Benzoic acid ethers

Determination of the yield of diazomethane in codistillates of ether or other solvents is achieved, for occasional cases, most conveniently by titration an exactly weighed sample of benzoic acid (ether solution) in excess over the expected amount of diazomethane is added to an aliquot of the diazomethane solution. Methyl benzoate is formed rapidly and almost quantitatively. The unreacted benzoic acid is then titrated with 0.1 m NaOH solution. 

Benzoates. Dissolve 0-5 g. of the amino acid in 10 ml. of 10 per cent, sodium bicarbonate solution and add 1 g. of benzoyl chloride. Shake the mixture vigorously in a stoppered test-tube remove the stopper from time to time since carbon dioxide is evolved. When the odour of benzoyl chloride has disappeared, acidify with dilute hydrochloric acid to Congo red and filter. Extract the solid with a little cold ether to remove any benzoic acid which may be present. RecrystaUise the benzoyl derivative which remains from hot water or from dilute alcohol. 

Hydrolysis of benzanilide. Place 5 g. of benzanilide and 50 ml. of 70 per cent, sulphuric acid in a small flask fitted with a reflux condenser, and boU gently for 30 minutes. Some of the benzoio acid will vapourise in the steam and solidify in the condenser. Pour 60 ml. of hot water down the condenser this will dislodge and partially dissolve the benzoic acid. Cool the flask in ice water filter off the benzoic acid (anifine sulphate does not separate at this dilution), wash well with water, drain, dry upon filter paper, and identify by m.p. (121°) and other tests. Render the filtrate alkaline by cautiously adding 10 per cent, sodium hydroxide solution, cool and isolate the aniline by ether extraction. Recover the ether and test the residue for anifine (Section IV,100). 

If the benzoyl derivative is soluble in alkali, precipitate it together with the benzoic acid derived from the reagent by the addition of hydrochloric acid filter and extract the product with cold ether or light petroleum (b.p. 40-60°) to remove the benzoic acid. 

Pour the aqueous solution remaining from the ether extraction with stirring into a mixture of 80 ml. of concentrated hydrochloric acid, 80 ml. of water and about 100 g. of crushed ice. Filter the precipitated benzoic acid at the pump, wash it with a little cold water, drain, and recrystallise from boiling water. The yield of benzoic acid (colourless crystals), m.p. 121°, is 18g. 

To obtain crystalline perbenzoic acid, dry the moist chloroform solution with a little anhydrous sodium or magnesium sulphate for an hour, filter, and wash the desiccant with a little dry chloroform. Remove the chloroform under reduced pressure at the ordinary temperature whilst carbon dioxide is introduced through a capillary tube. Dry the white or pale yellow residue for several hours at 30-35° under 10 mm. pressure. The yield of crystalline perbenzoic acid, m.p. about 42°, which is contaminated with a little benzoic acid, is 22 g. It is moderately stable when kept in the dark in a cold place it is very soluble in chloroform, ethyl acetate and ether, but only shghtly soluble in cold water and in cold hght petroleum. 

The benzoic acid may be separated by steam distillation or by saturating the aqueous mixture of sodium salts with sulphur dioxide whilst maintaining the temperature below 40° the benzoic acid precipitates and can be separated by filtration or extraction with ether. Acidification of the filtrate with hydrochloric acid liberates the pyruvic acid. The pjTuvic acid may be oxidised < lth hydrogen peroxide to the arylacetic acid, for example ... 

To determine the exact diazomethane content, allow an aliquot portion of the ethereal diazomethane solution to react with an accurately weighed amount (say, about 1 g.) of A. R. benzoic acid in 60 ml. of anhydrous ether. The solution should be completely decolourised, thus showing that the benzoic acid is present in excess. Dilute the solution with water and titrate the excess of benzoic acid with standard 0 IN alkali using phenolphthalein as indicator. 

Separations based upon differences in the chemical properties of the components. Thus a mixture of toluene and anihne may be separated by extraction with dilute hydrochloric acid the aniline passes into the aqueous layer in the form of the salt, anihne hydrochloride, and may be recovered by neutralisation. Similarly, a mixture of phenol and toluene may be separated by treatment with dilute sodium hydroxide. The above examples are, of comse, simple apphcations of the fact that the various components fah into different solubihty groups (compare Section XI,5). Another example is the separation of a mixture of di-n-butyl ether and chlorobenzene concentrated sulphuric acid dissolves only the w-butyl other and it may be recovered from solution by dilution with water. With some classes of compounds, e.g., unsaturated compounds, concentrated sulphuric acid leads to polymerisation, sulphona-tion, etc., so that the original component cannot be recovered unchanged this solvent, therefore, possesses hmited apphcation. Phenols may be separated from acids (for example, o-cresol from benzoic acid) by a dilute solution of sodium bicarbonate the weakly acidic phenols (and also enols) are not converted into salts by this reagent and may be removed by ether extraction or by other means the acids pass into solution as the sodium salts and may be recovered after acidification. Aldehydes, e.g., benzaldehyde, may be separated from liquid hydrocarbons and other neutral, water-insoluble hquid compounds by shaking with a solution of sodium bisulphite the aldehyde forms a sohd bisulphite compound, which may be filtered off and decomposed with dilute acid or with sodium bicarbonate solution in order to recover the aldehyde. 

Benzyl chloride readily forms a Grignard compound by reaction with magnesium in ether with the concomitant formation of substantial coupling product, 1,2-diphenylethane [103-29-7]. Benzyl chloride is oxidized first to benzaldehyde [100-52-7] and then to benzoic acid. Nitric acid oxidizes directly to benzoic acid [65-85-0]. Reaction with ethylene oxide produces the benzyl chlorohydrin ether, CgH CH20CH2CH2Cl (18). Benzylphosphonic acid [10542-07-1] is formed from the reaction of benzyl chloride and triethyl phosphite followed by hydrolysis (19). 

The 0- and -monochloro- and 2,4- and 3,4-dichlorobenzotrichlorides are iatermediates ia the manufacture of the corresponding chlotinated benzoic acids and benzoyl chlorides. Fluotination of the chlotinated benzotrichlorides produces the chlotinated benzotrifluorides, iatermediates ia the manufacture of dinitroaniline and diphenyl ether herbicides (76). 

Pyrogallol monomethyl ether has been prepared by the methylation of pyrogallol with dimethyl sulfate or methyl iodide by the decarboxylation of 2,3-dihj droxy-4-methoxy-benzoic acid and by the methylation of pyrogallol carbonate with diazomethane and subsequent hydrolysis. The method described is taken from the improved procedure of Baker and Savage for the preparation of pyrogallol monomethyl ether from o-vanillin by oxidation with hydrogen peroxide. 

Benzoic acid [65-85-0] M 122.1, m 122.6-123.1, pK 4.12. For use as a volumetric standard, analytical reagent grade benzoic acid should be carefully fused to ca 130 (to dry it) in a platinum crucible, and then powdered in an agate mortar. Benzoic acid has been crystd from boiling water (charcoal), aq acetic acid, glacial acetic acid, C6H6, aq EtOH, pet ether (b 60-80 ), and from EtOH soln by adding water. It is readily purified by fractional crystn from its melt and by sublimation in a vacuum at 80. ... 

Zincon (o-[l-(2-bydroxy-5-sulfo)-3-phenyl-5-formazono]-benzoic acid) [135-52-4] M 459.4. Main impurities are inorganic salts which can be removed by treatment with dilute acetic acid. Organic contaminants are removed by refluxing with ether. It can be recrystd from dilute H2SO4. [Fichter and Schiess Chem Ber 33 751 1900.]... 

Tropacocaine (Benzoyl-ili-tropeine), CuHj gOgN, was discovered by Giesel in Java coca leaves and has since been found in Peruvian coca. Its preparation from the former source has been described by Hara and Sakamoto, It crystallises in needles, m.p. 49°, is insoluble in water, but soluble in alcohol, ether or dilute ammonia and is generally prepared by benzoylating /t-tropine, and purified as the hydrochloride. Its alcoholic solution is alkaline and optically inactive. The hydrochloride forms needles, m.p. 271° (dec.), and the hydrobromide leaflets. The aurichloride separates in minute yellow needles, m.p. 208°, from hot aqueous solutions the picrate has m.p. 238-9°. When heated with hydrochloric acid or baryta water the alkaloid is hydrolysed to benzoic acid and -tropine. ... 

Evidence that the actual methylation of the anion can be divided into SnI, Eq. (3), and Sx2 types, Eq, (4), is provided by a whole series of investigations. " The terms S l and 8 2 must be taken to mean reactions with, respectively less or greater nucleophilic participation of the anion in the transition state. The importance of oriented ion pairs" in the solvents of low polarity frequently used in reactions involving diazomethanc, e.g., the ions formed by a diazoalkane and benzoic acid in ether, should be emphasized. The expression oriented ion pair means that, because of insufficient solvation, the ions are not individually solvated but exist as ion pairs within a solvent cage. The orientation within the ion pair is defined electrostatically, and this orientation fixes the path for the productdetermining step. Several indications (cf, foo otes 22-24) in the literature indicate the occurrence of carbonium ions and oriented ion pairs in Broensted-type equilibria of the type of Eq. (2). 

In a variation of the scheme above, alkylation of p-hydroxy-benzoic acid with cyclohexyl iodide affords the cyclohexyl ether, 55. (Under alkaline reaction conditions, the ester formed concurrently does not survive the reaction.) Acylation of the acid chloride obtained from 55 with the preformed side chain (56) gives cyclomethycaine (57). ... 

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chlonoformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

An alcohol-free solution of diazomethane in ether is prepared as in Chapter 17, Section III. This solution is approximately 0.5 M in diazomethane and may be standardized by titration as follows benzoic acid (0.6 g, approx. 0.005 mole) is weighed accurately into an Erlenmeyer flask and suspended in 5 ml of ether. The diazomethane solution (approx. 5 ml) is added from a buret with swirling, care being taken that an excess of unreacted benzoic acid remains (the yellow color of the diazomethane should be completely discharged). The excess benzoic acid is now titrated with standard 0.2 N sodium hydroxide solution, and the concentration of diazomethane is calculated. 

On oxidation with permanganate of potassium, this phenol ether yields tetramethoxy benzoic acid, C H(OCH3)4COOH, melting at 87°. 

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