Sciencemadness Discussion Board - dinitrobenzofuroxan derivatives

dinitrobenzofuroxan derivatives

nitro-genes - 23-4-2015 at 17:24

Hi everyone,

Noticed there is no thread about dintrobenzofuroxan derivatives, some of which, like KNDBF (attachment) are implemented as environmentally green primer compositions.

I'm no chemist, but would it be possible to do a synthesis from paracetamol? Treat acetaminophen with HNO3 to introduce a nitro group in ortho position (relative to the acetanillide group), then hydrolyzation to yield 2-nitroanilline (http://en.wikipedia.org/wiki/2-Nitroaniline). The furoxan group supposedly can be formed from oxidizing the 2-nitroanilline using hypochlorite solution. Then HNO3+H2SO4 to nitrate this further?

Not sure where the nitro group will end up from the first nitration from acetaminophen, due to the additional hydroxyl group, which is not present in acetanillide and in para position. ALso not sure if the second nitration will succeed.

http://www.wydawnictwa.ipo.waw.pl/cejem/vol-9-4-2012/Sarlaus...

[Edited on 24-4-2015 by nitro-genes]

APO - 23-4-2015 at 22:54

From everything I've seen so far, it does look like acetaminophen usually does indeed favor addition of a single nitro group to the ortho-position relative to the "acetanilide" group, namely if you just do a normal mixed acid nitration it will work fine[1], giving 4-acetamino-3-nitrophenol, if you use nitrous acid, then the pH will affect where the nitro group ends up[2&3]. Hydrolysis of 4-acetamino-3-nitrophenol would then result in 4-amino-3-nitrophenol.

[1]: Possible route to resorcinol from Tylenol / Paracetamol?
[2]: Colorimetryof Serum Acetaminophen(Paracetamol)in Uremia
[3]: Nitration processes of acetaminophen in nitrifying activated sludges

Now, just to clarify, you're wondering if you could use 4-amino-3-nitrophenol in the same way you would use 2-nitroaniline to form some sort of furoxan, which you could then nitrate, correct?

I am a bit confused because the PDF you linked has no reference to 2-nitroaniline, it only references 3-nitroaniline. Do you have a reference for 2-nitroaniline being used to form a furoxan?

nitro-genes - 24-4-2015 at 02:25

The synthesis of benzofuroxan from 2-nitro anilline is listed in US 4185018, they mention introducing hypochlorite solution to ethanolic solution of 2-nitro anilline. They also refer to Org. Synth., Vol. IV, page 74 ff, (1963) for the synthesis. This seems really appealing, since no obscure chemicals seem to be needed to produce the benzofuroxan moiety itself. I haven't read every detail yet though, it was more of a late night idea that I just had to post. :-)

Further reading: https://books.google.nl/books?id=wfJHAAAAQBAJ&pg=PA174&a...

Page 167

If the nitration to the dinitro compund doest work, maybe Boulton-Katritzky rearrangement using K2CO3 is possible before nitration step? Will the furoxan group survive mixed acid treatment?

[Edited on 24-4-2015 by nitro-genes]

PHILOU Zrealone - 25-4-2015 at 04:51

The hydroxy group is the stronger inducer of orientation (vs aminoacetyl) and thus, the orientation of the nitration will be in ortho of it and not in meta!
The resulting product of nitration with HNO3 of para-acetamino-phenol (paracetamol) will thus be the 2-nitro and not the 3-nitro.

It seems that HNO2/NO2(-) may favor the introduction of a nitro in position 3 ... this is complex chemistry and goes probably via help of the vicinal acetamino group... nitrosation and oxydation to nitro group...or obscure nitrite addition.

To get to 4,6-dinitro-7-hydroxybenzofuroxan, one would have to start from meta-:
-nitrophenol
-aminophenol
-nitroaniline
-chlorophenol

Ortho azido-nitro-aromatics also turn upon mild heating into benzofuroxan by mutual oxydoredox of the azido and nitro groups into nitroso groups.

The synthesis scheme proposed by nitro-genes looks interesting but the para-amino-phenol (even if nitrated as 3-nitro-4-amino-phenol) is very prone to oxydation into para-quinon-ic compounds.
I would suggest to start from 3-chloro-2,4-dinitro-phenol; then azidation with NaN3 to get 3-azido-2,4-dinitrophenol; heating to get 5-nitro-6-hydroxy-benzofuroxan and final nitration to get the desired 5,7-dinitro-6-hydroxy-benzofuroxan.

APO - 25-4-2015 at 19:44

In the first link I referenced [1], it links to a patent that specifically names the compound received by mixed acid nitration using HNO3/H2SO4 as "3-nitro-4-substituted aminophenol", which I called 4-acetamino-3-nitrophenol. Meaning that for that particular process, among others, the nitro group is usually added adjacent to the acetamino group. Most of what I have seen shows the compound resulting from nitration or nitrite addition as having the nitro group in the meta (3) position, however I have also seen some references as having it in the ortho (2) position. All I can really gather from this mix of data is that you can pretty much pick whatever isomer you want, however, what you get is very dependent on reagents used and reaction conditions.

It looks like during nitrite addition, at a pH lower then 5.5, which is apparently a deciding factor on what happens: nitrous acid generated in situ oxidizes the acetaminophen to it's corresponding quinone-acetyl-imine, which then becomes the Michael donor, the nitrite acts as the Michael acceptor, and Michael addition takes place. This also typically gives a higher yield, but, if OTC is the goal, just a guess since we're starting with acetaminophen, nitrites might not be available. That's why I kind of focused on mixed acid nitration.

Both the OP's proposed synthesis and PHILOU Zrealone's sound like interesting approaches.

Are we looking at something preferably OTC and or starting from acetaminophen, or just whatever works?

nitro-genes - 27-4-2015 at 15:26

Many thanks for the replies, Should have been more clear in the first post: nitrites, azides, hydrazine sulfate, TCCA are at my disposal, but the idea was indeed to do the synthesis completely OTC. I don't care for the bang of the final product, and I'm not necessarily looking for KDNP, just the idea of synthesizing benzofuroxan derivatives from incredibly OTC chemicals seemed pretty sexy. :cool:

So, just to sun it up, mixed acids will likely produce 4-acetamino-3-nitrophenol, but hypochlorite oxidation will likely produce benzoquinones despite partial deactivation by the nitro group? Like said before, I'm no chemist, but I was sort of hoping the formation of the benzofuroxan group itself might be favorable instead of oxidation. With my limited knowleadge, the furoxan group seems to "add" a lot ot stability to the ring, but could be wrong here. How does the elimination of the NH2 group proceed during oxidation, what intermediates, similar to those leading to benzofuroxan formation? If the hydroxy group is oxidized first, the benzofuroxan is unlikely to form probably? Another problem might be additional chlorination of the ring by hypochlorite, but I read something about sulfite (wine making) addition to prevent this. Didn't have much time past weekend, but I will look into it. Still hoping this may actually be a viable synthesis somehow.

Another interesting approach is introducing a 3-amino group to 2,4,6 trinitrophenol --> US 8404897 B2. Lithium can be obtained from batteries, but hydroxyl amine isn't really OTC (nitromethane is not easily obtained around here).

[Edited on 27-4-2015 by nitro-genes]

APO - 27-4-2015 at 21:13

You're very welcome, thank you for the great idea and references. I'm far from a chemist too, but: It seems like production of 4-acetamino-3-nitrophenol, whether it be through mixed acid nitration or nitrite addition, is possible, but like I wrote before, you would need to follow a very good procedure, very stringently, in order to receive the desired isomer.

Here is the OrgSyn prep of benzofurazan oxide from 2-nitroaniline referenced by patent US 4185018. The yields are actually very good! One should note that the hypochlorite is added to the 2-nitroaniline in a solution of potassium hydroxide dissolved in ethanol at a low temperature. Given what all that entails, I think that may eliminate a few of the foreseen possible issues such as chlorination of the ring or the hydroxide group inferring, since the yield is not really being cut down by any haloform that would usually occur with ethanol, it makes me think that furoxan formation is more favorable, and pretty quick. If oxidation still presented an issue, maybe gelatin could be used in the same way it's used in hydrazine prep?

Another approach would be to take the product after hydrolysis, convert the amine to an azide, and then heat to form the furoxan. Converting the amine to an azide could be done in a few different ways in this case, but that lengthens the process by two to three steps, so I think we should focus on the hypochlorite approach first.

Regarding the hydroxylamine, maybe this would work?

nitro-genes - 28-4-2015 at 03:35

Thanks for looking up that reference from org syn! :-) Read the rescorcinol from paracetamol thread you linked to, seems a happy coincidence that KOH can also be used for the hydrolysis of the amide. What temperature should the hydrolysis take place? Will the nitro group survive? The hypochlorite oxidation using KOH/etOH may be a perfect one step procedure to invoke both hydrolysis and oxidation to furoxan at the same time.What did worry me is that in the org syn procedure of hypochlorite oxidation, tarry compounds are mentioned forming above 10C, this may not bode well with the hydroxy group in para position maybe. :-)

EDIT: Have extracted some 50 grams of pure acetominophen from paracetamol using boiling ethanol. Will try both the mixed acid synthesis at very low temperatures as well as the HNO2 synthesis. I foresee big red clouds for the first approach, so small quantaties at first. :-)

[Edited on 28-4-2015 by nitro-genes]

APO - 29-4-2015 at 03:17

You're most welcome! Hydrolysis can be done with either an acid or base, HCl, NaOH, or KOH will all work. References on hydrolysis of acetaminophen and related compounds that I've seen generally cite the process as taking place in a boiling water bath or sometimes at reflux. From what I've seen, the nitro group should not be affected. I think that the hydrolysis and furoxan formation need to be separate steps due to the temperature difference that they're usually carried out in, and the acetic acid formed in the reaction would cause all kinds of problems. It looks like always being at or close to 0 ℃ is very critical to prevent side reactions during furoxan formation.

Now regarding mixed acid nitration, here is the procedure for the synthesis of 4-acetamino-3-nitrophenol from chinese patent CN1966495A, re-written to be more clear, since it was not perfectly translated:

First, 80ml of 98% sulfuric acid was added to a 150ml four-necked flask equipped with a stirrer and a thermometer. It was then stirred and cooled to below 10 ℃, at which point, 9.4g of acetaminophen was added. It was further cooled to below 10 ℃ again. Then a solution of 3.7ml of 98% sulfuric acid and 3.8ml of 96% nitric acid was added drop wise. The addition was complete after 2 hours. Then under strong stirring, the solution was poured into a large mix of crushed ice slurry. The precipitated yellow crystals were then filtered off and dried to give 9.2g of 4-acetamino-3-nitrophenol, in yield of 75.6%, with a melting point of 162 ℃.

I would also advise to prepare the sulfuric and mixed acid solution before hand, and then pre-chill them in a freezer several hours prior to use. Then to run the whole reaction cooled by a salt-ice bath, keeping the mixed acid solution addition slow enough to stay well below 10 ℃. Maybe have an extra bath in the freezer ready encase the first one starts to warm up. You may also want to wash the filtered product with cold saturated sodium bicarbonate solution and then with more water just to completely neutralize it. Of course a four-necked flask isn't totally necessary, I'm sure you can use whatever setup you have as long as the reaction conditions remain the same. I'd personally like to see the nitration first, rather than nitrite addition, since it's slightly more controversial and we've gathered more info on it, anyway, best of luck.

Also post pictures!

I will also gather more info on nitrite addition, and post back here with a possible procedure.

nitro-genes - 30-4-2015 at 01:10

Ok, nitration went much smoother than anticipated. I did't use HNO3, I was out, and didn't want to distill something if nitrate salts could be used instead. :-)

7.7 grams of absolutely anhydrous ammonium nitrate was dissolved in 20 ml 98% sulfuric acid at room temperature, this was put at -20., resulting a a clear syrupy liquid. In a separate beaker, 60 ml of 98% sulfuric acid was poured and also put at -20. The next day, 9.4 grams of acetaminophen was dissolved in the 60 ml of sulfuric acid (while on salted ice bath), only very slight exotherm occured, so addition of the AN/SA was directly done after. Using a pipet the AN/SA was slowly allowed to drip in the SA/Acetaminophen solution, temperature did not went over 0 degrees at all times, addition was done over the course of about 15 minutes, almost no smell of NOx was noticed, but very faint smell of acetic acid was. An interesting note is that the solution went instantly from sort of orange to almost red with the addition of the last drops of AN/SA, which seems a good indication for completion of the reaction. The mixture was poured in 300 ml of icecold water upon which a orange-yellow solid precipitated. This was washed with another 300 ml of icecold water and collected to dry. It has low water solubility, stains like picric acid and sodium bicarbonate produced a bright red solution. Looking at the solubility of the potassium salt right now, as it is in the fridge.

Some additional notes, exotherm is really manageable, salted icebath doesn't seem obligatory, crushed ice should work fine with maybe slightly longer addition time. For the next synth I will try to minimize the amount of 98% SA needed.

The nitration also produced a small amount of sticky, chewing gum like stuff, probably left overs from the binder/sugars in the acetaminophen tablets. Either that or polyanilline like derivatives may have formed during the reaction. It's probably better to either start with the pure stuff or do proper recrystallization from ethanol first. (I simply evaporated everything at low temp).

Question remains which isomer we have produced, though the nitration itself seems to work. Also wonder how sensitive this stuff is to hydrolysis/oxidation by air, with some of the entrapped acid remaining from the synthesis. Bicarbonate neutralization to produce the sodium salt may be a better option, but how best to proceed for the hydrolysis/hypochlorite oxidation?

[Edited on 30-4-2015 by nitro-genes]

nitro-genes - 30-4-2015 at 03:33

The chewing gum residues are definitely from the binder within the tablet. Any ideas for purifying acetaminophen from tablets? It is not sold in pure form, crystallization from ethanol may be diffucult, as solubility doesn't seem to drop hard with temperature. Maybe water-ethanol mixtures couls be used. The tablets likely contain starches, stearic acid, waxes and titanium/silicon oxides, The first two are probably hard to get rid of. Maybe using just enough ethanol at lower temperatures can extract mostly acetaminophen. Will try different methods.

Attachment: Paracetamol solubility.pdf (91kB)
This file has been downloaded 11571 times

[Edited on 30-4-2015 by nitro-genes]

APO - 30-4-2015 at 19:20

Very nice work! I was curious how it would work using a nitrate salt to substitute pure nitric acid; you got two birds with one stone. No pictures?

I'm aware I offered fairly conservative advise, you can never be too safe.

I was going to ask about the acetaminophen that you extracted, and whether you recrystallized it or not, but purity did not really sound like it would effect the reaction very adversely. Most acetaminophen tablets also use some form of cellulose as a binder, so my guess would be that the gummy stuff is probably mostly nitrocellulose and nitrostarch. The acetaminophen can also be oxidized to it's quinone, in which case it will either polymerize, which could also be part of the gummy stuff, or it will still be nitrated, and go on to form the other isomer we talked about. Igniting some of the gummy stuff would probably reveal more about what it is.

If you want to purify the acetaminophen, try to dissolve as much as you can in a solvent, filter to get rid of binders, then like you said, try to re-crystallize. If you have a soxhlet extractor, then maybe extraction using a solvent in which those impurities have little to no solubility could yield a more pure product. It does not sound totally necessary to me though.

Based on how you describe the nitration, I would think that the nitrated product primarily consists of the isomer we want.

The sodium bicarbonate solution was intended just to neutralize any remaining acid, not to form a salt, I totally forgot about that pesky hydroxide group.

Regarding hydrolysis, here is a student procedure that includes hydrolysis of p-nitroacetanilide to p-nitroaniline. The piece of interest reads:

"1. Place 2.5 g of p-nitroacetanilide and 13ml of 70% H2SO4 in a round-bottomed flask.

2. Reflux the mixture for 20min.

3. pour the hot solution into 250ml of cold water taken in a beaker

4. Neutralize with 10% NaOH.

5. Cool and filter the yellow crystalline product on a Buchnerfunnel. Wash it thoroughly with water."

From what I've read H2SO4 actually works very well for the hydrolysis of acetaminophen and other acetanilide like compounds. So, you should simply replace the 2.5g of p-nitroacetanilide with 2.72g of the nitrated product, scale procedure to work for however much product you have, then follow the procedure up to step three. After that, you should filter to get the product, wash with cold water to neutralize it, and let it dry. Finally, weigh the dry product.

After you do that, report back with the details of the procedure, how it went, and the results. Then I have some ideas to share on furoxan formation, and will write a procedure to try. Sound good? Also please try to post pictures this time!

Notes:

The sulfuric acid really has to be diluted to 70%, or else sulfonation will occur in preference to hydrolysis.

I especially need the weight of the dry product (after hydrolysis) to do the stoichiometry for the furoxan formation procedure.

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

Info on nitrite addition is very sparse so far, so that may have to wait.

nitro-genes - 1-5-2015 at 02:25

A small amount of the ehtanol extracted acetaminophen was dissolved in the least amount of ethanol:water (2:1) at room temperature, chewing gum like stuff remained, so the residues are from the tablets itself, it feels waxy, but does not dissolve in heptane. I think I just shouldn't have boiled the ethanol to extract the acetaminophen, which lead to slight yellowing of the solution anyway, probably due to slight hydrolysis/oxidation of the acetaminophen. Next time room temperature will be used.

70% sulfuric acid at reflux seems pretty harsh conditions, are you sure of this protocol? Wouldn't want something like this to happen. https://www.youtube.com/watch?v=h4pNXAtPJp8

To be honest, the idea of doing the hydrolysis in boiling KOH/etOH solution prior to hypochlorite addition seems to good to pass up. What was your idea of the side reactions occuring with the acetate present? Formation of cyclic N,N dioxides, or oxidation of the acetate to CO2, screwing up stoichiometry? I don't think these will occur at this temperature and pH at a rate that would give serious byproducts.

I'll devide the putative 4-acetamino-3-nitrophenol in two portions to try both methods, I want to try the oxidation to the furoxan in very small quantities at first anyway. I have a feeling there might be tears

[Edited on 1-5-2015 by nitro-genes]

nitro-genes - 1-5-2015 at 08:07

12.5 grams of NaOH were dissolved in 50 ml water and put on ice, chlorine was produced from TCCA + HCl and bubbled through until 10 grams had been absorbed.

1.96 grams of KOH was dissolved in 18 grams of EtOH and heated to dissolve. Then, 3 grams of the putative 4-acetamino-3-nitrophenol was added and boiled for 30 minutes. A dark red suspension/solution developed immediately, but upon boiling, dissolution remained incomplete. At -10 degrees C, 21.75 grams of the fresh hypochlorite solution was added anyway, keeping temperature below 5 degrees. Solution did not change colour, small whiff smelled like almonds with definite slight smell of chloropicrin. Allowing the solution to warm up after the last addition did not produce large exotherm or lot of gas production (although bubbling could be heard), small amount acidified with HCl produced no smell of chlorine.

Seems like oxidation doesn't directly produce the furoxan, although hydrolysis may have been incomplete due to incomplete dissolution int he ethanolic KOH, or the hydroxy benzofuroxan/potassium salt formed is soluble in the ethanol/water mixture, or the wrong isomer is produced during the nitration. The latter seems more likely IMO, note that most of the references for production of 4-acetamino-3-nitrophenol start with O-acetylation, seems Philou was right afterall. :-) Although I will try seperate hydrolysis step using HCl or H2SO4 as well, but i'm pretty sure now it won't work.

Too many probabilities to exclude IMO, is there a test to distinguish 4-acetamino-3-nitrophenol from 4-acetamino-2-nitrophenol?

[Edited on 1-5-2015 by nitro-genes]

APO - 1-5-2015 at 18:18

Good to know you've made progress regarding the acetaminophen purification, and further perplexed me regarding what that gummy stuff is.

The use of 70% sulfuric acid may be a bit extraneous, but from what little literature I've looked at, no problems are stated before reaching 80% concentration. It states that once you reach or go above 80% concentration, favor all the sudden massively slants towards sulfonation instead of hydrolysis, but no immediate oxidation or charring is blatantly reported. Also keep in mind that it is not nearly as dehydrating as concentrated sulfuric acid, and that once hydrolysis starts, the reaction begins to self dilute via release of acetic acid.

The initial assumption regarding issues that acetate could cause reaction wise was that if hydrolysis was done in situ that the formation of acetate would drive the pH down, cause a need for an increasingly large excess of potassium hydroxide, and just seemed to add unnecessary variables to consider. If there was not enough potassium hydroxide to compensate for the formation of the salt, as well as release of formation of acetate, then they would form in equilibrium, or worst case, free acetic acid could react with the hypochlorite solution to form hypochlorous acid, cause oxidation, or cause side reactions, in any case, further driving down the pH. I assumed that the pH was required to stay really high since a very concentrated solution of hypochlorite is prepared for use, and a marginal excess of potassium hydroxide is already used. Despite all this though, the more I consider it, the more it seems possible, as long as you have more than enough potassium hydroxide to form the salt, form the acetate, and keep the pH very high. Excess of potassium hydroxide seems very important, if there is not more than enough for what all I mentioned, things are in equilibrium, pH is too low, and things are not being pushed towards furoxan formation. Another modification I would make is to use just one form of hydroxide for both halves of the procedure, that way there is not a mix of sodium and potassium ions to confuse which furoxan salt would be received.

The patent and the section of the thread I referenced do NOT start from O-acetylation, they specifically start nitration using freshly prepared acetaminophen. However, I see your point that the ambiguity of the isomer may be causing an effect. I will look into ways to differentiate isomers, and look into sure fire ways to get the isomer we want. Could you slow down on the experimenting a little? I think you might be moving a little too fast and jumping to conclusions. There is a lot that goes into this to consider before going all out.

Boffis - 1-5-2015 at 19:21

@ nitrogenes, I have been following your very interesting experiments with interest as I am looking at preparing 5-hydroxybenzotriazole via the 3-nitration of paracetamol, reduction to the 3,4 diaminophenol (with or without prelimenary hydrolysis) and then react this compound with sodium nitrite to give the required triazole.

The benzene ring in the 5-hydroxy compound is more susceptable to oxidation and halogenation than the unsubstituted compound, infact according to the literature, hypochlorite first chlorinates the benzene ring to a perchloro-4,5-diketone and then cleaves it to 4-carboxytriazole-5-(trichloromethyl) ketone (see T Zincke JLAC 311 (1900) p276-329 [epic read for triazole fans

]). Given the likely similarity between the two systems is it possible that the hydroxybenzofuroxan is being chlorinated as fast as it is formed using up the hypochlorite quickly leaving much unreacted starting material?

By the way, hydrolysis with KOH in a small volume of alcohol is likely to give a ppt of the K salt of the nitrophenol that is probably going to be sparingly soluble in alcohol. I think you would be better to use wáter and then ppt the free aminonitrophenol by carefully neutralising with HCl and use the isolated product.

Just a thought

APO - 1-5-2015 at 20:39

I was worried about the solubility of the potassium salt too, I thought about using HCl also, but not in the exact same way. Thanks for the info on chlorination and extra insight. Nitro-genes has peaked my interest on one-pot/single step hydrolysis/furoxan formation, anyone have any ideas on how to make it work?

nitro-genes - 2-5-2015 at 03:35

Haha, the mystery of the waxy substance that doesn't dissolve easily in water or heptane... I think I solved it, it's probably phlegmatized (fatty acid bound) starch or sugar with intermediate polarity. Saw it as one of the contents in some tablet formulation. Whatever it is, it doesn't seem to be extracted to the same extent when just enough ethanol is used at room temperature with long stirring, so that is easy.

Was worried too about the solubility of the potassium salt which seems a serious problem for the conversion to the furoxan (if at all possible). It might be that the potassium-amino salt after hydrolysis is more soluble in ethanol than the potassium-acetamino salt, but I really doubt it. I was maybe jumping to conclusions, but seen Boffis post and considering all posibilities, the problem is that the number of uncertainties at this point at the various stages is too large to exclude by continuing experimentation, that is why we really need to determine somehow which isomer is formed during the nitration.

@APO, if you recalculate the molar ratios used for the hydrolysis/hypochlorite oxidation, you'll find I already compensated the amount of KOH for the acetate :-)

[Edited on 2-5-2015 by nitro-genes]

APO - 2-5-2015 at 06:08

I see now that you compensated for the acetate portion of it, by my rough calculation, your molar ratio of KOH to putative 4-acetamino-3-nitrophenol was ~2.28:1. Still, IF solubility wasn't an issue, and pH/concentration didn't effect the reaction too much, then molar ratio of KOH to putative 4-acetamino-3-nitrophenol would have to be at least ~3.1:1. Crunching the numbers I'm a bit confused on how you figured the amounts you used for the last procedure.

Once I figure out how to differentiate isomers and etc, I will post here ASAP.

nitro-genes - 3-5-2015 at 10:35

@ Boffis, interesting compounds these benzoriazoles, what is your plan with them? :-) How are you planning to to the reduction of the nitro-group? I was thinking, how specific would sulfide reduction be, could this be used to distinguish between the isomers?

Boffis - 3-5-2015 at 19:28

@ nitro-genes. My interest in the 1,2,3 triazoles is as ligands or parts there-of. I am interested in a wide variety of heterocyclic compounds and potentially even the benzofuroxans. The hydroxybenzotriazole suffer benzene ring cleavage much more readily than the parent compound so it is possible to make triazole-substituted glyoxalic acids in addition the the usual triazole-4,5-dicarboxylic acid I have made before.

My plan (prior to reading this thread) was to try the nitration of paracetamol with excess nitrite/acid as described in the Japan paper posted in another thread. Hydrolyse the product with conc HCl and then reduce the resulting hydrochloride with Zn or Fe powder. I am not sure whether the nitro-group would be reactive enough to react with say sodium sulphide but it would be worth a try; I would probably have to isolate the free base after reduction though. One reduced to an o-diamine I would react it immediately with nitrous acid as its probably rather prone to oxidation.

Does any one know if sodium sulphide will reduce the o-nitro group in 2,4-dinitroaniline? This might offer an alternative route from chloro or bromo benzene via the 2,4 dinitrohalobenzene and 2,4 dinitroaniline to nitrobenzotriazole. For your synth you you wouldn´t even need this reduction you could run the hypochlorite oxidation on the nitroaniline to give 5-nitrobenzofuroxan. The nitro group will probably make the benzene ring less readily oxidable. The nitro group could then be reduce to an amine to make the benzene ring reactive enough to nitrate further. But of course this probably defeats the object which is to start with paracetamol!

There is a lot of interesting stuff posted on the DDNP thread and reading through some of the papers there is a fair amount of disagreement as to which isomer is produced under different condition and so any data such as Mp is suspect. However, there is a good deal of data on on the 3-nitro-4-acetamidophenol that suggests a Mp of 218-220 C. If you plug this value into the older papers by Mendola et al you may be able to discern the true identity of the compound they made.

Your idea that reduction of your compound may give you a clue to its identity may have some merit since o-nitrophenol are generally reducible by sulphides while I don´t know about the m-nitro position. There is a fair bit of information on this reaction though in various threads.

nitro-genes - 8-5-2015 at 16:42

Would this be useful as a very simple OTC route? Making a dough from urea and picric acid and baking in the oven?

Somewhere remote though... Anyone has full tekst?

http://www.nrcresearchpress.com/doi/abs/10.1139/cjr46b-026?j...

Boffis - 8-5-2015 at 17:57

There are several preparation of 2-nitroanilines via this route, 2,4-dinitroaniline from 2,4-dinitrochlorobenzene (its a patent and its on this site somewhere, and this preparation of 2,4,6-trinitroaniline (picramide). I have been meaning to try this as I found an old German paper that desribes the reduction of the ortho-nitro group to an o-diamine with sodium sulphide (as with picramic acid) form which I can prepare a dinitrotriazole (I hope

) but you may be able to prepare the appropriate dinitrofuroxan instead. The CJC is usually fairly reliable.

Attached is the Can J Chem ref;

Attachment: Picramide preparation Can J Res Spencer & Wright 1946.pdf (220kB)
This file has been downloaded 1317 times

Here is the patent for dinitroaniline;
Attachment: 2,4-Dinitroaniline via urea US 1752998.pdf (70kB)
This file has been downloaded 1087 times

nitro-genes - 9-5-2015 at 02:46

Thanks for the full text! Definitely going to try this on a small scale. Wanted to know how the reaction proceeded and was also curious whether they would address possible sublimation issues with the picric acid at these temperatures. The synthesis of 2,4 dinitrochlorobenzene was already described in the "pentryl" thread in prepblication, but these are a lot of steps. Synthesis of picric acid has 90%+ yield, if indeed the acetone soluble product described in the paper is a yield of 90% TNA from TNP, this would mean an incredibly effiicent route to trinitroanilline.

nitro-genes - 11-5-2015 at 05:49

The synthesis of trinitroaniline from picric acid and urea works perfectly as described. In a beaker with teflonized (gas tape) lid, 23 grams of finely powdered recrystallized TNP was intimately mixed with 18 grams of finely powdered urea. This was (outside in the shed) heated for 24 hours at 180 deg C in a small electric oven. An extra oven temperature indicated that the temperature remained between 170 and 178 degrees C at all times. The mix melted producing an orange liquid, that gradually became a distinct dark red. White fumes were emitted during the reaction, consisting most likely of NH3 and CO2, probably recombining to ammonium carbonate in the air, giving the white fumes.

After 24 hours at 175 and cooling, 150 ml of water was added. It was a PITA to get it all to form a suspension, forming a glassy subtance, that needs considerable effort to break up under water. The suspension was filtered and after drying of the resulting brown powder, was dissolved in 150 ml acetone at 40 degrees. Brown insolubile stuff remained, while an orange solution of TNA was obtained. To this was added very slowly while stirring on the hotplate, 150 ml water and then boiled until no smell of acetone could be noticed. This gave 17 grams TNA of a orange/yellow colour, melting point around 180-190 ish (hotmplate, so not very acurate). :-)

I have a hunch for a OTC procedure for the selective reduction of one ortho nitro group, will post results in a few days. :-)

EDIT: This procedure is dangerous enough as it is, and only to be performed outside and with recrystallized TNP. Do not use a metal lid for the reaction, volatilization of the picric acid was evident, creating a yellow film covering the entire reaction vessel. Contamination with metal picrates can possibly lead to detonation of the entire mix!!! Also make sure that both the TNP and urea are finely powdered and mixed PRIOR to heating/melting.

[Edited on 11-5-2015 by nitro-genes]

Boffis - 11-5-2015 at 16:58

Nice work nitro-genes! 17g is a pretty good yield for such a brutal method and almost exactly the reported yield. Did you keep the brown stuff? my understanding from the paper is that more picramide and some cyanuric acid can be recovered from it.

Somewhere amongst my papers I have one on the action of hydrogen sulphide on picramide to produce 3,5-dinitro-1,2-diaminobenzene (3,5-dinitro-o-phenylenediamine). I´ll dig it out but its not an obvious title as a quick searchy on my HD failed to find it.

Found it! it´s a whole-volume pdf so I´ll have to do a bit of pruning but here is the ref.

Norton & Elliott, Berichte v11, p327 (1878)

I´ve posted this ref before in the triazole thread so I may have been posted under the references wanted section already.

[Edited on 12-5-2015 by Boffis]

nitro-genes - 12-5-2015 at 01:34

The brown stuff is partly a condensation product of the cyanuric acid and formed picramide indeed, I thought about acidifying the brown suspension using HCl and boiling it for some time to hydrolyse, possibly resulting in a slightly higher yield. Addition of a dipolar aprotic solvent would be a much safer synthesis, the use of sulfolane for the TNP-TNA conversion at high temperatures has been described and patented, can anyone think of another possible OTC solvent, maybe propylenecarbonate?

https://e-reports-ext.llnl.gov/pdf/332580.pdf
US7057072

For the reduction, alternatively, ascorbic acid might be useful as well. Supposedly, dinitro and mononitro anilines cannot be reduced by ascorbic acid, which could mean that ascorbic acid might be able to robustly reduce a single nitro group for TNA. When I boiled a very small amount of TNA/NaOH with NaAscorbate, a brown powder came out of solution, which would be the most likely colour for the diamino, dinitrobenzene. Will try this on larger scale soon.

[Edited on 12-5-2015 by nitro-genes]

Rosco Bodine - 12-5-2015 at 05:30

Quote: Originally posted by nitro-genes

The synthesis of trinitroaniline from picric acid and urea works perfectly as described. In a beaker with teflonized (gas tape) lid, 23 grams of finely powdered recrystallized TNP was intimately mixed with 18 grams of finely powdered urea. This was (outside in the shed) heated for 24 hours at 180 deg C in a small electric oven. An extra oven temperature indicated that the temperature remained between 170 and 178 degrees C at all times. The mix melted producing an orange liquid, that gradually became a distinct dark red. White fumes were emitted during the reaction, consisting most likely of NH3 and CO2, probably recombining to ammonium carbonate in the air, giving the white fumes.

After 24 hours at 175 and cooling, 150 ml of water was added. It was a PITA to get it all to form a suspension, forming a glassy subtance, that needs considerable effort to break up under water. The suspension was filtered and after drying of the resulting brown powder, was dissolved in 150 ml acetone at 40 degrees. Brown insolubile stuff remained, while an orange solution of TNA was obtained. To this was added very slowly while stirring on the hotplate, 150 ml water and then boiled until no smell of acetone could be noticed. This gave 17 grams TNA of a orange/yellow colour, melting point around 180-190 ish (hotmplate, so not very acurate). :-)

I have a hunch for a OTC procedure for the selective reduction of one ortho nitro group, will post results in a few days. :-)

EDIT: This procedure is dangerous enough as it is, and only to be performed outside and with recrystallized TNP. Do not use a metal lid for the reaction, volatilization of the picric acid was evident, creating a yellow film covering the entire reaction vessel. Contamination with metal picrates can possibly lead to detonation of the entire mix!!! Also make sure that both the TNP and urea are finely powdered and mixed PRIOR to heating/melting.

[Edited on 11-5-2015 by nitro-genes]

Interesting. I must wonder what would be the result if the Spencer and Wright synthesis was applied to styphnic acid instead of picric acid. Using the same proportion for urea would one of the hydroxyls of the styphnic acid remain intact, possibly to combine with byproduct ammonia?

Also there would seem to be safety concerns about this reaction for reason of the elevated temperatures and the nature of the nitro compounds being heated. So I must wonder also if danger lurks which is an unquantified "variable"

[Edited on 12-5-2015 by Rosco Bodine]

Boffis - 12-5-2015 at 06:29

@nitro-genes. I have seen that patent before but had forgotten about it. However, it has given me an idea.

Instead of sulfolane how about refluxing DMSO, this compound can be purchased easily on line and is fairly cheap and boils at 189 C only slightly above the required reaction temperature. Another possible solvent is N-methylpyrrolidone with a slightly higher boiling point (202 C)

Rosco Bodine - 12-5-2015 at 06:53

For a solvent moderating the reaction even something like kerosene or other middle paraffin petroleum could work, but will possibly slow down the already slow reaction. Softening the solidified chunk from the unmodified reaction might be facilitated by hot xylene. If it (hopefully) forms a hot syrup it could be streamed into boiling hot vigorously stirred H2O and a lot of the xylene will steam distill away leaving the particles in suspension for later filtering and redissolving in acetone.

Boffis - 12-5-2015 at 07:00

I think at least one of the reactant should be soluble in the solvent /dilutant. Ethylene glycol may also work and I have both n-heptanol (Bp 175 C) and n-octanol (Bp 195 C) too.

Alternatively why not just use more urea as both a reaction and flux/dilutant?

[Edited on 12-5-2015 by Boffis]

Rosco Bodine - 12-5-2015 at 08:17

Forming urea picrate first as an intermediate could also be useful.

nitro-genes - 12-5-2015 at 09:15

IMO, from a practical standpoint, regarding isolation of the TNA, the solvent needs to be soluble in (hot) water or acetone/water mixtures to some extent. The water extraction to remove the excess urea after heating is already pretty messy, imagine a sticky viscous hydrophobic oil thrown into the mix. :-) Might still work, if careful recrystallization is performed after the acetone extraction, leaving the solvent mostly in solution, but this would need a lot of work probably to optimize. Moreover, if the reactant(s) are not soluble in the melt/solution then phase seperation will occur and no reaction.

DMSO/propylene carbonate would probably a better option, though DMSO would have been such a logical choice, that it seems strange sulfolane is used in the patent. I was thinking... some plasticizers are pretty water soluble and largely aprotic, triethyl citrate for example (used as food additive) although I'm not sure if they can stand the reactants and conditions applied, without transesterification occuring with the TNA.

A very interesting candidate IMO: Dot4 brake fluid consists mostly of butoxy triglycol, although pretty much water insoluble. Dot 3 brakefluid is much more water soluble IIRC, this is maybe the the best completely OTC solvent on my list, although it is still protic and will probably condense with the urea. :-)

Adding more urea probably won't work, according to the Spencer paper, it leads to more cyanuric acid and more of the acetone insoluble brown stuff. However...

From patent --> US3785796
"However, on searching the literature, it became obvious from an article in the Russian Journal of Applied Chemistry, vol. 40, 9, p. 1989 (1967) and from the work done by Meiser, supra, that ammonium sulfate was slightly soluble in urea. The Russian article stated that a eutectic point existed at 121.5° C. and at this temperature, a mixture of 9 percent ammonium sulfate and 91 percent urea was liquid. "

Without a suitable OTC solvent, it might still be interesting to examine the outcome for some ammonium salts/urea eutectics, that may lead to less formation of cyanuric acid, condensing with the TNA, lowering yield. This is probably the reason why ammonium salts are used in the patent.

@ Rosco, the idea of performing the reaction with TNR instead of TNP is an interesting idea! Does TNR have similar decomposition temperature compared to TNP? If I'm able to find a suitable solvent, I might give it a shot...

[Edited on 12-5-2015 by nitro-genes]

Rosco Bodine - 12-5-2015 at 12:32

Checking further I don't think styphnic acid will work the same as picric acid heated with urea because the ammonium styphnate byproduct detonates on heating.

nitro-genes - 12-5-2015 at 16:29

Hmm, detonation of reactants is never a good thing...

Offtopic These KC300 nitrile gloves can easily rupture, I didn't notice but one fingernail was stained bright yellow from TNP solution. Who would have thought one of these could be so convenient, I hope she didn't notice.

https://www.google.nl/search?q=nail+file&source=lnms&...

[Edited on 13-5-2015 by nitro-genes]

nitro-genes - 13-5-2015 at 16:32

Had some dot 4 brakefluid lying around and diammonium phosphate (yeast nutrient salt for wine making, called DAP). Did some testing, looking at stability and solubility without TNP added. Unfortunately, brakefluid does not dissolve DAP. When heated for some time with urea, a solution was obtained, that after cooling solidified to one crystalline mass. TNA heated in BF does not dissolve, but is recoverable by adding hot water and filtering. I'm out of TNP, so couldnt test solubility.

DAP gives among the best yields of TNA (87-94%) in sulfolane conversions and is easily and purely obtained as yeast nutrient base or fertilizers. All we need is an OTC, polar aprotic solvent. I could find DMSO as health product online, but it was like 40 dollars for 250 ml.

[Edited on 14-5-2015 by nitro-genes]

Rosco Bodine - 17-5-2015 at 05:22

Quote: Originally posted by nitro-genes

Ok, nitration went much smoother than anticipated. I did't use HNO3, I was out, and didn't want to distill something if nitrate salts could be used instead. :-)

7.7 grams of absolutely anhydrous ammonium nitrate was dissolved in 20 ml 98% sulfuric acid at room temperature, this was put at -20., resulting a a clear syrupy liquid. In a separate beaker, 60 ml of 98% sulfuric acid was poured and also put at -20. The next day, 9.4 grams of acetaminophen was dissolved in the 60 ml of sulfuric acid (while on salted ice bath), only very slight exotherm occured, so addition of the AN/SA was directly done after. Using a pipet the AN/SA was slowly allowed to drip in the SA/Acetaminophen solution, temperature did not went over 0 degrees at all times, addition was done over the course of about 15 minutes, almost no smell of NOx was noticed, but very faint smell of acetic acid was. An interesting note is that the solution went instantly from sort of orange to almost red with the addition of the last drops of AN/SA, which seems a good indication for completion of the reaction. The mixture was poured in 300 ml of icecold water upon which a orange-yellow solid precipitated. This was washed with another 300 ml of icecold water and collected to dry. It has low water solubility, stains like picric acid and sodium bicarbonate produced a bright red solution. Looking at the solubility of the potassium salt right now, as it is in the fridge.

Some additional notes, exotherm is really manageable, salted icebath doesn't seem obligatory, crushed ice should work fine with maybe slightly longer addition time. For the next synth I will try to minimize the amount of 98% SA needed.

The nitration also produced a small amount of sticky, chewing gum like stuff, probably left overs from the binder/sugars in the acetaminophen tablets. Either that or polyanilline like derivatives may have formed during the reaction. It's probably better to either start with the pure stuff or do proper recrystallization from ethanol first. (I simply evaporated everything at low temp).

Question remains which isomer we have produced, though the nitration itself seems to work. Also wonder how sensitive this stuff is to hydrolysis/oxidation by air, with some of the entrapped acid remaining from the synthesis. Bicarbonate neutralization to produce the sodium salt may be a better option, but how best to proceed for the hydrolysis/hypochlorite oxidation?

[Edited on 30-4-2015 by nitro-genes]

In the DDNP thread there was some consideration of the nitration of paracetmol / acetaminophen as a route to isopicramic acid, and/or its acetyl derivative and this was never completely sorted out from the literature references. But this may be what is your product. Your acetaminophen nitration product may be isopicramic acid directly or after deacetylation, isopicramic acid, which may be diazotized to form iso-DDNP.

Depending upon conditions I think it is possible the nitration product could be a mixture of isopicramic acid and as an impurity the acetyl derivative of isopicramic acid. Your noting some odor of acetic acid would indicate at least a partial deacetylation, and to what extent is unknown. If deacetylation was complete then your product would be isopicramic acid. To whatever extent the deacetylation did not complete, the product would be a mixture of the deacetylated and the acetylated forms.

In either case, your product is a precursor for diazotization to iso-DDNP. The interesting, intriguing possibility about iso-DDNP is that it may be a better initiator than the better known DDNP. Also possible, iso-DDNP is more easily made from a precursor gotten directly from nitration which requires no sulfide reduction of a trinitrophenol as is done to produce the ordinary picramic acid, since isopicramic acid can be gotten directly from a mild reaction condition dinitration of acetaminophen, preserving the amino group already present on the ring. If iso-DDNP is a better initiator produced by fewer steps from a more easily nitrated precursor, that could make iso-DDNP more desirable and economical than the more commonly known DDNP. Potentially, iso-DDNP could prove to be superior and more easily and cheaply made than the better known DDNP.

See this post in the DDNP thread.

http://www.sciencemadness.org/talk/viewthread.php?tid=439&am...

[Edited on 17-5-2015 by Rosco Bodine]

PHILOU Zrealone - 17-5-2015 at 07:41

Oxydative Nitration of acetaminophen may also produce nitranilic acid via paraquinone.
HO-C6H4-NH2 -oxydation-> O=C(CH=CH)2C=NH
O=C(CH=CH)2C=NH + H2O -acid-> O=C(CH=CH)2C=O + NH4(+)
O=C(CH=CH)2C=O -HNO3-> O=C(CNO2=CNO2)2C=O

Ortho-dinitro suffers from nitro-nitrite switch so
O=C(CNO2=CONO)2C=O + 2 H2O --> O=C(CNO2=COH)2C=O + 2 HONO (H2O + NO + NO2)
O=C(CNO2=COH)2C=O is nitranilic acid but the sequence is
cyclo(-C(NO2)=C(OH)-CO-C(NO2)=C(OH)-CO-) so one side of the quinone is (-C(NO2)=C(OH)-) and the other is (-C(OH)=C(NO2))...
All pairs of groups are para to each other 2,5-dihydroxy-3,6-dinitro-para-quinone...
The two ketonic groups, the two nitro groups and the two hydroxy groups.

Note that by virtue of proton jump and resonance between enol-keton form: 2,5-dihydroxy-3,6-dinitro-para-quinone is also 4,5-dihydroxy-3,6-dinitro-ortho-quinone

Not counting with the nitro-nitronic resonance that allows the protons to jump from each group to the other one.
So any corner of the hexaring may hold a proton with a given resonance conformation.

Really a beautifull molecule.

[Edited on 17-5-2015 by PHILOU Zrealone]

nitro-genes - 17-5-2015 at 17:08

Isopicramic acid from paracetamol seems an interesting possibility, the synthesis of N-methylated isopicramic acid is described in US3641154 and supposedly gives good yields. Here they use N-methyl or N-isoproppyl derivatives for the nitration, so the question is if the N-acetyl group from acetaminophen is protective enough to survive the nitration. If not, oxidation like philou pointed out might become more favorable. Thanks for working that out, I was curious how the amine group would be replaced by the keto-enol group. Would the use of ammonium nitrate for the nitration be protective, since excess NH4+ (although AN also partly dehydrates to nitramine in SA IIRC) would be present during the reaction? slwoing down the O=C(CH=CH)2C=NH + H2O -acid-> O=C(CH=CH)2C=O + NH4(+) step? I used AN instead of NA or NaO3 since AN/SA generally produces very little NOx, which would be the likely main oxidizing species in the mix, leading to paraquinones. (True?)

Another PITA of this synthesis I can see is the necessity to neutralize most of the mixed acids (ph 4)in order to precipitate the product. Not only would it use a large amount of NaOH, but will lead to a huge exotherm in which most of the product is likely oxidized in the partly diluted acids. A more sophisticated way to isolate the product may be beneficial, although perhaps the N-acetyl isopicramic acid is less soluble in the mixed acids than the N-methyl and isopropyl products described in the patent. The (likely) mono nitro variant synthesized earlier did precipitate pretty well...

Speaking of an OTC route to DDNP:

Just for fun I thought of maybe another feasible, alternative route to picramic acid. (Acetyl)Salicylic acid --> 98% H20SO4, 110 deg. C for 45 minutes --> p-sulfosalicylic acid --> dilution to 25-50% H2SO4 --> 1/3 mol TCCA 40-75 deg. C --> 3-chloro sulfosalicylic acid --> saturated NaCl and chilling, filtering --> nitration to 2-chloro 4,6 dinitrophenol --> ammonia --> picramic acid.

1. http://repository.ias.ac.in/78824/1/78824.pdf
2. http://www.sciencemadness.org/talk/viewthread.php?tid=24147

Anyway, kind of busy right now, though I have some purified acetaminophen left so will give it a try soon

[Edited on 18-5-2015 by nitro-genes]

Rosco Bodine - 17-5-2015 at 23:26

The nitration conditions of US3641154 are applicable.

It was GB24409 that described a nitration of paracetamol to produce the 2,6-dinitro, 4-acetylaminophenol which is the acetyl derivative of isopicramic acid. In the patent this was an intermediate intended to be reduced to provide an amino derivative which was the interest of the patent. For our purpose the dinitration product of paracetamol is de-acetylated by treatment with hydrochloric acid, which results in isopicramic acid. In the alternative heating the dinitrated paracetamol with dilute sulfuric acid should likewise accomplish the de-acetylation under milder conditions than hydrolysis using HCl and give isopicramic acid.

The analogous benzoylated compound being de-benzoylated by HCl to isopicramic acid was reportedly heated with HCl at 130C for 12 hours, which would be autoclave conditions. So the method of de-acetylation by heating with dilute H2SO4 would seem to be more convenient.

See page 1204 (journal page number) of the journal article
by Meldola and Stephens attached. There is described an analogous de-acetylation using dilute H2SO4, saying the acetyl compound was "readily hydrolyzed" by heating with dilute H2SO4. With no high temperature like 130C being stated as for HCl, this description would suggest ordinary conditions for the de-acetylation by H2SO4.

A more complete description of the hydrolysis accomplished debenzoylation using H2SO4 is described in the Chemical World article page 327 by Meldola, Hale, and Thompson. It seems probable the same procedure will likewise accomplish the de-acetylation in the same manner as de-benzoylation.

The isopicramic acid is then diazotized, to provide iso-DDNP
4-diazo-2,6-dinitrophenol.

Attachment: Berichte der deutschen chemischen Gesellschaft, Volume 38, Issue 2 (p 1593-1599).pdf (348kB)
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Attachment: Pages from Journal_of_the_Chemical_Society pg308.pdf (434kB)
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[Edited on 19-5-2015 by Rosco Bodine]

Rosco Bodine - 14-6-2015 at 09:06

Quote: Originally posted by APO

In the first link I referenced [1], it links to a patent that specifically names the compound received by mixed acid nitration using HNO3/H2SO4 as "3-nitro-4-substituted aminophenol", which I called 4-acetamino-3-nitrophenol. Meaning that for that particular process, among others, the nitro group is usually added adjacent to the acetamino group. Most of what I have seen shows the compound resulting from nitration or nitrite addition as having the nitro group in the meta (3) position, however I have also seen some references as having it in the ortho (2) position. All I can really gather from this mix of data is that you can pretty much pick whatever isomer you want, however, what you get is very dependent on reagents used and reaction conditions.

Precisely. It seems quite nuanced according to conditions and perhaps order of addition and the ratio of reactants what is gotten as a result for the first entering nitro group, and for second and third also. The course of synthesis can be finessed and steered when the factors which govern are identified. It is very interesting and I have been straining my brain looking at this subject for more than a year, trying to sort it out from the earliest references, including a Reverdin and Dresel article requested today which should provide original information about the 4-acetamino-3-nitrophenol, mp. ect.

Attached are 2 Reverdin and Dresel articles

On journal page 440 of the Archives des sciences physiques et naturelles by Reverdin and Dresel are several

melting points stated for the m-nitro-p-aminophenol. I am still reading to find the acetyl derivative / precursor mp which is 4-acetamino-3-nitrophenol, on page 442. The Chinese patent has later reported 162C mp for the acetyl derivative.

Japanese pharmacists have reported in 1989 the mp for 4-acetamino-3-nitrophenol as 139C

See attached file: A NEW NITRATION PRODUCT, 3-NITRO-4-ACETAMIDOPHENOL, OBTAINED FROM ACETAMINOPHEN WITH NITROUS ACID

Attachment: Reverdin and Dresel, Archives des sciences physiques et naturelles, 1904, 18, 433 to 444.pdf (392kB)
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Attachment: Mononitroderivate des p - Aminophenols. Mittheilnngen.-reverdin 1904.pdf (245kB)
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Attachment: A NEW NITRATION PRODUCT, 3-NITRO-4-ACETAMIDOPHENOL, OBTAINED FROM ACETAMINOPHEN WITH NITROUS ACID.pdf (178kB)
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[Edited on 6/15/2015 by Rosco Bodine]

nitro-genes - 24-11-2015 at 17:16

Many dinitrobenzofuroxans have been described (CL14,CL17 etc), although I've never seen a dihydroxy dinitro benzofuroxan. Wonder how stable it would be, if it exists at all, seems it can form a very stable resonance structure.

Considering 1,4 benzoquinone and hydroxylamine are pretty OTC, how about this for a synthesis. All steps up to the nitration of 1-Chloro-3,5-dihydroxybenzene are desribed in literature and give reasonable to good yields.

The second reaction is interesting, never seen this type of rearangement/addition reaction type for a nitroso compound before, supposedly, it gives high yields as well (87%). Is it possible o-nitrosophenol (o-benzoquinone monooxime) would also result in a 1-chloro-3,5 dimethoxyaniline derivative from the same reaction with MeOH/HCl? In that case phenol, or possibly even salicylic acid might be a more convenient starting point. Even more OTC would be the replacement of MeOH by EtOH.

Reaction is described here (available in the reference section):

Reaction of some 1,4-benzoquinone mono-oximes with methanolic hydrogen chloride (Melvyn V. Sargent)J. Chem. Soc., Perkin Trans. 1, 1982, 1095-1098DOI: 10.1039/P19820001095

[Edited on 25-11-2015 by nitro-genes]

PHILOU Zrealone - 26-11-2015 at 03:19

@Nitro-genes,
Very nice finding that easy conversion of p-nitrosophenol (1,4-benzoquinone monoxime) into a resorcinol derivative.

In your synthesis scheme/diagram:
-you forgot the hypophosphorous acid under HNO2 (3rd Arrow); H3PO3 (taking one O away as H3PO4) but it could be substitued by ethanol (then leaving oxydized as ethanal but this process yields some dimeric compound (biphenyls)).

-The first starting compound could be phenol and NaNO2/HCl instead of less OTC-ish p-benzoquinone and hydroxylamine

.

-The NaN3 addition must be stoechiometric otherwise the very acidic Azido-TriNitro-Resorcinol (ATNR) will set the extra azide as HN3 free (very toxic and gaseous like HCN).

-The last step with K2CO3 is also risky, I wouldn't heat ATNR K salt; it would be wiser to heat the water solution of ATNR free acid, thus without K2CO3 and only add K2CO3 in the cold when the de-dinitrogenation has ended.

-Last but not least you are a NITRO-GENIUS

the furoxan ring can be formed by the azido group with the NO2 group on the right of it; thus forming the dihydroxy-dinitrobenzofuroxan you depicted; but also it could react with the NO2 group left of it forming just the very same compound by virtue of a beautifull molecular symetry

[Edited on 26-11-2015 by PHILOU Zrealone]

nitro-genes - 26-11-2015 at 11:04

Thanks, the mechanism seems similar to a Bamberger rearrangement, though with extra substitution to a chloro rescorcinol. Very interesting reaction, apparently, some redox involved here, amazing that the quinone monooxime (p-nitrosophenol) seems to have a higher redox potential than nascent chlorine. Any thoughts on what the outcome might be when H2SO4/MeOH or H2SO4/water is used?

Not sure if phenol and nitrite may be a suitable starting point. Starting from phenol and nitrite results in mainly o-nitrosophenol IIRC, not sure how this would behave during the rearrangement, compared to p-nitrosophenol. On the other hand, there is this german patent about selective formation of p-nitrososalicylic acid from nitrous acid and salicylic. This seems controversial though, as other papers and patents suggest decarboxylation and formation of o-nitrosophenol is favored. A closer look at the stoichiometry and conditions involved may be worthwhile.

In the paper attached they indeed use the hypophosphorous acid method for deamination (92% yield), I was contemplating whether the rearrangement and deamination via the diazotization could be achieved in one step considering the anhydrous MeOH used. Didn't know the -ol mediated deamination resulted in biphenyl formation and ethanal (which may also introduce by products).

Alternative to hypophosphorous may be using hydrogenperoxide (percarbonate):
Deamination of aromatic amines
US 4577046 A

The sensitivity of the compound (if it exists) is an unknown, its salts, including the potassium, may be interesting and perhaps could be used as reasonably stable primary explosives with a likely very high density. If the above synthesis from phenol or salicylic acid could be used instead, it could also represent an affordable and up scalable synthesis.

An alternate synthesis may be styphnic acid --> TMHI/hydoxylamine and lithium, or magnesiumethoxide in MeOH or other aporotic polar solvent (VNS) --> 1,3 dihydroxy-2,4,6-trinitro 5-aminobenzene --> diazotization and azide substitution

Or:
3,5-dinitroaniline --> pentanitroaniline --> 1,3 dihydroxy-2,4,6-trinitro 5-aminobenzene --> diazotization and azide substitution

[Edited on 27-11-2015 by nitro-genes]

Boffis - 26-11-2015 at 16:27

@nitro-genes. I wondered what you wanted this paper for! We interesting idea indeed.

Let us know how you get on

I would imagine that by analogy with hydroxynitrobenzene they are are more sensetive than their hydroxy free counterparts.

nitro-genes - 28-11-2015 at 03:58

Hey Boffis

Saw you posted the reference paper in the reference section, thanks! Looking at the possibility for an alternate starting point for the p-benzoquinone first. If p-nitrosphenol can be produced selectively, maybe it is possible to cut some corners and to go directly in one reaction to 3-chlororescorcinol, although that may be pushing it.

nitro-genes - 29-11-2015 at 13:39

Interesting document concerning the bamberger mechanism under different conditions, works much different than I thought.

It also lists the same reaction type with MeOH and sulfuric, producing the anisole.

Attachment: Bamberger mechanism.pdf (1.2MB)
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Some further information on the decarboxylation of salicylic acid was found, although relatively little info could be found on this type of reaction.

Nitrite decarboxylation salicylic.jpg - 119kB

Elimination/nitroso addition of salicylic acid using nitrous acid may (or may not) be a more conveniant route to o-benzoquinone monooximes than direct nitrosation of phenol, though I couldn't find a a good synthesis protocol for the conversion. Decarboxylation/nitrosation of aspirin (acetyl salicylic acid) may work even better producing less byproducts, presumably rearranging only after hydrolysis of the acetyl group. All info combined it seems possible that nitrite mediated decarboxylation of (acetyl) salicylic acid and MeOH/Sulfuric acid mediated rearangement of the resulting nitroso compounds may produce m-dimethoxy aniline derivatives.

Although supposedly 3,5 dinitrosalicylic acid does not decarboxylate upon nitrous acid treatment under normal conditions, it may be interesting what the result would be after heating with 1 mole equivalent of nitrosyl sulfuric acid and trying the rearangement.

The latter probably won't work though...

[Edited on 30-11-2015 by nitro-genes]

PHILOU Zrealone - 2-12-2015 at 07:52

Nitrosation of phenols with HNO2 goes usually in para of the phenolic group; except if the para position is occupied; then it goes in ortho of the OH group.

The specific case of salicylic acid probably comes from the sequence -C(OH)=C-C(=O)-
if you look closely to it:
-C(OH)=C-C(=O)- <==> -C(=O)-CH2-C(=O)-
so the transcient methylene bridge between two keto groups may nitrosate easily (this is a known fact... 2,4-pentadione turns easily into 2,3,4-pentan-trione monoxime)
-C(=O)-CH2-C(=O)- + HO-N=O --> -C(=O)-C(=N-OH)-C(=O)- + H2O
-C(=O)-C(=N-OH)-C(=O)- <==> -C(=O)-CH(-N=O)-C(=O)-
The presence of the nitroso or oxime group in alfa will favourize the decarboxylation of the beta ketonic acid (such acids are already thermally unstable)
CH3-CO-CH2-CO2H -heat-> CH3-CO-CH3 + CO2

nitro-genes - 5-12-2015 at 18:56

Interesting indeed, wondered why salicylic acid decarboxylated so much more easily then the meta isomer, never thought this would still apply for aromatic molecules.

Did a quick experiment in trying the decarboxylation of salicylic acid using nitrite today. Reaction was done as outlined in:

Notes - Nitrosodecarboxylation, Ronald Henry J. Org. Chem. 1958, 23 (4), pp 648–650
DOI: 10.1021/jo01098a634

The salicylic acid was dissolved in ethanol/water, after which 1 molar equivalent of sodium nitrite, dissolved in the least amount of water, was added at once. There was immediate and strong fizzing of the solution, which only lasted a minute or so, then only weak gas production was noticed. Besides the ethanol smell there was also a faint sweet smell, probably ethylnitrite. When left stirring at ambient temperature for a couple of hours the solution went from colourless to a pronounced canary yellow. Upon acidifying using 37% sulfuric acid and cooling, a pale yellow precipiate resulted.

A common problem using nitrosation of phenol to produce the monooxime is that the nitrosophenol formed can react further with the phenol still present in the solution/suspension to form all kinds of by products. Ideally, these side reactions would be absent due to the presence of the deactivating carboxyl group. Could it really be this simple, of so why doesn't this seem to be used commercially?

In the aricle there are some holes IMO though, for instance, they perform the reaction with equimolar amounts of salicylic acid and nitrite, then continue to make no effort of isolating the nitroso product, other than to mention a very minor amount (2% or so) of the nitrosalicylic acid could be steam distilled (which presumably could only have come from oxidation by an excess of nitrite). Also, there is no mention of possible side reactions, such as oxidation of the ethanol by the nitrous acid, which can result in fulminate like oxidation compounds. Starting to wonder if the CO2 is comming from the salicylic acid or ethanol oxidation.

Maybe rerunning the reaction with only the least amount of ethanol or only using water and very long reaction times would be better? The melting points of salicylic acid and the monooxime are too close for me to distingoush between the two, maybe someone could redo the reaction and take an accurate melting point some day.

Another thing is that another article mentions the likely product to be a nitrosodimer. Would this still rearrange using MeOH/HCl? Are the dimer/monomers interchangeable?

EDIT:
Dried a small amount of the resulting compound, I'm starting to wonder whether it really is p-nitrosophenol. It dissolved in water with a brilliant yellow colour, but there is no reaction to a strong NaOH solution, nor does it explode when heated, like many MSDS seem to suggest. It seems to simply burn, maybe somewhat more energetic than salicylic acid alone. Maybe the pure compound can be dissolved in water and measure acidity, the pKa of the nitrosophenol should be much higher than that of any salicylic/nitro(so)salicylic acids present.

[Edited on 6-12-2015 by nitro-genes]