Pihkal

by Alexander Shulgin

  Does this make sense?

  The three carbon sticking out job gives rise to MDA and to MDMA and to many homologues that are interesting materials discussed at length in these Book II comments. This is the usual item of commerce, available from both domestic and foreign suppliers. But the four-carbon sticking out job will produce totally weird stuff without any apparent relationship to psychedelics, psychoactives or psychotropics whatsoever. I know of one chemical supply house which supplied the weird compound, and they never did acknowledge their unusual use of the term piperonyl. There is a simple difference of properties which might be of value. The three carbon (correct) ketone is an oil with a sassafras smell that is always yellow colored. The four carbon (incorrect) ketone has a weak terpene smell and is white and crystalline. There should be no difficulties in distinguishing these two compounds. But unprincipled charlatans can always add mineral oil and butter yellow to otherwise white solids to make them into yellow oils. Caveat emptor.

  110 MDMC; EDMA; 3,4-ETHYLENEDIOXY-N-METHYLAMPHETAMINE

  SYNTHESIS: To a solution of 27.6 g protocatechualdehyde (3,4-dihydroxybenzaldehyde) in 250 mL acetone there was added 57 g finely powdered anhydrous K2CO3 and 43 g 1,2-dibromoethane. The mixture was held at reflux for 16 h, and then the acetone removed by evaporation. The remaining tar-like goo was distributed between equal volumes of H2O and CH2Cl2, and the phases separated by centrifugation.

  The organic phase was washed with 2x50 mL 5% NaOH, and the solvent removed under vacuum. The residue (22.0 g with the smell of the starting halide) was distilled to give a fraction that boiled at 110

  !C at 0.25 mm/Hg to yield 3,4-ethylenedioxybenzaldehyde (1,4-benzodioxane-6-carboxaldehyde) as a white oil weighing 6.88 g.

  This spontaneously crystallized to give white solids that melted at 50-51 !C.

  A solution of 6.64 g 3,4-ethylenedioxybenzaldehyde in 40 mL

  nitroethane was treated with 0.26 g anhydrous ammonium acetate and held at reflux for 3 days. TLC analysis showed that there was much aldehyde remaining unreacted, so an additional 0.7 g ammonium acetate was added, and the mixture held at reflux for an additional 6 h. The excess nitroethane was removed under vacuum. The residue was dissolved in 30 mL hot MeOH which, with patience and slow cooling, finally deposited a heavy yellow-gold powder. This product 1-(3,4-ethylenedioxyphenyl)-2-nitro-propene melted at 95-96 !C and weighed 6.03 g when air dried to constant weight. Recrystallization from either MeOH or EtOAc gave the product as a yellow solid, but without any improvement in mp.

  A solution of 4.0 g of 1-(3,4-ethylenedioxyphenyl)-2-nitropropene was made in 30 mL warm acetic acid. This was added to a suspension of 16

  g elemental electrolytic iron in 75 mL acetic acid. The mixture was heated on the steam bath, and an exothermic reaction set in at about 70 !C. Heating was continued and the reaction allowed to proceed until the mass was a thick gray color and a dirty scum had been formed on the surface. After about 2 h, the entire mix was poured into 2 L

  H2O and filtered free of a little residual unreacted iron which was washed with CH2Cl2. The filtrate and washes were extracted with 3x100

  mL CH2Cl2 and the pooled organic extracts washed with 2x50 mL 5% NaOH.

  Removal of the solvent gave 3.38 g of an amber oil which was distilled. The product 1-(3,4-ethylenedioxyphenyl)-2-propanone distilled as a white oil, at 105-110 !C at 0.2 mm/Hg. It weighed 2.74

  g.

  To 2.0 g. of 1 inch squares of light-weight aluminum foil there was added a solution of 50 mg mercuric chloride in 70 mL water. After standing at room temperature for 30 min, the H2O was drained away, and the amalgamated aluminum washed twice with H2O, and shaken as dry as possible. There was then added, promptly and in immediate sequence, a solution of 3 g methylamine hydrochloride in 3 mL H2O, 9 mL IPA, 7.25

  mL 25% NaOH, 2.70 g of 1-(3,4-ethylenedioxyphenyl)-2-propanone, and 18

  mL IPA. The mixture was heated on the steam bath until an exothermic reaction set in, and then it was continuously swirled as the reaction proceeded. When the aluminum was consumed, there was a colorless gray sludge, and this was filtered and washed with 2x10 mL MeOH. The combined mother liquors and washes were stripped of solvent under vacuum. The two phase residue was suspended in 400 mL H2O containing sufficient H2SO4 to make the resulting water solution acidic to pH

  paper. This was washed with 3x50 mL CH2Cl2, made basic with 25% NaOH, and the product extracted with 3x50 mL CH2Cl2. The resulting 3.01 g slightly amber residue oil was distilled at 110-120 !C at 0.25 mm/Hg to give 2.53 g of a white oil, which did not appear to absorb carbon dioxide. This was dissolved in 12 mL IPA, neutralized with 1 mL

  concentrated HCl and diluted with anhydrous Et2O to the point of initial turbidity. There separated white crystals of 3,4-ethylenedioxy-N-methylamphetamine hydrochloride (MDMC) which weighed, when air dried to constant weight, 2.53 g.

  DOSAGE: 200 or more mg.

  DURATION: 3 - 5 h.

  QUALITATIVE COMMENTS: (with 150 mg) A flood of paresthesia at the 30

  minute point, and then nothing. There was the development of a plus one-and-a half effect over the next hour with the tendency to drift into a dozing state with hypnogogic imagery. There were colored letters in the periphery of my visual field. There was no appetite loss nor was there any blood pressure rise. And no eye jiggle or teeth clenching. I was out of the experience in 4 to 5 hours. A repeat of this level a few days later gave a bare possible threshold with no other effects.

  (with 200 mg) There was something unmistakable at 45 minutes, with hints of nystagmus. Possibly MDMA-like, with no indicators of anything psychedelic. Subtle return to baseline, and there were no after-effects.

  (with 250 mg) Alert at 40 minutes, and to a clear ++ at an hour.

  Slight something in the eye muscles. Dropping thirty minutes later, and baseline at three hours.

  (with 250 mg) I am at a bare threshold at best.

  EXTENSIONS AND COMMENTARY: What a strange and completely unsatisfactory compound! In the original run-up from low levels to increasing higher levels, there never was a dosage that was a minus, that had no effect. At every level, something was thought to be there, usually at a level of a single plus or thereabouts. But with different people, different responses. There is no way of guessing what an active level might be, or how consistent that level might be between different people, or for that matter what the responses are that might be expected at that level.

  This was yet one more effort to find an MDMA-like substitute by the miniscule manipulation of the MDMA molecule. Perhaps a small molecular change might leave the particular magic of the MDMA action alone, but eliminate the serotonin neuron problem in test animals.

  Maybe the serotonin neuron change is essential for MDMA to have the action it has. Who can tell?

  The original name that this compound got, during the several explorations of MDMA analogues, was based on the nickname for MDMA which was Adam. HADUEM was mentioned with the hydroxy compound, MADAM

  with the 6-methyl homologue, and FLADAM with the 6-fluoro analogue.

  This compound got the sobriquet MACADAM from that horrible black gooey mess generated at the aldehyde stage. This was shortened to RCS and eventually the RCS was added to the MDMA parent name. Thus, MDMC. It doesnUt really make sense; EDMA is more reasonable. But then there is no reason why MDMC should make sense.

  111 MDMEO; N-METHOXY-MDA; 3,4-METHYLENEDIOXY-N-METHYOXYAMPHETAMINE

  SYNTHESIS: To a solution of 20.9 g methoxyamine hydrochloride in 75 mL

  MeOH (a strongly acidic solution) there was added 4.45 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.10 g sodium cyanoborohydride. There was the immediate formation of a solid phase, and the evolution of what appeared to be hydrogen cyanide. To this there were added about 4 mL 5% NaOH which brought the pH to the vicinity of 3 or 4. Another 1.0 g of sodium cyanoborohydride was added (no gas evolution this time) and stirring was continued at ambient temperature for 6 days. All was added to 500

>   mL H2O, acidified with 10 mL HCl, and extraction with 3x100 mL CH2Cl2

  removed almost all the color. The aqueous phase was made basic with 25% NaOH, and extracted with 4x100 mL CH2Cl2. Evaporation of the solvent from these extracts yielded 1.8 g of a pale yellow oil which, on distillation at 90-95 !C at 0.5 mm/Hg, gave a 1.6 g fraction of an absolutely white, viscous, clear oil. This was dissolved in 8 mL IPA and neutralized with concentrated HCl. The product was an exceptionally weak base, and appropriate end points must be respected on the external pH paper (yellow to red, rather than purple to orange). Anhydrous Et2O was added to the point of turbidity, and as soon as crystallization had actually started, more Et2O was added with stirring, for a net total of 200 mL. After a couple of h standing, the fine white crystalline 3,4-methylenedioxy-N-methoxyamphetamine hydrochloride (MDMEO) was removed by filtration, Et2O washed, and air dried to constant weight. There was obtained 1.7 g of a product with a mp of 143-146 !C. The proton NMR was excellent with the N-methoxyl group a sharp singlet at 4.06 ppm. Anal. (C11H16ClNO3) N.

  DOSAGE: greater than 180 mgs.

  DURATION: unknown

  EXTENSIONS AND COMMENTARY: Why the interest in the N-methoxy analogue of MDA? There are several reasons. One, this is an isostere of MDE

  and it would be interesting to see if it might serve as a primer to the promotion of the effectiveness of other drugs (see primer discussion under MDPR). In one experiment, wherein a 60 microgram dosage of LSD was used an hour and a half after a 180 milligram load of MDMEO, there was no augmentation of effects. Thus, it would appear not to be a primer. Another reason for interest was that the material, although having an extremely similar overall structure to most of the active MD-series compounds, is very much a weaker base.

  And MDOH, which is also a very much weaker base than MDA, still shows the action and potency of MDA. And, as this compound appears to be inactive, base strength is not a sole predictor of activity.

  The ultimate reason for making MDMEO was, of course, that it could be made. That reason is totally sufficient all by itself.

  112 MDMEOET; N-METHOXYETHYL-MDA;

  3,4-METHYLENEDIOXY-N-(2-METHOXYETHYL)AMPHETAMINE

  SYNTHESIS: A crude solution of methoxyethylamine hydrochloride was prepared from 17.7 g methoxyethylamine and 20 mL concentrated HCl with all volatiles removed under vacuum. This was dissolved in 75 mL MeOH

  and there was added 4.45 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.3 g sodium cyanoborohydride. Concentrated HCl in MeOH was added as required to maintain the pH at about 6 as determined with external, dampened universal pH paper. About 4.5 mL were added over the course of 5

  days, at which time the pH had stabilized. The reaction mixture was added to 400 mL H2O and made strongly acidic with an excess of HCl.

  After washing with 2x100 mL CH2Cl2 the aqueous phase was made basic with 25% NaOH, and extracted with 4x75 mL CH2Cl2. Removal of the solvent under vacuum yielded 6.0 g of an amber oil that was distilled at 110-120 !C at 0.2 mm/Hg. There was obtained 4.7 g of a crystal-clear white oil that was dissolved in 30 mL IPA and neutralized with 45 drops of concentrated HCl producing a heavy mass of spontaneous crystals that had to be further diluted with IPA just to be stirred with a glass rod. These were diluted with 200 mL of anhydrous Et2O, removed by filtration, and washed with additional Et2O. After air drying there was obtained 4.9 g of 3,4-methylenedioxy-N-(2-methoxyethyl)amphetamine hydrochloride (MDMEOET) with a mp of 182.5-183 !C. Anal. (C13H20ClNO3) N.

  DOSAGE: greater than 180 mg.

  DURATION: unknown.

  EXTENSIONS AND COMMENTARY: This is another example of the replacement of a neutral atom out near the end of a chain, with a more basic and a more polar one. MDMEOET would be called an isostere of MDBU in that it has the same shape, with a methylene unit (the CH2) replaced by an oxygen atom. No activity turned up with either compound, so nothing can be learned from this particular example of change of polarity.

  113 MDMP; a,a,N-TRIMETHYL-3,4-METHYLENEDIOXY-PHENETHYLAMINE; METHYLENEDIOXYMEPHENTERMINE

  SYNTHESIS: To a well stirred solution of 1.64 g of 1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane (see under MDPH for its preparation) in 10 mL anhydrous THF there was added a suspension of 0.38 g LAH in 25 mL THF. All was held at reflux for 24 h, the excess hydride was destroyed by the addition of 1.5 mL

  H2O, and sufficient aqueous NaOH was added to make the reaction mixture basic and flocculant enough to be filterable. The inorganic solids were removed by filtration and, following washing with THF, the combined filtrate and washings were stripped of organic solvent under vacuum. The residue was dissolved in 100 mL Et2O and washed with 2x50

  mL saturated aqueous NaHCO3. After drying the organic phase with anhydrous MgSO4, the solvent was removed under vacuum to give a yellow oil. This was dissolved in 50 mL absolute EtOH and neutralized with concentrated HCl. Removal of the solvent under vacuum yielded an off-white solid that was recrystallized from an EtOH/EtOAc mixture to provide 0.84 g of a,a,N-trimethyl-3,4-methylenedioxyphenethylamine hydrochloride (MDMP) with a mp of 206-208 !C. The NMR spectrum showed the a,a-dimethyl pair as a singlet at 1.38 ppm. Anal. (C12H18ClNO2) C,H,N.

  DOSAGE: above 110 mg.

  DURATION: perhaps 6 hours.

  QUALITATIVE COMMENTS: (with 60 mg) There was a faint, dull alerting at just over a half hour. The time sense was out of order, and an absence of visuals but a generalized attentiveness to my surroundings was suggestive of MDMA. Nothing remained at the six hour point.

  (with 110 mg) There was a light-headedness, and a complete absence of libido. Nothing in any way psychedelic, but there are hints of discomfort (jaw tension) that will bear close watching at higher dosages. It might evolve at higher levels into something like MDMA.

  EXTENSIONS AND COMMENTARY: This is one of several candidates for clinical use as a substitute for MDMA, but there will have to be a much broader study of its qualitative action in man. It is clearly not psychedelic at these modest levels, and in in vitro animal studies it was apparently inactive as a serotonin releaser. The warped logic for looking at phentermine analogs was discussed in the comments that concerned MDPH. The initials used here have been chosen with care.

  MDM should not be used as it has found some currency as an abbreviation for MDMA (Methylene-Dioxy-Methamphetamine). MDMP fits neatly with Methylene-Dioxy-Me-Phentermine.

  114 MDOH; N-HYDROXY-MDA; 3,4-METHYLENEDIOXY-N-HYDROXYAMPHETAMINE

  SYNTHESIS: To a well stirred solution of 14.8 g hydroxylamine hydrochloride in 120 mL MeOH there was added 3.6 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.0 g sodium cyanoborohydride. The oxime, prepared from the ketone and hydroxylamine in MeOH with pyridine, may be substituted for these two components. Concentrated HCl was added over the course of a couple of days, to keep the pH near neutrality. When the reaction was complete, it was added to H2O, made strongly acidic with HCl, and washed with 3x100 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and reextracted with 3x100 mL of CH2Cl2. The extracts were pooled, and the solvent removed under vacuum to give 1.7

  g of an oily residue which, with pumping under a hard vacuum for a few minutes, changed to a white solid. This can be Kugelrohred if the vacuum is sufficiently good to keep the temperature during the distillation below 100 !C. The extremely viscous distillate formed crystals immediately upon wetting with IPA. It was dissolved in 20 mL

  of warm IPA and neutralized with concentrated HCl, with the titration end-point being red rather than orange on universal pH paper. Modest addition of Et2O allowed the formation of 3,4-methylenedioxy-N-hydroxyamphetamine hydrochloride (MDOH) as white crystals, which weighed 1.4 g when air dried. If the temperature of distillation exceeded 100 !C, there was extensive decomposition during distillation, with the formation of 3,4-methylenedioxyamphetamine (MDA) and the oxime of the ketone. Under these circumstances, the only base isolated was MDA. The surest isolation procedure was
to obtain MDOH as the free base, as a crystalline solid which could be recrystallized from 5 volumes of boiling IPA. The free base had a mp of 94-95 !C (and should not be confused with the oxime of 3,4-methylenedioxyphenylacetone which has a mp of 86-88 !C since the mixed mp is depressed, mp 56-62 !C, or with the free base of MDA which is an oil). Anal. (C10H13NO3) N. The hydrochloride salt had a mp of 149-150 !C (and should not be confused with the hydrochloride of MDA which has a mp of 185-186 !C since the mixed mp is depressed, mp 128-138 !C). Anal. (C10H14ClNO3) N. Acetic anhydride can serve as a useful tool for distinguishing these materials. MDA gives an N-acetyl derivative with an mp of 92-93 !C. MDOH gives an N,O-diacetyl derivative with a mp of 72-74 !C. Methylenedioxyphenylacetone oxime gives an O-acetyl derivative that is an oil.

  DOSAGE: 100 - 160 mg.

  DURATION: 3 - 6 h.

  QUALITATIVE COMMENTS: (with 100 mg) I felt hampered the first hour by some internal barrier, which prevented total enjoyment. However, this began to break through in a wonderful way just before the supplement was offered. Since I felt I was beginning to move through the barrier, I declined the supplement, particularly since I was anxious to compare the after-effects with my first experience. I had found the first time very remarkable, but felt unusually tired for several days following. I feel it is important to know whether this is a specific drug-induced effect, or the result of psychological phenomena. The experience continued in a rich, meaningful way. There was a marvelous inner glow, the warmth from all the other participants was wonderful to feel, nature was most beautiful. There were no dramatic breakthroughs, or rushes of insight or energy, but just a wonderful contemplative space where things gently unfolded as you put your attention on them.