Organic Syntheses, Coll. Vol. 1, p.327 (1941); Vol. 5, p.71 (1925).
.—In a 5-l. round-bottomed flask
are placed 90 g. (0.54 mole) of chloral hydrate
and 1200 cc. of water. To this solution are then added, in order: 1300 g. of crystallized sodium sulfate (Note 1)
; a solution of 46.5 g. (0.5 mole) of aniline (Note 2)
in 300 cc. of water to which 51.2 g. (43 cc., 0.52 mole) of concentrated hydrochloric acid
(sp. gr. 1.19) has been added to dissolve the amine (Note 3)
; and, finally, a solution of 110 g. (1.58 moles) of hydroxylamine hydrochloride (Note 4)
in 500 cc. of water. The flask is heated over a wire gauze by a Meker burner
so that vigorous boiling begins in about forty to forty-five minutes. After one to two minutes (Note 5)
of vigorous boiling the reaction is complete. During the heating period, some crystals of isonitrosoacetanilide
separate. On cooling the solution in running water the remainder crystallizes, is filtered with suction, and air-dried. The yield is 65–75 g.
per cent of the theoretical amount) of a product melting at 175°
.—Six hundred grams (326 cc.) of concentrated sulfuric acid
(sp. gr. 1.84) is warmed to 50° in a 1-l. round-bottomed flask
fitted with an efficient mechanical stirrer
, and, to this, 75 g. (0.46 mole) of dry (Note 6) isonitrosoacetanilide
is added at such a rate as to keep the temperature between 60° and 70° but not higher (Note 7)
. External cooling should be applied at this stage so that the reaction can be carried out more rapidly. After the addition of the isonitroso compound
is finished, the solution is heated to 80° and kept at this temperature for about ten minutes to complete the reaction. Then the reaction mixture is cooled to room temperature and poured upon ten to twelve times its volume of cracked ice. After standing for about one-half hour, the isatin
is filtered with suction, washed several times with cold water to remove the sulfuric acid
, and then dried in the air. The yield of crude isatin
, which melts at 189–192°
, is 47–52 g.
per cent of the theoretical amount). This product is pure enough for many purposes (Note 8)
For purification, 200 g.
of the crude product is suspended in 1 l. of hot water and treated with a solution of 88 g. of sodium hydroxide
in 200 cc. of water. The solution is stirred mechanically and the isatin
passes into solution. Dilute hydrochloric acid
is then added, with stirring, until a slight precipitate appears. This requires about 290–300 cc. of an acid made by diluting one volume of concentrated hydrochloric acid
(sp. gr. 1.19) with two volumes of water (Note 9)
. The mixture is then filtered at once, the precipitate is rejected, and the filtrate is made acid to Congo red paper with hydrochloric acid
. The solution is then cooled rapidly, and the isatin
which separates is filtered with suction and dried in the air. The pure product thus obtained weighs 150–170 g. (Note 10)
and (Note 11)
and melts at 197–200°
may also be crystallized from three times its weight of glacial acetic acid
. In this case it is obtained in large brown-red crystals which melt at 196–197°
Several runs were made in which the amounts of water and sodium sulfate
were varied over a considerable range, and this concentration was found to give the best yield of product of good quality. The sodium sulfate
seems to have more than a salting-out effect. If a saturated solution of sodium chloride
is used no product is obtained.
boiling over a 2° range was used in these experiments. The ordinary "pure" grade gives slightly lower yields.
If the aniline
is not in solution, a considerable quantity of tarry material is formed during the heating period. No tar is formed when the method described is used.
Longer heating of the reaction mixture gives a lower yield of dark-colored product.
The reaction does not start below 45–50° but becomes too violent above 75–80°. If the temperature becomes too high, the entire run is lost by charring. Stirring is needed to prevent local overheating.
In some smaller preparations when the sulfuric acid
solution was poured on ice a yellow compound precipitated, which was shown to be the oxime of isatin. It has also been isolated from the acid mother liquors from which the isatin
has separated. The oxime probably owes its formation to the hydrolysis of some unaltered isonitrosoacetanilide
(J. P. Wibaut,1
The correct amount of acid that must be added to precipitate the impurities but not the isatin
will vary with different samples of crude isatin
. If too much acid is added, some isatin
comes down with the impurities. This may be saved and added to a subsequent run.
The yield of isatin
is lower than for some of its derivatives. The explanation given in the literature is that some sulfonation occurs during the treatment with sulfuric acid
, with corresponding loss of product.
This method can be applied successfully to other isatin
derivatives. Thus, under the same conditions, 54 g. of p-toluidine
gives 75–77 g.
per cent of the theoretical amount) of isonitrosoaceto-p-toluidine
melting at 162°
. Eighty grams of this isonitroso compound
treated as described under isonitrosoacetanilide
gives 65–68 g.
per cent of the theoretical amount) of crude 5-methyl isatin
melting at 179–183°
. This is purified as described under isatin
by solution in sodium hydroxide
and partial neutralization to throw out the impurities or by recrystallization from three parts of glacial acetic acid
. The purified 5-methyl isatin
melts at 187°
This preparation is referenced from:
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