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Author: Subject: Preparation of anthranilic acid
Sauron
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[*] posted on 30-3-2008 at 02:25
Preparation of anthranilic acid


This compound, o-aminobenzoic acid, or aniline-2-carboxylic acid, is usually prepared, per Vogel, from phthalimide by treatment with hypobromite or hypochlorite.

I made some phthalimide a couple years ago by three different methods.

Phthalic anhydride and ammonium hydroxide
Pthalic anhydride and urea
Phthalic anhydride and ammonium carbonate

All of which worked nicely.

But I never managed to get Vogel's procedure to work, for making anthranilic acid.

I have now compared Vogel with the procedure in "Fundamental Processes of Dye Chemistry", q.v. and find Vogel somewhat wanting.

However, even the more detailed and somewhat larger scale procedure in this book, is rather fiddly and at some junctures vague.

I therefore propose an entirely different route.

2-nitrobenzoic acid is a commercial product and not too costly.

Org.Syn. has a procedure for the low pressure (3 atm.) hydrogenation of p-aminobenzoic acid ethyl ester with PtO2 catalyst. Sounds like a job for my Parr 3911 shaker type hydrogenator. This apparatus was designed by Roger Adams for use with his catalyst, and he happens to be author of this procedure. The yield is quantitative.

Other reductions are referenced.



[Edited on 30-3-2008 by Sauron]

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Klute
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[*] posted on 30-3-2008 at 02:37


I had the idea of reducing ethyl p-nitrobenzoate to benzocaine, using Zn/CaCl2. The yields are said to be moderate, but i think a CTH (not having a Parr shaker myself :) )could work nicely here, though i haven't got any specific reference to back this up.
I was thinking of chlorinating p-TsOH, oxydizing the chloro-sulfonic acid at the methyl group with dilute HNO3, removing the sulfonic group as in the o-chlorobenzoic thread, then esterification and reduction.

The only difference i though was keeping the sulfonic group on during the methyl oxydation, as i would be using dilute HNO3. I don't think any di-nitration could accur with those conditions, but i prefer staying on the safe side. I guess some displacement of the sulfonic group can happen in those conditions though.
Just an foolish idea, but if after nitrating TsOH with mixed acids, could diluting the mixture directly oxidize the methyl group (dilute HNO3) AND remove the sulfonic group (dilute H2SO4)? That a long shot, and could give rise to isomer formation, but it would save alot of time! one-pot-3-reactions..

Sorry if i'm drifting away.
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Sauron
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[*] posted on 30-3-2008 at 02:59


There's two Model 3911 sets, at least one of them including the 4833 controller, on offer right now. The asking price is $400 each. I know how to get 25% off that, but I already have this model and its controller. These are in Michigan and are US voltage.

This is the 500 ml model. I paid that much for the 3911, and bouth the controller seperately for almost as much again. So whoever gets these will be getting a great deal. Almost makes me wish I needed more than one of them. But, I don't, although I do lust after the two liter version.

Anyone interested PM me for details.




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benzylchloride1
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[*] posted on 31-3-2008 at 19:36


I produced about 50 grams of phthalimide several weeks ago for this synthesis. I planning on try it a soon as a get some more MnO2 for making the required bromine. Did you use glacial acetic acid in the end to precipitate it? Tomorrow, in ochem lab, I am going to synthesize P-aminobenzoic acid from p-acetotoluidide. This uses the same precipitation procedure. I want to make some anthranillic acid to produce benzyne which will be used in some Diels-Alder reactions.
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[*] posted on 26-3-2009 at 00:11


I have also attempted the Dye chemistry synth and am planning to try again this weekend. Has anyone had success using the method described in dye chemistry?
The part that seems vague to me is the quantity of hypochlorite solution to use. It mentions using 2 mol of NaOH for each mole of NaOCl, but it also mentions putting in 20cc of NaOH immediately beore use. Do I calculate the quantity of NaOCl based on this total figure? How important is the accuracy of the amount of NaOCl? For the quantities described I calculaed the amount of NaOCl to use at about 1300ml but i dont feel confident in my calculations.

I'm also interested to know how important it is to neutralise it at 80 since other sources mention cooling it before neutralising.

It also mentioned (elsewherre) not to use too much HCl because it could destroy the anthranilic, but then it says the filtrate is acidifed with 40cc of HCl and 12cc glacial.

I'd be very interested to hear if anyone could shed light the above points. If only I had a Par apparatus.
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[*] posted on 28-3-2009 at 21:26


O-aminobenzoic acid is a amino acid and has a very narrow isoelectric point. This means that it only precipitates at a certain pH in high yeild. I was able to obtain about 15g of crude anthranilic acid from this reaction. The neutralization is the tricky part. The reaction mixture is first brought to about pH 7 with hydrochloric acid and glacial acetic acid is slowly added with stirring until precipitation of the dark colored product is nearly complete; easy to over shoot. The product is then filtered off and recrystallized from water. The product is tan in color and melts sevral degrees below the theoretical value.



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PHILOU Zrealone
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[*] posted on 31-3-2009 at 01:46


One could consider starting from easily available ortho-nitrotoluene.

CH3-C6H4-NO2 -KMnO4/H(+)-> HO2C-C6H4-NO2
HO2C-C6H4-NO2 -Fe/HCl-> HO2C-C6H4-NH2

Ortho aminobenzoic acid can be diazotised diluted in an inert solvant and lead by gentle warming to a strange coupling reaction by concomitant decarboxylation and denitrogenation forming (C6H4)°° diradical species...
If nothing else is present in the media to react, two of those gather to form a linear tricyclic compound, two benzene ring joined by a cyclobutane ring (Ar=Ar)



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[*] posted on 31-3-2009 at 03:05


It has been made from o-nitrotoluene 3 times in the literature, but with NaOH or KOH, and the yield is only 13-15%.
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[*] posted on 31-3-2009 at 04:02


Quote: Originally posted by S.C. Wack  
It has been made from o-nitrotoluene 3 times in the literature, but with NaOH or KOH, and the yield is only 13-15%.


Strange, the oxydation of alkyl part of aromatic ring, especialy with a NO2 protective group must be very high even in pushed conditions...conversion of toluene to benzoic acid is nearly 100%...




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S.C. Wack
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[*] posted on 31-3-2009 at 14:49


I was wrong on the number of references; I forgot about the patent, and the Russian article.

The original 1899 BASF patent from o-nitrotoluene and NaOH:
GB189918319
DE114839

The latest (1972) article that I am aware of is this one.

All other references to this that I am aware of are given there. The local library has closed journal access for some time now, anyone interested in the references in the article will have to rely on Russian good will and Wiley archive access.

This route may be worthwhile for some despite the low yield.
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S.C. Wack
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[*] posted on 5-7-2009 at 11:15


Well I see that espacenet only supports full (very long) urls now. Nice of them to change that. Do the manual number search if you want to see the patents.

So after two years I finally have full journal access again...Z. angew. 385 (1900) [1 part o-nitrotoluene, 1 part KOH, 1/2 part water, 5 hr reflux] if anyone cares: http://ifile.it/iywpnc3

[Edited on 5-7-2009 by S.C. Wack]
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[*] posted on 5-7-2009 at 14:16


I have been thinking about synthesizing anthranilic acid, what about o-xylene to phthalic acid via potassium permananate then phthalic acid to phthalic anhydride by heating and then any of the methods mentioned by Sauron to anthranilic acid?

Alternatively "oxidation of naphthalene tetrachloride (prepared from naphthalene, potassium chlorate and hydrochloric acid) with nitric acid" can supposedly yield phthalic acid but I haven't seen any experimental procedures for that either.

[Edited on 6-7-2009 by crazyboy]




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[*] posted on 6-7-2009 at 07:59


Here is the synthesis from "Experimental organic chemistry - principles and practice"
Quote:


Procedure
Dissolve 8.0g of sodium hydroxide in 30ml of distilled water in a 100ml erlenmeyer flask containing a magnetic stirrer bar and cool the solution with stirring in an ice bath. Add the bromine [2.1ml, 6.5g, 41mmol] (CARE!) in one portion and stir the mixture vigorously until all of the bromine has reacted [look for the disappearance of the brown colouration] and the mixture has cooled to ca. 0*C. Continue vigorous stirring and add all of the finely powdered phthalimide [5.9g, 40mmol] to the solution, followed by a solution of a further 5.5g of sodium hydroxide in 20ml of water. Remove the ice bath, allow the temperature of the mixture to rise spontaneously to ca. 70*C and continue stirring for a further 10 min. Cool the clear solution in an ice bath with stirring (if the mixture is cloudy, filter under gravity before cooling), and add concentrated hydrochloric acid dropwise with a pipette until the solution is just neutral when a drop is spotted onto universal indicator paper (ca. 15ml should be necessary). If too much acid is added, the mixture may be brought back to neutrality by adding further quantities of sodium hydroxide solution, but it is better to avoid this by careful addition of acid in the first instance. Transfer the mixture to a 500ml beaker (foaming occurs in the next stage) and precipitate the 2-aminobenzoic acid by addition of glacial acetic acid (ca. 5ml). Filter off the precipitate with suction, wash the residue with 10ml of cold water and dissolve it in the minimum quantity of boiling water containing a little activated charcoal. Filter the hot solution to remove the charcoal and cool the filtrate with ice. Filter off the pure acid with suction, dry the residue with suction on the filter for 5 min and complete the drying to constant weight in an oven at 100-120*C.

[Edited on 6-7-2009 by DJF90]
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S.C. Wack
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[*] posted on 12-7-2009 at 14:28


Quote: Originally posted by crazyboy  
what about o-xylene to phthalic acid


If you happen to have o-xylene, maybe you have some sodium azide as well. In Angew. Chem. 45, 536 (1932) a bunch of amines are made using the Schmidt reaction: aniline, benzylamine, phenethylamine, etc... and the title cpd., from o-phthalic acid. They say that with 4.15 g. of the acid with 10 ml. conc. H2SO4 and 40 ml. CHCl3 and a temperature maintained at 45-50C by the slow addition of 4.9 g. NaN3, they obtained 2.7 g. anthranilic acid (yield 80%) and 0.1 g. o-phenylenediamine. No workup details; see volume 3 of Organic Reactions.

[Edited on 12-7-2009 by S.C. Wack]
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[*] posted on 12-7-2009 at 17:48


No I don't have sodium azide. I plan on separating o-xylene from meta and para xylenes using the procedure detailed in COPAE:

"When the mixed xylenes are treated with about their own weight of 93 per cent sulfuric acid for 5 hours at 50°, the o-xylene (b.p. 144°) and the m-xylene (b.p. 138.8°) are converted into water-soluble sulfonic acids, while the p-xylene (b.p. 138.5°) is unaffected. The aqueous phase is removed, diluted with water to about 52 per cent acidity calculated as sulfuric acid, and then heated in an autoclave at 130° for 4 hours. The m-xylene sulfonic acid is converted to m-xylene, which is removed. The o-xylene sulfonic acid, which remains in solution, may be converted into o-xylene by autoclaving
at a higher temperature."




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[*] posted on 13-7-2009 at 18:46


Aniline used to be mfgd. by heating phenol in a sealed tube with ammonia. If that reaction is applied to salicylic acid, would anthranilic acid be the result? I suppose there may be steric hindrance.
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[*] posted on 13-7-2009 at 19:09


In the scimad library, in one of the dye-chemistry books, they refer to producing (di)methylaniline by autoclaving aniline with methanol. This + Hoffman-Martius rearrangement + some oxidation should yield anthranilic.
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[*] posted on 13-7-2009 at 20:51


Those reactions require temperatures in the range of 200 to 250 C, and 50 bar or higer pressures.

Salicylic acid would likely decarboxylate, likely you'd have to use ammonium carbamate ( "ammonium carbonate" ) as a source of ammonia and CO2 to prevent that. At the temperatures required I suspect the para isomer would predominate.

As for the methylaniline route, you left out protecting the amino group and aromatic ring against oxidation, which will add at least two more steps.

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[*] posted on 18-4-2011 at 11:33


What is the reaction between phthalic anhydride and urea? Under what conditions does this occur?



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