The 1 Mol Mescaline Adventure: A High-Yielding Synthesis from 3,4,5 – TMBA to Mescaline HCl
Preface:
Here is a standard run with the latest(-ish) techniques, utilizing 2-HEAA as the catalyst in the Henry Reaction in the first part, and a NaBH4 + CuCl2 reduction in the second. This time the synthesis was monitored with TLC (thin-layer chromatography). This is pretty much the same as the 2C-B write-up up to 2C-H, but now the scale is larger, and the yields even better.
One can also consult this guide when out to make 2C-H, 2C-E from 2C-E benzaldehyde, amphetamine from P2NP, etc...
We really need more Mescaline in the world and it is really not all too difficult to make, so let's get cracking.
Chem info:
3,4,5-Trimethoxybenzaldehyde (C10H12O4, 3,4,5-TMBA) Molecular Weight (M.W.):
196.2 g/ mol, white to slightly yellow solid, flakes. Slightly soluble in water, IPA, MeOH (wiki states in MeOH: 0.1g/ mL). Melting Point: 73 °C
3,4,5-Trimethoxy-β-nitrostyrene (C11H13NO5, 1,2,3-Trimethoxy-5-[(E)-2-nitroethenyl]benzene, 3,4,5-TMNS) M.W.
239.225 g/ mol, bright yellow solid needles or fine powder. Not at all soluble in room temp. water, not very soluble in room temp IPA, methanol (MeOH). Melting Point: 72 - 73 °C
Nitromethane (CH3NO2, NM) M.W.
61.04 g/ mol, density: 1.1371 g/ cm3, slightly fruity smelling clear liquid. Boiling Point: 101.2 °C
Ethanolamine (C2H7NO, monoethanolamine, MEA) M.W.
61.084 g/ mol, density: 1.0117 g/ cm3, viscous colourless liquid with an ammoniacal waft, might fume a bit. Boiling Point: 170 °C
Acetic acid (CH3COOH, AcOH, glacial acetic acid or GAA) M.W.
60.052 g/ mol, density of liquid form: 1.049 g/cm3, heavy vinegar smell. Melting Point: 16 to 17 °C, Boiling Point: 118 – 119 °C
Isopropyl alcohol (IPA) Density: 0.786 g/cm3, Boiling Point: 82.6 °C
Optional: To use as the TLC eluent we need hexane and ethyl acetate (EtOAc)
Part 1:
Synthesis of 3,4,5-TMNS (3,4,5-trimethoxy-beta-nitrostyrene) from 3,4,5-TMBA (3,4,5-trimethoxybenzaldehyde), scale of 250 g / ~1.3 mol+ (The Pretty Bit, Henry Reaction)
1) Start with
250.68 g TMBA or 1.277 mol. Suspend/ dissolve this in
7x IPA or 1760 mL IPA. Use a 5 L beaker with magnetic stirring on a hotplate. Most likely everything will not dissolve at this point.
Previously I ran the reaction without IPA in an excess of AcOH + NM, but the reaction occurs too quickly and everything turns into a thick paste/ mush, I believe it would not go to completion and no crystals would form as well. Possibly lots of unreacted TMBA was trapped in the porridge.
It seems that with IPA it takes longer to react, but the mixture does not seize up and the product crystallizes beautifully as the reaction mixture cools. Yields are satisfactory using IPA as well.
2) Prepare a
15% mol. eq. of 2-HEAA (2-Hydroxyethylammonium acetate) in a separate beaker. Or 0.19155 mol MEA or 11.7 g or
11.56 mL with a bit more
AcOH, 0.192 mol or ~
11 mL. In a beaker pour acetic acid onto MEA, the mixture heats up quite a bit, smoke is released, and it becomes much thicker and more viscous. You could just pour the ethanolamine straight into reaction mixture, but it really does release a lot of heat, so probably illogically I do this separate and wait for it to cool to "protect" the TMBA. As well you can suck away the fumes easier.
Later, during the course of the reaction I decide to pour an
additional 50 mL MEA straight into into the reaction mixture as it seemed the reaction was going slow, so a 15% mol. eq. might not be enough.
3) In total will use a 2x mol amount of AcOH (an excess). Or 2.554 mol. Already used 0.192 mol making the 2-HEAA, so 2.362 or ~
135 mL additional acetic acid. However, later on I add 300 mL more AcOH to help dissolve the benzaldehyde. So just use as much to make sure the benzaldehyde
just dissolves with mild heating. That way when the mixture cools after you have decided the reaction is over, crystals will crash out and grow in the beaker.
4) Use a 1.05 mol. eq. or 1.34085 mol or 81.845 g or ~
72 mL of NM. Reaction starts to proceed slowly at this point, so we need a catalyst. But before adding the 2-HEAA (or straight MEA), make sure the 3,4,5-TMBA is fully dissolved and the liquid is clear (maybe a light yellow). Heating will help to dissolve.
5) Add in the 2-HEAA and still some of the benzaldehyde is not dissolved, so add 80 mL NM, helps to finally fully dissolve the substrate.
6) Will be running the reaction monitoring on TLC plates. After some experimentation I figure out that a
6:2 hexane: EtoAc mixture is ideal as an eluent. But mix 6.5 mL n-hexane with 2 mL EtoAc by error. A 250 mL beaker was the developing chamber for cheap
25 x 75 mm sized TLC plates from AliExpress.
GF254 type
silica gel.
Beforehand,
50 mg of the benzaldehyde was dissolved in
2 mL IPA and kept in a glass vial. This was the benzaldehyde standard (labelled as
Be on the plates).
Run TLC on the first plate 35 min after the addition of the 2-HEAA in hopes of seeing something unexpected. The reaction mixture I draw with a regular pipette and dilute one drop with 0.5 mL fresh IPA. To spot on the TLC plates used a micropipette and 1.5 μL drops.
Rx (reaction) and
Co (combined spot) were about the same as the
Be control. Spots maybe a bit large.
7) After 1 h 25 min add the additional
50 mL MEA, as the reaction seemed to be going slow, don't think it changed much. There is significant colour change at this point, and the liquid is turning more and more yellow. Smoke or some sort of mist forms on the surface of the reaction mixture after addition of MEA, suck it away.
8 ) Take TLC after 1 h 45 min and it does seem to show two spots with some sort of product, a tail above the 3,4,5-TMBA, but there is clearly lots of unreacted BA left. Heating continues...
9) ... and take another plate after 2 h 30 min, but to mix things up I decide to try a different eluent, Make one with 5 mL DCM and 0.2 mL MeOH. The DCM pulls the
Be spot too high, This eluent mixture was more polar than hexane and ethyl acetate one.
10) After 3h TLC shows that much 3,4,5-TMBA remains, so at 3 h 20 min add
30 mL more NM.
11) Made a few more TLC plates and finally after about
7 hours of the reaction running between 50 – 60 °C but mostly at
55 °C, with gentle magnetic stirring, TLC shows only the faintest or no 3,4,5-TMBA spot. At this point the colour change of the liquid had gone from a yellow, to a darker yellow, to an orange then all the way to a dark ruby red. The colour also seems to be a good indicator of when all of the 3,4,5 – TMBA has reacted, in these conditions look out for a dark blood ruby red but not blackish colour.
12) Once removed from heat, stirring stopped, crystals grow fairly quickly and within an hour the beaker is full of
yellow needles. Leave to sit at room temp. overnight.
Now be careful working with the formed nitrostyrene, it is an irritant, and will especially make you sneeze and wheeze. Makes your nose runny, so in general wear a mask when really digging into it.
13) Vacuum filter and set aside the mother liquor to freeze in the freezer to collect a second crop.
14) While still in the Büchner funnel, wash with room temp dH2O.
Wash with a large amount, maybe
700 mL, let the crystals sit and fully soak in the water as well. There is no harm done, they do not dissolve in water. Make sure no smell of AcOH remains, this is what I want to avoid, in the next step water or IPA is no big deal as that is where the reaction will take place, but AcOH is something to avoid. As well AcOH is hard to evaporate and smells bad. That is another advantage of using more IPA in the procedure.
No need to wash with any 10% sodium bisulfite sol. as TLC showed no benzaldehyde remained.
15) Take TLC of the final product. The control
Be or BA (benzaldehyde) lane has an
Rf of 0.5 (eluent front travelled 6.1 cm while the spot travelled 3.05), while the NS (nitrostyrene) lane has a slightly higher
Rf of 0.56. The spot is slightly yellow as the product is yellow. In the Co (combined) lane, there is a NS hat on the BA. Only one spot of nitrostyrene in the NS lane, product seems to be pure, the reaction is a success.
During the course of the reaction, monitoring on TLC, you will see that the hat (nitrostyrene product) will become brighter and the head (3,4,5- TMBA) will fade.
16) From the freezer collect the second crop of crystals. Some more have fallen out, but it is a different colour, bit more greenish-yellow and darker, but they might be more dense. For some reason wash with 10% sodium bisulfite sol. to see what happens, no adduct is formed. Then wash with water.
17) Take TLC of the reaction mixture, and it also shows something similar to nitrostyrene, meaning there should be more product dissolved to collect, but somewhere along the line I forget to dump cold water into the final reaction mixture. The liquid was still a dark red, adding water should have precipitated more crystals. But had dumped out the reaction mixture already.
18) Fully fan dry both crops, the second crop I could have washed with water a bit more as there was a slight odour of acetic acid. Drying does not present a problem and have a fine yellow powder from the first and a more green denser powder from the second crop. Both look very good.
19) I do not recrystallize the batch. There is no benzaldehyde in there, it is dry and looks very clean, don't see a reason to use litres and litres of MeOH in an arduous Re-x and then loose half the product. This turns out to be the correct decision. In the following reaction I still get a good yield, so a re-x is not a prerequisite in this synthesis. It can be skipped if your product is obviously clean.
Yield is 207.26 g from the first crop, 30.74 g from the second. A combined
238 g or 0.995 mol. This is a
75% yield. Would certainly have been higher if I collected a third crop.
Findings and Observations:
To compare, 3,4,5-TMBA is much slower to react than 2,5-DMB. The reaction took about 7 hours in these conditions. The total amount of liquid to dissolve the benzaldehyde just above room temp was about
7.85x its weight. One improvement could be to speed up the reaction, using more heat might help in this case but in general ethanolamine in IPA works well and in pretty good yields to make Mescaline nitrostyrene.
As well, monitoring with TLC helped so much to know what was going on and what decisions to make. Now I know a whole bunch, and now you know. And now I know that if you have some bomb ass looking nitrostyrene then a recrystallization will be a waste of time and nerves. Go ahead and just dump it onto the NaBH4 like we are about to do in the next step.
This link might help as well: hxxps://www.sciencemadness.org/whisper/viewthread.php?tid=157292&page=2
