This is 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 this file. 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. A SHORT INDEX TO THE PHENETHYLAMINES This short index to the phenethylamines lists the 179 entries that follow in alphebetical order. The abbreviation PEA is for phenethylamine, and A is for amphetamine. The long index includes all synonyms and is in Appendix A. Code Compact chemical name 1 AEM a-Ethyl-3,4,5-trimethoxy-PEA 2 AL 4-Allyloxy-3,5-dimethoxy-PEA 3 ALEPH 4-Methylthio-2,5-dimethoxy-A 4 ALEPH-2 4-Ethylthio-2,5-dimethoxy-A 5 ALEPH-4 4-Isopropylthio-2,5-dimethoxy-A 6 ALEPH-6 4-Phenylthio-2,5-dimethoxy-A 7 ALEPH-7 4-Propylthio-2,5-dimethoxy-A 8 ARIADNE 2,5-Dimethoxy-a-ethyl-4-methyl-PEA 9 ASB 3,4-Diethoxy-5-methoxy-PEA 10 B 4-Butoxy-3,5-dimethoxy-PEA 11 BEATRICE 2,5-Dimethoxy-4,N-dimethyl-A 12 BIS-TOM 2,5-Bismethylthio-4-methyl-A 13 BOB 4-Bromo-2,5,beta-trimethoxy-PEA 14 BOD 2,5,beta-Trimethoxy-4-methyl-PEA 15 BOH beta-Methoxy-3,4-methylenedioxy-PEA 16 BOHD 2,5-Dimethoxy-beta-hydroxy-4-methyl-PEA 17 BOM 3,4,5,beta-Tetramethoxy-PEA 18 4-Br-3,5-DMA 4-Bromo-3,5-dimethoxy-A 19 2-Br-4,5-MDA 2-Bromo-4,5-methylenedioxy-A 20 2C-B 4-Bromo-2,5-dimethoxy-PEA 21 3C-BZ 4-Benzyloxy-3,5-dimethoxy-A 22 2C-C 4-Chloro-2,5-dimethoxy-PEA 23 2C-D 4-Methyl-2,5-dimethoxy-PEA 24 2C-E 4-Ethyl-2,5-dimethoxy-PEA 25 3C-E 4-Ethoxy-3,5-dimethoxy-A 26 2C-F 4-Fluoro-2,5-dimethoxy-PEA 27 2C-G 3,4-Dimethyl-2,5-dimethoxy-PEA 28 2C-G-3 3,4-Trimethylene-2,5-dimethoxy-PEA 29 2C-G-4 3,4-Tetramethylene-2,5-dimethoxy-PEA 30 2C-G-5 3,4-Norbornyl-2,5-dimethoxy-PEA 31 2C-G-N 1,4-Dimethoxynaphthyl-2-ethylamine 32 2C-H 2,5-Dimethoxy-PEA 33 2C-I 4-Iodo-2,5-dimethoxy-PEA 34 2C-N 4-Nitro-2,5-dimethoxy-PEA 35 2C-O-4 4-Isopropoxy-2,5-dimethoxy-PEA 36 2C-P 4-Propyl-2,5-dimethoxy-PEA 37 CPM 4-Cyclopropylmethoxy-3,5-dimethoxy-PEA 38 2C-SE 4-Methylseleno-2,5-dimethoxy-PEA 39 2C-T 4-Methylthio-2,5-dimethoxy-PEA 40 2C-T-2 4-Ethylthio-2,5-dimethoxy-PEA 41 2C-T-4 4-Isopropylthio-2,5-dimethoxy-PEA 42 gamma-2C-T-4 4-Isopropylthio-2,6-dimethoxy-PEA 43 2C-T-7 4-Propylthio-2,5-dimethoxy-PEA 44 2C-T-8 4-Cyclopropylmethylthio-2,5-dimethoxy-PEA 45 2C-T-9 4-(t)-Butylthio-2,5-dimethoxy-PEA 46 2C-T-13 4-(2-Methoxyethylthio-2,5-dimethoxy-PEA 47 2C-T-15 4-Cyclopropylthio-2,5-dimethoxy-PEA 48 2C-T-17 4-(s)-Butylthio-2,5-dimethoxy-PEA 49 2C-T-21 4-(2-Fluoroethylthio)-2,5-dimethoxy-PEA 50 4-D 4-Trideuteromethyl-3,5-dimethoxy-PEA 51 beta-D beta,beta-Dideutero-3,4,5-trimethoxy-PEA 52 DESOXY 4-Me-3,5-Dimethoxy-PEA 53 2,4-DMA 2,4-Dimethoxy-A 54 2,5-DMA 2,5-Dimethoxy-A 55 3,4-DMA 3,4-Dimethoxy-A 56 DMCPA 2-(2,5-Dimethoxy-4-methylphenyl)- cyclopropylamine 57 DME 3,4-Dimethoxy-beta-hydroxy-PEA 58 DMMDA 2,5-Dimethoxy-3,4-methylenedioxy-A 59 DMMDA-2 2,3-Dimethoxy-4,5-methylenedioxy-A 60 DMPEA 3,4-Dimethoxy-PEA 61 DOAM 4-Amyl-2,5-dimethoxy-A 62 DOB 4-Bromo-2,5-dimethoxy-A 63 DOBU 4-Butyl-2,5-dimethoxy-A 64 DOC 4-Chloro-2,5-dimethoxy-A 65 DOEF 4-(2-Fluoroethyl)-2,5-dimethoxy-A 66 DOET 4-Ethyl-2,5-dimethoxy-A 67 DOI 4-Iodo-2,5-dimethoxy-A 68 DOM 4-Methyl-2,5-dimethoxy-A 69 gamma-DOM 4-Methyl-2,6-dimethoxy-A 70 DON 4-Nitro-2,5-dimethoxy-A 71 DOPR 4-Propyl-2,5-dimethoxy-A 72 E 4-Ethoxy-3,5-dimethoxy-PEA 73 EEE 2,4,5-Triethoxy-A 74 EEM 2,4-Diethoxy-5-methoxy-A 75 EME 2,5-Diethoxy-4-methoxy-A 76 EMM 2-Ethoxy-4,5-dimethoxy-A 77 ETHYL-J N,a-diethyl-3,4-methylenedioxy-PEA 78 ETHYL-K N-Ethyl-a-propyl-3,4-methylenedioxy-PEA 79 F-2 Benzofuran-2-methyl-5-methoxy-6- (2-aminopropane) 80 F-22 Benzofuran-2,2-dimethyl-5-methoxy-6- (2-aminopropane) 81 FLEA N-Hydroxy-N-methyl-3,4-methylenedioxy-A 82 G-3 3,4-Trimethylene-2,5-dimethoxy-A 83 G-4 3,4-Tetramethylene-2,5-dimethoxy-A 84 G-5 3,4-Norbornyl-2,5-dimethoxy-A 85 GANESHA 3,4-Dimethyl-2,5-dimethoxy-A 86 G-N 1,4-Dimethoxynaphthyl-2-isopropylamine 87 HOT-2 2,5-Dimethoxy-N-hydroxy-4-ethylthio-PEA 88 HOT-7 2,5-Dimethoxy-N-hydroxy-4-(n)-propylthio-PEA 89 HOT-17 2,5-Dimethoxy-N-hydroxy-4-(s)-butylthio-PEA 90 IDNNA 2,5-Dimethoxy-N,N-dimethyl-4-iodo-A 91 IM 2,3,4-Trimethoxy-PEA 92 IP 3,5-Dimethoxy-4-isopropoxy-PEA 93 IRIS 5-Ethoxy-2-methoxy-4-methyl-A 94 J a-Ethyl-3,4-methylenedioxy-PEA 95 LOPHOPHINE 3-Methoxy-4,5-methylenedioxy-PEA 96 M 3,4,5-Trimethoxy-PEA 97 4-MA 4-Methoxy-A 98 MADAM-6 2,N-Dimethyl-4,5-methylenedioxy-A 99 MAL 3,5-Dimethoxy-4-methallyloxy-PEA 100 MDA 3,4-Methylenedioxy-A 101 MDAL N-Allyl-3,4-methylenedioxy-A 102 MDBU N-Butyl-3,4-methylenedioxy-A 103 MDBZ N-Benzyl-3,4-methylenedioxy-A 104 MDCPM N-Cyclopropylmethyl-3,4-methylenedioxy-A 105 MDDM N,N-Dimethyl-3,4-methylenedioxy-A 106 MDE N-Ethyl-3,4-methylenedioxy-A 107 MDHOET N-(2-Hydroxyethyl)-3,4-methylenedioxy-A 108 MDIP N-Isopropyl-3,4-methylenedioxy-A 109 MDMA N-Methyl-3,4-methylenedioxy-A 110 MDMC N-Methyl-3,4-ethylenedioxy-A 111 MDMEO N-Methoxy-3,4-methylenedioxy-A 112 MDMEOET N-(2-Methoxyethyl)-3,4-methylenedioxy-A 113 MDMP a,a,N-Trimethyl-3,4-methylenedioxy-PEA 114 MDOH N-Hydroxy-3,4-methylenedioxy-A 115 MDPEA 3,4-Methylenedioxy-PEA 116 MDPH a,a-Dimethyl-3,4-methylenedioxy-PEA 117 MDPL N-Propargyl-3,4-methylenedioxy-A 118 MDPR N-Propyl-3,4-methylenedioxy-A 119 ME 3,4-Dimethoxy-5-ethoxy-PEA 120 MEDA 3,4-Ethylenedioxy-5-methoxy-A 121 MEE 2-Methoxy-4,5-diethoxy-A 122 MEM 2,5-Dimethoxy-4-ethoxy-A 123 MEPEA 3-Methoxy-4-ethoxy-PEA 124 META-DOB 5-Bromo-2,4-dimethoxy-A 125 META-DOT 5-Methylthio-2,4-dimethoxy-A 126 METHYL-DMA N-Methyl-2,5-dimethoxy-A 127 METHYL-DOB 4-Bromo-2,5-dimethoxy-N-methyl-A 128 METHYL-J N-Methyl-a-ethyl-3,4-methylenedioxy-PEA 129 METHYL-K N-Methyl-a-propyl-3,4-methylenedioxy-PEA 130 METHYL-MA N-Methyl-4-methoxy-A 131 METHYL-MMDA-2 N-Methyl-2-methoxy-4,5- methylenedioxy-A 132 MMDA 3-Methoxy-4,5-methylenedioxy-A 133 MMDA-2 2-Methoxy-4,5-methylenedioxy-A 134 MMDA-3a 2-Methoxy-3,4-methylenedioxy-A 135 MMDA-3b 4-Methoxy-2,3-methylenedioxy-A 136 MME 2,4-Dimethoxy-5-ethoxy-A 137 MP 3,4-Dimethoxy-5-propoxy-PEA 138 MPM 2,5-Dimethoxy-4-propoxy-A 139 ORTHO-DOT 2-Methylthio-4,5-dimethoxy-A 140 P 3,5-Dimethoxy-4-propoxy-PEA 141 PE 3,5-Dimethoxy-4-phenethyloxy-PEA 142 PEA PEA 143 PROPYNYL 4-Propynyloxy-3,5-dimethoxy-PEA 144 SB 3,5-Diethoxy-4-methoxy-PEA 145 TA 2,3,4,5-Tetramethoxy-A 146 3-TASB 4-Ethoxy-3-ethylthio-5-methoxy-PEA 147 4-TASB 3-Ethoxy-4-ethylthio-5-methoxy-PEA 148 5-TASB 3,4-Diethoxy-5-methylthio-PEA 149 TB 4-Thiobutoxy-3,5-dimethoxy-PEA 150 3-TE 4-Ethoxy-5-methoxy-3-methylthio-PEA 151 4-TE 3,5-Dimethoxy-4-ethylthio-PEA 152 2-TIM 2-Methylthio-3,4-dimethoxy-PEA 153 3-TIM 3-Methylthio-2,4-dimethoxy-PEA 154 4-TIM 4-Methylthio-2,3-dimethoxy-PEA 155 3-TM 3-Methylthio-4,5-dimethoxy-PEA 156 4-TM 4-Methylthio-3,5-dimethoxy-PEA 157 TMA 3,4,5-Trimethoxy-A 158 TMA-2 2,4,5-Trimethoxy-A 159 TMA-3 2,3,4-Trimethoxy-A 160 TMA-4 2,3,5-Trimethoxy-A 161 TMA-5 2,3,6-Trimethoxy-A 162 TMA-6 2,4,6-Trimethoxy-A 163 3-TME 4,5-Dimethoxy-3-ethylthio-PEA 164 4-TME 3-Ethoxy-5-methoxy-4-methylthio-PEA 165 5-TME 3-Ethoxy-4-methoxy-5-methylthio-PEA 166 2T-MMDA-3a 2-Methylthio-3,4-methylenedioxy-A 167 4T-MMDA-2 4,5-Thiomethyleneoxy-2-methoxy-A 168 TMPEA 2,4,5-Trimethoxy-PEA 169 2-TOET 4-Ethyl-5-methoxy-2-methylthio-A 170 5-TOET 4-Ethyl-2-methoxy-5-methylthio-A 171 2-TOM 5-Methoxy-4-methyl-2-methylthio-A 172 5-TOM 2-Methoxy-4-methyl-5-methylthio-A 173 TOMSO 2-Methoxy-4-methyl-5-methylsulfinyl-A 174 TP 4-Propylthio-3,5-dimethoxy-PEA 175 TRIS 3,4,5-Triethoxy-PEA 176 3-TSB 3-Ethoxy-5-ethylthio-4-methoxy-PEA 177 4-TSB 3,5-Diethoxy-4-methylthio-PEA 178 3-T-TRIS 4,5-Diethoxy-3-ethylthio-PEA 179 4-T-TRIS 3,5-Diethoxy-4-ethylthio-PEA PHENETHYLAMINES #1 AEM; a-ETHYLMESCALINE; 2-AMINO-1-(3,4,5-TRIMETHOXYPHENYL)BUTANE; 1-(3,4,5-TRIMETHOXYPHENYL)-2-AMINOBUTANE SYNTHESIS: To a solution of 45 g 3,4,5-trimethoxybenzaldehyde in 1.2 L IPA, there was added 125 g nitropropane and 67.5 g t-butylammonium acetate and the reaction mixture was held at reflux for 16 h. This was poured into 6 L H2O, and extracted with 2x250 mL hexane. The pooled extracts were stripped of solvent under vacuum giving a residue that slowly set to a crystalline mass. On filtering, there was obtained 9.4 g of a crude yellow product which, on recrystallization from hexane provided 8.7 g of slightly sticky bright yellow crystals of 2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1, with a mp of 71-73 deg C. A second recrystallization from hexane gave fine yellow crystals with a mp of 72-73 deg C. Attempts at the preparation of this nitrostyrene by the more conventional methods with ammonium acetate in acetic acid led either to the formation of a white product C23H30N2O8 which was composed of a molecule of the nitrostyrene, one of the benzaldehyde itself, and a molecule of ammonia, or to 3,4,5-trimethoxybenzonitrile, from reaction with the decomposition products of nitropropane. A stirred suspension of 5.9 g LAH in 310 mL anhydrous Et2O was held at a gentle reflux in an inert atmosphere. A solution of 8.5 g 2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1 in 125 mL Et2O is added drop-wise over the course of 0.5 h. The reaction was maintained at reflux for 6 h, then cooled, and the excess hydride destroyed by the cautious addition of 300 mL 1.8 N H2SO4. The phases were separated, and the aqueous phase brought to a pH of 6 by the addition of a saturated Na2CO3 solution. The neutral solution was brought to a boil, and clarified by filtration through paper. To the hot filtrate there was added a solution of 8.9 g picric acid in 100 mL boiling EtOH. The mixture was stirred and cooled, with the formation of a heavy yellow crystalline mass. After standing in the ice tub for several hours the mixture was filtered, providing 8.0 g of the picrate salt with a mp of 176-181 deg C from H2O. A solution of this salt in 300 mL boiling H2O was treated with 60 mL concentrated HCl. On cooling, there was a deposition of picric acid, which was removed by filtration. The aqueous filtrate was washed with 3x50 mL nitrobenzene, then with 3x50 mL Et2O. The pH was brought above 9 by the addition of aqueous NaOH, and the filtrate was extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a nearly colorless oil, which was dissolved in 300 mL anhydrous Et2O and saturated with hydrogen chloride gas. The white crystals of 2-amino-1-(3,4,5-trimethoxyphenyl)butane hydrochloride (AEM) were removed by filtration, Et2Owashed, and air dried. They weighed 4.72 g. DOSAGE: greater than 220 mg. DURATION: unknown. EXTENSIONS AND COMMENTARY: The extension of the two-carbon chain of mescaline by alpha-methylation to the three carbon chain of TMA approximately doubled the potency of the compound. And it was felt to be a completely logical possibility that, by extending it one more carbon atom, to the four carbon chain of alpha-ethyl-mescaline, it might double again. And following that logical progression, the doubling of potency with each additional carbon atom, the factor would be 2 to the 7th power by the alpha-octyl (or 256x that of mescaline, or a milligram as active dose) and with a side chain of a 70-carbon alkyl group (alpha-heptacontylmescaline) it would take just a single molecule to be intoxicating. This was rich fantasy stuff. As an active compound, just where would it go in the brain? With an 80-carbon side-chain, would one-thousandth of a single molecule be enough for a person? Or might a single molecule intoxicate a thousand people? And how long a chain on the alpha-position might be sufficient that, by merely writing down the structure on a piece of paper, you would get high? Maybe just conceiving the structure in your mind would do it. That is, after all, the way of homeopathy. Maybe it was just as well that this added two-carbon side-chain with lowered activity was already enough to disprove the doubling pattern. But by the time this non-activity had been learned, the alpha series had already been pushed out quite aways. The machinery of making the appropriate nitroalkane was straightforward, by reaction of the alkyl halide with nitrous acid, and separating the unwanted nitrite ester from the wanted nitroalkane by fractional distillation. The nitrostyrenes all formed reasonably although often in terrible yields, and reduced reasonably, and all formed crystalline picrates for isolation and crystalline hydrochloride salts for pharmacological manipulation. But since the first of these, AEM, was not active, there was no enthusiasm for tasting anything higher. This family was never published; why publish presumably inactive and thus uninteresting material? The Table presents the properties of the precursor nitrostyrenes, and the product picrate and hydrochloride salts, at least whatever information I can still find after thirty years: TABLE. Physical Properties of the a-Alkylmescaline Homologues and their Precursor Nitrostyrenes Code Name NS mp deg C picrate mp deg C HCl mp deg C APM Alpha-propylmescaline 82-83 214-218 ABM Alpha-butylmescaline 73-74 169-174 182-184 AAM Alpha-amylmescaline 54-55 162-163 155-158 AHM Alpha-hexylmescaline 51-52 ASM* Alpha-heptylmescaline 43-44 AOM Alpha-octylmescaline ** ANM Alpha-nonylmescaline 46-47 *** AUM Alpha-undecylmescaline *** * S is for septyl, to distinguish heptyl from hexyl. **Never made, as no nonylbromide could be located to make the needed nitrononane. ***The synthesis got as far as the nitrostyrene stage when the inactivity of AEM was determined, and the project was dropped. #2 AL; 4-ALLYLOXY-3,5-DIMETHOXYPHENETHYLAMINE; 3,5-DIMETHOXY-4-ALLYLOXYPHENETHYLAMINE SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for its preparation), 100 mg decyltriethylammonium iodide, and 13.6 g allyl iodide in 50 mL anhydrous acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux for 16 h. The color changed from a near-black to a light yellow. The mixture was filtered, the solids washed with acetone, and the solvent from the combined filtrate and washes removed under vacuum. The residue was suspended in acidified H2O, and extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with 2x50 mL 5% NaOH, once with dilute HCl (which lightened the color of the extract) and then stripped of solvent under vacuum giving 12.4 g of an amber-colored oil. This was distilled at 125-137 deg C at 0.1 mm/Hg to yield 5.7 g of 3,5-dimethoxy-4-allyloxyphenylacetonitrile as a yellow oil. Anal. (C13H15NO3S) C,H. A suspension of 4.0 g LAH in 150 mL anhydrous THF under N2 was cooled to 0 deg C and vigorously stirred. There was added, dropwise, 2.8 mL 100% H2SO4, followed by 5.5 g 3,5-dimethoxy-4-allyloxyphenylacetonitrile in 10 mL anhydrous THF. The reaction mixture was stirred at 0 deg C for a few min, then brought to a reflux on the steam bath for 30 min. After cooling back to room temperature, there was added sufficient IPA to destroy the excess hydride, followed by sufficient 10% NaOH to form granular solids. These were removed by filtration, and washed with 20 mL IPA. The filtrate and washes were stripped of solvent under vacuum andthe residue added to 100 mL dilute H2SO4. This was washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and extracted with 2x75 mL CH2Cl2. These extracts were pooled, the solvent removed under vacuum, and the residue distilled at 110-120 deg C at 0.4 mm/Hg to give 4.9 g of a colorless oil. This was dissolved in 15 mL IPA, neutralized with concentrated HCl (55 drops required), and diluted with 50 mL Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 4.9 g of 3,5-dimethoxy-4-allyloxyphenethylamine hydrochloride (AL) as white crystals. DOSAGE: 20 - 35 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 24 mg) I first became aware of something in about 10 minutes, a pleasant increase in energy. By 20 minutes it was getting pronounced and was a nice, smooth development. During the next hour positive and negative feelings developed simultaneously. Following a suggestion, I ate a bit of food even though I had not been hungry, and to my surprise all the negative feelings dropped away. I felt free to join the others wherever they were at. I moved into the creative, free-flowing kind of repertoire which I dearly love, and found everything enormously funny. Much of the laughter was so deep that I felt it working through buried depressions inside me and freeing me. From this point on, the experience was most enjoyable. The experience was characterized by clear-headedness and an abundance of energy which kept on throughout the day and evening. At one point I went out back and strolled along to find a place to worship. I had a profound sense of the Presence and great love and gratitude for the place, the people, and the activities taking place. The come-down from the experience was very gradual and smooth. Food tasted wonderful. I went to bed late, and quite ready for bed, although the energy was still running. However, sleep was not long in coming. (with 24 mg) The onset was extremely gradual and graceful, with the first alert that one could really sense at about 50 minutes. This was succeeded by a slow gentle climb to the peak at one hour and fifteen minutes. The experience itself left all of the sensory modalities functional; speech was cogent and rather fluid. In fact, there was an unusual ease of free association. All throughout the session, the talk was high in spirits and somehow indicative of an inner excitement. Affect was entirely pleasant, but not exalting nor conducive to insight or to problem solving. There were no requirements for withdrawal into the self. The material seemed wholly social in nature. No visual, auditory or olfactory sharpening was in evidence. The plateau for this material seemed unusually long. I was unable to sleep for several hours, and took 25 mg Librium before sleep arrived. The next day was a lethargic and slow one, with the inner feeling that the effects had not worn off until the middle of the day following ingestion. (with 35 mg) I was a distinct +1 in 35 minutes and a +2 by the end of the hour. My head congestion in no way cleared up, absolving the material from having that particular virtue. The entire experience was somewhat dissociated Q I could not connect with my feelings. Although my mind remained clear, there was a hangover feeling at the end of the experiment. EXTENSIONS AND COMMENTARY: This compound was first explored in Prague by Leminger. He provided only the synthetic details and the statement that it was the most active compound that he had studied, with activity at 20 milligrams, with perceptual changes, color enhancement, and difficult dreams during sleep that night. Some effects persisted for more than 12 hours. Dosages above 35 milligrams remain unexplored. As AL is one of the most potent 3,4,5-trisubstituted phenethylamines yet described, and since the corresponding amphetamines are of yet greater potency, it would be a good guess that 4-allyloxy-3,5-dimethoxyamphetamine (3C-AL) would be an interesting compound to explore. It could be made from syringaldehyde in reaction with allyl iodide, followed by the formation of a nitrostyrene with nitroethane, followed by reduction with aluminum hydride. It is, as of the present time, both unsynthesized and unexplored. #3 ALEPH; DOT; PARA-DOT; 2,5-DIMETHOXY-4-METHYLTHIOAMPHETAMINE SYNTHESIS: A solution of 2.3 g 2,5-dimethoxy-4-(methylthio)benzaldehyde (see under 2C-T for its synthesis) in 7.5 mL nitroethane was treated with 0.45 g anhydrous ammonium acetate and heated on the steam bath for 6 h. The excess solvent/reagent was removed under vacuum leaving a mass of orange crystals as residue. These were ground up under 10 mL MeOH, col-lected by filtration, washed with a little MeOH, and air dried to provide 2.6 g crude 1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene. After recrystallization from 140 mL boiling MeOH, filtering and drying there was in hand 1.8 g of bright orange crystals with a mp of 137-138 deg C. Anal. (C12H15NO4S) C,H,N,S. A suspension of 1.4 g LAH in 10 mL anhydrous Et2O and 40 mL anhydrous THF was put under an inert atmosphere and, with good stirring, brought up to a gentle reflux. A solution of 1.8 g 1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene in 30 mL anhydrous THF was added dropwise at a rate that maintained the reflux. Heating and stirring were maintained for an additional 7 h, then the reaction mixture was allowed to return to room temperature. There was added 1.6 mL H2O (dissolved in a little THF), followed by 1.6 mL 15% NaOH, and finally another 4.8 mL H2O. Stirring was continued until all the curdy solids had turned white. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and the washings were combined, and the solvent removed under vacuum. The residue was 1.3 g of a colorless oil that solidified. Its mp of 90-93 deg C was improved slightly to 91-93 deg C with recrystallization from hexane. The product was dissolved in 25 mL warm IPA, neutralized with concentrated HCl (0.57 mL required) and then diluted with 100 mL anhydrous Et2O. After a moment's delay, the white crystalline product appeared. It was removed by filtration, washed with Et2O, and air dried to provide 1.2 g 2,5-dimethoxy-4-methylthioamphetamine hydrochloride (ALEPH) with a mp of 200-201 deg C. Recrystallization from IPA gave an analytical sample with a mp of 204-205 deg C. Anal. (C12H20ClNO2S) C,H; N: calcd, 5.04; found, 5.52. DOSAGE: 5 - 10 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 5 mg) The initial hints of action were physical Q warming of first the legs, and then a comfortable warmth spread over the entire body. Intense intellectual stimulation, one that inspired the scribbling of some 14 pages of handwritten notes. Which is a pretty good record for an experience that is almost entirely non-verbal. The afterglow was benign and rich in empathy for everything. And by the sixth hour I was quite hungry. (with 10 mg) There was a rapid shift of frame of reference that made simple tasks such as reading and tuning the radio quite alien. I happened to catch the eyes of Pretty Baby, the cat, at the same moment she looked at me, and she turned and fled. I am able to interact with people on the telephone quite well but mechanical things, such as arranging flowers or alphabetizing names, are beyond me. Driving would be impossible. EXTENSIONS AND COMMENTARY: This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as a potentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level, specifically at 0.25 micrograms, at 11:30 AM on September 3, 1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom in a phenethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the final product in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at a time. Maybe dust in the air? Maybe some skin contact with the free base? Now, I know there was nothing, but the possibility of extraordinary potency was real, and I did indeed wash everything down anyway. In fact, it took a total of 18 trials to work the experimental dosage up to as much as a single milligram. In retrospect, overly cautious. But retrospection, as they say, is cheap. The 5 milligram experiment, briefly quoted from above, is the stuff of Chapter 14 of this book, important in that it gives an interesting example of some thought processes associated with psychedelic intoxication, ego-inflation, and what might be thought of as bits of mania. As is always the case with peak experiences that happen to be catalyzed by drugs, this extraordinary event could not be duplicated. At 7 milligrams there was an uneventful +1, and some 10 milligrams was needed to generate a full +3 experience. The first clue of the erratic nature of the Aleph family came from an independent assay by a colleague of mine, one who was very familiar with such states of consciousness, but for whom this was not a time for peak experiences. At 10 milligrams he told me that he had had only mild effects which he found relatively uninteresting. As it stands, ALEPH remains relatively unexplored. Its two positional isomers are entered here as ORTHO-DOT and META-DOT. Three higher homologues have been more thoroughly looked at, and the generic name ALEPH (the first letter of the Hebrew alphabet) was given this group on the basis that they might have extraordinary properties in common. But the real treasure came in the exploring of the 2-carbon homologues, the compounds that make up the 2C-T family. Here, there proved to be much less uncertainty as to reasonable dosages, and much more richness in the subjective nature of the experience. #4 ALEPH-2; 2,5-DIMETHOXY-4-ETHYLTHIOAMPHETAMINE SYNTHESIS: A solution of 2.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde (see under 2C-T-2 for its synthesis) in 12 mL nitroethane was treated with 0.4 g anhydrous ammonium acetate and heated on the steam bath for 3 h. All volatiles were removed under vacuum, leaving a residue that set up as brilliant red crystals. These were mechanically removed from the evaporation flask, blown free of nitroethane vapor, and recrystallized from boiling EtOH, producing 1.8 g pale orange crystals, with a mp of 110-112 deg C. Recrystallization from 20 mL boiling IPA gave, after filtering and air drying, 1.70 g light orange crystals of 1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene with a mp of 112-113 deg C. A suspension of 1.2 g LAH in 75 mL anhydrous THF was put under an inert atmosphere and, with good stirring, brought up to a gentle reflux. A solution of 1.5 g 1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene in 20 mL anhydrous THF was added dropwise. Heating and stirring were maintained for an additional 24 h, and then the reaction mixture was allowed to come back to room temperature with stirring. There was added 1.4 mL H2O (dissolved in a little THF), followed by 1.4 mL 15% NaOH and finally another 4.2 mL H2O. Stirring was continued until all the curdy solids had turned white. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and the washings were combined, and the solvent removed under vacuum. The residue was 1.1 g of a pale amber oil. This was dissolved in 6 mL IPA, neutralized with concentrated HCl (about 8 drops were required) and then diluted with 150 mL anhydrous Et2O. The slightly cloudy solution was stirred for a couple of min, then there was the formation of a heavy white crystalline mass. This was removed by filtration, washed with Et2O, and air dried to provide 1.1 g 2,5-dimethoxy-4-ethylthioamphetamine hydrochloride (ALEPH-2) with a mp of 128-130 deg C with decomposition. DOSAGE: 4 - 8 mg DURATION: 8 - 16 h. QUALITATIVE COMMENTS: (with 4 mg) There was a warm feeling in the total body and a light pressure in the head that changed with time into the feeling of a balloon without any anatomical definition. The usual color perception was not very much increased, and my vision was not sharpened as it was with DOM. Rather, I noticed waves of movement, very smooth and not too busy. Both my tactile perception and auditory acuity were enhanced. The main effect for me was, paradoxically, an easier handling of the outer world. None of the jitters of amphetamine. The body feeling is good, healthy, and I am at peace with the body-mind dualism. These are pretty much personal comments Q I will write up the pharmacological points later. (with 5 mg) This turned out to be a day of extraordinary visuals and interpretations. About two hours into it, I felt that the effects were still climbing, but there was a marvelous onset of visual distortions and illusions, right at the edge of hallucination. The logs in the fireplace were in continuous motion. The notepaper I was writing on seemed to scrunch and deform under the pressure of the pen. Nothing would stay still; everything was always moving. There was a phase of unabated inflation. The intensity was noticeably dropping at the five hour point and I observed considerable residual shakes and a muscular tremor. Even towards midnight there was some tooth-rubbiness, but I was able to get a somewhat fretful though adequate sleep. (with 5 mg) I was exposed to a number of new environments and it was difficult to completely separate the experience into what was seen differently and what was seen for the first time. The Santa Cruz Mystery Spot should have been bizarre but it was simply hokey. And yet the boardwalk that should have been depressing was totally magical. The day was unworldly and I ended up with considerable muscular weakness. All in all, I handled it well, but I probably won't do it again. (with 7 mg) An amazing unification of visual hallucination seen only in the very fine detail of something, and what must be considered retinal hallucination. There is no one-to-one correspondence between the many retinal cells of the high-resolution part of the eye. Thus, the mind can pick and choose, sometimes from the right eye, and sometimes from the left. And so a small curve or bump can become whatever you wish. For a moment. And then it chooses again, but differently. Is all of our perceived world as subjective as this? (with 8 mg) Extreme intoxication, but almost no visual phenomena. Even well into the evening, I know I absolutely could not drive. Why? I don't know, since this experiment, at least, seemed to be quite free of strange colors and wiggly lines and streaks of light. It's that I don't trust that the reality I see is the same reality that the other driver might see. I am very much the center of the world about me, and I don't think I could trust anyone else to fully respect my reality. EXTENSIONS AND COMMENTARY: As with ALEPH itself, and in most ways with the entire ALEPH family, there is no predictability of the dose/response relationship. One person had expressed his psychic isolation by taking and maintaining a fetal position in relative hibernation for several hours and with substantial amnesia; this at a four milligram dose. Yet another person, at fully twice this amount, was aware of a slight light-headedness that could in no way be measured as more than a bare threshold. But by the time this erratic nature had become apparent, the ALEPHS had been assigned and made, up to and including ALEPH-7. ALEPH-3 was intended to be the methallylthio compound, 2,5-dimethoxy-4-(beta-methallylthio)amphetamine. The thioether (2,5-dimethoxyphenyl beta-methallyl sulfide) was easily made from 2,5-dimethoxythiophenol (see 2C-T-2 for its preparation) with 3.4 g dissolved in a solution of 1.7 g KOH in 25 mL boiling EtOH, and 2.72 g methallyl chloride, heated 1 h on the steam bath, poured into 250 mL H2O, extracted with 3x100 mL CH2Cl2, and solvent removal yielding 4.4 g of the sulfide as an amber oil. An effort to convert this to 2,5-dimethoxy-4-(beta-methallylthio)benzaldehyde (7.2 g POCl3, 6.7 g N-methylformanilide, 4.2 g of the crude sulfide from above, 15 min heating on the steam bath, H2O hydrolysis, hexane extraction of the residues from a CH2Cl2 extraction) produced 3.1 g of a peppermint-smelling oil that distilled at 140-160 deg C at 0.3 mm/Hg and which did indeed have an aldehyde group present (by proton NMR) but the rest of the spectrum was a mess, and the project was abandoned. Several years later, this entire project was reinitiated, and the aldehyde was obtained as a yellow crystal, but again it was not pursued. At that time, the earlier try had been totally forgotten, and a brand new ALEPH- (or 2C-T-) number had been assigned; i.e., 20. Thus, the corresponding phenethylamine (2,5-dimethoxy-4-(beta-methallylthio)phenethylamine), had it ever been made, which it was not, would have been called either 2C-T-3 or 2C-T-20, and the amphetamine homologue would probably have been ALEPH-20. A closely related 2C-T-X compound was also started quite a while later Q this was the allylthio homologue of the methallyl material 2C-T-3 or 2C-T-20. Its place in the flow of things is evident from its numbering, 2C-T-16. A mixture of 2,5-dimethoxythiophenol and KOH and allyl chloride in MeOH gave 2,5-dimethoxyphenyl allyl sulfide as a white oil which boiled at 110-125 deg C at 0.25 mm/Hg. This, with POCl3 and N-methylformanilide provided 2,5-dimethoxy-4-(allylthio)benzaldehyde which distilled at 140-160 deg C at 0.4 mm/Hg and could be recrystallized from MeOH as a pale yellow solid. Reaction of this aldehyde in nitroethane in the presence of ammonium acetate (steam bath for 2.5 h) provided 2,5-dimethoxy-4-allylthio-beta-nitrostyrene as red crystals from acetonitrile. Its mp was 114-115 deg C. Anal. (C13H15NO4S) C,H. This has not yet been reduced to the final amine, 2,5-dimethoxy-4-allylthiophenethylamine, 2C-T-16. The corresponding amphetamine would be, of course, ALEPH-16. ALEPH-5 was to be the cyclohexylthio analogue (2,5-dimethoxy-4-cyclohexylthioamphetamine). The thioether (2,5-dimethoxyphenyl cyclohexyl sulfide) was successfully made from 1.7 g 85% KOH pellets in 25 mL hot EtOH, 3.4 g 2,5-dimethoxythiophenol (again, see under 2C-T-2 for its preparation), and 4.9 g cyclohexyl bromide, 3 h on the steam bath, into 500 mL H2O, extraction with 3x100 mL CH2Cl2, washing the extracts with 5% NaOH, and evaporation to yield 5.2 g of an amber oil. The aldehyde, (made from 6.1 g POCl3 and 5.4 g N-methylformanilide, heated until claret colored, then treated with 5.0 g of the above crude thioether, heating for 20 min on the steam bath, into 300 mL H2O, and over-night stirring) was obtained as 3.1 g of a flesh-colored solid that was clearly neither pure nor completely correct. Repeated partitioning with organic solvents and cooling and scratching the residues finally provided a pale orange crystal (1.3 g, mp 88-93 deg C) which, after twice recrystallizing from MeOH, gave 0.4 g of pale yellow crystals with a mp 95-96 deg C and a textbook perfect NMR in CDCl3 (CHO, 1H (s) 10.41; ArH 2H (s) 6.93, 7.31; OCH3, 6H, (2s) at 3.88 and 3.92; CH, 1H br. at 3.34; and (CH2)5 10H br. at 1.20-2.34). The nitrostyrene was prepared from 200 mg of the above aldehyde in 1.2 mL nitroethane and 0.1 g ammonium acetate overnight on the steam bath, the solvent removed to give an orange oil that spontaneously crystallized after a few months' standing. This was never characterized, but sits there on the shelf to be reduced to ALEPH-5 some inspired day. The two-carbon homo-logue of this (2,5-dimethoxy-4-cyclohexylthiophenethylamine) will someday be called 2C-T-5 (if it is ever made). The remaining members of this family, ALEPH-4, ALEPH-6, and ALEPH-7 have actually been prepared and they have all been entered here in Book II, under their own names. #5 ALEPH-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOAMPHETAMINE SYNTHESIS: A solution of 2.0 g 2,5-dimethoxy-4-((i)-propylthio)benzaldehyde (see under 2C-T-4 for its synthesis) in 12 mL nitroethane was treated with 0.4 g anhydrous ammonium acetate and heated on the steam bath for 12 h, then allowed to stir for another 12 h at room temperature. The excess solvent/reagent was removed under vacuum leaving a residue as a heavy deep orange two-phase oily mass. This was brought into one phase with 2 mL MeOH and then, with continued stirring, everything spontaneously crystallized. This product was removed by filtration and, after washing sparingly with cold MeOH and air drying, yielded 2.0 g of 1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene as orange crystals with a mp of 96-98 deg C. After recrystallization from 15 mL boiling 95% EtOH, filtering and air drying to constant weight, there was obtained 1.6 g of orange crystals with a mp of 99-100 deg C. A suspension of 1.0 g LAH in 100 mL warm THF was stirred under a N2 atmosphere and heated to a gentle reflux. To this there was added, dropwise, a solution of 1.2 g 1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene in 20 mL anhydrous THF. This mixture was held at reflux for 1 day, then stirred at room temperature for 2 days. There was then added, slowly and with caution, 1 mL of H2O, followed by 1 mL of 15% NaOH, and finally by another 3 mL of H2O. Stirring was continued until the reaction mixture became white and granular, then all solids were removed by filtration and the filter cake was washed with additional THF. The filtrate and washings were combined, and the solvent removed under vacuum to give 1.1 g of residue which was an almost white oil. This was dissolved in 6 mL IPA, neutralized with concentrated HCl (10 drops were required) and then diluted with 200 mL anhydrous Et2O. The resulting slightly turbid solution was clarified by filtration through a sintered glass filter, and the clear and slightly yellow filtrate was allowed to stand. A fine white crystalline product slowly separated over the next few h. This product, 2,5-dimethoxy-4-(i)-propylthioamphetamine hydrochloride (ALEPH-4) was removed by filtration, and after washing with Et2O and air drying, weighed 0.5 g and had a mp of 146-147 deg C, with prior sintering at 144 deg C. DOSAGE: 7 - 12 mg. DURATION: 12 - 20 h QUALITATIVE COMMENTS: (with 7 mg) Things started off going downhill, initially negative with tension and depression, but as the momentum developed, so did the positive effect. My discomfort continued to develop, but I was struck by the visual beauty of the trees and the small stream that flowed off the mountain. My experience continued to grow, simultaneously, in both the negative and the positive direction. Physically I was uncomfortable and found my breathing difficult, but I acknowledged a rapture in the very act of breathing. All moved over to the plus side with time, and the evening was gorgeous. I have never seen the sky so beautiful. The only flaw was when I choked on some lemonade and it seemed to me I almost drowned. I have been extremely conscious of eating, drinking and swallowing ever since. I barely slept the whole night and awoke extremely tired. I felt that the experience continued for many days, and I feel that it is one of the most profound and deep learning experiences I have had. I will try it again, but will block out more time for it. (with 8 mg) There was without question a plus two, but none of the edges of unreality that are part of LSD. The sounds that are just outside of my hearing are intriguing, and distract me from the eyes-closed imagery that is just barely possible with music while lying down. But, going outside, there were no obvious sources of the sounds that I heard. Could I drive? I suspect so. I took a shower and did just that Q I drove to San Francisco without incident, and walked amongst the many strange faces on the downtown streets. (with 12 mg) The experience was very intense but completely under control except for a twenty minute period right in the middle of it. I had to get away from everything, from everyone. There was a sense of being surrounded and moved in upon that was suffocating. I was weighed down with everything Q physical, psychic, emotional. My clothes had to come off, my hair had to be released, my shoes went, I needed to move away from where I was, to somewhere else, to some new place, any new place, with the hope that my other old place wouldn't follow me. Pretty soon I found I was myself, I could breathe again, and I was OK. Rather sheepishly, I dressed and rejoined the group. The rest of the day was spectacular, but those few minutes were scary. What if I couldn't have escaped? EXTENSIONS AND COMMENTARY: Again, there are hints and suggestions of complexities. These, and several other reports, suggest some sensory confusion, and interpretive aspects that are to some extent threatening. There is an underlying suggestion of body toxicity. I know of no experiment that exceeded 12 milligrams and I would not be able to predict what might come forth at higher dosages. I personally choose not to try them. #6 ALEPH-6 2,5-DIMETHOXY-4-PHENYLTHIOAMPHETAMINE SYNTHESIS: To a 300 mL three-neck round-bottom flask set up with a magnetic stirrer and protected with a N2 atmosphere, there was added 75 mL hexane, 3.5 g tetramethylethylenediamine, and 4.2 g p-dimethoxybenzene. The reaction mixture was cooled to 0 deg C with an external ice bath, and there was then added 19 mL of 1.6 M butyllithium in hexane. With stirring, the reaction was brought up to room temperature, and there were produced loose, creamy solids. There was then added, as a solid and portionwise, 6.6 g diphenyldisulfide which resulted in an exothermic reaction and the production of a nearly clear solution. After stirring an additional 10 min, the reaction was quenched in 500 mL of dilute NaOH. The hexane phase was separated, and the aqueous phase extracted with 4x100 mL CH2Cl2 The organic extracts were combined, washed with dilute HCl and the solvents were removed under vacuum to provide 6.0 g of 2,5-dimethoxyphenyl phenyl sulfide as an impure amber oil. A small sample was saved for microanalysis and NMR, and the re-mainder converted to the corresponding benzaldehyde. A mixture of 6.1 g POCl3 and 5.4 g N-methylformanilide was heated for 3 min on the steam bath, and then added to the remainder of the above-described 2,5-dimethoxyphenyl phenyl sulfide. The reaction became immediately a deep red and, after heating on the steam bath for 0.5 h, was dumped into a large quantity of H2O, producing a granular brown solid. This was removed by filtration, and washed sparingly with cold MeOH (the washes were saved). The resulting pale yellow solids were recrystallized from 20 mL boiling absolute EtOH providing, after cooling, filtration and air drying, 4.4 g of extremely pale yellow crystals of 2,5-dimethoxy-4-(phenylthio)benzaldehyde. This had a mp of 119-119.5 deg C. All washes and mother liquors were combined, flooded with H2O and extracted with CH2Cl2. This solvent was removed under vacuum, and the residue (a viscous oil) was dissolved in a little EtOH which, on cooling in dry ice, gave 1.2 g of a second crop of the aldehyde, mp 117-119 deg C. Recrystallization from 5 mL 95% EtOH gave an additional 0.4 g product with a mp of 118-119 deg C. This mp was not improved by recry-stallization from cyclohexane. The NMR specrum was excellent, with OCH3 singlets (3H) at 3.45 and 3.80 ppm; ArH singlets at 6.28 and 7.26 ppm, the C6H5 as a broad peak centered at 7.50, and the CHO proton at 10.37 ppm. A solution of 4.4 g 2,5-dimethoxy-4-(phenylthio)benzaldehyde in 32 mL nitroethane was treated with 0.8 g anhydrous ammonium acetate and heated on the steam bath for 21 h. The excess solvent/reagent was removed under vacuum, leaving a dark red oil as residue. After much diddling and fiddling around, this set up as a crystalline mass. These solids were ground under 20 mL cold MeOH and filtered, providing 5.3 g of the crude nitrostyrene as an orange crystalline residue product after air-drying. This was ground up under 10 mL MeOH, the insolubles collected by filtration, washed with a little MeOH, and air dried to provide 5.3 g crude 1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene as yellow crystals, with a mp of 100-102 deg C (with prior sintering at about 98 deg C). This was recrystallized from 50 mL boiling 95% EtOH. After cooling in an ice bath, it was filtered, washed with EtOH, and air drying provided gold-yellow crystals with a mp of 105-106 deg C. The proton NMR was excellent (in CDCl3). A suspension of 2.0 g LAH in 100 mL refluxing THF, under an inert atmosphere and with good stirring, was treated with a solution of 3.5 g 1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene in 20 mL anhydrous THF added dropwise at a rate that maintained the reflux. Heating and stirring were maintained for an additional 36 h, and then the reaction mixture was stirred at room temperature for an additional 24 h. There was added 2.0 mL H2O (dissolved in a little THF), followed by 2.0 mL 15% NaOH, and finally another 6.0 mL H2O. Stirring was continued until all formed solids had turned white. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and the washings were combined and the solvent removed under vacuum. The residue was 2.8 g of an oil that quite obviously contained some H2O. This was dissolved in 400 mL CH2Cl2, washed first with dilute NaOH and then with 4x150 mL 1N HCl. The organic phase was stripped of solvent under vacuum, yielding a pale amber oil that crystallized. This was ground first under Et2O, giving 3.4 g of a yellow solid. This was then ground under 10 mL of acetone, yielding 2.4 g of a white crystalline solid that darkened at 170 deg C, sintered at 187 deg C and had a mp of 191-193 deg C. This was dissolved in 20 mL hot 95% EtOH, and diluted with 40 mL Et2O to provide a clear solution which, after a minute's scratching with a glass rod, deposited 2,5-dimethoxy-4-phenylthioamphetamine hydrochloride (ALEPH-6) as white solids. After filtration and air drying, the weight was 1.8 g, with a mp of 194-195 deg C. The dilute HCl washes, after being made basic with aqueous NaOH and extraction with CH2Cl2 gave a trivial quantity of additional product. DOSAGE: greater than 40 mg. DURATION: probably long. QUALITATIVE COMMENTS: (with 30 mg) I had an alert at the one hour point, and in another hour there was a clear 1+. There was a not well defined, gentle un-worldliness. And it was still there quite unchanged twelve hours later. In a group I find that all voices about me are of equal intensity and equal importance. But this is not at all distracting. This will be a long lived thing for sure. (with 40 mg) I am into a subtle but real effect, no more than one plus, but real. I feel primed, but nothing more. It is not interfering with work, maybe even helping with it. After another hour of static one-plusness I decided to use it as a primer to LSD, using the usual 60 microgram quantity that is standard for primer studies. The combination showed definite synergism, with a rapid show of the LSD effects (within fifteen minutes) and an almost three plus effect. This is most unusual for the usual 60 microgram challenge amount. An absolutely delightful intoxication that had sufficiently descended towards baseline that I accepted a ride to a party that evening in Marin County to attend a poetry reading. There I felt myself at baseline and accepted (unusual for me) a little marijuana. And with the utmost quiet and delicacy, a rather incredible change of state took place. The most memorable event was the awareness of a clarinet playing somewhere, and the sneaky sounds from it actually coming along the carpet out of the dining room and into the hallway and through the door and into the room where I was, and all of them gathering at my feet like docile kittens waiting for me to acknowledge them. I did, non-verbally, and I was amazed at the many additional follow-up sounds that came from the same clarinet along the same twisty path along the floor and through the door and into my space, over what seemed to be the next million hours. I ended up with a marvelous collection of notes and phrases at my feet, and I felt somehow honored. My speech sounded OK to me, but I knew that it would be odd to the ears of others, so I kept quiet. A final measure of the weirdness of the ALEPH-6/LSD/Pot combination was the viewing of the Larkspur ferry at its dock, abandoned for the evening and with no one aboard it, and with all that clean, dry sleeping space going to waste with so many people sleeping on the streets these days. Once home, I slept soundly and for a long while. Incredible experience. EXTENSIONS AND COMMENTARY: In a sense, this compound was a disappointment. The beauty of putting a whole new ring into an active structure is that it provides a marvelous vehicle for introducing new substituents in new arrangements. Had Aleph-6 been a cleanly active and potent compound, then the new phenyl group could have been made electronegative to varying degrees (with methoxy substitution for example) or electropositive to varying degrees (with trifluoromethyls or nitros) and this fine-tuning could have been extremely rewarding. But this material had the earmarks of one of those forever threshold things. The 40 milligram experiment was hopelessly compromised, and nothing higher was ever scheduled or tried. The two-carbon homologue, 2,5-dimethoxy-4-phenylthiophenethylamine, or 2C-T-6, has never even been synthesized, let alone assayed. #7 ALEPH-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOAMPHETAMINE SYNTHESIS: A solution of 2.6 g 2,5-dimethoxy-4-((n)-propylthio)benzaldehyde (see under 2C-T-7 for its synthesis) in 20 mL nitroethane and 0.5 g anhydrous ammonium acetate was heated on the steam bath overnight. The excess solvent/reagent was removed under vacuum leaving an orange oil as a residue that cry-stallized spontaneously. This crude product was recrystallized from 20 mL boiling MeOH to give, after cooling, filtering, and air drying, 2.4 g of 1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene as orange crystals. Its mp was 83-84 deg C with prior sintering at 81 deg C. A suspension of 1.5 g LAH in 150 mL of warm anhydrous THF was stirred under an inert atmosphere and brought up to a gentle reflux. A solution of 2.3 g 1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene in 25 mL anhydrous THF was added dropwise at a rate that maintained the reflux. Heating and stirring were continued for 2 days, and then the reaction mixture was allowed to stir at room temperature for an additional 2 days. There was added 1.5 mL H2O (dissolved in 10 mL THF), followed by 1.5 mL 15% NaOH, and finally another 4.5 mL H2O. Stirring was continued until all the curdy solids had turned white. The reaction mixture was filtered, and the filter cake washed with slightly wet THF. The filtrate and the washings were combined, and the solvent removed under vacuum. The residue was about 2 mL of an amber colored oil that was dissolved in 200 mL CH2Cl2. This solution was washed with first dilute NaOH, and then with saturated brine. Removal of the solvent gave a pale amber oil that was dissolved in 10 mL IPA, neutralized with about 14 drops of concentrated HCl, and diluted with 200 mL anhydrous Et2O. The clear solution was decanted from a little gritty material, and then set aside to allow the formation of 2,5-dimethoxy-4-(n)-propylthioamphetamine hydrochloride (ALEPH-7) as fine white crystals. After filtration and air drying, there was obtained 1.8 g of an off-white powder. DOSAGE: 4 - 7 mg. DURATION: 15 - 30 h. QUALITATIVE COMMENTS: (with 4 mg) At the second hour I had a paraesthetic twinge or two (all pins and needles), and then felt quite relaxed, quite willing to let this play itself out. In the evening my ears still feel 'popped' and there is a little bit of physical awareness. There is not much fun with this. The night following, I was unable to sleep and only dozed slightly, but I seemed to be OK the next day. (with 6 mg) The alert was felt within a half hour, and then nothing more. Then, over the next two hours, there was the evolution of an extremely neutral state. I danced wildly to a record of Keith Jarrett, but somehow didn't care for his style. I fell apart emotionally, with tears and a feeling of total loss of everything. Everything was visible to me only in some strange wide-angle lens viewing. I went for a walk, a waste of time. I tried classical music, but only jazz was acceptable. It was a couple of days before I lost the residual strangeness feeling. Never again. (with 7 mg) I did this alone, and in retrospect I wish I had not. Somewhere between the hours 2 and 3, I got to a full +++, and I was concerned that I saw the effects still developing. Where would it go now? There was no reality loss as with LSD, no shakes or shimmers, but an intense and profound +++ of something characterized only by the absence of extremes. And I am frightened because this is still deepening. A couple of calls to friends were not successful, but I found an ally in the Palo Alto area, and I told him I was coming to visit. My greater than one hour drive there was okay only because I had programmed every move ahead of time. In retrospect, to drive was completely stupid, and I certainly will never do it again, under any circumstances. But, there I was. I knew which lane I would be on, on the S.F. Bay Bridge, at every moment of my travels. The middle lane through the tunnel. The second from the left when descending into San Francisco. The white lane-marker stripes were zipping up past my lateral field of vision as I drove, those that were to my right zipped past my right eye, those to the left past my left eye. Like disturbed fruit flies leaving an over-ripe peach. But, as everything had been preprogrammed, there were no surprises. I made it successfully, and my baby-sitting friend probed, with a blend of curiosity, love, and envy, my uncaring state. And in the course of the next couple of hours, this state evolved into a friendly, familiar place. I was still fully +++, but now for the first time I was at peace with it. A fruit salad tasted heavenly. By midnight I was able to doze lightly, and the next day I was sure that there were some residual effects. The second evening's sleep repaired everything. The neutralness was something new to me. I don't like not caring. Was this the "Beth" state of the strange twenty minutes seen by SL in the ALEPH-4 experience? (with 7 mg) Strange, pleasant, unexciting, long-lasting. The induced state was characterized by: clear unintoxicated central field of vision, concentration but with the periphery sensed as being filled with a kind of strangeness, and also something sensed inside, at the back of the head. A feeling of something waiting to erupt, which never does. I had a faint touch of amusement, yet no part of the experience had the depth or richness of other compounds. No tremors. Slight visuals, but only when looked for. Hunger not present, but food tasted fine when eaten. Mildly pleasant but one would not take it again unless bored stiff. EXTENSIONS AND COMMENTARY: This drug was the first definition of the term, Beth state. There is something of the Fournier Transform in any and all drug experiments. A psychedelic drug experience is a complex combination of many signals going all at the same time. Something like the sound of an oboe playing the notes of the A-major scale. There are events that occur in sequence, such as the initial A, followed by B, followed by C-sharp and on and on. That is the chronology of the experience, and it can be written down as a series of perceived phenomena. The notes of the scale. Black quarter notes, with flags at the tops of their staffs, going up the page of music. But within each of these single events, during the sounding of the note "A," for example, there is a complex combination of harmonics being produced at the same time, including all components from the fundamental oscillation on up through all harmonics into the inaudible. This mixture defines the played instrument as being an oboe. Each component may be shared by many instruments, but the particular combination is the unique signature of the oboe. This analogy applies precisely to the study of psychedelic drugs and their actions. Each drug has a chronology of effect, like the notes of the A-major scale. But there are many components of a drug's action, like the harmonics from the fundamental to the inaudible which, taken in concert, defines the drug. With musical instruments, these components can be shown as sine waves on an oscilloscope. One component, 22%, was a sine wave at a frequency of 1205 cycles, and a phase angle of +55!. But in psychopharmacology? There is no psychic oscillo-scope. There are no easily defined and measured harmonics or phase angles. Certainly, any eventual definition of a drug will require some such dissection into components each of which makes some contribution to the complex whole. The mental process may some day be defined by a particular combination of these components. And one of them is this Beth state. It is a state of uncaring, of anhe-donia, and of emotionlessness. Many drugs have a touch of this Beth state, ALEPH-7 more than most. If a sufficient alphabet of effects (I am using the Alephs, Beths, Gimels, and Daleths of the Hebrew as token starters only) were to be accumulated and defined, the actions of new materials might someday be more exactly documented. Could depression, euphoria, and disinhibition for example, all be eventually seen as being made up of their component parts, each contributing in some measured way to the sum, to the human experience? The psychologists of the world would be ecstatic. And drugs such as ALEPH-7 might be useful in helping to define one of these parts. #8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE; 1-(2,5-DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE; 2,5-DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE SYNTHESIS: In 50 mL of benzene there was dissolved 31.6 g 2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 2C-D for its preparation), 20.2 mL 1-nitropropane, and 6 mL cyclohexylamine. This solution was held at reflux in a Dean Stark apparatus for 24 h, effectively removing the water of reaction. Upon cooling, there was deposited 19.6 g of 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene as brilliant orange crystals. The mp, after recrystallization from MeOH, was 114-115 deg C and a second recrystallization increased the mp another 2 deg C. Anal. (C13H17NO4) C,H,N. A suspension of 12.5 g LAH in 600 mL anhydrous THF was stirred magnetically, and brought up to a reflux. To this there was added, dropwise, 15.0 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene dissolved in 150 mL THF. Refluxing was continued for 15 h and, after cooling, the excess hydride was decomposed by the addition of 12.5 mL H2O. The inorganic salts were made loose and granular by the addition of 12.5 mL 15% NaOH followed by an additional 37.5 mL H2O. These solids were removed by filtration, and the filter cake was washed with THF. The combined filtrate and washings were stripped of solvent under vacuum. The residue was dissolved in anhydrous Et2O, and treated with hydrogen chloride gas, yielding 1-(2,5-dimethoxy-4-methylphenyl)-2-aminobutane hydrochloride (ARIADNE) as white crystals which, after recrystallization from IPA, weighed 11.4 g and had a mp of 232.5-234.5 deg C. Anal. (C13H22ClNO2) C,H,N,Cl. The racemic mixture was resolved into its optical isomers by the formation of salts with (+)-2beta-nitrotartranilic acid (to give the "S" isomer) or with (+)-2beta-chlorotartranilic acid (to give the "R" isomer). The "R" isomer can also be prepared by the reductive amination of 1-(2,5-dimethoxy-4-methylphenyl)-2-butanone (from the above nitrostyrene and elemental iron) with (+)-a-methyl benzylamine followed by the hydrogenolysis of the benzyl group. DOSAGE: as psychedelic, unknown. DURATION: short. QUALITATIVE COMMENTS: (with 12 mg) I believe that my mood has distinctly improved, and my sleep that evening was excellent. This is physically benign. (with 32 mg) There was some sort of threshold that lasted for a couple of hours. (with 25 mg of the "R" isomer) There is the alert of a psychedelic, with none of the rest of the package. Perhaps a bit of paranoia. And by the fifth hour everything is largely gone. EXTENSIONS AND COMMENTARY: How does one discover a new drug for a malady that does not exist in experimental animals? Drugs that interfere with sleep, or with appetite, or with some infecting bacterium, are naturals for animal screening, in that animals sleep, eat, and can be easily infected. But there are lots of syndromes that involve a state of mind, and these are uniquely human. Many of the psychopharmacological anti-this or anti-that agents address ailments such as anxiety, psychosis, paranoia, or depression, which are only known in man. So how does one discover a new drug in areas such as these? If one has in hand a drug that is known to be effective in one of these human ailments, an animal assay can be set up to give some measurable response to that specific drug, or a biochemical property can be rationalized as being related to a mechanism of action. And with the known drug as a calibration, and restricting your search to structurally related compounds, you can find structural relatives that give the same responses. But how does one find a new class? One way is to kind of stumble into it as a side-line of human experimentation with new psychedelics. But it is really difficult to pick up the clues as to what will be a good anti-depressant if you are not depressed. This compound, to which I had given the name of ARIADNE as the first of my ten "classic ladies" (I'll say more about them later), was not really a stimulant of any kind, certainly it was not a psychedelic, and yet there was something there. It had been explored rather extensively as a potential psychotherapeutic ally by a friend of mine. He said that there seemed to be some value in a few of his patients who had some underlying depression, but not much of anything with the others. So, I decided to call it an anti-depressant. I had mentioned some of this history one time when I was giving an address at a conference on the East Coast, and my host (who happened to be the research director at a large pharmaceutical house) asked if I would send him a sample. His company did many animal tests, one of which showed that it was not hallucinogenic (a cat whose tail erected dramatically with DOM did nothing with ARIADNE) and another that showed re-motivation (some old maze-running monkeys who had decided not to run any more mazes changed their minds with ARIADNE). So patents were obtained for the "R" isomer, the more effective isomer, covering its use for such things as the restoring of motivation in senile geriatric patients. And a tradename of Dimoxamine was assigned it, despite several voices that held out for Ariadnamine. But it didn't have what was needed to make it all the way to the commercial market Many, many analogues of ARIADNE have been made, and for a variety of reasons. In the industrial world there is research backup carried out, not only for the discovery of new things, but also for patent protection of old things. Several dozen analogues of ARIADNE have been made and pharmacologically evaluated, and some of them have been put into the published literature. The major points of variation have been two: keep the 4-position methyl group intact, and make the variations on the alpha-carbon (propyl, butyl, dimethyl, phenyl, benzyl, phenethyl, etc. Q an extensive etc.) or: keep the alpha-position ethyl group intact and make the variations on the 4-position (chloro, iodo, methylthio, carboxy, etc. Q again, an extensive etc.). Some of these analogues I had made, and sent in for animal screening. The high potency of DOB suggested the bromo-counterpart of ARIADNE. The making of this entailed the proteo counterpart, 1-(2,5-dimethoxyphenyl)-2-aminobutane. Reaction of 2,5-dimethoxybenzaldehyde with nitropropane in benzene in a Dean Stark apparatus with cyclohexylamine as a catalyst produced 1-(2,5-dimethoxyphenyl)-2-nitrobutene, which crystallized as orange crystals from MeOH with a mp of 47-47.5 deg C. Anal. (C12H15NO4) C,H,N. This was reduced to the amine 1-(2,5-dimethoxyphenyl)-2-aminobutane with LAH in ether, and this gave a hydrochloride salt with a mp of 172-174 deg C after recrystallization from acetonitrile. The free base of this compound was brominated in acetic acid to give 1-(2,5-dimethoxy-4-bromophenyl)-2-aminobutane which yielded a white hydrochloride salt with a mp of 204-206 deg C following recrystallization from IPA. The isomeric non-brominated analogue, 1-(3,4-dimethoxyphenyl)-2-aminobutane was made and explored by the Chemical Warfare group at Edgewood Arsenal; its code number is EA-1322. Several of the alpha-ethyl analogues of ARIADNE were N,N-dialkylated, and were target compounds for halogenation with radio-iodine or radio-fluorine, for evaluation as potential brain blood-flow indicators. In these studies. all examples followed a common flow diagram. The reaction of the appropriate benzaldehyde and nitropropane, using N,N-dimethylethylenediamine as a catalyst and following recrystallization from MeOH, gave the corresponding 1-aromatic-2-nitro-1-butene (the nitrostyrene) which, by reduction with elemental iron, gave the corresponding 2-butanone (which was distilled at about 0.3 mm/Hg). This led, by reductive amination with dimethylamine hydrochloride and sodium cyanoborohydride, to the corresponding N,N-dimethyl product which was distilled at about 0.3 mm/Hg and which, in no case, either formed a solid HCl salt or reacted with carbon dioxide from the air. From 2,4-dimethoxybenzaldehyde, the nitrostyrene appeared as yellow crystals, the ketone as a white oil, and the product N,N-dimethyl-1-(2,4-dimethoxyphenyl)-2-aminobutane as a white oil. From 2,5-dimethoxybenzaldehyde, the nitrostyrene formed bright yellow crystal, the ketone was an off-white oil, and the product N,N-dimethyl-1-(2,5-dimethoxyphenyl)-2-aminobutane was a white oil. From 3,5-dimethoxybenzaldehyde, the nitrostyrene formed pale yellow crystals that discolored on exposure to the light, the ketone was an off-white clear oil, and the product N,N-dimethyl-1-(3,5-dimethoxyphenyl)-2-aminobutane was a white oil. From 2,6-dimethoxybenzaldehyde, the nitrostyrene was obtained as orange crystals, and was not pursued further. A number of ARIADNE analogues have been made, or at least started, purely to serve as probes into whatever new areas of psychopharmacological activity might be uncovered. One of these is a HOT compound, and one is a TOM compound, and a couple of them are the pseudo (or near-pseudo) orientations. The HOT analogue was made from the nitrostyrene precursor to ARIADNE itself, reduced not with LAH or AH (which would give the primary amine), but rather with sodium borohydride and borane dimethylsulfide. The product, 1-(2,5-dimethoxy-4-methylphenyl)-N-hydroxy-2-aminobutane hydrochloride, was a white crystalline material. The 5-TOM analogue got as far as the nitrostyrene. This was made from 2-methoxy-4-methyl-5-(methylthio)benzaldehyde (see under the 5-TOM recipe for its preparation) and nitropropane in acetic acid, and gave bright yellow crystals. The true pseudo-analogue is the 2,4,6-trimethoxy material based on TMA-6, which is the "real" pseudo-TMA-2. The nitrostyrene from 2,4,6-trimethoxybenzaldehyde and nitropropane crystallized from MeOH/CH3CN as fine yellow crystals, and this was reduced with AH in cold THF to 1-(2,4,6-trimethoxyphenyl)-2-aminobutane which was a bright, white powder. And the near-pseudo analogue? First, what is near-pseudo? I have explained already that the "normal" world of substitution patterns is the 2,4,5. Everyone knows that that is the most potent pattern. But, the 2,4,6 is in many ways equipotent, and has been named the pseudo-stuff. The "real," or "true" pseudo-stuff. So what is the "near" pseudo-stuff? I am willing to bet that the rather easily obtained 2,3,6-trisubstitution pattern, and the much more difficult to obtain 2,3,5-substitution pattern, will produce treasures every bit as unexpected and remarkable as either the 2,4,5- or the 2,4,6- counterparts. These are neither "real" nor "pseudo," but something else, and I will find a name for them when the time comes, something weird from the Greek alphabet. And this will double again the range of possible exploration. The TMA-5 analogue mentioned came from 2,3,6-trimethoxybenzaldehyde and nitropropane using cyclohexylamine as a catalyst (yellow-orange solids) which was reduced to the amine with AH. This hydrochloride salt is an air-stable white powder. All of these materials remain unexplored. Somewhere in the wealth of compounds implicit in the many structural variables possible (the normal versus the pseudo versus the near-pseudo patterns, coupled with the wide variety of promising substituents that can be placed on the 4-position, together with the availability of the the unexplored members of the Ten Classic Ladies harem), it would seem inescapable that interesting compounds will emerge. Just what is this all about the ten "Classic Ladies?" In the chemical struc-ture of DOM, there is a total of nineteen hydrogen atoms. Some of these are indis-tinguishable from others, such as the three hydrogen atoms on a methyl group. But there are exactly ten "types" of hydrogen atoms present. And, not having much, if any, intuition as to just why DOM was so powerful a psychedelic, I decided to systematically replace each of the ten unique hydrogens, one at a time of course, with a methyl group. And I planned to give the resulting materials the names of famous ladies, alphabetically, as you walk around the molecule. ARIADNE was the first of these, the methyl for a hydrogen atom on the methyl group of the amphetamine chain. It was Ariadne who gave the long piece of thread to Theseus to guide him through the mazes of the Labyrinth so he could escape after killing the Minotaur. The record is fuzzy as to whether, after the successful killing, she went with him, or let him go on alone. A methyl group on the nitrogen atom produced BEATRICE. There is the legendary Beatrijs of the Dutch religious literature of the 14th century, and there is the Beatrice from Beatrice and Benedict (of Berlioz fame). But the one I had in mind was the lady from Florence whom Dante immortalized in the Divina Commedia, and she is entered under her own name in this footnote. Replacing the alpha-hydrogen of DOM with a methyl group would give the phentermine analogue which is named CHARMIAN. You may be thinking of Cleopatra's favorite attendant, but I was thinking of the sweet wife of a very dear friend of mine, a lady who has been in a state of gentle schizophrenia for some forty years now. The MDA analogue of CHARMIAN has been described in this foornote under the code name of MDPH. CHARMIAN, herself, has been synthesized and is of very much reduced potency in animals, as compared to DOM. It has not been tried in man as far as I know. The two beta-hydrogen atoms of DOM are distinct in that, upon being replaced with methyl groups, one would produce a threo-isomer, and the other an erythro-isomer. I have named them DAPHNE (who escaped from Apollo by becoming a laurel tree which was, incidentally, named for her) and ELVIRA (who might not be too well known classically, but whose name has been attached to Mozart's 21st piano concerto as its slow movement was used as theme music for the movie Elvira Madigan). I don't know if either of this pair has been made Q I started and got as far as the cis-trans mixture of adducts betweeen nitroethane and 2,5-dimethoxy-4-methylacetophenone. Whoever finally makes them gets to assign the names. I had made and tested the corresponding homologues of DMMDA that correspond to these two ladies. And there are five positions (2,3,4,5 and 6) around the aromatic ring, each of which either carries a hydrogen atom or a methyl group that has a hydrogen atom. There is the 2-methoxy group which can become a 2-ethoxy group to produce a compound called FLORENCE. Her name is the English translation of the Italian Firenze, a city that, although having a female name, has always seemed thoroughly masculine to me. There is the 3-hydrogen atom which can become a 3-methyl group to produce a compound called GANESHA. This is a fine elephant-headed Indian God who is the symbol of worldly wisdom and also has been seen as the creator of obstacles. Here I really blew it; the Classic Lady turned out to be a Classic Gentle-man; not even the name is feminine. There is the 4-methyl group which can become a 4-ethyl group to produce a compound called HECATE who presided over magic arts and spells. There is the 5-methoxy group which can become a 5-ethoxy group to produce a compound called IRIS, who is the Goddess of the rainbow. And there is the 6-hydrogen atom which can become a 6-methyl group to produce a compound called JUNO, who is pretty much a lady's lady, or should I say a woman's woman. GANESHA, 2,5-dimethoxy-3,4-dimethylamphetamine has been made, and has proven to be an extraordinary starting point for a large series of potent phenethylamines and amphetamines which are described in this book. HECATE was given a synonym early in this process, and is now known as DOET (2,5-dimethoxy-4-ethylamphetamine). IRIS has also been entered under her name, and the other ethoxy homologue, FLORENCE, would be easily made based on the preparation of the phenethylamine analogue, 2CD-2ETO. Perhaps it has already been made somehow, somewhere, as I have noted that I have claimed its citrate salt as a new compound in a British patent. And, finally, JUNO (3,6-dimethoxy-2,4-dimethylamphetamine) has been made (from 2,5-dimethoxy-m-xylene, which was reacted with POCl3 and N-methylformanilide to the benzaldehyde, mp 53-54 deg C, and to the nitrostyrene with nitroethane, mp 73-74 deg C from cyclohexane, and to the final amine hydrochloride with LAH in THF). Rather amazingly, I have had JUNO on the shelf for almost 14 years and have not yet gotten around to tasting it. #9 ASB; ASYMBESCALINE; 3,4-DIETHOXY-5-METHOXYPHENETHYLAMINE SYNTHESIS: To a solution of 32 g of 5-bromobourbonal in 150 mL DMF there was added 31 g ethyl iodide and 32 g of finely ground 85% KOH pellets. There was the formation of a purple color and a heavy precipitate. On gradual heating to reflux, the color faded to a pale yellow and the precipitate dissolved over the course of 1 h. The heating was continued for an additional 1 h. The reaction mixture was added to 1 L H2O, and extracted with 2x150 mL of petroleum ether. The extracts were pooled, washed with 2x200 mL 5% NaOH and finally with H2O. After drying over anhydrous K2CO3 the solvents were removed under vacuum to yield 36 g of crude 3-bromo-4,5-diethoxybenzaldehyde as an amber liquid. This was used without purification for the following step. Distillation at 105-115 deg C at 0.3 mm/Hg provided a white sample which did not crystallize. Anal. (C11H13BrO3 ) C,H. A mixture of 36 g 3-bromo-4,5-diethoxybenzaldehyde and 17 mL cyclohexylamine was heated with an open flame until it appeared to be free of H2O. The residue was put under a vacuum (0.4 mm/Hg) and distilled at 135-145 deg C, yielding 42 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine as a viscous light greenish oil. This slowly set to a crystalline glass with a mp of 60-61 deg C. Recrystallization from hexane gave a white crystalline product without any improvement in the mp. Anal. (C17H24BrNO2) C,H. This is a chemical intermediate to a number of active bases, taking advantage of the available bromine atom. This can be exchanged with a sulfur atom (leading to 5-TASB and 3-T-TRIS) or with an oxygen atom as described below. A solution of 18 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine in 250 mL anhydrous Et2O was placed in an atmosphere of He, stirred magnetically, and cooled with an external dry ice/acetone bath. Then 36 mL of a 1.5 M solution of butyllithium in hexane was added over 2 min, producing a clear yellow solution. This was stirred for 10 min. There was then added 30 mL of butyl borate at one time, the stirring continued for 5 min. The stirred solution was allowed to return to room temperature. There was added 150 mL of saturated aqueous ammonium sulfate. The Et2O layer was separated, and the aqueous phase extracted with another 75 mL Et2O. The combined organic phases were evaporated under vacuum. The residue was dissolved in 100 mL MeOH, diluted with 20 mL H2O, and then treated with 15 mL 35% H2O2 added over the course of 2 min. This mildly exothermic reaction was allowed to stir for 15 min, then added to 500 mL H2O. This was extracted with 2x100 mL CH2Cl2 and the solvent removed under vacuum. The residue was suspended in 150 mL dilute HCl and heated on the steam bath for 0.5 h. Stirring was continued until the reaction was again at room temperature, then it was extracted with 2x75 mL CH2Cl2. These extracts were pooled and extracted with 3x100 mL dilute aqueous KOH. The aqueous extracts were washed with CH2Cl2, reacidified with HCl, and reextracted with 2x75 mL CH2Cl2. These extracts were pooled, and the solvent removed under vacuum to yield a brown residue. This was distilled at 107-127 deg C at 0.4 mm/Hg to yield 8.3 g of 3,4-diethoxy-5-hydroxybenzaldehyde as an oil that set to a tan solid. Recrystallization from cyclohexane gave a white product with a mp of 70.5-71.5 deg C. Anal. (C11H14O4) C,H. A solution of 8.3 g of 3,4-diethoxy-5-hydroxybenzaldehyde and 3.0 g KOH in 75 mL EtOH was treated with 5 mL methyl iodide and stirred at room temperature for 5 days. The reaction mixture was added to 400 mL H2O and extracted with 2x50 mL CH2Cl2. The extracts were pooled, washed with 2x150 mL dilute NaOH, and the solvent removed under vacuum. The residual oil was distilled at 95-110 deg C at 0.3 mm/Hg to yield 8.2 g of 3,4-diethoxy-5-methoxybenzaldehyde as a pale yellow liquid. This product was a crystalline solid below 20 deg C but melted upon coming to room temperature. It was analyzed, and used in further reactions as an oil. Anal. (C12H16O4) C,H. To a solution of 6.4 g 3,4-diethoxy-5-methoxybenzaldehyde in 40 mL nitromethane there was added about 0.5 g anhydrous ammonium acetate, and this was held at reflux for 1 h. The excess solvent/reagent was removed under vacuum, producing a red oil which set up to crystals. These were recrystallized from 40 mL boiling MeOH to yield 3.0 g of 3,4-diethoxy-5-methoxy-beta-nitrostyrene as yellow plates, with a mp of 89-90 deg C. Anal. (C13H17NO5) C,H. A solution of 3.0 g LAH in 150 mL anhydrous THF under He was cooled to 0 deg C and vigorously stirred. There was added, dropwise, 2.1 mL of 100% H2SO4, followed by the dropwise addition of a solution of 3.5 g 3,4-diethoxy-5-methoxy-beta-nitrostyrene in 30 mL anhydrous THF, over the course of 10 min. The addition was exothermic. The mixture was held at reflux on the steam bath for 30 min. After cooling again, the excess hydride was destroyed with IPA, followed by the addition of 10% NaOH sufficient to covert the aluminum oxide to a white, granular form. This was removed by filtration, the filter cake washed with IPA, the mother liquor and filtrates combined, and the solvents removed under vacuum to provide a yellow oil. This residue was added to 100 mL dilute H2SO4 producing a cloudy suspension and some yellow insoluble gum. This was washed with 2x75 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 2x75 mL CH2Cl2. The solvent was removed from these pooled extracts and the residue distilled at 110-135 deg C at 0.4 mm/Hg to provide 2.0 g of a colorless liquid. This was dissolved in 7 mL IPA, neutralized with about 40 drops of concentrated HCl, followed by 50 mL anhydrous Et2O with stirring. The initially clear solution spontaneously deposited a white crystalline solid. This was diluted with an additional 30 mL Et2O, let stand for 1 h, and the solids removed by filtration. After Et2O washing, the product was air-dried to yield 1.25 g of 3,4-diethoxy-5-methoxyphenethylamine hydrochloride (ASB) with a mp of 142-143 deg C. Anal. (C13H22ClNO3) C,H. DOSAGE: 200 - 280 mg. DURATION: 10 - 15 h. QUALITATIVE COMMENTS: (with 240 mg) There was a pleasant and easy flow of day-dreaming thoughts, quite friendly and somewhat erotic. There was a gentle down-drift to my starting baseline mental status by about midnight (I started at 9:00 AM). I never quite made it to a +++, and rather regretted it. (with 280 mg) The plateau of effect was evident by hour two, but I found the experience lacking the visual and interpretive richness that I had hoped for. Sleep was very fitful after the effects had largely dropped Q it was hard to simply lie back and relax my guard Q and even while being up and about the next day I felt a residual plus one. Over all, there were few if any of the open interactions of 2C-B or LSD. Some negative side seemed to be present. (with 280 mg) The entire session was, in a sort of way, like being in a corridor outside the lighted halls where a beautiful mescaline experience is taking place, sensing the light from behind a grey door, and not being able to find my way in from the dusky underside passageways. This is sort of a gentle sister of mescaline, but with a tendency to emphasize (for me, at this time) the negative, the sad, the struggling. Sleep was impossible before the fifteenth hour. When I tried, I got visions of moonlight in the desert, with figures around me which were the vampire-werewolf aspect of the soul, green colored and evil. I had to sit quietly in the living room and wait patiently until they settled back to wherever they belonged and stopped trying to take over the scene. During the peak of the experience, my pulse was thready, somewhat slowed, and uneven. There was a faint feeling of physical weirdness. EXTENSIONS AND COMMENTARY: This specific amine was a target for a single study in cats many years ago, in Holland, using material obtained from Hoffman La Roche in Basel. Their findings are hard to evaluate, in that 200 milligrams was injected into a 3.75 kilogram cat (53 mg/Kg), or about twice the dosage that they used in their studies with metaescaline. Within 5 minutes there were indications of catatonia, and within a half hour the animal was unable to walk. This condition persisted for two days, at which time the animal died. Although this dose was many times that used in man, perhaps hints of the physical unease and long action are there to be gleaned. The consensus from over a half dozen experiments is that there is not enough value to be had to offset the body load experienced. A comment is needed on the strange name asymbescaline! In the marvelous world of chemical nomenclature, bi- (or di-) usually means two of something, and tri- and tetra- quite reasonably mean three and four of something. But occasionally there can be an ambiguity with bi (or tri or tetra) in that bi some-thing-or-other might be two something-or-others hooked together or it might be two things hooked onto a something-or-other. So, the former is called bi- and the latter is called bis-. This compound is not two escalines hooked together (bi-escaline) but is only one of them with two ethyl groups attached (bis-escaline or bescaline). And since there are two ways that this can be done (either symmetrically or asymmetrically) the symmetric one is called symbescaline (or SB for short) and this one is called asymbescaline (or ASB for short). To complete the terminology lecture, the term tri- becomes tris- (the name given for the drug with all three ethoxy groups present in place of the methoxys of mescaline) and the term tetra- mutates into the rather incredible tetrakis-! #10 B; BUSCALINE; 4-(n)-BUTOXY-3,5-DIMETHOXYPHENETHYLAMINE SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for preparation), 100 mg decyltriethylammonium iodide, and 11 g n-butyl bromide in 50 mL anhydrous acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux for 10 h. An additional 6 g of n-butyl bromide was added to the mixture, and the refluxing continued for another 48 h. The mixture was filtered, the solids washed with acetone, and the solvent from the combined filtrate and washes removed under vacuum. The residue was suspended in acidified H2O, and extracted with 3x175 mL CH2Cl2. The pooled extracts were washed with 2x50 mL 5% NaOH, once with dilute HCl, and then stripped of solvent under vacuum giving 13.2 g of a deep yellow oil. This was distilled at 132-145 deg C at 0.2 mm/Hg to yield 5.0 g of 4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile as a pale yellow oil which set up to crystals spontaneously. The mp was 42-43 deg C. Anal. (C14H19NO3) C H N. A solution of AH was prepared by the cautious addition of 0.67 mL of 100% H2SO4 to 25 mL of 1.0 M LAH in THF, which was being vigorously stirred under He at ice bath temperature. A total of 4.9 g of 4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile was added as a solid over the course of 10 min. Stirring was continued for another 5 min, then the reaction mixture was brought to reflux on the steam bath for another 45 min. After cooling again to room temperature, IPA was added to destroy the excess hydride (about 5 mL) followed by 10 mL of 15% NaOH which was sufficient to make the aluminum salts loose, white, and filterable. The reaction mixture was filtered, the filter cake washed with IPA, and the mother liquor and washes combined and the solvent removed under vacuum to yield an amber oil. This residue was treated with dilute H2SO4 which generated copious solids. Heating this suspension effected solution, and after cooling, all was washed with 3x50 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 2x100 mL CH2Cl2. The extracts were evaporated to a residue under vacuum, and this was distilled at 128-138 deg C at 0.5 mm/Hg yielding 3.8 g of a colorless oil. This was dissolved in 40 mL IPA, neutralized with concentrated HCl (about 55 drops required) and, with vigorous stirring, 80 mL of anhydrous Et2O was added which produced fine white plates. After standing for several h, the product was filtered, washed with 20% IPA in Et2O, and finally with Et2O. Air drying yielded 3.9 g of 4-(n)-butyloxy-3,5-dimethoxyphenethylamine hydrochloride (B) with a mp of 152-153 deg C. An analytical sample melted at 155-157 deg C. Anal. (C14H24ClNO3) C,H,N. DOSAGE: greater than 150 mg. DURATION: several hours. QUALITATIVE COMMENTS: (with 120 mg) There is a strange taste, not really bitter, it does not linger. The slight change of baseline has certainly disappeared by the eighth hour. No noticeable changes in either the visual or the auditory area. (with 150 mg) Throughout the experiment it was my impression that whatever effects were being felt, they were more in body than mind. The body load never mellowed out, as it would have with mescaline, after the first hour or two. Mental effects didn't develop in any interesting way. I was aware of brief heart arrhythmia. Tummy was uncomfortable, off and on, and there was light diarrhea. Even as late as the fifth hour, my feet were cold, and the whole thing left me with a slightly uncomfortable, 'Why did I bother?' feeling. EXTENSIONS AND COMMENTARY: There is a jingle heard occasionally in chemical circles, concerning the homologues of methyl. It goes, "There's ethyl and propyl, but butyl is futile." And to a large measure this is true with the 4-position homologues of mescaline. This butyl compound, B or Buscaline, had originally been patented in England in 1930 without any physical or pharmacological description, and the few physical studies that had involved it (lipophilic this and serotonin that) suggested that it was less active than mescaline. In principle, the 5-, the 6-, the 7- and the on-up homologues might be called amylescaline (possibly pentescaline?), hexescaline, heptescaline (possibly septescaline), and God-knows-what-scaline. They would certainly be easily makeable, but there would be little value that could be anticipated from nibbling them. In keeping with the name B (for butoxy), these would be known as A (for amyloxy, as the use of a P could confuse pentoxy with propoxy), as H (for hexyloxy, but careful; this letter has been used occasionally for DMPEA, which is Homopiperonylamine), and as S (the H for heptyloxy has been consumed by the hexyloxy, so let's shift from the Greek hepta to the Latin septum for the number seven). It seems most likely that the toxic symptoms that might well come along with these phenethylamines would discourage the use of the dosage needed to affect the higher centers of the brain. The same generally negative feeling applies to the amphetamine counterparts 3C-B, 3C-A, 3C-H and 3C-S. A brief reiteration of the 2C-3C nomenclature, to avoid a possible misunderstanding. The drug 2C-B is so named in that it is the two-carbon chain analogue of the three-carbon chain compound DOB. The drug 3C-B is so named because it is the three-carbon chain analogue of the two-carbon chain compound Buscaline, or more simply, B. There is no logical connection whatsoever, either structural or pharmacological, between 2C-B and 3C-B. #11 BEATRICE; N-METHYL-DOM; 2,5-DIMETHOXY-4,N-DIMETHYLAMPHETAMINE SYNTHESIS: A fused sample of 5.0 g of white, crystalline free base 2,5-dimethoxy-4-methylamphetamine, DOM, was treated with 10 mL ethyl formate, and held at reflux on the steam bath for several h. Removal of the solvent gave 5.5 g of a white solid, which could be recrystallized from 15 mL MeOH to give 3.8 g of fine white crystals of 2,5-dimethoxy-N-formyl-4-methylamphetamine. An analytical sample from ethyl formate gave granular white crystals. To a stirred suspension of 4.0 g LAH in 250 mL anhydrous Et2O at reflux and under an inert atmosphere, there was added, by the shunted Soxhlet technique, 4.2 g of 2,5-dimethoxy-N-formyl-4-methylamphetamine as rapidly as its solubility in hot Et2O would allow. The mixture was held at reflux for 24 h and then stirred at room temperature for several additional days. The excess hydride was destroyed with the addition of dilute H2SO4 (20 g in 500 mL water) followed by the additional dilute H2SO4 needed to effect a clear solution. The Et2O was separated, and the aqueous phase extracted with 100 mL Et2O and then with 2x250 mL CH2Cl2. Following the addition of 100 g potassium sodium tartrate, the mixture was made basic with 25% NaOH. The clear aqueous phase was extracted with 3x250 mL CH2Cl2 These extracts were pooled, and the solvent removed under vacuum. The residual amber oil was dissolved in 400 mL anhydrous Et2O, and saturated with hydrogen chloride gas. The white crystals that formed were removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 4.2 g of product with a mp of 131.5-133.5 deg C. This product was recrys-tallized from 175 mL boiling ethyl acetate to give 3.5 g 2,5-dimethoxy-4,N-di-methylamphetamine hydrochloride (BEATRICE) as pale pink crystals with a mp of 136-137 deg C. A sample obtained from a preparation that employed the methyl sulfate methylation of the benzaldehyde adduct of DOM had a mp of 125-126 deg C and presented a different infra-red spectrum. It was, following recrystallization from ethyl acetate, identical to the higher melting form in all respects. DOSAGE: above 30 mg. DURATION: 6 - 10 h. QUALITATIVE COMMENTS: (with 20 mg) There was a gentle and demanding rise from the one to the three hour point that put me into an extremely open, erotic, and responsive place. I had to find a familiar spot to orient myself, and the kitchen served that need. As the experience went on, it showed more and more of a stimulant response, with tremor, restlessness, and a bit of trouble sleeping. But there was no anorexia! An OK experience. (with 30 mg) There is a real physical aspect to this, and I am not completely happy with it. There is diarrhea, and I am restless, and continuously aware of the fact that my body has had an impact from something. The last few hours were spent in talking, and I found myself still awake some 24 hours after the start of the experiment. The mental was not up there to a +++, and yet the physical disruption was all that I might care to weather, and exceeds any mental reward. When I did sleep, my dreams were OK, but not rich. Why go higher? EXTENSIONS AND COMMENTARY: This is another example of the N-methyl homologues of the psychedelics. None of them seem to produce stuff of elegance. It is clear that the adding of an N-methyl group onto DOM certainly cuts down the activity by a factor of ten-fold, and even then results in something that is not completely good. Three milligrams of DOM is a winner, but even ten times this, thirty milligrams of N-methyl-DOM, is somewhat fuzzy. In the rabbit hyperthermia studies, this compound was some 25 times less active than DOM, so even animal tests say this is way down there in value. This particular measure suggests that the active level in man might be 75 milligrams. Well, maybe, but I am not at all comfortable in trying it at that level. In fact I do not intend to explore this any further whatsoever, unless there is a compelling reason, and I see no such reason. For the moment, let us leave this one to others, who might be more adventurous but less discriminating. In browsing through my notes I discovered that I had made another N-substitution product of DOM. Efforts to fuse free-base DOM with the ethyl cyclopropane carboxylate failed, but the reaction between it and the acid chloride in pyridine gave the corresponding amide, with a mp of 156-157 deg C from MeOH. Anal. (C16H23NO3) C,H,N. This reduced smoothly to the corresponding amine, N-cyclopropyl-2,5-dimethoxy-4-methylamphetamine which formed a hydrochloride salt melting at 153-156 deg C. I can't remember the reasoning that led to this line of synthesis, but it must not have been too exciting, as I never tasted the stuff. #12 BIS-TOM; 4-METHYL-2,5-bis-(METHYLTHIO)AMPHETAMINE SYNTHESIS: A solution of 9.0 g 2,5-dibromotoluene in 50 mL petroleum ether was magnetically stirred under a He atmosphere. To this there was added 50 mL of a 1.6 M hexane solution of butyllithium, and the exothermic reaction, which produced a granular precipitate, was allowed to stir for 12 h. The mixture was cooled to 0 deg C and there was then added 7.5 g dimethyldisulfide. There was a heavy precipitate formed, which tended to become lighter as the addition of the disulfide neared completion. After 20 min additional stirring, the reaction mixture was poured into H2O that contained some HCl. The phases were separated and the aqueous phase extracted with 50 mL Et2O. The organic phase and extract were combined, washed with dilute NaOH, and then with H2O. After drying over anhydrous K2CO3, the solvent was removed under vacuum and the residue distilled to give a fraction that boiled at 75-85 deg C at 0.3 mm/Hg and weighed 5.3 g. This was about 80% pure 2,5-bis-(methylthio)toluene, with the remainder appearing to be the monothiomethyl analogues. A completely pure product was best obtained by a different, but considerably longer, procedure. This is given here only in outline. The phenolic OH group of 3-methyl-4-(methylthio)phenol was converted to an SH group by the thermal rearrangement of the N,N-dimethylthioncarbamate. The impure thiophenol was liberated from the product N,N-dimethylthiolcarbamate with NaOH treatment. The separation of the phenol/thiophenol mixture was achieved by a H2O2 oxidation to produce the intermediate 3-methyl-4-methylthiophenyldisulfide. This was isolated as a white crystalline solid from MeOH, with a mp of 78-79 deg C. Anal. (C16H18S4) C,H. It was reduced with zinc in acetic acid, and the resulting thiophenol (a water-white liquid which was both spectroscopically and microanalytically correct) was methylated with methyl iodide and KOH in MeOH to give the desired product, 2,5-bis-(methylthio)toluene, free of any contaminating mono-sulfur analogues. A solution of 3.9 g of 2,5-bis-(methylthio)toluene in 20 mL acetic acid was treated with a crystal of iodine followed by the addition of 3.5 g elemental bromine. This mixture was heated on the steam bath for 1 h, which largely discharged the color and produced a copious evolution of HBr. Cooling in an ice bath produced solids that were removed by filtration. Recrystallization from IPA gave 1.9 g of 2,5-bis-(methylthio)-4-bromotoluene as a white crystalline solid with a mp of 133-134 deg C. Anal. (C9H11BrS2) C,H. An alternate synthesis of this intermediate was achieved from 1,4-dibromobenzene which was converted to the 1,4-bis-(methylthio)benzene (white crystals with a mp of 83.5-84.5 deg C) with sodium methylmercaptide in hexamethylphosphoramide. This was dibrominated to 2,5-dibromo-1,4-bis-(methylthio)benzene in acetic acid (white platelets from hexane melting at 195-199 deg C). This, in Et2O solution, reacted with BuLi to replace one of the bromine atoms with lithium, and subsequent treatment with methyl iodide gave 2,5-bis-(methylthio)-4-bromotoluene as an off-white solid identical to the above material (by TLC and IR) but with a broader mp range. A solution of 2.4 g 2,5-bis-(methylthio)-4-bromotoluene in 100 mL anhydrous Et2O, stirred magnetically and under a He atmosphere, was treated with 10 mL of a 1.6 M solution of butyllithium in hexane. After stirring for 10 min there was added 2.5 mL N-methylformanilide which led to an exothermic reaction. After another 10 min stirring, the reaction mixture was added to 100 mL dilute HCl, the phases were separated, and the aqueous phase extracted with 2x50 mL Et2O. The combined organic phase and extracts were dried over anhydrous K2CO3, and the solvent removed under vacuum. The partially solid residue was distilled at 140-150 deg C at 0.2 mm/Hg to give a crystalline fraction that, after recrystallization from 15 mL boiling IPA gave 2,5-bis-(methylthio)-4-methylbenzaldehyde as a yellow-brown solid which weighed 1.1 g and had a mp of 107-109 deg C. An analytical sample from MeOH melted at 110-111 deg C with an excellent IR and NMR. Anal. (C10H12OS2) C,H. An alternate synthesis of this aldehyde employs the 2,5-bis-(methylthio)toluene described above. A CH2Cl2 solution of this substituted toluene containing dichloromethyl methyl ether was treated with anhydrous AlCl3, and the usual workup gave a distilled fraction that spontaneously crystallized to the desired aldehyde but in an overall yield of only 11% of theory. To a solution of 0.5 g 2,5-bis-(methylthio)-4-methylbenzaldehyde in 15 mL nitroethane there was added 0.15 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 1 h. The excess solvent was removed under vacuum and the residue was dissolved in 10 mL boiling MeOH. This solution was decanted from a little insoluble residue, and allowed to cool to ice bath temperature yielding, after filtering and drying to constant weight, 0.55 g of 1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene as pumpkin-colored crystals with a mp of 90-91 deg C. This was not improved by recrystallization from EtOH. Anal. (C12H15NO2S2) C,H. A cooled, stirred solution of 0.5 g LAH in 40 mL THF was put under an inert atmosphere, cooled to 0 deg C with an external ice bath, and treated with 0.42 mL 100% H2SO4, added dropwise. A solution of 0.5 g 1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene in 20 mL anhydrous THF was added over the course of 5 min, and the reaction mixture held at reflux for 30 min on the steam bath. After cooling again to ice temperature, the excess hydride was destroyed by the addition of IPA and the inorganics were converted to a loose, white filterable form by the addition of 1.5 mL 5% NaOH. These solids were removed by filtration and the filter cake was washed with 2x50 mL IPA. The combined filtrate and washings were stripped of solvent under vacuum to give a residue that was a flocculant solid. This was suspended in dilute H2SO4 and extracted with 2x50 mL CH2Cl2, and the combined organics extracted with 2x50 mL dilute H3PO4. The aqueous extracts were made basic, and the product removed by extraction with 2x75 mL CH2Cl2. After removal of the solvent under vacuum, the residue was distilled at 126-142 deg C at 0.2 mm/Hg to give 0.2 g of product which crystallized in the receiver. This was dissolved in 1.5 mL hot IPA, neutralized with 4 drops of concentrated HCl, and diluted with 3 mL anhydrous Et2O to give, after filtering and air drying, 0.2 g. of 2,5-bis-(methylthio)-4-methylamphetamine hydrochloride (BIS-TOM) as white crystals with a mp of 228-229 deg C. Anal. (C12H20ClNS2) C,H. DOSAGE: greater than 160 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 160 mg) I was vaguely aware of something in the latter part of the afternoon. A suggestion of darting, physically (when going to sleep), but nothing at the mental level. This is as high as I will go. EXTENSIONS AND COMMENTARY: It is reasonable, in retrospect, to accept that BIS-TOM is not an active compound. The replacement of the 2-position oxygen of DOM with a sulfur atom (to give 2-TOM) dropped the potency by a factor of 15x, and the replacement of the 5-position oxygen with a sulfur atom (to give 5-TOM) dropped the potency by a factor of about 10x. It would be a logical calculation that the replacement of both oxygen atoms with sulfur might drop the potency by a factor of 150x. So, with DOM being active at maybe 5 milligrams, a logical prediction of the active level of BIS-TOM would be 750 milligrams. And maybe this would be the right level, but with the hints of neurological disturbance that seemed to be there at 160 mg, there was no desire to go up by a factor of five again. The rewards would simply not be worth the risks. The 2-carbon analogue, 2C-BIS-TOM, was prepared from the intermediate aldehyde above, first by reaction with nitromethane to give the nitrostyrene as tomato-colored crystals from EtOAc, mp 145-146 deg C. Anal. (C11H13NO2S2) C,H. This was reduced with AH to give 2,5-bis-(methylthio)-4-methylphenethylamine hydrochloride as ivory-colored crystals with a mp of 273-277 deg C. Although there are many interesting psychedelic drugs with sulfur atoms in them (the TOM's, the TOET's, the ALEPH's and all of the 2C-T's), there just aren't many that contain two sulfur atoms. BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably also fail, as the phenethylamines are rarely more potent than the corresponding amphetamines. This leaves 2C-T-14 as the remaining hope, and its synthesis is still underway. #13 BOB; beta-METHOXY-2C-B; 4-BROMO-2,5-beta-TRIMETHOXYPHENETHYLAMINE SYNTHESIS: To a vigorously stirred suspension of 2.1 g 4-bromo-2,5-dimethoxy-beta-nitrostyrene [from 4-bromo-2,5-dimethoxybenzaldehyde and nitromethane in acetic acid with ammonium acetate as a catalyst, mp 157-158 deg C, anal. (C10H10BrNO4) C,H] in 20 mL anhydrous MeOH, there was added a solution of sodium methoxide in MeOH (generated from 0.5 g metallic sodium in 20 mL anhydrous MeOH). After a few min there was added 10 mL acetic acid (no solids formed) followed by the slow addition of 50 mL of H2O. A cream-colored solid was produced, which was removed by filtration and washed well with H2O. After air drying the product, 1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane, weighed 2.0 g. An analytical sample from MeOH was off-white in color and had a mp of 119-120 deg C. Anal. (C11H14BrNO5) C,H. A solution of LAH (15 mL of 1 M solution in THF) was diluted with an equal volume of anhydrous THF, and cooled (under He) to 0 deg C with an external ice bath. With good stirring there was added 0.38 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 1.0 g 1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane as a solid over the course of 5 min. After an hour of stirring at 0 deg C, the temperature was brought up to a gentle reflux on the steam bath for 30 min. There was no vigorous exothermic reaction seen, unlike that with the syntheses of BOD, BOH and BOM. The reaction mixture was cooled again to 0 deg C, and the excess hydride was destroyed by the cautious addition of IPA. This was followed by sufficent dilute aqueous NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed first with THF fol-lowed by IPA. The combined filtrate and washings were stripped of solvent under vacuum and dissolved in dilute H2SO4, with the apparent generation of yellow solids. This was washed with 2x50 mL CH2Cl2, and the aqueous phase made basic with NaOH. This was extracted with 2x50 mL CH2Cl2, and the pooled extracts were stripped of solvent under vacuum. The residue was distilled at 130-150 deg C at 0.2 mm/Hg to give 0.2 g of product as a clear white oil. This fraction was dissolved in 10 mL IPA, and neutralized with 4 drops concentrated HCl. The addition of 30 mL anhydrous Et2O allowed the formation of 4-bromo-2,5,beta-trimethoxyphenethylamine hydrochloride (BOB) as a fine white crystalline product. This was removed by filtration, washed with Et2O, and air dried. There was obtained 0.1 g white crystals with a mp of 187-188 deg C. Anal. (C11H17BrClNO3) C,H. DOSAGE: 10 - 20 mg. DURATION: 10 - 20 h. QUALITATIVE COMMENTS: (with 10 mg) I don't know if it was me this day, or if it was the chemical, but I got into a granddaddy of a paranoid, sociopathic snit, without feeling and without emotion. I was indifferent to everything. Later on, there was some improvement, with body tingling (good, I'm pretty sure) and a sense of awareness (good, I guess) but I still canceled my evening dinner company. All in all, pretty negative. (with 10 mg) I had to get away and into myself, so I weeded in the vegetable garden for almost an hour. Then I lay down in the bedroom, and enjoyed a magnificent vegetable garden, in Southern France, in my mind's eye. An extraordinary zucchini. And the weeds had all been magically pulled. In another couple of hours a neurological over-stimulation became apparent, and I spent the rest of the day defending myself. In the evening, I took 100 milligrams phenobarbital which seemed to smooth things just enough. Too bad. Nice material, otherwise. (with 15 mg) The erotic was lustful, but at the critical moment of orgasm, the question of neurological stability became quite apparent. Does one really let go? Everything seemed a bit irritable. The tinnitus was quite bad, but the excitement of the rich altered place I was in was certainly worth it all. Through the rest of the day, I became aware of how tired I was, and how much I wanted to sleep, and yet how scared I was to give myself over to sleep. Could I trust the body to its own devices without me as an overseeing caretaker? Let's risk it. I slept. The next day there was a memory of this turmoil. Clearly the first part of the experience might have been hard to define, but it was quite positive. But the last part makes it not really worth while. EXTENSIONS AND COMMENTARY: This compound, BOB, is the most potent of the BOX series. And yet, as with all of the members of this family, there are overtones of physical concern, and of some worry as to the integrity of the body. There may well be a separation of activity with the two optical isomers, but there is not a tremendous push to explore this particular family much further. They can't all be winners, I guess. What would be the activities of compounds with a sulfur instead of an oxygen at the beta-oxygen position? What would be the nature of action if there were an alpha-methyl group, making all of these into amphetamine derivatives? Or what about both a sulfur and a methyl group? And what about the isomers that are intrinsic to all of this, the threo- and the erythro- and the "D's" and the "L's"? All this is terra incognita, and must someday be looked into. It is chemically simple, and pharmacologically provocative. Someone, somewhere, someday, answer these questions! #14 BOD; beta-METHOXY-2C-D; 4-METHYL-2,5,beta-TRIMETHOXYPHENETHYLAMINE SYNTHESIS: A solution of 39.6 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitrostyrene (see recipe for 2C-D for its preparation) in 300 mL warm MeOH was prepared. Separately, a solution of 9 g elemental sodium in 150 mL MeOH was also prepared. This sodium methoxide solution was added to the well-stirred nitrostyrene solution, which resulted in a dramatic loss of color. There was then added 75 mL acetic acid, and all was poured into 2 L H2O. This was extracted with 3x100 mL CH2Cl2. The pooled extracts were stripped of solvent, and the 35 g of residue was treated with 5 mL MeOH, allowed to stand for a short while, decanted from some insoluble residue, and the separated clear solution kept at 0 deg C overnight. There was the deposition of a yellow crystalline product which, after removal by filtration and air drying, weighed 9.7 g. Recrystallization from 25 mL MeOH gave, after filtering and drying, 8.4 g of canary-yellow crystals of 1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane with a mp of 78-79 deg C. Evaporation of the mother liquors from the filtration of the first crop yielded 3.8 g of additional product which, upon recrystallization from 11 mL MeOH, provided another 2.7 g with a mp of 77-78 deg C. Further workup of the mother liquors yielded only impure starting nitrostyrene. A solution of LAH (96 mL of 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 2.4 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 10.8 g 1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane. There was immediate discoloration. After the addition was complete, the reaction mixture was held at reflux on the steam bath for 2 h. After cooling again, the excess hydride was destroyed with 4 mL IPA and the reaction mixture made basic with 15% NaOH. The insoluble inorganic salts were removed by filtration, and the filter cake was washed first with THF, and then with IPA. The bright yellow filtrate and washes were pooled and stripped of solvent under vacuum, yielding 14 g of a yellow oil. This was suspended in 1 L dilute H2SO4 to give an ugly, cloudy, yellow-orange mess. Extraction with 3x75 mL CH2Cl2 removed much of the color, and the remaining aqueous phase was made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2. Evaporation of the solvent under vacuum gave 9 g of a pale amber oil which was distilled at 115-130 deg C at 0.4 mm/Hg. The water-white distillate was dissolved in 15 mL IPA, neutralized with concentrated HCl, and then diluted with 70 mL anhydrous Et2O. After a few min, white crystals formed, and these were removed by filtration and Et2O washed. When air-dried to constant weight, 4.49 g brilliant white crystals of 4-methyl-2,5,beta-trimethoxyphenethylamine hydrochloride (BOD) with a mp of 171-172 deg C with decomposition, were obtained. The mother liquors on standing deposited 0.66 g additional crystals which were impure and were discarded. Anal. (C12H20ClNO3) C,H. DOSAGE: 15 - 25 mg. DURATION: 8 - 16 h. QUALITATIVE COMMENTS: (with 20 mg) There were some very pleasant visuals starting at 2-2.5 hours and continuing to 4-5 hours after the beginning of the experiment. Open eye visuals seem to come on after staring at particular areas, such as the living room ceiling or at trees. The surroundings tended to move slightly. There was no flowing of the images at all. When looking at the pine trees, the needles appeared crystal clear and sharply defined, with strong contrasts. Though the mental effect is difficult to define, I am not sure it was all that great. I did become tired of the effect (along with the confusion) after 8 hours, and was quite happy to note that it did taper off in the early evening. I am not particularly sure I would want to try this material again. (with 20 mg) For the first three or so hours, the beauty of the experience was marred by a strange discomfort. There was some queasiness, and I felt a sluggishness of mind. Then I began moving in and out of a pleasant place, and finally the discomfort completely dissolved and the experience turned full on. Height of beauty, visual perception. Lights below are amazing. Outside, marvelous sense of Presence. There is not an elation, as often with other materials, but a strong, even powerful sense of goodness, inner strength, solidity. (with 25 mg) This was quite quick. The onset of the experience was apparent within a half hour, and we were both at +++ within the hour. Body load minimal. There was very little visual, compared with some materials. Very interesting eyes-closed, but not continually Q just now and then an intense vision might flash. Very benign and friendly and pleasant and good-humored feeling. Superb for conversation and conceptualization. (with 25 mg) The body load was quite noticeable for everyone. But the general state of mind was excellent; everyone was extremely relaxed and funny. Puns, insults, delightful amusement. Not very much insight work possible. Juices were needed and tolerated well, but no one was particularly hungry. Sleep was difficult for most people, not deep and not too refreshing. Excellent material, but body price a bit too much for the mental effects. Pleasant, and I wouldn't hesitate to take it again, but nothing very memorable except the tremendous humor and laughter, which was truly delightful. EXTENSIONS AND COMMENTARY: This compound, BOD, was the first exploratory member of a new family of phenethylamines. This family is called the BOX series because an oxygen atom has been put on the benzylic carbon (the "benzyl-oxy" or "BO") of each of several well studied drugs with recognized substituent patterns on the aromatic ring. The "X" would be "D," as used here with BOD, making reference to 2C-D, it would be a "B" in BOB making reference to 2C-B, etc. Actually the original thought was to make the "O" into an "OM" for methoxy, as this would allow more versatility in the naming of things such as ethoxys ("OE") or hydroxys ("OH"), but the methoxylated 2C-B analogue would have come out as BOMB, so the idea was dropped. Actually, the concept of naming of drugs with some acronym that is pronounceable has led into some interesting byways. Some examples have been unintended. I have heard DOM pronounced "dome" and DOET pronounced as "do it." And elsewhere I have mentioned the embarrassing occasions where the TOM and TOET families were pronounced "the toms and twats." Some examples have had names that have been contractions of popular names, such as XTC for ecstasy. And there are instances where a name might be proposed simply to irritate the newspaper people. An early street suggestion for PCP was FUK, and a current name for free-base methamphetamine is SNOT. And marijuana is fondly called SHIT by its aficionados. The final "A" on government groups such as the CIA or the DEA or the FDA is strongly reminscent of the final "A" which stands for amphetamine in things such as TMA and MDMA. Might there someday be a drug such as 4-cyclopropylmethyl-N-isopropylamphetamine (CIA), or 3,5-dimethoxy-4-ethylamphetamine (DEA)? It has just occurred to me that there is already a 4-fluoro-2,5-dimethoxyamphetamine (FDA), but I have already named it DOF. If all drugs were known only by publicly embarrassing names, there might be less publicity given them by the press. Back to the commentary on BOD. The rationale for this inclusion of a beta-oxygen atom into the structure of a phenethylamine is based directly on the chemistry that occurs naturally in the brain. The phenethylamine neurotransmitter, dopamine, is converted both in the brain and in the body to the equally important transmitter norepinephrine by just this sort of transformation. There is the enzymatic addition of an oxygen atom to the "benzylic" position of dopamine. And identical chemistry goes on with tyramine in a number of plants and animals, with a similar addition of oxygen to form octopamine, so-named for its discovered presence in the salivary glands of Octopus vulgaris. In the first explorations in the "OX" series, this oxygen was intentionally blocked with a methyl group, to ease its entry into the brain, and increase the possibilities of its being active as a psychedelic. As mentioned above, the "D" in "OD" follows from its ring orientation pattern being the same as that of 2C-D (and this, originally from the mimicking of the pattern of DOM). All of these D- compounds have the 2,5-dimethoxy-4-methyl ring-substitution pattern. An interesting complication is also part of this structure package. The added methoxy group (or hydroxy group, see recipe for BOHD) also adds a new asymmetric center, allowing for the eventual separation of the material into two optical isomers. And at such time as the corresponding amphetamine homologues might be made and studied, the presence of yet another chiral center (under the alpha-methyl group) will demand that there be actually two racemic compounds synthesized, and a total of four isomers to contend with, if really careful and thorough work is to be done. A parallel chemistry to all of this follows the addition of sodium ethoxide (rather than sodium methoxide) to the nitrostyrene. The final product, then, is the ethoxy homologue 2,5-dimethoxy-beta-ethoxy-4-methylphenethylamine, or BOED. It is down in human potency by a factor of three, with a normal dosage being 70-75 milligrams. It has a ten hour duration, and is both anorexic and diuretic. There have been no visual effects or insights reported, but rather simply a highly intoxicated state. Two synonyms, two definitions, and an expression of admiration. The word norepinephrine is synonymous with noradrenalin, and the word epinephrine is synonymous with adrenalin. The distinctions are that the first in each case is American and the second British. And the term "chiral" indicates a potential asymmetry in a molecule that would allow eventual separation into two optical isomers. The term "racemic" refers to a mixture of these two isomers which has not yet been separated into the individual components. A racemic mixture is called a racemate and, from the point of view of the human animal (which is completely asymmetric), must be considered as a mixture of two structurally identical but optically mirror-image isomers, which can be potentially separated and which will certainly have different pharmacologies. And the admiration? This is directed to the explorer who ventured close enough to an octopus to locate its salivary glands and to discover a phenethylamine there! #15 BOH; beta-METHOXY-3,4-METHYLENEDIOXYPHENETHYLAMINE SYNTHESIS: To a solution of 30 g piperonal in 100 mL acetic acid there was added 20 mL nitromethane and 10 mL cyclohexylamine. After heating on the steam bath for 1.5 h, the reaction mixture started to crystallize. The mixture was cooled in an ice bath, and the heavy mass of deposited crystals removed by filtration and washed with 20 mL acetic acid. All was supended in 100 mL warm MeOH, cooled again, and filtered to give 24.5 g of 3,4-methylenedioxy-beta-nitrostyrene as canary-yellow crystals, with a mp of 158-160 deg C. Reduction of this compound with LAH gives rise to MDPEA, which is a separate entry with a recipe of its own. To a vigorously stirred suspension of 20 g 3,4-methylenedioxy-beta-nitro -styrene in 100 mL anhydrous MeOH there was added a freshly prepared solution of 5.5 g elemental sodium in 100 mL MeOH. The nitrostyrene goes into solution over the course of 5 min. There was then added, first, 50 mL acetic acid with the stirring continued for an additional 1 min. There was then added 300 mL H2O. An oil separated and was extracted into 200 mL CH2Cl2. The organic extract was washed with 500 mL dilute aqueous NaHCO3, followed by 500 mL H2O. Removal of the solvent gave a residue that was distilled at 128-145 deg C at 0.4 mm/Hg, providing 16.6 g of a yellow viscous liquid which slowly crystallized. An analytical sample was recrystallized from four volumes of MeOH to give 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane as bright yellow crystals with a mp of 58-59 deg C. Anal. (C10H11NO5) C,H. A solution of LAH (100 mL of 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 2.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 12 g 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane over the course of 2 min. There was an immediate loss of color. After a few minutes further stirring, the temperature was brought up to a reflux with a heating mantle. There was a gentle gas evolution for a few min, followed by an exothermic reaction that exceeded the capacity of the condenser. Once the reaction had subsided, the unreacted hydride was destroyed with a minimum of IPA, and 15% NaOH was added to convert the inorganics to a loose white filterable mass. The reaction mixture was filtered, and the filter cake washed thoroughly with THF. The combined filtrate and washes were stripped of solvent under vacuum, providing an orange oil. This was dissolved in 400 mL dilute H2SO4, which was washed with 3x75 mL CH2Cl2. After making the aqueous phase basic, it was extracted with 2x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue distilled at 103-112 deg C at 0.5 mm/Hg. There was obtained 2.5 g of a colorless, viscous oil which was dissolved in 25 mL IPA, neutralized with 45 drops of concentrated HCl, and finally diluted with 30 mL anhydrous Et2O. There was thus formed beta-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (BOH) as a fine white crystalline product. The mp was 105-106.5 deg C, with bubbling and darkening. The mp properties proved to be inconsistent, as the salt was a hydrate. Recrystallization from CH3CN, or simply heating to 100 deg C in toluene, converted the salt to an anhydrous form, with mp of 152-153 deg C. Anal. (C10H14ClNO3) C,H. DOSAGE: 80 - 120 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 90 mg) Distinct body awareness in an hour. The threshold is mostly physical. Faint sense of inside warmth, skin prickling, cold feet, loose bowels, anorexia. By the fifth hour, I was on the downslope, and in retrospect I found it good humored but not insightful. (with 100 mg) There was a vague nausea, and a chilling of the feet. It reached a real plus two, with dilated pupils and quite a thirst. How can one describe the state? There were no visuals, and I was not even stoned. I was just very turned on. And I was completely back to baseline by hour number six. EXTENSIONS AND COMMENTARY: There are several reports of a nice, mild mood enhancement in the 20-40 milligram dosage area, but searches for psychedelic effects at higher levels gave a strange mix of some sort of an altered state along with bodily discomfort. The BOH name for this member of the BOX family follows the convention discussed in the BOD recipe Q with RHS for homopiperonylamine, the simplest of the muni-metro family, q.v. The demethylated homologue of BOH is BOHH, and is the methylenedioxy analogue of norepinephrine. It might well hydrolytically open up in the body to provide this neurotransmitter, and serve as some sort of transmitter in its own right. It is discussed under DME. Maybe there is something to the concept that when you imitate a neurotransmitter too closely, you get a hybrid gemisch of activity. The term "pro-drug" is used to identify a compound that may not be intrinsically active, but one which metabolizes in the body to provide an active drug. I feel the term should have been pre-drug, but pro-drug was the word that caught on. BOH may well act in the body as a pro-drug to norepinephrine, but with the temporary blocking of the polar functions with ether groups, it can gain access to the brain. And once there, it can be stripped of these shields and play a direct neurological role. I uncovered a very similar analogy in the tryptamine world some years ago. Just as norepinephrine is a neurotransmitter, so is serotonin. And I found that by putting an O-ether on the indolic phenol (to hide its polarity) and an alpha-methyl group next to the primary amine (to protect it from metabolic deaminase), it became an extremely potent, and most complex, psychedelic. This was the compound alpha,O-dimethylserotonin, or a,O-DMS. There is an uncanny analogy between this tryptamine and the phenethylamine BOH. Somehow the quiet voice deep inside me says, don't use too much, too quickly. Maybe one of the optical isomers is the body thing, and the other isomer is the mind thing. So far, only the racemic mixture has been tasted, to the best of my knowledge. #16 BOHD; 2,5-DIMETHOXY-beta-HYDROXY-4-METHYLPHENETHYLAMINE SYNTHESIS: A solution of 0.4 g 1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane (see preparation in the recipe for BOD) in 3.0 mL acetic acid was heated to 100 deg C on a steam bath. There was added 1.0 g powdered zinc, followed by additional acetic acid as needed to maintain smooth stirring. After 0.5 h there was added 1.0 mL concentrated HCl and, following an additional few minutes heating, the reaction mixture was poured into 300 mL H2O. After washing the aqueous phase with 3x75 mL CH2Cl2, the mixture was made basic with 25% NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent and distillation of the residue at 130-140 deg C 0.25 mm/Hg gave an oil that, on dissolving in IPA, neutralization with concentrated HCl, and the addition of anhydrous Et2O, gave beautiful white crystals of 2,5-dimethoxy-beta-hydroxy-4-methylphenethylamine hydrochloride (BOHD). The yield was 0.2 g, and the mp was 180-181 deg C. The infrared spectrum was that of an amine salt with a strong OH group present. Anal. (C11H18ClNO3) C,H. DOSAGE: greater than 50 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 50 mg) At about the two hour point, there was a precipitous drop of blood pressure (from 120/72 to 84/68) although the pulse stayed steady at 60. This trend had been apparent in earlier trials, and was being watched carefully. No further tests are planned. EXTENSIONS AND COMMENTARY: The usual method of making beta-ethanolamine such as this is through the reduction of the cyanohydrin of the corresponding benzaldehyde and, in fact, that method is described in the recipe for DME. This above procedure was actually part of an exploration of different agents that might be used in the reduction of the intermediate nitroalkane. This product was the unexpected result of trying zinc. Why the potent cardiovascular effect seen by this compound? There are a couple of points that might argue for some adrenolytic toxicity. This material is a beta-ethanolamine and, with maybe one or two exceptions, clinically used beta-receptor blockers are beta-ethanolamines. In fact, a few of these so-called beta-blockers actually have two methoxy groups on the aromatic rings, also a property of BOHD. The antidiabetic drug Butaxamine (BW 64-9 in the code of Burroughs Wellcome) is identical to BOHD except that the 4-methyl group is on the alpha-carbon instead, and there is a tertiary butyl group on the nitrogen atom. Another point involves the proximity of the beta-hydroxy group and the methoxyl oxygen atom in the 2-position of the ring. There is going to be a strong hydrogen-bonding with this orientation, with the formation of a stable six-membered ring. This might help obscure the hydrophilic nature of the free hydroxyl group and allow the compound to pass into the brain easily. If this group is masked by an easily removed group such as an acetate ester, one gets the compound beta-acetoxy-3,4-dimethoxy-4-methylphenethylamine (BOAD) which is similar to BOHD as a hypotensive. The code-naming procedure used here (and elsewhere here in Book II) is: (1) to use RBOS as the alert to there being an oxygen on the benzyl carbon of a phenethylamine (it is a benzyl alcohol); (2) if there is just one more letter (a third and last letter) it will identify the 2C-X parent from which it has been derived [RBS comes from 2C-B, RDS comes from 2C-D, RHS comes from homopiperonylamine (MDPEA) rather than from 2C-H, RMS comes from mescaline, and in every case the beta-substituent is a methoxy group]; and (3) if there are four letters, then the fourth letter is as above, and the third letter (the next to last letter) is the substituent on that benzylic oxygen. With a three letter code, the substituent is a methyl group, an RHS for a third letter of four makes it a hydroxyl group, and an RAS for the third letter is an acetyl group, and an RES is for an ethyl group. A similar sort of cryptographic music was composed by Du Pont in their three-number codes for the Freons. The first number was one less than the number of carbons in the molecule, the second number was one more than the number of hydrogens in the molecule, the third number was the exact number of fluorines in the molecule, and the rest of the bonds were filled with chlorines, Thus Freon 11 (really Freon 011) was trichlorofluoromethane and Freon 116 was hexafluoroethane. Complex, yes. But both systems are completely straightforward, and flexible for future creations. A few additional examples of similar beta-ethanolamines are scattered throughout Book II and they have, in general, proved to be uninteresting, at least as potential psychedelic compounds. #17 BOM; beta-METHOXYMESCALINE; 3,4,5,beta-TETRAMETHOXYPHENETHYLAMINE SYNTHESIS: To a vigorously stirred suspension of 9.0 g beta-nitro-3,4,5-trimethoxystyrene (see under the recipe for M for the preparation of this intermediate) in 50 mL anhydrous MeOH there was added a solution obtained from the addition of 2.0 g metallic sodium to 50 mL anhydrous MeOH. The bright orange color faded to a light cream as the nitrostyrene went into solution. After 3 min there was added 30 mL acetic acid, which produced white solids, and this was followed by further dilution with 150 mL H2O. The formed solids were removed by filtration, washed well with H2O, and recrystallized from 150 mL boiling MeOH. After removal of the product by filtration and air drying to constant weight, there was obtained 6.9 g of 1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane as fine, cream-colored crystals. The mp was 143-144 deg C, and the Rf by TLC (silica-gel plates and CH2Cl2 as moving phase) was identical to that of the starting aldehyde. Anal. (C12H17NO6) C,H. A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 6 g of solid 1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane over the course of 2 min. There was some gas evolution. After 5 min additional stirring, the temperature was brought up to a reflux with a heating mantle. There was a gentle gas evolution for a few minutes, followed by an exothermic reaction with vigorous gas evolution. Once everything had settled down, the reaction mixture was held at reflux temperature for an additional 2 h. The excess hydride was destroyed by the addition of IPA and 15% NaOH was added to convert the inorganic salts to a loose white filterable mass. The reaction mixture was filtered, and the filter cake washed thoroughly with THF. The combined filtrate and washes were stripped of solvent under vacuum which provided a red-brown liquid. This was dissolved in dilute H2SO4 and washed with 3x75 mL CH2Cl2. After making the aqueous phase basic with NaOH, it was extracted with 2x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the colorless residue distilled at 120-150 deg C at 0.3 mm/Hg. There was obtained 2.8 g of a colorless oil which was dissolved in 30 mL IPA and neutralized with concentrated HCl, allowing the spontaneous formation of the hydrochloride salt. This was diluted with 75 mL anhydrous Et2O, yielding 2.8 g 3,4,5,beta-tetramethoxyphenethylamine hydrochloride (BOM) as a white crystalline product. This had a mp of 198.5-199.5 deg C. Anal. (C12H20ClNO4) C,H. DOSAGE: greater than 200 mg. DURATION: unknown. EXTENSIONS AND COMMENTARY: There are some indicators of central activity with assays involving both the 120 milligram and the 180 milligram levels, but nothing that can be rated as over a plus one. It can be seen with the two active members of the BOX series (BOD and BOB) that the potency is about equal to, or a little more (up to a factor of maybe x2), than the analogue without the methoxyl group on the aliphatic chain. If this formula were to hold in the relationship between mescaline and BOM, the active level might well be in the 200-400 milligram range. But at the moment, it remains unknown. Again, the name of the compound (BOM) is from the RBO-S prefix of this family (from benzyl + oxy), plus the RMS of mescaline (which has provided the ring substitution pattern). #18 4-BR-3,5-DMA; 3,5-DIMETHOXY-4-BROMOAMPHETAMINE SYNTHESIS: The starting material 3,5-dimethoxy-4-bromobenzoic acid (made from the commercially available resorcinol by the action of methyl sulfate) was a white crystalline solid from aqueous EtOH with a mp of 248-250 deg C. Reaction with thionyl chloride produced 3,5-dimethoxy-4-bromobenzoyl chloride which was used as the crude solid product, mp 124-128 deg C. This was reduced with tri-O-(t)-butoxy lithium aluminum hydride to produce 3,5-dimethoxy-4-bromobenzaldehyde which was recrystallized from aqueous MeOH and had a mp of 112-114 deg C. Anal. (C9H9BrO3) C,H. This aldehyde, with nitroethane and anhydrous ammonium acetate in acetic acid, was converted to the nitrostyrene 1-(3,5-dimethoxy-4-bromophenyl)-2-nitropropene, with a mp of 121-121.5 deg C. Anal. (C11H12BrNO4) C,H,N. This was reduced at low temperature with just one equivalent of LAH, to minimize reductive removal of the bromine atom. The product 3,5-dimethoxy-4-bromoamphetamine hydrochloride (4-BR-3,5-DMA) was isolated in a 37% yield and had a mp of 221-222 deg C. Anal. (C11H17BrClNO2) C,H,N. DOSAGE: 4 - 10 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 3 mg) This is certainly no placebo. At about 2 hours I felt some analgesia and numbing in my extremities, but if there were any sensory distortions, they were barely perceptible. (with 6 mg) There is a very shallow threshold, no more. (with 10 mg) I can certainly confirm the indications of anesthesia that were hinted at. It was for me central in nature, however. I could (this at three hours) pierce a skin pinch on my left arm with no bother except for the emerging of the needle due to skin resistance. There was little bleeding. And multiple needle prickings into the thumb abductor were not felt. A quick plunge of the tip of my little finger into boiling water elicited reflex response, but no residual pain. Judgment was OK, so I stayed out of physical trouble, luckily! The perhaps ++ was dropping in the fourth or fifth hour, and by the tenth hour there were few effects still noted, except for some teeth-rubbiness and a burning irritation at the pin-prick area, so feeling is back. No sleep problems at just past midnight. EXTENSIONS AND COMMENTARY: Here is a complex and, at the moment, totally undefined drug. There were two independent reports of analgesia, yet a thorough screen in experimental animals, conducted by a major pharmaceutical house, failed to confirm any of it. A ++ report does not necessarily reflect a psychedelic effect, since this quantitative measure of the level of activity represents the extent of impairment of function, regardless of the nature of the drug producing it. In other words, if you were experiencing the effects of a drug that would in your judgment interfere with safe and good driving, this would be a ++ whether your performance was being limited by a psychedelic, a stimulant, a hypnotic or a narcotic. None of the quantitative reports ever mentioned any sensory distortion (analgesia is a loss, not a distortion) or visual effect. Perhaps 4-BR-3,5-DMA showed its ++ as a narcotic. But then, the rats had said no. #19 2-BR-4,5-MDA; 6-BR-MDA; 2-BROMO-4,5-METHYLENEDIOXYAMPHETAMINE SYNTHESIS: A solution of 3,4-methylenedioxyamphetamine (MDA) in acetic acid was treated with elemental bromine, generating the hydrobromide salt of 2-bromo-4,5-methylenedioxyamphetamine in a yield of 61% of theory. The mp was 221-222 deg C. Anal. (C10H13Br2NO2) C,H,Br. DOSAGE: 350 mg. DURATION: unknown. EXTENSIONS AND COMMENTARY: Both the synthetic and the pharmacological details for this compound are sparse. There has been only a single report of the human activity of this drug in the literature, and the statement has been offered that the effects are amphetamine-like. No other qualitative comments have been made available, and neither I nor anyone in my circle has tried it, personally. Someday, perhaps. But at that high level, perhaps not. #20 2C-B; 4-BROMO-2,5-DIMETHOXYPHENETHYLAMINE SYNTHESIS: A solution of 100 g of 2,5-dimethoxybenzaldehyde in 220 g nitromethane was treated with 10 g anhydrous ammonium acetate, and heated on a steam bath for 2.5 h with occasional swirling. The deep-red reaction mixture was stripped of the excess nitromethane under vacuum, and the residue crystallized spontaneously. This crude nitrostyrene was purified by grinding under IPA, filtering, and air-drying, to yield 85 g of 2,5-dimethoxy-beta-nitrostyrene as a yellow-orange product of adequate purity for the next step. Further purification can be achieved by recrystallization from boiling IPA. In a round-bottomed 2 L flask equipped with a magnetic stirrer and placed under an inert atmosphere, there was added 750 mL anhydrous THF, containing 30 g LAH. There was then added, in THF solution, 60 g 2,5-dimethoxy-beta-nitrostyrene. The final solution was a dirty yellow-brown color, and it was kept at reflux temperature for 24 h. After cooling, the excess hydride was destroyed by the dropwise addition of IPA. Then 30 mL 15% NaOH was added to convert the inorganic solids to a filterable mass. The reaction mixture was filtered and the filter cake washed first with THF and then with MeOH. The combined mother liquors and washings were freed of solvent under vacuum and the residue suspended in 1.5 L H2O. This was acidified with HCl, washed with with 3x100 mL CH2Cl2, made strongly basic with 25% NaOH, and reextracted with 4x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, yielding 26 g of oily residue, which was distilled at 120-130 deg C at 0.5 mm/Hg to give 21 g of a white oil, 2,5-dimethoxy-phenethylamine (2C-H) which picks up carbon dioxide from the air very quickly. To a well-stirred solution of 24.8 g 2,5-dimethoxyphenethylamine in 40 mL glacial acetic acid, there was added 22 g elemental bromine dissolved in 40 mL acetic acid. After a couple of min, there was the formation of solids and the simultaneous evolution of considerable heat. The reaction mixture was allowed to return to room temperature, filtered, and the solids washed sparingly with cold acetic acid. This was the hydrobromide salt. There are many complicated salt forms, both polymorphs and hydrates, that can make the isolation and characterization of 2C-B treacherous. The happiest route is to form the insoluble hydrochloride salt by way of the free base. The entire mass of acetic acid-wet salt was dissolved in warm H2O, made basic to at least pH 11 with 25% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent gave 33.7 g of residue which was distilled at 115-130 deg C at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50 mL H2O containing 7.0 g acetic acid. This clear solution was vigorous stirred, and treated with 20 mL concentrated HCl. There was an immediate formation of the anhydrous salt of 2,5-dimethoxy-4-bromophenethylamine hydrochloride (2C-B). This mass of crystals was removed by filtration (it can be loosened considerably by the addition of another 60 mL H2O), washed with a little H2O, and then with several 50 mL portions of Et2O. When completely air-dry, there was obtained 31.05 g of fine white needles, with a mp of 237-239 deg C with decomposition. When there is too much H2O present at the time of adding the final concentrated HCl, a hydrated form of 2C-B is obtained. The hydrobromide salt melts at 214.5-215 deg C. The acetate salt was reported to have a mp of 208-209 deg C. DOSAGE: 12 - 24 mg. DURATION: 4 - 8 h. QUALITATIVE COMMENTS: (with 16 mg) A day at the Stanford museum. Things were visually rich, yet I felt that I was reasonably inconspicuous. The Rodin sculptures were very personal and not terribly subtle. I saw Escher things in the ceiling design, when I decided to sit in a foyer somewhere and simply pretend to rest. Walking back, the displays seen in the bark of the eucalyptus trees, and the torment and fear (of others? of themselves?) in the faces of those who were walking towards us, were as dramatic as anything I had seen in the art galleries. Our appetites were enormous, and we went to a smorgasbord that evening. A rich experience in every possible way. (with 20 mg) The drug effect first became known to me as a shift of colors toward golden and rose tones. Pigments in the room became intensified. Shapes became rounder, more organic. A sensation of lightness and rivulets of warmth began seeping through my body. Bright lights began pulsing and flashing behind my closed lids. I began to perceive waves of energy flowing through all of us in unison. I saw all of us as a gridwork of electrical energy beings, nodes on a bright, pulsating network of light. Then the interior landscape shifted into broader scenes. Daliesque vistas were patterned with eyes of Horus, brocades of geometric design began shifting and changing through radiant patterns of light. It was an artist's paradise Q representing virtually the full pantheon of the history of art. (with 20 mg) The room was cool, and for the first hour I felt cold and chilled. That was the only mildly unpleasant part. We had been hanging crystals earlier that day, and the visions I had were dominated by prismatic light patterns. It was almost as if I became the light. I saw kaleidoscopic forms Q similar to, but less intense than, when on acid Q and organic forms like Georgia O'Keefe flowers, blossoming and undulating. My body was flooded with orgasms Q practically from just breathing. The lovemaking was phenomenal, passionate, ecstatic, lyric, animal, loving, tender, sublime. The music was voluptuous, almost three-dimensional. Sometimes the sound seemed distorted to me, underwater like. This was especially so for the less good recordings Q but I could choose to concentrate on the beauty of the music or the inadequacy of the sound's quality, and mostly chose to concentrate on the beauty. (with 24 mg) I am totally into my body. I am aware of every muscle and nerve in my body. The night is extraordinary Q moon full. Unbelievably erotic, quiet and exquisite, almost unbearable. I cannot begin to unravel the imagery that imposes itself during the finding of an orgasm. Trying to understand physical/spiritual merging in nature Q . EXTENSIONS AND COMMENTARY: Four quotations were chosen arbitrarily from literally hundreds that have worked their ways into the files. The vast majority are positive, ranging from the colorful to the ecstatic. But not all are. There are people who choose not to go into the corporeal but, rather, prefer the out-of-body experience. They express discomfort with 2C-B, and seem to lean more to the Ketamine form of altered state, one which dissociates body from mind. There have been reports of several overdoses that prove the intrinsic safety of this compound. Prove is used here in the classic British sense; i.e., to challenge. "The proof of the pudding is in the eating," is not a verification of quality, but an inquiry into the quality itself. (The French simplify all this by using two separate verbs for prove.) One overdose was intentional, the other accidental. (with 64 mg) I found only mild visual and emotional effects at the 20 milligram dose, so I took the remaining 44 milligrams. I was propelled into something not of my choosing. Everything that was alive was completely fearsome. I could look at a picture of a bush, and it was just that, a picture, and it posed no threat to me. Then my gaze moved to the right, and caught a bush growing outside the window, and I was petrified. A life-form I could not understand, and thus could not control. And I felt that my own life-form was not a bit more controllable. This was from the comments of a physician who assured me that he saw no neurological concerns during this dramatic and frightening experience. (with 100 mg) I had weighed correctly. I had simply picked up the wrong vial. And my death was to be a consequence of a totally stupid mistake. I wanted to walk outside, but there was a swimming pool there and I didn't dare fall into it. A person may believe that he has prepared himself for his own death, but when the moment comes, he is completely alone, and totally unprepared. Why now? Why me? Two hours later, I knew that I would live after all, and the experience became really marvelous. But the moment of facing death is a unique experience. In my case, I will some day meet it again, and I fear that I will be no more comfortable with it then than I was just now. This was from the comments of a psychologist who will, without doubt, use psychedelics again in the future, as a probe into the unknown. Many of the reports that have come in over the years have mentioned the combination of MDMA and 2C-B. The most successful reports have followed a program in which the two drugs are not used at the same time, nor even too closely spaced. It appears that the optimum time for the 2C-B is at, or just before, the final baseline recovery of the MDMA. It is as if the mental and emotional discoveries can be mobilized, and something done about them. This combination has several enthusiastic advocates in the psychotherapy world, and should be the basis of careful research when these materials become legal, and accepted by the medical community. A generalized spectrum of 2C-B action can be gleaned from the many reports that have been written describing its effects. (1) There is a steep dose response curve. Over the 12 to 24 milligram range, every 2 milligrams can make a profound increase or change of response. Initially, one should go lightly, and increase the dosage in subsequent trials by small increments. A commonly used term for a level that produces a just perceptible effect is "museum level." This is a slightly-over-threshold level which allows public activities (such as viewing paintings in a museum or scenery watching as a passenger in a car) to be entered into without attracting attention. There can be considerable discomfort associated with being in the public eye, with higher doses. (2) The 2C-B experience is one of the shortest of any major psychedelic drug. Wherever you might be, hang on. In an hour or so you will be approaching familiar territory again. (3) If there is anything ever found to be an effective aphrodisiac, it will probably be patterned after 2C-B in structure. There are two "Tweetios" known that are related to 2C-B. (See recipe #23 for the origin of this phrase.) The 2-EtO- homologue of 2C-B is 4-bromo-2-ethoxy-5-methoxyphenethylamine, or 2CB-2ETO. The unbrominated benzaldehyde (2-ethoxy-5-methoxybenzaldehyde) had a melting point of 47.5-48.5 deg C, the unbrominated nitrostyrene intermediate a melting point of 76-77 deg C, and the final hydrochloride a melting point of 185-186 deg C. The hydrobromide salt had a melting point of 168.5-169.5 deg C. It seems that one gets about as much effect as can be had, with a dosage of about 15 milligrams, and increases above this, to 30 and to 50 milligrams merely prolong the activity (from about 3 hours to perhaps 6 hours). At no dose was there an intensity that in any way resembled that of 2C-B. The 2,5-DiEtO- homologue of 2C-B is 4-bromo-2,5-diethoxyphenethylamine, or 2CB-2,5-DIETO. The unbrominated impure benzaldehyde (2,5-diethoxybenzaldehyde) had a melting point of about 57 deg C, the unbrominated impure nitrostyrene intermediate a melting point of about 60 deg C, and the final hydrochloride a melting point of 230-231 deg C. The hydrobromide salt had a melting point of 192-193 deg C. At levels of 55 milligrams, there was only a restless sleep, and strange dreams. The active level is not yet known. I have been told of some studies that have involved a positional rearrangement analogue of 2C-B. This is 2-bromo-4,5-dimethoxyphenethylamine (or 6-BR-DMPEA). This would be the product of the elemental bromination of DMPEA, and it has been assayed as the hydrobromide salt. Apparently, the intravenous injection of 60 milligrams gave a rapid rush, with intense visual effects reported, largely yellow and black. Orally, there may be some activity at the 400 to 500 milligram area, but the reports described mainly sleep disturbance. This would suggest a stimulant component. The N-methyl homologue of this rearranged compound was even less active. #21 3C-BZ; 4-BENZYLOXY-3,5-DIMETHOXYAMPHETAMINE SYNTHESIS: A solution of 268 g 2,6-dimethoxyphenol and 212 g allyl bromide in 700 mL dry acetone was treated with 315 g anhydrous K2CO3 and held at reflux for 16 h. The solvent was removed under vacuum, and the residue dissolved in H2O and extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with 5% NaOH, then with H2O, and the solvent removed under vacuum. The residue, which weighed 245 g, was stirred and heated in an oil bath to 230 deg C at which point an exothermic reaction set in. The heating was maintained at 230 deg C for 0.5 h, and then the reaction mixture distilled. There was obtained a total of 127 g of 5-allyl-1,3-dimethoxy-2-hydroxybenzene as a colorless distillate, that was identical in all respects to natural 5-methoxyeugenol obtained from Oil of Nutmeg. A solution containing 40.4 g 5-methoxyeugenol and 26.6 g benzyl chloride in 65 mL EtOH was added, all at once, to a hot and well stirred solution of 11.7 g KOH in 500 mL EtOH. The potassium salt of the phenol crystallized out immediately. By maintaining reflux conditions, this slowly redissolved, and was replaced by the steady deposition of KCl. After 6 h, the reaction mixture was cooled, and the solids removed by filtration. The filtrate was stripped of solvent under vacuum to give 57 g of crude 5-allyl-2-benzyloxy-1,3-dimethoxybenzene. This was dissolved in a solution of 60 g KOH in 80 mL EtOH and heated on the steam bath for 16 h. The reaction mixture was quenched in 500 mL H2O, and extracted with 2x200 mL CH2Cl2. Removal of the solvent under vacuum gave 35.6 g of crude 2-benzyloxy-1,3-dimethoxy-5-propenylbenzene. To a stirred, ice-cold solution of 33.6 g of the above impure 2-benzyloxy-1,3-dimethoxy-5-propenylbenzene and 13.6 g pyridine in 142 mL acetone, there was added 24.6 g tetranitromethane. After stirring for 3 min, there was added a solution of 7.9 g KOH in 132 mL H2O, followed by additional H2O. The oily phase that remained was H2O washed, and then diluted with an equal volume of MeOH. This slowly set up to yellow crystals, which were removed by filtration and washed sparingly with MeOH. There was obtained 9.2 g 1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene with a mp of 84-85 deg C. An analytical sample, from EtOH, had a mp of 86-87 deg C. To a refluxing suspension of 5.5 g LAH in 360 mL anhydrous Et2O under an inert atmosphere, there was added 8.6 g 1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene by letting the condensing Et2O leach out a saturated solution from a modified Soxhlet condenser. The addition took 1.5 h and the refluxing was maintained for an additional 4 h. After cooling, the excess hydride was destroyed by the cautious addition of 330 mL of 1.5 N H2SO4. The aqueous phase was heated up to 80 deg C, filtered through paper to remove a small amount of insoluble material, and treated with a solution of 8 g picric acid in 150 mL boiling EtOH. Cooling in the ice chest overnight gave globs of the amine picrate, but no clear signs of crystallization. These were washed with cold H2O, then dissolved in 5% NaOH to give a bright yellow solution. This was extracted with 3x150 mL CH2Cl2, the solvent removed under vacuum, the residue dissolved in 300 mL anhydrous Et2O, freed from a little particulate material by filtration through paper, and then saturated with hydrogen chloride gas. There was thus obtained, after filtering, Et2O washing and air drying, 2.5 g 4-benzyloxy-3,5-dimethoxyamphetamine hydrochloride (3C-BZ) as a white solid with a mp of 161-164 deg C. DOSAGE: 25 - 200 mg. DURATION: 18 - 24 h. QUANTITATIVE COMMENTS: (with 25 mg) I went into an emotionally brittle place, and for a while I was uncomfortable with childhood reminiscences. The seeing of my family's Christmas tree in my mind was almost too much. I cried. (with 50 mg) The action is distinct Q wakeful Q alerting and wound up. Hypnogogic imagery, and I could not sleep at night with my mind doing many uncontrolled, tangential, busy things. I had fleeting nausea early in the process. (with 100 mg) I took this in two portions. Following 50 milligrams I was aware of a slight light-headedness at a half-hour, but there was little else. At 1 1/2 hours, I took the second 50 milligrams and the augmentation of effects was noted in another half hour. The experience quietly built up to about the fifth hour, with some erotic fantasy and suggestions of changes in the visual field. I could not sleep until the twelfth hour, and my dreams were wild and not too friendly. There was no body threat from this, but I was not completely baseline until the next day. I am not too keen to do this again Q it lasts too long. (with 100 mg) No effects. (with 150 mg) This is in every way identical to 100 micrograms of LSD. (with 180 mg) I can compare this directly to TMA which was the material I took last week. Many similarities, but this is unquestionably more intense than the TMA was at 200 milligrams. It is hard to separate the degree of impact that this drug has, from the simple fact that it lasts forever, and I was getting physically tired but I couldn't sleep. There is some amphetamine-like component, more than with TMA. EXTENSIONS AND COMMENTARY: Two points are worthy of commentary; the potency and the promise of 3C-BZ. As to potency, there is such uncertainty as to the effective dose, that it is for all intents and purposes impossible to predict just what dose should be considered for a person's first time with this. The choice of quotations was made with the intention of giving a picture of this scatter. A total of ten subjects have explored this compound, and the very broad range given above, 25 to 200 milligrams, reflects the degree of variation that has been encountered. Which is a shame, because the concept of a new ring such as is found here on the 4-position would have allowed an extremely wide array of substituents. Electron-rich things, electron-poor things, heavy things, light things, and on and on. This could have been a location of much variation, but it is a possibility that the uncertainties of dosage might extrapolate to these novel ring substitutions as well. Only a single variation was made, the 4-fluorobenzyl analogue. This was prepared following exactly the procedure given here for 3C-BZ, except for the replacement of benzyl chloride with 4-fluorobenzyl chloride. The allyl intermediate was an oil, but the propenyl isomer gave solids with a melting point of 59-60 deg C from hexane. The nitrostyrene was a yellow crystalline solid from methanol with a melting point of 98-99 deg C. The end product, 3,5-dimethoxy-4-(4-fluorobenzyloxy)amphetamine hydrochloride (3C-FBZ) was a white solid with a melting point of 149-150 deg C. It has been assayed only up to 4 milligrams and there was absolutely no activity of any kind observed at that level. #22 2C-C; 2,5-DIMETHOXY-4-CHLOROPHENETHYLAMINE SYNTHESIS: (from 2C-H) The free base of 2,5-dimethoxyphenethylamine was generated from its salt (see recipe for 2C-H for the preparation of this compound) by treating a solution of 16.2 g of the hydrochloride salt in 300 mL H2O with aqueous NaOH, extraction with 3x75 mL CH2Cl2, and removal of the solvent from the pooled extracts under vacuum. The colorless residue was dissolved in 75 mL glacial acetic acid (the solids that initially formed redissolved completely) and this was cooled to 0 deg C with an external ice bath. With vigorous stirring, there was added 4.0 mL of liquid chlorine, a little bit at a time with a Pasteur pipette. The theoretical volume was 3.4 mL, but some was lost in pipetting, some on contact with the 0 deg C acetic acid, and some was lost by chlorination of the acetic acid. The reaction turned a dark amber color, was allowed to stir for an additional 10 min, then quenched with 400 mL H2O. This was washed with 3x100 mL CH2Cl2 (which removed some of the color) then brought to neutrality with dilute aqueous NaOH and treated with a small amount of sodium dithionite which discharged most of the color (from deep brown to pale yellow). The reaction was made strongly basic with aqueous KOH, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed once with H2O and the solvent was removed under vacuum leaving about 10 mL of a deep amber oil as residue. This was dissolved in 75 mL IPA and neutralized with concentrated HCl which allowed spontaneous crystallization. These crystals were removed by filtration, washed with an additional 20 mL IPA, and air-dried to constant weight. There was thus obtained 4.2 g 2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) with a mp of 218-221 deg C. Recrystallization from IPA increased this to 220-222 deg C. The position of chlorination on the aromatic ring was verified by the presence of two para-protons in the NMR, at 7.12 and 7.20 ppm from external TMS, in a D2O solution of the hydrochloride salt. Synthesis from 2C-B. To a solution of 7.24 g 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 4.5 g phthalic anhydride in 100 mL anhydrous DMF there was added molecular sieves. After 16 h reflux, the reaction mixture was cooled and the sieves removed by filtration. The addition of a little CH2Cl2 prompted the deposition of yellow crystals which were recrystallized from EtOH. The resulting 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane weighed 7.57 g and had a mp of 141-142 deg C. Anal. (C18H16BrNO4) C,H,N,Br. A solution of 14.94 g of 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane and 4.5 g cuprous chloride in 300 mL anhydrous DMF was heated for 5 h at reflux. The cooled mixture was poured into 20 mL H2O that contained 13 g hydrated ferric chloride and 3 mL concentrated HCl. The mixture was maintained at about 70 deg C for 20 min, and then extracted with CH2Cl2. After washing the pooled organic extracts with dilute HCl and drying with anhydrous MgSO4, the volatiles were removed under vacuum to provide a solid residue. This was recrystallized from EtOH to provide 12.18 g of 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane as yellow needles that had a mp of 138-140 deg C. Anal. (C18H16ClNO4) C,H,N,Cl. To 60 mL absolute EtOH there was added 12.2 g 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane and 2.9 mL of 100% hydrazine. The solution was held at reflux for 15 min. After cooling, the cyclic hydrazone by-product was removed by filtration, and the alcoholic mother liquors taken to dryness under vacuum. The residue was distilled at 145-155 deg C at 0.05 mm/Hg to give 5.16 g of a clear, colorless oil. This was dissolved in anhydrous Et2O and treated with hydrogen chloride gas, producing 2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) as white crystals with a mp of 220-221 deg C. Anal. (C10H15Cl2NO2) C,H,N. DOSAGE: 20 - 40 mg. DURATION: 4 - 8 h. QUALITATIVE COMMENTS: (with 20 mg) This is longer lived than 2C-B, and there is a longer latency in coming on. It took an hour and a half, or even two hours to get there. It had a slight metallic overtone. (with 24 mg) I was at a moderately high and thoroughly favorable place, for several hours. It seemed to be a very sensual place, but without too much in the way of visual distraction. (with 40 mg) There were a lot of visuals Q something that I had noted at lower levels. There seems to be less stimulation than with 2C-B, and in some ways it is actually sedating. And yet I was up all night. It was like a very intense form of relaxation. EXTENSIONS AND COMMENTARY: Other reports mention usage of up to 50 milligrams which seems to increase yet further the intensity and the duration. I have one report of an intravenous administration of 20 milligrams, and the response was described as overwhelming. The effects peaked at about 5 minutes and lasted for perhaps 15 minutes. The halogens represent a small group of atoms that are unique for a couple of reasons. They are all located in a single column of the periodic table, being monovalent and negative. That means that they can be reasonably stable things when attached to an aromatic nucleus. But, being monovalent, they cannot be modified or extended in any way. Thus, they are kind of a dead end, at least as far as the 2C-X series is considered. The heaviest, iodine, was explored as the phen-ethylamine, as 2C-I, and as the amphetamine as DOI. These are the most potent. The next lighter is bromine, where the phenethylamine is 2C-B and the amphetamine is DOB. These two are a bit less potent, and are by far the most broadly explored of all the halides. Here, in the above recipe, we have the chlorine counterpart, 2C-C. There is also the corresponding amphetamine DOC. These are less potent still, and much less explored. Why? Perhaps because chlorine is a gas and troublesome to handle (bromine is a liquid, and iodine is a solid). The fluorine analogue is yet harder to make, and requires procedures that are indirect, because fluorine (the lightest of all the halides) is not only a gas, but is dangerous to handle and does not react in the usual halogen way. There will be mention made of 2C-F, but DOF is still unexplored. The treatment of the 2C-B phthalimide described above, with cuprous cyanide rather than cuprous chloride, gave rise to the cyano analog which, on hydrolysis with hydrazine, yielded 2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with hot, strong base gave the corresponding acid, 2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of either of these compounds has been made in the human animal, as far as I know. #23 2C-D; LE-25; 2,5-DIMETHOXY-4-METHYLPHENETHYLAMINE SYNTHESIS: Into 1 L H2O that was being stirred magnetically, there was added, in sequence, 62 g toluhydroquinone, 160 mL 25% NaOH, and 126 g dimethyl sulfate. After about 2 h, the reaction mixture was no longer basic, and another 40 mL of the 25% NaOH was added. Even with stirring for a few additional days, the reaction mixture remained basic. It was quenched in 2.5 L H2O, extracted with 3x100 mL CH2Cl2 and the pooled extracts stripped of solvent under vacuum. The remaining 56.4 g of amber oil was distilled at about 70 deg C at 0.5 mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The aqueous residues, on acidification, provided a phenolic fraction that distilled at 75-100 deg C at 0.4 mm/Hg to give 5.8 g of a pale yellow distillate that partially crystallized. These solids (with mp of 54-62 deg C) were removed by filtration, and yielded 3.1 g of a solid which was recrystallized from 50 mL hexane containing 5 mL toluene. This gave 2.53 g of a white crystalline product with a mp of 66-68 deg C. A second recrystallization (from hexane) raised this mp to 71-72 deg C. The literature value given for the mp of 2-methyl-4-methoxyphenol is 70-71 deg C. The literature value given for the mp of the isomeric 3-methyl-4-methoxyphenol is 44-46 deg C. This phenol, on ethylation, gives 2-ethoxy-5-methoxytoluene, which leads directly to the 2-carbon 2CD-5ETO (one of the Tweetios) and the 3-carbon Classic Lady IRIS. A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide was heated for 10 min on the steam bath, and then there was added 30.4 g of 2,5-dimethoxytoluene. Heating was continued for 2.5 h, and the viscous, black, ugly mess was poured into 600 mL of warm H2O and stirred overnight. The resulting rubbery miniature-rabbit-droppings product was removed by filtration and sucked as free of H2O as possible. The 37.2 g of wet product was extracted on the steam-bath with 4x100 mL portions of boiling hexane which, after decantation and cooling, yielded a total of 15.3 g of yellow crystalline product. This, upon recrystallization from 150 mL boiling hexane, gave pale yellow crystals which, when air dried to constant weight, represented 8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde, and had a mp of 83-84 deg C. Anal. (C8H12O3) C,H,N. The Gattermann aldehyde synthesis gave a better yield (60% of theory) but required the use of hydrogen cyanide gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3 g malononitrile in absolute EtOH, treated with a drop of triethylamine, was an orange crystalline product. A sample recrystallized from EtOH gave a mp of 138.5-139 deg C. A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde in 30 g nitromethane was treated with 1.1 g anhydrous ammonium acetate and heated for 50 min on the steam bath. Stripping off the excess nitromethane under vacuum yielded orange crystals which weighed 12.2 g. These were recrystallized from 100 mL IPA providing yellow crystals of 2,5-dimethoxy-4-methyl-beta-nitrostyrene which weighed, when dry, 7.70 g. The mp was 117-118 deg C, and this was increased to 118-119 deg C upon recrystallization from benzene/heptane 1:2. To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under an inert atmosphere, there was added 7.7 g 2,5-dimethoxy-4-methyl-beta-nitrostyrene in 35 mL THF over the course of 0.5 h. This reaction mixture was held at reflux for 24 h, cooled to room temperature, and the excess hydride destroyed with 25 mL IPA. There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The granular gray mass was filtered, and the filter cake washed with 2x50 mL THF. The combined filtrate and washes were stripped of their volatiles under vacuum to give a residue weighing 7.7 g which was distilled at 90-115 deg C at 0.3 mm/Hg to provide 4.90 g of a clear, white oil, which crystallized in the receiver. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl which produced immediate crystals of the salt. These were dispersed with 80 mL anhydrous Et2O, filtered, and washed with Et2O to give, after air drying to constant weight, 4.9 g of fluffy white crystals of 2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D). The mp was 213-214 deg C which was not improved by recrystallization from CH3CN/IPA mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 deg C. The acetamide, from the free base in pyridine treated with acetic anhydride, was a white crystalline solid which, when recrystallized from aqueous MeOH, had a mp of 116-117 deg C. DOSAGE: 20 - 60 mg. DURATION: 4 - 6 h. QUALITATIVE COMMENTS: (with 10 mg) There is something going on, but it is subtle. I find that I can just slightly redirect my attention so that it applies more exactly to what I am doing. I feel that I can learn faster. This is a `smart' pill! (with 20 mg) Butterflies in stomach whole time. OK. This is about the right level. In retrospect, not too interesting. Primarily a stimulant, not entirely physically pleasant. The visual is not too exciting. I am easily distracted. One line of thought to another. I feel that more would be too stimulating. (with 30 mg) I was into it quite quickly (not much over three-quarters of an hour) and got up to a ++ by the end of an hour. There is something unsatisfactory about trying to classify this level. I had said that I was willing to increase the dose to a higher level, to break out of this not-quite-defined level into something psychedelic. But I may not want to go higher. Under different circumstances I would not mind trying it at a considerably lower dosage, perhaps at the 10 or 15 milligrams. I do not have a comfortable label on this material, yet. (with 45 mg) There was a rocket from the half-hour to the one and a half hour, from nothing up to a +++. Somehow the intimacy and the erotic never quite knit, and I feel that I am always waiting for the experience to come home. Talking is extremely easy, but something is missing. Appetite is good. I am down by the fifth hour, and sleep is comfortable. This compound will take some learning. (with 75 mg) This is a +++, but the emphasis is on talking, not on personal interacting. I am putting out, but my boundaries are intact. I was able to sleep at the sixth hour. Communication was excellent. This is fast on, but not too long lived. Maybe a therapy tool? (with 150 mg) A truly remarkable psychedelic, one which could compare favorably with 2C-B. There are intense colors, and I feel that more would be too much. EXTENSIONS AND COMMENTARY: Wow! This particular compound is what I call a pharmacological tofu. It doesn't seem to do too much by itself, always teasing, until you get to heroic levels. But a goodly number of experimental therapists have said that it is excellent in extending the action of some other materials. It seems to boost the waning action of another drug, without adding its own color to the experience. Yet, the comment above, on the high level of 150 milligrams, is a direct quote from the use of this compound in Germany (where it is called LE-25) in therapeutic research. This is probably the most dramatic example of the loss of potency from an amphetamine (DOM, active at maybe 3 milligrams) to a phenethylamine (only one tenth as active). It is so often the case that the first of a series is not the most interesting nor the most potent member. As intriguing and as difficult-to-define as the 2C-D story might be, the next higher homologue of this set, 2C-E, is maximally active at the 15 to 20 milligram level, and is, without any question, a complete psychedelic. The N-monomethyl and the N,N-dimethyl homologues of 2C-D have been synthesized from 2C-D. The N-monomethyl compound was obtained by the quaternization of the Schiff's base formed between 2C-D and benzaldehyde with methyl sulfate, followed by hydrolysis; the hydrochloride salt had a melting point of 150-151 deg C, from EtOH. The N,N-dimethyl compound resulted from the action of formaldehyde-formic acid on 2C-D; the hydrochloride salt had a melting point of 168-169 deg C from EtOH/ether. These two compounds were some ten times less effective in interfering with conditioned responses in experimental rats. There is no report of their having been explored in man. I have learned of an extensive study of ethoxy homologues of a number of the phenethylamines in the 2C-X series; they have been collectively called the "Tweetios." This Sylvester and Tweety-bird allusion came directly from the compulsive habit of trying to alleviate the boredom of driving long distances (not under the influence of anything) by the attempt to pronounce the license plates of cars as they passed. The first of this series of compounds had a name that indicated that there was an ethoxy group at the 2-position, or 2-EtO, or Tweetio, and the rest is history. In every compound to be found in the 2C-X family, there are two methoxy groups, one at the 2-position and one at the 5-position. There are thus three possible tweetio compounds, a 2-EtO-, a 5-EtO- and a 2,5-di-EtO-. Those that have been evaluated in man are included after each of the 2C-X's that has served as the prototype. In general, the 2-EtO- compounds have a shorter duration and a lower potency, the 5-EtO- compounds have a relatively unchanged potency and a longer time duration; the 2,5-di-EtO- homologues are very weak, if active at all. The 2-EtO-homologue of 2C-D is 2-ethoxy-5-methoxy-4-methylphenethylamine, or 2CD-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-tolualdehyde) had a melting point of 60.5-61 deg C, the nitrostyrene intermediate a melting point of 110.5-111.5 deg C, and the final hydrochloride a melting point of 207-208 deg C. The hydrobromide salt had a melting point of 171-173 deg C. At levels of 60 milli-grams, there was the feeling of closeness between couples, without an appreciable state of intoxication. The duration was about 4 hours. The 5-EtO- homologue of 2C-D is 5-ethoxy-2-methoxy-4-methylphenethylamine, or 2CD-5ETO. The benzaldehyde (5-ethoxy-2-ethoxy-4-tolualdehyde) had a melting point of 81-82 deg C, and the details of this synthesis are given in the recipe for IRIS. The nitrostyrene intermediate had a melting point of 112.5-113.5 deg C and the final hydrochloride salt had a melting point of 197-198 deg C. The hydro-bromide salt had a melting point of 158-159 deg C. At dosage levels of 40 to 50 milli-grams, there was a slow, gradual climb to the full effects that were noted in about 2 hours. The experience was largely free from excitement, but with a friendly openness and outgoingness that allowed easy talk, interaction, humor, and a healthy appetite. The duration of effects was 12 hours. The 2,5-di-EtO- homologue of 2C-D is 2,5-diethoxy-4-methylphenethylamine, or 2CD-2,5-DIETO. The benzaldehyde (2,5-diethoxy-4-tolualdehyde) had a melting point of 102-103 deg C, the nitrostyrene intermediate a melting point of 108-109 deg C, and the final hydrochloride salt a melting point of 251-252 deg C. At a level of 55 milligrams, a plus one was reached, and what effects there were, were gone after four hours. #24 2C-E; 2,5-DIMETHOXY-4-ETHYLPHENETHYLAMINE SYNTHESIS: A suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 100 g acetyl chloride. This slurry was added to a vigorously stirred solution of 110 g p-dimethoxybenzene in 300 mL CH2Cl2. Stirring was continued at ambient temperature for an additional 40 min, then all was poured into 1 L water and the phases separated. The aqueous phase was extracted with 2x100 mL CH2Cl2 and the combined organic phases washed with 3x150 mL 5% NaOH. These washes, after combination and acidification, were extracted with 3x75 mL CH2Cl2 and the extracts washed once with saturated NaHCO3. Re-moval of the solvent under vacuum provided 28.3 g of 2-hydroxy-5-methoxyaceto-phenone as yellow crystals which, on recrystallization from 2 volumes of boiling MeOH and air drying, provided 21.3 g of product with a mp of 49-49.5 deg C. Ethyl-ation of this material serves as the starting point for the synthesis of 2CE-5ETO. The CH2Cl2 fraction from the base wash, above, was stripped of solvent on the rotary evaporator to give a residual oil that, on distillation at 147-150 deg C at the water pump, provided 111.6 g of 2,5-dimethoxyacetophenone as an almost white oil. In a round bottom flask equipped with a reflux condenser, a take-off adapter, an immersion thermometer, and a magnetic stirrer, there was placed 100 g 2,5-dimethoxyacetophenone, 71 g 85% KOH pellets, 500 mL of triethylene glycol, and 125 mL 65% hydrazine. The mixture was brought up to a boil by heating with an electric mantle, and the distillate was removed, allowing the temperature of the pot contents to continuously increase. When the pot temperature had reached 210 deg C, reflux was established and maintained for an additional 3 h. After cooling, the reaction mixture and the distillate were combined, poured into 3 L water, and extracted with 3x100 mL hexane. After washing the pooled extracts with water, the solvent was removed yielding 22.0 g of a pale straw-colored liquid that was free of both hydroxy and carbonyl groups by infrared. This was distilled at 120-140 deg C at the water pump to give 2,5-dimethoxy-1-ethylbenzene as a white fluid product. Acidification of the spent aqueous phase with concentrated HCl produced a heavy black oil which was extracted with 3x100 mL CH2Cl2. Removal of the solvent on the rotary evaporator yielded 78 g.of a black residue that was distilled at 90-105 deg C at 0.5 mm/Hg to provide 67.4 g of an orange-amber oil that was largely 2-ethyl-4-methoxyphenol. This material could eventually be used as a starting material for ethoxy homologues. However, remethylation (with CH3I and KOH in methanol) provided some 28 g additional 2,5-dimethoxyethylbenzene. A solution of 8.16 g of 2,5-dimethoxy-1-ethylbenzene in 30 mL CH2Cl2 was cooled to 0 deg C with good stirring and under an inert atmosphere of He. There was then added 11.7 mL anhydrous stannic chloride, followed by 3.95 mL dichloromethyl methyl ether dropwise over the course of 0.5 h. The stirred reaction mixture was allowed to come up to room temperature, then held on the steam bath for 1 h. The reaction mixture was poured into 1 L water, extracted with 3x75 mL CH2Cl2, and the pooled extracts washed with dilute HCl. The organic phase was stripped under vacuum yielding 10.8 g of a dark viscous oil. This was distilled at 90-110 deg C at 0.2 mm/Hg to yield a colorless oil that, on cooling, set to white crystals. The yield of 2,5-dimethoxy-4-ethylbenzaldehyde was 5.9 g of material that had a mp of 46-47 deg C. After purification through the bisulfite complex, the mp increased to 47-48 deg C. The use of the Vilsmeier aldehyde synthesis (with POCl3 and N-methylformanilide) gave results that were totally unpredictable. The malononitrile derivative (from 0.3 g of this aldehyde and 0.3 g malononitrile in 5 mL EtOH and a drop of triethylamine) formed red crystals which, on recrystallization from toluene, had a mp of 123-124 deg C. A solution of 21.0 g of the unrecrystallized 2,5-dimethoxy-4-ethylbenzaldehyde in 75 g nitromethane was treated with 4 g of anhydrous ammonium acetate and heated on the steam bath for about 2 h. The progress of the reaction was best followed by TLC analysis of the crude reaction mixture on silica gel plates with CH2Cl2 as the developing solvent. The excess solvent/reagent was removed under vacuum yielding granular orange solids that were recrystallized from seven volumes of boiling MeOH. After cooling in external ice-water for 1 h, the yellow crystalline product was removed by filtration, washed with cold MeOH and air dried to give 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene. The mp was 96-98 deg C which improved to 99-100 deg C after a second recrystallization from MeOH. A total of 120 mL of 1.0 M solution of LAH in THF (120 mL of 1.0 M) was transferred to a 3 neck 500 mL flask, under an inert atmosphere with good magnetic stirring. This solution was cooled to deg C with an external ice-water bath, and there was then added 3.0 mL of 100% H2SO4 over the course of 0.5 h. This was followed by a solution of 5.85 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene, in 40 mL of warm THF. The reaction mixture was stirred for 0.5 h, brought to room temperature, heated on the steam bath for 0.5 h, and then returned to room temperature. The addition of IPA dropwise destroyed the excess hydride, and some 4.5 mL of 5% NaOH produce a white cottage cheese, in a basic organic medium. This mixture was filtered, washed with THF, and the filtrate evaporated to produce 2.8 g of an almost white oil. The filter cake was resuspended in THF, made more basic with additional 15 mL of 5% NaOH, again filtered, and the filtrate removed to provide an additional 2.8 g of crude product. These residues were combined and distilled at 90-100 deg C at 0.25 mm/Hg to give a colorless oil. This was dissolved in 30 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O to provide, after spontaneous crystallization, filtration, washing with Et2O, and air drying, 3.87 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) as magnificent white crystals. A similar yield can be obtained from the reduction of the nitrostyrene in a suspension of LAH in THF, without the use of H2SO4. With 11.3 g of LAH in 300 mL dry THF, there was added, dropwise, a solution of 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene in 75 mL THF over the course of 2 h. The mixture was kept at reflux for an additional 8 h, and killed by the careful addition of 11 mL H2O, followed with 11 mL 15% NaOH, and finally another 33 mL of H2O. This mass was filtered, washed with THF, and the combined filtrates and washes evaporated to a residue under vacuum The approximately 15 mL of residue was dissolved in 300 mL CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated HCl. On shaking the mixture, there was deposited a mass of the hydrochloride salt which was diluted with a quantity of additional H2O. The organic phase was extracted with additional dilute HCL, and these aqueous phases were combined. After being made basic with 25% NaOH, this phase was again extracted with 3x75 mL CH2Cl2 and after the removal of the solvent, yielded 12.6 g of a colorless oil. This was dissolved in 75 mL of IPA and neutralized with concentrated HCl. The solidified mass that formed was loosened with another 50 mL IPA, and then filtered. After Et2O washing and air drying there was obtained 7.7 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) as lustrous white crystals. Anal. (C12H20ClNO2) C,H. DOSAGE: 10 - 25 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 16 mg) There was a strange devil-angel pairing. As I was being told of the ecstatic white-light ascent of my partner into the God-space of an out-of-body experience, I was fighting my way out of a brown ooze. She saw the young Jesus at the bottom of a ladder drifting upwards step by step to some taking-off place, and I saw all the funny gargoyles around the base of the ladder surrounded by picnic bunting. For me it was the 4th of July, rather than Easter!S (with 20 mg) The view out of the window was unreal. The garden was painted on the window, and every petal of flower and tuft of grass and leaf of tree was carefully sculptured in fine strokes of oil paint on the surface of the glass. It was not out there; it was right here in front of me. The woman who was watering the plants was completely frozen, immobilized by Vermeer. And when I looked again, she was in a different place, but again frozen. I was destined to become the eternal museum viewer. (with 25 mg) I have a picture in my living room that is a stylized German scene with a man on horseback riding through the woods, and a young girl coming out to meet him from the nearby trees. But she was not just 'coming out.' He was not just riding through the woods. The wind was blowing, and his horse was at full gallop, and his cape was flapping in the storm, and she was bearing down upon him at full bore. The action never ceased. I became exhausted. (with 25 mg) Within minutes I was anxious and sweaty. Each person has his own brand of toxic psychosis Q mine always starts with the voices in my head talking to me, about all my worst fears, a jumble of warnings and deep fears spinning faster. Twenty minutes later this complex chaos passed as quickly as it had come. At lower dosages 2C-E has been a truly enjoyable esthetic enhancer. But it really has a steep dose/response curve. EXTENSIONS AND COMMENTARY: Here is another of the magical half-dozen. The range is purposefully broad. At 10 milligrams there have been some pretty rich +++ experiences, and yet I have had the report from one young lady of a 30 milligram trial that was very frightening. My first experience with 2C-E was really profound, and it is the substance of a chapter within the story. The amphet-amine homologue is DOET, which is not only much longer in action, but considerably more potent. Several people have said, about 2C-E, "I don't think I like it, since it isn't that much fun. But I intend to explore it again." There is something here that will reward the experimenter. Someday, the full character of 2C-E will be understood, but for the moment, let it rest as being a difficult and worth-while material. A very much worth-while material. One Tweetio of 2C-E is known. The 5-EtO-homologue of 2C-E is 5-ethoxy-4-ethyl-2-methoxyphenethylamine, or 2CE-5ETO. The nitrostyrene intermediate had a melting point of 110-110.5 deg C, and the final hydrochloride a melting point of 184-185 deg C. The effective level of 2CE-5ETO is in the 10 to 15 milligram range. It is gentle, forgiving, and extremely long lived. Some 3 to 4 hours were needed to achieve plateau, and on occasion experi-ments were interrupted with Valium or Halcion at the 16 hour point. After a night's sleep, there were still some effects evident the next day. Thus, the dose is comparable to the parent compound 2C-E, but the duration is 2 to 3 times longer. It was given the nickname "Eternity" by one subject. #25 3C-E; 3,5-DIMETHOXY-4-ETHOXYAMPHETAMINE SYNTHESIS: A solution of 3.6 g syringaldehyde (3,5-dimethoxy-4- hydroxybenzaldehyde) in 50 mL MeOH was combined with a solution of 3.7 g 85% KOH in 75 mL warm MeOH. This clear solution suddenly set up to crystals of the potassium salt, too thick to stir satisfactorily. To this suspension there was added 7.4 g ethyl iodide (a large excess) and the mixture was held at reflux temperature with a heating mantle. The solids eventually loosened and redissolved, giving a clear amber-colored smooth-boiling solution. Refluxing was maintained for 2 days, then all volatiles were removed under vacuum. The residue was dissolved in 400 mL H2O, made strongly basic with 25% NaOH, and extracted with 4x100 mL CH2Cl2. The pooled extracts were washed with saturated brine, and the solvent removed under vacuum to give 3.3 g of a pale amber oil which set up as crystals of 3,5-dimethoxy-4-ethoxybenzaldehyde with a mp of 47-48 deg C. A small sample recrystallized from methanol had a mp of 48-49 deg C. A solution of 3.3 g 3,5-dimethoxy-4-ethoxybenzaldehyde in 25 mL nitroethane was treated with 0.5 g anhydrous ammonium acetate and heated on the steam bath for 36 h. The solvent/reagent was removed under vacuum giving a thick yellow-orange oil that was dissolved in two volumes hot MeOH. As this cooled, crystals appeared spontaneously, and after cooling in ice for a short time, these were removed by filtration and washed sparingly with cold MeOH, Air drying to constant weight provided 2.2 g 1-(3,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene with a mp of 84-85 deg C. The mother liquors, on standing overnight, deposited large chunks of crystalline material which was isolated by decantation, ground up under a small amount of methanol, then recrystallized from 60% EtOH. A second crop of 0.7 g of the nitrostyrene was thus obtained, as canary-yellow crystals with a mp of 83-85 deg C. A solution of 2.7 g 1-(3,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene in 20 mL anhydrous THF was added to a suspension of 2.0 g LAH in 150 mL warm THF. The mixture was held at reflux for 48 h. After stirring at room temperature for another 48 h, the excess hydride was destroyed by the addition of 2.0 mL H2O in 10 mL THF, followed by 2.0 mL 15% NaOH and then an additional 6.0 mL H2O. The inorganic salts were removed by filtration, and the filter cake washed with THF. The combined mother liquor and washings were stripped of solvent under vacuum leaving a yellow oil with some inorganic salts still in it. This was dissolved in 300 mL CH2Cl2, washed with dilute NaOH, and extracted with 3x150 mL 1 N HCl. The pooled extracts were washed once with CH2Cl2 made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. The combined organics were washed with saturated brine, and the solvent removed under vacuum to yield about 2 mL of a colorless oil. This was dissolved in 10 mL IPA, neutralized with concentrated HCl (10 drops were required), and diluted with 125 mL anhydrous Et2O. The slight cloudiness gradually became the formation of fine white crystals. After standing at room temperature for 2 h, these were removed, Et2O washed, and air dried. There was thus obtained 1.9 g of 3,5-dimethoxy-4-ethoxyamphetamine hydrochloride (3C-E) as brilliant white crystals. DOSAGE: 30 - 60 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 40 mg) It developed into a strange and indefinable something. It is unworldly. I am very much in control, but with an undertone of unreality that is a little reminiscent of high doses of LSD. If there were a great deal of sensory input, I might not see it. And if I were in complete sensory quiet I would miss it, too. But just where I am, I can see it. Eerie state of awareness. And by the 8th hour I am sober, with no residue except for some slight teeth clenching, and pretty much disbelieving the whole thing. (with 60 mg) Visuals very strong, insistent. Body discomfort remained very heavy for first hour. Sense of implacable imposition of something toxic for a while. I felt at the mercy of uncomfortable physical effects Q faint or pre-nausea, heavy feeling of tremor (although tremor actually relatively light) and general dis-ease, un-ease, non-ease. Kept lying down so as to be as comfortable as possible. Fantasy began to be quite strong. At first, no eyes closed images, and certainly anti-erotic. 2nd hour on, bright colors, distinct shapes Q jewel-like Q with eyes closed. Suddenly it became clearly not anti-erotic. That was the end of my bad place, and I shot immediately up to a +++. Complex fantasy which takes over Q hard to know what is real, what is fantasy. Continual erotic. Image of glass-walled apartment building in mid-desert. Exquisite sensitivity. Down by ? midnight. Next morning, faint flickering lights on looking out windows. EXTENSIONS AND COMMENTARY: This is an interesting closing of the circle. Although mescaline launched the entire show, the first half could be called the amphetamine period, with variations made on all aspects of the molecule except for that three-carbon chain. And it was found that the 4-substitution position was of paramount importance in both the potency and the quality of action of a compound. Then, looking at the long-ignored chain, lengthening it by the addition of a carbon atom eliminated all psychedelic effects and gave materials with reduced action. The action present was that of an antidepressant. But removing a carbon atom? This returned the search to the world of mescaline, but with the knowledge of the strong influence of the 4-position substituent. The two-carbon side-chain world was rediscovered, principally with 2C-B and 2C-D, and the 4-ethoxy-analogue of mescaline, E. This second half of the show could be called the phenethylamine period. And with compounds such as 3C-E which is, quite simply, Escaline (or E) reextended again to a 3-carbon chain amphetamine, there is a kind of satisfying closure. A fascinating compound, but for most subjects a little too heavy on the body. #26 2C-F; 2,5-DIMETHOXY-4-FLUOROPHENETHYLAMINE SYNTHESIS: A solution of 76.6 g 2,5-dimethoxyaniline in 210 mL H2O containing 205 mL fluoroboric acid was cooled to 0 deg C. with an external ice bath. There was then added, slowly, a solution of 35 g sodium nitrite in 70 mL H2O. After an additional 0.5 h stirring, the precipitated solids were removed by filtration, washed first with cold H2O, then with MeOH and finally Et2O. Air drying yielded about 100 g of the fluoroborate salt of the aniline as dark purple-brown solids. This salt was pyrolyzed with the cautious application of a flame, with the needed attention paid to both an explosion risk, and the evolution of the very corrosive boron trifluoride. The liquid that accumulated in the receiver was distilled at about 120 deg C at 20 mm/Hg, and was subsequently washed with dilute NaOH to remove dissolved boron trifluoride. The product, 2,5-dimethoxyfluorobenzene, was a fluid, straw-colored oil that weighed 7.0 g. To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135 g of anhydrous stannic chloride. There was then added, dropwise, 26 g of dichloromethyl methyl ether at a rate that precluded excessive heating. The reaction mixture was allowed to come to room temperature over the course of 0.5 h, and then quenched by dumping into 500 g shaved ice containing 75 mL concentrated HCl. This mixture was stirred for an additional 1.5 h. The separated organic layer was washed with 2x100 mL dilute HCl, then with dilute NaOH, then with H2O and finally with saturated brine. Removal of the solvent under vacuum yielded a solid residue that was recrystallized from aqueous EtOH yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde with a mp of 99-100 deg C. A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde in 15 mL acetic acid containing 1 g nitromethane was treated with 0.2 g anhydrous ammonium acetate, and heated on the steam bath for 4 h. After cooling, and following the judicious addition of H2O, crystals separated, and additional H2O was added with good stirring until the first signs of oiling out appeared. The solids were removed by filtration, and recrystallized from acetone to give 2.0 g of 2,5-dimethoxy-4-fluoro-beta-nitrostyrene with a mp of 159-162 deg C. To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an inert atmosphere, there was added a THF solution of 2.0 g 2,5-dimethoxy-4-fluoro-beta-nitrostyrene. The reaction mixture was stirred at room temperature for 2 h and then heated briefly at reflux. After cooling, the excess hydride was destroyed by the cautious addition of H2O, and when the reaction was finally quiet, there was added 2 mL of 15% NaOH, followed by another 6 mL of H2O. The basic insolubles were removed by filtration, and washed with THF. The combined filtrate and washes were stripped of solvent, yielding a residual oil that was taken up in 10 mL of IPA, neutralized with concentrated HCl, and the generated solids diluted with anhydrous Et2O. The white crystalline 2,5-dimethoxy-4-fluorophenethylamine hydrochloride (2C-F) was recrystallized from IPA to give an air-dried product of 0.5 g with a mp of 182-185 deg C. DOSAGE: greater than 250 mg. DURATION: unknown QUALITATIVE COMMENTS: (with 250 mg) Even at 250 milligrams, the effects were slight and uncertain. There may have been some eyes-closed imagery above normal, but certainly not profound. At several hours there was a pleasant lethargy; sleep was completely normal that night. EXTENSIONS AND COMMENTARY: A number of graded acute dosages were tried, and it was only with amounts in excess of 100 milligrams that there were any baseline disturbances at all. And at no dose that was tried was there any convincing indication of believable central effects. The three-carbon amphetamine analogue of 2C-F would quite logically be called DOF (2,5-dimethoxy-4-fluoroamphetamine). It has been prepared by reaction of the above benzaldehyde with nitroethane (giving 1-(2,5-dimethoxy-4-fluorophenyl)-2-nitropropene, with a melting point of 128-129 deg C from ethanol) followed by LAH reduction to DOF (the hydrochloride salt has a melting point of 166-167 deg C, after recrystallization from ether/ethyl acetate/ethanol). Animal studies that have compared DOF to the highly potent DOI and DOB imply that the human activity will be some four to six times less than these two heavier halide analogues. As of the present time, no human trials of DOF have been made. #27 2C-G; 2,5-DIMETHOXY-3,4-DIMETHYLPHENETHYLAMINE SYNTHESIS: To a clear solution of 40.4 g flake KOH in 400 mL warm EtOH there was added 86.5 g 2,3-xylenol followed by 51.4 g methyl iodide. This mixture was held at reflux for 2 days, stripped of volatiles under vacuum, the residues dissolved in 1 L of H2O, and extracted with 4x200 mL CH2Cl2. The pooled extracts were washed with 5% NaOH until the washes remained basic. Following a single washing with dilute HCl, the solvent was removed under vacuum, and the residue, 41.5 g of a pungent smelling amber oil, spontaneously crystallized. The mp of 2,3-dimethylanisole was 25-26 deg C and it was used without further purification in the next step. From the aqueous basic washes, following acidification, extraction, and solvent removal, there was obtained 46.5 g crude unreacted xylenol which could be recycled. A mixture of 205 g POCl3 and 228 g N-methylformanilide was allowed to incubate at room temperature until there was the development of a deep claret color with some spontaneous heating. To this, there was added 70.8 g 2,3-dimethylanisole, and the dark reaction mixture heated on the steam bath for 2.5 h. The product was then poured into 1.7 L H2O, and stirred until there was a spontaneous crystallization. These solids were removed by filtration, H2O washed and air dried to give 77.7 g of crude benzaldehyde as brown crystals. This was distilled at 70-90 deg C at 0.4 mm/Hg to give 64.8 g of 2,3-dimethyl-4-methoxybenzaldehyde as a white crystalline product with a mp of 51-52 deg C. Recrystallization from MeOH produced an analytical sample with a mp of 55-55.5 deg C. Anal. (C10H12O2) C,H. The malononitrile derivative (from the aldehyde and malononitrile in EtOH with a drop of triethylamine) had a mp of 133-133.5 deg C from EtOH. Anal. (C13H12N2O) C,H,N. Recently, this aldehyde has become commercially available. A solution of 32.4 g 2,3-dimethyl-4-methoxybenzaldehyde in 800 mL CH2Cl2 was treated with 58.6 g 85% m-chloroperoxybenzoic acid and held at reflux for 3 days. After cooling to room temperature, the white solids (m-chlorobenzoic acid) were removed by filtration (about 40 g when dry). The filtrate was extracted with several portions of saturated NaHCO3 (on acidification, this aqueous wash yielded additional m-chlorobenzoic acid) and the organic solvent removed under vacuum. The crystalline residue (weighing 32 g and deeply colored) was dissolved in 150 mL boiling MeOH to which there was added 18 g of solid NaOH and the solution heated on the steam bath for a few min. The mixture was added to 800 mL H2O, and a little surface scum mechanically removed with a piece of filter paper. The solution was acidified with concentrated HCl, depositing 30.9 g of a tan solid. Recrystallization from H2O gave 2,3-dimethyl-4-methoxyphenol as white needles, with a mp of 95-96 deg C. Anal. (C9H12O2) H; C: calcd, 71.06; found 70.20. The N-methyl carbamate was made by the treatment of a solution of the phenol (1 g in 75 mL hexane with 5 mL CH2Cl2 added) with 2 g methyl isocyanate and a few drops of triethyl amine. The pale pink solids that separated were recrystallized from MeOH to give a product that had a mp of 141-142 deg C. Anal. (C11H15NO3) C,H,N. To a solution of 23.1 g flake KOH in 250 mL hot EtOH there was added 61.8 g 2,3-dimethyl-4-methoxyphenol followed by 60 g methyl iodide. This was held under reflux for 12 h, then stripped of solvent under vacuum. The residue was dissolved in 1.2 L H2O, acidified with HCl, and extracted with 3x200 mL CH2Cl2. The combined extracts were washed with 3x100 mL 5% NaOH, and the solvent was removed under vacuum. The residue set up as an off-white mass of leaflets weighing 37.7 g after filtering and air drying. Recrystallization from MeOH gave 2,3-dimethyl-1,4-dimethoxybenzene as white solids, with a mp of 78-79 deg C. Anal. (C10H14O2) C,H. An alternate route leading from 2,3-xylenol to this diether via nitrogen-containing intermediates was explored. The sequence involved the reaction of 2,3-xylenol with nitrous acid (4-nitroso product, mp 184 deg C dec.), reduction with sodium dithionite (4-amino product, mp about 175 deg C), oxidation with nitric acid (benzoquinone, mp 58 deg C), reduction with sodium dithionite (hydro-quinone) and final methylation with methyl iodide. The yields were inferior with this process. A mixture of 88 g POCl3 and 99 g N-methylformanilide was allowed to incubate until a deep claret color had formed, then it was treated with 36.5 g 2,3-dimethyl-1,4-dimethoxybenzene and heated on the steam bath for 3 h. It was then poured into 1 L H2O, and stirred until the formation of a loose, crumbly, dark crystalline mass was complete. This was removed by filtration, and dissolved in 300 mL CH2Cl2. After washing first with H2O, then with 5% NaOH, and finally with dilute HCl, the solvent was removed under vacuum yielding 39.5 g of a black oil that solidified. This was extracted with 2x300 mL boiling hexane, the extracts were pooled, and the solvent removed under vacuum. The yellowish residue crystallized to give 32.7 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde with a mp of 46-47 deg C. Repeated recrystallization from MeOH raised the mp to 59-60 deg C. The malononitrile derivative was prepared (aldehyde and malononitrile in EtOH with a few drops triethyl amine) as yellow crystals from EtOH, with a mp of 190-191 deg C. Anal. (C14H14N2O2) C,H; N: calcd, 11.56; found, 11.06, 11.04. To a solution of 16.3 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde in 50 mL nitromethane there was added 3.0 g anhydrous ammonium acetate, and the mixture was heated on the steam bath overnight. There was then added an equal volume of MeOH, and with cooling there was obtained a fine crop of yellow crystals. These were removed by filtration, washed with MeOH, and air dried to provide 4.4 g of 2,5-dimethoxy-3,4-dimethyl-beta-nitrostyrene with a mp of 120-121 deg C which was not improved by recrystallization from MeOH (50 mL/g). The mother liquors of the above filtration were diluted with H2O to the point of permanent turbidity, then set aside in a cold box. There was a chunky, granular, tomato-red crystal deposited which weighed 2.5 g when dry. It had a mp of 118-119.5 deg C, which was undepressed in mixed mp with the yellow sample. Both forms had identical NMR spectra (2.20, 2.25 CH3; 3.72, 3.84 OCH3; 6.80 ArH; 7.76, 8.28 CH=CH, with 14 cycle splitting), infrared spectra, ultra violet spectra (max. 324 nm with shoulder at 366 nm in EtOH, two peaks at 309 and 355 nm in hexane), and microanalyses. Anal. (C12H15NO4) C,H,N. A solution of LAH (56 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.52 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 3.63 g 2,5-dimethoxy-3,4-dimethyl-beta-nitrostyrene in 36 mL anhydrous THF over the course of 1 h. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for about 5 min, then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 9 mL IPA followed by 2.5 mL 15% NaOH and finally 7.5 mL H2O. The reaction mixture was filtered, and the filter cake washed first with THF and then with IPA. The filtrate was stripped of solvent under vacuum and the residue was distilled at 110-120 deg C at 0.2 mm/Hg to give 2.07 g of 2,5-dimethoxy-3,4-dimethylphenethylamine as a clear white oil. This was dissolved in 10 mL IPA, neutralized with concentrated HCl, and then diluted with 25 mL anhydrous Et2O. The crystals that formed were filtered, Et2O washed, and air dried to constant weight. There was obtained 2.13 g of beautiful white crystals of 2,5-dimethoxy-3,4-dimethylphenethylamine hydrochloride (2C-G) with a mp of 232-233 deg C. Anal. (C12H20ClNO2) C,H. DOSAGE: 20 - 35 mg. DURATION: 18 - 30 h. QUALITATIVE COMMENTS: (with 22 mg) I am completely functional, with writing and answering the telephone, but the coffee really tastes most strange. While the mental effects (to a ++ only) were dispersing, the body still had quite a bit of memory of the day. Sleep was fine, and desirable, in the early evening. (with 32 mg) Superb material, to be classified as a 'true psychedelic' unless one is publishing, in which case it could be best described as an 'insight-enhancer' and obviously of potential value in psychotherapy (if one would wish to spend 30 hours in a therapy session!). I suppose it would be best to simply stick with the insight-enhancing and skip the psychotherapy. Just too, too long. There was not any particular visual impact, at least for me. The non-sexual and the anorexic aspects might indeed change, with increasing familiarity. Remains to be seen. The length of the experience is against its frequent use, of course, which is a pity, since this one is well worth investigating as often as possible. (with 32 mg) There was, at the very beginning, a certain feeling of non-physical heat in the upper back which reminded me of the onset of various indoles, which this ain't. The energy tremor was quite strong throughout, but somehow the body was generally at ease. (with 32 mg) At a plateau at two hours, with just a bit of tummy queasi-ness. And I am still at the plateau several hours later. Sleep finally at the 18th hour, but even after getting up and doing all kinds of things the next day, I was not completely baseline until that evening. And a couple of days more for what is certainly complete repair. That is a lot of mileage for a small amount of material. EXTENSIONS AND COMMENTARY: Here is the first example, ever, of a phen-ethylamine that is of about the same potency as therelated three-carbon amphetamine. At first approximation, one is hard put to distinguish, from the recorded notes, any major differences either in potency, in duration, or in the nature of activity, between 2C-G and GANESHA itself. I had always thought of the phenethylamines as being somewhat weaker than the corresponding amphetamines. Sometimes a little weaker and sometimes a lot weaker. But that is a totally prejudiced point of view, an outgrowth of my earliest comparisons of mescaline and TMA. That's the kind of thing that can color one's thinking and obscure what may be valuable observations. It is equally valid to think of the phenethylamines as the prototypes, and that the amphetamines are somewhat stronger than the corresponding phenethylamines. Sometimes a little stronger and sometimes a lot stronger. Then the question suddenly shifts from asking what is different about the phenethylamines, to what is different about the amphetamines? It is simply a historic fact, that in most of my exploring, the amphetamine was made and evaluated first, and so tended to slip into the role of the prototype. In any case, here the two potencies converge. #28 2C-G-3; 2,5-DIMETHOXY-3,4-(TRIMETHYLENE)PHENETHYLAMINE; 5-(2-AMINOETHYL)-4,7-DIMETHOXYINDANE) SYNTHESIS: To a solution of 22 g of KOH in 250 mL of hot EtOH, there was added 50 g of 4-indanol and 75 g methyl iodide. The mixture was held at reflux for 12 h. There was then added an additional 22 g KOH followed by an additional 50 g of methyl iodide. Refluxing was continued for an additional 12 h. The mixture was poured into 1 L H2O, acidified with HCl, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed with 5% NaOH, then with dilute HCl, and the solvent was removed under vacuum. The residue of crude 2,3-(trimethylene)anisole weighed 56.5 g and was used without further purification in the following reaction. A mixture of 327 g N-methylformanilide and 295 g POCl3 was allowed to incubate until a deep claret color had formed. To this there was then added 110 g of crude 2,3-(trimethylene)anisole, and the mixture heated on the steam bath. There was a vigorous evolution of gases, which largely quieted down after some 4 h of heating. The reaction mixture was added to 4 L H2O and stirred overnight. The oily aqueous phase was extracted with 3x200 mL CH2Cl2, and after combining the extracts and removal of the solvent there was obtained 147 g of a black, sweet-smelling oil. This was distilled at 182-194 deg C at the water pump to yield 109.1 g of a pale yellow oil. At low temperature, this crystallized, but the solids melted again at room temperature. Gas chromatography of this product on OV-17 at 185 deg C showed detectable starting anisole and N-methylformanilide (combined, perhaps 5% of the product) and a small but real isomeric peak, (about 5%, slightly faster moving than the title aldehyde, again about 5% of the product) of what was tentatively identified as the ortho-aldehyde (2-methoxy-3,4-(trimethylene)-benzaldehyde). The bulk of this crude product (74 g) was redistilled at 110-130 deg C at 0.3 mm/Hg to give 66 g of 4-methoxy-2,3-(trimethylene)benzaldehyde as a nearly colorless oil which set up as a crystalline solid. A portion on porous plate showed a mp of 28-29 C. A gram of this aldehyde and a gram of malononitrile in 25 mL of EtOH was treated with a few drops of triethylamine and gave pale yellow crystals of the malononitrile derivative. This, upon recrystallization from 50 mL boiling EtOH, had a mp of 176-176.5 deg C. Anal. (C14H12N2O) C,H,N. A side path, other than towards the intended targets 2C-G-3 and G-3, was explored. Reaction with nitroethane and anhydrous ammonium acetate gave the 2-nitropropene analogue which was obtained in a pure state (mp 74-75 deg C from MeOH) only after repeated extraction of the crude isolate with boiling hexane. Reduction with elemental iron gave the phenylacetone analogue which was reductively aminated with dimethylamine and sodium cyanoborohydride to give N,N-dimethyl-4-methoxy-2,3-(trimethylene)amphetamine. This was designed for brain blood-flow volume studies after iodination at the 5-position, a concept that has been discussed under IDNNA. It has never been tasted by anyone. The corresponding primary amine, 4-methoxy-2,3-(trimethylene)amphetamine has not yet even been synthesized. A solution of 34.8 g 4-methoxy-2,3-(trimethylene)benzaldehyde in 800 mL CH2Cl2 was treated with 58.6 g of 85% m-chloroperoxybenzoic acid and held at reflux for 3 days. After cooling and standing for a few days, the solids were removed by filtration and washed sparingly with CH2Cl2. The combined filtrate and washings were washed with 200 mL saturated NaHCO3, and the solvent removed, yielding 43.5 g of a deeply colored oil. This was dissolved in 150 mL MeOH to which was added 9 g NaOH and all heated to reflux on the steam bath. After 1 h, a solution of 9 g NaOH in 20 mL H2O was added, heated further, then followed by yet another treatment with 9 g NaOH in 20 mL H2O followed by additional heating. All was added to 800 mL H2O, washed once with CH2Cl2 (which removed a trivial amount of material) and then acidified with HCl. The dark crystals that were generated were filtered and air dried to constant weight, yielding 27.5 g dark but nice-looking crystals with a mp of 89-91 deg C. By all counts, this should have been the product phenol, 4-methoxy-2,3-(trimethylene)phenol, but the microanalysis indicated that the formate ester was still there. Anal. (C10H12O2) requires C = 73.08, H = 7.37. (C11H12O3) requires C = 68.73, H = 6.29. Found: C = 69.04, 68.84; H = 6.64, 6.58. Whatever the exact chemical status of the phenolic hydroxyl group might have been, it reacted successfully in the following methylation step. To a solution of 10 g KOH in 100 g EtOH (containing 5% IPA) there was added 27.5 g of the above 89-91 deg C melting material, followed by 25 g methyl iodide. The mixture was held at reflux overnight. All was added to 800 mL H2O, acidified with HCl, and extracted with 3x100 mL CH2Cl2. The combined extracts were washed with 3x100 mL 5% NaOH, then once with dilute HCl, and the solvent removed under vacuum yielding 20.4 g of a fragrant crystalline residue. This was recrystallized from 60 mL boiling MeOH to give, after filtering and air drying, 16.0 g of 1,4-dimethoxy-2,3-(trimethylene)benzene (4,7-dimethoxyindane) with a mp of 86-88 deg C. Anal. (C11H14O2) C,H. To a mixture of 39.0 g of N-methylformanilide and 35.9 g POCl3 that had been allowed to stand at ambient temperature until deeply claret (about 45 min) there was added 15.8 g of 1,4-dimethoxy-2,3-(trimethylene)benzene. The mixture was heated on the steam bath for 4 h and then poured into 600 mL H2O. After stirring overnight there was produced a heavy crystalline mass. This was removed by filtration and, after air drying, was extracted with 3x100 mL boiling hexane. Pooling and cooling these extracts yielded 9.7 g of salmon-colored crystals with a mp of 67-68 deg C. This was recrystallized from 25 mL boiling EtOH to give, after filtration, EtOH washing, and air drying to constant weight, 7.4 g of 2,5-dimethoxy-3,4-(trimethylene)benzaldehyde, with a mp of 71-72 deg C. The mother liquors on cautious treatment with H2O, yielded, after EtOH recrystallization, 1 g additional product. Anal. (C12H14O3) C,H. A solution of 150 mg aldehyde and an equal weight of malononitrile in 2.3 mL EtOH treated with 3 drops triethylamine gave immediate yellow crystals of the malononitrile derivative, with a mp of 161-162 deg C. Anal. (C15H14N2O2) C,H,N. A solution 3.7 g 2,5-dimethoxy-3,4-(trimethylene)benzaldehyde in 15 g nitromethane was treated with 0.7 g anhydrous ammonium acetate and heated on the steam bath for 14 h. The volatiles were removed under vacuum, and the residue set up to 3.5 g dark crystals, which melted broadly between 126-138 deg C. Recrystallization of the entire mass from 70 mL boiling EtOH gave 3.2 g burnished gold crystals with a mp of 129-137 deg C. A further recrystallization of an analytical sample from MeOH gave 2,5-dimethoxy-3,4-(trimethylene)-beta-nitrostyrene as yellow crystals with a mp of 146-147 deg C. Anal. (C13H15NO4) C,H. To a cold solution of LAH in THF (40 mL of a 1 M solution) well stirred and under an inert atmosphere, there was added dropwise 1.05 mL freshly prepared 100% H2SO4. There was then added, dropwise, a solution of 2.39 g 2,5-dimethoxy-3,4-(trimethylene)-beta-nitrostyrene in 25 mL THF. The bright yellow color was discharged immediately. After the addition was complete, stirring was continued for an additional 20 min, and the reaction mixture brought to a reflux on the steam bath for another 0.5 h. After cooling, the excess hydride was destroyed with IPA (8 mL required) followed by sufficient 15% NaOH to convert the inorganics into a loose, filterable mass. This was removed by filtration, and the filter cake washed with THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in dilute H2SO4. After washing with CH2Cl2, the aqueous phase was made basic with 25% NaOH and extracted with 3x75 mL CH2Cl2. After removal of the solvent under vacuum, the residue was distilled at 125-160 deg C at 0.45 mm/Hg to yield 0.80 g of a white oil. This was dissolved in 8 mL IPA, neutralized with 20 drops of concentrated HCl (the salt crystals started to form before this was completed) followed with the addition of 65 mL anhydrous Et2O. The white crystalline mass was filtered, washed with Et2O, and air dried to provide 1.16 g of 2,5-dimethoxy-3,4-(trimethylene)phenethylamine hydrochloride (2C-G-3) with a mp of 214-216 deg C with decomposition. Anal. (C13H20ClNO2) C,H. DOSAGE: 16 - 25 mg. DURATION: 12 - 24 h. QUALITATIVE COMMENTS: (with 16 mg) It came on in little leaps and bounds. All settled, and then it would take another little jump upwards. I am totally centered, and writing is easy. My appetite is modest. Would I drive to town to return a book to the library? No ever-loving way! I am very content to be right here where I am safe, and stay with the writing. It does take so much time to say what wants to be said, but there is no quick way. A word at a time. (with 22 mg) I walked out for the mail at just about twilight. That was the most courageous thing that I could possibly have done, just for one lousy postcard and a journal. What if I had met someone who had wanted to talk? Towards evening I got a call from Peg who said her bean soup was bubbling in a scary way and what should she do, and I said maybe better make soap. It was that kind of an experience! Way up there, lots of LSD-like sparkles, and nothing quite really making sense. Marvelous. (with 25 mg) There was easy talking, and no hint of any body concern. Sleep that evening was easy, and the next day was with good energy. EXTENSIONS AND COMMENTARY: The positives of a completely intriguing altered state free from apparent physical threats, are here coupled with the negative of having to invest such a long period of time. There is a merry nuttiness which can give a joyous intoxication, but with the underlying paranoia of how it looks to others. There is an ease of communication, but only within surroundings that are well-known and friendly. This might be a truly frightening experience if it were in an unfamiliar or unstructured environment. The numbering of this compound, and all the extensions of GANESHA, have been made on the basis of the nature of the stuff at the 3,4-position. Here there are three atoms (the trimethylene bridge) and so 2C-G-3 seems reasonable. With this logic, the dimethylene bridge would be 2C-G-2 (and the corresponding amphetamine would be G-2, of course). But these compounds call upon a common intermediate which is a benzocyclobutene, OK in principle but not yet OK in practice. The right benzyne reaction will be there someday, and the dimethylene analogues will be made and assayed. But, in the meantime, at least the names have been assigned. #29 2C-G-4; 2,5-DIMETHOXY-3,4-(TETRAMETHYLENE)PHENETHYLAMINE; 6-(2-AMINOETHYL)-5,8-DIMETHOXY-TETRALIN SYNTHESIS: To a solution of 49.2 g 5,6,7,8-tetrahydronaphthol (5-hydroxytetralin) in 100 mL MeOH, there was added 56 g methyl iodide followed by a solution of 24.8 g KOH pellets (85% purity) in 100 mL boiling MeOH. The mixture was heated in a 55 deg C bath for 3 h (the first white solids of potassium iodide appeared in about 10 min). The solvent was stripped under vacuum, and the residues dissolved in 2 L H2O. This was acidified with HCl, and extracted with 4x75 mL CH2Cl2. After washing the organic phase with 3x75 mL 5% NaOH, the solvent was removed under vacuum to give 48.2 g of a black residue. This was distilled at 80-100 deg C at 0.25 mm/Hg to provide 33.9 g 5-methoxy-1,2,3,4-tetrahydronaphthalene as a white oil. The NaOH washes, upon acidification and extraction with CH2Cl2 gave, after removal of the solvent under vacuum and distillation of the residue at 0.35 mm/Hg, 11.4 g of recovered starting phenol. A mixture of 61.7 g POCl3 and 54.3 g N-methylformanilide was heated on the steam bath for 15 min which produced a deep red color. This was added to 54.3 g of 5-methoxy-1,2,3,4-tetrahydronaphthalene, and the mixture was heated on the steam bath for 2 h. The reaction mixture was quenched in 1.2 L H2O with very good stirring. The oils generated quickly turned to brown granular solids, which were removed by filtration. The 79 g of wet product was finely triturated under an equal weight of MeOH, filtered, washed with 20 mL ice-cold MeOH, and air dried to yield 32.0 g of 4-methoxy-5,6,7,8-tetrahydronaphthaldehyde as an ivory-colored solid. The filtrate, on standing, deposited another 4.5 g of product which was added to the above first crop. An analytical sample was obtained by recrystallization from EtOH, and had a mp of 57-58 deg C. Anal. (C12H14O2) C,H. To a solution of 25.1 g 4-methoxy-5,6,7,8-tetrahydronaphthaldehyde in 300 mL CH2Cl2 there was added 25 g 85% m-chloroperoxybenzoic acid at a rate that was commensurate with the exothermic reaction. Solids were apparent within a few min. The stirred reaction mixture was heated at reflux for 8 h. After cooling to room temperature, the solids were removed by filtration and washed lightly with CH2Cl2. The pooled filtrate and washes were stripped of solvent under vacuum and the residue dissolved in 100 mL MeOH and treated with 40 mL 25% NaOH. This was heated on the steam bath for an hour, added to 1 L H2O, and acidified with HCl, producing a heavy crystalline mass. This was removed by filtration, air dried, and distilled at up to 170 deg C at 0.2 mm/Hg. There was thus obtained 21.4 g of 4-methoxy-5,6,7,8-tetrahydronaphthol as an off-white solid with a mp of 107-114 deg C. An analytical sample was obtained by recrystallization from 70% EtOH, and melted at 119-120 deg C. Hexane is also an excellent recrystallization solvent. Anal. (C11H14O2) C,H. As an alternate method, the oxidation of the naphthaldehyde to the naphthol can be achieved through heating the aldehyde in acetic acid solution containing hydrogen peroxide. The yields using this route are consistently less than 40% of theory. A solution of 21.0 g of 4-methoxy-5,6,7,8-tetrahydronaphthol in 100 mL acetone in a 1 L round-bottomed flask, was treated with 25 g finely ground anhydrous K2CO3 and 26 g methyl iodide. The mixture was held at reflux on the steam bath for 2 h, cooled, and quenched in 1 L H2O. Trial extraction evaluations have shown that the starting phenol, as well as the product ether, are extractable into CH2Cl2 from aqueous base. The aqueous reaction mixture was extracted with 3x60 mL CH2Cl2, the solvent removed under vacuum, and the residue (19.6 g) was distilled at 90-130 deg C at 0.3 mm/Hg to give 14.1 g of an oily white solid mixture of starting material and product. This was finely ground under an equal weight of hexane, and the residual crystalline solids removed by filtration. These proved to be quite rich in the desired ether. This was dissolved in a hexane/CH2Cl2 mixture (3:1 by volume) and chromatographed on a silica gel preparative column, with the eluent continuously monitored by TLC (with this solvent system, the Rf of the ether product was 0.5, of the starting phenol 0.1). The fractions containing the desired ether were pooled, the solvent removed under vacuum and the residue, which weighed 3.86 g, was dissolved in 1.0 mL hexane and cooled with dry ice. Glistening white crystals were obtained by filtration at low temperature. The weight of 5,8-dimethoxytetralin isolated was 2.40 g and the mp was 44-45 deg C. GCMS analysis showed it to be largely one product (m/s 192 parent peak and major peak), but the underivitized starting phenol has abysmal GC properties and TLC remains the best measure of chemical purity. A well-stirred solution of 3.69 g 5,8-dimethoxytetralin in 35 mL CH2Cl2 was placed in an inert atmosphere and cooled to 0 deg C with an external ice bath. There was then added, at a slow rate, 4.5 mL anhydrous stannic chloride, which produced a transient color that quickly faded to a residual yellow. There was then added 2.0 mL dichloromethyl methyl ether, which caused immediate darkening. After a few min stirring, the reaction mixture was allowed to come to room temperature, and finally to a gentle reflux on the steam bath. The evolution of HCl was continuous. The reaction was then poured into 200 mL H2O, the phases separated, and the aqueous phase extracted with 2x50 mL CH2Cl2. The organic phase and extracts were pooled, washed with 3x50 mL 5% NaOH, and the solvent removed under vacuum. The residue was distilled at 120-140 deg C at 0.3 mm/Hg to give 3.19 g of a white oil that spontaneously crystallized. The crude mp of 1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde was 70-72 deg C. An analytical sample from hexane had the mp 74-75 deg C. The GCMS analysis showed only a single material (m/s 220, 100%) with no apparent starting dimethoxytetralin present. Attempts to synthesize this aldehyde by the Vilsmeier procedure (POCl3 and N-methylformanilide) gave complex mixtures of products. Synthetic efforts employing butyllithium and DMF gave only recovered starting material. To a solution of 1.5 g 1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde in 20 g nitromethane there was added 0.14 g anhydrous ammonium acetate and the mixture heated on the steam bath for 50 min. The rate of the reaction was determined by TLC monitoring, on silica gel with CH2Cl2 as the moving solvent; the Rf of the aldehyde was 0.70, and of the product nitrostyrene, 0.95. Removal of the volatiles under vacuum gave a residue that spontaneously crystallized. The fine yellow crystals that were obtained were suspended in 1.0 mL of MeOH, filtered, and air dried to yield 1.67 g 2,5-dimethoxy-beta-nitro-3,4-(tetramethylene)styrene with a mp of 151.5-152.5 deg C. Anal. (C14H17NO4) C,H. DOSAGE: unknown. DURATION: unknown EXTENSIONS AND COMMENTARY: The road getting to this final product reminded me of the reasons why, during the first few billion years of the universe following the big bang, there was only hydrogen and helium. Nothing heavier. When everything had expanded enough to cool things sufficiently for the first actual matter to form, all was simply very energetic protons and neutrons. These were banging into one-another, making deuterium nuclei, and some of these got banged up even all the way to helium, but every time a helium nucleus collided with a particle of mass one, to try for something with mass five, the products simply couldn't exist. Both Lithium-5 and Helium-5 have the impossible half-lives of 10 to the minus 21 seconds. Hence, in the primordial soup, the only way to get into something heavier than helium was to have a collision between a couple of the relatively scarcer heavy nuclei, or to have a three body collision. Both of these would be extremely rare events, statistically. And if a few got through, there was another forbidden barrier at mass 8, since Beryllium-8 has a half life of 10 to the minus 16 seconds. So everything had to wait for a few suns to burn down so that they could process enough helium into heavy atoms, to achieve some nuclear chemistry that was not allowed in the early history of the universe. And in the same way, there were two nearly insurmountable barriers encountered in getting to 2C-G-4 and G-4. The simple act of methylating an aromatic hydroxyl group provided mixtures that could only be resolved into components by some pretty intricate maneuvers. And when that product was indeed gotten, the conversion of it into a simple aromatic aldehyde resisted the classic procedures completely, either giving complex messes, or nothing. And even now, with these two hurdles successfully passed, the presumed simple last step has not yet been done. The product 2C-G-4 lies just one synthetic step (the LAH reduction) away from completion, and the equally fascinating G-4 also that one last reduction step from being completed. Having gotten through the worst of the swamp, let's get into the lab and finish up this challenge. They will both be active compounds. #30 2C-G-5; 3,6-DIMETHOXY-4-(2-AMINOETHYL)BENZONORBORNANE SYNTHESIS: To a stirred solution of 25 g 3,6-dihydroxybenzonorbornane (from Eastman Kodak Company) in 200 mL acetone there was added 200 mg decyltriethylammonium iodide, 40 g of powdered anhydrous K2CO3, and 55 g methyl iodide. The mixture was held at reflux with a heating mantle overnight. After re-moval of the solvent under vacuum, the residue was added to 2 L of H2O, acidified with concentrated HCl, and extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with 2x150 mL 5% NaOH and once with dilute HCl, and the solvent was removed under vacuum to give 19.0 g of a black oil as a residue. This was distilled at 90-115 deg C at 0.3 mm/Hg to yield 15.5 g of an orange oil which set up as a crystalline solid. The product, 3,6-dimethoxybenzonorbornane, had a mp of 35-37 deg C from hexane or 40-41 deg C from MeOH. Anal. (C13H16O2) C,H. A solution of 4.6 g POCl3 and 4.6 g N-methylformanilide was heated briefly on the steam-bath until the color had become deep claret. There was then added 3.05 g of 3,6-dimethoxybenzonorbornane and the solution was heated on the steam bath for 12 h. The black, tarry reaction mixture was poured into H2O, and after hydrolysis, the H2O was decanted and the insoluble residues were washed alternately with H2O and with CH2Cl2. The combined washes were separated, and the aqueous phase extracted with 2x50 mL CH2Cl2. The combined organic fractions were washed with 5% NaOH, and the solvent removed under vacuum. The fluid, black residue was distilled at 130-140 deg C at 0.3 mm/Hg to give 1.17 g of an almost white oil. This was dissolved in 1 mL MeOH, and cooled to -50 deg C to give a white crystalline solid that was removed by filtration and washed sparingly with -50 deg C MeOH and air dried. There was obtained 0.83 g 3,6-dimethoxy-4-formylbenzonorbornane with a mp of 37-40 deg C which could be increased, by wasteful recrystallization from MeOH, to 53-54 deg C. An intimate mixture of this product with the starting diether (mp 40-41 deg C) was a liquid at room temperature. Anal. (C14H16O3) C,H. To a solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane in 20 g nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 45 min. The excess reagent/solvent was removed under vacuum, and the residue was dissolved in 20 mL boiling MeOH. A speck of seed crystal started a heavy crystallization of orange crystals which were removed by filtration and washed with MeOH. After drying, the product 3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane was yellow, weighed 3.47 g, and had a mp of 88-89 deg C. Recrystallization of an analytical sample from MeOH did not improve this mp. Anal. (C15H17NO4) C,H. A solution of LAH (46 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 3.4 g 3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane in 30 mL anhydrous THF. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath for 10 min, and then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 7 mL IPA, followed by 2 mL 15% NaOH and 5 mL H2O, which gave an easily filtered white granular solid. This was removed by filtration, and the filter cake was washed with THF. The combined filtrate and washes were stripped of solvent under vacuum providing a pale amber oil which was distilled at 150-160 deg C at 0.3 mm/Hg to give 1.45 g of a white oil. This was dissolved in 7 mL IPA, and neutralized with 15 drops of concentrated HCl. There was then added 25 mL anhydrous Et2O and, after a short delay, white crystals formed spontaneously. These were removed by filtration, Et2O washed, and air dried to constant weight, yielding 1.13 g of 3,6-dimethoxy-4-(2-aminoethyl)benzonorbornane hydrochloride (2C-G-5). The mp was 199-200 deg C. Anal. (C15H22ClNO2) C,H. DOSAGE: 10 - 16 mg. DURATION: 32 - 48 h. QUALITATIVE COMMENTS: (with 14 mg) I was well aware of things at the end of two hours, and I was totally unwilling to drive, or even go out of the house. I was reminded continuously of 2C-B with its erotic push, and the benign interplay of colors and other visual effects. But it is so much longer lived. I am a full +++, very stoned, and there is no believable sign of dropping for another several hours. There is a good appetite (again, 2C-B like), and I managed to sleep for a few hours, and all the next day I was spacey and probably still a plus one. The day yet following, I was finally at a believable baseline. Both of these days were filled with what might be called micro doze-offs, almost like narcolepsy. Maybe I am just sleep deprived. (with 16 mg) The first effects were felt within one hour, and full effects between 2 1/2 and 3 hours. Tremendous clarity of thought, cosmic but grounded, as it were. This is not at all like LSD, and is a lot mellower than the 2C-T family. For the next few hours it was delightful and fun and I felt safe and good-humored. I got to sleep without much difficulty while still at a plus three, and my dreams were positive and balanced, but I awoke irritable and emotionally flattened. I did not want to interact with anyone. The first 16 hours of this stuff were great, and the second 16 hours were a bit of a drag. Just twice as long as it ought to be. (with 16 mg) I was at full sparkle within three hours, and I continued to sparkle for the longest time. The tiredness that comes after a while probably reflects the inadequacy of sleep. I was aware of something still going on some two days later. EXTENSIONS AND COMMENTARY: In the eventual potency assessment of a drug, there must be some consideration of not only the dosage needed, but the duration of effects. The area under the curve, so to speak. By these measures, this phenethylamine is a record breaker, in that it is not only amongst the most potent, but it goes on and on and on. There are a couple of chemical commentaries. One, the miserable phenol-to-ether-to-aldehyde series of steps, so maddeningly unsatisfactory in the 2C-G-4 process, was completely comfortable here. The reactions rolled, and the yields were most satisfactory. Secondly, this is one of the few phenethylamines that is a racemate. The strange geometry of the norbornane ring carries within it a chiral character, so this compound is potentially resolvable into two optically active forms. That might be quite a task, but it would have the value of providing for the first time a pair of isomers that were asymmetric in the 3,4-aliphatic part of the molecule. To the extent that some insight into the geometry of the receptor site can be gleaned from the absolute configurations of active agonists, here is a compound where the subtle variations are over there at the ring substitution area of the structure, rather than at the well-explored alpha-carbon atom. Some day I might try to resolve this drug into its optical isomers. But I suspect that it might be quite difficult. A number of chemical variations of 2C-G-5 are obvious. The dihydroxybenzonorbornane compound that was the starting point of all this was certainly the adduct of cyclopentadiene and benzoquinone, with the double bond reduced. The same chemistry with 1,3-cyclohexadiene would give a two-carbon bridge instead of the one-carbon bridge of norbornane and, after hydrogenation, would provide a non-chiral analog with two ethylene bridges between the 3- and 4-position carbons. This is a cyclohexane ring connected, by its 1- and 4-positions, to the two methyl groups of 2C-G. With six carbons in this aliphatic mess, the compound is probably best called 2C-G-6. It should be easily made, and it is certain to be very potent. And there are potentially several other Diels Alder dienes that might serve with benzoquinone as the dieneophile. There are aliphatic things such as hexa-2,4-diene and 2,3-dimethylbutadiene. The textbooks are filled with dozens of diene candidates, and benzquinone will always provide the two oxygens needed for the eventual 2,5-dimethoxy groups of the phenethylamine. #31 2C-G-N; 1,4-DIMETHOXYNAPHTHYL-2-ETHYLAMINE SYNTHESIS: A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was heated to the boiling point, and treated with 28.5 g stannous chloride at a rate that maintained a continuous rolling boil. At the completion of the addition, the reaction mixture was saturated with anhydrous hydrogen chloride, and held at reflux on the steam bath for 2 h. The reaction mixture was poured into 700 mL H2O and treated with aqueous NaOH. During the addition there was transient development of a curdy white solid which redissolved when the system became strongly basic. This was extracted with 3x200 mL CH2Cl2 and the pooled extracts were washed first with H2O, then with dilute HCl, and finally again with H2O. Removal of the solvent under vacuum yielded 15.75 g of a low melting black flaky crystalline material which was distilled at 160-180 deg C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass with a mp of 78-86 deg C. Recrystallization from 75 mL boiling MeOH provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88 deg C. A mixture of 20.0 g POCl3 and 22.5 g N-methylformanilide was allowed to stand at room temperature for 0.5 h which produced a deep claret color. To this there was added 9.4 g 1,4-dimethoxynaphthalene and the mixture was heated on the steam bath. The reaction mixture quickly became progressively darker and thicker. After 20 min it was poured into 250 mL H2O and stirred for several h. The solids were removed by filtration, and washed well with H2O. The wet crude product (a dull yellow-orange color) was dissolved in 125 mL boiling EtOH to give a deep red solution. On cooling, this deposited a heavy crop of crystals that was removed by filtration, and washed with cold EtOH. There was obtained, after air-drying to constant weight, 7.9 g 1,4-dimethoxy-2-naphthaldehyde as white crystals with a mp of 119-121 deg C. This was not improved by further recrystallization. The malononitrile derivative, from the aldehyde and malononitrile in EtOH with a drop of triethylamine, had a mp of 187-188 deg C. A solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde in 13.5 g nitromethane was treated with 0.7 g anhydrous ammonium acetate, and heated on the steam bath for 1 h. The excess reagent/solvent was removed under vacuum giving a residue that spontaneously crystallized. This crude product was removed with the aid of a few mL MeOH, and pressed on a sintered funnel with modest MeOH washing. There was obtained 3.6 g (when dry) of old-gold colored crystals with a mp of 146-148 deg C. Recrystallization from 140 mL boiling EtOH gave 3.0 g 1,4-dimethoxy-2-(2-nitro-vinyl)naphthalene as deep gold-colored crystals with a mp of 146-147 deg C. A small sample, upon recrystalization from MeOH, melted at 143-144 deg C. Anal. (C14H13NO4) C,H. A solution of LAH (50 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.32 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 2.80 g 1,4-dimethoxy-2-(2-nitrovinyl)naphthalene in 40 mL anhydrous THF. There was an immediate loss of color. After 1 h stirring at 0 deg C, the temperature was brought up to a gentle reflux on the steam bath for 20 min, then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 7 mL IPA followed by 5.5 mL 5% NaOH. The reaction mixture was filtered, and the filter cake washed with several portions of THF. The combined filtrate and washings were stripped of solvent under vacuum providing 3.6 g of a pale amber oil that was distilled at 145-160 deg C at 0.2 mm/Hg to give 1.25 g of product as an absolutely white oil. This was dissolved in 7 mL IPA, and neutralized with concentrated HCl forming immediate crystals of the hydrochloride salt in the alcohol solvent. Thirty mL of anhydrous Et2O was added, and after complete grinding and mixing, the hydrochloride salt was removed by filtration, Et2O washed, and air dried to constant weight. The spectacular white crystals of 1,4-dimethoxynaphthyl-2-ethylamine hydrochloride (2C-G-N) weighed 1.23 g and had melting properties of darkening at 190 deg C, and decomposing in the 235-245 deg C area. Anal. (C14H18ClNO2) C,H. DOSAGE: 20 - 40 mg. DURATION: 20 - 30 h. QUALITATIVE COMMENTS: (with 24 mg) The effects were interestingly colored by the reading of Alan Watts' Joyous Cosmology during the coming-on period. The only body negatives were some urinary retention and a feeling of a shallow but continuing amphetamine stimulation. But not enough to be actually jingly, nor to interfere with sleep that evening. There is not much psychedelic here, but there is something really going on anyway. This has some similarities to the antidepressant world. (with 35 mg) Much writing, much talking, and there was considerable residual awareness the next day. Somehow this material is not as friendly as the other 2C-G's. (with 35 mg) Thinking is clear. No fuzziness, no feeling of being pushed. None of the walking on the fine middle line between light and dark that is the excitement and the threat of LSD. This is just a friend, an ally, which invites you to do anything you wish to. [comment added two days later] RMy sleep was not deep enough, but it was pleasant and relatively resting. The whole next day I was feeling happy, but with an overlay of irritability. Strange mixture. By bedtime the irritability had become a mild depression. I feel that there might have been a threshold continuing for a couple of days. The character of my dreaming had the stamp of drug on it. This compound, in retrospect, presents some problems that cause a faint unease. EXTENSIONS AND COMMENTARY: There is always a wish in the design of new compounds to find something that is of interesting activity, with an aromatic ring at some location pretty much away from the site of activity. This would then allow some subtle fine-tuning of the nature of the action by putting any of a wide range of electron pushing or electron pulling groups on that ring. But here, with 2C-G-N, by the time the ring got put into place, the activity was already on the wane, and the action was too long, and there are indicators of some not completely friendly effects. Ah well, some other molecule, some other time. #32 2C-H; 2,5-DIMETHOXYPHENETHYLAMINE SYNTHESIS: A solution of 50 g 2,5-dimethoxybenzaldehyde in 100 g nitromethane was treated with 5 g of anhydrous ammonium acetate, and heated on the steam bath for 4 h. The solution was decanted from a little insoluble material, and the solvent removed under vacuum. The clear oily residue was dissolved in 100 mL boiling IPA which, after standing a moment, set up as dense crystals. After returning to room temperature, these were removed by filtration, the product was washed with IPA and air dried, yielding 56.9 g 2,5-dimethoxy-beta-nitrostyrene as spectacular yum-yum orange crystals with a mp of 119-120 deg C. An analytical sample, from ethyl acetate, melted at 120-121 deg C. A suspension of 60 g LAH in 500 mL anhydrous THF was placed under an inert atmosphere, stirred magnetically, and brought up to reflux temperature. There was added, dropwise, 56 g of 2,5-dimethoxy-beta-nitrostyrene dissolved in THF, and the reaction mixture was maintained at reflux for 36 h. After being brought to room tem-perature, the excess hydride was destroyed with 40 mL IPA, followed by 50 mL of 15% NaOH. An additional 100 mL THF was required for easy stirring, and an additional 150 mL H2O was needed for complete conversion of the aluminum salts to a loose, white, filterable consistency. This solid was removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in dilute H2SO4. Washing with 3x75 mL CH2Cl2 removed most of the color, and the aqueous phase was made basic with aqueous NaOH and reextracted with 3x100 mL CH2Cl2. Removal of the solvent yielded 39.2 g of a pale amber oil that was distilled. The fraction boiling at 80-100 deg C at 0.4 mm/Hg weighed 24.8 g and was water-white product amine. As the free base, it was suitable for most of the further synthetic steps that might be wanted, but in this form it picked up carbon dioxide rapidly when exposed to the air. It was readily converted to the hydrochloride salt by dissolution in 6 volumes of IPA, neutralization with concentrated HCl, and addition of sufficient anhydrous Et2O to produce a permanent turbidity. Crystals of 2,5-dimethoxyphenethylamine hydrochloride (2C-H) spontaneously formed and were removed by filtration, washed with Et2O, and air dried. The mp was 138-139 deg C. DOSAGE: unknown. DURATION: unknown. EXTENSIONS AND COMMENTARY: I know of no record of 2C-H ever having been tried by man. It has been assumed by everyone (and probably correctly so) that this amine, being an excellent substrate for the amino oxidase systems in man, will be completely destroyed by the body as soon as it gets into it, and thus be without action. In virtually all animal assays where it has been compared with known psychoactive drugs, it remains at the "less-active" end of the ranking. It is, however, one of the most magnificent launching pads for a number of rather unusual and, in a couple of cases, extraordinary drugs. In the lingo of the chemist, it is amenable to "electrophilic attack at the 4-position." And, in the lingo of the psychopharmacologist, the "4-position is where the action is." From this (presumably) inactive thing have evolved end products such as 2C-B, 2C-I, 2C-C, and 2C-N. And in the future, many possible things as might come from a carbinol group, an amine function, or anything that can stem from a lithium atom. #33 2C-I; 2,5-DIMETHOXY-4-IODOPHENETHYLAMINE SYNTHESIS: A mixture of 7.4 g phthalic anhydride and 9.05 g of 2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its preparation) was heated with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was poured out into a crystallizing dish yielding 14.8 g of a crude solid product. This was recrystallized from 20 mL CH3CN, with care taken for an endothermic dissolution, and an exothermic crystallization. Both transitions must be done without haste. After filtration, the solids were washed with 2x20 mL hexane and air dried to constant weight. A yield of 12.93 g of N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide was obtained as electrostatic yellow crystals, with a mp of 109-111 deg C. A sample recrystallized from IPA was white, with a mp of 110-111 deg C. Anal. (C18H17NO4) C,H,N. To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide in 130 mL warm (35 deg C) acetic acid which was being vigorously stirred, there was added a solution of 10 g iodine monochloride in 40 mL acetic acid. This was stirred for 1 h, while being held at about 30 deg C. The reaction mixture was poured into 1500 mL H2O and extracted with 4x75 mL CH2Cl2. The extracts were pooled, washed once with 150 mL H2O containing 2.0 g sodium dithionite, and the solvent removed under vacuum to give 16.2 g of N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide as yellow amber solids with a mp of 133-141 deg C. This mp was improved by recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow solid with mp 149-151 deg C. A small sample from a large quantity of IPA gives a white product melting at 155.5-157 deg C. A solution of 12.2 g N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide in 150 mL hot IPA was treated with 6.0 mL of hydrazine hydrate, and the clear solution was heated on the steam bath. After a few minutes there was the generation of a white cottage cheese-like solid (1,4-dihydroxyphthalizine). The heating was continued for several additional h, the reaction mixture cooled, and the solids removed by filtration. These were washed with 2x10 mL EtOH, and the pooled filtrate and washes stripped of solvent under vacuum giving a residue which, when treated with aqueous hydrochloric acid, gave 3.43 g of voluminous white crystals. This, after recrystallization from 2 weights of H2O, filtering, washing first with IPA and then with Et2O, and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) as a white microcrystalline solid, with a mp of 246-247 deg C. Anal. (C10H15ClINO2) C,H,N. DOSAGE: 14 - 22 mg. DURATION: 6 - 10 h. QUALITATIVE COMMENTS (with 0 mg) I was present at a group meeting, but was only an observer. With zero milligrams of 2C-I, I was able to get to a delightful plus 2.5 in about five minutes after I arrived at your place, and absorbed the ambience of the folks who had actually imbibed the material. My level lasted about four hours and came down at about the same time as did the others. There were no after-effects experienced except for a pleasant languor. (with 15 mg) Comfortable onset. Most notable are the visuals, patterning like 2C-B (Persian carpet type), very colorful and active. Much more balanced emotional character, but still no feeling of insight, revelation, or progress toward the true meaning of the universe. And at 5 1/2 hours drop-off very abrupt, then gentle decline. I would like to investigate museum levels. (with 16 mg) There was an immediate alert within minutes. As usual, it was only an awareness, then nothing happened for a while. In retrospect, I see some type of activity or awareness within 40 minutes, which then builds up over time. The peak was at 2 hours and seemed to maintain itself for a while. Near the peak, there was some hallucinogenic activity, though not a lot. The pictures in the dining room had color and pattern movement that was fairly detailed. Focusing on other areas, such as walls or the outside of the house, produced little activity, though I tried. There was certainly a lot of color enhancement. There was also that peculiar aspect of the visual field having darkened or shadowed areas. These darker areas seemed to shift around to some degree. That aspect seems to be similar to 2C-B. I don't think I was more than +2.5 at the peak. Coming down was uneventful. I was down within 6 hours. I had no problems driving home, nor were there any difficulties with sleep. There were no body problems with this material. I ate like a horse. (with 16 mg) The 16 was a bit much, I realized, because my body was not sure of what to do with all the energy. Next time I'll try 14 or 15. However, my conversations were extremely clear and insightful. The degree of honesty was incredible. I was not afraid to say anything to anyone. Felt really good about myself. Very centered, in fact. A bit tired at day's end. Early bedtime. (with 20 mg) I think there is slightly less than full immersion in the sensual, with this material, compared with 2C-B, but I suspect it's more a matter of getting used to the language of 2C-I and the feelings Q getting tuned to a slightly different frequency, really Q rather than that the material is less sensual or less easy to use sensually. Just different frequency, and we are very, very used to 2C-B. Good on the body. Transition, for me, not as strongly dark as 2C-B. But it could certainly take a lot more exploring, if we were able to give the time (about 9 hours) to it. Next day: sleep excellent. Energy next day unusually good. Quite tired by evening. EXTENSIONS AND COMMENTARY: The frequent comparisons between 2C-I and 2C-B stem, without doubt, from a bit of chemical suggestion. The two compounds have structures that are truly analogous, in technical terms. In one, there is a strategically located iodine atom, and in the other, an identically placed bromine atom. These are directly above and below one-another in the periodic table. And what is particularly maddening to the synthetic diddler, is that they cannot be lengthened, or shortened, or squooshed around in any way. You can't make a longer and narrower version of a bromine atom, as you can do with, say, a butyl group. You've got what you've got, like it or not. No subtle variations. But, on the brighter side of the picture, you have a heavy atom here, and this atom is intrinsic to the central activity of the compound. So, these materials are naturals for radio-labelling experiments. 2C-I has been made radioactive with radio-iodine, but the most impressive findings have been made with the 3-carbon analog, DOI. One quotation from an observer of a group experiment is enclosed; an experiment with zero milligrams being taken. This is a instructive observation of what has been called a Rcontact high. There is one Iodotweetio known. In Scrabble, would you challenge a word that had seven of its eleven letters as vowels? Especially if the vowels were, specifically, iooeeio? It sounds just a little like the noise coming out of Old McDonald's farm. But a Tweetio there is, namely, the 2-EtO-homologue of 2C-I. This is 2-ethoxy-4-iodo-5-methoxyphenethylamine, or 2CI-2ETO. The hydrochloride salt was a white, crystalline product with a melting point of 175-175.5 deg C. The threshold level of activity was seen at an oral dose of 5 milligrams, and the generated effects were completely dispersed in a couple of hours. Most interestingly, larger doses, of up to 50 milligrams orally, seem to produce no more intense an effect, but simply to stretch out this threshold for an additional couple of hours. At no level that has been tried, has 2CI-2EtO produced even a plus-two response. Where else can one go, from 2C-I? The iodine is the fourth, and the last of the so-called halogens, at the bottom of the classical periodic table. But, thanks to the miracles that have accompanied us into the nuclear age, there is a fifth halide now known, Astatine. All of its isotopes are radioactive, however, and it seems unlikely that there will ever be an entry (other than this one) for 2,5-dimethoxy-4-astatophenethylamine. What might be speculated as to its activity? Probably similar in potency to 2C-I, requiring maybe 10 or 20 milligrams. The duration would be dicey to measure, since the isotope with the longest known half-life is half decayed in about 8 hours, and the longest lived natural isotope (for those who insist on natural rather than man-made things) is half decayed in less than a minute. Two predictions would be pretty solid. You might have quite a job accumulating your 10 milligrams of Astatine, as the most that has so far been made at one time is only about 0.05 micrograms, approximately a millionth of the amount needed. And the second prediction? You would not survive the screaming radiation that would bombard you if you could get the needed 5 or 10 milligrams of radio-astatine onto that magic 4-position, and the resulting 2C-A into your tummy! #34 2C-N; 2,5-DIMETHOXY-4-NITROPHENETHYLAMINE SYNTHESIS: A cooled, stirred solution of 1.0 g 2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its preparation) in 20 mL glacial acetic acid was treated with 3.3 mL 70% HNO3 in small portions, with the reaction temperature kept down with periodic cooling. After the addition was completed, the stirring was continued until there was the spontaneous separation of a yellow solid. This was 2,5-dimethoxy-4-nitrophenethylamine nitrate (2C-N) which was obtained after removal by filtration, washing with Et2O and air drying, as a fluffy yellow solid. This weighed 1.04 g and melted, with decomposition, in the area of 170-180 deg C, depending on the rate of heating. A solution of 0.8 g of this nitrate salt in 50 mL H2O was made basic with aqueous NaOH. Extraction with 3x50 mL CH2Cl2, and removal of the solvent under vacuum gave the free base as a residue. This was distilled at 130-150 deg C at 0.35 mm/Hg to give an orange-red oil that weighed 0.5 g and set up as crystals. This was dissolved in 3 mL IPA, neutralized with 7 drops of concentrated HCl (the color lightened considerably at the titration end point) and diluted with 5 mL anhydrous Et2O. There was the formation of the hydrochloride salt which was a pumpkin-colored crystalline mass. After removal by filtration, Et2O washing and air drying, these crystals weighed 0.44 g. The mp, 193-195 deg C, was not improved by recrystallization from any of several solvents (MeOH, IPA, CH3CN). The perchlorate salt was a yellow solid from MeOH, with a mp of 211 deg C, with decomposition. Nitration of 2C-H in a mixture of acetic acid and acetic anhydride produced the acetamide derivative of 2C-N as yellow crystals with a mp 142.5-143 deg C. For the nitrate salt: Anal. (C10H15N3O7) C,H. This was the form used for all human titrations. DOSAGE: 100 - 150 mg. DURATION: 4 - 6 h. QUALITATIVE COMMENTS: (with 120 mg) This came on very fast Q I was aware of it within a half hour, and it got as far as it would go by an hour. There are similarities to MDMA, but missing is the benign anti-stress component. I am light-headed, and there just might be a little eye wiggling. And then it dropped right off to nothing within a couple of hours. (with 150 mg) There may have been some visual changes, I'm not sure. But the talking was extremely easy. If there were no other things to use, this would be excellent, but there are other compounds available. This doesn't have too high a priority. (with 150 mg) Am I enjoying it? Not exactly, but I am in a good mood. There is not the light-filled energy that some other materials can provide. By six hours, pretty much baseline. Strange material, but okay. Final score: body +3, mind +2, barely. EXTENSIONS AND COMMENTARY: A most consistent feature with 2C-N was the fact that in every report, somewhere, there is the note that it somehow came up just a little short of expectations. From the esthetic point of view, the pure salt is yellow rather than the usual white color, so the solutions that are to be consumed are by definition also yellow colored. From the structural point of view, the 4-nitro group, like the 4-bromo group of 2C-B, is a dead-end. It cannot be stretched or compressed or lengthened or shortened. This unique aspect demands that you have to live with what you have, as there are no subtle ways of modifying the molecule. With 2C-B, the end product was a total winner; there was no wish to modify it. With 2C-N the end product is something a little less, and there is no way to modify it. #35 2C-O-4; 2,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE SYNTHESIS: To a solution of 3.10 g 85% KOH pellets in 30 mL warm MeOH there was added 6.16 g 2,5-dimethoxyphenol (there was immediate darkening) followed by 8.5 g isopropyl iodide. The reaction mixture was heated on the steam bath for 3.5 h. White crystals of KI appeared at the end of the first h. The mixture was poured into 800 mL H2O (it was still basic) and acidified with HCl. This was extracted with 3x100 mL CH2Cl2, and the combined extracts washed with 2x100 mL 5% NaOH. The organic phase was stripped of solvent under vacuum, and the residual dark amber oil (6.4 g) distilled at 110-130 deg C at 0.7 mm/Hg. There was obtained 5.7 g of 1,4-dimethoxy-2-(i)-propoxybenzene as a white oil. A mixture of 10 g N-methylformanilide and 10 g POCl3 was heated on the steam bath for 10 min producing a deep claret color. To this there was added 5.1 g of 1,4-dimethoxy-2-(i)-propoxybenzene, and the immediately exothermic reaction mixture was heated on the steam bath for 45 min. It was then poured into 800 mL H2O which was stirred until the dark oil changed into loose, light-colored solids. These were removed by filtration giving 5.7 g of an amber crystalline product with a mp of 76-78 deg C. This was dissolved in an equal weight of MeOH, and heated to a solution which was clear at the boiling point. This was brought to 0 deg C and held there for several hours, yielding 2,5-dimethoxy-4-(i)-propoxybenzaldehyde as a fine, off-white crystalline product which, after filtering and air drying, weighed 4.03 g. The mp was 79-80 deg C with prior shrinking at 71 deg C. Anal. (C12H16O4) C,H. A solution of 3.9 g 2,5-dimethoxy-4-(i)-propoxybenzaldehyde in 20 g nitromethane was treated with 0.17 g anhydrous ammonium acetate and heated on the steam bath for 1.25 h. The progress of the condensation was readily followed by a TLC analysis of the reaction mixture. With silica gel plates, the starting aldehyde and the product nitrostyrene had Rf's of 0.16 and 0.50 resp., using CH2Cl2 as a developing solvent. The excess solvent was removed under vacuum to give a red residue that was dissolved in 10 mL boiling MeOH. The solution spontaneously crystallized giving, after filteration and air drying, 4.1 g of orange crystals of 2,5-dimethoxy-beta-nitro-4-(i)-propoxystyrene. A solution of LAH (60 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.60 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 4.0 g 2,5-dimethoxy-beta-nitro-4-(i)-propoxystyrene as a solid, perhaps 200 mg at a time. There was an immediate loss of color after each addition. The final pale salmon-colored solution was stirred for 2 h as it returned to room temperature. The excess hydride was destroyed by the cautious addition of 8 mL IPA, which was followed by 5 mL 15% NaOH followed, in turn, by sufficient additional THF to make the suspension of inorganic salts loose and filterable. The reaction mixture was filtered, and the filter cake washed with additional THF. The filtrate and washings were combined and stripped of solvent under vacuum providing 4.6 g of a pale amber oil. This was dissolved in dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent under vacuum yielded 2.3 g of residue which was distilled at 115-125 deg C at 0.3 mm/Hg to give 0.94 g of a clear white oil. This was dissolved in 5 mL IPA, neutralized with 12 drops of concentrated HCl, and diluted with 10 mL anhydrous Et2O. White crystals of 2,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (2C-O-4) separated, and were removed by filtration, Et2O washed, and air dried. The final weight was 0.58 g. DOSAGE: greater than 60 mg. DURATION: unknown QUALITATIVE COMMENTS: (with 60 mg) I became aware of something in the front part of my head, and there was a lot of yawning. The body was aware of the experiment. But also there was a general exhilaration and excitement, which lasted for a few hours. At best, I am at a plus one. EXTENSIONS AND COMMENTARY: The full activity of 2C-O-4 is yet to be discovered. It represents an interesting hybrid lying in between several fascinating compounds. First and foremost, all these carry the 2,4,5-trisubstitution which has consistently proven to be the most interesting and the most active of the phenethylamines. And with very few exceptions, the 2- and the 5- are methoxyl groups. The sulfur analogues in this area, compounds with an alkylthio group at the 4-position of the 2,5-dimethoxyphenethylamine backbone, are the 2C-T things. The replacement of a sulfur with an oxygen, quite rightly, should give rise to the 2C-O counterparts. And they have been given the same numbering system that was bestowed upon the RTS series. 2C-T-4 was the 4-isopropylthio compound and one of the most interesting of this family. And so, quite reasonably, the oxygen coun-terpart should be the 2C-O-4 analogue, and should be one of the first explored. The extension of the 4-alkoxy-group led to the discovery of the TMA-2 Q MEM Q MIPM Q MPM Q MBM series of amphetamine analogues. The 2-carbon counterparts of these would be a fascinating series to explore, I thought, if there was some encouragement to be had from a preliminary try in this field. This was a first shot in the dark, the actual trial example, and it certainly didn't provide much encouragement. The three-carbon analogue, MIPM, was made (q.v.) but not explored, following the disappointing trials of MPM. If this area is ever re-opened, the numbering should reasonably follow the sulfur materials. The 4-ethoxy material would be 2C-O-2, the 4-(n)-propoxy compound 2C-O-7, and the 4-(n)-butoxy compound 2C-O-19. These are the exact analogues of 2C-T-2, 2C-T-7, and 2C-T-19, resp., and the 2-carbon homologues of MEM, MPM, and MBM. The simplest member of this series, the methyl counterpart, is 2C-O, and it is the obvious analogue of 2C-T. This is also called 2,4,5-TMPEA, and its story is presented elsewhere. But, with the probable low eventual potency of 2C-O-4, I feel that the 2C-O series will not be an exciting one. #36 2C-P; 2,5-DIMETHOXY-4-(n)-PROPYLPHENETHYLAMINE SYNTHESIS: To a stirred solution of 138 g p-dimethoxybenzene in 400 mL CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL CH2Cl2 which contained 92.5 g propionyl chloride. After stirring for 1.5 h the reaction mixture was poured into 2 L H2O containing ice. The phases were separated, and the aqueous fraction was extracted with 2x100 mL CH2Cl2. The organic phase and the extracts were pooled, washed once with H2O, and then with 2x100 mL 5% NaOH. The solvent from the organic phase was removed under vacuum, yielding a deeply colored residue. This was distilled at 150-165 deg C at 20 mm/Hg yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored oil. Acidification of the sodium hydroxide extract, extraction with CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that slowly crystallized. These solids, on recrystallization from MeOH, provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a mp of 47-48 deg C. The same Friedel Crafts reaction, conducted on the same scale in CS2 rather than in CH2Cl2, required reduced temperature (5 deg C) and a 24 h reaction period. This solvent variation, with the same workup and isolation, gave 76 g of 2,5-dimethoxypropiophenone as a pale amber oil boiling at 130-137 deg C at 4 mm/Hg. A total of 150 g mossy zinc was amalgamated by treatment with a solution of 15 g mercuric chloride in 1 L H2O. After swirling for 0.5 h, the H2O phase was removed by decantation and the zinc added to a 1 L three neck flask. To this there was added 20 mL H2O and 20 mL concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone dissolved in 50 mL EtOH. This mixture was held at reflux with a heating mantle overnight, with the occasional addition of HCl as needed to maintain acidic conditions. After cooling to room temperature, the residual solids were removed by filtration, and the filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase). Sufficient H2O was then added to allow extraction with 2x100 mL additional CH2Cl2 with the organic solvent being the lower phase. The combined organic extracts were washed twice with 5% NaOH, followed by one washing with dilute acid. Removal of the solvent under vacuum yielded 18 g of a dark brown oil that was distilled at the water pump to yield 7.2 g of 2,5-dimethoxypropylbenzene as a light yellow oil boiling at 90-130 deg C. A mixture of 22 g 2,5-dimethoxypropylbenzene, 23 g POCl3 and 22 g N-methylformanilide was heated on the steam bath for 1.5 h. The hot, dark reaction mass was poured into 1 L H2O, which allowed the eventual separation of 2,5-dimethoxy-4-(n)-propylbenzaldehyde as a clear yellow oil weighting 14 g. Although the homologous 4-ethyl and 4-butyl benzaldehydes were clean crystalline solids, this propyl homologue remained an oil. Gas chromatographic analysis showed it to be about 90% pure, and it was used as obtained in the nitrostyrene steps with either nitromethane (here) or nitroethane (under DOPR). To a solution of 13 g 2,5-dimethoxy-4-(n)-propylbenzaldehyde in 100 mL nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture held at reflux for 1 h. Removal of the solvent/reactant under vacuum yielded a spontaneously crystallizing mass of orange solids that was removed with the help of a little MeOH. After filtering and air drying there was obtained 7.5 g 2,5-dimethoxy-beta-nitro-4-(n)-propylstyrene with a mp of 118-122 deg C. Recrystallization from CH3CN gave an analytical sample with a mp 123-124 deg C. Anal. (C13H17NO4) N. In a 1 L round bottomed flask with a magnetic stirrer under a He atmosphere there was added 120 mL 1 M LAH in tetrahydrofuran. This stirred solution was cooled with an external ice bath, and there was added, dropwise, 3.2 mL of 100% H2SO4, freshly made by the addition of 13.5 g 20% fuming H2SO4 to 15.0 g of ordinary 96% concentrated H2SO4. When the addition was complete, a total of 7.2 g of dry 2,5-dimethoxy-beta-nitro-4-(n)-propylstyrene was introduced as solids in several batches, against a flow of He, over the course of 20 min. The reaction mixture was allowed to come to room temperature, and stirred for an additional 0.5 h, then brought to reflux for 10 min on the steam bath. The excess hydride was destroyed with 18 mL IPA, and then sufficient 15% NaOH was added which made the aluminum oxides distinctly basic and of a filterable texture. The inorganics were removed by filtration, and the filter cake washed with additional THF. The combined filrate and washes were stripped of solvent, yielding several g of a pale yellow oil that was suspended in a large quantity of dilute H2SO4. The aqueous phase was filtered free of insolubles, washed with a little CH2Cl2, and made basic with aqueous NaOH. This was extracted with 3x40 mL CH2Cl2 and, after the removal of the solvent under vacuum, the residual 2 g of off-white oil was distilled. A fraction that distilled at 100-110 deg C at 0.3 mm/Hg was water white, weighed 1.59 g and spontaneously crystallized. This fraction was dissolved in 7.5 mL warm IPA and neutralized with 0.6 mL concentrated HCl. The spontaneous crystals of 2,5-di-methoxy-4-(n)-propylphenethylamine hydrochloride (2C-P) were suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air dried. The weight was 1.65 g and the mp was 207-209 deg C with prior sintering at 183 deg C., Anal. (C13H22ClNO2) N. DOSAGE: 6 - 10 mg. DURATION: 10 - 16 h. QUALITATIVE COMMENTS: (with 6 mg) I was not feeling so good. Hangover, I guess. The material was so gentle in coming on, and soon my body became jangled. Thinking was easy. Verbalizing was easy. Being comfortable with my body was not. My back hurt and then my legs hurt. My lower back was in spasm. At first I did not particularly like what this drug was doing to my body, but took a good look at it and decided that I was the culprit. Took a good look at my drinking so much, and decided that I didn't need it. So much energy was going through me I didn't know what to do with it. The whole day was spent in physical discomfort. Food tasted good, and we nibbled all day. My stomach was bloated. Next day I was more or less like a zombie. I was wiped out. (with 8 mg) Comes on slowly, not feeling intently until into 2nd hour. I feel slight discomfort but override it responding to music. I take in air, directing it inside to heal uncomfortable places, open up my clogged sinuses. Wonderful experience of clean, fresh, healing air. Find that discomfort zone is places where I think there is something wrong with me. I dissolve these places with the feeling I'm OK. Like myself better and better, and find more reasons to enjoy and appreciate myself. I find this material powerful, and an excellent working material. Under other circumstances, would probably spend more time working alone inside, where there were great openings, and some of the most beautiful visuals I have seen for a long time. Usually I do not get visuals. I like the long action. I feel that this material worked for a good week after the experience, with internal processes taking place, many insights, and energy running. At times the energy was a little uncom-fortable, but could always be quelled by taking a moment for deep relaxation or looking directly at the internal process. I feel that much good internal work has been done, a lot of it unconscious. (with 9 mg) At the one hour point, I am barely off of baseline. It is not until almost the third hour that the experience is fully developed, and once there it is maintained for another four hours. I was well grounded but rather diffuse. I explored writing (which went quite well), interpretation (pictures and reading both OK) and talking (very good). This is an excellent level, and probably near the max. (with 12 mg) Slow and even rise. At five minutes to seven (suddenly the clock time makes no sense at all) I am at a 3+ and feel that I have not yet plateau'd. Erotic was excellent. Music good. Eyes-closed imagery very different place than usual experiences. Slow, calm, strong images from an area that has no apparent connection with usual waking world, yet underlies all of it. A cool, wise place which has its own rules. All emotions and feeling available, but there is a cool perspective which informs all thinking. Talking superb and fun, and it was possible to feel our bodies healthy and full of determination to remain so, despite obvious faults and self-indulgences. Could do a lot of learning with this material, but probably not a group thing. It would lend itself too easily to hypnotic power-games, and it would be too easy to open up the shared consciousness level, which would be frightening to a lot of people and bring about necessary escapes such as sickness. Excellent feeling the next day. EXTENSIONS AND COMMENTARY: There is certainly a broad mixture of experiences with 2C-P but, on the whole, probably more favorable than not. There was one report of an experience in which a single dosage of 16 mg was clearly an overdose, with the entire experiment labeled a physical disaster, not to be repeated. A consistent observation is that there may not be too much latitude in dosage between that which would be modest, or adequate, and that which would be excessive. The need for individual titration would be most important with this compound. #37 CPM; CYCLOPROPYLMESCALINE; 4-CYCLOPROPYLMETHOXY-3,5-DIMETHOXYPHENETHYLAMINE SYNTHESIS: To a solution of 2.8 g homosyringonitrile (see under E for synthesis) in 20 ml acetone containing about 50 mg decyltriethylammonium iodide, there was added 3.0 g cyclopropylmethyl chloride and 5.0 g NaI. Stirring was continued during a color change from pale yellow to blue. There was then added 2.9 g of finely powdered anhydrous K2CO3, resulting in a beautiful turquoise color. The mixture was held at reflux on the steam bath for 3 h, which discharged all color. The solvent was removed under vacuum, and the residues were added to 100 mL H2O. This solution was extracted with 3x75 mL CH2Cl2, the extracts were pooled, washed with 2x50 mL 5% NaOH, and the organic solvent removed under vacuum. The residual oil weighed 4.2 g, and was distilled at 140-155 deg C at 0.4 mm/Hg to yield 4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile as a colorless oil weighing 2.8 g which spontaneously crystallized. Its mp was 44-44.5 deg C after recrystallization from MeOH/H2O. Anal. (C14H17NO3) C,H. A suspension of 1.3 g LAH in 65 mL anhydrous THF under He was cooled to 0 deg C with stirring, and 0.85 mL of 100% H2SO4 was slowly added. Then, with continued stirring, a THF solution of 2.7 g of 4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile in 50 mL THF was added dropwise. After the addition was complete, the mixture was brought to a boil briefly on the steam bath, cooled, and treated with sufficient IPA to destroy the excess hydride. Then there was added an amount of 15% NaOH sufficient to produce a loose filterable solid form of aluminum oxide. This was removed by filtration, and the filter cake washed with THF. The pooled filtrate and washes were stripped of solvent, and the residue was dissolved in dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 2x50 mL of CH2Cl2. After removal of the solvent, the residue was distilled at 128-140 deg C at 0.4 mm/Hg to yield 2.5 g of a white oil. This was dissolved in 10 mL IPA, and treated with 30 drops of concentrated HCl which was just sufficient to demonstrate acidity as judged by external dampened pH paper. The addition of 25 mL anhydrous Et2O to the stirred solution allowed, in a few minutes, the product 4-cyclopropylmethoxy-3,5-dimethoxyphenethylamine hydrochloride (CPM) to spontaneously crystallize as a fine white solid. The yield was 1.8 g, and a second crop of 0.8 g was obtained from the IPA/Et2O mother liquors. The mp was 172-173 deg C. Anal. (C14H22ClNO3) C,H. DOSAGE: 60 - 80 mg. DURATION: 12 - 18 h. QUALITATIVE COMMENTS: (with 70 mg) I was surprised at the fast development of this drug, with the knowledge that it was a long-laster. Twenty minutes into it I was aware of some changes, and by the end of one and a half hours there was a complete plus three. The most remarkable property is the eyes-closed imagery. No, not just imagery but fantasy. It is not completely benign, but it locks into music with an extraordinary fit. I was at one moment keenly aware of my body touching the rug, the tactile aspects of my surroundings, and then I would find that my world was simply my personal sphere of reality that kept engulfing everything about me, all completely augmented by the music. Constructed by the music. I hoped that I wouldn't offend anyone else around me with this growing world of mine. Eyes open, there was not that much of note. Not much insight. Not much in the way of visuals. By the eighth hour an effort to sleep showed me how exposed and vunerable I was, and when I closed my eyes I needed my guards against this fantasy world. Even at the twelth hour there was no easy way to relax and sleep. Use higher dosages with caution. (with 70 mg) There is a goodly amount of eyes-closed patterning but I found external sounds to be irritating. Voices, and even music, seemed to be intrusive. I didn't want to share my space with anyone. I was reminded of mescaline, in that I kept losing the awareness of the drug's role in my experience. Visual exaggerations are probably right around the corner. The residual effects were too much to ignore, but 100 milligrams of phenobarb at about the twelth hour allowed me to lie down quietly. (with 80 mg) A wild day of profound philosophy, with discussions of the art of molecules, the origins of the universe, and similar weighty trivia. Much day-dreaming in erotic areas, but by and large, it went on a bit too long. I was tired. EXTENSIONS AND COMMENTARY: In the literary world, the guy who is on your side, your leader, your champion, is the protagonist and the guy he battles, your enemy, is the antagonist. These same roles are played in the world of pharmacology, but the names are slightly changed. A drug which does the needed or expected thing is called the agonist rather than protagonist, but the drug that gets in its way is still called the antagonist. The cyclopropylmethyl group plays an interesting role in the world of narcotics. There are numerous examples of opiates with a methyl group attached to a nitrogen atom which are famous for being valuable in producing analgesia and sedation. These run the gamut from natural alkaloids such as morphine and codeine, to synthetic variants such as Dilaudid and Percodan. And yet, with most of these narcotics, when the methyl on the nitrogen is removed, and a cyclopropylmethyl group put into its place, the agonist becomes an antagonist. Oxycodone (the active narcotic thing in Percodan) becomes Naltrexone, a drug that will immediately snap a heroin victim out of his overdose. Cyclopropylmescaline (CPM) is a molecule that is very simply mescaline itself, with a methyl group removed from an oxygen atom and a cyclopropylmethyl group put on instead. Might CPM be not only inactive, but actually block the action of mescaline? Interesting concept. But it turned out to be entirely wrong. The amphetamine analog of CPM should be easily made from the alkyl-ation of syringaldehyde with cyclopropyl chloride, followed by conventional reaction of the resulting aldehyde with nitroethane, and finally a reduction step. There is no reason to believe that the resulting compound 3,5-dimethoxy-4-cyclo-propyloxyamphetamine (3C-CPM) would be any shorter acting than CPM. #38 2C-SE; 2,5-DIMETHOXY-4-METHYLSELENEOPHENETHYLAMINE SYNTHESIS: A suspension of 5.65 g 1,4-dimethoxybenzene in 100 mL petroleum ether containing 6.5 mL N,N,N',N'-tetramethylethylenediamine was magnetically stirred, placed in an inert atmosphere, and cooled to 0 deg C with an external ice bath. There was then added 27 mL of 1.6 M butyllithium in hexane. The solids present went into solution, and after a few min continued stirring, a fine precipitate appeared. The reaction was allowed to stir while coming up to room temperature. There was then added 4.8 g dimethyl diselenide which led to an exothermic reaction, bringing the petroleum ether up to a reflux and showing a color change from white to yellow, to light green, to an eventual brown, all over the course of 30 min. After 2 h additional stirring, the reaction was quenched by pouring into dilute NaOH. The organic phase was separated, and the aqueous phase extracted with 2x75 mL Et2O. The pooled organics were washed first with dilute NaOH, then with dilute HCl, and then the solvent was removed under vacuum. Distillation of the residue at 0.4 mm/Hg gave an early fraction (75-100 deg C) that solidified in the receiver and was largely unreacted dimethoxybenzene. A pale yellow oil distilled from 100 to 120 deg C which proved to be largely 2,5-dimethoxyphenyl methyl selenide. Microanalysis gave C = 49.86, 49.69; H = 5.32, 5.47. As C9H12SeO2 requires C = 46.76, H = 5.23, there is approximately 13% dimethoxybenzene present (C8H10O2 requires C = 69.54, H = 7.29). This mixture was used as such, without further purification. A mixture of 1.25 g POCl3 and 1.1 g N-methylformanilide was warmed on the steam bath for several min until the color had become a deep claret. There was then added 1.5 g of the 87% pure 2,5-dimethoxyphenyl methyl selenide and the steam bath heating continued for an additional 25 min. The very tarry reaction mixture was poured into 100 mL H2O, producing fine yellow solids almost immediately. These were removed by filtration and distilled at 0.2 mm/Hg. A first fraction distilling up to 100 deg C was a mixture of unreacted ethers and what appeared to be 2,5-dimethoxybenzaldehyde. A second cut distilled at 140-150 deg C, solidified to a yellow solid in the receiver, and weighed 1.2 g. A small amount of this product (with mp 91-96 deg C) was recrystallized from MeOH to give an analytic sample of 2,5-dimethoxy-4-(methylseleneo)benzaldehyde with a mp 88-92 deg C. All efforts to achieve a tighter melting range were unsuccessful. Anal. (C10H12O3 Se) C,H. Although this benzaldehyde migrates normally on a silica gel TLC plate (Rf of 0.4 employing CH2Cl2 as a solvent) when it is once completely dried on the plate, there seems to be some irreversible reaction with the silica, and the spot will no longer move at all. To a solution of 0.85 g 2,5-dimethoxy-4-(methylseleneo)benzaldehyde in 10 mL nitromethane there was added 150 mg anhydrous ammonium acetate, and the solution was heated for 35 min on the steam bath. Removal of the volatiles under vacuum yielded brick-red solids (1.1 g) which were ground under a small amount of MeOH, filtered, and air dried. This yielded 0.88 g of solid 2,5-dimethoxy-4-methylseleneo-beta-nitrostyrene with a mp of 170.5-171.5 deg C. Recrystallization from IPA or from toluene gave no improvement of mp. Anal. (C11H13NO4Se) C,H. A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 0.53 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 0.85 g 2,5-dimethoxy-4-methylseleneo-beta-nitrostyrene in 20 mL hot anhydrous THF. There was an immediate discoloring. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for 0.5 h, then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of IPA and, when there was no further activity, the reaction mixture was poured into 500 mL dilute H2SO4. This was washed with 2x100 mL CH2Cl2, and then made basic with 5% NaOH. The milky aqueous phase was extracted with 2x100 mL CH2Cl2, and extensive centrifuging was required to obtain a clear organic phase. Evaporation of the pooled extracts gave 1.6 g of an oil that crystallized. This was distilled at 130-140 deg C at 0.15 mm/Hg providing 0.6 g of a white oil that set to a crystalline solid melting at 87-89 deg C. This was dissolved in 4 mL boiling IPA, neutralized with 8 drops of concentrated HCl and the formed solids further diluted with IPA with a little anhydrous Et2O. This crystalline product was removed by filtration, washed with Et2O, and air dried to constant weight, yielding 2,5-dimethoxy-4-methylseleneophenethylamine hydrochloride (2C-SE) with a mp of 240-241 deg C. DOSAGE: perhaps 100 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 50 mg) My tongue feels as if I had eaten hot food. Overall I got up to a plus 1, and found the effects to be completely benign. I wandered about within the Graves exhibit at the Oakland Museum but there seemed to be only minor enhancement of the visual input. (with 70 mg) The water solution of this material has an unspeakable smell. But there is no lasting taste, thank heaven. This is up to a 1.5 + and probably half again would be an effective dose. The first awareness was at 45 minutes, and the plateau lasted from 1.5 hours to about the fourth hour. I was at certain baseline at 8 hours. EXTENSIONS AND COMMENTARY: With an entirely new hetero atom in the molecule (the selenium), and with clear indications that large dosages would be needed (100 milligrams. or more), some discretion was felt desirable. There was certainly an odd taste and an odd smell. I remember some early biochemical work where selenium replaced sulfur in some amino acid chemistry, and things got pretty toxic. It might be appropriate to get some general animal toxicity data before exploring those dosages that might get to a +++. What doors are opened by the observation that the selenium analog of 2C-T is an active compound? The potency appears to be in the same ball park, whether there is a sulfur atom or a selenium atom there. From the point of view of the thing that is hung onto the hetero-atom, the selenium, the most active (and as first approximation the most safe) analogue would be the same ones that are the most potent with sulfur. These would probably be the Se-ethyl, the Se-propyl, or the Se-isopropyl, the analogs of S-ethyl, S-propyl, and S-isopropyl. If one were to be systematic, these would be called 2C-SE-2, 2C-SE-4, and 2C-SE-7. And a very special place might be held for 2C-SE-21, the analogue of 2C-T-21. Not only is this of high potential potency, but it would certainly be the first time that both fluorine and selenium are in the same centrally active drug. In fact, might not this compound, 2C-SE, be the first compound active within the human CNS with a selenium atom in it? It is certainly the first psychedelic with this atom in it! From the point of view of the hetero-atom itself, there are two more known below selenium in the Periodic Table. Each deserves some special comment. The next atom, directly below selenium, is tellurium. It is more metallic, and its com-pounds have a worse smell yet. I heard a story about a German chemist, many years ago, who was carrying a vial of dibutyl telluride in his pocket in a passenger coach from here to there in Germany, back at about the turn of the century. It fell to the floor and broke. No one could remain in the car, and no amount of decontamination could effectively make the smell tolerable. Scratch one railway coach. But the compound, 2C-TE, would be readily makeable. Dimethyl ditelluride is a known thing. However, the atom below tellurium (and at the bottom of that particular column of the Periodic Table) is the element polonium. Here one must deal in terms of theory, as far as human activity goes, since there are no non-radioactive isotopes of polonium. The only readily available isotope is that with mass 210, which is also called Radium F, and is an alpha-particle emitter. If this were ever to be put into a living organism, and if it were to seek out and hang around some particular site of action, that area would be thoroughly and completely cooked by alpha-particle emission. It would be a fun academic exercise to make 2C-PO (2,5-dimethoxy-4-methylpoloneophenethylamine), but in no way could it ever go into anyone. I knew an eminent physiologist named Dr. Hardin Jones (now dead) who always argued that the continuing use of drugs would burn out the pleasure center of the brain. It is a certainty that 2C-PO would, quite literally, do this. If I ever made it, I would call it HARDINAMINE in his honor. There was an interesting observation associated with the making of 2C-SE. In the synthesis of many of the sulfur compounds (of the 2C-T family) is was quite common to find, when there was a quantity of some organic sulfide let go as a by-product of a reaction on a warm summer night, a number of flies coming into the lab to pay a visit. On the first synthesis of the starting material for 2C-SE, a quantity of CH3SeH was let go into the environment. Within minutes, there were two beautiful dragonflies in the lab. A coincidence certainly, but somehow, it was a nice message to receive. #39 2C-T ; 2,5-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE SYNTHESIS: A solution of 149 g sodium thiosulfate in 300 mL H2O was vigorously stirred. To this there was added, over the course of 10 min, a solution of 43.2 g benzoquinone in 200 mL acetic acid. After an additional 1 h stirring at room temperature, all volatiles were removed under vacuum. The residual syrup slowly set up as crystals which, after grinding under brine, were removed by filtration and washed with additional brine. These were dissolved in MeOH, clarified by filtration through a Celite bed, and the clear filtrate stripped of solvent under vacuum. The yellow, powdery sodium 2,5-hydroxyphenylthiosulfate weighed 67 g when dry. This intermediate was dissolved in aqueous HCl (50 g in 200 mL H2O containing 400 mL concentrated HCl), cooled with an external ice bath, and treated with 250 g zinc dust added at a rate that kept the temperature below 60 deg C. About 1.5 h were required, and caution must be taken concerning the poisonous hydrogen sulfide that evolves. An additional 50 mL concentrated HCl was added, and the aqueous phase decanted from the unreacted zinc metal. This was extracted with 6x100 mL Et2O, and these extracts were pooled, washed with brine, and the solvent removed under vacuum to yield 33.1 g of 2,5-dihydroxythiophenol as pale yellow needles with a mp of 118-119 deg C. A solution of 118.6 g KOH pellets in 200 mL H2O was placed under N2, and to it was added 24.0 g 2,5-dihydroxythiophenol. With vigorous stirring, there was then added 160 g methyl sulfate at a rate that maintained the temperature at about 60 deg C. This took about 2 h. After the addition was complete, the mixture was held at reflux for 3 h, and allowed to stir at ambient temperature overnight. It was then filtered, and the filtrate extracted with 6x100 mL Et2O, the extracts pooled, washed with 2x50 mL brine, dried over anhydrous Na2SO4, and the solvent removed under vacuum. The residue was distilled at 86-88 deg C at 0.04 mm/Hg to provide 25.9 g of 2,5-dimethoxythioanisole as a white oil that crystallized on standing. Its mp was 33-34 deg C. An alternate preparation of this compound follows the direct methylation of 2,5-dimethoxythiophenol (see under 2C-T-2 for the preparation of this common intermediate) with methyl iodide. To 40 mL dry CH2Cl2 there was added 6.07 g 2,5-dimethoxythioanisole, and this was cooled to 0 deg C under N2. To this well stirred solution there was added 13.02 g stannic chloride over the course of 2 min. This was followed by the drop-wise addition of dichloromethyl methyl ether over 5 min, and the reaction mixture allowed to stir for an additional 15 min. After returning to room temperature, it was stirred for an additional 1 h. The reaction mixture was poured over 15 g ice, and the organic phase separated, washed with 3x25 mL 3 N HCl, with 3x50 mL brine and, after drying over anhydrous Na2SO4, the solvent was removed under vacuum. The residue was a solid and, after recrystallization from MeOH/H2O, gave 5.86 g 2,5-dimethoxy-4-(methylthio)benzaldehyde with a mp of 95-97 deg C. Purification via the bisulfite complex provided an analytical sample with mp of 99-100 C. Anal. (C10H12O3S) C,H,S. The malononitrile derivative (from equal weights of the aldehyde and malononitrile in EtOH with a drop of triethylamine as catalyst) was recrystallized from an equal volume of EtOH to give orange crystals with a mp of 185-186 deg C. Anal. (C13H12N2O2S) C,H,N,S. A solution of 2.1 g 2,5-dimethoxy-4-(methylthio)benzaldehyde in 7.5 mL nitromethane was treated with 0.45 g anhydrous ammonium acetate and held at steam bath temperature for 6 h. The deep red solution was stripped of solvent to give a residue that spontaneously crystallized. This was ground up under 12 mL MeOH, filtered, and washed with MeOH to yield, after air-drying, 1.7 g of 2,5-dimethoxy-4-methylthio-beta-nitrostyrene as orange solids. Recrystallization from EtOH provided rust-orange colored crystals with a mp of 165.5-166 deg C. Anal. (C11H13NO4S) C,H,N; S: calcd, 12.56; found, 11.96. To a gently refluxing mixture of 1.4 g LAH in 40 mL anhydrous THF under an inert atmosphere there was added, dropwise, 1.7 g 2,5-dimethoxy-4-methylthio-beta-nitrostyrene in 25 mL THF. The refluxing was continued for 18 h, and the stirring continued for another day at room temperature. There was then added 1.5 mL H2O (diluted with a little THF), 1.5 mL 15% NaOH, and finally 4.5 mL H2O. The white aluminum oxide salts were removed by filtration, and the filter cake washed with THF. The filtrate and washings were combined and stripped of solvent under vacuum yielding a straw-colored residue that crystallized (mp 81-92 deg C without purification). This residue was dissolved in 25 mL IPA and neutralized with concentrated HCl. The slightly pink solution spontaneously crystallized. There was added 100 mL anhydrous Et2O, and the white crystalline mass of 2,5-dimethoxy-4-methylthiophenethylamine hydrochloride (2C-T) was removed by filtration, washed with Et2O, and air dried. The final weight was 1.0 g, and had a mp of 232-237 deg C. Recrystallization from EtOH provided an analytical sample with mp 240-241 deg C. IPA was not a good recrystallization solvent. Anal. (C11H18ClNO2S) C,H,N,S. DOSAGE: 60 - 100 mg. DURATION: 3 - 5 h. QUALITATIVE COMMENTS: (with 60 mg) Poetry was an easy and natural thing. Both the reading of it and the writing of it. This is a potential MDMA substitute since it opens things up but it doesn't do anything to get in the way. (with 75 mg) I am already aware at a quarter of an hour into it! It develops very quickly but very quietly. There are no visuals at all but, rather, a tactile sensitivity, with warm close feelings. This could be very erotic. There is some fantasy to music, but nothing very demanding. The viewing of pictures doesn't do much either. The drop-off was extremely relaxed, with a good body feeling. At the fifth hour I was able to drift into an excellent, deep sleep with busy dreams. In the morning I felt refreshed and active, without apparent deficit. (with 75 mg) I got up to a thin and fragile plus two, but there was a continuing feeling of a hooded cloak brought down over my head. Nothing obvious Q it is transparent Q but it somehow separated me from everything around me. I do not think the overall experiment was worth it. (with 100 mg) Material all right, but a little bit along the lines of a 'generic' psychedelic effect. Sharper edges than 2C-B. The one true negative, which has been pretty consistent with this drug, is that there is a certain emotional removal. One teeny step removed. One is connected with feelings, certainly, but there is a tendency for the intellect to be more evident, in me, than the heart. All this is moderately so. Nothing extreme. Pretty good material, but there are more inter-esting ones. However, if you are looking for a really short one, this is one of the answers. For most people. For me, it's still around 5 to 6 hours long. I wish we had more shorties, indeed. (with 125 mg) There was some physical tummy uncertainty, but once that was past, talking was extremely easy. This is probably really psychedelic, but I am not really sure why, as there is not much in the way of visuals. Dropping was noted just after hour number three, and I was at baseline three hours later. EXTENSIONS AND COMMENTARY: The earliest work with the sulfur atom was with the three-carbon chain materials, the ALEPHs. It was only after a considerable time of working with them, and trying to come to peace with their property of being so different from person to person as to potency, that the two-carbon homologues were looked at. Although the first of these (this compound, called 2C-T) was prepared at the same time as ALEPH-1, there was a lapse of about four years between their trials. The relatively low potency of 2C-T was a bit discouraging. But the methodical pursuit of the higher 2C-T's (to parallel the higher ALEPHs) proved to be a treasure house, and they have been explored much further than any of the ALEPHs. A note on the RTS in 2C-T. Many, in fact most, of the 2C's have their name based on the last letter of the amphetamine prototype. 2C-B from DOB, 2C-C from DOC, 2C-I from DOI, 2C-N from DON, etc. And since the original name for ALEPH-1 was DOT (the desoxy- and a thiomethyl group at the 4-position), the 2C-T naming followed this general pattern. And as a note on the subsequent numbering, they (both the ALEPHs and the 2C-T's) are assigned numbers as they are thought up. There is no structural significance in the number but they have been, like the houses on the streets in residential Tokyo, assigned numbers in strict historical order, documenting the sequence of construction rather than the relative position down the side of the street. Both of the homologous mono-ethoxy Tweetios of 2C-T have been synthesized and evaluated. The 2-EtO-homologue of 2C-T is 2-ethoxy-5-methoxy-4-methylthiophenethylamine, or 2CT-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-(methylthio)benzaldehyde) was an oil, the nitrostyrene intermediate had a melting point of 137-138 deg C, and the final hydrochloride a melting point of 215-216 deg C. The effects were felt very quickly, and there was a blurring of vision. However, the highest dose tried, 50 milligrams, was not able to produce a greater-than-plus one state, and what did occur, lasted for only 4 hours. The 5-EtO-homologue of 2C-T is 5-ethoxy-2-methoxy-4-methylthio-phenethylamine, or 2CT-5ETO. The benzaldehyde (5-ethoxy-2-methoxy-4-(methyl-thio)benzaldehyde) was impure, and had a melting point of about 66 deg C, the nitrostyrene intermediate a melting point of 133-134 deg C, and the final hydrochloride a melting point of 184-185 deg C. There was a body awareness and modest eyes-closed visuals following the use of 30 milligrams of 2CT-5ETO. The experience was quiet, peaceful, contemplative, and insightful. The duration was perhaps 15 hours and Halcion was needed to allow sleep. There were a lot of dreams, and the next day was restful. #40 2C-T-2; 2,5-DIMETHOXY-4-ETHYLTHIOPHENETHYLAMINE SYNTHESIS: To a solution of 165 g 1,4-dimethoxybenzene in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2x75 mL CH2Cl2. The original organic phase and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride, a yellow crystalline solid with a mp of 115-117 deg C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 deg C. The following reaction is also a very vigorous one and must be performed in a well ventilated place. To a solution of 400 mL 25% H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride, and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 deg C an exothermic reaction took place at the spot where the zinc was placed. Additional dollups of zinc were added, and each small exothermic reaction site was spread about with the glass stirring rod. Finally, the reaction spread to the entire solid surface layer, with a melting of the acid chloride and an apparent boiling at the H2O surface. The remainder of the 80 g of zinc dust was added as fast as the size of the reaction container would allow. After things subsided again, the heating was continued for 1 h on the steam bath. After the reaction mixture had cooled to room temperature, it was filtered through paper in a Buchner funnel, and the residual metal washed with 100 mL CH2Cl2. The two-phase filtrate was separated, and the lower, aqueous phase was extracted with 2x75 mL CH2Cl2. The addition of 2 L H2O to the aqueous phase now made it the upper phase in extraction, and this was again extracted with 2x75 mL CH2Cl2. The organic extracts were pooled (H2O washing is more trouble than it is worth) and the solvent removed under vacuum. The light amber residue (30.0 g) was distilled at 70-80 deg C at 0.3 mm/Hg to yield 25.3 g 2,5-dimethoxythiophenol as a white oil. This chemical is certainly not centrally active, but it is a most valuable precursor to all members of the 2C-T family. To a solution of 3.4 g of KOH pellets in 75 mL boiling EtOH, there was added a solution of 10.0 g 2,5-dimethoxythiophenol in 60 mL EtOH followed by 10.9 g ethyl bromide. The reaction was exothermic with the immediate deposition of white solids. This was heated on the steam bath for 1.5 h, added to 1 L H2O, acidified with HCl, and extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with 100 mL of 5% NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl ethyl sulfide which was a pale amber oil, weighed about 10 g and which was sufficiently pure for use in the next reaction without a distillation step. A mixture of 19.2 POCl3 and 18.0 g N-methylformanilide was heated briefly on the steam bath. To this claret-colored solution there was added the above 2,5-dimethoxyphenyl ethyl sulfide, and the mixture heated an additional 20 min on the steam bath. This was then added to 500 mL of well-stirred warm H2O (pre-heated to 55 deg C) and the stirring continued for 1.5 h by which time the oily phase had completely solidified to a brown sugar-like consistency. The solids were removed by filtration, and washed with additional H2O. After being sucked as dry as possible, these solids were dissolved in 50 mL boiling MeOH which, after cooling in an ice-bath, deposited almost-white crystals of 2,5-dimethoxy-4-(ethylthio)-benzaldehyde. After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 11.0 g of product with a mp of 86-88 deg C. Recrystallization of a small sample again from MeOH provided an analytical sample with mp 87-88 deg C. Anal. (C11H14O3S) C,H. To a solution of 11.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde in 100 g of nitromethane there was added 0.5 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 80 min (this reaction progress must be monitored by TLC, to determine the point at which the starting aldehyde has been consumed). The excess nitromethane was removed under vacuum leaving a residue that spontaneously set to orange-red crystals. These were scraped out to provide 12.9 g crude 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene with a mp of 152-154 deg C. A sample recrystallized from toluene was pumpkin colored and had a mp of 148-149 deg C. Another sample from acetone melted at 149 deg C sharp, and was light orange. From IPA came spectacular fluorescent orange crystals, with a mp 151-152 deg C. Anal. (C12H15NO4S) C,H. A suspension of 12.4 g LAH in 500 mL anhydrous THF was stirred under He. To this there was added 12.4 g 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene in a little THF, and the mixture was held at reflux for 24 h. After the reaction mixture had returned to room temperature, the excess hydride was destroyed by the cautious addition of 60 mL IPA, followed by 20 mL of 5% NaOH followed, in turn, by sufficient H2O to give a white granular character to the oxides. The reaction mixture was filtered, and the filter cake washed first with THF and then with MeOH. Removing the solvents from the combined filtrate and washings under vacuum provided 9.5 g of a yellow oil. This was added to 1 L dilute HCl and washed with 2x100 mL CH2Cl2 which removed all color. After making the aqueous phase basic with 25% NaOH, it was extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum to provide 7.3 g of a pale amber oil. Distillation at 120-130 deg C at 0.3 mm/Hg gave 6.17 g of a clear white oil. This was dissolved in 80 mL IPA and neutralized with concentrated HCl, forming immediate crystals of 2,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (2C-T-2). An equal volume of anhydrous Et2O was added and, after complete grinding and mixing, the salt was removed by filtration, washed with Et2O, and air dried to constant weight. The resulting white crystals weighed 6.2 g. DOSAGE: 12 - 25 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 12 mg) I don't feel this for fully an hour, but when I do it is quite a weight. It feels good to work it through. It is OK to be with pain. You can't eliminate it. And it is OK to contact your deep pools of anger. And all of it stems from the lack of acknowledgment. All the macho carrying on, the fights, the wars, are ways of demanding attention, and getting even for not having had it in one's life. I am experiencing more deeply than ever before the importance of acknowledging and deeply honoring each human being. And I was able to go through and resolve some judgments with particular persons. (with 20 mg) I chose 2C-T-2 at this dose level because the lateness of getting started, and I wanted a shorter experience with my daughter and her family around. I feel, however, that I have somewhat less of a body load with 2C-T-7. Today I was badly in need of the help that might possibly come from this material, and today it was my ally. I sorely needed the type of help that it afforded. The result was to work off the heavy feeling of tiredness and lack of motivation that had been hounding me. The next day I felt that I had dropped my burden. (with 20 mg) There is a neutralness to this. I am at the maximum, and I am asking myself, 'Am I enjoying this?' And the answer is, 'No, I am experiencing it.' Enjoyment seems beside the point. It is a rather intensely matter-of-fact +3. Is it interesting? Yes, but mostly in expectation of further developments. Is it inspiring? No. Is it negative? No. Am I glad I took it? Yes. Not glad. Satisfied and contented. This is a controlled +3. No threat. The body is all right. Not superbly healthy Q but OK. Of no interest, either way. If I were to define the body's state, I would have to define it in image. The image is of a not comfortable state of being clenched. Clenched? Well, carefully bound in control. (with 22 mg) A slow onset. It took an hour for a plus one, and almost another two hours to get to a +++. Very vivid fantasy images, eyes closed, but no blurring of lines between "reality" and fantasy. Some yellow-grey patterns a la psilocybin. Acute diarrhea at about the fourth hour but no other obvious physical problems. Erotic lovely. Good material for unknown number of possible uses. Can explore for a long time. Better try 20 milligrams next time. (with 25 mg) I was at a +++ in an hour! It is most difficult to do even ordinary things. I took notes but now I can't find them. This is much too high for anything creative, such as looking at pictures or trying to read. Talking is OK. And to my surprise I was able to get to sleep, and a good sleep, at the seven hour point. EXTENSIONS AND COMMENTARY: There is a considerable parallel between 2C-T-2 and 2C-T-7, and both have proven to be excellent tools for introspection. The differences are largely physical. With 2C-T-2, there is more of a tendency to have physical disturbances such as nausea and diarrhea. And the experience is distinctly shorter. With 2C-T-7, physical disturbances are less common, but you are into the effects for almost twice as long. Both have been frequently used in therapy as follow-ups to MDMA. A point of potential misidentification should be mentioned here. 2C-T-2 has occasionally been called, simply, T-2. This abbreviated nickname has also been used for T-2 Toxin, a mycotoxin of the Tricothecene group, formed mainly by the Fusarium spp. This is the infamous "warfare agent" in Southeast Asia, which was finally identified as bee feces rather than a Soviet military adventure. T-2 and 2C-T-2 are radically different compounds. All three Tweetios of 2C-T-2 have been made and looked at through human eyes. The 2-EtO-homologue of 2C-T-2 is 2-ethoxy-4-ethylthio-5-methoxyphenethylamine, or 2CT2-2ETO. The benzaldehyde (2-ethoxy-4-ethylthio-5-methoxybenzaldehyde) had a melting point of 73-75 deg C, the nitrostyrene intermediate a melting point of 122-123 deg C, and the final hydrochloride a melting point of 202-204 deg C. Fifty milligrams was a completely effective level. The effects were felt very quickly. Vision was blurred, and there were intense eyes-closed visuals and the generation of a pleasant, contemplative mood. Baseline was re-established in five or six hours, but sleep was restless, with weird dreams. Nasal administration showed considerable variation between individuals, but a typical dose was 10 milligrams. The 5-EtO-homologue of 2C-T-2 is 5-ethoxy-4-ethylthio-2-methoxyphenethylamine, or 2CT2-5ETO. The benzaldehyde (5-ethoxy-4-ethylthio-2-methoxybenzaldehyde) had a melting point of 49 deg C, but it was impure. The nitrostyrene intermediate melted at 107-108 deg C, and the final hydrochloride had a melting point of 180 deg C. At levels of 20 milligrams, there was a slow, gentle climb to a full effect at the third or fourth hour. The flooding of thoughts and easy conversation lasted for many hours, and on some occasion a sedative was needed at the 16 hour point. There was a feeling of being drained for the following day or two. Some intoxication was still noted in the second day. Again it is true here, as had been stated as a generality, that the 5-Tweetio analogues have potencies similar to that of the parent compound, but show a much longer duration. The nickname of "forever yours" had been applied. There may indeed be insight, but 24 hours' worth is an awful lot of insight. The 2,5-DiEtO-homologue of 2C-T-2 is 2,5-diethoxy-4-ethylthiophen-ethylamine, or 2CT2-2,5DIETO. The benzaldehyde, 2,5-diethoxy-4-(ethylthio)benzaldehyde, had a melting point of 84-85 deg C, the nitrostyrene intermediate a melting point of 123-124 deg C, and the final hydrochloride a melting point of 220-221 deg C. Levels that were evaluated from 10 to 50 milligrams were not particularly different in intensity, but were progressively longer in duration. At 50 milligrams there was a nervousness and edginess during the early part of the experience, but for the next several hours there was evident both energy and high attentiveness. There were few if any sensory alterations. There were no negatives on the following day. The duration was perhaps nine hours. #41 2C-T-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE SYNTHESIS: To a solution of 2.5 g of KOH pellets in 40 mL hot EtOH, there was added 5.4 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) and 8.7 g isopropyliodide. White solids appeared in a few min, and the reaction mixture was heated on the steam bath overnight. This mixture was added to 200 mL H2O followed by additional aqueous NaOH to raise the pH to a deep purple-blue on universal pH paper. This was extracted with 3x75 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue distilled at 100-110 deg C at 0.2 mm/Hg to yield 6.9 g of 2,5-dimethoxyphenyl isopropyl sulfide as a pale yellow oil. It has a very light, pleasant smell of apples. A mixture of 4.8 g POCl3 and 4.5 g N-methylformanilide was stirred and allowed to stand at room temperature for 1 h To this claret-colored solution was added 3.0 g of 2,5-dimethoxyphenyl isopropyl sulfide, producing an exothermic reaction and immediate reddening. This was heated for 0.5 h on the steam bath, then quenched in 200 mL of warm H2O producing immediate crystals. Stirring was continued for a few min, and then the solids were removed by filtration, washed with H2O and sucked as dry as possible. When they were ground up under an equal weight of cold MeOH, refiltered and air dried, they gave 2.35 g of 2,5-dimethoxy-4-(i-propylthio)benzaldehyde as pale yellow solids (in some runs this was a pale lime-green color) with a mp of 89-90 deg C. A wasteful recrystallization from MeOH gave pale yellow crystals with a mp of 90 deg C sharp. To a solution of 6.7 g 2,5-dimethoxy-(i-propylthio)benzaldehyde in 40 g of nitromethane there was added 0.10 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h. The excess reagent/solvent was removed under vacuum yielding 8.9 g of orange solids. This was recrystallized from 200 mL boiling MeOH providing 6.2 g of 2,5-dimethoxy-beta-nitro-4-(i-propyl-thio)styrene as lustrous golden orange platelets. A solution of LAH (80 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 2.1 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 5.74 g 2,5-dimethoxy-beta-nitro-4-(i-propylthio)styrene as a solid, a bit at a time. After 15 min further stirring, the temperature was brought up to a gentle reflux on the steam bath for another 15 min, then allowed to stand at room temperature overnight. After cooling again to 0 deg C, the excess hydride was destroyed by the addition of 7 mL IPA followed by 6 mL 15% NaOH which was sufficent to give a white granular character. The reaction mixture was filtered and the filter cake washed with THF. The filtrate and washings were pooled, stripped of solvent under vacuum providing 3.9 g of a pale amber oil which was dissolved in 250 mL dilute H2SO4. This was washed with 3x75 mL CH2Cl2 which removed the residual yellow color. After making basic with 25% NaOH, the product was extracted with 3x75 mL CH2Cl2 and the solvent removed under vacuum to give 2.72 g of a residue which was distilled at 140-145 deg C at 0.2 mm/Hg to give 2.42 g of a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl. This gave a clear solution which, with good stirring, was diluted with 100 anhydrous Et2O to provide 2.40 g 2,5-dimethoxy-4-(i)-propyl-thiophenethylamine hydrochloride (2C-T-4) as white crystals. DOSAGE: 8 - 20 mg. DURATION: 12 - 18 h. QUALITATIVE COMMENTS: (with 8 mg) Visual effects set in at about two hours. There was much color enhancement, particularly of green, and some flowing of colors. The bright impressionistic picture of the little girl, in the bathroom, was particularly good for the visuals to take over, especially when I was concentrating on urinating. The shadows in the large picture above the fireplace would change constantly. I could not either control or turn off these effects during the middle period (3-6 hours). From the physical point of view, something early in the experience simply didn't feel right. Both my lower legs tended to fall asleep, and this seemed to spread to my hands and lower arms. It was uncomfortable and although I was apprehensive at first it didn't get any worse with time so I ignored it. This is not one my favorite materials, and it takes too long to wear off. If I were to do it again I would settle for 4 or 5 milligrams. It may well cut out the extremity problem amd still allow for a pleasant experience. (with 9 mg) An important characteristic of this experience was the sense of letting go and flowing with it. Just follow where it leads. This seemed to lead to a growing euphoria, a feeling of clearing out of body residues, and the handling of very impressive insights. My thinking continued to grow in clarity, visual perception was crystal clear, and it was a joy to simply look over the scenery, enjoy the beauty, enjoy the companionship, and ponder whatever came to mind. This clarity of body and mind lasted the rest of the evening with a wonderful feeling of peace and centeredness. I still felt a lot of push from the chemical at bed time, causing some tiredness, and allowing very little sleep. I kept working at what had taken place, all night, just to release the experience. (with 14 mg) Very rational, benign, and good humored. The insight and calm common to the 2C-T's are present, with less of the push of body-energy which makes 2C-T-2 difficult for some people. There are no particular visuals, but then I tend to screen them out consistently, except in cases of mescaline and LSD and psilocybin, so I can't judge what others would experience in the visual area. The eyes-closed imagery is very good without being compelling. The decline is as gradual and gentle as the onset. I am fully capable of making phone calls and other normal stuff. Music is marvelous, and the body feels comfortable throughout. (with 14 mg) Persistent cold feet, and an uncertain stomach when moving around. Brilliant color trails reminiscent of 2C-B. But a change is occurring and I can't talk myself out of it. There are dark corners. If I were with other people, this would bring out the worst in me, which can be pretty bad. (with 19 mg) I was caught by the TV. Leonard Bernstein conducting West Side Story. I think I know every note. This was a 1985 rehearsal with the goofs and the sweat. And now Peter, Paul and Mary, grown older along with the songs we all sang. Where Have All the Flowers Gone Q and an audience of grown-older people singing Puff the Magic Dragon like earnest children and probably crying along with me. It is good to have lived through the 60's and not to be in them now. Now there's a new song about El Salvador and it's the battle all over again on a different field, but it will always be so, until and unless. Now, in the 80's, I don't get really angry anymore. I am more warrior than angry protester, and that's a much better way to be. In fact, I am quite happy to be where I am. I know a lot more about the game, and what it is, and why it is played, and I have a good idea about my part in it, and I like the part I've chosen. (with 22 mg) The transition took place over three hours, an alert in 30 minutes followed by a slow and gentle climb. I found it difficult, not physically but mentally since I was for a while locked into the illogical and disconnected aspects of human experiences and expressions, particularly laws and pronouncements and unseeing prejudices, most of which I was picking up from reading the Sunday paper book reviews. As time went on, things became less pushy and I came to be at ease with very positive feelings about everything going on. No self-rejecting aspect at all. Sleep was excellent, but the next day things went slowly and I had to nap a bit. Next time, maybe 18 milligrams. EXTENSIONS AND COMMENTARY: There are shades of the variability of the Alephs. Some observers are overwhelmed with colors and visual activity; others volunteer their absence. And a very wide range of dosages represented, from an estimated 4 or so milligrams for full effects, to something over 20 milligrams without any loss of control. That is an unusually wide lattitude of activity. And a rich variety of effects that might be experienced. The same wide range of effective dosages was also observed with the corresponding Tweetio. The 2-EtO-homologue of 2C-T-4 is 2-ethoxy-5-methoxy-4-(i)-propylthiophenethylamine, or 2CT4-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-(i-propylthio)benzaldehyde had a melting point of 43-44 deg C, the nitrostyrene intermediate a melting point of 77-79 deg C, and the final hydrochloride a melting point of 153.5-154 deg C. There were practically no differences between trials at 5 milligram increments within the 10 and 25 milligram range. Each produced a gentle plus two level of effect which lasted for some 10 hours. A code name of "tenderness" was felt to be appropriate, as there was a peaceful meditative inner receptiveness and clarity noted, with an honest connection felt with those who were present during the experience. Sleep was not comfortable. I have heard 2C-T-4 referred to as T-4. There is a potent explosive used by terrorists called cyclotrimethylenetrinitramine, known by the code name RDX, or T-4. There is also a T-4 term that refers to thyroxine, an amino acid in the body. The drug 2C-T-4 is neither an explosive nor an amino acid, I am happy to say. #42 gamma-2C-T-4; 2,6-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE) SYNTHESIS: A stirred solution of 8.3 g 3,5-dimethoxy-1-chlorobenzene and 7.2 g isopropylsulfide in 100 mL anhydrous Et2O was cooled with an external ice bath, and then treated with 67 mL 1.5 M lithium diisopropylamide in hexane which was added over the course of 10 min. The reaction mixture was allowed to return to room temperature and the stirring was continued for 0.5 h. The mixture was poured into dilute H2SO4, the organic layer was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The organic phases were combined, dried over anhydrous K2CO3, and the solvent removed under vacuum. The resulting 4.54 g of almost colorless oil was distilled at 85-95 deg C at 0.1 mm/Hg to give 4.2 g of 3,5-dimethoxyphenyl isopropyl sulfide as a colorless oil, showing a single spot on TLC with no indication of starting chlorobenzene. The product formed a picrate salt, but this had an unsatisfactory mp character (partly melting at 45-47 deg C, and then completely at about 80-90 deg C). The microanalysis for this picrate was low in the carbon value, although the hydrogen and nitrogen were excellent. Anal. (C17H19N3O9S) H,N; C: calcd, 46.25; found, 44.58, 44.45. To a well-stirred solution of 4.1 g 3,5-dimethoxyphenyl isopropyl sulfide and 3.5 mL N,N,N',N'-tetramethylethylenediamine in 25 mL anhydrous Et2O that had been cooled to -78 deg C with a dry-ice/acetone bath, there was added 10 mL 2.5 M hexane solution of butyllithium. The mixture was allowed to return to room temperature, and there was added 3.5 mL DMF which caused the yellow color to progressively darken. The reaction mixture was poured into dilute H2SO4, the Et2O layer was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The solvent was removed from the combined organic phases, and the residue distilled at 0.15 mm/Hg to give two fractions. One, boiling at 120-140 deg C, was 0.98 g of a pale yellow mobile liquid, which was part starting sulfide and part product aldehyde by TLC. The second cut, boiling at 160-180 deg C, was a viscous liquid, weighed 1.66 g, and was largely 2,6-dimethoxy-4-(i-propylthio)benzaldehyde. This formed a crystalline anil with 4-methoxyaniline (by fusing equimolar amounts of the two with a flame) which, after recrystallization from MeOH, gave fine yellow crystals with a mp of 87.5-89 deg C. Anal. (C19H23NO3S) C,H. A solution of 0.8 g 2,6-dimethoxy-4-(i-propylthio)benzaldehde in 10 mL nitromethane was treated with 0.2 g anhydrous ammonium acetate and heated on the steam bath for 1 h. The excess reagent/solvent was removed under vacuum, and the residue spontaneously solidified. This was recrystallized from 5 mL MeOH to give 0.70 g 2,6-dimethoxy-beta-nitro-4-(i)-propylthiostyrene as a pale yellow fluffy solid, with a mp of 83-84.5 deg C. Anal. (C13H17NO4S) C,H. A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under He to 0 deg C with an external ice bath. With good stirring there was added 0.54 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 0.54 g 2,6-dimethoxy-beta-nitro-4-(i)-propylthiostyrene in a small volume of anhydrous THF. The color was discharged immediately. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for about 10 min, and then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of IPA followed by sufficent 15% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed well with THF. The filtrate was stripped of solvent under vacuum and the residue dissolved in 100 mL of dilute H2SO4. This was washed with 2x50 mL CH2Cl2 (the washes were saved, see below), made basic with aqueous NaOH, and then extracted with 2x50 mL CH2Cl2. The residue remaining after the removal of the solvent was distilled at 130-140 deg C at 0.05 mm/Hg to give 0.11 g of a white oil. This was dissolved in 10 mL IPA, neutralized with 5 drops of concentrated HCl and diluted with 50 mL anhydrous Et2O. After filtration of the formed crystals, Et2O washing, and air drying, there was obtained 80 mg of 2,6-dimethoxy-4-(i)-propylthiophenethylamine hydrochloride (gamma-2C-T-4) as fine white crystals. The removal of the solvent from the CH2Cl2 washes of the dilute H2SO4 solution gave a H2O-soluble white solid that proved to be the sulfate salt of the product. This provided, after making the H2O solution basic, extraction with CH2Cl2, and solvent removal, the free base that was converted, as described above, to a second crop of the hydrochloride salt. DOSAGE: above 12 mg. DURATION: probably short. QUALITATIVE COMMENTS: (with 8 mg) I might actually be up to a plus 1, and with a very good feeling. But I cannot say how long it lasted, and it was probably pretty short. It just sort of faded away. (with 12 mg) At the 25 minute point I am reminded of the experiment, and in another quarter hour I am into something. Will this be another forever threshold? I feel very good, but there is no sparkle. EXTENSIONS AND COMMENTARY: Here is another example of the presentation of a compound for which there has not yet been an effective level determined. Why? For a very good reason. This is an example of a whole class of compounds that I have called the pseudos, or the gamma-compounds. Pseudo- as a prefix in the literary world generally stands for "false." A pseudopod is a thing that looks like a foot, but isn't one. A pseudonym is a fictitious name. But in chemistry, it has quite a different meaning. If something has a common name, and there is a second form (or isomer, or shape, or orientation) that is possible and it doesn't have a common name, it can be given the name of the first form with a Rpseudo-S attached. Ephedrine is the erythro-isomer of N-methyl-beta-hydroxyamphetamine. There is a second stereoisomer, the threo- isomer, but it has no trivial name. So it is called pseudoephedrine, or the "Sudafed" of sinus decongestant fame. The pseudo-psychedelics are the 2,4,6-trisubstituted counterparts of the 2,4,5-trisubstituted psychedelics. Almost all of the 2,5-dimethoxy-4-something-or-other compounds are active and interesting whether they be phenethylamines or amphetamines, and it is an exciting fact that the 2,6-dimethoxy-4-something-or-other compounds are going be just as active and just as interesting. A number of examples have already been mentioned. TMA-2 is 2,4,5-trimethoxyamphetamine (a 2,5-dimethoxy-substituted compound with a methoxyl at the 4-position). The pseudo- analogue is TMA-6 (2,4,6-trimethoxyamphetamine) and it is every bit as potent and fascinating. Z-7 could be called pseudo-DOM, and although it is quite a bit down in potency, it is an active drug and will both demand and receive much more clinical study some day. Will the other 2,4,5-things spawn 2,4,6-things that are active? Without a shadow of a doubt. Chemically, they are much more difficult to synthesize. The 2,5-dimethoxy orientation made the 4-position a natural and easy target. The 2,6-dimethoxy orientation pushes for 3-substitution, and the 4-position is completely unnatural. Tricks are needed, but tricks have now been found. The above synthesis of pseudo-2C-T-4 shows one such trick. This is, in my opinion, the exciting chemistry and psychopharmacology of the next decade. Well over half of all the psychedelic drugs mentioned in Book II are 2,4,5-trisubstituted compounds, and every one of them has a (potentially active) 2,4,6-pseudo-counterpart. It goes yet further. The antidepressant series of "Ariadne" compounds are 1-phenyl-2-aminobutanes. But the 1-phenyl is again a 2,4,5-trisubstituted compound. The 2,4,6-isomer will give rise to a pseudo-Ariadne family, and I will bet that they too will be antidepressants. The 1-phenyl-2-aminobutane analog of gamma-2C-T-4 is the 2,4,6-analogue and it has been prepared as far as the nitrostyrene. It has not yet been reduced, so it is not yet been evaluated, but it could be a most remarkable psycho-pharmacological probe. And it goes yet yet further. Think back to the six possible TMA's. TMA and TMA-3 were relatively inactive. And TMA-2 and TMA-6 were the interesting ones. The first gave rise to the last twenty years of psychedelic chemistry, and the other (as speculated upon above) will give rise to the forthcoming ten years. But what of TMA-4 and TMA-5? Both showed activity that was more than TMA but less than that of the -2 or -6 isomers. Could they, some day, provoke yet other families of psychedelics? Maybe the 3-position of these two might be focal points of leverage as to psychological activity. What are the letters that follow y in the Greek alphabet? If I remember correctly, the next letter is the last letter, omega. So, I guess that Nature is trying to tell us something, that the -4 and -5 isomers will not engender interesting families. What a pity. The chemistry is so unthinkably difficult that it would have been a true challenge. My next incarnation, maybe? #43 2C-T-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE SYNTHESIS: To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under the recipe for 2C-T-2 for its preparation) and 7.4 g (n)-propylbromide dissolved in 20 mL MeOH. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for 0.5 h, added to 800 mL H2O, additional aqueous NaOH added until the pH was basic, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed with dilute NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl (n)-propyl sulfide which was obtained as a pale yellow oil, and which weighed 8.9 g. It had a light pleasant fruity smell, and was sufficiently pure for use in the next reaction without distillation. A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 8.9 g of 2,5-dimethoxyphenyl (n)-propyl sulfide, and the mixture heated an additional 25 min on the steam bath. This was then added to 800 mL of well-stirred warm H2O (pre-heated to 55 deg C) and the stirring continued until the oily phase had completely solidified (about 15 minutes). The resulting brown sugar-like solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, they were dissolved in an equal weight of boiling MeOH which, after cooling in an ice-bath, deposited pale ivory colored crystals. After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 8.3 g of 2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde with a mp of 73-76 deg C. Recrystallization from 2.5 volumes of MeOH provided a white analytical sample with mp 76-77 deg C. The NMR spectrum in CDCl3 was textbook perfect, with the two aromatic protons showing singlet signals at 6.81 and 7.27 ppm, giving assurance that the assigned location of the introduced aldehyde group was correct. To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde in 20 g of nitromethane there was added 0.23 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The clear orange solution was decanted from some insoluble material and the excess nitromethane removed under vacuum. The orange-yellow crystalline material that remained was crystallized from 70 mL boiling IPA which, on slow cooling, deposited 2,5-dimethoxy-beta-nitro-4-(n)-propylthiostyrene as orange crystals. After their removal by filtration and air-drying to constant weight, they weighed 3.6 g, and had a mp of 120-121 deg C. Anal. (C13H17NO4S) C,H. A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 3.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.4 g 2,5-dimethoxy-beta-nitro-4-(n)-propylthiostyrene in 50 mL anhydrous THF. There was an immediate loss of color. After a few min further stirring, the tem-perature was brought up to a gentle reflux on the steam bath, then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of IPA (21 mL required) followed by sufficent 5% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (15 mL was used). The reaction mixture was filtered and the filter cake washed first with THF and then with IPA. The filtrate and washes were combined and stripped of solvent under vacuum providing about 6 g of a pale amber oil. Without any further purification, this was distilled at 140-150 deg C at 0.25 mm/Hg to give 4.8 g of product as a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl forming immediate crystals of the hydrochloride salt in the alcohol solvent. An equal volume of anhydrous Et2O was added, and after complete grinding and mixing, 2,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (2C-T-7) was removed by filtration, Et2O washed, and air dried to constant weight. The resulting spectacular white crystals weighed 5.2 g. DOSAGE: 10 - 30 mg. DURATION: 8 - 15 h. QUALITATIVE COMMENTS (with 20 mg) A wonderful day of integration and work. Took about 2 hours for the onset. Some nausea on and off Q that seemed to cycle periodically throughout the day. Visuals were great, much like mescaline but less sparkly. Lots of movement and aliveness Q velvety appearance and increased depth perception. Neck and shoulder tension throughout the day along with legs. I would periodically notice extreme tightness of muscles, and then relax. Working was very integrative. Back and forth constantly between wonderful God-space Q similar to MDMA but more grounded Q then always back to sadness. I felt that it really showed me where I was unfinished, but with self-loving and tolerance. Tremendous processing and letting go. Seeing things very clearly and also able to laugh at my trips. Lots of singing. In spite of shoulder tension, vocal freedom and facility were very high. I felt my voice integrated and dropped in a way it never had before, and that remained for several days. Able to merge body, voice, psyche and emotions with music and then let go of it as a role. I also realized and gave myself permission to do whatever it takes to get free. I let go of Dad with tragic arias. The next day I let go of Mom by singing Kaddish for her, and merging with it. (with 20 mg) I lay down with music, and become engrossed with being as still as possible. I feel that if I can be totally, completely still, I will hear the inner voice of the universe. As I do this, the music becomes incredibly beautiful. I see the extraordinary importance of simply listening, listening to everything, to people and to nature, with wide open receptivity. Something very, very special happens at the still point, so I keep working on it. When I become totally still, a huge burst of energy is released. And it explodes so that it takes enormous effort to quiet it all down in order to be still again. Great fun. (with 25 mg) This was a marvelous and strange evening. This 2C-T-7 is good and friendly and wonderful as I remember it. I think it is going to take the place of 2C-T-2 in my heart. It is a truly good material. I got involved with a documentary on television. It was about certain people of Bolivia, people living in the high mountains and about a small village which Q perhaps alone among all the places in the country Q maintains the old Inca ways, the old traditions, the old language. Which is, I gather, against the law in Bolivia. It showed a yearly meeting of shamans and it was quite clear that hallucinogens played a major part in this meeting. The shaman faces, male and female, were startling in their intensity and earthy depth. The Virgin Mary is worshipped as another version of the ancient Pacha Mama, the Earth Mother. Wonderful dark, vivid look at places and people who are not usually to be seen or even known about. (with 30 mg) The visuals have an adaptable character to them. I can use them to recreate any hallucinogenic substance I have known and loved. With open eyes, I can go easily into LSD flowing visuals, or into the warm earth world of Peyote, or I can stop them altogether. With closed eyes, there are Escher-like graphics with a lot of chiaroscuro, geometric patterns with oppositional play of sculptured light and dark values. Green light. EXTENSIONS AND COMMENTARY: If all the phenethylamines were to be ranked as to their acceptability and their intrinsic richness, 2C-T-7 would be right up there near the top, along with 2C-T-2, 2C-B, mescaline and 2C-E. The range is intentionally extended on the lower side to include 10 milligrams, as there have been numerous people who have found 10 or so milligrams to be quite adequate for their tastes. One Tweetio related to 2C-T-7 has been made and evaluated. This is the 2-EtO-homologue of 2C-T-7, 2-ethoxy-5-methoxy-4-(n)-propylthiophenethyl-amine, or 2CT7-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-(n-propyl-thio)benzaldehyde had a melting point of 69-71 deg C, the nitrostyrene intermediate a melting point of 106-106.5 deg C, and the final hydrochloride a melting point of 187-189 C!. At the 20 milligram level, the effects were felt quickly, and the eyes-closed visuals were modest but real. It was very short-lived, with baseline recovery at about the fifth hour. The next day there was an uncomfortable headache which seemed on an intuitive level to be an after-effect of the compound. The unusual properties of a number of N-methyl-N-(i)-propyltryptamines suggested the possibility of something like a similar set of N-methyl-N-(i)-propylphenethylamines. Why not try one from 2C-T-7? The thought was, maybe N-methylate this compound, then put on an isopropyl group with reductive alkylation, using acetone as the carbon source and sodium cyanoborohydride. Towards this end, the free base of 2C-T-7 (from one gram of the hydrochloride) was refluxed for 2 h in 1.3 g butyl formate, and on removing the solvent/reactant the residue spontaneously crystallized. This formamide (0.7 g) was reduced with lithium hydride in cold THF to provide 2,5-dimethoxy-4-(n)-propyl-N-methyl-phenethylamine, METHYL-2C-T-7, which distilled at 150-170 deg C at 0.4 mm/Hg. A very small amount of the hydrochloride salt was obtained (65 milligrams) and it had a brown color. Too small an amount of an impure product; the entire project was dropped. #44 2C-T-8; 2,5-DIMETHOXY-4-CYCLOPROPYLMETHYLTHIOPHENETHYLAMINE SYNTHESIS: To a solution of 2.8 g of KOH pellets in 25 mL hot MeOH, there was added a mixture of 5.9 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) and 5.0 g of cyclopropylmethyl bromide. There was an immediate exothermic reaction with spontaneous boiling and the formation of white crystals. This was heated on the steam bath for 4 h, and then added to 400 mL of H2O. After extraction with 3x75 mL CH2Cl2, the pooled extracts were washed first with dilute NaOH, then with saturated brine, then the solvent was removed under vacuum. The residue, 8.45 g of crude 2,5-dimethoxyphenyl cyclopropyl methyl sulfide, was distilled at 120-140 deg C at 0.3 mm/Hg to give a white oil weighing 7.5 g. A mixture of 13.5 g POCl3 and 13.5 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 7.28 g of 2,5-dimethoxyphenyl cyclopropylmethyl sulfide, and the spontaneously exothermic mixture was heated for an additional 10 min on the steam bath, and then quenched in 400 mL of 55 deg C H2O with good stirring. After a few minutes a reddish solid phase separated. This was removed by filtration, and washed with additional H2O. After sucking as dry as possible, this 8.75 g of ochre-colored solid was dissolved in 14 mL of boiling MeOH, and after cooling, filtering, washing sparsely with MeOH, and air drying, gave 7.27 g of white solid crystals of 2,5-dimethoxy-4-(cyclopropylmethylthio)benzaldehyde. The proton NMR spectrum was impeccable; CHO 9.38, ArH 7.27, 6.81 2 s., OCH3 3.93, 3.90 2 s., SCH2 t. 2.96, CH2, m. 1.72, and CH2, t. 1.11. To a solution of 6.6 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde in 82 g of nitromethane there was added 0.12 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 6 h. The reaction mixture was allowed to stand overnight producing a heavy crystallization crop. Filtration, washing lightly with MeOH, and air drying gave 4.72 g of orange crystals of 2,5-dimethoxy-4-cyclopropylmethylthio-beta-nitrostyrene as yellow crystals. The evaporation of the mother liquors and grinding of the resulting solids with MeOH provided another 2.0 g of the product. A solution LAH (40 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.05 mL 100% H2SO4 dropwise over 10 min, to minimize charring. This was followed by the addition of 2.95 g 2,5-dimethoxy-4-cyclopropylmethylthio-beta-nitrostyrene as a solid, over the course of 10 min. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 6 mL IPA followed by 3 mL 15% NaOH which gave the aluminum oxide as a curdy white solid. The reaction mixture was filtered, and the filter cake washed with additional THF. The filtrate and washes were stripped of solvent under vacuum providing about 1.8 g of a colorless oil. The addition of dilute H2SO4 produced a thick mass of white solids. This was washed with CH2Cl2, and the remaining aqueous phase, still containing solids, was made basic with 25% NaOH. The aqueous phase was extracted with 3x75 mL CH2Cl2, and the combined extracts stripped of solvent under vacuum. The result was 1.4 g of colorless oil. This was distilled at 150-165 deg C at 0.2 mm/Hg to give 1.2 g of a white oil. This was dissolved in 6 mL IPA, neutralized with 0.6 mL concentrated HCl producing spontaneous white crystals. These were diluted with 8 mL additional IPA, and suspended under 60 mL anhydrous Et2O to provide, after filtering and air drying, 1.13 g of 2,5-dimethoxy-4-cyclo-propylmethylthiophenethylamine hydrochloride (2C-T-8) as white crystals. DOSAGE: 30 - 50 mg. DURATION: 10 - 15 h. QUALITATIVE COMMENTS: (with 30 mg) Bad taste, worse smell. But I like it. I can paint easily, and wouldn't hesitate to take a little more next time, but this is enough with no one to talk to. Manual dexterity good. Body rather warm. Wouldn't mind fooling around. In retrospect, it has a smooth onset, and is not too stimulating. This is a good one. (with 40 mg) This is beginning to develop at one and a half hours into it. High energy, good feeling. I have had a heavy, dense feeling between me and my work for several days now, but this is rapidly dissolving, and with this loss, the day continues into one of the most remarkable experiences I have ever had. Excellent feelings, tremendous opening of insight and understanding, a real awakening as if I had never used these materials effectively before. For the next several hours it was an internal journey for me; I wished to interact with myself. I cannot recall all the details, but I did review many aspects of myself and my personal relations. I know that I am the better for all of this. (with 40 mg) I first noted the effects at three quarters of an hour, and at two hours I have pain in my sinuses. My head is split in two Q this is not being two or three different people Q this is one person with a head living in two different universes at the same time. Not a crisis experience, but one of extreme and prolonged discomfort. Hypersensitivity to light, noise, motion, with the belief that it would not go away when the chemical wore off. My visual and spatial perceptions were divided in two along a vertical axis, with both halves moving in uncoordinated ways. A feeling that the eyes were working independently of each other. Nausea without vomiting, even when I tried to. Vertigo became intolerable if I closed my eyes or lay down, so I felt that I would never lie down or close my eyes again. Problems with 'boundaries.' The outside environment seemed to be getting inside my head. The parts of myself seemed to either separate uncontrollably or run together into someone I didn't know. A late movie, and Tranxene, and a little sleep all helped me out of this. However, a buzzing in the head, an uncertain balance, and an out-of-it feeling lasted for 3 days, and was still faintly present after a week. (with 43 mg) For the first two hours I rocked in place and felt quite happy not trying to 'do' anything useful or expected, but watched some excellent programs on TV. Later I sat at the typewriter and felt the energy and the opening of the particular kind of thinking-connection that I associate with 2C-T-2. I felt this very strongly; I was fully into my own energy and capable of being aggressive if I decided to. I was very good humored and completely anchored to the earth. In the late evening I went to bed and felt that I would not allow myself to sleep, since the tendency to go completely out of conscious body was quite strong. However, before I could get up and continue happily writing, as I intended, I fell asleep. I slept thoroughly, well, and woke up the next day with good energy and a willingness to get on with the day. (with 50 mg) The whole experience was somewhat negative, self-doubting, paranoid. Basically, I am not in a good place. No constructive values ever knit, and although there was a lot of talking, nothing positive developed. I was glad of sleep at about twelve hours into it, and this aspect of it was completely friendly. Next day, no deficit. Strange. Maybe too much. EXTENSIONS AND COMMENTARY: With 2C-T-8, there are as many negatives as there are positives, and the particular substitution pattern is not one to set the world on fire. The first step was made towards the synthesis of the 3-carbon counterpart, 2,5-dimethoxy-4-cyclopropylmethylthioamphetamine, ALEPH-8. The above benzaldehyde (2.2 g) was cooked overnight on the steam bath in nitroethane (20 mL) containing ammonium acetate (0.4 g) and when the solvent was removed, the residue was converted to orange crystals by the addition of a little MeOH. This was not pursued further. Although the cyclopropylmethyl group was quite something on the mescaline oxygen atom, it is less appealing on the 2C-T-X sulfur atom, and there is even less enthusiasm to put it into an ALEPH. That's the way it is, and who could have guessed! #45 2C-T-9; 2,5-DIMETHOXY-4-(t)-BUTYLTHIOPHENETHYLAMINE SYNTHESIS: To a well-stirred ice-cold suspension of 2.8 g p-dimethoxybenzene and 3.2 mL N,N,N',N'-tetramethylethylenediamine in 100 mL petroleum ether under an inert atmosphere of He, there was added 13 mL of a 1.6 N solution of butyllithium in hexane. The suspended dimethoxybenzene became opaque and there was a pale yellow color generated. The reaction mixture was warmed to room temperature which converted it to light white solids. After an additional 0.5 h stirring, there was added, slowly, 3.6 g of di-(t)-butyldisulfide. The yellow color deepened, the solids dissolved and, after 1 h, the color was a clear deep brown. This solution was poured into 100 mL dilute HCl and the organic phase was separated. The aqueous fraction was extracted with 3x75 mL CH2Cl2. The combined organic phases were washed with dilute aqueous NaOH, with H2O, and then stripped of solvents under vacuum. The residue was distilled at 95-105 deg C at 0.5 mm/Hg to provide 3.7 g of 2,5-dimethoxyphenyl (t)-butyl sulfide as a white, mobile liquid. Anal. (C12H18O2S) C,H. A solid derivative was found in the nitration product, 2,5-dimethoxy-4-(t)-butylthio-1-nitrobenzene, which came from the addition of 0.11 mL of concentrated HNO3 to a solution of 0.23 g of the above sulfide in 5 mL ice cold acetic acid. Dilution with H2O provided yellow solids which, on recrystallization from MeOH, had a mp of 92-93 deg C. Anal. (C12H17NO4S) C,H. Attempts to make either the picrate salt or the sulfonamide derivative were not satisfactory. A mixture of 72 g POCl3 and 67 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 28 g of 2,5-dimethoxyphenyl (t)-butyl sulfide, and the mixture heated for 10 min on the steam bath. This was then added to 1 L of H2O and stirred overnight. The residual brown oil was separated from the water mechanically, and treated with 150 mL boiling hexane. The hexane solution was decanted from some insoluble tars, and on cooling deposited a dark oil which did not crystallize. The remaining hexane was removed under vacuum and the residue combined with the above hexane-insoluble dark oil, and all distilled at 0.2 mm/Hg. An early fraction (70-110 deg C) was largely N-methyl-formanilide and was discarded. Crude 2,5-dimethoxy-4-(t-butylthio)benzaldehyde came over at 120-130 deg C and weighed 12.0 g. This was never satisfactorily crystallized despite the successful formation of seed. It was a complex mixture by TLC, containing several components. It was used for the next step as the crude distilled fraction. To a solution of 10 g impure 2,5-dimethoxy-(t-butylthio)benzaldehyde in 75 mL of nitromethane there was added 1.0 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath 1.5 h. Removal of the excess solvent/reagent under vacuum produced an orange oil that was (not surprisingly) complex by TLC and which would not crystallize. A hot hexane solution of this oil was allowed to slowly cool and stand at room temperature for several days, yielding a mixture of yellow crystals and a brown viscous syrup. The solids were separated and recrystallized from 40 mL MeOH to give 3.7 g 2,5-dimethoxy-4-(t)-butylthio-beta-nitrostyrene as fine lemon-yellow crystals, with a mp of 93-94 deg C. A second crop of 1.4 g had a mp of 91-92 deg C. Anal. (C14H19NO4S) C,H. A solution of LAH (70 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 2.1 mL 100% H2SO4 dropwise, over the course of 20 min. This was followed by the addition of 4.7 g 2,5-dimethoxy-4-(t)-butylthio-beta-nitrostyrene in 20 mL anhydrous THF. There was an immediate loss of color. After a few min further stirring, the mixture was allowed to come to room temperature, and the stirring was continued for 5 h. The excess hydride was destroyed by the cautious addition of 10 mL IPA followed by 6 mL 15% NaOH and finally 6 mL H2O. The loose white solids were removed by filtration, and the filter cake washed with THF. The filtrate and washes were combined and, after stripping off the solvent under vacuum, there was obtained 4.66 g of a pale yellow oil. Without any further purification, this was distilled at 0.2 mm/Hg. A first fraction came over at up to 120 deg C and was a light colorless oil that was not identified. The correct product distilled at 130-160 deg C as a pale yellow viscous oil that weighed 1.66 g. This was dissolved in 10 mL IPA, neutralized with 20 drops of concentrated HCl and diluted with 80 mL anhydrous Et2O. After standing a few min there was the spontaneous generation of white crystals of 2,5-dimethoxy-4-(t)-butylthiophenethylamine hydrochloride (2C-T-9) which were removed by filtration, and air dried. The weight was 1.10 g. DOSAGE: 60 - 100 mg. DURATION: 12 - 18 h. QUALITATIVE COMMENTS: (with 90 mg) 2C-T-9 tastes the way that old crank-case motor oil smells. I was up to something above a plus two at the third hour. Although there were no visuals noted, I certainly would not choose to drive. Somehow this does more to the body than to the head. I feel that the effects are waning at maybe the sixth hour, but there is a very strong body memory that makes sleeping difficult. Finally, at sometime after midnight and with the help of a glass of wine, some sleep. (with 125 mg) There was a steady climb to a +++ over the first couple of hours. So far, the body has been quite peaceful without any strong energy push or stomach problems, although my tummy insists on being treated with quiet respect, perhaps out of habit, perhaps not. At the fifth hour, the body energy is quite strong, and I have the choice of focusing it into some activity, such as love-making or writing, or having to deal with tapping toes and floor-pacing. For a novice this would be a murderously difficult experience. Too much energy, too long a time. I suppose I could get used to it, but let me judge by when I get to sleep, and just what kind of sleep it is. It turned out that sleep was OK, but for the next couple of days there was a continuing awareness of some residue in the body Q some kind of low-level poisoning. I feel in general that there is not the excitement or creativity to connect with, certainly not enough to justify the cost to the body. EXTENSIONS AND COMMENTARY: The three-carbon analog of 2C-T-9 (this would be one of the ALEPH series) has never been made and, for that matter, none of the higher numbered 2C-T's have had the amphetamine counterparts synthesized. They are, as of the present time, unknown compounds. This nifty reaction with di-(t)-butyl disulfide worked so well, that three additional disulfides that were at hand were immediately thrown into the chemical program, with the quick assignment of the names 2C-T-10, 2C-T-11, and 2C-T-12. The lithiated dimethoxybenzene reaction with 2,2-dipyridyl disulfide produced 2,5-dimethoxyphenyl 2-pyridyl sulfide which distilled at 135-150 deg C at 0.4 mm/Hg and could be recrystallized from cyclohexane containing 2% EtOH to give a product that melted at 66-67.5 deg C. Anal. (C13H13NO2S) C,H. This would have produced 2,5-dimethoxy-4-(2-pyridylthio)phenethylamine (2C-T-10) but it was never pursued. The same reaction with di-(4-bromophenyl) disulfide produced 2,5-dimethoxyphenyl 4-bromophenyl sulfide which distilled at 150-170 deg C at 0.5 mm/Hg and could be recrystallized from MeOH to give a product that melted at 72-73 deg C. Anal. (C14H13BrO2S) C,H. This was being directed towards 2,5-dimethoxy-4-(4-bromophenylthio)phenethylamine (2C-T-11) but it also was abandoned. The same reaction with N,N-dimorpholinyl disulfide produced virtually no product at all, completely defusing any plans for the synthesis of a novel sulfur-nitrogen bonded base 2,5-dimethoxy-4-(1-morpholinothio)phenethylamine (2C-T-12). One additional effort was made to prepare a 2C-T-X thing with a sulfur-nitrogen bond. The acid chloride intermediate in the preparation of 2,5-dimethoxythiophenol (as described in the recipe for 2C-T-2) is 2,5-dimethoxybenzenesulfonyl chloride. It reacted smoothly with an excess of diethylamine to produce 2,5-dimethoxy-N,N-diethylbenzenesulfonamide which distilled at 155 deg C at 0.13 mm/Hg and which could be recrystallized from a 4:1 mixture of cyclohexane/benzene to give a product with a melting point of 41-42 deg C and an excellent proton NMR. This amide proved totally refractory to all efforts at reduction, so the target compound, 2,5-dimethoxy-4-diethylaminothiophenethylamine, has not been made. It has not even been given a 2C-T-X number. #46 2C-T-13; 2,5-DIMETHOXY-4-(2-METHOXYETHYLTHIO)PHENETHYLAMINE SYNTHESIS: To a solution of 3.25 g of KOH pellets in 25 mL hot MeOH, there was added 6.8 g of 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) followed by 4.73 g of 2-methoxyethylchloride. This mixture was heated on the steam bath for 0.5 h, then added to 500 mL H2O. This very basic aqueous phase was extracted with 3x100 mL CH2Cl2, the extracts pooled, and back-washed with 5% NaOH. The solvent was removed under vacuum to give 8.82 g of a white oil. Distillation gave 2,5-dimethoxyphenyl 2-methoxyethyl sulfide with a bp 115-125 deg C at 0.3 mm/Hg, and a weight of 6.65 g. A mixture of 10 g POCl3 and 10 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 6.16 g of 2,5- dimethoxyphenyl 2-methoxyethyl sulfide. There was an immediate exothermic reaction and gas evolution. The mixture was heated for 15 min on the steam bath, at which time there was no starting sulfide present by TLC. This was then added to 500 mL of well-stirred warm H2O (pre-heated to 55 deg C) and the stirring continued until only a thin oily phase remained. This was extracted with CH2Cl2, the extracts were combined, and the solvent removed under vacuum. The residue was extracted with 5 sequential 20 mL portions of boiling hexane which deposited crystals on cooling. Filtering gave a total of 4.12 g crystalline solids. Recrystallization from MeOH gave a poor yield of a cream-colored crystal with a mp of 68-69 deg C. A more efficient purification was achieved by distillation (155-168 deg C at 0.3 mm/Hg) yielding 3.50 g of 2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde as a pale yellow solid, with a mp of 67-68 deg C. A faster moving (by TLC) trace component with an intense fluo-rescence persisted throughout the entire purification scheme, and was still present in the analytical sample. Anal. (C12H16O4S) C,H. To a solution of 3.41 g 2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde in 50 g of nitromethane there was added 0.11 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h, at which time the starting aldehyde had largely disappeared by TLC (silica gel plates with CH2Cl2 as the developing solvent) and a faster moving nitrostyrene product was clearly visible. The clear orange solution was stripped of the excess nitromethane under vacuum producing a yellow oil that crystallized yielding 3.97 g of a yellow solid with a mp of 99-104 deg C. Recrystallization of a small sample from MeOH produced (when dry) yellow electrostatic crystals of 2,5-dimethoxy-4-(2-methoxyethylthio)-beta-nitrostyrene with a mp of 107 deg C sharp. From IPA the product is a burnished gold color with the mp 106-107 deg C. Anal. (C13H17NO5S) C,H. A solution of LAH (40 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 3.07 g 2,5-dimethoxy-4-(2-methoxyethylthio)-beta-nitrostyrene in small portions, as a solid, over the course of 10 min. There was a considerable amount of gas evolved, and a little bit of charring. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 8 mL IPA followed by 3 mL 15% NaOH which gave the reaction mixture a curdy white granular character. The reaction mixture was filtered, the filter cake washed with THF, and filtrate and washes were stripped of solvent under vacuum providing about 3 g of a pale amber oil. This was dissolved in about 40 mL CH2Cl2 and extracted with 200 mL dilute H2SO4 in three portions. All of the color remained in the organic phase. The pooled aqueous extracts were washed with CH2Cl2, then made basic with 25% NaOH, extracted with 3x75 mL CH2Cl2, and the combined extracts pooled and stripped of solvent under vacuum. The 2 g pale yellow oily residue was distilled at 155-165 deg C at 0.2 mm/Hg to give 1.23 g of a clear white oil. This was dissolved in IPA, neutralized with concentrated HCl, and diluted with anhydrous Et2O to produce crystals of 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine hydrochloride (2C-T-13). After filtration, washing with Et2O, and air drying, this white crystalline product weighed 0.89 g. DOSAGE: 25 - 40 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 25 mg) I felt it was somewhat noisy as we went into the experience. This noisiness lasted only about an hour, then stopped. At the peak, which seemed to be at about 1 to maybe 1.5 hours, some eyes-closed visuals appeared. There was a white field with colored visuals, at times geometric in shape. These eye-closed images were pleasant and I enjoyed them when I did not concern myself with, or listen to, the conversation. There was an eyes-open change in color, the ivy became a little lighter or maybe a little stronger in color. I'm not sure which. I felt there was a gradual diminishing of activity (whatever that undefined activity was) starting at 2 to 2.5 hours, and coming close to baseline at 6 PM. The descent was pleasant and I would say pleasurable. The experience did not lead to any confusion which I sometimes notice in other experiences. There was no problem with anorexia. We ate constantly during the experience. The grapes and other fruit were lovely. This is one of the few times I would say that I would try a higher dose. Maybe 30 or 33 milligrams. I suspect the experience would be similar, with just a heightened peak at 1 hour and perhaps a little more body effect. It may well be one to try with one's wife. (with 28 mg) There was a strange, disturbing twinge exactly eight minutes after starting this, that asked me, `Should I have done this?' I answered, `Yes' and the twinge disappeared. And then there was nothing until the expected time of development, at a half hour when I felt a light head and slight dizziness. There was a solid plus two for a couple of hours. I paid careful attention for auditory oddities that I had noted before, but they were not there. In an earlier trial (with 20 milligrams) the radio had the sound of being located in the outdoors with the sounds coming through the wall and into the room where I was. I was at a neutral baseline at about seven hours. (with 35 mg) There was a quiet climb, but it was marred with some tummy unquiet, and an annoying persistence of diarrhea. I was very impressed with eyes-closed patterning, which seemed to do its own thing independently of the music. I was clearly up to a +++, but there was a feeling that as soon as it got there it started to go away again. There was no there, there. Yet there were a couple of touches of introspection, of seriousness which I had to respect. (with 40 mg) There were four of us, and the entry was individual for each of us. Two of us were nauseous. One volunteered a statement, almost a confession, of too much food and drink in the immediate past. One of us needed his cigarette right now, and then he saw that he was killing himself, and he swore off. Don't know if it will last, however. At the two and a half hour point there is a consensus that this has gone its route and will lose its impact, so three of us decided to supplement on 2C-T-2. Six milligrams proves to be a little light so, some four hours later, we each took another six milligrams. Excellent. In a while we discoved that we were very hungry, and food tasted marvelous. Headaches acknowledged in the early evening, but the extension from T-13 to T-2 seemed to be absolutely correct. And as of the next day, the non-smoker was still a non-smoker. EXTENSIONS AND COMMENTARY: Most of the synthetic adventures of putting a basic something aways out from the benzene ring, at the four-position, have involved subtle things such as unsaturated bonds or three-membered rings. This was the first try with the actual use of a different atom (an oxygen). What about other heteroatoms such as sulfur or nitrogen or silicon or phosphorus, or some-such? The sulfur counterpart of 2C-T-13 was named 2C-T-14, and was immediately launched. The reaction of 2,5-dimethoxythiophenol and KOH with 2-methyl-thioethyl chloride in hot MeOH gave 2,5-dimethoxyphenyl 2-methylthioethyl sulfide as a white oil (boiling point of 140-160 deg C at 0.3 mm/Hg). This underwent a normal Vilsmeier reaction (phosphorous oxychloride and N-methylformanilide) to give 2,5-dimethoxy-4-(2-methylthioethylthio)benzaldehyde with a melting point of 64-64.5 deg C from MeOH. This, in nitromethane containing a little ammonium acetate, was heated on the steam bath for 10 hours and worked up to give an excellent yield of 2,5-dimethoxy-4-(2-methylthioethylthio))-beta-nitrostyrene as garish orange-red "Las Vegas" colored crystals from acetonitrile, with a melting point of 126-127 deg C. And as of the moment, this is sitting on the shelf waiting to be reduced to the target compound 2,5-dimethoxy-4-(2-methylthioethylthio)phenethylamine hydrochloride, or 2C-T-14. Will it be active? I rather suspect that it will be, and I'll bet it will be longer-lived than the oxygen model, 2C-T-13. #47 2C-T-15; SESQUI; 2,5-DIMETHOXY-4-CYCLOPROPYLTHIOPHENETHYLAMINE SYNTHESIS: To a solution of 3.3 g of KOH pellets in 150 mL hot MeOH, there was added 10 g 2,5-dimethoxythiophenol (see recipe for 2C-T-2 for its preparation) followed by 10 g 1-bromo-3-chloropropane. The reaction was exothermic, and immediately deposited white solids of KCl. The reaction mixture was warmed for a few min on the steam bath, and then quenched in H2O. The basic reaction mixture was extracted with 3x75 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum. The residual oil was distilled at 145-155 deg C at 0.2 mm/Hg to give 16.5 g of 2,5-dimethoxyphenyl 3-chloropropyl sulfide as a clear, colorless oil. A solution of the lithium amide of 2,2,6,6-tetramethylpiperidine was prepared by the addition of 20 mL of 2.6 M butyllithium in hexane to a well stirred hexane solution of the piperidine in 100 mL hexane, under an atmosphere of He. The reaction was exothermic, formed a white solid precipitate, and was allowed to continue stirring for a few min. There was then added 6.5 g 2,5-dimethoxphenyl 3-chloropropyl sulfide, and a strongly exothermic reaction ensued. This was stirred for 30 min and then poured into dilute H2SO4 (the progress of the reaction must be followed by TLC, silica gel plates, CH2Cl2:petroleum ether 50:50 to determine when it is done; in one run over 2 h were required for completion of the reaction). The organic phase was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The combined organic phases were washed first with dilute NaOH, then with dilute HCl, then the solvents were removed under vacuum. The residue was distilled to provide 2,5-dimethoxyphenyl cyclopropyl sulfide as a pale yellow liquid that boiled at 100-115 deg C at 0.1 mm/Hg. The use of other bases to achieve this cyclization were less successful. Incomplete cyclization resulted from the use of lithium diisopropyl amide and, if the conditions were made more vigorous, there was dehydrohalogenation to the allyl sulfide. An unexpected difficulty was that the allyl sulfide (from elimination) and the 3-chloropropyl sulfide (starting material) behaved in an identical manner on TLC analysis. They were easily separated, however, by GC analysis. A completely different approach to the synthesis of this sulfide was explored through the reaction of cyclopropyllithium with an aromatic disulfide, thus avoiding the base-promoted cyclization step. A solution of 2.6 g di-(2,5-dimethoxyphenyl)disulfide (from 2,5-dimethoxythiophenol and hydrogen peroxide, bp 220-230 deg C at 0.3 mm/Hg) was made in anhydrous Et2O, and well stirred. In a separate flask, under an atmosphere of He, 4 mL of 2.6 M butyllithium was added to a solution of 1.2 g cyclopropyl bromide in 20 mL anhydrous Et2O. This mildly exothermic combination turned a bit cloudy, was stirred for 1 h, then trans-ferred with an air-tight syringe to the above-described Et2O solution of the aromatic disulfide. A heavy precipitate formed, and stirring was continued for an additional 0.5 h. The reaction mixture was then poured into H2O, the layers separated, and the aqueous phase extracted with CH2Cl2. The extracts were pooled, washed with dilute aqueous KOH, and the solvents removed under vacuum. Distillation gave 0.7 g of 2,5-dimethoxyphenyl cyclopropyl sulfide with identical gas chromatographic behavior to the sample prepared by the cyclization of the chloropropylthio compound. A mixture of 7.2 g POCl3 and 6.7 g N-methylformanilide was heated on the steam bath until it was claret red. To this there was added 4.5 g of 2,5-di-methoxyphenyl cyclopropyl sulfide, and the exothermic combination heated on the steam bath for about 5 min. The deep red, bubbling reaction mixture was added to 150 mL H2O and stirred until all oils had been converted into loose solids. These were then removed by filtration, washed with H2O, and sucked as dry as possible. They were dissolved in boiling MeOH which, after cooling in an ice-bath, deposited yellow crystals of 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde that weighed 3.43 g after air drying, and had a mp of 97-99 deg C. Anal. (C12H14O3S) C,H. To a solution of 3.0 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde in 40 g of nitromethane there was added 0.2 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 3 h. The excess nitromethane was removed under vacuum yielding 3.4 g orange crystals. These were recrystallized from 150 mL boiling IPA containing a little toluene. After cooling, filtering, and air drying there were obtained 2.75 g of 2,5-dimethoxy-4-cyclopropylthio-beta-nitro-styrene as pumpkin-colored crystals with a mp of 159-160 deg C. Anal. (C13H15NO4S) C,H. A solution of LAH (40 mL of a 1 M. solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 2.5 g 2,5-dimethoxy-4-cyclopropylthio-beta-nitrostyrene in 40 mL anhydrous THF over the course of 15 min. There was an immediate loss of color. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath and held there for 2 h. After recooling, there was added IPA (to destroy the excess hydride) followed by sufficent 15% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and washes were stripped of solvent under vacuum providing a yellow oil that was treated with dilute H2SO4. This produced a flocculant white solid, apparently the sulfate salt of the product. This was washed with 4x75 mL CH2Cl2 which removed most of the yellow color. The aqueous phase was made basic with aqueous NaOH and extracted with 3x75 mL CH2Cl2. Removal of the solvent under vacuum gave a light yellow colored oil that was distilled at 0.3 mm/Hg. The fraction boiling at 140-150 deg C was a colorless, viscous oil that weighed 1.97 g. This was dissolved in a few mL IPA, and neut-ralized with concentrated HCl forming immediate cottage cheese-like crystals of the hydrochloride salt. This was diluted by suspension in anhydrous Et2O, removed by filtration, and air dried to give 1.94 g of 2,5-dimethoxy-4-cyclopropylthiophenethylamine hydrochloride (2C- T-15) that had a mp of 203-5-204.5 deg C. Anal. (C13H20ClNO2S) C,H. DOSAGE: greater than 30 mg. DURATION: several hours. QUALITATIVE COMMENTS: (at 30 mg) I was somewhere between a threshold and a plus one for several hours, and appeared to be quite talkative in the evening. EXTENSIONS AND COMMENTARY: The commonly used name for 2C-T-15, during its synthesis, was SESQUI. The general name for a 15-carbon terpene is sesquiterpene, from the Latin prefix for one and a half. The active level of 2C-T-15 is not known. The highest level yet tried was 30 milligrams orally, and there had been threshold reports pretty regularly all the way up from 6 milligrams. But no definite activity yet. This compound is isosteric with the isopropyl group as seen in the analogous compound 2C-T-4 (the three carbons are in exactly the same positions, only the electrons are located differently) and it is a little surprising that the potency appears to be considerably less. Just over 20 milligrams of the latter compound was overwhelmingly psychedelic. The entire mini-project of hanging cyclic things onto the sulfur atom was an interesting problem. This is the three carbon ring. The six carbon ring (the cyclohexyl homologue) was discussed as 2C-T-5 in the recipe for of ALEPH-2. The cyclobutyl and cyclopentyl homologs were assigned the names of 2C-T-18 and 2C-T-23, respectively, and their preparations taken as far as the nitrostyrene and the aldehyde stages, respectively, before the project ran out of steam. Towards the cyclobutyl homologue, a solution of 2,5-dimethoxythiophenol and cyclobutyl bromide in DMSO containing anhydrous potassium carbonate was stirred for several hours at room temperature and yielded 2,5-dimethoxyphenyl cyclobutyl sulfide as a white oil that boiled at 135-140 deg C at 0.3 mm/Hg. Anal. (C12H16O2S) C,H. This was brought to react with a mixture of phosphorus oxy-chloride and N-methylformanilide producing 2,5-dimethoxy-4-(cyclobutylthio)benzaldehyde that had a melting point of 108-109.5 deg C from MeOH. Anal. (C13H16O3S) C,H. Coupling with nitromethane in the presence of ammonium acetate produced 2,5-dimethoxy-4-cyclobutylthio-beta-nitrostyrene as lustrous orange crystals from boiling acetonitrile, melting point 160-161 deg C. Anal, (C14H17NO4S) C,H. This will some day be reduced to 2,5-dimethoxy-4-cyclobutylthiophenethylamine hydrochloride, 2C-T-18. Towards the cyclopentyl homologue, a solution of 2,5-dimethoxythiophenol and cyclopentyl bromide in DMSO containing anhydrous potassium carbonate was stirred for several hours at room temperature and yielded 2,5-dimethoxyphenyl cyclopentyl sulfide as a white oil that boiled at 135-145 deg C at 0.3 mm/Hg. This was brought to react with a mixture of phosphorus oxychloride and N-methylformanilide producing 2,5-dimethoxy-4-(cyclopentylthio)benzaldehyde as yellow crystals from MeOH. This will some day be converted to the nitrostyrene and then reduced to 2,5-dimethoxy-4-cyclopentylthiophenethylamine hydrochloride, 2C-T-23. #48 2C-T-17; NIMITZ; 2,5-DIMETHOXY-4-(s)-BUTYLTHIOPHENETHYLAMINE SYNTHESIS: To a solution of 2.6 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) and 5.8 g (s)-butyl bromide. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for a few h, the solvent removed under vacuum, and the resulting solids dissolved in 250 mL H2O. Additional aqueous NaOH was added to bring universal pH paper to a full blue color. This was extracted with 3x40 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl (s)-butyl sulfide which was a pale yellow oil, weighing 10.12 g. It was sufficiently pure for use in the next reaction without a distillation step. A mixture of 15.1 g POCl3 and 14.1 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 9.4 g of 2,5-dimethoxyphenyl (s)-butyl sulfide, and the mixture heated for 35 min on the steam bath. This was then added to 200 mL of well-stirred warm H2O (pre-heated to 55 deg C) and the stirring continued until the oily phase had completely solidified (about 15 min). These light brown solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, these solids (12.14 g wet) were ground under an equal weight of MeOH which produced a yellowish crystalline solid with a mp of 76-81 deg C. Recrystallization of a 0.4 g sample from an equal weight of boiling MeOH provided 0.27 g of 2,5-dimethoxy-4-(s-butylthio)benzaldehyde as a pale cream-colored crystalline material with a mp of 86-87 deg C. To a solution of 8.0 g of the crude 2,5-dimethoxy-4-(s-butylthio)benzaldehyde in 40 g of nitromethane there was added 0.38 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The reddish colored solution was decanted from some insoluble tan material and the excess nitromethane removed under vacuum. The heavy red oil that remained was diluted with an equal volume of boiling MeOH, and allowed to return to room temperature. The orange-colored crystals that slowly formed were removed by filtration and, after air drying, weighted 6.24 g. This was again recrystallized from an equal volume of MeOH, yielding 2,5-dimethoxy-4-(s-butylthio)-beta-nitrostyrene as yellow, somewhat beady crystals that weighed (when dry) 3.50 g and which had a mp of 62-65 deg C. A small portion of this fraction was crystallized yet again from MeOH to provide an analytical sample that was yellow-orange in color, and had an mp of 68-69 deg C. Anal. (C13H17NO4S) C,H. A solution of LAH (120 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 3.3 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.83 g 2,5-dimethoxy-4-(s-butylthio)-beta-nitrostyrene in 80 mL anhydrous THF dropwise over the course of 2 h. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 18 mL IPA followed first by 5 mL of 15% NaOH and then by 15 mL of H2O. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and washing were combined and stripped of solvent under vacuum providing about 8.5 g of a pale amber oil. Without any further purification, this was distilled at 135-150 deg C at 0.4 mm/Hg to give 6.12 g of a clear white oil. This was dissolved in 30 mL IPA, and neutralized with 2.1 mL of concentrated HCl forming crystals immediately. Another 10 mL of IPA was added to allow the solids to be finely dispersed, and then about 100 mL of anhydrous Et2O were added. The solids were removed by filtration, Et2O washed, and air dried to constant weight. The product, 2,5-dimethoxy-4-(s)-butylthiophenethylamine hydrochloride (2C-T-17) was obtained as spectacular white crystals, weighing 5.67 g. DOSAGE: 60 - 100 mg. DURATION: 10 - 15 h. QUALITATIVE COMMENTS: (with 60 mg) This material took fully three hours to get into its maximum effect. I never was at a +++, quite, and I am not sure why it is really active, but I know it is. There does not seem to be any interference with my concentration or mental coordination, but I wouldn't want to drive right now. Good appetite in the evening, for a Chicago-style pizza, and there was no Tomso effects (the rekindling of a psychedelic effect with alcohol) with a glass of wine. An over-all good and instructive ++, no visuals, totally benign. There is no hesitation in doing it again some day. (with 100 mg) A small fragment hadn't dissolved when I drank the solution, and it must have stuck to the back of my mouth, because it made a searing spot that burned for 5 minutes. The first central effects were noted at an hour. The plateau stretched from the 3rd to the 7th hour, then tapered off quite quickly. My sleep was fitful, with some hints of nervous sensitivity. I felt that there were some residuals even into the next morning. A truly heavy psychedelic, but with very few explicit sensual changes or unusual perceptions to justify that comment. Why is it heavy? It just is. This dosage is high enough. EXTENSIONS AND COMMENTARY: An interesting, and quite logical, habit that seems to always pop up when a lot of talk and energy become directed at a specific compound, is the habit of using a nickname for it. The Tweetios are an example, and in the 2C-T-X family I had mentioned the term SESQUI. Here, this compound was called NIMITZ, for the obvious reason that the major freeway from Oakland to San Jose, the Nimitz freeway, was also called State Highway 17. Its name has been changed to Interstate 880, and I guess it could now only be used as a reference point if efforts were being made for a 2C-T-880. The reason that 2C-T-17 is of special theoretic interest is that it is one of the very first of the active psychedelic compounds (along with 2C-G-5) to have a potential optically active center on the side of the ring away from the nitrogen atom. One of the oldest and best studied variants of the phenethylamine chain are the alpha-methyl homologues, the substituted amphetamines. Here there is an asymmetric carbon atom right next to the amine group, allowing the molecule to be prepared in either a right-hand way or a left-hand way. The "R" or the "S" isomer. And in the several studies that have looked at such isomers separately, it has always been the "R" isomer that has carried the psychedelic effects. This probably says something about the nitrogen end, the metabolic end, the "north" end of the receptor site that recognizes these compounds, and suggests that there is some intrinsic asymmetry in the area that binds near to the basic nitrogen atom. But very little is known of the receptor's "south" end, so to speak, the geometry of the area where the opposite end of the molecule has to fit. Here, with 2-C-17, there is a secondary butyl group, and this contains an asymmetric carbon atom. But now this center of asymmetry is clear across the benzene ring from the nitrogen, and should certainly be in some entirely new part of the receptor site. Why not make this compound with the "R" and the "S" forms in this new and unusual location? Why not, indeed! Why not call them the right-lane and the left lane of the Nimitz? Fortunately, both "R" and "S" secondary butyl alcohols were easily obtained, and the synthesis given above for the racemic compound was paralleled for each of these isomers, separately. Is there any chemistry that is different with the specific optical isomers from that which has been reported with the racemic? There certainly is for the first step, since the butyl alcohols rather than the butyl bromides must be used, and this first step must go by inversion, and it cannot be allowed any racemization (loss of the optical purity of the chiral center). The synthesis of 2C-T-17 "R" required starting with the "S" isomer of secondary butanol. The "S" 2-butanol in petroleum ether gave the lithium salt with butyllithium which was treated with tosyl chloride (freshly crystallized from naphtha, hexane washed, used in toluene solution) and the solvent was removed. The addition of 2,5-dimethoxythiophenol, anhydrous potassium carbonate, and DMF produced "S"-2,5-dimethoxyphenyl s-butyl sulfide. The conversion to "R"-2,5-dimethoxy-4-(s-butyl-thio)benzaldehyde (which melted at 78-79 deg C compared to 86-87 deg C for the racemic counterpart) and its conversion in turn to the nitrostyrene, "S"-2,5-dimethoxy-4-(s)-butylthio-beta-nitrostyrene which melted at 70-71 deg C compared to 68-69 deg C for the racemic counterpart, followed the specific recipes above. The preparation of the intermediates to 2C-T-17 "S" follows the above precisely, but starting with "R" 2-butanol instead. And it is at these nitrostyrene stages that this project stands at the moment. It would be fascinating if one of the two optically active 2C-T-17's carried all of the central activity, and the other, none of it. What is more likely is that the spectrum of effects will be teased apart, with one isomer responsible for some of them and the other isomer responsible for the others. Then, again, maybe the south end of the receptor site in the brain is totally symmetric, and the two optical antipodes will be indistinguishable. An incidental bit of trivia Q yet another bit of evidence that we are all totally asymmetric in our personal body chemistry. "R" and "S" secondary butanols smell different. The "R" has a subtle smell, which is rather fragrant . The "S" is stronger, hits the nasal passages harder, and reminds one of isopropanol more than does the "S" isomer. #49 2C-T-21; 2,5-DIMETHOXY-4-(2-FLUOROETHYLTHIO)PHENETHYLAMINE SYNTHESIS: To a solution of 6.9 g of KOH pellets in 100 mL hot MeOH, there was added 13.0 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) followed by 9.6 g 2-fluoroethyl bromide. The reaction was exothermic, with the immediate deposition of white solids. This was allowed to stand for 2 h, added to 1 L H2O, and extracted with 3x75 mL CH2Cl2. The extracts were pooled and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl 2-fluoroethyl sulfide which was a colorless oil and weighed 17.2 g. It was sufficiently pure for use in the next reaction without a distillation step. A mixture of 26.8 g POCl3 and 24.8 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 17.0 g of 2,5- dimethoxyphenyl 2-fluoroethyl sulfide, and the mixture heated an additional 25 min on the steam bath. This was then added to 1.5 L of well-stirred warm H2O (pre-heated to 55 deg C) and the oily phase that formed solidified almost immediately. This brown sugar-like product was removed by filtration, and washed with additional H2O. After sucking as dry as possible, the residual solids (weighing 19.0 g wet) were dissolved in an equal weight of boiling MeOH which, after cooling in an ice-bath, deposited pale ivory colored crystals of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde. This was air dried to constant weight, which was 15.1 g. To a solution of 15.0 g 2,5-dimethoxy-(2-fluoroethylthio)benzaldehyde in 75 mL nitromethane there was added 1.35 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 70 min (the progress of the reaction must be followed by continuous TLC monitoring). The clear deeply-colored solution was decanted from some insoluble material and the excess nitromethane removed under vacuum. There resulted 17.78 g of almost dry brick-red crystals which were dissolved in 110 mL boiling EtOAc. After cooling overnight in the refrigerator, the crystalline product was removed, washed with EtOAc, and air dried. There was obtained 14.33 g of 2,5-dimethoxy-4-(2-fluoroethylthio)-beta-nitro-styrene as bright orange crystals. A solution of LAH (140 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 3.7 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.9 g 2,5-dimethoxy-4-(2-fluoroethylthio)-beta-nitrostyrene in 40 mL of hot anhydrous THF (a heat lamp was needed to keep the nitrostyrene in solution). As the nitrostyrene entered the hydride solution, there was an immediate loss of color. After 1 h stirring at room temperature, the temperature was brought up to a gentle reflux on the steam bath, then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of 15 mL IPA and the inorganic solids were made white and filterable by the addition of 15 ml 15% NaOH. The loose cottage-cheesy solids were removed by filtration, and washed with additional THF. The filtrate and washes were pooled and stripped of solvent under vacuum providing 7.39 g of a pale amber oil. This was dissolved in 600 mL dilute H2SO4, and washed with 3x50 mL CH2Cl2 (which removed the light yellow color). The aqueous phase was made strongly basic with 25% NaOH, extracted with 3x75 mL CH2Cl2 and, after pooling, the solvent was removed under vacuum leaving 4.91 g of product as an oil. This was distilled at 145-160 deg C at 0.4 mm/Hg giving 3.91 g of a white oil. This was dissolved in 40 mL IPA and neutralized with 35 drops of concentrated HCl. The beautiful white solids that formed were removed by filtration, and washed with IPA. All were suspended in, and ground under, 40 mL anhydrous Et2O, refiltered and air dried. The final weight of 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine hydrochloride (2C-T-21) was 4.07 g of glistening white crystals. DOSAGE 8 - 12 mg. DURATION: 7 - 10 h. QUALITATIVE COMMENTS: (with 6 mg) I noticed something undefined within five minutes which went away. Within 15 minutes I noticed a definite awareness of activity. There was a progressive increase in awareness of something happening over the next two hours with a plateau of perhaps an hour then occurring. The nature of the happening, as usual, was not clear. During the experience I was more talkative than I usually am. I seemed to be interacting with all others. There was no euphoria but, then, there was no body load or nausea, nor was there any nystagmus. I found a little mental confusion at the peak and there was some searching in my memory bank for the right chips at times. I lost the entire line of one of my conversations at one point during the plateau and had to ask what I was talking about. I tested my visual field on a painting and with sufficient concentration I could get the center part to wiggle a little. I didn't try to observe anything with my eyes closed. I feel that there was something physical about the eyes. In the evening, after-images were quite intense, and the next day my eyes seemed tired or bothered. What can I say? The material was pleasant and I certainly got the feeling of being high but not getting too much out of it. There were no insights or "ah-hahs." I wonder if periodic and frequent use (say twice a day) at the one or two milligram level would be a positive mood enhancer? (with 8 mg) Comes on very gradually and slowly. Takes about an hour to feel. Reasonably intense in two hours, ++. Very pleasant material, enhancing communication, clear thinking, good feeling. There is a feeling of closeness; the bondedness with the group grows steadily during the day, reaching a highly rewarding level. For me a couple of firsts regarding food. I was hungry only two hours into it. I usually don't want food 'til well down as I usually feel that it interferes with the experience. And, also, I nibbled constantly as I felt that there was nothing in my body. And I enjoyed it thoroughly, feeling only the warmth and energy, with no contrary developments. There was a nice feeling of inner strength and peace. (with 8 mg) It was very difficult to fix the times of ascent or descent. Some chilling during onset but not later. And there was some yawning and ear-popping. It is easy on the body, in no way threatening. This time I am very relaxed and somewhat lethargic; the visuals are not too pronounced. Excellent sleep. (with 10 mg) I find I can use it if I set my energy in a direction I really want to go in. Otherwise I can just be stoned and self-indulgent. Not out-of-body cosmic at all. But it's good material, an ally, not presenting hidden negatives. (with 12 mg) Well ... 12 milligrams is quite enough for a +3, which was established within the first hour and plateau'd by the end of the second. Body felt quite safe, again, but there was considerable push of energy. I did not feel par-ticularly interested in doing anything like writing and in fact preferred to watch television while rocking a bit on the couch, to ease the push. Mood was faintly grim, but not more than faintly. I noted something that I hadn't seen before with this material: time slowing. The first two hours seemed to last a very long time. There was no anorexia. It wasn't until 10 PM [fifth hour] that the idea of writing had any appeal at all. By then, I was still +3 but a lot more at ease. I wrote two letters and enjoyed the process. Sleep was fine. My mood next day was slightly introverted, not very spontaneous for a while. Late in the afternoon, it was a lot better. EXTENSIONS AND COMMENTARY: This is about as potent a phenethylamine as they come. There are a couple in the 2C-G family that are similar in potency, but they are much longer lived. The motivation for the use of the beta-fluoroethyl group can be seen under the discussion of DOEF, where there was an amalgamation of two lines of reasoning: the imitation of potent serotonin agonists with a need of including an atom (the fluorine) that is potentially labelable with a positron emitter. And the mass-18 isotope of fluorine, with a half-life of just under 2 hours, is ideal for many biological studies. In fact, much of the research work being carried out by the Nuclear Medicine group in Berkeley is based on the analogy between a halogen atom and a beta-fluoroethyl group. There are some similarities in pharmacology so that if there is a bromine or an iodo atom present in a drug, it is a fair guess that the corresponding beta-fluoroethyl would also be active. In a sense, the cute (and chemically impossible) idea of putting a bromo atom on the sulfur of the 2C-T family is nicely satisfied by using the beta-fluoroethyl group instead (which is chemically completely possible). A logical extension of 2C-T-21 is the three carbon amphetamine analogue which should be, by comparing structures and activities, a very potent and in-teresting material in its own rights. This would be 2,5-dimethoxy-4-(2-fluoroethylthio)amphetamine or, following the nomenclature used with the earlier members of this series, ALEPH-21. A solution of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde (see earlier in this recipe) in nitroethane with ammonium acetate gave 1-(2,5-dimethoxy-4-(2-fluoroethylthio)phenyl)-2-nitropropene as yellow-orange crystals from MeOH with a melting point of 102-104 deg C. And that is where the project now stands. It has not yet been reduced to the amine. This phenethylamine, 2C-T-21, was the last of the 2C-T's to be completed. A couple of other sulfur analogues have been given numbers, and have been started, but the syntheses are still at some intermediate state. The (n)-butyl compound, named 2C-T-19, has been taken to the nitrostyrene stage. Reaction between 2,5-dimethoxythiophenol and (n)-butylbromide with KOH gave 2,5-dimethoxyphenyl (n)-butyl sulfide as a colorless oil. This, with phosphorus oxychloride and N-methylformanilide, provided 2,5-dimethoxy-4-(n-butylthio)benzaldehyde as pale orange solids from MeOH, with a melting point of 78-79 deg C. This, with nitromethane and ammonium acetate, gave 2,5-dimethoxy-4-(n-butylthio)-beta-nitrostyrene, with a melting point of 133-134 deg C from either IPA or acetonitrile. The 2,2,2-trifluoroethyl compound, which I have named 2C-T-22, has been taken to the benzaldehyde stage. Reaction between 2,5-dimethoxythiophenol and 2,2,2-trifluoroethyliodide with KOH gives 2,5-dimethoxyphenyl 2,2,2-trifluoroethyl sulfide as a very pale amber oil. This, with phosphorus oxychloride and N-methylformanilide provided 2,5-dimethoxy-4-(2,2,2-trifluoroethyl)benzaldehyde as crystals that proved to be exceedingly difficult to purify. Yellow solids can be obtained from several solvents, and they melt in the 70 deg C area. The initially isolated fraction melted at 69-72 deg C and showed three major spots by both TLC and GCMS. The largest GC peak was the correct product with a parent peak of 280 m/e, and cracking fragments at 154 and 234 m/e. A small sample was finally obtained from hexane with a melting point of 78-79 deg C but I am not sure that even it is particularly pure. Not surprisingly, the reaction of this crude benz-aldehyde with nitromethane and ammonium acetate gave a nitrostyrene product that was a complex mixture. And there that project also rests. A couple of additional efforts warrant comment. The reaction between trifluoromethyliodide and 2,5-dimethoxythiophenol should have produced 2,5-dimethoxyphenyl trifluoromethyl sulfide, but it didn't produce anything. And one more. What about a bare thio group at the 4-position in this 2C-T-family? Maybe this can be protected through everything as the disulfide, and be reduced at the last step! The disulfide, 2,5-dimethoxyphenyl disulfide (see under 2C-T-15) was aimed towards the needed bis-aldehyde with phosphorus oxychloride and N-methylformanilide, but all that came out of this were black oils and tars. This has also been abandoned for now. And it has just occurred to me that there is yet another effort that is certain-ly worth making, inspired by the observation that 2,2-difluoroethyl iodide is commercially available and not prohibitively expensive. It, with 2,5-dimethoxythiophenol, and following the obvious steps to the aldehyde, the nitrostyrene, and the final amine, would produce 2,5-dimethoxy-4-(2,2-difluoroethylthio)phenethylamine hydrochloride. It lies exactly half way between the highly potent 2C-T-21 (the mono-fluoro), and the yet to be finished 2C-T-22 (the trifluoro). Let's be weird, and call it 2C-T-21.5. I will wager mucho that it will be very potent. #50 4-D; 3,5-DIMETHOXY-4-TRIDEUTEROMETHOXY-PHENETHYLAMINE SYNTHESIS: To a solution of 34.0 g homosyringonitrile (3,5-dimethoxy-4-hydroxyphenylacetonitrile, see under ESCALINE for its preparation) in 350 mL acetone containing 0.5 g decyltriethylammonium iodide, there was added 25 g trideuteromethyl iodide followed by 50 g of finely powdered anhydrous K2CO3. This mixture was held at reflux on a steam bath for 12 h, added to 2 L of dilute HCl, and extracted with 3x100 mL of CH2Cl2. The extracts were washed with 5% NaOH, and the solvent removed under vacuum, yielding 28.0 g yellow solids. These were distilled at 135-150 deg C at 0.5 mm/Hg providing 19.4 g 3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile which melted at 76.5-77.5 deg C after crystallization from toluene, or 77-78 deg C from methylcyclohexane/CHCl3 3:1. The mp of the proteo-reference compound, from toluene, was 77-78.5 deg C. The OCD3 stretch in the infra-red occured at 2072 cm-1. A solution of 275 mL of 1.0 M LAH in THF was cooled under He to 0 deg C and treated with 7.25 mL 100% H2SO4 added very slowly with vigorous stirring. A solution of 19.3 g 3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile in 200 mL anhydrous THF was added slowly, and following the addition stirring was continued for 20 min. The reaction mixture was brought to a reflux for 30 min on a steam bath, cooled again to 0 deg C, and the excess hydride destroyed with 25 mL IPA. About 15 mL of 15% NaOH was required to convert the solids to a filterable white consistency. These were removed by filtration, the cake washed with IPA, the filtrates and washes were combined, and the solvent removed under vacuum leaving a white oil as residue. This was dissolved in 1.5 L dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent from these extracts under vacuum yielded 18.5 g of a colorless oil which was distilled at 120-150 deg C at 0.5 mm/Hg to provide 13.5 g of a white oil. This was dissolved in 70 ml IPA and neutralized with concentrated HCl, producing spontaneous crystals. These were removed by filtration, washed first with IPA then with anhydrous Et2O. After air drying, the final yield of 3,5-dimethoxy-4-trideuteromethoxyphenethylamine hydrochloride (4-D) was 13.50 g. DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the hydrochloride salt). DURATION: 12 h. QUALITATIVE COMMENTS: (with 275 mg) The onset was smooth and gradual. Within the hour, the slight queasiness I experienced (not as much as with mescaline) completely disappeared. Some visual enhancement, good energy, good communication. It was a very special day for me as I was in a good place pretty much the whole day, and able to communicate clearly without deeper feelings getting in the way. While most enjoyable, and at times remarkable fun, I did not experience the intensity I am familiar with, with mescaline. (with 300 mg) The taste was bitter to a moderate degree but faded fast. About 40 minutes later the first stirrings of pleasurable experience came on. It was very mild. Twenty minutes after that an unease of the stomach was apparent, and it stayed with me until I ate some crackers an hour or so later. I got no sharpened visual reactions and no physical instability at any time. I did feel a quickening of thought and verbal flow; again, this was mild and unlike my earlier mescaline patter. (with 350 mg) A rapid onset Q alert in 20 minutes. Climbed to a plus two in about one hour and stayed there. During the first two hours had a slight queasiness or pre-nausea, and cold hands and feet, but this all disappeared completely and I became very hungry during the whole latter half of the experience. I did not eat much at any one time, but did a lot of snacking and everything tasted good. Very pleasant after the plateau was reached. Pretty good visuals with eyes closed, but not as bright as 2C-B. Very little visuals with eyes open Q some movement and flow of objects Q pupils dilated. Spent most of the day lying down Q had no aversion to conversation but it felt good just to be still. I was in a funny place I can't quite describe Q I was in an 'alert lassitude,' a state of 'interested detachment,' or a place of 'vibrating equanimity' or whatever. While trying to recapture the day, it seemed to me that it was a good day, but that nothing much had really transpired. However, upon reflection, I am startled to find that several important shifts took place. It was a day that allowed some peaceful gear-shifting in the mind. (with 400 mg) Not a great taste. Some type of awareness at approx. 20 minutes. Considerable nausea peaking at about 1 hr. Some nausea continued through the experience but became quite low. I enjoyed the color show considerably. Trees outside would change color in a wave-like manner. The book-covers upstairs would also change colors and become distorted. Brightly lighted items would undergo the same thing. Believed I could suppress the vision, but concentrating on something would cause it to easily undergo the color and visual changes. Evidently I had little problem following the conversation downstairs, but I remained somewhat quiet. Had an element of confusion that seemed to last for some 4 or 5 hours. Had no problems dropping off to sleep that evening. EXTENSIONS AND COMMENTARY: The effects of 4-D and beta-D are similar to one-another, both as to dosage and effect. And with both, there is a close parallel to those reported from mescaline. It is reasonable to assume that the human body handles these materials in the same manner, although no metabolic studies have ever been published. A similar deuterium substitution pattern is of course completely feasible with TMA and related 3,4,5-trimethoxy-substituted analogues. Some studies have supported the idea that the ability to remove methyl groups from such aromatic ethers might be correlated to endogenous schizophrenia. It is possible to imagine that, in such individuals, the effects of substituting trideuteromethyl groups for normal methyl groups might result in psychopharmacological differences of action. Two reports exist that describe metabolic products of mescaline that have lost this methyl group on the 4-position oxygen. It is possible that these might be produced in abnormal quantities in mentally ill subjects. There are also similar reports of the 3-methoxyl group being demethylated in man. Here, studies with 3,5-D (3,5-bis-trideuteromethoxy-4-methoxyphenethylamine) might reveal some differences in quantitative responses in man. These are extremely minor metabolites, however. I suspect that more extensive studies will establish that 4-D, 3,5-D and beta-D all have properties indistinguishable from one-another, at least in healthy subjects. #51 beta-D; 3,4,5-TRIMETHOXY-beta,beta-DIDEUTEROPHENETHYLAMINE SYNTHESIS: To a solution of 13.6 g homosyringonitrile (see under ESCALINE for its preparation) in 150 mL acetone containing 200 mg decyltriethylammonium iodide and 30 g of finely powdered anhydrous K2CO3, there was added 20 g methyl iodide. The mixture was held at reflux for 18 h in a heating mantle with effective stirring. This was added to 1 L H2O, acidified with concentrated HCl, and extracted with 3x75 mL CH2Cl2. The extracts were pooled, washed with 2x100 mL 5% NaOH, once with dilute HCl, once with saturated brine, and the solvent was removed under vacuum. The pale yellow residue was distilled at 130-150 deg C at 0.3 mm/Hg to yield 12.9 g of 3,4,5-trimethoxyphenylacetonitrile as an off-white solid. Upon crystallization from methylcyclohexane/CHCl3 it was white and had a mp of 77-78 deg C. Attempts to prepare this compound by the theoretically appealing route from 3,4,5-trimethoxybenzaldehyde to N,N-dimethyl-3,4,5-tri-methoxybenzylamine (reductive amination with dimethylamine), to 3,4,5-trimethoxy-N,N,N-trimethylbenzylammonium iodide (methylation with methyl iodide), and then to 3,4,5- trimethoxyphenylacetonitrile (with some source of cyanide ion) gave excellent yields in the first two steps, and no product at all in the last step. A solution of 20.6 g of 3,4,5-trimethoxphenylacetonitrile in 70 g pyridine was treated with 15 mL 99+% D2O and held at reflux for 24 h. All volatiles were stripped first under vacuum and finally with a hard vacuum at room temperature in a Kugelrohr apparatus. The dark residue was treated again with another 30 mL pyridine and another 15 mL 99+% D2O. The flask was protected with a drying tube and held at reflux for another 24 h. Again, all volatiles were stripped, and the residue distilled at 110-130 deg C at 0.25 mm/Hg to yield 16.77 g of an almost white solid. The GCMS verified this chemical to be 3,4,5-trimethoxy-beta,beta-dideuterophenylacetonitrile, with a parent peak at m/e 209 and no visible peak at m/e 207. A solution of 250 mL of 1 M LAH in THF was cooled under He to 0 deg C and treated with 6.8 mL 100% H2SO4 added very slowly with vigorous stirring. A solution of 18.23 g 3,4,5-trimethoxy-beta,beta-dideuterophenyl-acetonitrile in 200 mL anhydrous THF was added slowly, and following the addition stirring was continued for 20 min. The reaction mixture was brought to a reflux for 30 min on a steam bath, cooled again to 0 deg C, and the excess hydride destroyed with 15 mL IPA. About 10 mL of 15% NaOH was required to convert the solids to a filterable white consistency. These were removed by filtration, the cake washed with IPA, the filtrates and washes were combined, and the solvent removed under vacuum leaving 17 g of a white oil as residue. This was dissolved in 2 L dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent from these extracts under vacuum yielded 10.3 g of a colorless oil which was distilled at 120-130 deg C at 0.3 mm/Hg to provide 9.2 g of a white oil. This was dissolved in 50 ml IPA and neutralized with concentrated HCl, producing spontaneous crystals. These were diluted with 50 mL anhydrous Et2O, removed by filtration, washed first with Et2O/IPA, and then with anhydrous Et2O. After air drying, the final yield of 3,4,5-trimethoxy-beta,beta-dideuterophenethylamine hydrochloride (beta-D) was 10.0 g of white needles. DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the hydrochloride salt). DURATION: 12 h. QUALITATIVE COMMENTS: (with 200 mg) The onset was very gradual and very gentle. At about an hour and a half I was rather out of my body (at least I wasn't aware of my body, it felt so light). I was listening to Berlioz Requiem, and it took me to the highest realm. I was totally caught up in the magnificence of the music, of the genius it took to compose it, the love it took to complete it, and the devotion of the composer. I felt as though this music had been written for me. What came next is hard to remember because I was so taken with this experience which came only 1 1/2 hours after ingestion. I wondered what time it was and how come I was having a peak experience so soon, because this material was supposed to reach its peak after two hours. Well, now we can revise the records, heh? Incidentally this material is really good for interior work. It was a magnificent experience Q one of the best. (with 275 mg) I begin to feel it in 15 minutes, stomach getting squeamish. Looking up into the clouds, becoming absorbed in them, watching light grow in intensity, stomach feelings disappeared. Became totally absorbed by the music. Listening to Boito's Prologue to Mephistopheles Q exquisitely beautiful, dramatic. Lying on the couch, the music continuing, I was suddenly filled with enormous power. I realized that raw, male power was pouring through me as I had never before experienced it. I was wild, totally self satisfied, and completely oblivious of others and their needs. I wanted to strike out, to win, to conquer. I felt what conquerers have felt in the past, the unbridled passion to vanquish everything. I could see how such misguided power could lead nations to war. Wanting still more power, I was about to find out if God would grant me the power to destroy the world if I wished it, when I felt a gentle kiss on my brow. My wife had leaned over just in time to save the world. (with 275 mg) Never had I had such a magnificent appreciation of God. It was clear that if I minded my business and turned to Him to learn as I had been doing today, then I could continue to grow and learn in a most wonderful way. It became crystal clear to me that I didn't have to help anybody or heal anybody, as everyone can turn directly to the source for their needs. An earth-shaking experience. (with 300 mg) I had extreme nausea, and vomited. This had a very hard impact on me, and I had to retreat with a paranoia that swept over me without warning. I lay down and let it sweep on, and through this came several very important insights. At least they were important to me. It was about the fourth hour before I could emerge from my retreat, and at that time I knew that I had answered some troublesome personal problems. It was a satisfactory day, but I probably shall not repeat it. (with 350 mg) Strong body awareness started within 15 minutes. Visual activity started within half an hour. Visuals were typical kinds, but seemed to arrive earlier. A strong experience of pleasantness started and continued throughout the experience. I tended to internalize to some extent. Ended on a water bed at maybe an hour and a half, pulled covers over me, and went inward with considerable visuals but not much insight. I felt good about where I was. I would not mind being there again, so something was going well. I am not sure how long this continued. The visuals decreased somewhere around the 5th or 6th hour. After 8 or 9 hours, activity considerably decreased. I felt quite clear and reasonably centered. Would I do this again? The answer is yes. (with 500 mg) I consumed the material over a period of twenty minutes, and at the 1 hour 45 minute point, haven't had any nausea, but I am still careful not to bounce around. Am absolutely grounded even though I am completely into the experience. No more that state in which it is possible to seriously consider trying to rise two inches above the floor and skim, as I do so expertly in dreams. As a matter of fact I haven't had those dreams for some time now. This material doesn't allow the straddling of realities as does ordinary mescaline. I know where my realities are, and reality is, basically, where my center is. Thus I am grounded in the physical reality even when the doors are open to non-physical levels. EXTENSIONS AND COMMENTARY: The 4-D and the beta-D are two of five obvious deuterium isomer derivatives of mescaline. The three remaining are: (1) 3,5-D (4-methoxy-3,5-bis-trideuteromethoxyphenethylamine); (2) 2,6-D (2,6-di-deutero-3,4,5-trimethoxyphenethylamine); and (3) a-D (a.a-dideutero-3,4,5-tri-methoxyphenethylamine). I fully expect both 3,5-D and 2,6-D to be indistinguishable from mescaline in effect, since it is known that not much metabolism takes place in man at these locations of the molecule. The last compound, a-D, could be quite a different matter. The principal metabolite of mescaline is 3,4,5-trimethoxyphenylacetic acid, and this product requires enzymatic attack at the exact position where the deuteriums will be located. To the extent that they are harder to remove (come off more slowly or to a lesser degree), to that extent the molecule will be more potent in man, and the dosage required for effects will be less. The compound will be easily made by the reduction of 3,4,5-trimethoxyphenylacetonitrile with lithium aluminum deuteride. And if there is a believable difference between a-D and mescaline, it will be necessary to synthesize each of the two optically active a-mono-deutero analogs. That will be quite a challenge. Some years ago I performed a fascinating series of experiments with another isotopically labeled mescaline derivative. This was beta-14C labeled material, which I self-administered on three occasions, at three different levels. One dosage was with 350 milligrams, a second a few weeks later was with 4 milligrams, and a third was a few weeks later yet, with about 60 micrograms. In each case, exactly the same absolute quantity of radioactivity was administered, so the metabolic distribution was equally visible. Only the weight dosage was different. Urinary analysis was run for each experiment for the presence of unchanged mescaline, and for the primary metabolite, 3,4,5-trimethoxyphenylacetic acid. The smaller the dosage, the proportionately larger amount of mescaline was oxidized to the inactive acetic acid, and the smaller amount was excreted in an unchanged state. It seemed to me that there might be a finite capacity of the body to oxidatively deaminate mescaline, and at larger and larger dosages, this capacity became increasingly depleted. Perhaps this is why mescaline requires such a large dosage to be effective in man. #52 DESOXY; 3,5-DIMETHOXY-4-METHYLPHENETHYLAMINE SYNTHESIS: To a well-stirred solution of 31 g 2,6-dimethoxytoluene in 200 mL CH2Cl2 there was added 11 mL elemental bromine, a portion at a time. There was a copious evolution of HBr and the color gradually faded from deep red to straw. The reaction mixture was poured into 500 mL H2O, and the organic layer separated, washed first with dillute NaOH and finally with dilute HCl. The solvent was removed under vacuum, and the residue distilled at 85-90 deg C at 0.4 mm/Hg to provide 44 g of 3-bromo-2,6-dimethoxytoluene as a white oil. A well-stirred solution of 42 mL diisopropylamine in 100 mL petroleum ether was placed in a He atmosphere and cooled to 0 deg C with an external ice-water bath. There was then added 120 mL of a 2.5 M solution of n-butyllithium in hexane, producing a clear but viscous solution of the lithium amide. Maintaining this temperature, there was added 100 mL of anhydrous THF, followed by 10 mL dry CH3CN, which produced an immediate white precipitate. A solution of 23 g of 3-bromo-2,6-dimethoxytoluene in 75 mL anhydrous THF was then added which produced a light red color. The reaction mixture was allowed to come to room temperature. The color became progressively darkened, eventually becoming a deep red-brown. After 0.5 h, the reaction mixture was poured into 500 mL of dilute H2SO4, the layers were separated, and the aqueous layer extracted with 2x75 mL CH2Cl2. The organics were combined, the solvent removed under vacuum, and the residue distilled. Discarding a first fraction, the cut boiling at 125-165 deg C at 0.3 mm/Hg was collected. This light yellow fraction spontaneously crystallized and weighed 11.0 g. Trituration under 20 mL petroleum ether provided 1.72 g of 3,5-dimethoxy-4-methylphenylacetonitrile as a yellowish solid. A solution of LAH in anhydrous THF under nitrogen (20 mL of a 1.0 M solution) was cooled to 0 deg C and vigorously stirred. There was added, dropwise, 0.54 mL 100% H2SO4, followed by 1.5 g 3,5-dimethoxy-4-methylphenylacetonitrile as a solid. The reaction mixture was stirred at 0 deg C for a few min, then brought to room temperature for 1 h, and finally to a reflux on the steam bath for 30 min. After cooling back to 0 deg C there was added IPA until no more hydrogen was evolved, followed by sufficient 15% NaOH to produce a granular texture. The white solids were removed by filtration, and washed with THF. The filtrate and washes were stripped of solvent under vacuum, the residue added to 150 mL dilute H2SO4 and washed with 2x50 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. These extracts were pooled, the solvent removed under vacuum, and the residue distilled at 110-120 deg C at 0.45 mm/Hg to give a colorless viscous oil. This was dissolved in 10 mL of IPA, neutralized with 10 drops of concentrated HCl and diluted with 20 mL anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 0.55 g 3,5-dimethoxy-4-methylphenethylamine (DESOXY) as white crystals. DOSAGE: 40 - 120 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 40 mg) Initially I felt very chilled, so I lay down under a blanket. Eyes-closed imagery became very dream-like and my general state was felt as having lost my center. Also, not much in touch with feelings, sense of strangeness, almost alien view of the world. Not through recog-nizable eyes. Neither pleasant nor unpleasant, just strange. Was able to drift into sleep very easily, or sleep-like trance state, with disconnected, far-out imagery. After 3 hours the nausea was gone, I was able to get up and explore. A little food went down well. No drive, no strong focus in any direction. Feel this was a quite fascinating experience. Completely down by six hours. Would go a bit slowly because of slight hints of neurological sensitivity Q the instant chilling and a tendency to dart on going to sleep. The nervous system does not feel over-exposed, but all of a sudden there will be a millisecond of auditory hallucination, or an out-of-the-blue startle. So take it easy going up. [Some 24 hours after this experiment had been completed, and a normal baseline re-established, a complex and psycho-logically disruptive syndrome occurred, that lasted for the better part of a week. The temporal juxtaposition between the use of desoxy and the subsequent "spiritual crisis" initially suggested some possible connection, but in retrospect the events seem to be unrelated]. (with 40 mg) I have offered to be a control on an experiment where there had been a close relationship between a trial with desoxy and what might have been a psychotic break, or some kind of so-called spiritual emergency. These two events lay within a day of one another. I was aware of my 40 milligram dosage at about three-quarters of an hour into the experiment, and felt that there was no more in-tensification at the two-hour point. At that time I felt distinctly spaced but with a very good feeling, and I could see no reason not to increase the dosage at some future time. There was a good and mellow mood, and enjoyment in escapist reading. The only physical oddity that I noted was that there had been no urge to urinate, and only a small amount of quite concentrated urine was passed rather late in the experiment. I was at baseline at the fifth hour, and there was nothing unusual at any time during the following week. (with 100 mg) The stuff has a sweet taste! There was a slight heart-push in the early awareness period, with a pulse up to 100 and a feeling of pressure in the chest. There were no apparent visual enhancements, but the eyes-closed imagery to music was noteworthy. Thinking skills and conversation seemed to be fully under control, if not enhanced. There was none of the colorful psychedelic world of mescaline, but this might be just around the corner; perhaps with a larger dose. This is a comfortable in-between level. Sleep was not possible at the sixth hour, but two hours later, it was easy and very restful. There was no negative price to pay the next day. EXTENSIONS AND COMMENTARY: All substituents that are involved with the several drugs being discussed in this writing are really things that are stuck like warts on the benzene ring that is central to every phenethylamine. Some of these warts are things attached with a oxygen atom; there are some of these in every single compound in this story. No oxygen atom, no psychedelic effect. Without them, one has stimulants or, more frequently, no effects at all. But the removal of an oxygen atom (in those cases where there is more than one) can radically change the nature of the effects seen. This is the exact meaning of the term "desoxy." "Des", without, and "oxy", the oxygen. Since this drug is simply the structure of mescaline with the oxygen at the 4-position plucked out of the picture, the first impulse was to abbreviate this compound as DOM for des-oxymescaline. However, a long, long time ago, in a universe far, far away, a compound was synthesized that had a methoxy group replaced by a methyl, and it was already named DOM. This was the first of the STP analogs, and the initials stood for desoxy (DO, losing an oxygen) and methyl (M, having it replaced with a methyl group). These are two different worlds. One M stands for Mescaline, and the other M stands for Methyl. Let's call it 4-desoxymescaline, or simply DESOXY, and be exact. This drug is a prime example of a pharmacological challenge directed to the metabolic attack at the 4-position as a mechanism for the expression of biological activity. A methoxy group there would allow easy removal of the methyl group from the oxygen by some demethylation process, but a bare methyl group there cannot be removed by any simple process. It must be removed by a very difficult oxidation. This is not the first time that oxygen atoms have been removed from the mescaline molecule. Both the 3,5-dideoxymescaline (3,5-dimethyl-4-methoxyphenethylamine) and 3,4,5-trideoxymescaline (also called desoxymescaline in the literature, but really tri-desoxymescaline or 3,4,5-trimethylphenethylamine) have been studied in the cat, and have shown extraordinary pharmacological profiles of CNS action. The trimethyl compound showed behavior that was interpreted as being intense mental turmoil, accompanied by a startling rise in body temperature. The significance is hard to determine, in that LSD gave similar responses in the cat, but mescaline was without effects at all. No human studies have been made on these compounds, just animal studies. But they might prove upon trial in man to be most revealing. They would have to be performed with exceptional care. The 3-carbon chain amphetamines that correspond to these mescaline look-alikes with one or more methoxy groups replaced with methyl groups, are largely untested and would require independent and novel syntheses. The 3,4,5-trimethylamphetamine is known, and is known to be very hard on experimental cats. A mescaline analogue with a bromo atom in place of the 4-methoxyl group is an analogue of mescaline in exactly the same way that DOB (a very potent am-phetamine) is an analog of TMA-2 (the original trisubstituted amphetamine). This analogue, 3,5-dimethoxy-4-bromoamphetamine, has been found to be a most effective serotonin agonist, and it is a possibility that it could be a most potent phenethylamine. But, as of the present time, it has never been assayed in man. #53 2,4-DMA; 2,4-DIMETHOXYAMPHETAMINE SYNTHESIS: To a solution of 10 g 2,4-dimethoxybenzaldehyde in 50 mL nitroethane there was added 0.5 g anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h. The excess solvent/reagent was removed under vacuum, and the residue oil dissolved in 25 mL boiling MeOH. On cooling, this deposited yellow crystals of 1-(2,4-dimethoxyphenyl)-2-nitropropene that, after filtering, MeOH washing, and air drying, weighed 10.2 g and had a mp of 78-79 deg C. A magnetically stirred suspension of 6.0 g LAH in 300 mL anhydrous Et2O was brought up to a gentle reflux under a He atmosphere. A total of 8.5 g 1-(2,4-dimethoxyphenyl)-2-nitropropene was introduced into the reaction mixture by allowing the condensed Et2O to leach it from a modified Soxhlet condenser. After the addition was complete, the reaction was held at reflux for an additional 24 h. After cooling with an external ice bath, the excess hydride was destroyed by the cautious addition of H2O. When the exothermic reaction had subsided, there was added 500 mL H2O, 150 g potassium sodium tartrate, and sufficient base to bring the pH above 9. The phases were separated, the organic phase dried over anhydrous MgSO4, the drying agent removed by filtration, and the clear filtrate then saturated with anhydrous HCl gas to produce white crystals of 2,4-dimethoxyamphetamine hydrochloride (2,4-DMA) with a mp of 146-147 deg C. DOSAGE: greater than 60 mg. DURATION: short. QUALITATIVE COMMENTS: (with 60 mg) This is definitely threshold, or even a bit more. There is a lot of amphetamine-like component, and a certain blush of euphoria. There is also a diffusion of association, so it's more than just amphetamine, no question about it. At the three-hour point, it is definitely quieting down. EXTENSIONS AND COMMENTARY: What can one say as to the active dosage of 2,4-DMA? Nothing. What can one say as to the duration? Probably short. The 60 milligram report given above is the highest level that I personally know of having been tried in man, and there is no hint as to what might be found at a fully active dose, or just where that dose might be. It might be fully speedy. It might be fully psychedelic. It might give a cardiovascular push that would be scary. Studies of 2,4-DMA on vascular strips (associated with serotonin action) were not impressive in comparison with structurally related psychedelics, and it seems as if its action might involve norepinephrine release. It is a reasonable guess that there would be cardio-vascular activity at higher levels. But it will only be with human trials, someday, that the answer will be known for sure. The meta-orientation of the two methoxyl groups does, however, greatly increase the susceptibility of the aromatic ring to electrophilic attack. This is one of the three possible meta-dimethoxy substituted amphetamines, and it is the best studied one in the pursuit of potential radio-halogen substituted brain blood-flow agents. This strategy is discussed under IDNNA; the other two meta-compounds are discussed under 3,4-DMA. The homologues of 2,4-DMA that were iodinated (or occasionally fluor-inated) were mono- or di-alkylated on the nitrogen, and the precursor that was common to all was the corresponding acetone. The above nitrostyrene, 1-(2,4-dimethoxyphenyl)-2-nitropropene, was reduced in acetic acid with elemental iron, and the base-washed extracts stripped of solvent and distilled (125-145 deg C at 0.5 mm/Hg) to give 2,4-dimethoxyphenylacetone as a water-white oil. The principal reductive amination product of this, the one that was most thoroughly explored with various halogenation schemes, was obtained by the reaction of 2,4-dimethoxyphenylacetone with dimethylamine and sodium cyanoborohydride. This product, 2,4-dimethoxy-N,N-dimethylamphetamine or 2,4-DNNA, distilled at 105-115 deg C at 0.4 mm/Hg and formed a perchlorate salt that melted at 98-98.5 deg C. This could be iodinated with the radio-iodide anion, when oxidized with chloramine-T in buffered sulfuric acid, to give the iodinated analogue (2,4-dimethoxy-N,N-dimethyl-5-iodoamphetamine) in an excellent yield. Radio-fluorination with acetyl hypofluorite gave the 5-fluoroanalogue (2,4-dimethoxy-N,N-dimethyl-5-fluoroamphetamine) in an acceptable yield. Both compounds went into a rat's brain to a pretty good extent, but both of them washed out too rapidly to be clinically interesting. A large family of other N-substituted homologues of 2,4-DMA were similarly prepared from the above ketone and sodium cyanoborohydride. Methylamine, ethylamine, propylamine, isopropylamine and hexylamine gave the corresponding N-alkyl homologues. The N,N-diethyl homologue was made from the primary amine, 2,4-DMA itself, with acetaldehyde and sodium cyanoborohydride but the product, N,N-diethyl-2,4-dimethoxyamphetamine, could not be converted into a crystalline hydrochloride salt. Yet another variation on these structures was launched, again with the design of making radio-iodination targets which are not psychedelic and thus might be useful clinically. In this variation, the nitrogen atom substitution pattern was held constant, with two methyl groups, as were the ring locations of the two oxygen atoms. But the identities of the alkyl groups on these oxygen atoms were varied. The synthetic procedure followed was to make the appropriate 2,4-dialkoxybenzaldehyde, convert it to the nitrostyrene with nitroethane, reduce this to the phenylacetone with elemental iron, and then reductively aminate this ketone with dimethylamine. Following this reaction scheme, five amphetamine homologues of 2,4-DMA were made, three with the 4-methoxy group maintained but the 2-position extended, and two with both groups extended symmetrically. These are: (1) N,N-dimethyl-2-ethoxy-4-methoxyamphetamine; (2) 2-(n)-butyloxy-N,N-dimethyl-4-methoxy-amphetamine; (3) 2-(n)-decyloxy-N,N-dimethylamphetamine; (4) 2,4-diethoxy-N,N-dimethylamphetamine; and (5) N,N-dimethyl-2,4-di-(i)-propoxyamphetamine. I believe that most of these have been iodinated and assayed in rats, and several of them appear quite promising. But none of them have been assayed in man, yet. The bromination product of 2,4-DMA (5-bromo-2,4-dimethoxyamphetamine, 5-Br-2,4-DMA) is way down in activity (see its recipe, separately). Since all iodo analogues are of about the same potency as the bromo counterparts, and since the addition of two methyl groups on the nitrogen does not appear to enhance central activity, I feel the iodination products of these N,N-dialkyl-dialkoxyamphetamines would not have any interesting psychopharmacology. There is something vaguely counterproductive, in my evaluation of things, when the goal of a research project is to avoid activity rather than to create it. Although this chemistry was completely fascinating and could have produced the world's best positron-emitting, brain-scanning diagnostic compound, I feel it quite unlikely that it would have produced the world's best insight-revealing, empathy-enhancing psychedelic, so this research direction never totally caught my fancy. I went on to other things. #54 2,5-DMA; DMA; 2,5-DIMETHOXYAMPHETAMINE SYNTHESIS: A solution of 10.0 g 2,5-dimethoxybenzaldehyde in 50 mL glacial acetic acid was treated with 6.8 g of nitroethane and 4.0 g of anhydrous ammonium acetate. This mixture was heated on the steam bath for 3 h and then the reagent/solvent was removed under vacuum. The residue was suspended in H2O and extracted with CHCl3. Removal of the solvent from the pooled extracts yielded 11.2 g of an impure 1-(2,5-dimethoxyphenyl)-2-nitropropene which, on recrystallization from 75 mL boiling MeOH, gave 6.7 g of product with a mp of 73-75 deg C. Anal. (C11H13NO4) C,H,N. This nitrostyrene has been periodically available commercially from a number of sources. A solution of 17.0 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene was prepared in 500 mL anhydrous Et2O. This solution was added slowly to a well-stirred suspension of 12.0 g LAH in 700 mL anhydrous Et2O. The mixture was then brought up to a reflux and maintained there for 20 h, cooled with an external ice bath, and the excess hydride destroyed by the cautious addition of H2O. Finally, a total of 500 mL H2O was added, followed by the addition of 300 g potassium sodium tartrate, and sufficient aqueous NaOH to bring the pH above 9. The two phases were separated, and the ether phase dried by the addition of anhydrous MgSO4. The drying agent was removed by filtration, and the clear filtrate saturated with a stream of anhydrous HCl gas. The formed crystals of 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) were removed by filtration, washed with anhydrous Et2O, and dried to constant weight of 16.3 g. Recrystallization from EtOH gave an analytical sample with a mp of 114-116 deg C. The hydrobromide salt is reported to melt at 129-131 deg C. DOSAGE: 80 - 160 mg. DURATION: 6 - 8 h. EXTENSIONS AND COMMENTARY: The qualitative information on 2,5-DMA is very sparse. I was up to a 1+ with 80 milligrams of the hydrochloride, and since it appeared to be totally a physical trip with tremors and some cardiovascular push and nothing of a sensory nature, I chose to explore it no further. A report from South America found the intoxication to be largely pleasant (this, at 75 milligrams), with an enhanced interest in one's surroundings, but no perceptual changes, no overt stimulation, and no gross physiological effects other than a slight mydriasis (dilation of the pupils). I have also been told of a single trial of 250 milligrams of the tartrate (this is equivalent to somewhere in the 150-200 milligram range of the hydrochloride salt, depending upon the acid/base ratio of the tartrate salt) with some "speedy" effects but still no sensory changes. A seizure of capsules reported by the drug law enforcement authorities some 20 years ago found that each contained some 200 milligrams of the hydrobromide salt. This is equivalent to 170 milligrams of the hydrochloride salt, and suggests that level may be an effective dosage. An intriguing, but little studied, analogue of 2,5-DMA is the compound with methyls in place of the methoxyls. 2,5-Dimethylamphetamine has been looked at, in man, as a potential anorexic, but there is little effect even at 150 milligrams. The 3,4-isomer, 3,4-dimethylamphetamine or xylopropamine, is an adrenergic agent and it has been found to be an analgesic in man at as little as 10 milligrams. This was assayed, rather remarkably, by attaching electrodes to the tooth fillings of the experimental subjects. But with this base, cardiovascular effects were not observed until doses of about 100 milligrams were administered, and toxic effects (nausea and vomiting) were reported at 150 milligrams. There was no suggestion of anything psychedelic. All three isomers of monomethylamphetamine have also been looked at in man. The ortho- and meta-isomers, 2-methyl- (and 3-methyl- ) amphetamine are weak anorexics. At doses of up to 150 milligrams orally, there were signs of stimulation noted Q talkativeness and loss of appetite. The para-isomer, 4-methyl-amphetamine or Aptrol, is more potent. At 75 milligrams (orally, in man) there is clear adrenergic stimulation, and at twice this dosage there are signs of mild toxicity such as salivation, coughing and vomiting. There is a mystery, at least to me, concerning the commercial production of 2,5-DMA. At regular intervals, there is a public announcement of the production quotas that are requested or allowed by the Drug Enforcement Administration, for drugs that have been placed in Schedules I or II. In the Schedule I category there are usually listed amounts such as a gram of this, and a few grams of that. These are probably for analytical purposes, since there are no medical uses, by definition, for drugs in this Schedule. But there is a staggering quantity of 2,5-DMA requested, regularly. Quantities in the many tens of millions of grams, quantities that vie with medical mainstays such as codeine and morphine. I have heard that this material is used in the photographic industry, but I have no facts. Somewhere I am sure that there is someone who has to keep a lot of very careful books! In the area of psychedelic drugs, the value of 2,5-DMA is mainly in its role as a precursor to the preparation of materials that can come from a direct electrophilic attack on the activated 4-position. These uses can be found under things such as DOB and DOI and DON. The radio-halogenation of N-substituted homologues of 2,5-DMA with hypoiodite or hypofluorite is part of an extensive study underway in the search for radio-labeled brain blood flow agents. The rationale for this work is to be found in the commentary under IDNNA. In essence it has been found that the N-substitution or N,N-disubstitution of 2,5-DMA where the 4-position is unsubstituted and thus available for the introduction of a radioactive nucleus can give rise to potentially useful drugs. Most of these 2,5-dimethoxy exploratory compounds were made by the reductive alkylation of 2,5-dimethoxy-4-(radio)iodophenylacetone, using various mono or dialkyl amines. This, too, is described under IDNNA. However, the study of various direct iodinations and fluoridations that would have the N,N-dimethyl substitution on the amphetamine nitrogen atom, would require the 4-proteo- analogue, and this was made from the above nitrostyrene. A solution of the above nitrostyrene, 22.3 g 1-(2,5-dimethoxyphenyl)-2-nitropropene in 100 mL acetic acid was added to a suspension of elemental iron in acetic acid (45 g in 250 mL) and worked up with water and base washing to give, after distillation at 92-106 deg C at 0.35 mm/Hg, 13.8 g 2,5-dimethoxyphenylacetone as a pale yellow oil. This underwent reductive amination with dimethylamine hydrochloride in MeOH solution, using sodium cyanoborohydride, to give the target compound 2,5-dimethoxy-N,N-dimethylamphetamine oxalate with a melting point of 133-134 deg C (4.6 g ketone gave 1.38 g of salt). Anal. (C15H23NO6) C,H. It has also been prepared by the N,N-dimethylation of 2,5-DMA directly, with formaldehyde and formic acid. This has been called 2,5-DNNA, or IDNNA without the "I." This intermediate, 2,5-DNNA, underwent direct radioiodination with labeled iodine monochloride in the presence of perchloric acid to give IDNNA with a 40% incorporation of isotope. Reaction with labeled acetyl hypofluorite, on the other hand, gave only a 2% in-corporation of the radio-isotope. This latter compound is, chemically, 4-fluoro-2,5-dimethoxy-N,N-dimethylamphetamine and, using the reasoning suggested above and with IDNNA, might best be encoded FDNNA. The 2,5-dimethylamphetamine analogue mentioned above was also explored in this IDNNA concept. The commercially available 2,5-dimethylbenzaldehyde was converted to the nitrostyrene with nitroethane (1-(2,5-dimethylphenyl)-2-nitropropene, yellow crystals with a melting point of 24.5-25.5 deg C) which reacted with elemental iron in acetic acid to give the ketone 2,5-dimethylphenylacetone (boiling at 140-150 deg C at 0.4 mm/Hg). Reductive amination with dimethylamine and sodium cyanoborohydride gave 2,5-DMNNA (2,5,N,N-tetramethylamphetamine) as a clear oil with a boiling point of 115-125 deg C at 0.35 mm/Hg. It gave poor yields of the 4-fluoro analogue with acetyl hypofluorite. All of these latter materials remain unevaluated in man. #55 3,4-DMA; 3,4-DIMETHOXYAMPHETAMINE SYNTHESIS: A solution of 33.2 g of veratraldehyde in 15.0 g nitroethane was treated with 0.9 g of n-amylamine and placed in a dark place at room temperature. In a day or so, separated H2O was apparent and, after a couple of weeks, the mixture completely solidified. The addition of 50 mL EtOH and heating effected complete solution and, on cooling, this provided 1-(3,4-dimethoxyphenyl)-2-nitropropene as yellow crystals, 29.0 g, with mp of 70-71 deg C. The more conventional reaction scheme, 6 h heating of a solution of the aldehyde and nitroethane in acetic acid with ammonium acetate as catalyst, gave a much inferior yield of product (33.2 g gave 14.8 g) of the same purity. Recrystallization from MeOH increased the mp to 72-73 deg C. To a refluxing suspension of 7 g LAH in 600 mL anhydrous Et2O, stirred and under an inert atmosphere, there was added 7.5 g 1-(3,4-dimethoxyphenyl)-2-nitropropene by allowing the returning condensed ether to leach out the material as a warm solution from a Soxhlet thimble. Following the completion of the addition of the nitrostyrene, refluxing was maintained for 24 h, and the reaction mixture allowed to stand several days at room temperature. The excess hydride was destroyed by the cautious addition of 500 mL H2O containing 40 g H2SO4, and the phases were separated. The aqueous phase was washed with both Et2O and CH2Cl2. There was then added 200 g potassium sodium tartrate, and the pH brought above 9 by the addition of aqueous NaOH. This clear solution was extracted with 3x150 mL CH2Cl2, the extracts were pooled, and the solvent removed under vacuum to give a residual oil. This was dissolved in Et2O, saturated with anhydrous HCl gas, and the resulting solids removed by filtration. Recrystallization from 10 mL acetone gave 1.35 g 3,4-dimethoxyamphetamine hydrochloride (3,4-DMA) as beautiful white crystals with a mp of 144-145 deg C. DOSAGE: a few hundred milligrams. DURATION: unknown. QUALITATIVE COMMENTS: (with 70 mg i.v.) [One patient received 0.004 mM/Kg of the hydrochloride salt intravenously and exhibited only slight increase in psychiatric symptoms; a comparable dosage in a second individual also elicited only insignificant changes.] (with 700 mg i.v.) [When one of these patients was reinjected at a later date with approximately 0.04 mM/Kg of 3,4-DMA a definite `mescaline-like' state was induced. The symptoms included colored hallucinations of geometric figures and occasional structured forms. The other individual experienced visual distortions, notable after-imagery, feelings of unreality, and paranoid ideas. Marked mydriasis and gross body tremors also occurred but apparently no hallucinations were experienced.] EXTENSIONS AND COMMENTARY: These "Qualitative Comments" are not explicit quotations from people who had taken 3,4-DMA. They are written descriptions by the observers who had given 3,4-DMA to psychiatric patients. This is one of the most outrageous chapters in the books on military medicine. The chemical warfare group within the U.S. Army explored many potential psychedelics by administering them to innocent patients with not even a thought of obtaining informed consent. These experiments took place at the New York State Psychiatric Institute (amongst other places) in the early 1960's. The Edgewood Arsenal code name for 3,4-DMA was EA-1316. A few non-military studies have indicated that 3,4-DMA is orally active at 160 milligrams, and so probably its potency by this more conventional route would fall midway between that of mescaline and of MDA. The 3-methoxy-4-other-than-methoxy things (such as hydroxy, ethoxy, allyloxy and methyl) are mentioned in the recipe for MEPEA. The alpha-ethyl homologue of 3,4-DMA, 2-amino-1-(3,4-dimethoxyphenyl)butane, and of other DMA's are discussed under the recipe for ARIADNE. There are a total of six possible amphetamine molecules with two methoxyl groups attached. The 3,4-orientation has always been the most appealing to the life scientists as this is the positional substitution pattern found in the natural neuro-chemicals dopamine, norepinephrine and epinephrine. These latter two are called noradrenalin and adrenalin in England. Two adjacent hydroxy groups represent the catechol in the well known word catecholamines. You might read in a textbook, "This is where nature placed the groups when she put the compounds in our brains. So that is where the groups might be the most interesting in a psychedelic." Why? I have never understood this kind of reasoning. If a possible psychedelic has just the exact oxygen positioning of a neurotransmitter, then, voila, that's why it is active. And if a possible psychedelic has some positioning of these oxygen atoms that is different than that of a neurotransmitter? Then voila again. That's why it is active. Both sound equally reasonable to me, and neither one even begins to address the fundamental question, how do the psychedelic drugs do what they do? A study in the human animal of the intimate effects of one of these neurotransmitter analogues might bring us a little bit closer to answering this fundamental question. But maybe it wouldn't, after all. Nothing has made much sense so far! Anyway, 3,4-DMA is one of the ten essential amphetamines that can, in theory, arise from the ten essential oils of the spice and herb trade. In this case, the origins are methyl eugenol and methyl isoeugenol. Two of these "different" isomers, 2,4-DMA and 2,5-DMA, have already been discussed in their own separate recipes. And the remaining three of the six possible DMA's that are "different" have been made and studied pharmacologically in animals but not in man. These are the 2,3-DMA, 2,6-DMA and the 3,5-DMA isomers. The products of their reaction with elemental bromine are discussed under META-DOB. Both the 2,6- and the 3,5-isomers, as the N,N-dimethyl homologues, have been looked at as potential radio-halogen recipients in the search for positron-emitting brain blood-flow indicators, as discussed in the recipe for IDNNA. Both were made from the appropriate nitrostyrene via the corresponding phenylacetone. The 2,6-isomer was derived from 2,6-dimethoxybenzaldehyde. This, in nitroethane and ammonium acetate, gave the nitrostyrene as canary-yellow crystals from MeOH that melted at 101.5-102.5 deg C. Elemental iron in acetic acid converted this nitrostyrene to 2,6-dimethoxyphenylacetone (a water-white oil with boiling point of 95-105 deg C at 0.4 mm/Hg. Anal. (C11H14O3) C,H) and reductive amination with dimethylamine and sodium cyanoborohydride gave 2,6-dimethoxy-N,N-di-methylamphetamine perchlorate (2,6-DNNA) with a melting point of 109-110 deg C. This base was readily fluorinated with 18F acetylhypofluorite and iodinated with chloramine-T-oxidized 122I iodide ion. It was also halogenated with (non-radioactive) bromine and iodine monochloride to give the corresponding 3-bromo-(and 3-iodo)-2,6-dimethoxy-N,N-dimethylamphetamines but these, in turn, did not react with radioactive acetyl hypofluorite. The 3,5-isomer followed precisely the same flow sheet. 3,5-Dimethoxybenzaldehyde gave the nitrostyrene (with a melting point of 87-88 deg C), the phenylacetone (with a boiling point of 110-130 deg C at 0.3 mm/Hg) and the product 3,5-dimethoxy-N,N-dimethylamphetamine perchlorate (3,5-DNNA) with a melting point of 100-101 deg C. This also reacted readily with 18F acetylhypofluorite and 122I-hypoiodite. Several alpha-ethyl homologues of these compounds have also been discussed in the recipe for ARIADNE. #56 DMCPA; 2-(2,5-DIMETHOXY-4-METHYLPHENYL)CYCLOPROPYLAMINE SYNTHESIS: To a solution of 25 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for the preparation) and 29.2 g malonic acid in 50 mL anhydrous pyridine, there was added 2 mL piperidine and this was heated on the steam bath for several h. The mixture was added to a solution of 125 mL concentrated HCl in 500 mL H2O at 0 deg C, and the solid product that was formed was removed by filtration, and washed with H2O. Recrystallization from aqueous EtOH yielded 31 g 2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 deg C. Anal. (C12H14O4) C,H. In a cooled high-pressure reaction vessel there was placed a suspension of 30 g 2,5-dimethoxy-4-methylcinnamic acid in 150 mL liquid isobutene. This was treated dropwise with 0.6 mL concentrated H2SO4, then sealed and brought to room temperature. After 48 h shaking, the vessel was cooled again to -10 deg C, opened, and poured into 200 mL of 10% Na2CO3. This was extracted with hexane, the pooled extracts washed with H2O, and the solvent removed to yield 17.0 g of (t)-butyl 2,5-dimethoxy-4-methylcinnamate as an amber oil. Anal. (C16H22O4) C,H. The cyclopropane ester was prepared by the reaction between 16 g (t)-butyl 2,5-dimethoxy-4-methylcinnamate and dimethylsulfoxonium methylide, prepared as described in the Kaiser reference in the acknowledgements. Hydrolysis of this ester gave 53% trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid which, after recrystallization from a MeOH/H2O mixture, had a mp of 136 deg C. Anal. (C13H16O4) C,H. A suspension of 4 g of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid in an equal volume of H2O, was treated with sufficient acetone to effect complete solution. This was cooled to 0 deg C and there was added, first, 2.0 g triethylamine in 35 mL acetone, followed by the slow addition of 2.5 g ethyl chloroformate in 10 mL acetone. This was stirred for 0.5 h, and then there was added a solution of 1.7 g NaN3 in 6 mL H2O, dropwise. After 1 h stirring at 0 deg C, the mixture was quenched by pouring into H2O at 0 deg C. The separated oil was extracted with Et2O, and extracts dried with anhydrous MgSO4. Removal of the solvent under vacuum gave a residue of the azide, which was dissolved in 10 mL anhydrous toluene. This solution was heated on the steam bath until the nitrogen evolution was complete, and the removal of the solvent under vacuum gave a residue of crude isocyanate as an amber oil. This intermediate isocyanate was dissolved in 5.4 g benzyl alcohol and the reaction mixture was heated on the steam bath for 6 h. The excess benzyl alcohol was removed by distillation, yielding trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane as a crystalline residue. This was recrystallized from an EtOAc/hexane mixture to give 6.13 g of a crystalline product with a mp of 107-108 deg C. Anal. (C20H23NO4) C,H,N. A solution of 1.5 g trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane in 120 mL MeOH containing 200 mg 10% Pd/C was shaken under hydrogen gas at 35 psig for 45 min. The solution was filtered through celite, and a sufficient amount of a solution of 5% HCl in EtOH was added to the filtrate to make it acidic. Removal of all volatiles under vacuum gave a solid residue that was recrystallized from an EtOH/ether mixture to give 0.98 g of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine hydrochloride (DMCPA) as white crystals with a mp of 210-211 deg C. DOSAGE: 15 - 20 mg. DURATION: 4 - 8 h. QUALITATIVE COMMENTS: (with 10 mg) The effects were quite real at an hour, but very hard to define. Nothing left at four hours, but my sleep was filled with bizarre and colorful dreams. Something was still working somewhere, at some level. (with 20 mg) I found myself lightheaded, and the thinness seemed to be, rather remarkably, on the left side of my brain. The experience was flighty. I was reminded of the aura that has been described preceding a convulsion. I was decoupled from my experience and from my environment. Not all of the control is there, and I am uncomfortable. But in an hour, there is complete control again, and I can relax my conscious guard which allows an easy plus three. With this, there was easy fantasy, erotic, quite a bit of movement in the visual field, and mild anorexia. The residual hyperreflexive thinness is largely gone, and not at all worrisome. This stuff is complicated, with a little too much of the physical. The next day was without any residues at all. EXTENSIONS AND COMMENTARY: Most of the human trials took place in the fifteen to twenty milligram range. Several reports describe some muscular tremor, especially in the earliest part of the experience, but this never seemed to be a concern. The efforts to lock imagery to music were not too successful. All of these clinical studies were conducted on the trans-compound, but on the racemic mixture. This has been resolved into the two optical isomers, but they have not been compared in man. The cis-mixture is unknown. This material is intimately related to tranylcypromine, a clinically proven antidepressant. This drug is a known monoamine oxidase inhibitor, and it is certainly possible that some of this pharmacological property might be found in DMCPA if it were to be looked for. The hints of physical toxicity at the higher doses assayed might suggest some such activity. This compound, DMCPA, was modeled directly after the structure of DOM, with the 2,5-dimethoxy-4-methyl substitution pattern. Another analogue of tranylcypromine, similarly modeled, is 3,4,5-trimethoxytranylcypromine, or trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT). It has been evaluated at levels of only 13 milligrams orally, and at this dose there were no hints of central activity. #57 DME; 3,4-DIMETHOXY-beta-HYDROXYPHENETHYLAMINE SYNTHESIS: To a solution of 10.2 g 3,4-dimethoxybenzaldehyde in 10 mL EtOH, cooled to 0 deg C, there was added a solution of 4.2 g KCN in 40 mL H2O. With good stirring, there was slowly added 10 mL concentrated HCl (caution: HCN is evolved) and the two-phase reaction mixture was allowed to continue stirring until there was the spontaneous formation of crystals. After a few days standing, these were removed by filtration and well washed with H2O. All was recrystallized from 75 mL of 50% MeOH and air dried to provide 6.95 g of the cyanohydrin 3,4-dimethoxy-a-hydroxyphenylacetonitrile. The mp was 104-106 deg C, which can be increased to 109 deg C by recrystallization from benzene. A well-stirred suspension of 4.7 g LAH in 500 mL anhydrous Et2O was brought up to a gentle reflux, and 4.7 g 3,4-dimethoxy-a-hydroxyphenylacetonitrile was leached in from a Soxhlet thimble, over the course of 3 h. The color of the ether solution progressed from yellow to green, to an eventual blue. The reflux was maintained for 16 h. After cooling again, there was added (carefully) a solution of 27 g H2SO4 in 500 mL H2O. The completely clear two-phase mixture was separated, and the aqueous phase treated with 87 g potassium sodium tartrate. The addition of 25% NaOH brought the pH >9, and this phase was extracted with 4x100 mL CH2Cl2. Removal of all the organic solvents under vacuum gave a residue that was part oil and part solid. This was extracted with 4x50 mL boiling Et2O, the extracts pooled, and saturated with anhydrous HCl gas. The 0.95 g of pale-yellow crystals that formed were removed by filtration, and finely ground under 5 mL CH3CN. There remained, after refiltration and air drying, 0.85 g of 3,4-dimethoxy-beta-hydroxyphenethylamine hydrochloride, DME, with a mp of 170-172 deg C. DOSAGE: greater than 115 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 115 mg) I was faintly nauseous about an hour after taking the compound, and perhaps I was more alert than usual in the evening. Substantially no effects. EXTENSIONS AND COMMENTARY: The rationale for exploring the beta-hydroxylated phenethylamines, especially those with oxygens at the biologically important 3- and 4-positions, has already been presented. Norepinephrine is a beta-hydroxylated phenethylamine with oxygens at these two ring positions. With DME, these are masked as two methyl ethers, and the initials DME stand for 3,4-dimethoxyphenyl-beta-ethanolamine. This is an alternate name for 3,4-dimethoxy-beta-hydroxyphenethylamine. An exactly analogous compound is 3,4-methylenedioxy-beta-ethanolamine, where the masking is done with the biologically more fragile methylenedioxy ether. Originally I had called this compound MDE (methylenedioxyethanolamine) but that code has been, since 1975, used exclusively for 3,4-methylenedioxy-N-ethylamphetamine, which is a recipe all by itself. Under the discussion of members of the BOX series, there is a methylenedioxyphenethylamine with a methoxyl group at the beta-position, and it is called BOH (q.v.). There, a reasonable code name for this specific compound is given, namely BOHH. RBOS stands for the beta-oxygen function on a phenethylamine; this is the heart of the BOX family. The RHS which is the third letter of BOHH stands for the free hydroxyl group. And the final RHS is for homopiperonylamine (which is the trivial name for the compound without the hydroxyl group). BOHH, or 3,4-methylenedioxy-beta-hydroxyphenethylamine, or 3,4-methylenedioxy-beta-ethanolamine, has also be assayed in man at up to 100 milligrams without any effects, and must be considered, as of now, to be inactive centrally. The possible toxic roles of beta-ethanolamines as potential adrenolytic agents, have been discussed in the BOHD recipe. And beware of the use of the code name MDE in the very old literature. It might be this BOHH compound. #58 DMMDA; 2,5-DIMETHOXY-3,4-METHYLENEDIOXYAMPHETAMINE SYNTHESIS: Apiole, as the crystalline essential oil 1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene, is isolated directly from commercial Oil of Parsley, by careful fractional distillation. It is the fraction that boils at 165-167 deg C at 27 mm/Hg. A solution of 19.8 g apiole in a mixture of 43 g KOH and 60 mL hot EtOH was heated in the steam bath for 24 h. With vigorous stirring, it was diluted with H2O, at a rate which the crystals that formed spontaneously could accumulate from the turbidity that was generated. When no more H2O could be added (there was persistent oiling out of material) the reaction mixture was filtered to give 12.1 g of an amber solid material. This was recrystallized from 20 mL boiling hexane, which was filtered while hot to remove insolubles. From the cooled filtrate, there was obtained 9.3 g of 2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene, isoapiole, as pale cream-colored solids. A stirred solution of 8.8 g 2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene and 3.9 g pyridine in 45 mL acetone was cooled to ice-bath temperatures, and treated with 7.9 g tetranitromethane. This extremely dark reac-tion was stirred at 0 deg C for 5 min, then quenched with a solution of 2.6 g KOH in 45 mL H2O. With continued stirring, there appeared yellow crystals of 1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene which, after filtering, washing with 50% acetone and air drying, weighed 8.0 g and had a mp of 110-111 deg C. To a well-stirred and gently refluxing suspension of 6.3 g LAH in 500 mL anhydrous Et2O, under an inert atmosphere, there was added 7.5 g 1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by leaching out the nitrostyrene from a thimble in a modified Soxhlet condenser apparatus. The addition took 1.5 h, and the refluxing was maintained for an additional 3 h. After cooling, the excess hydride was destroyed by the cautious addition of 300 mL of 1.5 N H2SO4. The aqueous phase was brought to a pH of 6 with Na2CO3. This was heated to 80 deg C and clarified by filtration though paper. The addition of a stochiometric amount of picric acid in boiling EtOH gave rise to precipitation of the product picrate as globs that did not crystallize. These were washed with cold H2O, then dissolved in 30 mL 5% NaOH. Extraction with 2x75 mL Et2O, and the stripping of the solvent from the pooled extracts, gave 3.1 g of an oily residue which, upon dissolving in 250 mL Et2O and saturation with anhydrous HCl gas, gave white crystals. These were removed by filtration, Et2O-washed, and air dried, to give 2.9 g of 2,5-dimethoxy-3,4-methylenedioxyamphetamine hydrochloride (DMMDA) that melted in the 165-175 deg C range. DOSAGE: 30 - 75 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 25 mg) The intoxication was there at an hour and a quarter, and I was hit with nausea with no particular warning. I am shaky, a little dilated in the eyes, and there is a modest depersonalization (reminding me of LSD). Time might be slightly slowed, and there is a mild ataxia in the legs. A couple of hours later, all effects are going away fast. I ate an apple, but maybe my mouth didn't work quite right. The apple was incredibly noisy. (with 32 mg) I am up to a 2 1/2 plus at something after two hours, with no apparent visuals, no push, no erotic. And a few hours later it is quietly slipping away. It felt completely safe, and without any conspicuous psychedelic action, at least at this level. (with 50 mg) I took graded doses of 10 milligrams every thirty minutes for a total of 50 milligrams, and there were no effects at all. (with 50 mg) In the middle of this all, I found myself getting into abstract thinking, and maybe some imagery as well. The effects were disappointingly light. (with 75 mg) This was equal to somewhere between 75 and 100 micrograms of LSD. I was caught up with the imagery, and there was an overriding religious aspect to the day. The experience had an esthetic value. I liked it. EXTENSIONS AND COMMENTARY: DMMDA was the first of the tetraoxygenated amphetamine derivatives that was ever explored in man, back in 1962. And it is not easy to find an acceptable single phrase to describe its action or an acceptable number to describe its potency. I have put the value of 10 mescaline units (M.U.) into the literature and this would imply that maybe 30 milligrams was an active dose. This is probably too low, and some day I would like to run an experiment with the entire research group with this compound to see just what it really does. The essential oil that corresponds to DMMDA is, of course, apiole from the Oil of Parsley, which again ties together the spice world and the amphetamine world. And there is isoapiole, also a natural thing. This pair represents the ring-substitution pattern of one of the ten essential oils and DMMDA is one of the ten essential amphetamines. Several people have asked me what I thought about the potential activity of a compound with a methyl group added to DMMDA. One of these possibilities would be the N-methylated derivative, 2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine, or METHYL-DMMDA (or DMMDMA for the dimethoxy-methylenedioxy-methamphetamine nomenclature). It is a MDMA analogue, and is described in the recipe for METHYL-MMDA-2. The placement of an added methyl group onto the beta-position of DMMDA, rather than on the nitrogen atom, produces a pair of stereoisomeric homologues. These are the threo- (or-trans-) and erythro- (or cis)-2,5-dimethoxy-beta-methyl-3,4-methylenedioxyamphetamines. They have never been assigned trivial names (my original codes for them were S-1495 and S-1496 which is not too intuitively informative). Their chemically proper names would have the 2-amino-3-substituted phenylbutane form. The synthesis of these DMMDA homologues started with the reduction of the nitrosyrene to the ketone (see under METHYL-MMDA-2 for this preparation), followed by methylation with fresh sodium isopropoxide and methyl iodide, to give the beta-methyl product. This formed the two possible oximes, one with a mp of 120 deg C, and the other from MeOH with a mp of 146 deg C. The 120 deg C oxime, with fresh sodium ethoxide gave threo-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane hydrochloride. This salt had a mp of 247-249 deg C. The 146 deg C oxime gave erythro-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane hydrochloride with a mp of 188-189 deg C. The threo-isomer showed a possible threshold effect at 80 milligrams, with hyperventilation and perhaps some mental muddiness. The erythro-isomer showed no effects, but it had been taken up only to 10 milligrams. The only other beta-methyl homologue of an active material that was explored chemically, was related to MDA. The ketone (3,4-piperonylacetone, see under MDMA) was methylated with sodium isopropoxide and methyl iodide, and a crystalline oxime was obtained. Reduction with Zn dust gave what appeared to be 2-amino-3-(3,4-methylenedioxyphenyl)butane hydrochloride, but there were sufficient uncertainties (possible dimethylation, only one oxime isolated, the need of strong reducing conditions) that the entire project was placed in, and still is in, an indefinite holding pattern. The similar analogues for DOM are the two Classic Ladies, DAPHNE and ELVIRA, and they, too, are for some time in the future. #59 DMMDA-2; 2,3-DIMETHOXY-4,5-METHYLENEDIOXYAMPHETAMINE DOSAGE: about 50 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 50 mg) I am into it; it is much like MDA. EXTENSIONS AND COMMENTARY: This is pretty sparse information upon which to build a picture of biological activity. First, the synthesis was done by someone else and, as I have not been able to find where the notes are, this will be the one recipe in the footnote without explicit directions incorporated. The procedure used was exactly the same as that described for DMMDA, except that the starting material was dillapiole rather than apiole. The dillapiole was obtained by the careful fractionation of Oil of Dill (as opposed to the isolation of apiole from the careful fractionation of Oil of Parsley). Isomerization to isodillapiole, nitration with tetra-nitromethane to give 1-(2,3-dimethoxy-4,5-methylenedioxyphenyl)-2-nitropropene, and its reduction with LAH in ether to give 2,3-dimethoxy-4,5-methylenedioxyamphetamine hydrochloride (DMMDA-2) proceeded in a precisely analogous manner to the preparation of DMMDA. And the pharmacological part is rather thin as well. I was not the taster, and can only quote what I had been given. This same observer found a threshold at 28 milligrams. Under other circumstances, this comment on DMMDA-2 would have been tucked into the commentary on DMMDA where it belongs, but the activity level was called for in a large review article, and on the basis of the above, both its initials and the value of 5x the potency of mescaline were permanently enshrined in the published literature. What is it really like? I don't know. Its structure is an appealing amalgamation of that of MMDA and MMDA-2, and it might be quite a winner if the dosage and the duration were known. It is, after all, one of the ten essential amphetamines, since dillapiole is one of the ten essential oils. At the time that DMMDA and DMMDA-2 were synthesized, I had visions of doing the same thorough study with these as I had set up with the TMA's (six possible, six done) and the MMDA's (six possible, five done). Here, too, with a pair of methoxy groups on an amphetamine skeleton, with a methylenedioxy ring thrown in, six isomers are possible but only these two have been prepared. The unknown ones will certainly be called DMMDA-3, -4, -5 and -6, but the assignments of code to structure haven't even been thought out yet. The remarkable and totally unexpected activity of DOM was discovered at about this time and it was a much more tempting direction to follow. The remaining four possible DMMDA's have been left to that famous time, a future Rrainy day. #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-beta-nitrostyrene with a mp of 142-143 deg 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-beta-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, "No 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 deg 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 deg C (mostly 188-192 deg 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 DOBU) 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg C was increased to 145-146 deg 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 deg C. Recrystallization from IPA brought this up to 207-208 deg 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 "R" 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 "R" 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 "R" 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 "S" isomer) There are no effects at all. (with 1.0 mg of the "S" 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 "R" isomer of DOB that is the more active than the racemic mixture, and the "S" 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 deg 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 deg C range (largely at 141-145 deg 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 deg 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 deg C. Recrystallization of an analytical sample from MeOH tightened the mp to 55-56 deg 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 deg 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 deg 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 deg 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 deg C from cyclohexane, nitrostyrene, yellow crystals from methanol, mp 95-96.5 deg C, and lithium aluminum hydride reduction) to give 2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp 168 deg 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 deg 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 deg 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 deg 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 deg 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 `gentle images' and `gentle 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 co