2,5-Dimethoxy-3,4-methylenedioxyamphetamine (DMMDA or DMMDA-1) is a lesser-known psychedelic drug of the phenethylamine and amphetamine chemical classes.[1] It was first synthesized by Alexander Shulgin and was described in his book PiHKAL.[1] Shulgin listed the dosage as 30–75 mg and the duration as 6–8 hours.[1] He reported DMMDA as producing LSD-like images, mydriasis, ataxia, and time dilation.[1] DMMDA isn't mentioned much in literature outside PiHKAL unlike 2C-B.[1]
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| Formula | C12H19NO4 |
| Molar mass | 241.287 g·mol−1 |
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Pharmacology
editThe mechanism behind the hallucinogenic effects of DMMDA has not been specifically established. In PiHKAL, Shulgin asserts that the subjective effects of 75 milligrams of DMMDA are equivalent to those of 75–100 microgram of LSD. LSD is a well-known partial agonist of the 5-HT2A receptor.[1] This may suggest that DMMDA is a classical psychedelic that is also an agonist or partial agonist of the 5-HT2A receptor.
Chemistry
editShulgin explains in his book that DMMDA has 6 isomers similar to TMA.[1] DMMDA-2 is the only other isomer that has been synthesized as of yet. DMMDA-3 could be made from exalatacin (1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene). Exalatacin can be found in the essential oil of both Crowea exalata and Crowea angustifolia var. angustifolia.[2] In other words, exalatacin is an isomer of both apiole and dillapiole, which can be used to make DMMDA and DMMDA-2 respectively. Additionally, yet another isomer of DMMDA could be made from pseudodillapiole or 4,5-dimethoxy-2,3-methylenedioxyallylbenzene.[3] The last two isomers of DMMDA are 5,6-dimethoxy-2,3-methylenedioxyamphetamine and 4,6-dimethoxy-2,3-methylenedioxyamphetamine.
Like all other amphetamine compounds, DMMDA and its regioisomer have two enantiomers due to the methyl group being in the alpha position of the ethyl group in position number 1 on the benzene ring.[4]
Precursors in the synthesis of DMMDA and its regioisomers.
Shulgin's synthesis
editShulgin describes the synthesis of DMMDA from apiole in his PiHKAL.[1] Apiole is subjected to an isomerization reaction to yield isoapiole by adding to solution of ethanolic potassium hydroxide and holding the solution at a steam bath.[1] Isoapiole is then nitrated via a Knoevenagel condensation to 2-nitro-isoapiole or 1-(2,3-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by adding it to a stirred solution of acetone and pyridine at ice-bath temperatures and treating the solution with tetranitromethane. The pyridine acts as a catalyst in this reaction.[1] 2,5-dimethoxy-3,4-methylenedioxybenzaldehyde can also be used as precursors in this step of the synthesis. The 2-nitro-isoapiole is finally reduced to freebase DMMDA by adding it to a well-stirred and refluxing suspension of diethylether and lithium aluminium hydride under an inert atmosphere.[1] The reduction can also be achieved with pressurized hydrogen. Finally, the freebase DMMDA converted into its hydrochloride salt.[1]
Alexander Shulgin's synthesis of DMMDA.
Modern synthetic methods
editShulgin's synthesis of DMMDA can reasonably be considered unsafe, at least by modern standards, since it uses tetranitromethane for its nitration reaction, which is toxic, carcinogenic and prone to detonating.[5] DMMDA can be made from apiole via other safer methods. Among other methods, DMMDA can be synthesize from apiole via the intermediate chemical 2,5-dimethoxy-3,4-methylenedioxyphenylpropan-2-one or DMMDP2P in the same manner as MDA is made from safrole.
DMMDP2P can be made from apiole via a Wacker oxidation with benzoquinone. DMMDP2P can be alternatively made by subjecting apiole to an isomerisation reaction to yield the thermodynamically stabler internal alkene, isoapiole, followed by a peracid oxidation and finally a hydrolytic dehydration.[6] The peracid oxidation can be accomplished by combining hydrogen peroxide with formic acid to create peracid, which is this case is peracetic acid. The hydrolysis is usually acid-catalyzed with sulphuric acid because sulphuric acid will also result in the intermediary isoapiole monoformyl glycol being dehydrated to DMMDP2P. Thus only one reagent, sulphuric acid, is needed for both the hydrolysis and dehydration and both reactions can be done in the same reaction vessel. The dehydration is the result of a pinacol rearrangement. Then the DMMDP2P can then be subjected to a reductive amination with a source of nitrogen, such as ammonium chloride or ammonium nitrate, and a reducing agent, such as sodium cyanoborohydride, an amalgam of mercury and aluminium or pressurized hydrogen, to yield freebase DMMDA.[7][8][9][10][11]
Modern synthesis of DMMDA.
General synthetic information
editSodium borohydride usually isn't used as a reducing agent due to it being much stronger than sodium cyanoborohydride; this usually results in byproducts such as 2,5-dimethoxy-3,4-methylenedioxy-1-α-hyroxypropylbenzene, in addition to the desired DMMDA. Reductive aminations are exothermic reactions. Thus it is necessary to employ different methods of cooling the reaction mixture to prevent overheating; this can be accomplished by using a large amount of solvent or an ice bath, for example. The use of an mercury amalgam is unsafe due to mercury's well-known toxic effects on the central nervous system. It is also worth noting that in addition to peracetic acid, other peracids can be used for the peracid oxidation of isoapiole and the analogues of isoallylbenzene in general. For example, combining nitric acid with hydrogen peroxide would result in the same reaction.[8][9][10][11]
The reductive amination of DMMDP2P.
References
edit- ^ a b c d e f g h i j k l Shulgin A, Shulgin A (1991). Pihkal: A Chemical Love Story. Transform Press. ISBN 0-9630096-0-5.
- ^ Brophy JJ, Goldsack RJ, Punruckvong A, Forster PI, Fookes CJ (July 1997). "Essential oils of the genus Crowea (Rutaceae)". Journal of Essential Oil Research. 9 (4): 401–409. doi:10.1080/10412905.1997.9700740.
- ^ US patent 4,876,277, Burke BA, Nair MG, "Antimicrobial/antifungal compositions", issued 1989-10-24, assigned to Plant Cell Research Institute, Inc., Dublin, Calif.
- ^ Campbell JL, Kafle A, Bowman Z, Blanc JC, Liu C, Hopkins WS (December 2020). "Separating chiral isomers of amphetamine and methamphetamine using chemical derivatization and differential mobility spectrometry". Analytical Science Advances. 1 (4): 233–244. doi:10.1002/ansa.202000066. PMC 10989161. PMID 38716384.
- ^ National Toxicology Program (2011). "Tetranitromethane" (PDF). Report On Carcinogens (12th ed.). National Toxicology Program. Archived (PDF) from the original on 2013-01-31. Retrieved 2012-08-14.
- ^ Cox M, Klass G, Morey S, Pigou P (July 2008). "Chemical markers from the peracid oxidation of isosafrole". Forensic Science International. 179 (1): 44–53. doi:10.1016/j.forsciint.2008.04.009. PMID 18508215.
- ^ Braun U, Shulgin AT, Braun G (February 1980). "Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine)". Journal of Pharmaceutical Sciences. 69 (2): 192–195. doi:10.1002/jps.2600690220. PMID 6102141.
- ^ a b Clayden J, Greeves N, Warren S (2012). Organic Chemistry. Oxford University Press. pp. 234–235. ISBN 978-0-19-927029-3.
- ^ a b Carey FA, Sundberg RJ (2007). Organic Chemistry B: Reactions and Synthesis. Springer. pp. 403–404. ISBN 978-0-387-68350-8.
- ^ a b Smith MB, March J (2007). March's Advanced Organic Chemistry. John Wiley & Sons. pp. 1288–1290. ISBN 978-0-471-72091-1.
- ^ a b Turcotte MG, Hayes KS (2001). Amines, Lower Aliphatic Amines, Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley & Sons.