Phthaleins, preparation

The method is based on the conversion of urea to amnionium carbonate and the estimation of the latter by titration with standard acid. For this purpose, two equal quantities of urea (or urine) are measured out into two flasks A and B. A is treated with 10 ml. of a strong urease preparation and some phenol-phthalein, warm water is added and the mixture is adjusted by the addition of V/io HCl from a burette A until the red colour is just discharged. This brings the mixture to about pH 8 (the optimum for urease) and also prevents loss of ammonia. 

The above simple experiments illustrate the more important properties of aliphatic acid chlorides. For characterisation, the general procedure is to hydrolyse the acid chloride by warming with dilute alkali solution, neutralise the resulting solution with dilute hydrochloric acid (phenol-phthalein), and evaporate to dryness on a water bath. The mixture of the sodium salt of the acid and sodium chloride thus obtained may be employed for the preparation of solid esters as detailed under Aliphatic Acids, Section 111,85. The anilide or p-toluidide may be prepared directly from the acid chloride (see (iii) above and Section III,85,i). 

Ethyl bis-(2,4-dinitrophenyl) acetate (indicator) the stock solution is prepared by saturating a solution containing equal volumes of alcohol and acetone with the indicator pH range colorless 7.4-9.1 deep blue. This compound is available commercially. The preparation of this compound is described by Fehnel and Amstutz, Ind. Eng. Chem., Anal. Ed. 16 53 (1944), and by von Richter, Ber. 21 2470 (1888), who recommended it for the titration of orange- and red-colored solutions or dark oils in which the endpoint of phenol-phthalein is not easily visible. The indicator is an orange solid which after crystallization from benzene gives pale yellow crystals melting at 150-153.5°C, uncorrected. 

For uniformity with the stmctures given in the Colourindex the ammonium radical (9) is used for the amino-substituted xanthenes and the keto form for the hydroxy derivatives. The xanthene dyes may be classified into two main groups diphenylmethane derivatives, called pyronines, and triphenylmethane derivatives (eg, (4)), which are mainly phthaleins made from phthaUc anhydride condensations. A third much smaller group of rosamines (9-phenylxanthenes) is prepared from substituted ben2aldehydes. The phthaleins may be further subdivided into the following fluoresceins (hydroxy-substituted) rhodamines (amino-substituted), eg, (6) and mixed hydroxy/amino-substituted. 

Phthaleins. Dyes of this class are usually considered to be triaryhnethane derivatives. Phenolphthalein [77-09-8] (23, R = CO) and phenol red [143-74-8] (23, R = SO2) are used extensively as indicators in colorimetric and titrimetric determinations (see Hydrogen-ION activity). These compounds are prepared by the condensation of phenol with phthaUc anhydride or i9-sulfoben2oic anhydride, respectively, in the presence of a dehydrating agent. 

Another method of preparation is as follows 1 33 parts of fluorescein are dissolved in 5 parts of ether and treated with 25 parts of selenium chloride in the same solvent. A yellowish-red precipitate separates, and after long stirring at the ordinary temperature the ether is distilled off. The residue is stirred with water, the mixture filtered and the residue now dissolved in sodium hydroxide. After further filtration the filtrate is treated with hydrochloric acid, which precipitates seleno-fluorescei n. Further purification is effected by solution in alkali and reprecipitation. A reddish-brown powder is obtained, soluble with fluorescence in alcohol, but insoluble in water. In concentrated sulphuric acid it dissolves to give an orange solution. Its alkali salts are very soluble in wrater, giving red solutions. This process may also be applied to phthalins, which are obtained by the reduction of phthaleins and their halogen derivatives. If the selenium chloride is replaced by the oxychloride similar products are obtained.2 In place of the phthalins specified in the patents quoted, their O-acetyl compounds or O-acetyl compounds of the phthaleins may be used in indifferent solvents. The products are different from those obtained by the action of selenium on fluoresceins in aqueous alkali solutions.3... 

Reaction IV. (a) Action of Dehydrating Agents on a Mixture of an Aromatic Hydrocarbon and an Aromatic Alcohol. (B., 6, 964.)—This reaction, which was discovered by Baeyer, gains importance from its similarity to the methods used in preparing such substances as phenol-phthalein and fluorescein (see pp. 107, 385). 

Even in the preparation of phenolphthalein a little of the simplest pyronine is obtained from an cotAo-phthalein first formed. 

The procedure usually is unsuitable for tertiary alcohols since the reaction with phthalic anhydride or succinic anhydride either fails or results in dehydration of the alcohol. A few tertiary alkyl phthalates, however, have been prepared and resolved by first converting the alcohols to sodium or potassium salts and allowing these to react79 80 with phthalic anhydride. This modification has been applied successfully to dUa- and /S-santalols81 and cB-linalool.81 As already mentioned, glycols cannot be resolved by this procedure because they form polymeric esters when heated with phthalic or succinic anhydride. Phenols also usually form phthaleins or other condensation products instead of simple acid esters. 

Acidity (as acetic acid) Mix 38 mL of sample with an equal volume of carbon dioxide-free water, add 0.1 mL of phenol-phthalein TS, and titrate with 0.1 A sodium hydroxide. Not more than 0.1 mL is required to produce a pink color. Aldehydes (as formaldehyde) Prepare a Sample Solution by diluting 2.5 mL of sample with 7.5 mL of water. Prepare a Standard Solution containing 40 p,g of formaldehyde in 10 mL of water. Add 0.15 mL of a 5% solution of 5,5-dimethyl-1,3-cyclohexanedione in alcohol to each solution, and evaporate on a steam bath until the Acetone is volatilized. Dilute to 10 mL with water, and cool quickly in an ice bath while stirring vigorously. Any turbidity produced in the Sample Solution does not exceed that produced in the Standard Solution. 

Transfer 7 to 25 g of sample, accurately weighed, into a 500-mL volumetric flask with the aid of several 50-mL portions of warm, ammonia-free water, dilute to volume with water, and mix. Neutralize 20.0 mL of the solution with 0.2 A barium hydroxide or 0.2 A sodium hydroxide, using phenolphthalein TS as the indicator, and add 10 mL of freshly prepared phenol-phthalein-formol solution (50 mL of 40% formaldehyde con-... 

Phthalein type dyes have been prepared from 2,3-dicarboxypyrazine by heating with phenols or aromatic amines and zinc chloride. For example, compound (25) was obtained with resorcinol (1353). Efforts to prepare 2,6-diaminopyrazine through a Curtius-Schmidt reaction on 2-acetamido-6-carboxypyrazine (with sodium azide, sulfuric acid, and trichloroacetic acid) proved unsuccessful (434). The preparation of bicyclic heterocyles from 2-amino-3-carboxypyrazines has been described in Section VIII. 1D(6). 

When a phthalein is prepared from phthalic anhydride and m-di-ethyl amino phenol the product known as rhodamine has the structure of a tri-phenyl methane derivative as follows ... 

In a related phthalein dye, however, this condition is fully met. The dye fluorescein is resorcinol phthalein and is made from phthalic anhydride or phthalyl chloride and resorcinol just as phenol phthalein is made from phthalic anhydride and phenol (p. 750). These relationships may be expressed as follows writing the final dye salt both as a tri-phenyl methane derivative (B) and as a pyronine (C). The reactions are exactly analogous to those given for the preparation of phenolphthalein and its dye salt (p. 750), some of the intermediate steps being omitted in the present case. 

Trihydroxymercuri phenolsulphone-phthalein is prepared in a similar manner to hydroxymercuri phenolphthalein. It is a purplish powder having a bronze lustre. When mercuric acetate reacts with phenolsuiphone phthalein in acetic acid solution, a mixture of hydroxymercuri and acetoxymercuri derivatives is produced. 

E) Preparation of Thymolphthalein. Prepare the reaction mixture, following the same procedure as in section (D). Use 6 g of th3unol, 3.7 g of phthalic anhydride, and 3-4 g of zinc chloride. Heat for 8 hours at 105-110°. Cool, and add 20 ml of a mixtme of equal parts of ether and benzene. Provide the tube with a micro condenser, and reflux in the water bath for fifteen minutes to dissolve the unreacted th3unol. Cool, and decant the solvent. Add 30 ml of methanol, heat to dissolve the phthalein, and pour the hot extract into a beaker. Repeat the extraction with 10-15 ml of alcohol. The residue consists of zinc chloride. Save it for future reference, if the yield of the phthalein is low. Add to the alcohohc extract water in small amounts until precipitation begins, and then cool. After an hour filter the crystals of thymolphthalein. If the product is colored, dissolve in the minimum amount of hot alcohol and precipitate by slow addition of water. 

F) Preparation of Sulfonphthaleins. The preparations described involve (1) hydrolysis of o-sulfobenzoic imide (saccharin) to the ammonium salt of o-sulfobenzoic acid (2) preparation of o-sulfo-benzoic anhydride (3) preparation of phenolsulfonphthalein (phenol red) (4) bromination of phenolsulfonphthalein to tetrabromo derivative (bromophenol blue) (5) preparation of o-cresolsulfon-phthalein (cresol red) (6) bromination of o-cresolsulfonphthalein to the dibromo derivative (bromocresol purple)The equations for the steps are ... 

A number of other phthaleins such as o-cresolphthalein, pyro-gallolphthalein, etc., as well as halogen substitution products of certain of the above-mentioned compounds have been prepared and partially investigated. In general, however, these additional indicators offer few advantages over the compounds described in detail. 

Preparation, purity, and properties of the sulfonephthaleins. The preparation of the various sulfonephthaleins from o-sulfobenzoic acid, molten zinc chloride, and a phenol (which may be halogen substituted) has been described by Clark and Lubs. A. Cohen has reported his method of obtaining xylenolsulfone-phthalein, while a number of other valuable sulfonephthaleins have become available through the work of Barnett Cohen. ... 

Phenolbenzein (Aurin, benzaurin, or rosolic acid) was prepared by W. R. Orndorff, R. C. Gibbs, and S. A. McNulty. In 33% potassium hydroxide, the compound forms a colorless solution (carbinol compound like the phthaleins). 

Irritant agents used in the treatment of constipation include cascara, sagrada, castor oil, senna, rhubarb, phenol-phthalein, and acetphenolisatin. Phenolphthalein is a constituent of many OTC preparations, including Ex-Lax and Feen-A-Mint. Most of these agents, with the exception of castor oil, are slow in their onset of action (24 hours). Castor oil is hydrolyzed to ricinoleic acid, the active cathartic. It has an onset of action of 2 to 6 hours. 

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