Reading the Primary Literature: Adams, Optical Rotation and Two Numbering Systems

What Adams established historical / ethnographic

The Illinois programme did the foundational structural chemistry of the cannabinoids with the tools of the late 1930s: fractional distillation, derivatisation, combustion analysis, melting points and polarimetry, and no spectroscopy worth the name. Out of it came the isolation and characterisation of cannabidiol, the structure of cannabinol established by synthesis, and the demonstration that cannabidiol rearranges under acid to a physiologically active tetrahydrocannabinol — the 1940 paper in the Journal of the American Chemical Society, sixth in the cannabidiol series, reports both the isomerisation to THC and the conversion of CBD to CBN in its title. The twelfth paper in the series, in 1941, is the one specifically on isomerisation to the tetrahydrocannabinols. It is worth registering what that means: the CBD-to-THC relationship, which is the load-bearing chemical fact in the entire modern hemp regulatory argument, was published in an open, mainstream chemistry journal eighty-five years ago.

Sources: Adams R 1940 · Adams R 1941

Why optical rotation became the name contested historical / ethnographic

Adams could separate two tetrahydrocannabinol isomers and could show that they were different, but he could not say where their double bonds were, because the methods that assign an alkene position — nuclear magnetic resonance above all — did not exist. What he could measure precisely was specific optical rotation. So the isomers were distinguished as the "high rotating" and "low rotating" tetrahydrocannabinols, with specific rotations around −240 and −165 degrees respectively. That was a perfectly rational choice: it named a reproducible physical observable rather than guessing at a structure. It also produced two decades of confusion in the literature, because rotation is a property of a sample as well as a molecule, papers reported it under varying conditions, and the mapping from rotation to structure was not settled until the double-bond positions were assigned in the 1960s. When reading anything from this period, treat a rotation-based name as a laboratory label rather than a structural assignment.

Contested — caveat. The operator source assigns "high rotating" to Δ8-THC and "low rotating" to Δ9-THC. That mapping is plausible and is repeated in secondary accounts, but it was not confirmed against the primary Adams papers in this pass. The rotation values themselves (about −240 and about −165) are reported consistently; treat the isomer assignment as unconfirmed.

Sources: Adams R 1941 · Adams R 1940 · Gaoni Y 1966

The Δ6a,10a series and the dimethylheptyl finding historical / ethnographic

Adams also made synthetic tetrahydrocannabinols with the double bond at the ring-fusion position, Δ6a,10a. The reason was practical: that isomer could be made with controlled stereochemistry using the methods available, where the natural isomers could not. It became the platform on which the first systematic cannabinoid structure-activity relationships were run, and the most consequential result to come off it was about the side chain rather than the rings — replacing the natural pentyl chain with a branched dimethylheptyl chain produced very large increases in activity, reported in the literature of the period as gains of several hundred-fold. That motif went on to appear in the most potent classical cannabinoids ever made, including the Hebrew University compounds, and the modern isolation of the naturally occurring heptyl homologue from the plant is a rediscovery of the same relationship from the other direction. The modern quantitative treatment of side-chain SAR, done on the Δ8 scaffold in 1999, is the reference to use for numbers.

Sources: Adams R 1940 · Adams R 1941 · Martin BR 1999 · Crocker PJ 1999 · Citti C 2019

Two numbering systems, both still in use

This is the most practically useful thing on the page. Cannabinoids can be numbered two ways, and both appear in the literature. The dibenzopyran convention numbers from the phenolic ring and treats the molecule as a substituted dibenzo[b,d]pyran; in it the principal alkene of the plant compound is at the 9 position and the stereocentres are C-6a and C-10a. The formal monoterpenoid convention numbers from the terpene ring; in it the same alkene is at the 1 position and the stereocentres are C-3 and C-4. Δ1-THC and Δ9-THC are the same molecule. Δ6-THC and Δ8-THC are the same molecule. The dibenzopyran system is now standard, but the monoterpenoid system was in general use through the 1960s and 1970s, which covers the Mechoulam-era papers that established the structures in the first place — and it persists in some analogue nomenclature. The consequence is concrete: a paper reporting the synthesis of Δ1-THC is reporting the synthesis of the compound everyone now calls Δ9-THC, and reading the older cannabinoid literature requires knowing which convention the author is using before interpreting a single number.

Sources: Gaoni Y 1966 · Razdan RK 1974 · Hanuš LO 2016 · Adams R 1941

A short reading protocol for pre-1980 cannabinoid papers historical / ethnographic

• Identify the numbering convention first. If the paper says Δ1 or Δ6 for the principal alkene, it is monoterpenoid numbering; add eight to translate to the modern names.
• Treat rotation-based names ("high rotating", "low rotating") as sample labels, not structural assignments.
• Expect purity to mean something different. Pre-chromatographic preparations were mixtures by modern standards, and biological potencies from that era carry that uncertainty.
• Expect potency to be reported as whole-animal activity rather than receptor affinity. Receptor binding constants postdate the identification of the cannabinoid receptors in the late 1980s, so no pre-1988 paper contains a Ki.
• Read the series, not the paper. The Adams cannabidiol papers are numbered parts of one programme, and a structural conclusion in part twelve may revise part six.

Sources: Adams R 1940 · Adams R 1941 · Gaoni Y 1966 · Razdan RK 1974 · Hanuš LO 2016