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Benignium
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Vanillin chemistry: Piperonal
I recently became aware of the surprising potential of vanillin as a precursor to various interesting compounds, notably those belonging to the class
of substituted phenethylamines. If you've encountered some of my other posts here on Sciencemadness, you may have deduced that psychoactive compounds
are a preferred way for me to study and learn chemistry. With that said, my goal with this thread, as the title suggests, is to only go so far as to
form the 3,4-methylenedioxy substituent, obtaining the corresponding benzaldehyde, piperonal. With that said, I do hope to eventually go on
to explore the phenethylamines further along this path as well. They're just not that high on my list of priorities right now.
Right. So, for the first step we are going to demethylate the vanillin. This reaction has a reputation of being somewhat tricky.
My understanding is that what likely happens is the formation of an organoaluminium intermediate which, in the case of our methoxy group, causes the
methyl to "make like a tree and fuck off". The methyl carbon gets yoinked (somebody please help me with the terminology) by a chloride, and the two
conveniently depart as gaseous chloromethane as illustrated by this crop of a picture I stole:
Much of the infamy here appears to stem from the fact that one should do their very best to exclude water from the reaction. So, naturally, I did not.
I had received my DCM practically anhydrous (P.F.A.) in a one liter bottle, and the amount I used here was, aside from a portion collected for later
recycling, the last of it. At no point did I dry any of it, so it was bound to contain quite a bit of moisture. The bigger problem, however, was my
pyridine. I had made it by the decarboxylation of nicotinic acid, and only removed water from it by doing a final distillation from a mixture with a
very liberal amount of sodium hydroxide. I also overloaded the 200 mm vigreux I was using with a 1000 mL RBF, painstakingly minimizing the benefits of
doing a fractional distillation.
At least the aluminium chloride I used was anhydrous. Shout out to Onyxmet!
The reaction
In a 1000 mL two-necked RBF was added methylene chloride (161 mL, 2.53 mol), vanillin (25 g, 164 mmol) and anhydrous aluminium chloride (24.87 g, 187
mmol). The mixture immediately took on a magenta color which developed to a stunning violet on standing. With powerful stirring, pyridine (58.5 g, 740
mmol) was added dropwise over 40 minutes at an ambient temperature of -15 deg. C. During addition, the reaction mixture went through a spectrum of
gorgeous pastel colors. Using the 250 mL addition funnel as an air-cooled condenser, the mixture was heated to reflux. After refluxing for 23 hours
hydrolysis was carried out by first adding 60 mL of dilute 5M hydrochloric acid, after which concentrated acid was added until two perfectly clear
phases were obtained and the aqueous phase was strongly acidic to litmus. In total, approximately 1.25 moles of acid was used.
Initial magenta color
Before the first drops of pyridine
Addition started
Addition complete
Nearing the end of reflux
Refluxing stopped
After the first drops of acid
After 60 mL of 5M acid
Completion of hydrolysis
The work up
The two phases were separated and the aqueous phase retained. This was then exhaustively extracted with several small portions of diethyl ether. The
extracts were pooled together and stripped of solvent. The residue was then dissolved in ethyl acetate and the solution was left to evaporate. Two
distinct-looking crystalline growths were observed. After the solvent had evaporated, recrystallization was attempted from water. Once more two kinds
of different crystals formed, even more distinct than before. Once complete, the crystalline mass was gently mixed to form a slurry and carefully
heated until, with swirling, the lighter-colored crystals could completely dissolve, conveniently leaving the darker material practically unaffected.
The remaining solids were filtered out and dried. The lighter material was then crystallized by once more chilling down the mother liquor and
collected. Melting points were determined for both, revealing the lighter solids to be unreacted vanillin (mp. <100°C and the darker solids as the
product, protocatechualdehyde (mp. 152.5-156°C).
The crude product was crushed into a fine powder and washed with three portions of boiling 60-90 petroleum ether to rid it of remaining vanillin. The
solubility of the product in the boiling pet ether was negligible. Finally, the product was recrystallized from toluene. Even in boiling toluene the
solubility of the product was absurdly low, but, interestingly, it was possible to assist the dissolution by adding some 5 mL of methanol and boiling
it all off as the azeotrope with toluene, keeping the product completely dissolved (in ~200 mL of toluene) even after reaching the boiling point of
pure toluene. After chilling down the toluene, uniform looking crystalline product weighing 1.25 (5.5% on starting vanillin) grams was obtained.
Aqueous phase containing the product
Ether extraction
Residue from ether
Crystals forming from ethyl acetate
Crystals forming from water
"Crystals" of crude product resembling L. williamsii (peyote cactus)
Washed product loaded into a flask that ended up being too small
Complete dissolution following addition of methanol
Crystals of protocatechuic aldehyde
Discussion
What a beautiful reaction! I'm not entirely sure whether all the different colors were typical or if they were just the result of impurities such as
water of which, as we've established, there was a significant amount. I am certain that this was a major factor in the poor yield. Another likely
reason, possibly directly linked to the presence moisture, was the reaction time which probably could have been increased to compensate. In the future
I will hopefully be able to observe the progress in most such cases as I've finally ordered a bunch of TLC plates. In any case, I doubt I would
increase the reaction time even if I could go back with this knowledge, as I don't feel the time:product ratio was quite there. I'd rather explore the
exciting world of using my damn molecular sieves to dry my reagents. Lastly, the amount of dichloromethane I used was considerably less than what was
used in the reference [link]. This may or may not have been detrimental. At the very least I think it was enough to sufficiently dissolve everything.
Overall I am happy having had any success at all as it does wonders to my confidence, particularly for whenever I repeat this experiment. I would very
much like to attempt the preparation of piperonal with a bit more starting material and at the same time retain a fair sample of this compound. It is
therefore most likely that a second attempt takes place before this thread concludes.
Now a little bit about the compound itself. I was initially intimidated to the point of slight anxiety by the reported instability of the compound.
However, I found that it fares just fine at reasonable temperatures for the amounts of time required to work at a normal pace. I believe it would do
well at room temperature even for prolonged periods of time. I will, however, be storing my sample in the refrigerator. If choosing to recrystallize
from toluene, the amount of time at or near the solvent's boiling point should be minimized. At 110°C the formation of some red amorphous degradation
product became evident in a matter of minutes. For this reason I would caution against xylenes or other higher-boiling alternatives. As for oxidation
by air, I observed no discernable degradation.
What else, what else...? Yeah, no, I think that's about the size of it. Thanks for dropping by! Feedback, questions and related experiences are all
greatly appreciated.
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karlos³
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Good job!
I used the same procedure on two aldol products of 3,5-dimethoxybenzaldehyde and octanal/nonanal, to make olivetol derivatives.
I still have one of them readily stored away.
Its a really neat and simple procedure.
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Benignium
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Thank you, karlos!
And oh my god does that sound cool! I recall doing some surface-level reading into what some obscure domestic source had described as "lichens that
produce a cannabinoid" or something to that exact effect. Years ago, when I barely knew any chemistry at all. I did run into olivetol then, and never
really gave it any thought since.
It's a whole 'nother world out there. I have so many questions!
How is the stability of the 3,5-dimethoxybenzaldehyde? As I understand it, benzaldehydes can be sensitive (to oxidation?) due to missing the 4-phenol.
How do you view this claim?
Carrying out syntheses into the direction of olivetol/cannabinoid derivatives, have you encountered any particularly memorable compounds in terms of
aroma, instability, toxicity etc.?
Which approach did you choose to get to 3,5-DMBA? Would it still be your choice?
What advice would you give for reattempting this procedure with vanillin? What would be the most important things to keep in mind to promote this
neatness and simplicity that you speak of yet my yield here does not reflect? Even if it's just simple things, it's good to be reminded.
Would you use the same reagents, or change something?
You'll have to excuse the bombardment, I'm a sucker for insight 
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karlos³
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Hehe 
Yeah well, the stuff is pretty stable, but I have to admit I just bought it.
Initially I thought I'd make it from 3,4,5-trimethoxybenzaldehyde(using finely divided sodium in THF, a day at RT, then hydrolysis with water... or
alkylation with an alkyl halide at 4-), but I took the easy route and just asked for a few grams of it.
Of course only after I got the 3,4,5-TMBA 
I still have some, its seven years old and barely degraded, also the remaining olivetol derivative.
The other was used up in a nonsuccessful experiment to react it with citral...
The other is saved for when I either have the right catalyst or the right reagent moiety on hand(like pulegone or such).
I have done this only twice so far, but I was surprised how well it has worked.
As for how I have proceeded, I can just point to the erowid article, I don't even know in which notebook(if I even have it anymore) the procedures is
noted down.
I think I did it just like they wrote there.
Really I do not have much memories on how I did that, its so long ago now.
I'll write you an U2U on such matter I guess.
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SWIM
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It's been a while since I concerned myself with this reaction, but I believe the intermediiate is a hetrocyclic compound formed by the aluminum
chloride coordinating with the methyl group and the aldehyde group.
It's all a little hazy, and I'll look it up, but I think this is why it won't work on the 4 methoxy isomer of this compound.
Nice reaction though.
If I remember it right, those guys at Monsanto who invented it got some high yields, but I don't see any reports of home chemists coming close.
But I bet you'll see some improvement with drier pyrridine.
Good luck on adding that methyl group. Are you thinking diiodomethane or dichloromethane?
That's one reaction I just don't get.
It looks kinda like a Willaimson ether synthesis (but on a phenol to make a phenol ether of course), but also looks terrifically hindered by the
structure so maybe it works some other way.
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draculic acid69
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Synthesis of custard donut complete:
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Texium
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Nice write-up! I worked with 3,4-dihydroxybenzaldehyde a LOT in undergrad, as it was the starting material for the natural product that I was
studying. It's annoying stuff to be sure. Even from reputable suppliers it comes as a beige/brown solid. We stored it in the fridge. I tried purifying
it a couple times by recrystallization from different solvents, and it only made it worse. Same with an attempt at preparing the bisulfite adduct,
recrystallizing and regenerating. Better to press on with the next step, as piperonal is much more stable and pleasant to work with.
My attempts at purifying the starting material were born out of curiosity rather than necessity. The first step in my synthesis was protecting the
phenols as silyl ethers. The di-TBS protected compound was much easier to purify and would come out as a nice off-white, waxy solid after trivial
column chromatography that would keep well in the fridge for months. I ran that protection reaction on a 40 gram scale once (which is a huge scale for
an academic lab; my PI was a bit anxious).
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clearly_not_atara
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Congratulations on beating Level 1. Level 2 is harder
Generally, results in the methylenation are much better if a high-boiling polar aprotic solvent such as DMSO or DMF can be used. This is practically
necessary if the reaction is to be run with DCM as otherwise the high rxn temperature cannot be achieved at normal pressure.
https://erowid.org/archive/rhodium/chemistry/methylenation.b...
...or, you can use water+TBAB in an autoclave:
https://pubs.acs.org/doi/full/10.1021/op0000529
[Edited on 04-20-1969 by clearly_not_atara]
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morganbw
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A really nice post and write-up. I have some desires to do some of the same chemistry but have not yet.
Thank you.
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SWIM
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I was wrong about the intermediate.
One aluminum chloride molecule coordinates with both the phenol and phenol ether groups.
It does form a ring however.
Looks like the reaction generates hydrochloric acid and methylpyrridine.
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Benignium
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SWIM - Thank you! I will be attempting the reaction with dichloromethane. I already have it and I'm fascinated by the concept of
using it as a reagent in this. Apparently the reaction proceeds in a Reimer-Tiemann-like manner:
I believe that with some practice and careful preparation a good yield should be attainable, but we'll see. Right now I'm wondering whether magnesium
dimethoxide could be used to decompose the water in pyridine quickly, since I wish to avoid having to wait days and clean the used sieves to recover
the last of my pyridine.
You seem to be absolutely correct about the methylpyridinium! I was left under the impression that the pyridine is there to promote the formation of
chloromethane as some intermediate, but apparently I got it wrong. I couldn't discern liberation of gas, but thought nothing of it since the reaction
is so lengthy and, assumedly, slow to proceed. I intended to try to reclaim the pyridine but this certainly thickens the plot. Here's a picture from
the demethylation article on Wikipedia:
Could you provide a reference for the ring formation?
Texium - Thank you for the valuable insight! It's unfortunate that even piperonal turns brown relatively quickly, but at least the
aroma stays unchanged. I have a small sample I derived from white peppercorns last year and it does not look particularly nice, though it was
discolored to begin with.
That all sounds pretty impressive for undergrad level! I certainly hope to get to work on something of that caliber as well.
clearly_not_atara - Thanks! It certainly feels like having lucked out with a video game boss fight.
Right now I'm planning to use DMSO. I found a very useful post made by an user called CycloKnight way back in 2003. [link] They carried out the reaction on a rather large scale but I believe I should be able to scale down and expect a comparable yield if all
goes well, which is nothing to take for granted, it turns out.
morganbw - You're very welcome!
[Edited on 25-2-2021 by Benignium]
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DraconicAcid
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That is a really cool-looking reaction. I'm not actually interested in piperonal, but I'd like to make the acid, and some esters thereof.....
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Amos
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Your write-ups are a real joy to read, although sorry about your yield. Are you taking any steps to analyze all of the washes and remaining liquid,
perhaps seeing if they contain a lot more solids?
What kind of camera are you using to get such lovely photos, by the way?
[Edited on 2-25-2021 by Amos]
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Benignium
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DraconicAcid - Which ones are you interested in and why, if you don't mind me asking? I checked out a few at random and the acetic
acid ester for one sounds like it would make a fantastic addition to a collection of aroma compounds!
Amos - Thank you, that's awesome to hear!
I use the camera on my iPhone XR. I also have a very decent DSLR but I never really break it out for snapshots like these. I believe it was Apple
quoting a photographer called Chase Jarvis saying "The best camera is the one that's with you.", and with capture quality like this within five
seconds from the moment that you see something you like, I have to say I completely agree.
I try my best to examine everything before discarding, and to recycle what I can before concentrating on responsible disposal. Here, I collected as
much of the starting vanillin from the ether extracts and the dichloromethane as was practical, and I'm confident that should I have missed any
product it would have come up by now. I still have the aqueous portion of the reaction mixture set aside. I plan to use bisulfite to get the rest of
the vanillin when I figure out if and how I'll go about trying to save the pyridine. It very likely contains only vanillin, since that's all that
appeared to get extracted by the last portions of ether.
I would absolutely love to be wrong.
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DraconicAcid
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Quote: Originally posted by Benignium  | DraconicAcid - Which ones are you interested in and why, if you don't mind me asking? I checked out a few at random and the acetic
acid ester for one sounds like it would make a fantastic addition to a collection of aroma compounds!
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Just for smells- methyl and ethyl piperonylate should be nice. Methyl and ethyl piperonate, too (but my hydrolysis of piperine didn't give a very
high yield of the acid, so I haven't tried that yet).
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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unionised
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If nothing else, I think that's the most impressive array of different colours I have seen in any reaction scheme.
Only slightly marred by the fact that none of the compounds and intermediates should be anything but white.
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Benignium
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Yikes!
That is great to know, though! Thanks for chiming in!
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Texium
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In theory they should be, but they never are. As I mentioned, even 99+% pure 3,4-dihydroxybenzaldehyde purchased from a chemical
vendor is brown. When I would do the silyl ether protection I would see nasty orange and occasionally even green impurities come off on the column.
Not enough to impact the yield considerably. Tiny amounts of strongly colored impurities will do that.
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zed
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I have received products from Aldrich that were tarry goop. Not this product, but some products.
It was supposed to be the good stuff. Well, as good as you could get, for that particular product.
Some things, jusy do not store well. Aldrich reps were very gracious, by the way, when I complained.... They offered return, or replacement. But,
the replacements would be from the same batch, and no-one-else in the known universe, offered the products at all. I was unhappy, but I had to make
do, with what was provided.
As for Heliotropine; I purchased it a few times, maybe 50 years ago, when it was no big deal. It was white, of heavenly aroma, and it stayed white.
Cheap too. I suppose such products are still available for some authorized buyers, but not however, for most of us.... For most of us, it is
pretty inaccessible.
If you want some, most likely you will have to make it.
Thank you for your write up.
[Edited on 27-2-2021 by zed]
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Syn the Sizer
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| Quote: Originally posted by DraconicAcid | | That is a really cool-looking reaction. I'm not actually interested in piperonal, but I'd like to make the acid, and some esters thereof.....
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I was interested in piperonal mainly just for the smell, I have heard it is unique. I never even considered the acid and esters of the acid, something
to add to my list.
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zed
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Your nervous system, or perhaps your "Spiritual Being", likes this stuff. It is a kind of ecstasy, just to inhale a big nose-full of it. It's a lot
like Vanilla, but it hits a special sweet spot.
Sad that it is so remote.
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Benignium
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The aroma really is something very special.
I read about piperonal turning brown on light exposure on PubChem and always just assumed that the same phenomenon affected my sample, but now I question this. Perhaps once again it's due to impurity.
Luckily there is a way to find out.
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Syn the Sizer
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See 2 more positive opinions on this scent of this compound. Now I really want to make a small sample.
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Syn the Sizer
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I finally got the time to actually find the patent.
This demonstrates a method of demethylating vanillin using aluminum bromide produced in situ from elemental bromine and elemental aluminum in an
variety of aryl solvents. They boast a ~90% yield.
They explain the advantages over other methods.
Attachment: US2975214.pdf (473kB)
This file has been downloaded 455 times
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DraconicAcid
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That's a cool reaction- and has the benefit of not requiring pyridine.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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