Conversion of CBD to THC

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

Known methods

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Phytocannabinoids exist like precursors to their pharmacologically active counterparts.[11][12] 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.[11]
  • "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."[11]

By heat

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CBD heated to 175,[13] or 250–300 °C may partially be converted into THC.[14] 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.[15]

  • 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:[16]
  • STP 0 minutes 0.20mg/g
  • 140-160C 20 minutes 0.27mg/g
  • 140-160C 60 minutes 0.05-0.15mg/g
  • 120C 45 minutes 0.27mg/g
  • 120C 90 minutes 0.20mg/g
  • 100C 90 minutes 0.25mg/g
  • 80C 120 minutes 0.24mg/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."[16]

With acid

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Mechanism of the acid catalyzed conversion of CBD into THC

CBD converts to various isomers of THC with catalysts in acidic environments.[17] A wide variety of acids can be used, though different conditions result in varying yield and formation of characteristic impurities.[18][19][20][21]

  • Catalytic acid solution in 5 minutes in a microwave oven with a 40% THC (Δ9-THC) and 35% Δ-8-Tetrahydrocannabinol yield.[22]
  • Adding protons until the CBD sterically-hindered alcohol functional group cyclises to the pyran ring of THC.[23]
  • Lewis acids.[24] - a continuous rather than batch implementation with similar materials[8]
  • Gaoni and Mechoulam[25] also 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%.[26][27] Using boron trifluoride, the yield was 70%[28] although purity was not given.[29]

With zeolite

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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."[30]

Purification

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Δ-8-Tetrahydrocannabinol to THC

[edit]

When CBD is treated with acid, Δ-8-Tetrahydrocannabinol may form as an impurity.[22] 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.[31][26][32]
  • 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 yeilded. 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.[33]

In vivo

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Oral

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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.[21][11] 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.[20]

History

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The conversion of CBD to THC by an acid based cyclization reaction was first patented by Roger Adams in the 1940s.[34]

See also

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References

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  1. ^ Adams R, Baker BR (September 1940). "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. doi:10.1021/ja01866a041.
  2. ^ Adams R, Pease DC, Cain CK, Clark JH (September 1940). "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. doi:10.1021/ja01866a040.
  3. ^ Adams R, Pease DC, Cain CK, Baker BR, Clark JH, Wolff H, et al. (August 1940). "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. doi:10.1021/ja01865a508.
  4. ^ Razdan RK (January 1981). "The Total Synthesis of Cannabinoids.". In ApSimon J (ed.). Total Synthesis of Natural Products. Vol. 4. John Wiley & Sons. pp. 185–262. doi:10.1002/9780470129678.ch2. ISBN 978-0-470-12953-1.
  5. ^ Bloemendal VR, van Hest JC, Rutjes FP (2020). "Synthetic pathways to tetrahydrocannabinol (THC): an overview". Organic & Biomolecular Chemistry. 18 (3203–3215): 3203–3215. doi:10.1039/D0OB00464B. hdl:2066/218829. PMID 32259175.
  6. ^ Bloemendal VR, Spierenburg B, Boltje TJ, van Hest JC, Rutjes FP (June 2021). "One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo-and heterogeneous Lewis acids". Journal of Flow Chemistry. 11 (2): 99–105. doi:10.1007/s41981-020-00133-2.
  7. ^ Hurrle T, Gläser F, Bröhmer MC, Nieger M, Bräse S (May 2021). "The Diels-Alder Approach towards Cannabinoid Derivatives and Formal Synthesis of Tetrahydrocannabinol (THC)". ChemistryOpen. 10 (5): 587–592. doi:10.1002/open.202000343. PMC 8121136. PMID 33988908.
  8. ^ a b Bassetti B, Hone CA, Kappe CO (May 2023). "Continuous-Flow Synthesis of Δ9-Tetrahydrocannabinol and Δ8-Tetrahydrocannabinol from Cannabidiol". The Journal of Organic Chemistry. 88 (9): 6227–6231. doi:10.1021/acs.joc.3c00300. PMC 10167683. PMID 37014222.
  9. ^ Ujváry I (February 2024). "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis. 16 (2): 127–161. doi:10.1002/dta.3519. PMID 37269160.
  10. ^ Capucciati A, Casali E, Bini A, Doria F, Merli D, Porta A (April 2024). "Easy and Accessible Synthesis of Cannabinoids from CBD". Journal of Natural Products. 87 (4): 869–875. doi:10.1021/acs.jnatprod.3c01117. PMID 38427968.
  11. ^ a b c d Huang S, Claassen FW, van Beek TA, Chen B, Zeng J, Zuilhof H, et al. (March 2021). "Rapid Distinction and Semiquantitative Analysis of THC and CBD by Silver-Impregnated Paper Spray Mass Spectrometry". Analytical Chemistry. 93 (8): 3794–3802. doi:10.1021/acs.analchem.0c04270. PMC 8023514. PMID 33576613.
  12. ^ Caprari C, Ferri E, Vandelli MA, Citti C, Cannazza G (May 2024). "An emerging trend in Novel Psychoactive Substances (NPSs): designer THC". Journal of Cannabis Research. 6 (1): 21. doi:10.1186/s42238-024-00226-y. PMC 11067227. PMID 38702834.
  13. ^ Daniels R, Yassin OA, Toribio JM, Gascón JA, Sotzing G (April 2024). "Re-Examining Cannabidiol: Conversion to Tetrahydrocannabinol Using Only Heat". Cannabis and Cannabinoid Research. 9 (2): 486–494. doi:10.1089/can.2022.0235. PMID 36516105.
  14. ^ Czégény Z, Nagy G, Babinszki B, Bajtel Á, Sebestyén Z, Kiss T, et al. (April 2021). "CBD, a precursor of THC in e-cigarettes". Scientific Reports. 11 (1): 8951. Bibcode:2021NatSR..11.8951C. doi:10.1038/s41598-021-88389-z. PMC 8076212. PMID 33903673.
  15. ^ Citti C, Russo F, Linciano P, Strallhofer SS, Tolomeo F, Forni F, et al. (2021). "Origin of Δ9-Tetrahydrocannabinol Impurity in Synthetic Cannabidiol". Cannabis and Cannabinoid Research. 6 (1): 28–39. doi:10.1089/can.2020.0021. PMC 7891213. PMID 33614950.
  16. ^ a b Moreno, T., Dyer, P., Tallon, S. (18 November 2020). "Cannabinoid Decarboxylation: A Comparative Kinetic Study". Industrial & Engineering Chemistry Research. 59 (46): 20307–20315. doi:10.1021/acs.iecr.0c03791. ISSN 0888-5885. Retrieved 17 May 2024.
  17. ^ Mechoulam R, Hanus L (December 2002). "Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects". Chemistry and Physics of Lipids. 121 (1–2): 35–43. doi:10.1016/s0009-3084(02)00144-5. PMID 12505688.
  18. ^ Gaoni Y, Mechoulam R (January 1966). "Hashish—VII: The isomerization of cannabidiol to tetrahydrocannabinols". Tetrahedron. 22 (4): 1481–1488. doi:10.1016/S0040-4020(01)99446-3.
  19. ^ Kiselak TD, Koerber R, Verbeck GF (March 2020). "Synthetic route sourcing of illicit at home cannabidiol (CBD) isomerization to psychoactive cannabinoids using ion mobility-coupled-LC-MS/MS". Forensic Science International. 308: 110173. doi:10.1016/j.forsciint.2020.110173. PMID 32028121.
  20. ^ a b Nelson KM, Bisson J, Singh G, Graham JG, Chen SN, Friesen JB, et al. (November 2020). "The Essential Medicinal Chemistry of Cannabidiol (CBD)". Journal of Medicinal Chemistry. 63 (21): 12137–12155. doi:10.1021/acs.jmedchem.0c00724. PMC 7666069. PMID 32804502.
  21. ^ a b Golombek P, Müller M, Barthlott I, Sproll C, Lachenmeier DW (June 2020). "Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature". Toxics. 8 (2): 41. doi:10.3390/toxics8020041. PMC 7357058. PMID 32503116.
  22. ^ a b Ramirez GA, Tesfatsion TT, Docampo-Palacios ML, Cruces I, Hellmann AJ, Okhovat A, et al. (March 2024). "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. doi:10.1021/acsomega.3c09794. PMC 10956408. PMID 38524441.
  23. ^ Peng H, Shahidi F (February 2021). "Cannabis and Cannabis Edibles: A Review". Journal of Agricultural and Food Chemistry. 69 (6): 1751–1774. doi:10.1021/acs.jafc.0c07472. PMID 33555188.
  24. ^ Marzullo P, Foschi F, Coppini DA, Fanchini F, Magnani L, Rusconi S, et al. (October 2020). "Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization". Journal of Natural Products. 83 (10): 2894–2901. doi:10.1021/acs.jnatprod.0c00436. PMC 8011986. PMID 32991167.
  25. ^ Gaoni Y, Mechoulam R (April 1964). "Isolation, structure, and partial synthesis of an active constituent of hashish". Journal of the American Chemical Society. 86 (8): 1646–1647. doi:10.1021/ja01062a046.
  26. ^ a b Mechoulam R, Braun P, Gaoni Y (August 1972). "Syntheses of 1 -tetrahydrocannabinol and related cannabinoids". Journal of the American Chemical Society. 94 (17): 6159–65. doi:10.1021/ja00772a038. PMID 5054408.
  27. ^ Mechoulam R, Gaoni Y (July 1965). "A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish". Journal of the American Chemical Society. 87 (14): 3273–5. doi:10.1021/ja01092a065. PMID 14324315.
  28. ^ Gaoni Y, Mechoulam R (January 1971). "The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish". Journal of the American Chemical Society. 93 (1): 217–24. doi:10.1021/ja00730a036. PMID 5538858.
  29. ^ US 20040143126, Webster GR, Sarna L, Mechoulam R, "Conversion of CBD to delta8-THC and delta9-THC", issued 15 July 2008, assigned to Full Spectrum Laboratories Ltd. 
  30. ^ US 11352337B1, Gindelberger D, "Zeolite catalyst and method for preparation of aromatic tricyclic pyrans", issued 7 June 2022, assigned to Acid Neutral Alkaline Laboratory. 
  31. ^ Mechoulam R, Braun P, Gaoni Y (August 1967). "A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols". Journal of the American Chemical Society. 89 (17): 4552–4. doi:10.1021/ja00993a072. PMID 6046550.
  32. ^ US Abandoned 20160199344, 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", published 14 July 2016, assigned to SVC Pharma LP 
  33. ^ US 4025516, Razdan RK, Dalzell HC, "Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans", issued 24 May 1977, assigned to Application filed by Sheehan John C Institute for Research Inc. 
  34. ^ https://patents.google.com/patent/US2419937A/en
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