Sciencemadness Discussion Board

synthesis of O-nitroaniline

danielforum - 7-1-2009 at 00:31

what is the best mechanism for the hydrolysis of nitroacetanilide?
how can be the ortho and para isomers of nitroaniline be separated without it undergoing to hydrolysis?

Sauron - 7-1-2009 at 00:48

Go to forum library and download FUNDAMENTAL PROCESSES OF DYE CHEMISTRY.

Also go to

The best way to prepare exclusively the ortho mononitroaniline is to block the 4-position with a sulphonic acid group. This means you want to prepare sulanilic acid (covered in both references, also in Vogel) and acetylate that to protect the amino group.

After nitration remove both the acetyl group and the
sulphonic acid group. Voila, 2-nitroaniline, no 4-nitroaniline at all

As a matter of principle UTFSE (Use the Fucking Search Engine) because this matter has been discussed before and more than once.

And btw, small o is ortho, large O is Oxygen, and this is not a nitro ester. These things do matter and have meaning..

This is really basic stuff. Read those books carefully and you will learn a lot.

Reference 4 from Org.Syn. procedure for o-nitrosulfanilic acid to o-nitroaniline:

Nietzki and Benckiser, Ber. 18, 295 (1885); Turner, Ber. 25, 986 (1892); Sakellarios, Ber. 58, 2286 (1925).

The monograph is attached

[Edited on 7-1-2009 by Sauron]

Attachment: CV1P0388.pdf (129kB)
This file has been downloaded 965 times

Sauron - 7-1-2009 at 06:11

The above is how to take the sulphonic acid off. Here is how to put it on: conc H2SO4. Oleum is better but not necessary.

See pahe from Vogel attached.

How to put on and take off the N-acetyl group?

Put on with Ac2O or AcCl

Take off with NaOH

Those directions are in Vogel as well. (Preparation of acetanilide).

Note that benzanilide, formanilide, oxanalide all also work same way.

[Edited on 7-1-2009 by Sauron]

Attachment: vogel_practical_ochem_3.pdf (58kB)
This file has been downloaded 1065 times

Maya - 7-1-2009 at 17:41

<<< synthesis of O-nitroaniline >>>

luckily I don't need to go that arduous route since a while back a nice soul sold me 1/2 kilo of pure o-nitroaniline at a good price!

Nicodem - 8-1-2009 at 00:12

Originally posted by danielforum
what is the best mechanism for the hydrolysis of nitroacetanilide?
how can be the ortho and para isomers of nitroaniline be separated without it undergoing to hydrolysis?

First of all, there is no oxygen in aniline so there can be no such thing as O-nitroaniline. Surely you meant o-nitroaniline instead ("o-" stands for the ortho position while "O-" stands for oxygen atom position - two completely different things!).
Nitroaniline can not be hydrolysed - you probably mean about how to selectively hydrolyse the ortho-nitroacetanilide in the presence of its para isomer? Formulate your question in a more sensible way and use references if you want to post in the Organic chemistry section. This way we will at least know you made the minimal possible effort to search for an answer yourself (as well as better know what the problem is about). Else, post in the Beginnings section where I'm moving this.

Sauron - 8-1-2009 at 05:49

See upthread, Nicodem, I already hammered him about the upper case O.As discussed in Fundamenta Processes of Dye Chemistry, the nitration of acetanilide (or another acylated aniline) has largely been supplanted industrially by the amination of o-nitrochlorobenzene, This is not very amateur friendly as the nitrochlorobenzene is toxic and the procedure reqiores an autoclave.

I prefer the nitration of acetanilide-4-sulfonic acid (N-acetylsulfanilic acid) which is dead easy to make, gives only the 2-nitro isomer, and is easy to get rid of the sulfonic group and the acetyl group - first concentrated acid, then calculated amound of NaOH and finally liberation from the sodium salt.

Most likely though this guy is having us do his school homework for him.

benzylchloride1 - 11-1-2009 at 21:14

I am going to buy some o-nitroaniline soon, but I am trying to produced the compound for fun. I started with aniline sulfate, added sulfuric acid and heated the mixture at about 150 celsius for about 8 hours. Currently I am working up the acetylation of 10 gramsof the sulfanillic acid I synthesized a year ago. The product did not melt at the recorded value of 214 celsius. I do not think that the sulfanillic acid was acetylated completely. I refluxed the 10 grams of sulfanillic acid with 15 mL of glacial acetic acid for 5 hours and then poured the mixture into water which precipitated a white solid which was filtered off. Acetic anhydride would work better, but I currently do not any in my lab.

Sauron - 11-1-2009 at 21:32

Acetyl chloride would work just as well as the anhydride and is easier to make or acquire.

Acetanilide is easy to get.

Formanilide is just as suitable, and for that, formic acid works perfectly.

Benzanilide and oxanilide are also viable alternatives. But formanilide is the industrial intermediate of choice for this reaction as it is cheapest. See Fundamental Processes of Dye Chemistry (forum library.) This book is IMO superior to Vogel in many ways and should not be regarded as a mere dye-chem book.

Nicodem - 12-1-2009 at 01:58

Benzylchloride1, you could try using aspirin for acetylating your sulfanillic acid like Jor did with aniline. See

Aqua-regia1 - 12-1-2009 at 12:43

I synthetised this compound for 3 weeks with orthoselective nitrating as follows:

Dissolve 0,1mol acetanilide in 40 ml acetic anhidrid and 40 ml glacial acetic acid. Nitrate this soluition with 6,7 g 100% fuming nitric acid (at least 95% equal molar)between 0-5 Celsius. 2 hours mixed away in 20 celsius, then pour the mixture on 125 g crushed ice. Filter the yellow cristalline precipitate, put back in the flask, and reflux with 80 ml 20% muriatic acid 30 sec, then added excess carefully 125 ml conc. ammonia solution. The cold mixture filter, and recristallise it from twice from etOH. The crude yield 90%, mp: 79-80 celsius. The twice recristallised yield is 8-9 g 61-65%. Mp.: 72-73 celsius.

Jor - 12-1-2009 at 13:49


I was not 100% sure it worked. I did this for school and had to do a very quick melting point test, and I'm not sure if it was very accurate. There is a small chance that my crystals were just plain acetylsalicylic acid.

I'm trying this reaction very soon, to test it again.
I have my aniline now. It's still colorless (fresh from Acros), but it is already opened (used it in a test-tube experiment with acetyl chloride), so I have to do it very soon, or I will have to distill it or decolorize it with activated carbon.

It's going to be done the next 3 weeks, so it can be tomorrow, but also after 3 weeks. I have no idea yet.

How can I test if I made the acetanilide, without melting point test? I have no melting point determination equipment. No TLC-paper either. Do you think normal paper will work as well?

It's really embarrasing to read my posts in that topic. I learned a lot since then. I mean, all those stupid questions I asked :P

[Edited on 12-1-2009 by Jor]

Nicodem - 13-1-2009 at 01:39

Jor, you underestimate your work. You did a good job, especially for a complete beginner in organic synthesis. Judging from your reaction work-up description you could have not obtained a product contaminated with any of the starting material. The mp, as inaccurate as you think you did it, as well as the description of needle-like crystals, are indicative of acetanilide. Also, the literature and theory confirm the route this reaction follows. I still believe you should write an article for Prepublication section.
Don't worry about your aniline degrading. We have years old aniline bottles in the lab and I never distil it before use even if they darken. The coloration is caused by tiny amounts of oxidation products that have no influence on the reagent quality.
You can measure the mp fairly accurately by using a thermometer and a test tube whose diameters fit closest if you immerse the test tube with the sample and thermometer in an oil bath and heat the oil really slowly. Not as accurate as a Thiele tube, or a microscope with a heating plate, and it also requires a much larger sample size, but for a home amateur it does well.

Sauron - 13-1-2009 at 03:36

@aqua_regia, this target does not require acetyl nitrate nitration, an expensive and hazardous procedure and not everyone has the luxuries of Ac2) and 100% fuming nitric acid.

All it takes to obtain exclusively the o-nitroaniline is a simple sulfonation which can be done with conc H2SO4 nothing fancy. Ordinary conc mitric acids for nitrating mixture are fine. The nitration is fast and done below 40 C. Removing the sulfonyl group is simple, boil with conc H2SO4 again and it pops off. Treat the o-nitroacetanilide as per Org.Syn. and you have o-nitroaniline.

I applaud your application of acetyl nitrate but I have seen those nitrations go badly awry and even when they behave they are costly of reagents.

[Edited on 13-1-2009 by Sauron]

Attachment: CV1P0388.pdf (129kB)
This file has been downloaded 706 times

Jor - 13-1-2009 at 03:40

I will first run some experiments, to confirm that this works. I want to be 100% sure. I believe you that my description must mean that acetanilide, but I will still run a few tests.

Today, I did it. So I take 1 mL of aniline and pour it in a test-tube (this is a large excess, maybe too much). I then realised I did not have any aspirin anymore, I used it all up. So I quickly made some with acetic anhydride, salicylic acid and phosphoric acid catalyst, as described in my webpage:

I made a quick 0,75g, and tested it with Fe(III). The test for phenolic -OH was negative, so it was pure. I added this to the aniline, and started heating with an alcohol burner. As soon as the reaction mixture melted, I put an thermometer in the mixture. I kept the temperature between 110-120C for 15-20 minutes.

The mixture quickly turned from colorless to brown, the rate of oxidation of aniline is highly likely to greatly accelerated at such temperatures. I then cooled to 60C and added 8mL of ethyl acetate, and shaked. Liquid was a little turbid, after shaking. I put a watch glass on the test-tube and went to university, where I am writing this now. When I get home I will proceed workup.

[Edited on 13-1-2009 by Jor]

Sauron - 13-1-2009 at 06:06

There is another route to exclusively o-nitroaniline, but from chlorobenzene.

It is described in Ullmann's, also in Fundamental Processes of Dye Chemistry at least in part.

Chlorobenzene is sulfonated and then nitrated in situ with potassium nitrate. The 2-nitrochlorobenzene-4-sulfonic acid is then reacted with aqueous ammonium hydroxide to yield the o-nitrosulfanilic acid, this is then treated with conc H2SO4 to give o-nitroaniline.

Org.Syn. has this procedure for 2,6-dinitroaniline. Reducing the amount of KNO3 added to the sulfonating mass limits the product to the mononitrochlorobenzenesulfonic acid.

Plenty of references in the Org.Syn. monograph, some of which doubtless will illustrate the mononitration as well.

The Org Syn procedure uses a low % oleum for the sulfonation but, conc H2SO4 will work, just takes longer. When all the chlorobenzene has dissolved in the acid, the sulfonation is complete.

A snag with this process for the mononitroaniline is that the ammonolysis in that case required an autoclave while for the dinitro compound it is simply done under reflux. I tend to overlook this detail because I have an autoclave. Mea culpa.

On the other hand I believe the general strategy (one pot sulfonation and nitration of the sulfonating mass with 1 equivalent of KNO3) is applicable to aniline. Or to acetanilide. Why not?

[Edited on 13-1-2009 by Sauron]

[Edited on 13-1-2009 by Sauron]

Attachment: CV4P0364.pdf (127kB)
This file has been downloaded 621 times

Jor - 13-1-2009 at 09:43

Well I think it is proven now that aspirin, acetylsalicylic acid, can be used as a N-acetylating agent, wich is very valuable for the hobbyist as both acetic anhydride and acetyl chloride are very hard to get.

I washed the ethylacetate solution with a bicabonate solution, followed by a 1M HCl solution. I evaporated the ethyl acetate, and was left with brownish flake-like crystals (like Wiki describes).
The melting point determinating in an oil bath was done. A mini-testtube was immersed in an oil bath and the bath was heated with my alcohol burner (I do not have Bunsen :( ). I was a hard thing to get it to temperature. At some point the acetanilide started to melt to a small extent, but then I heard a small bang. Probably a crack in my beaker, so I stopped heating immediatly. I measured the temperature of the oil touching the test-tube, it was I think 105C or something like that. I can't remember exactly, as the beaker stressed me out. I threw the beaker away.
I also did a test by simply heating a relatively large amount of the sample in a test-tube, in wich is thermometer is put. When it melts, the tempearture rose very quickly to about 110C, but I hadn't heated anymore since it melted, and it took some time for the thermometer to rise, so I think it was a little higher. Melting point acetanilide: 113-114C. acetylsalicylic acid: 135C.

I also threw a little bit of the sample in NaHCO3 solution. No bubbling, just a few VERY small bubbles on the crystals, probably some traces (Acetyl)salicylic acid. Heating strongly causes the solid to dissolve, but I couldn't see any gas evolution starting at the crystal's surface, just some gas evolution at the surface of the solid, undissolved, NaHCO3. Probably just some decomposition of NaHCO3 to CO2, Na2CO3 and water.

Because all my tests were not really accurate, again, I was thinking how to do another test. I added my final crystals left (well I have some more, but like 50mg) to a mini-test tube, and added some 15% KOH. I heated, the crystals dissappeard, and oily brown drops, appeared, floating in the liquid. Aniline! Hydrolysis product of acetanilide.

So I think i'm pretty sure it works.

I will post in republication, however not soon, due to lack of time.

Sauron - 13-1-2009 at 09:59

In the case of this reaction, N-acetylation can be replaced by N-formylation, or N-benzoylation, or other acylations. It is just a temporary PG. Formic acid is not hard to get and as it is a stronger acid that acetic, the acid works fine which acetic does not. There is no formic anhydride, and formyl chloride is not called for.

Acetyl chloride is not particularly hard to make. But why bother when formic acid works fine?

Jor - 13-1-2009 at 11:23

For acetyl chloride you need a strong chlorinating agent right? Like PCl5 or SOCl2.
I know you can name a lot of otehr chlorinating agents that will do the job (e.g. TCT?), and S2Cl2 AFAIK, but these all are toxic, hard to get chemicals for many.

Ofcourse you can replace it my N-formylation, but what if one wants to make acetanilide? You can't do that with formic acid. The fact is that aspirin is extremely available.

Im going to do the synthesis again and make pictures, I'm currently making some aspirin from salicylic acid. I'm too lazy to go to the pharmacy, when it is very cold, and i have a liter of Ac2O around. I can buy new stuff anyway when I want, and in worst case i can buy a liter of AcCl, and some NaOAc. But I hardly use the stuff, and if, very small amounts, so the liter will last me forever.

Sauron, i was in thailland. What an amazing country. :D

Sauron - 13-1-2009 at 11:40

If one wants to make acetanilide, then they have little choice but to acetylate, true enough and your trans-acetylation from acetylsalicylic acid is commendable.

But this thread is not about making acetanilide, except as a stepping stone to o-nitroaniline. As such acetanilide is highly replaceable.

There are alternatives to SOCl2, PCl3 and even TCT. How about benzoyl chloride? And there are others. However, this thread is about o-nitroaniline, so let's stick to the topic.

Also this nitration can be done without acylating the amino group at all. That is rather optional.

BTW when I want acetanilide I buy it. I have half a Kg around here somewhere. It is idle because I went ahead and bought o-nitroaniline, and that is sitting too because I bought o-phenylenediamine and so sn.

TCT is not a problem to buy here. Neither is benzoyl chloride, nor phthaloyl chloride. So making acyl chlorides is not a problem for me.

benzylchloride1 - 15-1-2009 at 10:51

I will try the transacylation of sulfanillic acid with acetylsalicyclic acid as soon as I get some more aspirin and as soon as my lab is operational again. I am currently installing PVC ducting for my fume hood and everything is torn apart.

nitro-genes - 22-3-2018 at 11:55

Without glacial acetic acid and acetic anhydride, would the following synthesis, starting from chlorobenzene be theoretically possible?

1. Sulfonation of chlorobenzene using 96-98% sulfuric acid, to produce mainly 4-chloro benzenesulfonic acid. (
2. Adding 1-1.5 mole eqvt of a nitrate salt (or HNO3) slowly to the sulfonation mix after cooling, and slowly ramping up the heat to produce 3-nitro 4-chloro benzene sulfonic acid. Or is the "normal" nitration of chlorobenzene already occuring through the sulfonic acid?
3. Reacting the isolated sulfonic acid with concentrated ammonia to produce 2-nitro aniline 4-sulfonic acid (Not sure what would be the most likely product formed here. Would the sulfonic acid group be substituted also? How much easier would the substitution of the chlorine group be with the 4-sulfonic acid present compared to 2-nitro chlorobenzene?. Would relflux temp be enough?)
4. Boiling the 2-nitro aniline 4-sulfonic acid with aquous sulfuric to yield 2-nitro aniline (

[Edited on 22-3-2018 by nitro-genes]

CuReUS - 23-3-2018 at 07:38

Quote: Originally posted by nitro-genes  
Or is the "normal" nitration of chlorobenzene already occuring through the sulfonic acid?

What do you mean by the " normal" nitration ?
you could make it in 3 steps by o-nitrating toulene,oxidising to o-nitrobenzoic acid followed by a schmidt reaction to get the target compound

Boffis - 23-3-2018 at 10:11

Hi nitro-genes, I presume you haven't got any aniline as this would be easier, avoiding the chloro group replacement by going via sulphanilic acid. Alternatively you could start with bought sulphanilic acid.

If you are going via your proposed route you might be better fusing the chloro nitrobenzene sulphonic acid with urea but I am not sure whether the sulphonic acid group would react under such harsh conditions.

[Edited on 23-3-2018 by Boffis]

nitro-genes - 23-3-2018 at 11:25

Thanks for the replies, the route going from chlorobenzene was considered, because, apart from acetanilide, I would also like to synthesize 2,4 dinitroaniline and 4-chloro aniline somewhere in the future. While looking at the o/p ratio produced from nitration of chlorobenzene (~40/60% IIRC), I started wondering if the nitration of chlorobenzene as published was actually occuring through the soluble sulfonic acid or as a intimately mixed two-phase reaction, as the former would possibly produce almost exclusively the o-nitro derivative. Not sure how much sulfonation would occur without oleum though.

A route from toluene would also be an option, though I'm out of permanganates for the oxidation at the moment and would rather save my precious homebrew NaN3 for something other than a large scale Schmidt reaction.

Would this also work instead: Attachment: Amides by microwave-assisted dehydration of ammonium salts of carboxylic acids.pdf (164kB)
This file has been downloaded 285 times

As for adding a protective group to aniline before nitration: Found this interesting reference describing the direct formation of N-carbamates by hofmann degradation of N-chloro benzamide in methanol. Benzamide itself is easy to make. Not sure if using ethanol instead of methanol would be possible regarding solubility and reactivity of TCCA and cyanuric and result in a similar carbamate reaction. Also not sure if the N-carbamate group itself would survive nitration and allow deprotection after, though this would be a very easy reaction, possibly even preventing directly handeling aniline itself. Could this reaction possibly be done with ethanolic sodium/potassium hydroxide instead of methoxide? From the patent attached it would seem even hypochlorite solution/NaOH is possible.

Attachment: Preparation of Methyl N-Substituted carbamates from amides through N-Chloroamides.pdf (159kB)
This file has been downloaded 238 times
Attachment: US4321402 - Carbamate process.pdf (875kB)
This file has been downloaded 233 times

Substitution of the chloro group by an aminogroup for 4-Chloro-3-nitrobenzenesulfonic acid is listed in molbase with 92% yield. Found the following reference, though wasn't able to find it:

"Pueskuellue, M. Orhan; Yildiz, Sulhiye; Goeker, Hakan Archiv der Pharmazie, 2010 , vol. 343, # 1 p. 31 - 39"

[Edited on 23-3-2018 by nitro-genes]

nitro-genes - 24-3-2018 at 03:45

Stupid, ethanol is much more easily oxidized than methanol, also the cyanuric by product is much more soluble in ethanol than in methanol, so this probably won't work.

It seems 3-nitro 4-chloro benzene 1-sulfonic acid can be made directly from chlorobenzene in almost quantitative yield (96%), at least using 100% sulfuric. Curious what reaction conditions and yield for the substitution of the chloro group by reaction with strong ammonia, ammonia/ethanol or urea, like Boffis suggested, would be (if possible at all). ( "The synthesis of 2-aminophenol-4-sulfonic acid" Milazzo, Joseph Salvatore, 1952)

Acetanilide can also be synthesized from aniline and acetic it seems.

From prepchem: ("

"100 g aniline and 150 g acetic acid are mixed in a round flask of one-litre capacity, fitted with an air-condenser, and boiled 10 to 12 hours. The tube forming the air-condenser should not be too long, in order that the water vapor may escape while the aniline and acetic acid are condensed. The hot reaction mixture is poured into hot water containing 30 g of concentrated hydrochloric acid. After cooling, the crude acetanilide is filtered washed with distilled water. The filtrate contains about 20-30 grams of aniline hydrochloride, which, could be regenerated. The acetanilide is dried at 110-120° C. The yield of acetanilide is 220-250 g. Acetanilide is purified by crystallization from hoe water forms white leafy crystals melting at 115° C, boiling at 295° C. By boiling with concentrated hydrochloric acid, acetanilide is hydrolyzed to aniline and acetic acid."

It noticed it is mentioned in literature several times that sulfonation of acetanilide, followed by nitration results in the sulfonic acid of 2-nitro aniline, wheras direct nitration results in mainly 4-nitro acetanilide. Does anyone have a reference for the sulfonation and nitration of acetanilide?

[Edited on 24-3-2018 by nitro-genes]

nitro-genes - 26-3-2018 at 16:09

Would the sulfonation/nitration also work for toluene? Adding toluene to a very large excess of 98% sulfuric, heat until homogenous. Add 1 to 1.1 mole eqvt of the strongest nitric possible. React at lowest temp possible that still allows nitration (15-40 C maybe?) for long timer (maybe up to several days). Add water (enough to dissolve sulfonic acids), filter off any DNT formed, heat under reflux, and collect relatively pure 2-nitro toluene? Or would a few % water in the sulfuric and the more activated unsulfonated toluene really still result in a mixture of isomers? Or would the temperature needed for the nitration be too high too not exclude ipso nitration enough?