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* Adding protons until the CBD sterically-hindered alcohol functional group cyclises to the pyran ring of THC.<ref name = Peng2021>{{cite journal | vauthors = Peng H, Shahidi F | title = Cannabis and Cannabis Edibles: A Review | journal = Journal of Agricultural and Food Chemistry | volume = 69 | issue = 6 | pages = 1751–1774 | date = February 2021 | pmid = 33555188 | doi = 10.1021/acs.jafc.0c07472 }}</ref>
* Adding protons until the CBD sterically-hindered alcohol functional group cyclises to the pyran ring of THC.<ref name = Peng2021>{{cite journal | vauthors = Peng H, Shahidi F | title = Cannabis and Cannabis Edibles: A Review | journal = Journal of Agricultural and Food Chemistry | volume = 69 | issue = 6 | pages = 1751–1774 | date = February 2021 | pmid = 33555188 | doi = 10.1021/acs.jafc.0c07472 }}</ref>
* Lewis acids.<ref name="pmid32991167">{{cite journal | vauthors = Marzullo P, Foschi F, Coppini DA, Fanchini F, Magnani L, Rusconi S, Luzzani M, Passarella D | title = Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization | journal = Journal of Natural Products | volume = 83 | issue = 10 | pages = 2894–2901 | date = October 2020 | pmid = 32991167 | pmc = 8011986 | doi = 10.1021/acs.jnatprod.0c00436 }}</ref> - a continuous rather than batch implementation with similar materials<ref name = "Bassetti_2023" />
* Lewis acids.<ref name="pmid32991167">{{cite journal | vauthors = Marzullo P, Foschi F, Coppini DA, Fanchini F, Magnani L, Rusconi S, Luzzani M, Passarella D | title = Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization | journal = Journal of Natural Products | volume = 83 | issue = 10 | pages = 2894–2901 | date = October 2020 | pmid = 32991167 | pmc = 8011986 | doi = 10.1021/acs.jnatprod.0c00436 }}</ref> - a continuous rather than batch implementation with similar materials<ref name = "Bassetti_2023" />

* Catalytic acid solution in 5 minutes in a microwave with a 40% Δ9 and 35% Δ8 yield<ref>{{cite journal | vauthors = Ramirez GA, Tesfatsion TT, Docampo-Palacios ML, Cruces I, Hellmann AJ, Okhovat A, Pittiglio MK, Ray KP, Cruces W | title = Ultrasonic or Microwave Modified Continuous Flow Chemistry for the Synthesis of Tetrahydrocannabinol: Observing Effects of Various Solvents and Acids | journal = ACS Omega | volume = 9 | issue = 11 | pages = 13191–13199 | date = March 2024 | pmid = 38524441 | pmc = 10956408 | doi = 10.1021/acsomega.3c09794 }}</ref>
* Catalytic acid solution in 5 minutes in a microwave with a 40% Δ9 and 35% Δ8 yield<ref>{{cite journal | vauthors = Ramirez GA, Tesfatsion TT, Docampo-Palacios ML, Cruces I, Hellmann AJ, Okhovat A, Pittiglio MK, Ray KP, Cruces W | title = Ultrasonic or Microwave Modified Continuous Flow Chemistry for the Synthesis of Tetrahydrocannabinol: Observing Effects of Various Solvents and Acids | journal = ACS Omega | volume = 9 | issue = 11 | pages = 13191–13199 | date = March 2024 | pmid = 38524441 | pmc = 10956408 | doi = 10.1021/acsomega.3c09794 }}</ref>
* (−)-Δ8-THC, which can be converted to trans-(−)-Δ9-THC by addition of HCl followed by dehydrochlorination<ref>{{cite journal | vauthors = Mechoulam R, Braun P, Gaoni Y | title = A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols | journal = Journal of the American Chemical Society | volume = 89 | issue = 17 | pages = 4552–4 | date = August 1967 | pmid = 6046550 | doi = 10.1021/ja00993a072 }}</ref><ref name = "Mechoulam_1972">{{cite journal | vauthors = Mechoulam R, Braun P, Gaoni Y | title = Syntheses of 1 -tetrahydrocannabinol and related cannabinoids | journal = Journal of the American Chemical Society | volume = 94 | issue = 17 | pages = 6159–65 | date = August 1972 | pmid = 5054408 | doi = 10.1021/ja00772a038 }}</ref><ref>{{cite patent | title = Methods for purifying trans-(-)-δ9-tetrahydrocannabinol and trans-(+)-δ9 tetrahydrocannabinol | inventor = Gutman AL, Etinger M, Fedotev I, Khanolkar R, Nisnevich G, Pertsikov B, Rukhman I, Tishin B | assign = Current Assignee SVC Pharma LP | pubdate = 14 July 2016 | status = Abandoned | url = https://patents.google.com/patent/US20160199344A1/en | country = US | number = 20160199344 }}</ref>
* (−)-Δ8-THC, which can be converted to trans-(−)-Δ9-THC by addition of HCl followed by dehydrochlorination<ref>{{cite journal | vauthors = Mechoulam R, Braun P, Gaoni Y | title = A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols | journal = Journal of the American Chemical Society | volume = 89 | issue = 17 | pages = 4552–4 | date = August 1967 | pmid = 6046550 | doi = 10.1021/ja00993a072 }}</ref><ref name = "Mechoulam_1972">{{cite journal | vauthors = Mechoulam R, Braun P, Gaoni Y | title = Syntheses of 1 -tetrahydrocannabinol and related cannabinoids | journal = Journal of the American Chemical Society | volume = 94 | issue = 17 | pages = 6159–65 | date = August 1972 | pmid = 5054408 | doi = 10.1021/ja00772a038 }}</ref><ref>{{cite patent | title = Methods for purifying trans-(-)-δ9-tetrahydrocannabinol and trans-(+)-δ9 tetrahydrocannabinol | inventor = Gutman AL, Etinger M, Fedotev I, Khanolkar R, Nisnevich G, Pertsikov B, Rukhman I, Tishin B | assign = Current Assignee SVC Pharma LP | pubdate = 14 July 2016 | status = Abandoned | url = https://patents.google.com/patent/US20160199344A1/en | country = US | number = 20160199344 }}</ref>
* Treatment of the purified Δ8 -THC with hydrogen chloride in the presence of zinc chloride gives the chloro compound which is isolated and subsequently treated with potassium tert-amylate to yield the desired (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol. 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.<ref>{{cite patent | title = Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans | inventor = Razdan RK, Dalzell HC | assign = Application filed by Sheehan John C Institute for Research Inc. | gdate = 24 May 1977 | url = https://patents.google.com/patent/US4025516A/en | country = US | number = 4025516 }}</ref>
* Treatment of the purified Δ8 -THC with hydrogen chloride in the presence of zinc chloride gives the chloro compound which is isolated and subsequently treated with potassium tert-amylate to yield the desired (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol. 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.<ref>{{cite patent | title = Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans | inventor = Razdan RK, Dalzell HC | assign = Application filed by Sheehan John C Institute for Research Inc. | gdate = 24 May 1977 | url = https://patents.google.com/patent/US4025516A/en | country = US | number = 4025516 }}</ref>
* Gaoni and Mechoulam<ref>{{cite journal | vauthors = Gaoni Y, Mechoulam R | title = Isolation, structure, and partial synthesis of an active constituent of hashish. | journal = Journal of the American Chemical Society | date = April 1964 | volume = 86 | issue = 8 | pages = 1646–1647 | doi = 10.1021/ja01062a046 }}</ref> also described a method for converting CBD to Δ9-THC comprising boiling a mixture of CBD in ethanol containing 0.05% hydrogen chloride for 2 hours. Percentage yield of Δ9-THC (Δ1-THC) was 2%.<ref name = "Mechoulam_1972" /><ref name="pmid14324315">{{cite journal | vauthors = Mechoulam R, Gaoni Y | title = A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish | journal = Journal of the American Chemical Society | volume = 87 | issue = 14| pages = 3273–5 | date = July 1965 | pmid = 14324315 | doi = 10.1021/ja01092a065 | url = }}</ref> Using boron trifluoride, the yield was 70%<ref name="pmid5538858">{{cite journal | vauthors = Gaoni Y, Mechoulam R | title = The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish | journal = Journal of the American Chemical Society | volume = 93 | issue = 1 | pages = 217–24 | date = January 1971 | pmid = 5538858 | doi = 10.1021/ja00730a036 }}</ref> although purity was not given.<ref>{{cite patent | title = Conversion of CBD to delta8-THC and delta9-THC | inventor = Webster GR, Sarna L, Mechoulam R | assign = Full Spectrum Laboratories Ltd. | gdate = 15 July 2008 | url = https://patents.google.com/patent/US20040143126A1/en | country = US | number = 20040143126 }}</ref>
* Gaoni and Mechoulam<ref>{{cite journal | vauthors = Gaoni Y, Mechoulam R | title = Isolation, structure, and partial synthesis of an active constituent of hashish. | journal = Journal of the American Chemical Society | date = April 1964 | volume = 86 | issue = 8 | pages = 1646–1647 | doi = 10.1021/ja01062a046 }}</ref> also described a method for converting CBD to Δ9-THC comprising boiling a mixture of CBD in ethanol containing 0.05% hydrogen chloride for 2 hours. Percentage yield of Δ9-THC (Δ1-THC) was 2%.<ref name = "Mechoulam_1972" /><ref name="pmid14324315">{{cite journal | vauthors = Mechoulam R, Gaoni Y | title = A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish | journal = Journal of the American Chemical Society | volume = 87 | issue = 14| pages = 3273–5 | date = July 1965 | pmid = 14324315 | doi = 10.1021/ja01092a065 | url = }}</ref> Using boron trifluoride, the yield was 70%<ref name="pmid5538858">{{cite journal | vauthors = Gaoni Y, Mechoulam R | title = The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish | journal = Journal of the American Chemical Society | volume = 93 | issue = 1 | pages = 217–24 | date = January 1971 | pmid = 5538858 | doi = 10.1021/ja00730a036 }}</ref> although purity was not given.<ref>{{cite patent | title = Conversion of CBD to delta8-THC and delta9-THC | inventor = Webster GR, Sarna L, Mechoulam R | assign = Full Spectrum Laboratories Ltd. | gdate = 15 July 2008 | url = https://patents.google.com/patent/US20040143126A1/en | country = US | number = 20040143126 }}</ref>


Revision as of 03:00, 11 July 2024

Cannabidiol (CBD) can be chemically converted into tetrahydrocannabinol (THC) via a ring-closing reaction. This cyclization can be acid-catalyzed or brought about by heating.[1][2][3][4][5][6]

Known methods

Plant cannabinoids exist like precursors to their pharmacologically active counterparts.[7] 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.[7]
  • "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."[7]

By heat

CBD heated to 175,[8] or 250–300 °C may partially be converted into THC.[9]

  • Heat is required to decarboxylate THCA to psychoactive cannabinoid THC. Likewise, CBDA turns into CBD.
  • From hemp plant material in an oven, cannabinoid concentration plots (time/temp) show THC:[10]
  • 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 begin to form with degradation (the loss is greatly reduced in the absence of oxygen).

  • "...the boiling point for THC has been determined at 157 °C, and the boiling point range for CBD sits between 160 and 180 °C."[10]

With acid

Mechanism of the acid catalyzed conversion of CBD into THC

CBD converts to various isomers of THC with catalysts in acidic environments.[11][12]

  • Adding protons until the CBD sterically-hindered alcohol functional group cyclises to the pyran ring of THC.[13]
  • Lewis acids.[14] - a continuous rather than batch implementation with similar materials[4]
  • Catalytic acid solution in 5 minutes in a microwave with a 40% Δ9 and 35% Δ8 yield[15]
  • (−)-Δ8-THC, which can be converted to trans-(−)-Δ9-THC by addition of HCl followed by dehydrochlorination[16][17][18]
  • Treatment of the purified Δ8 -THC with hydrogen chloride in the presence of zinc chloride gives the chloro compound which is isolated and subsequently treated with potassium tert-amylate to yield the desired (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol. 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.[19]
  • Gaoni and Mechoulam[20] also described a method for converting CBD to Δ9-THC comprising boiling a mixture of CBD in ethanol containing 0.05% hydrogen chloride for 2 hours. Percentage yield of Δ9-THC (Δ1-THC) was 2%.[17][21] Using boron trifluoride, the yield was 70%[22] although purity was not given.[23]

With zeolite

"Zeolites selected from the group consisting of analcime, chabazite, clinoptilolite, erionite, mordenite, phillipsite, and ferrierite."[24]

In vivo

There is a debated hypothesis that oral CBD could be converted into THC under acidic conditions in the stomach and then absorbed into the blood stream. However, neither THC nor any of its active metabolites have been detected in blood in animals or humans after ingesting CBD.[12][7] 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.[11]

References

  1. ^ 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. PMID 32259175.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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 Current Assignee SVC Pharma LP 
  19. ^ 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. 
  20. ^ 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.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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. 
  24. ^ US 11352337B1, Gindelberger D, "Zeolite catalyst and method for preparation of aromatic tricyclic pyrans", issued 7 June 2022, assigned to Acid Neutral Alkaline Laboratory. 
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