3,5.S The end point that soon becomes apparent, down the line, will be to have as many pigeon holes as compounds! And at the moment, this particular piece of the jigsaw puzzle doesnUt seem to fit anywhere at all.

  Perhaps both my neighboring molecular biologist and I are asking the wrong questions. I am looking at the molecules and asking, RWhat are they?S And he is following them and asking, RWhere do they go?S And neither of us is fully attentive to the question, RWhat do they do?S

  It is so easy to replace the word Rmind,S in our inquiries, with the word Rbrain.

  Yup. The operation of the mind can certainly be classified as a Rreasonably complexS phenomenon. I prefer Gdel's term. The mind is without question an RinterestingS phenomenon.

  94 J; BDB; 2-AMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE; 1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

  SYNTHESIS: The Grignard reagent of propyl bromide was made by the dropwise addition of 52 g 1-bromopropane to a stirred suspension of 14

  g magnesium turnings in 50 mL anhydrous Et2O. After the addition, stirring was continued for 10 min, and then a solution of 50 g piperonal in 200 mL anhydrous Et2O was added over the course of 30

  min. The reaction mixture was heated at reflux for 8 h, then cooled with an external ice bath. It was quenched with the addition of a solution of 75 mL cold, saturated aqueous ammonium chloride. The formed solids were removed by filtration, and the two-phase filtrate separated. The organic phase was washed with 3x200 mL dilute HCl, dried over anhydrous MgSO4, and the solvent removed under vacuum. The crude 62.2 g of 1-(3,4-methylenedioxyphenyl)-2-butanol, which contained a small amount of the olefin that formed by dehydration, was distilled at 98 !C at 0.07 mm/Hg to give an analytical sample, but the crude isolate served well in the next reaction. Anal. (C11H14O3) C,H.

  A mixture of 65 g crude 1-(3,4-methylenedioxyphenyl)-2-butanol and 1 g finely powdered potassium bisulfate was heated with a soft flame until the internal temperature reached 170 !C and H2O was no longer evolved.

  The entire reaction mixture was then distilled at 100-110 !C at 0.8

  mm/Hg to give 55 g of 1-(3,4-methylenedioxyphenyl)-1-butene as a colorless oil. Anal. (C11H12O2) C,H.

  To 240 mL of stirred and cooled formic acid there was added 30 mL H2O

  followed, slowly, by 45 mL of 35% hydrogen peroxide. There was then added a solution of 48 g 1-(3,4-methylenedioxyphenyl)-1-butene in 240

  mL acetone at a rate that maintained the internal temperature at less than 40 !C. After the addition, the reaction mixture was allowed to stand and stir for several additional days. The excess volatiles were removed under vacuum with the temperature never allowed to exceed 40

  !C. The residue was dissolved in 90 mL MeOH and diluted with 450 mL

  15% H2SO4. This mixture was heated on the steam bath for 2.5 h, cooled, and then extracted with 3x100 mL Et2O. The extracts were pooled, washed with 2x200 mL H2O, 2x200 mL 5% NaOH, 2x200 mL brine, and then dried over anhydrous MgSO4. After removal of the solvent under vacuum, the residue was distilled at 105-135 !C at 0.3 mm/Hg to give 28.2 g 1-(3,4-methylenedioxyphenyl)-2-butanone as an amber oil.

  Redistillation gave a colorless oil, with a bp of 98 !C at 0.11 mm/Hg.

  Anal. (C11H12O3) C,H. This intermediate ketone could be prepared by the Wittig reaction between piperonal and the derivative of triphenylphosphonium propyl bromide and dibutyldisulfide, followed by hydrolysis in a HCl/acetic acid mixture, but the yields were no better, Efforts to prepare this ketone by the iron and acid reduction of the appropriate nitrostyrene

  (1-(3,4-methylenedioxyphenyl)-2-nitro-1-butene, mp 64-65 !C)
were thwarted by the consistently unsatisfactory yield of the precursor from the reaction between piperonal and 1-nitropropane.

  A stirred solution of 20 g anhydrous ammonium acetate and 4.6 g 1-(3,4-methylenedioxyphenyl)-2-butanone in 50 mL MeOH was treated with 1.57 g sodium cyanoborohydride. Droplets of HCl were added as needed to maintain the pH at approximately 6. The reaction mixture was made basic with the addition of 250 mL dilute NaOH and extracted with 3x100

  mL CH2Cl2. The pooled organic extracts were extracted with 2x100 mL

  dilute H2SO4, the pooled aqueous extracts made basic again, and extracted again with 2x100 mL CH2Cl2. Removal of the solvent gave a residue which was distilled to give 2.6 g of a colorless oil which was dissolved in 15 mL IPA, neutralized with concentrated HCl, and diluted with an equal volume of anhydrous Et2O. Crystals of 2-amino-1-(3,4-methylenedioxyphenyl)butane hydrochloride (J) separated slowly. After filtering, Et2O washing, and air drying there was obtained 2.8 g of white crystals that melted at 159-161 !C. Anal.

  (C11H16ClNO2) C,H,N.

  DOSAGE: 150 - 230 mg.

  DURATION: 4 - 8 h.

  QUALITATIVE COMMENTS: (with 175 mg) The first stirrings were evident in a half hour, pleasant feelings, and without any untoward body effects. Within another half hour I was at a plus 2 and there it leveled off. I would be reluctant to drive a car, but I could were it necessary. There were no visual distortions, no giddiness, no introspective urges, and no rise to a psychedelic intoxication of any significance. After about an hour and a half at this level, I gradually dropped back over another two hours. Afterwards I was quite fatigued and languorous.