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Book II of PiHKAL: A Chemical Love Story, by Alexander & Ann Shulgin #154: 4-TIM
#154 4-TIM: 4-Thioisomescaline; 2,3-Dimethoxy-4-methylthiophenethylamine

#154 4-TIM SYNTHESIS: The mother liquors from the initial crystallization of the 2-TIM nitrostyrene (see under 2-TIM) was the source and raw material for all 4-TIM chemistry. Once the bulk of the 2-TIM nitrostyrene has been removed, these mother liquors could be processed to give the 4-TIM nitrostyrene. The easier procedure was to evaporate these mother liquors to a residue under vacuum, and hope for a spontaneous crystallization. If this failed, flash chromatography could be used. For reference purposes, the three nitrostyrenes involved in the 2-TIM/4-TIM problem movedon silica gel TLC with CHCl3 solvent in the following manner: 2,3-dimethoxy-4-methylthio-β-nitrostyrene (leading to 4-TIM), Rf = 0.61; 3,4-dimethoxy-2-methylthio-β-nitrostyrene (leading to 2-TIM), Rf = 0.54; and 3,4-dimethoxy-β-nitrostyrene (leading to DMPEA), Rf = 0.47. For flash chromatography, a small portion of the residue from the mother liquor was dissolved in CHCl3, and placed on a silica gel column. CHCl3 was used as the eluding solvent. The first material breaking through from the column was the 4-TIM nitrostyrene and on evaporation of this fraction, seed was obtained as gold-colored crystals that had a mp of 71–73 °C. This, when added to the residues from the described 2-TIM synthesis nitrostyrenes, started the crystallization process. The gummy solid that was produced was triturated under MeOH, and the crystals so revealed were removed by filtration. Recrystallization from 10 mL MeOH gave 1.9 g of solids. A second recrystallization from 5 mL MeOH provided 0.7 g of pumpkin-colored crystals of 2,3-dimethoxy-4-methylthio-β-nitrostyrene with a mp of 70–71 °C.

A solution of 1.2 g LAH in 20 mL anhydrous THF was cooled to 0 °C under He and stirred. There was added, dropwise, 0.8 mL of 100% H2SO4, followed by 0.9 g of 2,3-dimethoxy-4-methylthio-β-nitrostyrene dissolved in 20 mL THF. Stirring was continued for a few min as the reaction returned to room temperature, and then it was heated to a reflux for 5 min on the steam bath. The reaction was cooled again, EtOAc was added to destroy the excess hydride, followed by 25% NaOH added dropwise until a white granular precipitate was obtained. This was removed by filtration, and the filter cake was washed with 2×35 mL Et2O. The filtrate was extracted into 50 mL dilute H2SO4 which was washed with Et2O and, in turn, made basic again and extracted with 2×50 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum to give a residue of crude product. This distilled cleanly from 100–115 °C at 0.3 mm/Hg yielding 0.45 g of a clear white oil. This was dissolved in 6 mL IPA, neutralized with 5 drops of concentrated HCl, and diluted with 25 mL anhydrous Et2O. There was a deposition of white solids which were removed by filtration, washed with Et2O, and air dried. The 2,3-dimethoxy-4-methylthiophenethylamine hydrochloride so obtained (4-TIM) weighed 0.3 g and contained a molecule of H2O of crystallization. The mp was 212–213 °C. Anal. (C11H18ClNO2SaH2O) C,H,N.

DOSAGE: greater than 160 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) “Everything seemed normal. Pulse was under 80, there was nothing with eyes-closed, my appetite was normal. The compound was completely inactive.”

EXTENSIONS AND COMMENTARY: There has been much noise made about the effectiveness of an unusual substitution group at the 4-position of the phenethylamine molecule. Here is a methylthio group at this position, and it is an inactive compound. I was just a little bit surprised.

Page updated 30 March 2012 · This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License ·

About PiHKAL • info

This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Still others remain to be added.

I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore most of the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes page has further details.

Cautionary Note

“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 herein, 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.”

Alexander T. Shulgin

Copyright Notice

The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.

Ordering Information

PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.

Although Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them—and there’s still nothing quite like holding a real book in your hands.

PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.

Transform Press,
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