Niklas
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(Somewhat bad) Synthesis of Piperonal
I reckon piperonal (also commonly referred to as heliotropine) is a compound most of you will probably be familiar with. It is most commonly known for
being the precursor to MDA-class drugs, particularly the N-methyl analogue MDMA, on the more legal side it and its derivatives also find lots of use
as flavoring ingredients and perfumes though.
Fig.1: Structures of piperonal (left), MDA (middle) and MDMA (right)
There are multiple feasible approaches of making it as the amateur, with ozonolysis (or the Lemieux von-Rufloff reaction) of either piperic acid or
isosafrol being most commonly employed from what I can see.
Fig.2: Oxidative cleavage of piperic acid to piperonal by Lemieux von-Rudloff conditions
This has previously been documented on YouTube by both Chemplayer and Chemdelic, so if you want and overview on that method I recommend checking out
their videos regarding that topic [1][2].
This approach unfortunately has one major downside though, of both potential alkene precursors being relatively hard or really expensive to get on
scales that compensate for the quite unsatisfactory yield of the following cleavage.
An alternative approach would be the methenylation of protocatechulic aldehyde by the Williamson Ether synthesis, which itself can be made from either
vanillin by the action of aluminium chloride and pyridine [3] or from bourbonal by the action of concentrated sulfuric acid, second of those methods
generally seeming the most accessible, being previously documented in another thread [4].
Fig.3: Synthesis of protocatechulic aldehyde by demethylation of vanillin (left) or deethylation of bourbonal (right)
For the methenylation itself the use of diiodomethane would be ideal, but because of its significantly higher accessibility and lower molecular weight
DCM shall be employed. Following [5] on the example of unsubstituted methylenedioxybenzene the use of sodium hydroxide as the base and DMSO as the
solvent may be reasonably successful.
Fig.4: Proposed synthesis of piperonal by methenylation of protocatechulic aldehyde
To get things started, inside an 100 ml RBF, 9,12 g of sodium hydroxide (0,23 mol) were dissolved in 10 ml of dest. water and cooled back down to room
temperature. This was followed by 20 ml of DMSO and left to stirr for a couple of minutes, during which time things turned a uniform slushy
consistency (probably due to NaDMSYL precipitating). A Dimroth-condenser was attached and the flask was warmed to 95-100°C with the help of a heating
block, resulting in a clear colorless solution.
 
Fig.5/6: Slushy of presumably NaDMSYL (left) and eventual clear solution of the base (right)
To this 13,8 g of commercial protocatechulic aldehyde (0,1 mol) were added as a powder, instantly causing the mixture to discolor and eventually take
on an almost black color. Heating was continued for 30 more minutes, during which time a separate reflux apparatus containing 12 ml of DCM (0,19 mol)
in 30 ml DMSO, heated to 70°C with the help of a glycerol bath, was set up.
 
Fig.7/8: Strongly discolored solution of the protocatechulic aldehyde (left) and the apparatus used for the preparation (right)
The hot aldehyde solution was slowly added to the refluxing DCM solution in 4-6 ml portions each with the help of a pipette over the course of 45
minutes, and the reaction flask washed out with 5 more ml of DMSO. On each addition vigorous boiling of the DCM could be perceived, which could only
be contained by the use of ice water in the condenser.
The temperature of the glycerol bath was risen to 100-105°C, and heating was continued for approximately 3 hours. To isolate the piperonal a steam
destillation of the black mixture was performed until the destillate coming over was fully transparent.
 
Fig.9/10: Final reaction mixture after combining the two solutions (left) and performing the steam destillation (right)
In total almost 100 ml of destillate were collected, with lots of product freezing in the condenser. Things were extracted three times with DCM, the
pooled extracts were washed with 2 molar sodium hydroxide solution (this took up all the slight yellow color there was) and saturated brine, and dried
over sodium sulfate. The solvent was rotovaped off, and a vacuum of 0,3 mbar was pulled on the product to remove any dimethylsulfide present from
decomposition of DMSO. This resulted in a small quantity of crystalline off-white solid (0,97 g; 6,46%) with a melting point of around 30-35°C with a
clear residual dimethylsulfide smell.
 
Fig.11/12: Rotovaping off the DCM (left) and the final crystalline piperonal (right)
Obviously this outcome is far from satisfactory, and there is definitely room for improvement. I‘m not even fully sure where things went wrong this
badly, so definitely let me know your suggestions. I‘m personally under the suspicion that there may still be product in the reaction mix that
didn’t steam destill over quickly enough, so I‘m probably gonna try further steam destilling the black solution on the weekend.
Besides the yield being absolutely miserable, the presence of an dimethylsulfide contaminant makes the product basically useless for my originally
intended purpose of perfumery, so rather then trying to fully purify the already small quantity potentially losing most of it on the way, I decided to
perform a Henry reaction with Nitromethane according to Shulgin’s procedure for BOH so I at least end up with some nice colorful crystals [6].
Fig.13: Synthesis of 3,4-(methylenedioxy)-beta-nitrostyrene by Henry condensation of piperonal and nitromethane
In addition to the piperonal made in the previous procedure a small quantity of an old commercial sample was added to add up to 1,5 g of starting
material (10 mmol). This was dissolved in 5 ml of glacial acetic acid by swirling the flask and set in a heating block on a magnetic stirrer. To this
292,2 ul of ethylene diamine (4,37 mmol) was added with the help of an eppendorf pipette, followed by 1 ml of nitromethane (18,46 mmol), instantly
causing the colorless mixture to take on a yellow color.
 
Fig.14/15: Solution of the piperonal in GAA (left) and the reaction mixture after addition of the nitromethane (right)
Stirring was turned on and things were heated to 100°C for 45 minutes, during which time some yellow needles of product started precipitating. The
suspension was cooled in the fridge, and the solid was removed by vacuum filtration and washed with a little dest. water.
 
Fig.16/17: First precipitation of product (left) and the reaction mixture after cooling in the fridge (right)
For further purification the product was recrystallized from 1-propanol, resulting in some gorgeous thin yellow needles of
3,4-(methylenedioxy)-beta-nitrostyrene (1,34 g; 69,44%).
 
Fig.18/19: The air dried product (left) and its crystals under the microscope (right)
Sources:
[1] https://youtu.be/FjVVX_uASms?si=n0AG51hO9kl3eL6p
[2] https://youtu.be/thWbD1FO2iw?si=n5C4GA6eqfMpwTRx
[3] https://patents.google.com/patent/CN102241575B/en
[4] https://www.sciencemadness.org/whisper/viewthread.php?tid=15...
[5] https://www.erowid.org/archive/rhodium/chemistry/methylenati...
[6] Shulgin A., Shulgin A. (1991). PiHKAL. BOH; ß-METHOXY-3,4-METHYLENEDIOXYPHENYLETHYLAMINE. p.496
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clearly_not_atara
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I think it looks pretty nice.
I think you get the oxime or the nitrile or something if you reduce the nitrostyrene with CrCl2.
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jackchem2001
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DCM is said to act poorly as an alkylating agent due to an anomeric-type effect of its most favorable conformation. Perhaps some catalytic iodide in
the reaction would help.
In the same vain, diiodomethane could be accessed using DCM in a solvent which dissolves the iodide salt (e.g. NaI in EtOH or acetone) but not the
chloride. It is also higher boiling which again could help.
Alternatively, perhaps the acetal could be formed with formaldehyde.
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Niklas
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Quote: Originally posted by jackchem2001  | | DCM is said to act poorly as an alkylating agent due to an anomeric-type effect of its most favorable conformation. Perhaps some catalytic iodide in
the reaction would help. |
Seems like a good idea, with DMSO already being the solvent there shouldn’t be much else to change up besides adding a little potassium iodide to
the DCM solution. Will definitely try that out.
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Boffis
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Hi Niklas, another nice write-up! Its good to see some real chemistry still being done.
I have often wonder if it would be better to start from catechol --> methylenedioxybenzene --> piperonal.
With catechol there are fewer functional groups o worry about and there are many formylation methods then available to choose from.
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Niklas
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Thanks Boffis!
I’ve thought about that as well, tho I never came to a conclusion that fully satisfied me. Most of the really good OTC formylation approaches
(particularly Duff reaction) are unfortunately ortho-directing, and the alternative of doing a two-step approach via the Blanc-reaction followed by
Kornblum-oxidation (something similar should be documented on Erowid iirc), comes with the significant downside of forming highly carcinogenic BCME as
a byproduct in the first step..
Additionally I‘m really not sure about the accessibility of catechol for the average amateur. I know it is occasionally found in oxygen absorption
packs, but I feel like that’s a really expensive way of getting a reagent..
Like sure, I could personally use my catechol bought at Sigma and formylate that with my TCT / DMF purchased from TCI, but that feels like defeating
the purpose of publishing it here.
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yobbo II
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Catechol can be had in the Agri. store sometimes.
It is used for testing spuds.
https://cropwatch.unl.edu/potato/bruise_testing
Yob
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clearly_not_atara
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Glyoxylic acid is an interesting possibility. It is an extra step.
Alkyl glyoxylates are occasionally reported to undergo basically the same reaction. My hypothesis is that making them from dialkyl tartrates might be
easier than making glyoxylic acid from tartrate + periodate, because the resulting mixture of salts is very hard to separate and makes that method
harder (glyoxylate and iodate have similar solubility). Periodate can also work for the ester cleavage step, which is nice.
So the reaction of an alkyl glyoxylate with benzodioxole is the idea I'm most interested in working with benzodioxole. You could degrade the
methylenedioxymandelic ester in the usual fashion or possibly do something creative.
EDIT: Gathergood et al show ethyl glyoxylate reacting with various anilines and with 2-methylfuran, although they didn't give a yield for the reaction
with dimethylresorcinol (so it probably didn't work). But their catalyst was Cu(OTf)2, which is a relatively weak Lewis acid, so I think there's a
good chance that it works with a stronger catalyst or a Brønsted acid.
Jurczak et al show ethyl glyoxylate reacting with various toluenes using AlCl3 or SnCl4 as a catalyst. Still no anisoles. But if it works with both
toluene and phenol, anisole seems extremely likely, with the right catalyst. My hunch is that ZnCl2 would be good.
Attachment: gathergood2000.pdf (184kB)
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Attachment: jurczak2008.pdf (143kB)
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[Edited on 3-10-2024 by clearly_not_atara]
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Boffis
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@ clearly_not_atara; What's wrong with a reaction analogous to the guaiacol + glyoxalic acid route to vanillin? The only issue I see is that in this
reaction aqueous alkali is used in which both reactants are soluble. Where as the methylene-dioxybenzene ether will not be. But cold say methanol be
used as the solvent? Rather than using the less accessible glyoxalate ester.
@ Random; what are you on?
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clearly_not_atara
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Boffis: Unlike guaiacol, benzodioxole does not form a phenolate, so it does not react spontaneously without an acid catalyst. Alkali catalysis is not
available on benzodioxole. But with acid catalyst, usually some sticky crap is produced. I have heard that conc. H2SO4 at 0 C is a good system, but
this reagent is restricted now, and dehydrating sulfuric acid is unpleasant.
So the idea was to use things which are more soluble in np, allowing the product mandelate ester to be extracted from the rxn mixture. This might be a
less "sticky gunk" situation.
Also, Waffles SS said that the oxidation of tartaric acid with periodate was too much of a pain, and he preferred to use nitric acid and glyoxal
instead:
https://www.sciencemadness.org/whisper/viewthread.php?tid=77...
So here once again the production of the ester from dialkyl tartrate might be better, even though diethyl tartrate has a poor aqueous solubility. It
is nice to have fewer steps, but if you replace messy rxns with a few clean ones, that could be a bigger advantage, maybe.
EDIT: or the mandelic ester might be converted to the amide directly (slow) and subjected to the Weerman degradation:
https://en.wikipedia.org/wiki/Weerman_degradation
EDIT2: Fellinger et al describe the ester ammonolysis of ethyl benzoate, a reasonably hydrophobic model compound. Ammonium benzoate is a preferred
catalyst. But the paper used a stoichiometric amount of anhydrous ammonia in an ampoule, which is a bit unlike the more common practice of using an
excess of aqueous or alcoholic ammonia. Rxn time is about 400 hours for 75% conversion, which is obviously a little annoying.
[Edited on 5-10-2024 by clearly_not_atara]
Attachment: fellinger1938.pdf (298kB)
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Niklas
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I totally didn’t think of that, I remember seeing this method being used to make 4-hydroxybenzaldehyde a while back.
Definitely sounds promising with the right catalyst used.
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Niklas
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| Quote: Originally posted by Random |
Synthesis of 4-hydroxybenzaldehyde is still how I could say, subject to discussion.
...
I say that because there were various attempts at synthesizing it and also according to my personal memory it is not that easy to separate it from
other isomer. Is isomer how we call that.
[Edited on 6-10-2024 by Random] |
This paper makes it seem pretty viable
“The condensation of phenols with glyoxylic acid is known to be very specific for the formation of para isomer and generally ortho isomer is
absent.“
https://doi.org/10.1002/jctb.280360107
In any case the properties of 4-hydroxybenzaldehyde and salicylaldehyde should be fairly different, my guess would be that the unwanted ortho isomer
could easily be removed by steam destillation.
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Niklas
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On a different point, something that just came to my head.
I now think the main issue with the piperonal synthesis probably is the use of NaDMSYL and hydroxide as the base, which may cause the aldehyde to
disproportionate in a Cannizzaro like fashion.
So by using much weaker potassium carbonate instead, which shouldn’t impact the reactivity all that much considering the acidic nature of the phenol
hydrogens, this may result in a significant improvement of yield.
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clearly_not_atara
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| Quote: Originally posted by Niklas | On a different point, something that just came to my head.
I now think the main issue with the piperonal synthesis probably is the use of NaDMSYL and hydroxide as the base, which may cause the aldehyde to
disproportionate in a Cannizzaro like fashion.
So by using much weaker potassium carbonate instead, which shouldn’t impact the reactivity all that much considering the acidic nature of the phenol
hydrogens, this may result in a significant improvement of yield.
|
This is correct; in the original Bonthrone and Cornforth, the methylenation of protocatechualdehyde with hydroxide base gave a poor yield, but when
the rxn was later attempted in a forensic chemistry (lol) journal with K2CO3, the yield was around 80%.
The difficulty with K2CO3 is finding an appropriate solvent. NMP is a better solvent for potassium carbonate than are DMF or DMSO, and this is what
the researchers were using. IIRC, K3PO4 has a better solubility in more common solvents. Beitia et al describe its use in DMF at 100 C, in DMSO at 80
C, and in glycol ether solvents.
Attachment: k3po4_beitia2011.pdf (79kB)
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Attachment: gallagher2012.pdf (1MB)
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Niklas
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| Quote: Originally posted by clearly_not_atara |
The difficulty with K2CO3 is finding an appropriate solvent. NMP is a better solvent for potassium carbonate than are DMF or DMSO, and this is what
the researchers were using. IIRC, K3PO4 has a better solubility in more common solvents. Beitia et al describe its use in DMF at 100 C, in DMSO at 80
C, and in glycol ether solvents.
|
Somehow didn’t came across this paper, definitely some useful information right there.
It got me thinking about something I remember seeing in PHiKAL a lot..
What do you think of possibly using acetone as the solvent with some kind of quaternary ammonium phase-transfer catalyst added? I think I still have
some hexadecyltrimethylammonium bromide around I could test this with. I‘ve never seen it being utilized this way before, but maybe benzalkonium
chloride could act as an more generally accessible alternative as well.
Not that getting them is too difficult for me, I just really don’t like working with the common solvents you mentioned because of their difficulty
of fully being removed from the product. Not that it’s impossible, but it’s definitely a pain compared to a high volatility solvent like acetone.
(Admittedly, this may just be me being biased to some extent because of my previous work with polymers, but anyway xd)
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sykronizer
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getting back your piperonal
you might find that sodium metabisulphite (brewing sterilizer) is excellent at recovering these aldehydes as opposed to a lengthy steam distillation.
Once recovered, you could extract any unreacted di-hydroxy-aldehyde with a weak solution of sodium hydroxide.
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clearly_not_atara
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| Quote: Originally posted by Niklas |
Somehow didn’t came across this paper, definitely some useful information right there.
It got me thinking about something I remember seeing in PHiKAL a lot..
What do you think of possibly using acetone as the solvent with some kind of quaternary ammonium phase-transfer catalyst added? I think I still have
some hexadecyltrimethylammonium bromide around I could test this with. I‘ve never seen it being utilized this way before, but maybe benzalkonium
chloride could act as an more generally accessible alternative as well.
Not that getting them is too difficult for me, I just really don’t like working with the common solvents you mentioned because of their difficulty
of fully being removed from the product. Not that it’s impossible, but it’s definitely a pain compared to a high volatility solvent like acetone.
(Admittedly, this may just be me being biased to some extent because of my previous work with polymers, but anyway xd) |
It could work. I think that K2CO3 would probably be better for this, since an aqueous solution of it will contain fewer hydroxide ions.
Another possibility is 1,1-diethoxyethane, which might be a less carcinogenic alternative to the glycol ethers. I admit I'm basically guessing that
the properties are similar, but the molecules do look a lot alike. This is produced by the anodic oxidation of ethanol using a quaternary ammonium
chloride electrolyte, which you happen to have. See attached.
Attachment: Li2021.pdf (680kB)
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Texium
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Thread Split
11-10-2024 at 13:48 |
Mateo_swe
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You can make Benzodioxole from catechol and Ch2Cl2.
Then react this with glyoxylic acid to get 3,4-methylenedioxymandelic acid.
Then to piperonal using O2 and CuCl2 or using AgNo3.
See attached paper
Attachment: 1488-Bjorsvik.Liguori.Minisci.Synthesis.Vanillin.Isovanillin.Heliotropin160c.pdf (183kB)
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Niklas
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That’s definitely a nice one, didn’t expect it to be a documented approach honestly. Really promising yields as well, seems worth giving a try (as
far as the optimized alkylation procedure I‘m planning on trying next week ends up being unsatisfactory at least).
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Niklas
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Greetings everyone, I honestly ended up procrastinating on revisiting the synthesis again, but here we go finally.
As a disclaimer, the approach I tried still kinda quite sucks, while the yield isn’t as bad, and the product seems to at least be actually
pure this time, it’s still definitely not what I‘d consider satisfactory. Probably on me tho, I‘m starting to think that steam distillation
probably really just is an awful way of working the mixture up (don’t ask me why I ended up ignoring the advice given for that), and I may
eventually revisit the procedure using an extraction process in the workup (potentially by extracting with ethyl acetate, washing this with brine to
remove residual DMF, removing the solvent, and vacuum distilling the residue).
Anyway, here the actual synthesis now:
A 100 ml round-bottom-flask was charged with 6,91 g protocatechulic aldehyde (50 mmol), 16,59 g anhydrous potassium carbonate (120 mmol), 1 g
potassium iodide and 500 mg hexadecyltrimethylammoniumbromide. 60 ml of DMF were added dissolving most of the solids, resulting in a brown suspension
of undissolved carbonate. This was followed by the addition of 6,5 ml DCM (101,4 mmol), a condenser was attached, and the mixture was heated to 90°C
in a heating block for 36 h, where on analysis with TLC (3:1 n-hexane / ethylacetate) at the twelfth hour most of the starting material seemed to
already be converted. After cooling the resulting dark-brown solution was diluted with water, and the mixture was steam destilled until around 1600 ml
of destillate had been collected, at which point the destillate seemed no more cloudy with no more oil separating. This was extracted three times with
ethyl acetate (DCM heavily tends to form emulsions here), the yellowish extracts were washed with dilute brine, the solution dried over anhydrous
sodium sulfate, and the solvent removed under rotary evaporation. This resulted in a small quantity of a yellowish oil, which on cooling to -20°C in
the freezer solidified resulting in a white crystalline solid with a flowery smell. 3,00 g ; 40%
 
Fig.1-2: The progress of the reaction
Fig.3: Performing the steam distillation
Fig.4: Crystallized, still slightly wet piperonal
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clearly_not_atara
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Here's the problem: you used 50 mmol protocatechual and 100 mmol DCM, a 2x molar excess.
Gallagher et al used 3.62 mmol protocatechual and 78.3 mmol DCM, a 21x molar excess.
So if you try again with ten times as much dichloromethane... 
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Mateo_swe
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Nice experiments.
Well Cycloknight also got around 40% yield using NaOH, DMSO and DCM.
Im sure you read about it already but if you havent here is a link (pdf writeup in the end of the thread).
https://www.sciencemadness.org/whisper/viewthread.php?tid=14...
Maybee around 40-50% is all one can get if not raising the pressure in a closed vessel.
There is a older paper where they got really high yields using TBAB in a closed reactor but i dont remember where i put it.
I probably can dig it up if anyone want it.
If i remember correctly the pressure didnt rise especially high so it might be doable.
But putting flamable solvents in a closed steel vessel and heat it is only for the brave and stupid.
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Mateo_swe
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So i found the old patent, it´s US4183861 - Process for preparing aromatic methylenedioxy compounds.
They got a 70% yield of piperonal using DCM, TBAB, NaOH and protocatechulic aldehyde, doing the reaction in an autoclave.
The pressure increased to 2.4 atmospheres during the reaction.
That isn´t so much pressure, maybe one could do this in a stainless steel hydrothermal reactor (or a DIY variant).
I think even the glass pressure flasks can handle this pressure.
I guess doing the reaction in a autoclave (or closed reactor) will also have the same effect as doing it in an oxygen free environment.
This plus the pressure maybe will get higher yields.
I wonder why they added so much TBAB though, shouldn´t a much smaller amount work?
I mean, it´s just a catalyst and doesnt get consumed in the reaction.
Maybe one can recover the PTC easily for the next run.
But, one never know with these old patents.
Maybe they left some detail out that is needed for this to work as stated.
It´s a patent after all and maybe they didnt want their findings to be copied without paying them some fee, so they left a bit of the procedure out
so it couldnt be copied so easily.
But it might just work as specified also, only a test run would tell.
I add the patent pdf.
EXAMPLE 4: PIERONAL:
Methylene chloride (100 ml., 1.56 moles), tetrabutylammonium bromide (6.42 g., 0.02 moles) and water (200 ml.) are placed in an autoclave.
A total of 27.6 g. of protocatechic aldehyde (0.2 moles) and caustic soda (24 g., 0.6 moles) in water (20 ml.) are then added to the autoclave in
stages at a temperature of 70 degrees C.
The pressure within the autoclave increases to a maximum of 2.4 atmospheres and the reaction is completed within four hours.
The reaction mixture is allowed to cool to ambient temperatures and the organic phase is separated. Excess methylene chloride is recovered from
the organic phase by distillation and high purity piperonal (21 g., 70% yield) is isolated. The product is identified by gas chromatography and
infra-red spectrum analysis by comparing against a pure sample.
Upon substituting tetramethylarsonium chloride, for the tetrabutylammonium bromide of Example 4, and otherwise following the procedure
described therein, an identical piperonal product is obtained.
Attachment: US4183861 - Process for preparing aromatic methylenedioxy compounds (with a PTC in autoclave).pdf (385kB)
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Niklas
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| Quote: Originally posted by Mateo_swe |
The pressure increased to 2.4 atmospheres during the reaction.
That isn´t so much pressure, maybe one could do this in a stainless steel hydrothermal reactor (or a DIY variant).
I think even the glass pressure flasks can handle this pressure. |
That seems very quite achievable, I agree. Even just doing it in a “bomb pipe“ (that’s the literal translation from how we call it in German) by
just melting the mixture into a single use ampoule of somewhat thicker glass should definitely be an option, probably the cheapest of all.
And yeah, that catalyst quantity definitely seems quite excessive, tho scaling the quantity I used up to their scale won’t result in all that low of
an amount either (around 2 g I guess), as those quaternary ammonium salts just have a considerably high molecular weight. Either way I still
wouldn’t use more than those 2 g tho.
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Niklas
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| Quote: Originally posted by clearly_not_atara | Here's the problem: you used 50 mmol protocatechual and 100 mmol DCM, a 2x molar excess.
Gallagher et al used 3.62 mmol protocatechual and 78.3 mmol DCM, a 21x molar excess.
So if you try again with ten times as much dichloromethane...
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I guess I‘ll probably give that change a shot as far as I attempt the synthesis again, not like this will add much of any cost anyway. It does feel
like really excessive of an amount, but I honestly wouldn’t be surprised if it really does need that much to work properly.
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