A PRACTICAL METHOD FOR THE PREPARATION

OF PHENOLSULPHONEPHTHALEIN

EDGAR A. SLAGLE

Assistant in i!edicine in charge of the Chemical Division of the Laboratory of the

Medical Clinic, Johns Hopkins University

Received for publication, May 2, 1910 4

The work of Abel and Rowntree,’ and Rowntree and Geraghty

has shown that in phenolsulphonephthalein we have, without
doubt, one of the best adapted substances that chemistry has
furnished for testing the functional activity of the kidneys.
While the work of these investigators was in progress I prepared
the phenolsulphonephthalein that was used and experimented
to some extent on the most economical methods for its preparation.
In view of the fact that this substance will probably be widely
used in medicine and on accoun of numerous requests for material
it seemed advisable to publish a short account of the procedure
of preparation.
Phenolsulphonephthalein was first suggested by Remsen and
later described in detail by Sohon.2 This compound was first
made by Remsen and Sohon by the action of phenol on the an-
hydride of o-sulphobenzoic acid.
Since phenol can he obtained on the market pure and at a small
cost the economical preparation of the anhydride is the important
factor. This was early prepared by Fahlberg and Barge3 by the
action of acetyl chloride on the free acid; also by the action of
phosphorus I)entachloride on the neutral potassium salt, the re-
action being effected n a sealed tube at 170#{176} C.

This Journal, 1909. i, 231.

2 Amer. Chem, Jour., xx, 263.
8cr. d. chem. Ges., xxii, 754.

I
664 EDGAR A. SLAGLE

About the same time Remsen and Dohine’ obtained it as a

sublimate of fine needles by heating a mixture of the free acid
and phosphorous pentoxide at 130#{176}C.
Remsen and Sohon2 describe a method of treating the acid
potassium salt with phosphorous pentachloride and extracting
the anhydride from the melt by benzene. In this way the an-
hydride can be obtained in large colorless crystals, but the yield
is small and unless the reagents are carefully purified, dark tarry
products result.
In the course of this investigation it has been found that the
anhydride is most readily prepared by distilling the free acid
obtained from the acid ammonium salt of o-sulphobenzoic acid
with phosphorous pentoxide. The acid ammonium salt can be
obtained quantitatively from commercial saccharin (Benzoicsul-
phinide) which, however, is usually contaminaed, more or less,
with p-sulphaminebenzoic acid.
The method of obtaining the acid am.monium salt and from it
the free acid is described by Remsen and Dohn1e1 and Remsen
and Clark4 and is as follows:
One hundred grams of saccharin (Benzoic suiphinide) are added to
one and one-half liters of distilled water which contains 125 cubic
centimeters of chemically pure concentrated hydrochloric acid.
It will he found convenient to carry out the hydrolysis in a two liter
balloon flask with a small funnel placed in the neck. The mixture is
heated to gentle ebullition until the benzoic suiphinide is completely
hydrolyzed. The passing into solution of the sulphinate is indicative of
partial hydrolysis, as benzoic suiphinide itself is but slightly soluble in
water and practically insoluble dilute hydrochloric
in acid. An absolute
criterion as to the end of the reaction is the disappearance of the swet
taste which is characteristic of benzoic sulphinide. The best results am e
obtained when the temperature of the solution is kept near the boiling
point of water, and the solution at constant volum. The time r#{128}quired
for the hydrolysis varies according to the conditions, under the most
favorable conditions six to eight hours being necessary. After the coin-
Amer. Cheni. Jour., xi, 332.
2 Amer. Chem. Jour., xx, 257.
Amer. Chem. Jour., xi, 332.
Clark: Dissert., Johns Hopkins Univ., 1902.
 PHENOLSULPHONEPHTHALE1N 665

plete transformation of the henzoic suiphinide into the acid amrnoniurn

salt of orthosulphobenzoic acid, the solution of the latter is evaporated to
one-third its original volume and allowed to cool. The acid ammoniurn
salt crystallizes in large monoclinic plates. These are filtered off and the
mother-liquor evaporated to dryness ; constant stirring of the mass is
necessary during the progress of the last operation. Usually the dried
powdered acid ammonium salt is colored light brown, in consequence of
slight decomposition by heat. It can be obtained perfectly pure by re-
peatedwashingwithabsolute alcohol. For this purpose the salt is placed
in a large funnel and the alcohol allowed to percolate through it until
colorless. The salt is dried by pressing it between filter-paper or on
porous plates.
When the acid ammoniumn salt is dry it is treated in a large porcelain
dish with twice its weight of phosphorous pentachioride. Reaction
takes place spontaneously and the mass becomes semi-liquid. When the
reaction is complete, the mixture is thoroughly washed with cold water,
the chloride remaining as a heavy yellowish oil und.issolved. The chlor-
ide is then boiled with water until it is decomposed, and the resulting
liquid evaporated to complete dryness to drive off all the hydrochloric
acid. The reactions are all quantitative and the acid thus obtained is
pure.
The pure acid obtained in this way is pulverized and preserved over
sulphuric acid. When the anhydride is desired the acid is placed in a
short neck distilling bulb and phosphorous pentoxide added. Thorough
mixing is brought about by shaking the flask, when reaction takes place
and melting occurs. The mass is then gradually heated with a large
flame held in the hand and the anhydride distilled over as a colorless
liquid which immediately solidifies. When the drops begin to appear
colored brownish yellow and the black mass in the flask swells up the
distillation is discontinued. A convenient method is to distill the an-
hydride into a large weighed porcelain crucible, a second weighing gives
the amount of anhydride and then the phenol is weighed into this cru-
cible. The
crucible is then placed at once in an oven previously heated
to about 1300 C. The anhydride prepared in this manner is very unstable
and readily takes up water forming the acid, however the loss due to
decompostion by the distillation is slight, about ninety per cent of the
theoretical yield being obtained.
The fusion of the anhydride and phenol is carried out as described by
Remsen and Sohon. About twenty-four hours (and frequent stirring)
is required for complete reaction and the temperature must be care-
666 EDGAR A. SLAGLE

fully regulated at 130#{176}-135#{176}C.

Below this temperature the operation
does not progress well; above, decomposition occurs forming darker
colored products less soluble than phenolsulphonephthalein. After the
reaction the material presents a dark red fluorescent appearance and
smells of phenol. It is then disintegrated with hot water and boiled
until free from phenol; this concentrates the solution to such an extent
that nearly all of the phenolsulphonephthalein crystalizes out on
cooling. It is then filtered with suction and washed with water. This
generally furnishes the material in pure condition. It was not found
practical to use any dehydrating agent nor to purify the material by
dissolving in alkali and precipitating by acid.

By the above procedure one-half kilogram of phenolsulphone-

phthalein can be prepared at a cost, for chemicals alone, of about
seven dollars. This is about five times the yield that was obtained
from the other methods investigated.