Sciencemadness Discussion Board - Formylation of para-methoxyphenol: failure due to diformylation

Formylation of para-methoxyphenol: failure due to diformylation

turd - 23-3-2012 at 06:22

Let me interrupt your silly bickering with some honest cooking! Dilettante at work.

Introduction

2C-B (http://www.erowid.org/library/books_online/pihkal/pihkal020....), one of Shulgin's magical half-dozen, is a phenethylamine with dramatic visual effects. Due to its short duration and manageability, it is highly recommended for interested beginner psychonauts.

2-hydroxy-5-methoxy-benzaldehyde / 5-methoxy-salicylaldehyde is a key-precursor for the synthesis of 2C-B from OTC materials, necessary due to silly social restrictions. Klute brought to our attention a high yielding Mg-mediated formylation reaction (https://www.sciencemadness.org/whisper/viewthread.php?tid=10...). The method has been succesfully applied for the synthesis of the 5-ethoxy-analogue by Ullmann: https://www.sciencemadness.org/whisper/viewthread.php?tid=12... (and other postings in this thread). The literature mentions near quantitative yields for this reaction (Org. Biomol. Chem. 2483–2495 (2004)). Yet, some care has to be taken as the following failure demonstrates:

Experimental

80 ml MeOH (straight out of bottle) and 7.4 g Mg strips were stirred under exclusion of moisture using a "bubbler". The Mg showed serious signs of corrosion. To start the reaction, three small I2 crystals had to be added and gentle heat had to be applied. Once the reaction started, heat was removed. After evolution of H2 stopped, the flask was stoppered and left standing over night. There was lots of black crap from oxidized Mg.

The next day, 62 g p-methoxy-phenol was dissolved in 180 ml warm degassed toluene (straight out of the bottle).

The next day, spectacular crystals had formed, which were redisolved by applying gentle heat. The solution was added to the Mg(MeO)2 slush with stirring and moisture protection (dark green solution). Additional 100 ml degassed toluene were added. The reaction was refluxed for 15 min (white/grey precipitate) and the condenser replaced by a distillation bridge. 50 g of ground paraformaldehyde (directly out of bottle) were added over the course of 1h30, while distilling off a MeOH/toluene azeotrope. At the end of the addition the internal temperature had risen to 85°C. The reaction was then heated strongly to reach an internal temperature of 95°C in 15 min (Don't do that, see discussion below!!).

The reaction was cooled to RT and 400 ml 14% H2SO4 were added and stirred for 15 min. This is usually the nicest part of the reaction - weirdly the green part was not observed. The reaction was extracted twice with toluene, the organics washed thrice with H2O (the last washing produced a nasty emulsion which was broken by adding NaCl) and dried over Na2SO4. In total 400 ml of organic phase were obtained.

The volatiles were removed under vacuum and the residue distilled at reduced pressure. The first fraction distilled at 105-110°C. A yellow, intensely staining oil with melting point below room temperature was obtained (spectacular yellow crystals in the freezer). The distillation was stopped when the temperature suddenly shot up to >150°C. A few drops of the high temperature fraction were collected, which spontaneously crystallized.

The first fraction is probably the desired 5-methoxy-salicylaldehyde, 50 g (~66%), analytics not yet performed.
The second fraction was unambiguously identified as the diformylated product! There is a truckload of this stuff in the distilling flask! It crystallizes and seems to be relatively pure. If it weren't for that diformylation, yields must be close to quantitative!

Discussion

1) p-methoxy-phenol is reactive - don't heat the sucker, what a shame! What a waste!
2) The literature gives widely varying melting points for 5-methoxy-salicylaldehyde. My putative product certainly melts below RT. Maybe there's an azeotrope or something. The 5-ethoxy analogue was described as solid by Ullmann and I would expect the 5-methoxy to have a higher mp.
3) Argh! I'm pissed.

Edit: Fixed silly typo in title and in text.

[Edited on 23-3-2012 by turd]

Nicodem - 23-3-2012 at 07:31

Thank you for sharing your experience.

Quote: Originally posted by turd

The second fraction was unambiguously identified as the diformylated product!

Unambiguously identified as in measuring its mp or some other type of characterization? Or unambiguously because you can't think of any other possibility? Diformylation of phenols can usually be performed with the modified Duff reaction in trifluoroacetic acid. I did not check, but I can't remember seeing it done with the Mg-mediated formylation with formaldehyde. It would be quite interesting though, if it would be possible and effective. 2,6-Diformylphenols are of interest for the synthesis of the calixarenes and related compounds.

PS: 5-Methoxysalicylaldehyde is a liquid at room temperature. There are some erroneous mp reports in the literature which cause confusion.

turd - 23-3-2012 at 07:38

Quote: Originally posted by Nicodem

Unambiguously identified as in measuring its mp or some other type of characterization?

Melting point would be very ambiguous. It was characterized without any doubt as the 2,6-diformyl product. And there is lots of it!

Magic Muzzlet - 23-3-2012 at 07:59

WHy did you take so long? The reaction should be done in one go. I never get lower than 92% of product that performs well in a methylation or ethylation.
You need to add the 4-methoxyphenol to the methoxide and then don't reflux it but distill off the methanol Azeotrope until the INTERNAL temperature is 95-97C and then begin paraformaldehyde addition. Don't add it too rapidly, the temperature must stay within that range.
The mixture gels at around 85 or so as the phenolate precipitates but keep heating it, don't add the paraformaldehyde until it hits the stated temp... Takes about 20 mins to reach the correct temp if distilling at a reasonably rapid rate.
If you do it like that you don't need to vac distill but of course it is preferable.

I have heard if you don't hit that 95-97C range and start paraformaldehyde addition you will have lots of unreacted 4-methoxyphenol, but I am puzzled how you got some diformyl material

turd - 23-3-2012 at 08:43

Quote: Originally posted by Magic Muzzlet

WHy did you take so long?

Doing too many things at the same time!

Quote:

The mixture gels at around 85 or so as the phenolate precipitates but keep heating it, don't add the paraformaldehyde until it hits the stated temp... Takes about 20 mins to reach the correct temp if distilling at a reasonably rapid rate.
If you do it like that you don't need to vac distill but of course it is preferable.

Well, I knew from the para-ethoxy-phenol that starting addition at 70°C internal temperature works - so why bother.

Quote:

I have heard if you don't hit that 95-97C range and start paraformaldehyde addition you will have lots of unreacted 4-methoxyphenol

Are you positive that this is also true for para-alkoxyphenols? Or maybe only for unsubstituted phenol? The reaction certainly proceeded well at 70-85°C. It's very unlikely, but maybe there is a paradox effect that more MeOH means a faster reaction due to some solubility effects?

Quote:

but I am puzzled how you got some diformyl material

Must have been the "strong heating" at the end to reach an internal temperature of 95°C. That's what you get for being greedy - a sharp drop in yield. Next time only with TLC control!

Magic Muzzlet - 23-3-2012 at 08:53

I'm telling you that information from my personal experience having done that formylation on 4-methoxyphenol many times, I've never had it fail and my yields in consequent steps are normal. How do you know if the reaction "proceeded well" at the lower temperature? You cannot be sure.
I recommend to try it again with the better temp control, I tried addition of paraformaldehyde at the gelling point but the yield lowered to 85% or so and methylation gave dimethoxybenzene contamination, calling for bisulfite purification. There is always SOME left over starting phenol, but there is much more if you start addition at the lower temp.

Why bother, because this is a different substrate and performs differently in this formylation, it has been optimized.
You do not need to follow by TLC, take as long as needed for paraformaldehyde addition, then heat for 45mins to an hour and it will be done, but don't heat it strongly. Remember, 95-97C the whole time. I use a water bath, others have said it doesn't work in the water bath, well it does as I do it all the time! Maybe add some salt until you get the right temp in the boiling bath.
This also is no problem with water vapor if you are quick, just shield that particular neck...
Good luck

Edit: forgot to say I cover the bath in foil to prevent evaporation issues and such, maybe this accounts for the higher temp, at any rate it is the best solution for the spot on temperature and you can control it finely by making some vents if it becomes too hot

[Edited on 23-3-2012 by Magic Muzzlet]

peach - 23-3-2012 at 11:55

Ha! I just found the 10 or so grams of it I made last year sitting around in a container of odd bits. I thought I may as well try something with it or bin it so I could have the flask back. So I ran the Reimer Tiemann formylation with it last week.

-------------------------------------------------------------------------

I made up a solution of 26g NaOH in 32g of water. Whilst it was still hot, I tried rinsing the original flask out into something larger. Which didn't go well, as it re-solidifies immediately on contact with a cool surface. I upturned the flask and then gently warmed the glass to run it into a 250ml flask.

I determined the mass change as 9.8g. But I'd call that 9.5 since some of it probably ended up stuck on the walls of the funnel etc.

Warmed it to just over 70C. This is the point at which the contents melt. Began stirring. Not super effective since it tends to form a skin on it's surface and a crust on the cooler areas of the walls, but it's not too bad. I had wrapped the top hemisphere of the flask with wool. Setup for reflux and began dripping 13ml of chloroform in over 3h. Establishing a constant drip rate over that length of time is next to impossible, so I'd drip it for a while, switch it off, back on. The contents quickly go from a soft warm yellow to brown / black. Wondering about the stirring, I occasionally picked the flask up to give it a swirl by hand. It would foam up, almost to the base of the condenser, as the contents are above the boiling point of the chloroform.

I continued heating for an hour after the end of the addition, took it off, capped it, ran it under the tap to cool it down and then left it in the refrigerator overnight. Next morning I gradually acidified it with sulphuric to a pH of 5; the contents are all now in a liquid state, an oily layer appears atop the aqueous, it's all dark brown / black.

In the Reimer Tiemann example I was using, they steam distilled. I decided to try solvent extraction instead. I noted table salt sized solids within and thought it best to remove them because they'd only make the separations messier; vacuum filtered, few grams of solid in the cake. Rinsed the flask out with hot water and poured through.

Retained the filtrate and moved it to a sep funnel. A considerable amount of organic material was sticking to the walls of the filter funnel, the filter flask and sep funnel.

I decided to try using cyclohexane to wash it all towards the sep funnel (filter cake -> filter flask -> sep funnel). This didn't shift much. I then shook the resulting hexane with the filtrate and separated. The hexane was a yellow tone.

I set this aside and, suspecting the hexane (having zero polarity) wasn't picking up the material well enough, repeated the process with methylene chloride. This did a far superior job. It required around 100ml to 150ml to adequately move it all along and the organic phase was now black.

Keeping the two separate, I then removed the solvents and vacuum distilled the results.

From the cyclohexane I retrieved 1.7g of a yellow oil. From the methylene chloride, 3.85g. For a total of 5.6g.

It'd have probably been better ran under some inert gas. No emulsion problems with either solvent. Can be tricky to see the boundary with methylene chloride without holding it up to a light, due to the intense discolouration of both.

This was not something I was planning to do, and I haven't gotten round to checking precisely what's going on with the results as of yet, but I thought that may be of some interest to you. I'll see if I can get some TLC scans of it at some point; have been busy drawing graphs for the diethyl ether thread.

-------------------------------------------------------------------------

Before acidification:

The delightful separation:

The crude yellow oil that results:

[Edited on 24-3-2012 by peach]

turd - 24-3-2012 at 13:43

Quote: Originally posted by Magic Muzzlet

I'm telling you that information from my personal experience having done that formylation on 4-methoxyphenol many times, I've never had it fail and my yields in consequent steps are normal. How do you know if the reaction "proceeded well" at the lower temperature? You cannot be sure.

True that. To be sure I would have to do TLCs. But it looked exactly as it should: dissolution of the phenoxide, yellow/orange solution. Clearly the thing is reacting already at lower temperatures, even if not to completeness.

Quote:

You do not need to follow by TLC

Well, given that our results are so completely contradictory, I think redoing the reaction with TLC control is certainly called for. Now that I have genuine samples of the un-, mono- and diformylated products, it should be easy to do. But the 50 g aldehyde I got are enough for a long time, so it's quite down on my list of priorities.

On temperature control: my thermometer is quite long and certainly extended far into the solution (which can become a nuisance in viscous solutions, because the stir bar tends to smash into the thermometer). Unless I read it wrong - it's absolutely puzzling that I get massive diformylation in 15 min @ 85-95°C, when you get unconverted product with >1h at 95°C. Maybe I added the paraformaldehyde too quickly? What I did note though, was that when reaching 95°C the solution was getting quite turbid, so maybe it was already getting too concentrated. Maybe I miscalculated/mismeasured the amount of toluene?

@peach: That's very brave that you try the infamously dirty Reimer-Tiemann, when there's the clean Mg-mediated formylation! I don't think inert atmosphere will help a lot. IIRC I came across some references of Reimer-Tiemann with the same substrate giving close to quantitative yields. Was this one of the procedures you followed? And yes, your yellow oil is what my first fraction looks like - don't get it on your fingers - it stains nearly as badly as HNO3.

Edit: to/too typo

[Edited on 24-3-2012 by turd]

peach - 24-3-2012 at 15:06

Quote: Originally posted by turd

@peach: That's very brave that you try the infamously dirty Reimer-Tiemann, when there's the clean Mg-mediated formylation! I don't think inert atmosphere will help a lot. IIRC I came across some references of Reimer-Tiemann with the same substrate giving close to quantitative yields.
[Edited on 24-3-2012 by turd]

It's satisfying to go from such a mess to something approaching clean.

The reference I used yielded around 74%. After acidification they transferred the organic layer to some clean water and steam distilled. I expect some of the losses occurred just doing that, as it's a rather clingy affair. The same is true of solvent extracting. If I did it again, I think I could improve on that.

Quote:

don't get it on your fingers - it stains nearly as badly as HNO3.

Too late, it's already been on whilst cleaning the glass. And you're right.

Quote:

RIEMER-TIEMANN FORMYLATION OF 4-METHOXYPHENOL (Org. React. Vol 28 p16)

Into a 2000ml three neck flask was placed 125g (1 mol) 4-Methoxyphenol and a still hot solution of 320g (8 mol) NaOH in 400ml H2O (Addition while hot helps the phenol to dissolve and avoid carbonate formation). The flask was set with a reflux condenser, dropping funnel and thermometer (using a Claisen adaptor) and mechanical stirrer then heated to ~70°C on the oil bath. When this temperature had been reached, chloroform (160ml, 2 mol) was added dropwise (and portionwise) over the course of 4 hrs while maintaining the stirring and temperature, over this time the rxn became a very dark brown with a yellow green froth and a heavy brown precipitate (the sodium phenolate product). The reaction was allowed to stir for a further hour at the same temperature, allowed to cool and then transfered to a 5000ml flask with the aid of some hot water and subsequently acidified with H2SO4 (150-200ml 10 N). Acidification causes the product to rise to the top as a black oil. The black oil was transferred into a flask with some clean water and steam distilled (collect ~5000ml distillate). Quite a volume of black tar remains after this distillation. The yellow oil in the distillate was extracted with DCM and evaporated to yield 112g (74%) 2-hydroxy-5-methoxy-benzaldehyde, can be further purified by vacuum distillation under nitrogen (bp 133°C/15mmHg).

This material was sufficiently pure for methylation to 2,5-Dimethoxybenzaldehyde and gave a 76% yield with Dimethylsulfate in aqueous NaOH.

Note: The alkali salts of this salicylaldehyde are quite prone to atmospheric oxidation.

Have you got the reference you mentioned?

[Edited on 24-3-2012 by peach]

turd - 26-3-2012 at 00:27

Quote: Originally posted by peach

Quote:

Note: The alkali salts of this salicylaldehyde are quite prone to atmospheric oxidation.

Oh, I thought they were fairly stable. It's probably enough to degas your solvent(s) and add a bubbler.

Quote: Originally posted by peach

Have you got the reference you mentioned?

I had a look again - it's some Chinese stuff with an amine as base/catalyst. Never mind. BTW: Don't you have a university library nearby? The chemistry department often provides access to SciFinder/Beilstein/Gmelin...

Nicodem - 26-3-2012 at 08:43

Quote: Originally posted by turd

I had a look again - it's some Chinese stuff with an amine as base/catalyst.

Perhaps this one reference to Huaxue Xuebao posted by Smuv or this other form Huaxue Shiji? However, they are supposed to be para regioselective modifications. Are you sure that a tertiary amine catalyzed Reimer-Thiemann formylation of p-methoxyphenol was described anywhere?

turd - 27-3-2012 at 00:48

Quote: Originally posted by Nicodem

Perhaps this one reference to Huaxue Xuebao posted by Smuv or this other form Huaxue Shiji? [...]. Are you sure that a tertiary amine catalyzed Reimer-Thiemann formylation of p-methoxyphenol was described anywhere?

No, no and no.

Could also be an erroneous database entry or me imagining things. Both have happened before. I'll send the reference by U2U, maybe you can do something with it - I neither have access to the journal, nor can read Chinese!

DJF90 - 27-3-2012 at 10:19

Quote:
62 g p-methoxy-phenol

Thats a questionable scale there sir...

Quote:
The solution was added to the Mg(MeO)2 slush with stirring and moisture protection (dark green solution). Additional 100 ml degassed toluene were added. The reaction was refluxed for 15 min (white/grey precipitate) and the condenser replaced by a distillation bridge. 50 g of ground paraformaldehyde (directly out of bottle) were added over the course of 1h30, while distilling off a MeOH/toluene azeotrope. At the end of the addition the internal temperature had risen to 85°C. The reaction was then heated strongly to reach an internal temperature of 95°C in 15 min

whereas the order of things should be:

Quote:
You need to add the 4-methoxyphenol to the methoxide and then don't reflux it but distill off the methanol Azeotrope until the INTERNAL temperature is 95-97C [b}and then begin paraformaldehyde addition. Don't add it too rapidly, the temperature must stay within that range.

Quote:
The second fraction was unambiguously identified as the diformylated product!

And what exactly is unambiguous? If the compound is known and in the literature you can probably get away with 1H, 13C NMR and a melting point. If you have characterisation data, why don't you share it?

I dont mean to come across as rude or nit-picking, I just want answers. You might also want to work on a smaller scale in future, given the nature of the compound in question, and the active dose of your target material. One might mistake this example for "commercial production".

turd - 27-3-2012 at 23:35

1) You don't even know what my target is. It's not any of the 2C-X nor any other scheduled substance.

2) Yes - dilettante at work, see introduction - I didn't follow the published procedure. And found something unexpected. I knew that when I was opening this thread - there is no point in repeating this.

3) I'll share my data with people who a) can use it and b) I trust and c) don't appear condescending. I certainly don't have to prove anything to you. I couldn't care less whether you believe me or not.

[Edited on 28-3-2012 by turd]

DJF90 - 28-3-2012 at 03:11

Based on your intro I was led to believe you were aiming for 2C-B, especially as you make the following statement:

Quote:
But the 50 g aldehyde I got are enough for a long time, so it's quite down on my list of priorities.

I said I didnt mean to come across as rude (or condescending for that matter), I just think if you're after this material for a legitimate use (and hence scale is not really a factor) then why bother with the babble about drugs to start with. If its not 2C-X then why not share what you're working on? Why so secretive? I'm sure myself and others would be interested to see stuff done with this material, being how easily made it is. There will be many people here who are capable of using your data, so why not just put it up. You're saying you've made something, I'm saying prove it. This is how things are done in the scientific world my friend.

turd - 28-3-2012 at 11:00

Look, I have zero motivation to discuss non-chemistry related things in this thread. If I don't want to post my data to a public message board, then I will have my reasons. If someone is in the extremely unlikely situation of having use for my data, they can contact me by U2U.

I told you already that I don't care if you think I'm making this up. I also don't care what you think I'm doing and whether that is "legitimate" or not. So please stop derailing this thread - either post some chemistry or move it to one of the "Non-chemistry" fora.

[Edited on 28-3-2012 by turd]

DJF90 - 28-3-2012 at 12:47

I don't think you're making anything up, I just think its bad scientific form that you claim to have made something "unambiguously" yet you don't even report a melting point of the material, assuming you took one. If you're to say it coincides with a literature value, then who am I to say you're lying. Its just the fact you present no scientific evidence for your claims. If you have spectral data, then post it, either in the form of an attachment, image or even a list of peaks. There need not be anything to affiliate you with any of your sources for analytical data.

I couldn't care less if you're making questionable substances. Its not my problem if you wish to ingest them yourself either. I just wish to see good scientific method. You say it was characterised without doubt. Perhaps you should give others the chance to make their own interpretations of the data and (hopefully) agree with you.

Lambda-Eyde - 28-3-2012 at 13:01

Quote: Originally posted by turd
Look, I have zero motivation to discuss non-chemistry related things in this thread. If I don't want to post my data to a public message board, then I will have my reasons. If someone is in the extremely unlikely situation of having use for my data, they can contact me by U2U.

I told you already that I don't care if you think I'm making this up. I also don't care what you think I'm doing and whether that is "legitimate" or not. So please stop derailing this thread - either post some chemistry or move it to one of the "Non-chemistry" fora.

You are expected to follow scientific discourse on a science forum. Refusing to hand out data such as melting points or spectroscopic data, while claiming you have "unambiguously" identified the compound (implying you obviously have relevant data that you refuse to share) is quite frankly not the behavior that I (or any other) expect in scientific communications.

But you probably already know this, you are aware how serious science works, so why are you acting like this? If you actually didn't unambiguously identify your compound, but rather deduced it from some preliminary results (color, amount of reagent used etc.) then just say so. No reason to act so stubborn, what we're asking is to tell the whole story (as is expected) and not to become agressive when people ask you politely for something as trivial as a melting point...

Also, I really don't care if your ultimate target compound is scheduled or not; if it is a psychedelic, stimulant or something related then your scale of work isn't really acceptable here, whether or not it's actually illegal.

Edit: DJF90 beat me to it (mostly).

[Edited on 28-3-2012 by Lambda-Eyde]

Nicodem - 29-3-2012 at 10:37

Before this curiosity goes too personal, I will say that I checked the product identity evidence that turd so kindly provided me via U2U. I can witness that what he said about it being "characterized without any doubt as the 2,6-diformyl product" is absolutely true. I can tell you that his analysis data truly leave absolutely no doubt and would be sufficient to convince even the strictest reviewer. Turd consistently demonstrated his strictness in regard to the scientific method since he joined the forum. I don't know why he does not share the data publicly, but I trust he has his own reasons, so we should respect his decision. We should nevertheless be grateful for his contribution to the science of synthesis which will doubtlessly be useful to several other researchers as well. He could have kept the information for himself and avoid all this unpleasant questioning, yet he did what any scientist should.

DJF90 - 29-3-2012 at 15:54

I appreciate he may not share printouts of data due to the fact that sometimes institutional details are also present and he may not wish us to know with whom his is affiliated with. However, even a melting point range would be acceptable, yet he declines even this simplest of characterisation data. How revealing would it be to say his material "melts at xxx*C (lit. value yyy*C)"? I acknowldege that not many of us have access to NMR facilities as amatuers so every effort should be made to provide strong enough evidence for the constitution of a compound. While he has made this accessible to yourself, Nicodem, I think that if he's willing to provide experimental details publically then the supporting info should also be available, especially if he has access to something more rigorous than mp/bp ranges.

turd - 26-5-2012 at 08:43

Nothing special, but someone might find it useful, so I pluck it here:

2,5-Dimethoxybenzaldehyde

To a stirred suspension of 82 g K2CO3 (dried over night at 250°C and ground to a fine powder) and 50 g of the above 2-OH-5-MeO-benzaldehyde in 480 ml DMF was added 37 ml Me2SO4 in 5 aliquots. After the last addition the internal temperature had risen to 60°C. The reaction was stirred for 16h and poured into 1.5 l of ice water. The tan precipitate was filtered off and dried in a warm (~30°C) place to obtain 46.3 g of crude 2,5-diMeO-benzaldehyde. The filtrate was diluted to 4 l with water and cooled over night at 6°C, whereby 0.6 g of huge needles of 2,5-diMeO-benzaldehyde formed (see pretty pictures thread). The total nominal yield is 46.9 g (86%), but the product still contained appreciable amounts of water, which was observed by drops condensing on the walls of the container it was stored in. Furthermore, it is not very pure, giving a sharp drop in yield in the next step. Therefore the crude 2,5-diMeO-benzaldehyde should be recrystallized.

Ethylenediammonium diacetate

To a stirred solution of 40 g ethylenediamine in 200 ml n-PrOH, 80 g AcOH was added dropwise in such a way to keep the solution from boiling. At the end of the addition the solution darkened considerably. No precipitate occurred during the addition. The solution was then slowly cooled to room temperature to obtain needles of ethylenediammonium diacetate. The precipitate was filtered off and washed with MEK until colourless to give 110 g of slightly off-white product.

2,5-Dimethoxy-beta-nitrostyrene

44 g of 2,5-diMeO-benzaldehyde and 5 g ethylenediammonium diacetate were dissolved in 220 ml IPA by gentle application of heat. Minor impurities did not dissolve, but were not filtered off (big error!). 20.5 g MeNO2 was added and the solution stirred at RT. The solution progressively darkened and, probably due to the impurities acting as crystallization nuclei, at the 1h30 point the whole reaction suddenly precipitated. The crude orange nitrostyrene was filtered off and deemed of inferior quality and therefore recrystallized from EtOAc (cooling must be performed very slowly, because the nitrostyrene tends to crash out of the solution) to obtain 37 g (67%) of large needles of 2,5-diMeO-beta-nitrostyrene (see pretty pictures thread).

With the exception of dimethylsulfate all chemicals are available to the amateur.

PS: Thanks to all the people who participated in this thread without whining!

turd - 25-11-2012 at 04:42

Alright, finally got around to redo the Mg-mediated formylation of p-methoxyphenol. Again, the Mg(OMe)2 was prepared a week in advance which lead to a brick that took very long to dissolve on addition of paraformaldehyde, but eventually did dissolve completely. This time addition was started at 85°C, temperature kept at 95°C during addition and for ~30 min after addition. At the end, the reaction became turbid, presumably due to precipitation Mg-phenoxide.

And indeed, there was only very little high boiling fraction, not enough to bother isolating it. So apparently I really went overboard with additional heating the first time around. I still have the diformylated product as proof that I am not crazy.

Edit: typo

[Edited on 25-11-2012 by turd]

chemrox - 25-11-2012 at 15:58

Hey Turd,
Could you post the paper here?

turd - 27-11-2012 at 13:52

Not sure what you mean...?
I'm just repeating the work of Methyl.Magic (https://www.sciencemadness.org/whisper/viewthread.php?tid=10...) and Klute (https://www.sciencemadness.org/whisper/viewthread.php?tid=10...) in my characteristic dilettante way. The original paper is posted in the first linked thread.

lullu - 27-2-2015 at 04:07

Did anyone experience that the aldehyde won't solify under 4°C?
Even thin layers on a beaker wall in the fridge won't crystallize, toluene was removed by vacuum destillation and the product has a yellow/orange color.

DJF90 - 27-2-2015 at 05:14

Wikipedia gives the melting point as 50 *C. I suspect you're having trouble because your product is impure, or because you have residual toluene (which is the same problem, actually).

Ideally you'd stick your sample on the high vac line to try and remove any residual toluene. A better (and more accessible) idea may be to concentrate your product from methanol (methanol and toluene azeotrope...), and if you still have problems (possibly at that point from residual methanol) then concentrate again, this time from DCM.

I have this same issue at work sometimes. Product is a residue on the walls of the vial after concentrating fractions (chromatrographic purification) containing MeOH-EtOAc. A quick strip from DCM then leaves me with the familiar foamy solid I'm after.

lullu - 27-2-2015 at 05:40

Thanky DJF90, it is 2-Hydroxy-5-methoxybenzaldehyde not 2,5-Dimethoxybenzaldehyde which has its mp at 50°C.
I will try and see if there is another byproduct within it by TLC or if it is indeed toluene.
Using the azeotrope is a good idea. I'll try adding methanol and vacuum distilling it off before using it any further if that is the case.

lullu - 27-2-2015 at 07:59

Looks like there is indeed another product if I am not mistaken, separation is not very good with this solvent system ethylacetate:hexane and a drop nh3
(unfortunately the best result of the ones I've tried).
chloroform:ethylacetate gives only one spot without tailing.

chloroform:ethylacetate i2 stained (left side) this gives only two distinct spots

ethylacetate:hexane:nh3 trailing a lot but I think there are two products visible?

ethylacetate:hexane:nh3 i2 stained

[Edited on 27-2-2015 by lullu]

[Edited on 27-2-2015 by lullu]

DJF90 - 27-2-2015 at 09:29

I'm guessing you're new to TLC. What ratios of solvents did you use?

Why add ammonia? Thats really not going to help here.

An additional note that may help me troubleshoot this with you... you started with p-methoxyphenol and were attempting to make 2-hydroxy-5-methoxybenzaldehyde, right?

[Edited on 27-2-2015 by DJF90]

lullu - 27-2-2015 at 09:39

Quote: Originally posted by DJF90
I'm guessing you're new to TLC. What ratios of solvents did you use?

Why add ammonia? Thats really not going to help here.

Yes I am.

it was 1:1 ethylacetate:hexane volume wise and one drop 10% ammonia, I added it because I assumed it might help to stop the trailing.
The other run was 1:1 too.

The TLC without NH3 ran very fast the two dots are in fact on the upper end of the TLC, it looks like it is quite pure on this one, the other TLC looks like it is a mixture of two substances if I interpret it right.

[Edited on 27-2-2015 by lullu]

Yes the product I use for the TLC is in fact 2-hydroxy-5-methoxybenzaldehyde, I searched for vanillin TLC eluents but was not able to find some recommendation with solvents I have at hand.

[Edited on 27-2-2015 by lullu]

DJF90 - 27-2-2015 at 09:57

Heres what I would do:

1) Your sample looks to be too concentrated, hence the large amount of streaking. I would take half of your sample solution and dilute it with an equal volume of solvent (what is your sample made up in? DCM or chloroform is a good choice).

2) Take your TLC plate and mark three origins about 1cm off the baseline. Left one for starting material, right one for crude product, and the middle for a co-spot (both samples spotted in same place). You probably need to make up a sample of your starting material for this - I'd try for something like 5-10 mg per mL.

3) You mention that 1:1 EtOAc-Hexane runs almost to the top of the plate, and it looks like you have one species. This is because this solvent system is too polar - aim to get your spots towards the middle of the plate: Rfs between 0.1 and 0.8 will do nicely. I'm going to guess that 1:4 EtOAc-Hexane (by volume is convention) will be a good start.

4) Visualisation: If iodine is all you have on hand then fair enough. If your plates are F254 type, then fluorescence under UV (254 nm) would be a good place to start. If they're not fluorescent plates, then you may still have luck using a long wave UV source (a blacklight bulb is good for this and emits around 365 nm which is whats used in commercial UV lamps for TLC). If you have access to vanillin stain, I'd try that, too (instead of the iodine...)

lullu - 27-2-2015 at 10:11

Sample might be indeed too concentrated, it is diethyl ether.

I just ordered a 254nm UV-S. I'll run it on monday like you described and let you know.

Thank you DJF90, I really appreciate your time and efforts.

[Edited on 27-2-2015 by lullu]

DJF90 - 27-2-2015 at 11:53

I'll check back monday then. Feel free to send a U2U if you need help with anything else.

Chemosynthesis - 28-2-2015 at 08:29

I'd like to add that you may be using too broad of spots. You might have trouble fitting that cospot in there between the two you have unless you draw out a capillary or pipette tube over sooty flame and use that to spot your TLC. It helps with dilution as well, since a finer spot can afford to be a little more concentrated.

lullu - 2-3-2015 at 09:29

The spotting was indeed too high concentrated.
Here is the result:
Left side is pure 4-methoxyphenol, middle is the product mixed with it. Right side is the product after isolation without distillation.

The product of my Mg ortho formylation (with good temp control around 98°C. the whole time) contains a small amount of 4-methoxyphenol and another product besides 2-hydroxy-5-benzaldehyde it seems.

Very interesting

[Edited on 3-3-2015 by lullu]

DJF90 - 3-3-2015 at 00:26

That worked much better, well done. What eluent are you using for that separation?

You've confirmed an impurity by TLC. Now, what are you going to do about it?

I have a couple of suggestions:

a) Attempt to recrystallise a small portion from whatever solvent system the literature recommends. Then you can TLC the re-crystallised product against the crude and see if you've removed any of the impurities.

b) You could speculate that the spot with lowest Rf may be the benzoic acid (from aerial oxidation of the aldehyde). You could take a small amount of your crude into ether and wash with sodium bicarbonate solution. Then TLC the ether layer (at an appropriate dilution) to determine whether the impurity has been reduced/removed.

c) You mentioned distillation may be an option. Hopefully the other components are separable, but depending on scale you may have high losses due to surface area etc. (What scale are you working on?)

d) You could column it. Its quite a solvent intensive method for purification but it does work, although you may want to practice a bit first.

e) Do nothing about it. If the impurities won't interfere in the next reaction (if there is a next reaction...) then you could use the crude and perhaps achieve an easier separation at the next stage.

lullu - 3-3-2015 at 01:29

Quote: Originally posted by DJF90

That worked much better, well done. What eluent are you using for that separation?

1:4 ethyl acetate/n-heptane

Quote: Originally posted by DJF90

b) You could speculate that the spot with lowest Rf may be the benzoic acid (from aerial oxidation of the aldehyde). You could take a small amount of your crude into ether and wash with sodium bicarbonate solution. Then TLC the ether layer (at an appropriate dilution) to determine whether the impurity has been reduced/removed.

That is likely, although degassed and standing over argon it is a few weeks old now.
You think the diformylated product would be having a bigger Rf?

Would the bicarbonate wash not form a water soluble phenoxide with my intact phenolic aldehyde?

Quote: Originally posted by DJF90

c) You mentioned distillation may be an option. Hopefully the other components are separable, but depending on scale you may have high losses due to surface area etc. (What scale are you working on?)

Yes, distillation is not really an option at this scale, but if the second product is the diformyl product I will do it.

Quote: Originally posted by DJF90

e) Do nothing about it. If the impurities won't interfere in the next reaction (if there is a next reaction...) then you could use the crude and perhaps achieve an easier separation at the next stage.

Forming the bisulfite adduct after alkylation of the hydroxyl group and washing with NaOH solution might be the best method to get rid of the second product if it is indeed the oxidated aldehyde.

I will try and oxidize a sample and rerun TLC against it.
Once again thank you DJF90.

DJF90 - 3-3-2015 at 03:07

Quote: Originally posted by lullu

Quote: Originally posted by DJF90

That worked much better, well done. What eluent are you using for that separation?

1:4 ethyl acetate/n-heptane

Good to see I gave good advice.

Quote: Originally posted by lullu

Quote: Originally posted by DJF90

b) You could speculate that the spot with lowest Rf may be the benzoic acid (from aerial oxidation of the aldehyde). You could take a small amount of your crude into ether and wash with sodium bicarbonate solution. Then TLC the ether layer (at an appropriate dilution) to determine whether the impurity has been reduced/removed.

That is likely, although degassed and standing over argon it is a few weeks old now.
You think the diformylated product would be having a bigger Rf?

Would the bicarbonate wash not form a water soluble phenoxide with my intact phenolic aldehyde?

I'm not sure where the diformylated product would run. A bicarbonate wash should only remove any acid (if present) due to the appropriate pKa values (its not a strong enough base to deprotonate the phenol to any great degree).

Quote: Originally posted by lullu

Quote: Originally posted by DJF90

e) Do nothing about it. If the impurities won't interfere in the next reaction (if there is a next reaction...) then you could use the crude and perhaps achieve an easier separation at the next stage.

Forming the bisulfite adduct after alkylation of the hydroxyl group and washing with NaOH solution might be the best method to get rid of the second product if it is indeed the oxidated aldehyde.

If the impurity is the acid then a bicarbonate wash should remove it satisfactorily. Shouldn't be any need to form bisulfite adducts.

Quote: Originally posted by lullu

I will try and oxidize a sample and rerun TLC against it.
Once again thank you DJF90.

Try the wash with bicarbonate first. If the impurity isn't reduced or removed, then its probably not the acid.

If you have 2,4-DNPH use that to stain the plate. Aldehydes and ketones show up as orange spots on a yellow background - if that impurity stains too then its suggestive of the diformylated product.

lullu - 3-3-2015 at 03:38

Quote: Originally posted by DJF90

Good to see I gave good advice.

indeed!

Quote: Originally posted by DJF90

I'm not sure where the diformylated product would run. A bicarbonate wash should only remove any acid (if present) due to the appropriate pKa values (its not a strong enough base to deprotonate the phenol to any great degree).

Could you explain me how you estimate the pKa value of the 2-hydroxy-5-benzaldehyde?

Quote: Originally posted by DJF90

If you have 2,4-DNPH use that to stain the plate. Aldehydes and ketones show up as orange spots on a yellow background - if that impurity stains too then its suggestive of the diformylated product.

sadly I do not have access to it at the moment, it certainly seems like a good investment.
I'll try to wash it with bicarbonate and report on the results.

DJF90 - 3-3-2015 at 03:57

Quote: Originally posted by lullu

Quote: Originally posted by DJF90

I'm not sure where the diformylated product would run. A bicarbonate wash should only remove any acid (if present) due to the appropriate pKa values (its not a strong enough base to deprotonate the phenol to any great degree).

Could you explain me how you estimate the pKa value of the 2-hydroxy-5-benzaldehyde?

Well, phenol has a pKa of about 11. Methoxy group might increase that a little, but by far the dominant effect is that of the carbonyl group, allowing delocalisation onto the carbonyl oxygen. This increases the acidity of the phenol. Fortunately I have access to a license key for MarvinSketch, allowing use of the pKa feature:

EDIT: Actually a bicarbonate wash might remove much of the diformylated product also. The predicted pKa came out at 7.8, which is similar to bicarbonate.

[Edited on 3-3-2015 by DJF90]

lullu - 3-3-2015 at 05:01

Thank you so much!