DMMDA: Difference between revisions

{{short description|Psychedelic drug}}

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| Watchedfields = changed

| verifiedrevid = 414403427

| IUPAC_name = 1-(4,7-Dimethoxy-1,3-benzodioxol-5-yl)propan-2-amine

| image = DMMDA.svg

| image2 = DMMDA-3d-sticks.png

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| legal_CA = Schedule I

| legal_UK = Class A

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| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 15183-13-8

| UNII = Y6T4R5Z3VU

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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 21106291

| ChEMBL_Ref = {{ebicite|correct|EBI}}

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| C=12 | H=19 | N=1 | O=4

| smiles = CC(N)Cc1cc(OC)c2OCOc2c1OC

'''2,5-Dimethoxy-3,4-methylenedioxyamphetamine''' ('''DMMDA''' or '''DMMDA-1''') is a lesser-known [[psychedelic drug|psychedelic]] [[drug]] of the [[substituted phenethylamine|phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical class]]es.<ref name="isbn0-9630096-0-5">{{cite book | vauthors = Shulgin A, Shulgin A | title = Pihkal: A Chemical Love Story | publisher = Transform Press | year = 1991 | isbn = 0-9630096-0-5 | url = http://www.erowid.org/library/books_online/pihkal/pihkal058.shtml}}</ref> It was first [[Organic synthesis|synthesized]] by [[Alexander Shulgin]] and was described in his book ''[[PiHKAL]]''.<ref name="isbn0-9630096-0-5" /> Shulgin listed the [[Dose (biochemistry)|dosage]] as 30–75&nbsp;mg and the [[Time|duration]] as 6–8 hours.<ref name="isbn0-9630096-0-5" /> He reported DMMDA as producing [[LSD]]-like [[mental imagery|image]]s, [[mydriasis]], [[ataxia]], and time dilation.<ref name="isbn0-9630096-0-5" /> DMMDA isn't mentioned much in literature outside PiHKAL unlike [[2C-B]].<ref name="isbn0-9630096-0-5" />

== Pharmacology ==

The [[mechanism of action|mechanism]] behind the hallucinogenic effects of DMMDA has not been specifically established. In ''PiHKAL'', Shulgin asserts that the subjective effects of 75 [[milligram]]s of DMMDA are equivalent to those of 75–100 microgram of [[LSD]]. LSD is a well-known [[partial agonist]] of the [[5-HT2A receptor|5-HT_2A]] receptor.<ref name="isbn0-9630096-0-5" /> This may suggest that DMMDA is a classical psychedelic that is also an [[agonist]] or partial agonist of the [[5-HT2A receptor|5-HT_2A]] receptor.

== Chemistry ==

Shulgin explains in his book that DMMDA has 6 isomers similar to [[Trimethoxyamphetamine|TMA]].<ref name="isbn0-9630096-0-5" /> [[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.<ref name="oil">{{cite journal | vauthors = Brophy JJ, Goldsack RJ, Punruckvong A, Forster PI, Fookes CJ | title = Essential oils of the genus Crowea (Rutaceae). | journal = Journal of Essential Oil Research | date = July 1997 | volume = 9 | issue = 4 | pages = 401–409 | doi = 10.1080/10412905.1997.9700740 }}</ref> 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.<ref name="patent">{{cite patent| country = US| number = 4,876,277| status = patent| title = Antimicrobial/antifungal compositions| gdate = 1989-10-24| inventor = Burke BA, Nair MG | assign1 = Plant Cell Research Institute, Inc., Dublin, Calif. | url = https://patents.google.com/patent/US4876277A/en?oq=US4876277A}}</ref> 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 [[enantiomer]]s due to the methyl group being in the alpha position of the ethyl group in position number 1 on the benzene ring.<ref>{{cite journal | vauthors = Campbell JL, Kafle A, Bowman Z, Blanc JC, Liu C, Hopkins WS | title = Separating chiral isomers of amphetamine and methamphetamine using chemical derivatization and differential mobility spectrometry | journal = Analytical Science Advances | volume = 1 | issue = 4 | pages = 233–244 | date = December 2020 | pmid = 38716384 | doi = 10.1002/ansa.202000066 | pmc = 10989161 }}</ref>

:[[File:Pseudodillapiolesynthesis.png|350px|thumb|left|upright=1.2|Precursors in the synthesis of DMMDA and its regioisomers.]]{{clear-left}}

=== Shulgin's synthesis ===

Shulgin describes the synthesis of DMMDA from [[apiole]] in his ''PiHKAL''.<ref name="isbn0-9630096-0-5" /> 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.<ref name="isbn0-9630096-0-5" /> Isoapiole is then [[nitration|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.<ref name="isbn0-9630096-0-5" /> 2,5-dimethoxy-3,4-methylenedioxybenzaldehyde can also be used as precursors in this step of the synthesis. The 2-nitro-isoapiole is finally [[Reduction_of_nitro_compounds#Reduction_to_amines|reduced]] to [[free base|freebase]] DMMDA by adding it to a well-stirred and [[reflux|refluxing]] suspension of [[diethylether]] and [[lithium aluminium hydride]] under an inert atmosphere.<ref name="isbn0-9630096-0-5" /> The reduction can also be achieved with pressurized hydrogen. Finally, the freebase DMMDA converted into its [[hydrochloride]] salt.<ref name="isbn0-9630096-0-5" />

:[[File:2-nitro-isoapiole.png|600px|thumb|left|upright=1.2|Alexander Shulgin's synthesis of DMMDA.]]{{clear-left}}

=== Modern synthetic methods ===

Shulgin'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.<ref>{{ Cite web | url = https://ntp.niehs.nih.gov/ntp/roc/content/profiles/tetranitromethane.pdf | work = Report On Carcinogens | edition = 12th | year = 2011 | title = Tetranitromethane | access-date = 2012-08-14 | author = National Toxicology Program | publisher = [[National Toxicology Program]] | url-status = live | archive-url = https://web.archive.org/web/20130131171438/http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Tetranitromethane.pdf | archive-date = 2013-01-31 | author-link = National Toxicology Program }}</ref> 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 [[3,4-Methylenedioxyamphetamine|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 [[Baeyer-Villiger oxidation|peracid oxidation]] and finally a [[hydrolysis |hydrolytic]] [[dehydration]].<ref name="Cox_2008">{{cite journal | vauthors = Cox M, Klass G, Morey S, Pigou P | title = Chemical markers from the peracid oxidation of isosafrole | journal = Forensic Science International | volume = 179 | issue = 1 | pages = 44–53 | date = July 2008 | pmid = 18508215 | doi = 10.1016/j.forsciint.2008.04.009 }}</ref> 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 (chemistry)|amalgam]] of [[Mercury (element)|mercury]] and [[aluminium]] or pressurized hydrogen, to yield freebase DMMDA.<ref name="Braun_1980">{{cite journal | vauthors = Braun U, Shulgin AT, Braun G | title = Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine) | journal = Journal of Pharmaceutical Sciences | volume = 69 | issue = 2 | pages = 192–195 | date = February 1980 | pmid = 6102141 | doi = 10.1002/jps.2600690220 }}</ref><ref name="organic">{{cite book | vauthors = Clayden J, Greeves N, Warren S |title=Organic Chemistry |year=2012 |pages=234–235 |publisher=Oxford University Press |isbn=978-0-19-927029-3 |language=en}}</ref><ref name="advanced">{{cite book | vauthors = Carey FA, Sundberg RJ |title=Organic Chemistry B: Reactions and Synthesis |year=2007 |pages=403–404 |publisher=Springer |isbn=978-0-387-68350-8 |language=en}}</ref><ref name="March">{{cite book | vauthors = Smith MB, March J |title=March's Advanced Organic Chemistry |year=2007 |pages=1288–1290 |publisher=John Wiley & Sons |isbn=978-0-471-72091-1 |language=en}}</ref><ref name ="kirk-othmer">{{cite book | vauthors = Turcotte MG, Hayes KS |title=Amines, Lower Aliphatic Amines, Kirk-Othmer Encyclopedia of Chemical Technology |year=2001 |publisher=John Wiley & Sons |location=New York}}</ref>

:[[File:Modernfixed synthesis.png|600px|thumb|left|upright=1.2|Modern synthesis of DMMDA.]]{{clear-left}}

=== General synthetic information ===

Sodium 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.<ref name="organic" /><ref name="advanced" /><ref name="March" /><ref name ="kirk-othmer" />

:[[File:Reductiveaminationexample.png|500px|thumb|left|upright=1.2|The reductive amination of DMMDP2P.]]{{clear-left}}

== References ==

{{Reflist}}

{{Entactogens}}

[[Category:Substituted amphetamines]]

[[Category:Hydroxyquinol ethers]]

[[Category:Mescalines]]

[[Category:2,5-Dimethoxyphenethylamines]]

[[Category:Entactogens and empathogens]]