So I was sitting in my chair last night watching TV when the most
interesting Martha Stewart Living episode came on.
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"Good evening, and welcome to my show. Today I'd like to share
with you a very special family dessert that I like to call
Ecstasy. I find this to be the perfect dish to serve to
guests when the hot summer conversation turns to dull topics
like stocks, bonds, trading and long words such as 'indictment'.
Usually, after just a little bit of this dish the
conversation will correct itself onto happier topics rather
than simply circling around boring Wall St. subjects like a shark.
What follows is a simple recipe I like to use that can be
prepared with (mostly) common household chemicals and a little
bit of advance preperation. Make this in advance, and serve
the crystals in a decorative ice cream dish with a garnish of
mint for cheerful decoration! So without further ado
let's get started with this wonderful dish!
MDA synthesis using (mostly) common household chemicals and equipment
Synthesis route:
1. Freezing to obtain safrole.
2. Sulphuric acid to get MDP2Pol.
3. Household bleach to get MDP2P.
4. Ammonia solution + Zinc (dust or pennies) to get MDA.
5. Acid/base wash, freezing to crystalize product.
Ingredients: (suppliers in parentheses)
150ml pure sassafras oil (essential oil supplier, organic grocery store - essential oils section).
100ml 65-85% conc. sulphuric acid (drain cleaner at hardware store or chemical supply company).
300ml 30% hydrochloric acid (brick or driveway cleaner at hardware store, also called Muriatic acid at pool supply store).
1L household bleach (6%).
2L 5% vinegar (acetic acid 5%).
1L Sodium Hydroxide Solution = NaOH (drain cleaner / red-devil lye from hardware store)
Distilled water.
Pickling salt (NaCl).
pH paper or indicator (fish store, chemical supply company)
50g Zinc dust, or US pennies made after 1983 scrubbed down with steel wool to take off copper plating and expose zinc.
30% industrial strength ammonia (estimated at 17.6M - available at chemical supply company)
1L 70% Isopropyl alcohol (available from the pharmacy)
1L Xylene (paint stripper from hardware store)
Equipment:
Narrow mouthed flask.
Balance or kitchen scale with gram markings.
Industrial strength rubber gloves (hardware store).
Goggles (hardware store).
1L Glass seperatory funnel. (lab supply).
Optional Equipment:
Starch-KI paper. (lab supply)
Hydrometer. (fish store)
Labcoat.
Step 1 - Fractional Crystallization of Safrole: (~1-3 days, distillation is faster if you have the equipment)
[1]
Post 400671
(Arsenic: "You don't have a clue, do you?", Methods Discourse)[2]
Post 220835
(menthol_man: "Safrole Crystals", Methods Discourse)[3]
Post 107751 (missing)
(smokemouth: "DP Harma's Sassafras Freezing technique Modified - scwam", Methods Discourse)Place jar of sassafras oil in freezer for 1-3 days. Allow to freeze, crystals will form at the bottom.
(You may want to create some seed crystals to help this freeze, this involves chilling an open
watchglass/jar in the freezer before you start, then adding a few drops of sassy to the cold surface
to obtain seed crystals. See [3] for details.).
While this is freezing place jar of sulphuric acid, a cup with 1000ml distilled water, 1600ml vinegar,
and a jar of bleach in the refrigerator in preperation for steps 2 & 3. (At this point you may also want to make some
distilled water ice cubes to add for water in step 2 if you really want to help keep the temperature cold).
Freezing point of safrole is 11.2 C.
Pour liquid from top off.
Warm slightly to dissolve crystals. Refreeze. Again pour off liquid from top.
Repeat until crystals are clear.
Pure safrole should have a density of 1.1000 which can be measured with a hydrometer.
The remaining discussion will assume 100ml of safrole as reactant for step 2.
This is 110g of safrole = 110/162.1878 = .6782 mol.
Step 2 - Hydration of alkene to form the alcohol MDP2Pol: (~1 Hour, yield ~95%)
Hydration of safrole [3]
https://www.thevespiary.org/rhodium/Rhodium/chemistry/mdp2pol.html
General Theory - [4a]
http://www-scf.usc.edu/~chem322a/ppt/Chapter_08/322a_Ch_8_06.pdf
General Practice - [4b]
http://www.users.csbsju.edu/~kgraham/cps2.html
To the safrole in the ice bath slowly add 100ml 65%-85% conc. sulphuric stirring vigorously for 10 minutes
while keeping the temperature just warm enough so that the safrole does not freeze.
The reason for keeping the temperature low is that the reaction is subject to rearrangement and
may form MDP1Pol at higher temperatures (see [3]).
Wear goggles, gloves & preferentially do this in a flask pointed away from
you since there may be splattering as you add the sulphuric acid.
The mixture should become a homogenous reddish color.
(Be careful about letting this react too long, the sulphuric forms a
hyposulphate compound with the alkene and may start to polymerize).
Add 100ml of cold distilled water / distilled water ice cubes to the solution (watch for splattering)
and stir for an additional 15 minutes. Now add another 100ml cold distilled water,
200ml cold, dilute NaOH (slowly with plenty of stirring to keep the temperature cold!)
and salt. A greenish white alcohol
layer should form on top of the solution. Collect this oil by
using seperatory funnel to pour off the aqueous layer.
Step 3- Oxidation of MDP2Pol to form the ketone MDP2P: (~1.5 Hour, yield ~95% of step 2 = 90% of step 1)
[5]
http://www.sonoma.edu/users/t/trowbrda/335a/labs/oxidation.html
[6] Journal of Chemical Education Volume 58, p. 824
Original and best reference - [7] Stevens, Chapman and Weller, J. Org. Chem., 45, 2030 (1980).
Place the oil from step 2 in a 2L flask in a bowl of ice water. We are going to use household bleach as an oxidizing
agent to form MDP2P at a cold temperature with minimum rearrangements.
Do this step in a well ventilated area as some chlorine gas may be released
as the bleach decomposes.
First add 1600mL of cold(5%) vinegar, then, slowly add
800ml of cold bleach a small amount at a time with stirring so that the temperature remains cold.
Here we are aiming for a roughly 10% molar excess of bleach.
(The bleach reacts with the acetic acid to form hypochlorous acid - an
oxidizing agent. We cannot simply add the bleach to the dilute sulphuric
acid solution in step 2 because the suphuric acid will decompose the bleach
to chlorine gas and water).
In [7] Stevens et. al. find that household bleach (6%) is approximately 0.9 - 1.0 M
concentration depending on how old it is.
You will know you have an excess of bleach since the solution should be faintly greenish yellow
and a drop of it should turn starch-KI paper blue. (It's OK if you don't have starch-KI paper
here since all you need to do is make sure you have excess bleach.
The starch-KI paper turning blue indicates the prescence of hypochlorous acid.).
Allow the solution to react for approximately 1 hour.
If the reaction is complete, as indicated by a positive starch-KI test,
add dilute sodium hydroxide a little bit at a time until until the solution is slightly basic.
The solution should no longer turn starch-KI paper blue.
Add a small amount of salt to flask. A reddish oil should fall out of the bottom - this
oil is your ketone MDP2P.
Pour the liquid off the top into a second flask and keep the oil. (This is most easily done
via a seperatory funnel).
To the second flask add cold brine water, again more oil should fall out, pour the liquid
off the top and combine the two parts of oil.
Step 5 Reductive Amination (~2.5 Hours, yield ~88% of step 4 = 80% of step 1)
- Formation of imine from MDP2P:
[7] L.G. Wade, "Organic Chemistry, 5th Edition," p. 808
[8]
https://www.thevespiary.org/rhodium/Rhodium/chemistry/alhg.osmium.html
[9]
https://www.thevespiary.org/rhodium/Rhodium/chemistry/znhg.alhg.reductions.txt
To the tune of "Margaritaville"
[10]
http://cstl-cst.semo.edu/Hathaway/CH343/ChemSongs/Spring%202003/Hydrated%20Away%20in%20Organic%20Lab.doc
Reduction of imine to form MDA:
JACS is short for "Journal of the American Chemical Society"
Reductive amination with Zinc:
[10] Emerson, Dorf and Deutschman, "The Activation of Aromatic Halogen by Ortho Ammonium Salt Groups," JACS 62, 2159 (1940)
[11] Emerson, Dorf and Deutschman, "The Reductive Alkylation of Hindered Aromatic Primary Amines," JACS 63, 972, 2843 (1941)
Using Zn as a reducing agent - great overview and discussion of mechanisms - a must have:
[12] T. Nakabayashi, "Studies on the Mechanism of Clemmensen Reduction..." JACS 2, 3901 (1960)
[12b]
http://www.umich.edu/~chemh215/W00HTML/SSG4/ssg2/anim.htm
Microwave Chemistry Reductive Amination and Related:
[13] André Loupy (Ed), "Microwaves in Organic Synthesis", p. 81, p. 202
[14] Brittany Hayes, "Microwave Synthesis: Chemistry at the Speed of Light"
-- see review at
http://www.iscpubs.com/articles/al/a0306how.pdf
(Microwave Clemmensen Reduction? )
[15]
https://www.thevespiary.org/rhodium/Rhodium/chemistry/mw.carbonyl-red.txt
To the ketone from step 4, add a 10x molar excess of NH4OH.
So, .6782 mol / 17.6 * 100 = 385ml --> 400ml of 30% ammonia.
Add conc. HCl in parts to get the pH of the solution to 4.5 (~600ml HCl).
This will favor optimal speed of formation of the intermediate imine - from [7].
Add the HCl in a well ventilated area or under a fume hood as this will
give off copious white ammonium chloride fumes. If you have a large flask with an
addition funnel this would be the way to go.
Add 25g of zinc, 25g of NaCl and 200ml of 91% Isopropyl Alcohol to help solvate
the ketone. Allow the reaction to proceed at room termperature for two hours at which time
90% of the ketone should have reacted and gone into solution as an amine.
This could also be likely speeded up by refluxing, heating in the microwave [14],
or using a Zn/Hg amalgam as per [12]. Here, a fairly good reaction rate is obtained as is
so additional speedups were not attempted. Also, if one wanted to make MDMA
at this step simply use MeNH3 rather than NH4OH.
Theory:
NH4OH <--> NH3 + H2O
R=O + NH3 --> R=NH + H2O (imine formation)
R=NH + Zn + Cl + H+ --> R-NH2 + ZnCl
We are driving the reaction to favor amine formation by:
1. Using excess NH4OH.
2. Using an optimal pH to favor intermediate imine formation.
3. Reducing intermediate imines to amines so they cannot easily revert to the ketone.
4. Using relatively anhydrous conditions to favor the removal of water
(this can be increased by boiling the reaction and distilling
off water as it proceeds).
5. Adding NaCl to maintain a high Cl concentration -- see [12] for details.
This combination seems to give a faster and higher yield than reported in [10] and [11]
where the amount of HCl used likely created strongly acidic conditions that actually
inhibited fast amine formation.
Step 6 - Acid/base wash to remove product and crystallize. (1 Hour)
[16]
https://www.thevespiary.org/rhodium/Rhodium/chemistry/brightstar.mdma.html
step 6 and preceding paragraphs.
Pour off unreacted organic layer via sep funnel using a filter so that your zinc and
crystals at the bottom of the reaction mix don't clog the funnel.
Add any crystals back to the seperated aqueous layer. Add NaOH solution until pH test shows mixture is slightly
basic, zinc sludge should fall to the bottom and any crystals should redissolve.
(Most likely these crystals are largely NH4Cl but they may also contain some product).
Add the liquid to the sep funnel through a filter along with 300ml IPA.
A yellow organic top layer should form and the bottom layer should be clear.
IF THE BOTTOM/AQUEOUS LAYER IS NOT CLEAR ADD MORE IPA AND SHAKE - OTHERWISE YOUR AQUEOUS LAYER WILL
CONTAIN PRODUCT THAT YOU WILL BE DISCARDING!!
Take the yellow orgainc layer you have obtained and add 300ml xylene then slowly drip in dilute (~0.5M) HcL
until the pH of the solution is 5-6 - or just barely acidic. Now remove the oil/Xylene
layer via a seperatory funnel and keep the aqueous layer that contains your product.
Allow the aqueous layer to dry with mild heating to obtain your final product."
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After the show ended, I realized that I must have eaten something that agreed with me since
the TV was still off!! Being a curious chemist, I decided to test the above synthesis route
using 50ml of D-limonene (an inexpensive and widely available alkene). This gave the estimated
yields shown above, the yield in step 5 was estimated using the fact that the ketone is highly insoluble
so at the end of the amination reaction the amount of ketone/insoluble organic residue was measured to
obtain an estimate for how much of the reagent had dissolved as an amine. These early tests show
promise for this synthesis route but more work is needed to see how subject the alcohol and ketone
are to rearrangement even under cold conditions and with the mild oxidising agent of bleach.