isatoic anhydride synthesis

Isatoic Anhydride Synthesis

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Introduction:

Isatoic anhydride is a very useful intermediate in industry for making things and stuff. These can range from pesticides to muscle relaxant medications.

The following procedure starts from phathlic acid, undergoing thermal rearrangement to yield phthalic anhydride. Phthalic anhydride undergoes hydrazinolysis with urea to phthalimide. Phthalimide undergoes a reaction with sodium hydroxide to form that alkaline salt, which is then reacted with sodium hypochlorite and finally hydrochloric acid solution to make isatoic anhydride.

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Procedure:

100g phthalic acid (or phathlic anhydride contaminated with the acid) is heated until molten in a 250ml beaker on a hotplate and held at this temperature until the liquid goes clear, indicating loss of water and conversion to the anhydride.

This is poured out into a stainless steel pot and allowed to cool, before being crushed up and stored in a sealed container.
[It should be noted that Aluminium pie tins are better suited for this, as they can be deformed to help release the solidified disk of phthalic anhydride.]
A 76g of phathlic anhydride yield results.

50g of phthalic anhydride is mixed coarsely with 10g of urea.

This is rendered molten inside a 1L flask, at which point effervescence occurs, building in rate until it fully foams up into an expanded cake signalling completion of the reaction.

The flask is allowed to cool, and ~100ml demineralized water used to loosen the cake. The slurry is poured into a 500ml beaker and crushed with an Stainless steel spatula before being vacuum filtered and washed with 500ml more water to remove traces of urea. This is spread onto aluminium foil on a hotplate at 120C to dry. A 42g dry yield of phthalimide results.

In a 1L beaker, 42g phathlic acid, a stir bar and 100ml water are combined. To this is added 80g of ice, cubed or crushed, to lower the temperature. Stirring is engaged on medium and maintained until the completion of reaction.

11.6g sodium hydroxide is dissolved in ~50ml water, or enough to get it fully dissolved. This is poured into the beaker with the phathlic acid. If needed, more ice is added if previous ice has melted.

520g of 4.2% supermarket sodium hypochlorite bleach (unfortunately with detergents, avoid) is then poured in, ensuring melted ice is replaced. 4 minutes and 30 seconds later, 25g of ~33% Hydrochloric acid is added, and more ice added if needed. 4-8% NaOCl solution can be utilized, and the weights scaled. The solution turns from clear straw coloured to a red hue, and a precipitate begins to form. 4 minutes later, 12g 33% HCl is added.

The reaction temperature is raised to 25-30C until ice has fully melted. Once at this temperature, the reaction is held there for 40 minutes, resulting in a chocolate coloured precipitate in a reddish liquor.

The precipitate is vacuum filtered, and rinsed with ~3L water due to the detergents that were present in the bleach solution. Using plain sodium hypochlorite solution would likely only need ~500ml to wash ions out, but solubility in water of the isatoic anhydride is not very significant. A damp yield of 48g results.

The isatoic anhydride is dried at 60C on a hotplate in a glass dish. A melting point test is taken by placing a small sample of the isatoic anhydride in a drilled hole on a small aluminium cylinder on a tripod with a thermometer inserted into another hole next to the sample of the same depth. This is heated with a bunsen flame.

A melting point of 236 +/- 1C for the tan coloured isatoic anhydride is observed, as it melts and decomposes simultaneously. This is consistent with internet search engine results.

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Discussion:

Some improvements noted. Not a very difficult reaction route.

Maybe someone can recommend a recrystallization solvent for the isatoic anhydride

Conclusion:

It works.

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References

"Conversion of Phthalic Acid to Phthalic Anhydride", Magpie, lab constructor
http://www.sciencemadness.org/talk/viewthread.php?tid=25566

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Synthesis of phthalimide, VOGEL'S Textbook of Practical Organic Chemistry (5:th edition), page 1065-1066
Phthalimide:

Method 1. Place 100 g (0.675 mol) of phthalic anhydride and 105 mL of concentrated ammonia solution in a 1-litre round-bottomed flask fitted with a wide air condenser (10 mm in diameter). Heat on a sand bath, gradually at first until the mixture is in a state of quiet fusion and forms a homogeneous melt (the temperature reaches 300°C in about 1.5-2 hours; all the water is evaporatedduring the first hour). Shake the flask occasionally during the heating and push down any material whicj sublimes into the condenser with a glass rod. Pour the contents of the flask while still hot into a porcelain basin, allow to cool and grind to a fine powder in a mortar.The phthalimide (95 g, 96%) is practically pure and melts at 233-234°C. It may be recrystallised from EtOH, but the solubility is only slight (about 5%).Method 2. Intimately mix 99 g (0.67 mol) of pure phthalic anhydride and 20 g (0.33 mol) of urea, and placethe mixture in a 1-litre, long-necked, round-bottomed flask. Heat the flask in an oil bath at 130-135°C. When the contents have melte, effervescence commences and gradually increases in vigour; after 10-20 minutes, the mixture suddenly froths up to about three times the original volume (this is accompanied by rise in temperature to 150-160°C) and becomes almost solid. Remove the heat from beneath the bath and allow to cool. Add about 80 mL of water to disintegrate the solid in the flask, filter at the pump, wash with a little water and then dry at 100°C.The yield of phthalimide, m.p. 233°C (i.e practically pure), is 86 g (87%). If desired, the phthalimide may be recrystallised from 1200 mL of industrial spirit; the first crop consists of 34 g of m.p 234°C, but further quantities may be recovered from mother-liquor.

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Isatoic anhydride synthesis, Fire_ass_lean

http://www.tandfonline.com/doi/abs/10.1080/00304948209354906...
http://www.google.com/patents/US4328339

"50 g (.34 mole) of finely powdered phthalimide was added to a 1 liter erlenmeyer flask and 125 ml of water was added along with a stirbar. In a separate container, 14 g (.35 mole) of sodium hydroxide was added to a quantity of water sufficient to dissolve it. After the hydroxide solution had dissolved and cooled somewhat, it was added to the phthalimide in the flask and magnetic stirring started. After a minute or two, when almost all the phthalimide had dissolved, about 100 grams of crushed ice was added to the flask. Then, 295 g of 8.25% sodium hypochlorite (.33 moles) was added substantially all at once under vigorous stirring. More ice was added as it melted to keep the solution cold. 4 minutes and 30 seconds after the bleach addition, approximately 3/4 of a total of 41 g (.35 mole) of 31.45% hydrochloric acid was added in one portion. Some white precipitate was noted. Stirring was continued for another 4 minutes, then the remainder of the acid was added. The heat on the hotplate was turned on to speed the melting of the ice and to bring the mixture to about 20-30C. At that point the heat was turned off and the mixture was stirred for another 30 min. The mixture, which was a beige slurry with a slight pinkish tint, was suction filtered and washed several times with water. The cream colored filter cake was somewhat water-logged and resembled tapioca. It was dumped out onto a pyrex dish and heated on low heat on the hotplate for 12 hours to dry. The product darkened somewhat during drying and became a light tan powdery solid. Total weight was 54.6 g (98.7% yield).--Yield seemed somewhat high, perhaps because of residual moisture (it likes to hold on to its water and takes a long time to dry). OTOH, it could have just run superbly smoothly.The product dissolved easily in alkaline solution but not in acid. However, it dissolved slowly in hot concentrated hydrochloric acid with bubbling to give a clear solution that did not precipitate any solids on cooling (presumed hydrolysis to anthranilic acid with evolution of CO2). On dropwise addition of aqueous ammonia, a flocculant white precipitate appeared (presumed to be anthranilic acid) which re-dissolved on addition of sodium hydroxide solution. This may open up a new high yield route to anthranilic acid.This can be a tricky reaction to master. Timing is essential. The interval between the addition of bleach and the addition of acid depends on temperature and can vary somewhat, but the optimum time with icing seems to be around 5 minutes. In a clean reaction, the product is light colored and filters easily. It should not clog the filter paper.There should be no foaming of the reaction mixture upon acidification. If there is foaming, it means that the acid was added too soon and not all of the N-chloroamide has had time to rearrange. When this happens, the N-chloroamide hydrolyzes into phthalic acid, which precipitates and contaminates the product, and noxious chlorine-containing gases are evolved which produce a thick head of foam.If too much time elapses between the bleaching and acidification stages, side reactions will run rampant. The mixture will turn dark black and give a small yield of charcoal-colored crap. "















[Edited on 8-9-2014 by Templar]

[Edited on 8-9-2014 by Templar]

[Edited on 8-9-2014 by Templar]

[Edited on 9-9-2014 by Templar]

US patent 3,324,119 have some experimental data of different factors leading to a change in yield. The main factor is hydrolysis of phthalimide before hypochlorite is aded. I'd say it's possible to obtain the same intermediate without the need of high ph in the beggining of the reaction, but in this case phthalimide has extremely low solubility, so we either need a solvent like dmso, or we can continue to stick NaOH-water, but keep the temperature and the dissolution time as short as possible.
Also there's some info in the US 4,328,339 which is consistent with the above patent, and US 3,867,951 has some more information about influence of hydrolysis on the yields and also some nice time frame descriptions.
Picture from an article "Isatoic Anhydrides and Their Uses in Heterocyclic Synthesis", published in the "Heterocyclic Chemistry" Vol. 28 about some possible direct precursors of isatoic anhydride.


There's an overview of isocyanates properies and their characteristic reactions http://www.poliuretanos.com.br/Ingles/Chapter1/131Isocyanate...
So the reaction mechanism the way I see it after reading all this stuff:


UPD: Okay, I've encountered an article saying that the initial reaction of carboxylic acid with isocyanate leads to a mixed anhydride. http://www.sciencedirect.com/science/article/pii/S0040403904...


And a patent telling the same US20130338247



And even one more US20060167124


So there's no catalyst by amine (the last picture before the update most likely is not correct) but a direct conversion into carbamic-carboxylic anhydride.

[Edited on 22-4-2015 by byko3y]