Chemistry:Conversion of CBD to THC

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Short description: Synthesis of THC from CBD

Conversion of cannabidiol (CBD) to tetrahydrocannabinol (THC) can occur through a ring-closing reaction.[1][2][3] This cyclization can be acid-catalyzed[4] or brought about by heating.[5][6][7][8][9][10][11]

Known methods

Phytocannabinoids exist like precursors to their pharmacologically active counterparts.[12][13] At least three independent methods have successfully converted CBD to THC.

  • Despite the CBD and THC having the same molecular weight, multiple analytical methods are able to differentiate them.[12]
  • "on the recovery of both THC (86.7−90.0%) and CBD (92.3−95.6%). The slightly lower recovery of THC can be explained by the fact that THC is less polar than CBD and more likely to remain in the nonpolar sunflower oil."[12]

By heat

CBD heated to 175,[14] or 250–300 °C may partially be converted into THC.[15] Even at room temperature, trace amounts of THC can be formed as a contaminant in CBD stored for long periods in the presence of moisture and carbon dioxide in the air, with storage under inert gas required to maintain analytically pure CBD.[16]

  • Heat is required to decarboxylate the non-psychoactive phytocannabinoid THCA to its psychoactive form, THC. Likewise, CBDA turns into CBD.
  • From hemp plant material in an oven, cannabinoid concentration plots (time/temp) show THC:[17]
  • STP 0 minutes 0.20 mg/g
  • 140-160C 20 minutes 0.27 mg/g
  • 140-160C 60 minutes 0.05-0.15 mg/g
  • 120C 45 minutes 0.27 mg/g
  • 120C 90 minutes 0.20 mg/g
  • 100C 90 minutes 0.25 mg/g
  • 80C 120 minutes 0.24 mg/g

Multiple oxidation products form during degradation in the presence of oxygen, a process known as thermolysis In contrast, the absence of oxygen leads to a process called pyrolysis which significantly reduces the loss.

  • "...the boiling point for THC has been determined at 157 °C, and the boiling point range for CBD sits between 160 and 180 °C."[17]

With acid

Mechanism of the acid catalyzed conversion of CBD into THC

CBD converts to various isomers of THC with catalysts in acidic environments.[18] A wide variety of acids can be used, though different conditions result in varying yield and formation of characteristic impurities.[19][20][21][22]

  • Catalytic acid solution in 5 minutes in a microwave oven with a 40% Δ9-THC and 35% Δ8-THC yield.[23]
  • Adding protons until the CBD sterically-hindered alcohol functional group cyclises to the pyran ring of THC.[24]
  • Lewis acids[25][9]
  • Gaoni and Mechoulam[26] described a method for converting CBD to Δ9-THC comprising refluxing a mixture of CBD in ethanol containing 0.05% hydrogen chloride for 2 hours. Percentage yield of Δ9-THC (Δ1-THC) was 2%.[27][28] Using boron trifluoride, the yield was 70%[29] although purity was not given.[30]

With zeolite

Methods have been claimed for converting CBD to a mixture of Δ8-THC and Δ9-THC using "Zeolites selected from the group consisting of analcime, chabazite, clinoptilolite, erionite, mordenite, phillipsite, and ferrierite."[31]

Purification

Δ-8-Tetrahydrocannabinol to THC

When CBD is treated with acid, Δ-8-Tetrahydrocannabinol may form as an impurity.[23] Nevertheless, Δ-8-Tetrahydrocannabinol can be isolated and subsequently converted into THC.

  • Δ-8-Tetrahydrocannabinol, which can be converted to THC by addition of HCl followed by dehydrochlorination.[32][27][33]
  • Treatment of the purified Δ8 -THC under Lucas' reagent gives the chloro compound. Following treatment with potassium tert-amylate, the desired (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol is yielded. The Mechoulam and Petrzilka methods require three steps and involve at least two careful chromatographic separations to obtain (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol of high purity.[34]

In vivo

Oral

There is a debated hypothesis that oral CBD could be metabolized into THC under acidic conditions in the stomach and then absorbed into the bloodstream. However, neither THC nor any of its active metabolites have been detected in blood in animals or humans after ingesting CBD.[22][12] There is no direct evidence of the conversion of CBD to THC in the human gut; both CBD and THC are excreted unchanged within human feces.[21]

History

The conversion of CBD to THC by an acid based cyclization reaction was first patented by Roger Adams in the 1940s.[35]

See also

References

  1. ↑ "Structure of Cannabidiol. VII. A Method of Synthesis of a Tetrahydrocannabinol which Possesses Marihuana Activity.". Journal of the American Chemical Society 62 (9): 2405–2408. September 1940. doi:10.1021/ja01866a041. 
  2. ↑ "Structure of cannabidiol. VI. Isomerization of cannabidiol to tetrahydrocannabinol, a physiologically active product. Conversion of cannabidiol to cannabinol.". Journal of the American Chemical Society 62 (9): 2402–2405. September 1940. doi:10.1021/ja01866a040. 
  3. ↑ "Conversion of cannabidiol to a product with marihuana activity. A type reaction for synthesis of analogous substances. Conversion of cannabidiol to cannabinol.". Journal of the American Chemical Society 62 (8): 2245–2246. August 1940. doi:10.1021/ja01865a508. 
  4. ↑ Nivorozhkin, Alex; Palfreyman, Michael G. (2025-06-01). "Acid-Catalyzed Conversion of Cannabidiol to Tetrahydrocannabinols: En Route to Demystifying Manufacturing Processes and Controlling the Reaction Outcomes" (in en). Cannabis and Cannabinoid Research 10 (3): 377–388. doi:10.1089/can.2025.0015. ISSN 2578-5125. https://www.liebertpub.com/doi/10.1089/can.2025.0015. 
  5. ↑ "The Total Synthesis of Cannabinoids.". Total Synthesis of Natural Products. 4. John Wiley & Sons. January 1981. pp. 185–262. doi:10.1002/9780470129678.ch2. ISBN 978-0-470-12953-1. 
  6. ↑ "Synthetic pathways to tetrahydrocannabinol (THC): an overview.". Organic & Biomolecular Chemistry 18 (3203–3215): 3203–3215. 2020. doi:10.1039/D0OB00464B. PMID 32259175. 
  7. ↑ "One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo-and heterogeneous Lewis acids.". Journal of Flow Chemistry 11 (2): 99–105. June 2021. doi:10.1007/s41981-020-00133-2. 
  8. ↑ "The Diels-Alder Approach towards Cannabinoid Derivatives and Formal Synthesis of Tetrahydrocannabinol (THC)". ChemistryOpen 10 (5): 587–592. May 2021. doi:10.1002/open.202000343. PMID 33988908. 
  9. ↑ 9.0 9.1 "Continuous-Flow Synthesis of Δ9-Tetrahydrocannabinol and Δ8-Tetrahydrocannabinol from Cannabidiol". The Journal of Organic Chemistry 88 (9): 6227–6231. May 2023. doi:10.1021/acs.joc.3c00300. PMID 37014222. 
  10. ↑ "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis 16 (2): 127–161. February 2024. doi:10.1002/dta.3519. PMID 37269160. 
  11. ↑ "Easy and Accessible Synthesis of Cannabinoids from CBD". Journal of Natural Products 87 (4): 869–875. April 2024. doi:10.1021/acs.jnatprod.3c01117. PMID 38427968. 
  12. ↑ 12.0 12.1 12.2 12.3 "Rapid Distinction and Semiquantitative Analysis of THC and CBD by Silver-Impregnated Paper Spray Mass Spectrometry". Analytical Chemistry 93 (8): 3794–3802. March 2021. doi:10.1021/acs.analchem.0c04270. PMID 33576613. 
  13. ↑ "An emerging trend in Novel Psychoactive Substances (NPSs): designer THC". Journal of Cannabis Research 6 (1): 21. May 2024. doi:10.1186/s42238-024-00226-y. PMID 38702834. 
  14. ↑ "Re-Examining Cannabidiol: Conversion to Tetrahydrocannabinol Using Only Heat". Cannabis and Cannabinoid Research 9 (2): 486–494. April 2024. doi:10.1089/can.2022.0235. PMID 36516105. 
  15. ↑ "CBD, a precursor of THC in e-cigarettes". Scientific Reports 11 (1): 8951. April 2021. doi:10.1038/s41598-021-88389-z. PMID 33903673. Bibcode: 2021NatSR..11.8951C. 
  16. ↑ "Origin of Δ9-Tetrahydrocannabinol Impurity in Synthetic Cannabidiol". Cannabis and Cannabinoid Research 6 (1): 28–39. 2021. doi:10.1089/can.2020.0021. PMID 33614950. 
  17. ↑ 17.0 17.1 "Cannabinoid Decarboxylation: A Comparative Kinetic Study". Industrial & Engineering Chemistry Research 59 (46): 20307–20315. 18 November 2020. doi:10.1021/acs.iecr.0c03791. ISSN 0888-5885. https://pubs.acs.org/doi/10.1021/acs.iecr.0c03791. Retrieved 17 May 2024. 
  18. ↑ "Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects". Chemistry and Physics of Lipids 121 (1–2): 35–43. December 2002. doi:10.1016/s0009-3084(02)00144-5. PMID 12505688. 
  19. ↑ "Hashish—VII: The isomerization of cannabidiol to tetrahydrocannabinols.". Tetrahedron 22 (4): 1481–1488. January 1966. doi:10.1016/S0040-4020(01)99446-3. 
  20. ↑ "Synthetic route sourcing of illicit at home cannabidiol (CBD) isomerization to psychoactive cannabinoids using ion mobility-coupled-LC-MS/MS". Forensic Science International 308. March 2020. doi:10.1016/j.forsciint.2020.110173. PMID 32028121. 
  21. ↑ 21.0 21.1 "The Essential Medicinal Chemistry of Cannabidiol (CBD)". Journal of Medicinal Chemistry 63 (21): 12137–12155. November 2020. doi:10.1021/acs.jmedchem.0c00724. PMID 32804502. 
  22. ↑ 22.0 22.1 "Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature". Toxics 8 (2): 41. June 2020. doi:10.3390/toxics8020041. PMID 32503116. 
  23. ↑ 23.0 23.1 "Ultrasonic or Microwave Modified Continuous Flow Chemistry for the Synthesis of Tetrahydrocannabinol: Observing Effects of Various Solvents and Acids". ACS Omega 9 (11): 13191–13199. March 2024. doi:10.1021/acsomega.3c09794. PMID 38524441. 
  24. ↑ "Cannabis and Cannabis Edibles: A Review". Journal of Agricultural and Food Chemistry 69 (6): 1751–1774. February 2021. doi:10.1021/acs.jafc.0c07472. PMID 33555188. 
  25. ↑ "Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization". Journal of Natural Products 83 (10): 2894–2901. October 2020. doi:10.1021/acs.jnatprod.0c00436. PMID 32991167. 
  26. ↑ "Isolation, structure, and partial synthesis of an active constituent of hashish.". Journal of the American Chemical Society 86 (8): 1646–1647. April 1964. doi:10.1021/ja01062a046. 
  27. ↑ 27.0 27.1 "Syntheses of 1 -tetrahydrocannabinol and related cannabinoids". Journal of the American Chemical Society 94 (17): 6159–65. August 1972. doi:10.1021/ja00772a038. PMID 5054408. 
  28. ↑ "A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish". Journal of the American Chemical Society 87 (14): 3273–5. July 1965. doi:10.1021/ja01092a065. PMID 14324315. 
  29. ↑ "The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish". Journal of the American Chemical Society 93 (1): 217–24. January 1971. doi:10.1021/ja00730a036. PMID 5538858. 
  30. ↑ Webster GR, Sarna L, Mechoulam R, "Conversion of CBD to delta8-THC and delta9-THC", US patent 20040143126, issued 15 July 2008
  31. ↑ Gindelberger D, "Zeolite catalyst and method for preparation of aromatic tricyclic pyrans", US patent 11352337B1, issued 7 June 2022
  32. ↑ "A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols". Journal of the American Chemical Society 89 (17): 4552–4. August 1967. doi:10.1021/ja00993a072. PMID 6046550. 
  33. ↑ Gutman AL, Etinger M, Fedotev I, Khanolkar R, Nisnevich G, Pertsikov B, Rukhman I, Tishin B, "Methods for purifying trans-(-)-δ9-tetrahydrocannabinol and trans-(+)-δ9 tetrahydrocannabinol", US patent Abandoned 20160199344, published 14 July 2016
  34. ↑ Razdan RK, Dalzell HC, "Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans", US patent 4025516, issued 24 May 1977
  35. ↑ https://patents.google.com/patent/US2419937A/en



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