aromaticfanatic
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Nitrotoluene oxidation
I am preparing a total synthesis of benzocaine and one of the steps is oxidation of p-nitrotoluene. It seems simple in theory and I even found a paper
doing exactly what I wanted to do.
http://web.mst.edu/~tbone/Subjects/TBone/chem228/FS16Synthpr...
As well as a video that uses the same principle on toluene:
https://www.youtube.com/watch?v=b9cEfagdhSU
I was browsing around seeing if anyone had prepared anthranilic acid from the other nitrotoluene isomer, the ortho isomer. I came across someone
saying this:
"This is a better way than what I tried (just using nitrotoluenes) and I like it, provided you do get a good yield of ortho isomer.
In any case, the oxidation step works but it is tricky. You want to use a small amount of hydroxide in your reaction, as some is used up if I remember
correctly. It also takes a while and of course, workup stinks to high heavens, as does any mistake that allows nitrotoluene to escape.
This reaction has a side reaction that kills yield. If the oxidation is not done right, you will get a lot of gas evolution upon acidification. Also,
you don't want to add solid permanganate too fast (more side reaction) but also not too slowly (severely diminished yield) or all KMnO4 dissolved in
water (too much reaction volume). Perhaps one of the modern oxidants can do this thing better than permanganate. In any case, if done correctly the
yield can be 70-80% but I did not attain that."
Up until this point I was confident this reaction would not be problematic. Now I worry. I would be using a set up practically similar to the one in
the video where I utilize an addition funnel to slowly control the drip rate of KMnO4 solution into the p-nitrotoluene and water mix. While he didn't
provide any references, he states that using KMnO4 in solution would cause major yield drop due to too much solvent in the flask. As I am working on a
multi step synthesis with little desire to work with nitrotoluenes more than I have to, I really do not want to have a very low yielding reaction this
early in my synthesis.
I also do not want to utilize the dry addition of KMnO4 as I will be working in a poorly ventilated (until the garage door opens in case of emergency)
room (the system is not closed, there will be a gas outlet for any pressure to vent out of on top of the condenser column) and I do not like
nitrotoluene vapors.
Having said that, does anyone have experience with this particular reaction? Would it be viable to practice the reaction on just plain toluene first
to dial in the addition rates and general procedure? Having researched the toluene oxidation with KMnO4, toluene seems to have similar issues with
yield so my thought process is that the oxidation toluene and nitrotoluene should be similar enough that the highest yielding process of toluene
should translate to the highest yielding process for nitrotoluene as well. Is this a correct assumption?
I believe it would be since similar situations (adding KMnO4 too fast or slow, not refluxing enough, etc.) in toluene oxidation has resulted in lower
yields similarly to how nitrotoluene yields should be affected. The only major difference I could see is the difference in physical properties causing
wrong addition rate timing and the possibility of the nitro group interfering with the electron density (which I don't believe would matter for an
oxidation reaction, to my knowledge this just pertains to electrophilic and nucleophilic substitutions).
I should also add that I am aware that dichromates and other oxidizing agents work too with better yields but I do not have any dichromates and would
rather not work with them as of now.
[Edited on 24-12-2020 by aromaticfanatic]
[Edited on 24-12-2020 by aromaticfanatic]
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Fery
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I oxidized only toluene to benzoic acid yet. Decades ago. To a solution of KMnO4 in flask I added toluene and refluxed. Lasted for few hours until the
yellow color disappeared and changed to brown MnO2. Very likely some amount of KMnO4 decomposed due to high temperature... There is some temperature
which is "safe" and KMnO4 does not yet decompose, it is perhaps something like 85C or the temp 95 C mentioned in the document in your link. Mix of
toluene+water maybe boils at lower temperature than 100 C (vapors have certainly less than 100 C due to azeotrope formation) and perhaps the same for
nitrotoluene).
Your final goal is paraaminobenzoic acid... I read somewhere that nitrotoluenes under some catalyst (V2O5 ???, I can't find the source again) at some
extent transform into the product, the -NO2 group oxidizes the -CH3 group while reducing itself and thus the reaction forms -NH2 with -COOH
C6H4NO2CH3 -> C6H4NH2COOH
I can't remember whether the reaction conditions were suitable for lab. preparation, I do not remember the catalyst, but I think it was something like
V2O5.
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Pumukli
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Yes, Fery, they transform, at least the o-nitro variety, but the yield is inherently low, in the 20% range in the best cases. The reference is
somewhere in the anthranilic acid thread, because o-nitro toluene can be directly converted to anthranilic acid by the method. But it sucks. :-)
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aromaticfanatic
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Interesting I have not heard of V2O5 as a catalyst. Something I have thought of is adding a phase transfer catalyst. It is usually employed for the
toluene reaction to increase speed of reqction and theoretically yield. I might attempt using such a catalyst.
Yes you are correct, during the process of refluxing the toluene and water boil at the azeotrop temp of around 85C and as the toluene os oxidized the
temp slowly climbs up to 100C.
I'm hoping to try this reaction with toluene and getting the yields satisfactory. Then I'll hope that the process translates to the nitrotoluene as
well.
I'll do some more research on the oxidation of the o-nitrotoluene with KMnO4 as well. Thinking of it, I could use the o-nitrotoluene (with para and
meta isomers too) in the reaction flask and try to dial in the reaction using that. I believe the reaction would be even more closely related to the
para isomer than straight toluene.
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Metacelsus
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I did that oxidation (p-nitrotoluene -> p-nitrobenzoic acid) some years ago with KMnO4. It worked pretty well. I'll see if I can find my old notes.
OK I dug it up (from 2011), apparently I mixed:
1.00 g p-nitrotoluene
2.35 g potassium permanganate
10 mL water
1.25 mL 12 M HCl
and recovered 0.93 g p-nitrobenzoic acid.
Unfortunately I didn't record the order of addition, temperatures, or anything like that. I think the HCl was added after filtering out MnO2 in order
to precipitate the product, but I am not sure.
[Edited on 2020-12-24 by Metacelsus]
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Pumukli
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" I think the HCl was added after filtering out MnO2 in order to precipitate the product, but I am not sure."
You can be. Otherwise the MnO4- would had oxidized the HCl to chlorine, most probably.
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aromaticfanatic
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Quote: Originally posted by Metacelsus  | I did that oxidation (p-nitrotoluene -> p-nitrobenzoic acid) some years ago with KMnO4. It worked pretty well. I'll see if I can find my old notes.
OK I dug it up (from 2011), apparently I mixed:
1.00 g p-nitrotoluene
2.35 g potassium permanganate
10 mL water
1.25 mL 12 M HCl
and recovered 0.93 g p-nitrobenzoic acid.
Unfortunately I didn't record the order of addition, temperatures, or anything like that. I think the HCl was added after filtering out MnO2 in order
to precipitate the product, but I am not sure.
[Edited on 2020-12-24 by Metacelsus] |
Thank you! Do you by any chance remember if you had dissolved the KMnO4 or if you added it dry? Any chance you remember the reaction vessel too?
Interesting that you didn't perform the reaction in acidic or basic conditions. I wonder if that may be a partial reason for your good yield? I know
KMnO4 is more potent of an oxidizer in basic and acidic conditions.
This is assuming you added the HCl to precipitate the product at the end of course.
Either way this was some useful information so thank you.
While I don't have the nitrotoluene made yet (I may have some impurities in my toluene that need to be removed before nitration for obvious reasons) I
am hoping to get at least 5 grams of para nitrotoluene. The oxidation reaction will be done in my 3 necked RBF so that I can minimize the nasty
nitrotoluene vapors. I'm hoping to get at least 3 grams or so of nitrobenzoic acid. Then the reduction step I'm hopefully going to be able to recover
at least a gram (the pH control is difficult on that step since the PABA is a zwitterion) of PABA and then that final esterification might be what
makes or breaks my entire yield. I need to get my ethanol as dry as possible or else I risk some serious yield loss.
[Edited on 24-12-2020 by aromaticfanatic]
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stephill92
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When I did this I used about 50 ml of water for every gram of nitro toluene and added in the powder while refluxing the mixture. I would just let it
reflux until I couldn't see anymore purple color or until I thought it was done. Then you can just some acid to precipitate out the nitro benzoic
acid.
I got away with just using a condenser and a 500ml rbf.
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aromaticfanatic
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| Quote: Originally posted by stephill92 | When I did this I used about 50 ml of water for every gram of nitro toluene and added in the powder while refluxing the mixture. I would just let it
reflux until I couldn't see anymore purple color or until I thought it was done. Then you can just some acid to precipitate out the nitro benzoic
acid.
I got away with just using a condenser and a 500ml rbf. |
Interesting, did the vapors not bother you at all? Or did you add the KMnO4 through the condenser?
Do you remember what the yield was?
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stephill92
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When I did it I just added all the nitro toluene and water into the flask and added the powder down the condenser. It works but it’s kinda a pain to
clean so maybe a flask with more necks would be better.
I don’t remember the fumes being particularly bad but the final powder did still have a similar aroma. I think the yield was around high 80 but it
may have been inflated since the powder could still have retained water.
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aromaticfanatic
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| Quote: Originally posted by stephill92 | When I did it I just added all the nitro toluene and water into the flask and added the powder down the condenser. It works but it’s kinda a pain to
clean so maybe a flask with more necks would be better.
I don’t remember the fumes being particularly bad but the final powder did still have a similar aroma. I think the yield was around high 80 but it
may have been inflated since the powder could still have retained water. |
I see, thank you for that information! I may give this reaction multiple attempts with toluene and dialing in the addition rate and then trying it
with the primarily ortho isomer to see how well it translates. Then once that works out I'll try the para isomer and I'll just have to hope it works
with good yield. I supposed even a 40% yield wouldn't be the end of the world but I'd certainly have to make the next reaction steps highly efficient.
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