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Author: Subject: Interesting route to 4-methoxyphenol
tyro
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[*] posted on 10-11-2022 at 16:49
Interesting route to 4-methoxyphenol


The following publication details an approach to the monoetherification of 1,4-hydroquinone and various derivatives thereof, using NaNO2 as the free-radical initiator.

Selective Monoetherification of 1,4-Hydroquinone Promoted by NaNO2
DOI:10.2174/1385272811317100011

I had originally planned to approach 4-methoxyphenol using benzoquinone as the free-radical initiator; however, I had none on hand and didn't want to bother with making the stinky stuff...

It doesn't appear that this approach using sodium nitrite has been documented here (used site search and google), so I thought I'd share my account of it.

The Expirement:

55g Hydroquinone
1.72g NaNO2
28.75ml 96% H2SO4
500ml MeOH


To a 1L RBF filled with methanol was added hydroquinone and sodium nitrite with good mixing. Once everything had dissolved, sulfuric acid was added at a rate as to keep the reaction mixture relatively cool (temperature reached 45°C at peak). During addition of the sulfuric acid, the mixture transitioned from a light pink to a dark red-brown hue; there was evolution of some nitrogen dioxide. After addition of the sulfuric acid, the reactants were stirred for 22H at RT.

collected_evaporation.jpeg - 111kB

At this point, the reaction mixture was poured into a bowl and let to evaporate down to about 250ml under air flow of the fume hood.

evaporation.jpeg - 196kB reaction.jpeg - 121kB

This mixture was then transferred to a 500ml separatory funnel, 150ml of water was added, and then extracted with 5 x 50ml portions of toluene. Some methanol appeared to carry over.

sep1.jpeg - 118kB sep2.jpeg - 123kB
sep3.jpeg - 145kB sep4.jpeg - 114kB
sep5.jpeg - 164kB sep6.jpeg - 163kB

The pooled toluene extracts were then transferred to a 500ml flask, then subsequently 250ml flask, and the solvent volume was reduced under vacuum. (I'd normally use a water cooled condenser in a situation like this; not sure why I didn't. Rushing things? A fair bit of methanol and toluene ended up in the vacuum pump's trap... oh well).

reduce1.jpeg - 198kB 20220927_201546.jpg.modified.jpeg - 198kB

Once the volume of solvent had been considerably reduced, the remaining extract was placed in a 100ml flask, remaining solvent stripped, and then the 4-methoxyphenol was vacuum distilled over. A heat gun was used at times to aid the migration of the phenol along the condenser.

vac_dis1.jpeg - 192kB vac_dis2.jpeg - 2.6MB

Crude product.
vac_dis3.jpeg - 159kB

The crude product was recrystallized from heptane and toluene (roughly 1:3). Multiple stints in the freezer with some evaporation of the solvent mixture was required to get the remaining phenol out after the first crop of crystals.

final_product.jpeg - 254kB

Final yield was 32g of 4-methoxyphenol (51.6%). MP was measured to be 48°C-52°C (Lit 52.5°C).

I'm sure there were some losses in the workup. Also the reaction wasn't run for the full 24H, so perhaps that played into the yield being lower than in the paper.

Some Notes:

I ran this experiment at a couple other scales. One before this starting with 10g of hydroquinone, and one after using 44g. The 10g run was performed at RT, while the last one was done for 4h at reflux. In both cases, the reaction mixture never darkened quite like the run above, and the workup yielded less product.

I can't say for sure, but it seems like there might be a factor of concentration which comes in to play here. In these other cases not detailed, the concentration of the hydroquinone to methanol was < 1g/10ml, while the case above was > 1g/10ml. It's possible I goofed in some other way. Further investigation would be needed, though I doubt I'll re-visit the matter soon.

The smell of this is really interesting. I've previously made 1,4-dimethoxybenzene from hydroquinone and dimethyl carbonate. The dimethoxybenzene was intensely floral and sweet, almost candy-like, at the same time. Very unique. 4-methoxyphenol seems to sit in an interesting place: relatively close to the smell of dimethoxybenzene, but not as intense, with slight notes of phenol. Somewhat floral and medicinal at the same time.
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[*] posted on 10-11-2022 at 21:59


Well done, thanks for sharing!!! You performed a lot of steps, this synthesis is at some advanced level!
Interesting findings, there is big excess of methanol and the NaNO2 catalyzes only monoetherification, as there is also H2SO4 the catalyst is some nitrogen oxide - in the link they wrote about NO2 which oxidizes one -OH group of hydroquinone into =O (semiquinone) and this is the reactive intermediate which undergoes monoetherification.
Also thanks for describing the scent of the product! I like nice smelling compounds.
Your product after vacuum distillation has also interesting yellow color - perhaps it was caused by the presence of at least a little of quinones and then you purified your product by crystallization as the last step.
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[*] posted on 10-11-2022 at 23:19


Nice work, shame that the yield was on a rather low side. I'd be interested in seeing your synthesis of 1,4-dimethoxybenzene from hydroquinone and dimethyl carbonate too :)
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[*] posted on 11-11-2022 at 00:14


In these days I'm working on exactly the same synthesis. :) Especially for the scent! (Not the scent of the 4MeOPhe, but I'd like to prepare another "smelly" compound for which the synthesized 4MeOPhe is one of the starting materials.)

I use the NaNO2 method tyro posted (thanks, tyro, you saved me time to make crappy photos, yours are much better!) :)

I tried to "optimize" this route. Although I'm only at the 3rd iteration on a 1/10th scale as of tyro's, I found that the best isolated yield was 65% so far. I could achieve it when I neutralized the RM in Na2CO3/water and extracted the 4MeoPhe with chloroform, distilled the chloroform off at normal pressure and vacuum distilled the rest.
I also found that the dark reddish-black RM can be decolorized to straw color in 15 minutes by boiling it with a small amount of zinck powder. (I used this method to destroy the excess/remaining benzoquinone in the end and it gave this side effect.)

The vacuum distilled liquid was water clear (not yellowish) and gave snow white crystalls on cooling. The melting point was 54.3-55.4 C.)

Btw, 2 and a half hours reaction time was enough at around 25 Celsius. For 65% it is for sure. (Though there was a "lot" crystalls in the cooler/flasks and we all know that the last drops of such high boiling compound is hard to distill off under not too strong vacuum. I used a water aspirator, which could boil water around 19 Celsius. 4MeOPhe came over at 120 C but I had to increase the temperature of the hot plate to 300 C ! The contact was not the best, obviously, and it probably caused a lot of scorching in the end, despite the zinc powder.)

Btw2: on the photo of my "TLC challenge" of last week the first spot was hydroquinone, the others from the sampled reaction mixture of this synth. :)

Here's the result of the vacuum distillation: /The date on the pic is misleading. My phone restarted before the picture was taken and being a "dumb phone" it could not synchronize itself to a central clock./
IMG_20220131_125300205.jpg - 571kB

[Edited on 11-11-2022 by Pumukli]

[Edited on 11-11-2022 by Pumukli]
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[*] posted on 13-11-2022 at 13:39


@ tyro; nice work and an excellent write-up. There are echoes of this method in benignium's write-ups on the preparation of various substituted aldehydes in his Phenylethylamine thread. Keep up the good work.
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[*] posted on 12-12-2022 at 21:21


Fery - Glad you chimed in! I've come across a number of your posts prior to becoming active on the board. The ones where you're making nice smelling things are always fun to read about. I have zingerone in my queue to get to. Came across a paper detailing it's synthesis from vanillin and acetone, where the hydrogenation is accomplished with NaBH4 and (what seems like an excessive amount of) catalytic NiCl2. Hoping to get to it early next year.

xdragon - I've been meaning to make a thread on o-methylations using dimethyl carbonate. It's a pretty straightforward reaction, though not necessarily friendly from an equipment standpoint. Yields can vary, though I haven't necessarily run optimizations on each target.. It requires a vessel which can withstand a fair bit of pressure. I use a hydrothermal reactor rated for about 6MPa. I've run this reaction on a handful of substituted benzenes. It's been interesting trying to find the best workup afterwards for each target. Definitely a learning experience!

Pumukli - Thanks for sharing your experiences with this route! Good thinking on destroying the benzoquinones with zinc dust - I'll keep this in mind for future runs. And only 2.5 hours at 25C for reaction? Super interesting.. I'm curious if you've noticed anything with regard to concentration of hydroquinone in methanol affecting the reaction? Also, I had a similar experience with distilling - the hotplate was cranked all the way up, but the last bits of 4-methoxyphenol were stubborn in coming over. Even at 200mbar.

Boffis - Thanks! That thread was one of many motivators for becoming an active contributor. I've also had an ever growing feeling of wanting to give back to a community that I've learned so much from for nearly 10 years.
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[*] posted on 12-12-2022 at 23:20
Another potentially interesting route..


I'm currently working out another potentially interesting route to 4-methoxyphenol, starting from p-hydroxyacetanilide (acetaminophen/paracetamol).

I had previously thumbed through the benzoquinone from paracetamol in regard to making hydroquinone. This last experiment consumed the last of my hydroquinone, and, rather than buying more, I was thinking about making my own for the learning process (there are some interesting reactions I have yet to perform). Though it's not necessarily economically practical, I've become ensnared with the idea of arriving at 4-methoxyphenol from 4-hydroxyacetanilide.

The first thing that came to mind was hydrolysis of p-hydroxyacetanilide to p-hydroxyaniline, then diazotization and degredation of the aniline to hydroquinone, followed by the usual methods.

On the surface, this seemed like a lot of steps (4 total) and many potential areas for loss before even getting to making 4-methoxyphenol, especially if isolating in each step. This merely re-enforced the lack of economical benefit to this approach. But, again, I'm in it for the experience and to learn.

Then, I came across an interesting paper:

Functionalized alkoxy arene diazonium salts from paracetamol
https://doi.org/10.1039/b924619c

Here, they produce an O-alkylated, de-acetylated, diazonium derivative of 4-hydroxyacetanilide in a series of reactions taking place in a single reaction vessel. The prospect of running the reaction in a single vessel (and in only 3 steps) seemed appealing, but the steps and reagents they were using didn't seem to provide much advantage in the way of ease. In this case, the methoxy group would be set before diazotization, using methyl iodide, which seems less advantageous than getting there from the sort of free-radical reaction performed above.

Okay. So now what? I recalled that 4-hydroxyacetanalide undergoes undergoes metabolic transformations to a quinone derivative, which was discussed in the benzoquinone thread linked above. This, along with my understanding that diazonium salts degrade to different products under different conditions (see here), got me wondering if there might be some potential overlap in degradation mechanisms of the diazonium salts, acetaminophen's propensity to form quinone derivatives, and the reaction previously formed which relied on a benzoquinone intermediate.

After some searching, It seems there in fact is.

I found a thesis paper, which details some previous work on degradation of benzenediazonium chlorides in alcohols in the course of an investigation of the same on benzenediazonium sulfates. Here, the degradation of the benzenediazonium chloride in alcohol, leads to the corresponding alkoxyphenol in what is described as a free-radical reaction. Degradation of the sulfate form was a bit more troublesome, in that the benzene was produced more readily under similar conditions. Though this seems to be mitigated, by increasing the starting concentration of sulfuric acid (decomposition of the benzenediazonium salt frees more of the corresponding acid as the reaction proceeds).

So, at this point, I'm thinking:

One-pot reaction: acidic hydrolysis -> diazotization -> decomposition -> target, all under alcoholic conditions.

Seems much better than before! Only 3 steps, and no really special reagents.

But, it looks like there may be yet more room to improve..

While I was on this train of thought, I come across another reference:

The Mechanism of the Reaction of N-Nitrosoacetanilide with Methanol
https://doi.org/10.1021/ja01148a013

This seems to indicate that the previous mechanisms hold as well for degradation of aryl N-nitrosamines. They do however, seem to contest that the mechanism is free-radical in nature. In any case, the reaction appears to have similar parameters. Namely, that the benzene may be produced along with the alkoxyphenol in the case of the sulfate salt, and the ratio of products is dependent on the starting concentration of sulfuric acid and other factors like concentration of acetate and acetic acid (acetic acid is produced as a byproduct of the reaction in this case, and would be present in a one-pot reaction incorporating hydrolysis).

Where I'm at now is:

N-nitrosylation of 4-hydroxyacetanilide -> degradation -> 4-methoxyphenol, all in methanol.

This would be only 2 steps from acetaminophen to 4-methoxyphenol (likely contaminated with plain phenol).

Though using the diazonium or N-nitrosamide sulfate salts appears to lead to the corresponding benzene, rather than the alkoxyphenol, I'm thinking this is the best approach with respect to ease. Much easier to add conc sulfuric acid to methanol, than bubbling in dry HCL.

I've got a bit to hammer out before getting to trials here. But it seems promising on the surface.

Apologies if there are any glaring errors here, it's quite late here.

[Edited on 13-12-2022 by tyro]
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[*] posted on 14-12-2022 at 07:37


Apologies, I had a typo and it seems I can no longer edit it. N-nitrosylation should be N-nitrosation.
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[*] posted on 14-12-2022 at 07:41


I would be interested to find out what the nitrosation product of paracetamol is. If you get N-nitration, that's great. But if the phenol is deprotonated, then I would be inclined to expect ring nitrosation. So neutral to acidic conditions are recommended.



[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 14-12-2022 at 11:28


Thanks for your reply, clearly_not_atara!

I actually was reading the Possible route to resorcinol from Tylenol / Paracetamol thread the other day, where there was some discussion about the potential nitrosation of paracetamol. Along with a mention of the ambiguity of formed products

Deprotonation would occur in the presence of a base strong enough to act on phenol, right? Under my current thinking, the phenol would not be made into the phenoxide prior to reaction as it should be plenty soluble in methanol. NaNO2 and formed Na2SO4 pose no risk to deprotonation.

So what I'm thinking:

Methanol
1 eq paracetamol
2 eq H2SO4 (plus some additional amount to increase initial concentration for the decomposition, so that 4-methoxyphenol is favored over phenol)
1 eq NaNO2

Add acid, paracetamol to methanol, chill to 0C, slowly add solution of sodium nitrite in methanol (or perhaps water) while maintaining 0C. Once nitrosation is complete, warm reaction vessel to 40C and let decomposition occur.

Concerns/questions I'm currently doing some researching to resolve:

- Optimal volume of methanol for reaction to proceed and avoid potential sulfonation. Perhaps it makes sense to add the additional sulfuric acid for decomposition after nitrosation.

- Given lower solubility of sodium nitrite in methanol, would it make sense to add it as a concentrated aqueous solution? If attempting as a one-pot reaction, anhydrous conditions should be used during decomposition to avoid formation of, presumably, hydroquinone. Perhaps the formed sodium sulfate would be sufficient to pull the water out of the reaction.

- Should I expect the decomposition to eliminate all of the N-nitroso compound? Or perhaps some way to destroy any remaning after decomposition. I'm trying to avoid handling terribly carcinogenic materials.

- What are all the potential side products at each step, how might they affect the reaction, workup, and so on. Much is covered in the papers above, but I'd like to think through the specific ones formed in this reaction.

With regard to the ambiguity of the nitrosation product: I could potentially attempt an isolation prior to decomposition to try to analyze the product, but I'd really prefer not to deal with carcinogenic substances. Also, I'm unsure of the stability of this compound, as it seems many diazonium compounds seem prone to dangerous decomposition when concentrated. Not sure if the same holds for nitrosamines. It may be sufficient to elucidate the product formed from nitrosation from the decomposition products.
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[*] posted on 31-1-2023 at 18:28
Attempt with acetaminophen


Last weekend I got around to running a trial on the nitrosation and decomposition of acetaminophen in methanol with sulfuric acid.

I was unable to successfully extract any of the reaction product, but there were some interesting/encouraging aspects to the test.

--

Experimental:

5g (33.08 mmol) Acetaminophen
7g (66.5 mmol) 93.2% H2SO4
2.28g (33.08 mmol) NaNO2

Acetaminophen was added to a 50ml boiling flask and dissolved in 30ml of methanol. Then, sulfuric acid was added and the flask was put in an ice bath and cooled to ~2°C. Sodium nitrite dissolved in 3.2ml H2O was added using a dropper at such a rate that the temperature never exceeded 4°C (~15m). ~5-10ml methanol were used to rinse the beaker which had the sodium nitrite/water solution. A precipitate of sodium sulfate immediately formed at the beginning of addition and thickened considerably by the end. The mixture was then allowed to stir for 1h. Color through this time went from light pink, to light tan, then darker brown, and finally almost green towards the end.

1_1_start.jpg - 86kB 1_2_start_add.jpg - 112kB 1_3_end_add.jpg - 136kB 1_4_end_cool.jpg - 123kB


After 1h, the reaction mixture was allowed to warm to room temperature. As it reached around 20°C, a very small amount of bubbling was observed. The mixture was left to stir for 17h at RT. The bubbling seemed to drop off pretty significantly after a few hours, though it was pretty minimal to begin with. Color shifted to a dark crimson at the end.

2_1_rt.jpg - 155kB 2_3_rt.jpg - 176kB 2_6_rt.jpg - 188kB

2_7_rt.jpg - 144kB 2_8_rt.jpg - 143kB


The following day, the mixture was brought to reflux for 45m in an attempt to destroy any remaning nitrosamine. It was then allowed to cool and 1.32g (22.08 mmol) NaOH in ~10ml methanol was added. The solution remained acidic, possibly due to liberated acetic acid. Reflux was continued for 15m more, then the whole lot allowed to cool to RT. Once cool, the reaction mixture was vacuum filtered. The filtered precipitate had a very strong smell somewhere between phenol and p-dimethoxybenzene.

The filtrate was then reduced to 1/3 volume, added to a separatory funnel, diluted with 100ml H2O, and extracted with 3 portions of 15ml DCM. A black tarry layer formed above the DCM and remained in the aqueous phase. Solvent was then removed by boiling from the pooled extracts, but only a minuscule amount of a dark red oily substance remained. An attempt was made to further purify it by boiling it in n-heptane and decanting; nothing but more tar and interesting shades of red happened. The tar from the aqueous layer was also filtered off and some extraction attempts were made on it, but nothing of note came of this.

3_2_vac.jpg - 199kB

5_2_sep.jpg - 114kB 6_2_dcm.jpg - 161kB


7_1_misc.jpg - 145kB

7_2_misc.jpg - 138kB 7_3_misc.jpg - 183kB



Ultimately I abandoned the workup, as it got a bit messy and I wasn't seeing a clear path forward. The encouraging part of all of this was the smell. During the entirety of the attempted workup, the smell of phenol and p-methoxyphenol was abundantly clear. These would be two of the expected products of this reaction, as lined out in one of the papers I linked above.

I'm wondering if the use of water to dissolve the sodium nitrite might have negatively impacted things here. The total amount should have been just over the molar quantity needed to form the pentahydrate of sodium sulfate. However, I'm not certain that the salt is necessarily effective at pulling water from the solution.

Additionally, I'm not certain if neutralizing the sulfuric acid during workup was necessary or if too much water was added during dilution. It was also strange that addition of the DCM resulted in tar formation during extraction.

I didn't bother with a vacuum distillation, as I had issues purifying small amounts of this compound that way previously (or rather, it was a pain). Since I had luck with purifying with n-heptane in the route from hydroquinone, it seemed reasonable to try that for this approach. Perhaps it would be worth a shot to neutralize the reaction mixture totally, accounting as well for the liberated acetic acid, distill off the methanol, and vacuum distill what's left.

I'm going to chalk the lack of an isolated product to the fact that this was a trial run, I was making some guesses, and this was my first time running a nitrosation. With some tuning, I think there might be a viable path forward here. At least, it seems worth further investigation.
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[*] posted on 2-2-2023 at 06:36


Fantastic thread, tyro!

The paracetamol angle is fascinating, and I admire your ambition in working toward a one-pot procedure. I don't have much to contribute to this, but I know that the diazotization is similarly exploited in clandestine preparations of GBL/GHB from GABA, and I'm hopeful that the strategy can be feasible here as well. However, it seems to me like you had best protect the phenol via O-methylation first; the Liebermann reagent, a mixture of KNO2 and sulfuric acid, is used to identify phenolic compounds by exploiting their tendency to form colored indophenol compounds (this could explain the poorly soluble tar you observed on dilution).

[Edited on 2-2-2023 by Benignium]
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[*] posted on 3-2-2023 at 11:28


The reaction of acetaminophen with nitrous acid is qualitatively different from the reaction of nitrous acid with acetanilide. The phenolic group of acetaminophen activates the benzene ring such that you end up nitrosating/nitrating the ring competitively with the nitrosation of the amide nitrogen. This is why your reaction is a mess. Even if you protect the phenolic group there will likely still be ring reactivity competitive with amide nitrosation. If you want the monomethyl ether of hydroquinone you will need to methylate the phenol, hydrolyze the amide, and then convert the amino group to a phenol. Hydrolysis of acetaminophen to p-hydroxyaniline and then trying to convert the amino group directly to a methoxy group will be a frustrating learning experience.

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