Reproducibility is the heart of the scientific method, so all good chemists must keep a laboratory notebook. If you don’t record the details of your lab work it might not be possible for other researchers to reproduce it later. While the work of many scientists may languish in the yellowed pages of forgotten journals, there will never be a shortage of chemistry enthusiasts eager to repeat Alexander “Sasha” Shulgin’s syntheses. Starting with his freshman chemistry classes, through his employment at Dow Chemical, and into the years of independent psychedelic experimentation with his research group, Shulgin meticulously documented his syntheses in a series of notebooks that are currently being digitized and made publicly available. Presented here is an assortment of unpublished pages ranging from his first psychedelic synthesis to his later investigations of MDMA derivatives and γ-ray-emitting radiopsychedelics.
This is the earliest page in Shulgin’s collection. It is a photocopy he made at Dow around 1989 while he was collecting his previous research for PiHKAL, his phenethylamine magnum opus. The page illustrates the formation of the nitropropene precursor to TMA, or 3,4,5-trimethoxyamphetamine, which was his first foray into the synthesis of psychedelic amphetamines. TMA is an active compound, but it lacks the beatific serenity of its 2-carbon homologue, mescaline.
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This page details the synthesis of α-ethylmescaline via reduction of the nitrobutene precursor with lithium aluminium hydride. α-ethylmescaline proved to be an inactive mescaline homologue, but α-ethylation of other phenethylamines created promising compounds such as MBDB and ARIADNE, the (R)-enantiomer of which was patented for restoring motivation in senile geriatric patients under the trade name Dimoxamine.
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Formation of 3,4-methylenedioxyphenylacetone from isosafrole with formic acid and hydrogen peroxide. This ketone is an early intermediate in the synthesis of several known entactogens. An infamous misprint in the 3,4-methylenedioxyphenylacetone synthesis from Michael Valentine Smith’s book Psychedelic Chemistry reads “add 100ml H2O2 ” when it should read “add 100ml H2O.” All it takes is a superfluous subscript numeral to turn a simple substitution reaction into an explosive black fountain that will not stop!
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Formation of the nitropropene precursor to MADAM-6 (or, by way of the ketone and reductive amination with methylamine, 2-methyl-4,5-methylenedioxymethamphetamine). Shulgin found MADAM-6 to be inactive, but like all inactive compounds, it offered valuable insight into the structure-activity relationship of its relatives. Recent anecdotal reports suggest that the closely related aminotetralin compound MDMAT displays activity at doses around 500 mg, further indicating that substitution on the 6-position reduces potency in MDMA-type entactogenic compounds.
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This page shows planning for synthesis of iodine-131-labelled DOI. Radiolabelled DOI was a powerful tool for imaging the central distribution of serotonergic psychedelics as well as blood circulation in the brain. Eventually Shulgin developed a very fast synthesis that could produce radiolabelled DOI123 in less than one half-life of I123.
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Likely from the early-90s, this undated page features spectra from the GC-MS analysis of methcathinone, a stimulant derivative of ephedrine that achieved widespread popularity in the US around 1993. Shulgin was interested in testing drug samples to see if trace impurities could be used to elucidate the precursors and synthetic route.
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This pictured compound “MDMM4” is closely related to both the cactus alkaloid carnegine and the opium poppy alkaloid hydrocotarnine. Shulgin had a long standing fascination with the structural convergences in cactus and poppy isoquinolines, but the compound also bears a strong resemblance to the goldenseal alkaloid hydrastin and its semisynthetic derivative hydrastinine. Notably, it was the medical utility of hydrastinine as a hemostatic agent that inspired Merk to first synthesise MDMA in 1912. Shulgin sometimes used MDMM4 as an example when lecturing about his research process; the compound was not an answer to a question per se, but a stepping stone in his gradual exploration of structures that bridge various chemical and pharmacological classes. It is possible that Shulgin chose not to ingest MDMM4 due to its structural similarity to the endogenous neurotoxin salsolinol and so its activity remains unknown.
Archival material courtesy of the Shulgin Collection, donations can be made to support the digitization of Alexander Shulgin’s research via this link.
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