4 - acetanilide

When this is boiled for some time water is lost and acetanilide is obtained. 

This reaction is analogous to the formation of acetamide from ammonium acetate by the loss of water (p. 145). 

The anilide is better prepared by the ordinary method of introducing the acetyl group, viz., by using acetyl chloride or acetic anhydride. 

This reaction is also analogous to the one between ammonia and acetyl chloride by which acetamide is formed. 

Antifebrin.— Acetanilide is a common medicinal substance much used as a fever reducer under the name of antifebrin. It is a solid, crystallizing in glistening plates melting point 112°. It is slightly soluble in cold water, readily in hot water. Though not an ester it easily hydrolyzes reforming aniline and acetic acid. Other known anilides formed from aniline and formic acid, oxalic acid and benzoic 

The following sections shall exclusively deal with the elaborated syntheses of certain medicinal compounds prepared by using the acetylation methods, such as Acetanilide, Acetylsalicylic acid (Aspirin) Acetylacetone Phenacetin, Acetylcysteine and Paracetamol. 

1 (Method-I). It is prepared from aniline, acetic anhydride, sodium acetate and concentrated hydrochloric acid (12 N). 

The freshly redistilled aniline, is almost a colourless oily liquid which being practically insoluble in water. Therefore, before carrying out the acetylation aniline has got to be made soluble in the aqueous medium. It can be accomplished by adding requisite amormt of concentrated HCl whereby the highly reactive amino function easily takes up a proton from the dissociation of HCl in water, get protonated to yield aniline hydrochloride that is water-soluble. Subsequently, the soluble form of aniline is reacted with acetic anhydride in the presence of sodium acetate. The acetate ion obtained from the hydrolysis of the salt (sodium acetate) helps to sustain the acetylation reaction in the forward direction to 3ueld acetanilide completely. 

3 Chemicals Required, (i) Aniline 10 ml (Freshly redistilled to have almost a colourless product) iii) Acetic anhydride 13 ml Hi) Sodium acetate (crystalline) 16.5 g and (iv) Concentrated Hydrochloric acid (12 N) 9 ml. 

Always use finshly redistilled aniline to obtain better product and also proper yield. 

Mono-substitution products of primary amines cannot easUy be prepared by direct action of the appropriate reagent for example, bromination of aniline yields largely the 2 4 6-tribomo derivative and nitration results in much oxidation. If, however, the amino group is protected as in acetanilide, smooth substitution occurs. Thus with bromine, p-bromoacetanilide is the main product the small quantity of the ortho isomeride simultaneously formed can be easily eliminated by crystallisation. Hydrolysis of p-bromoacetanilide gives p-bromoaniline  

Nitration leads similarly to p-nitroacetanilide, which can be hydrolysed to p-nitroaniline  

Method 2. In a 500 ml. round-bottomed flask, equipped with a reflux condenser, place 20-5 g. (20 ml.) of aniline, 21 -5 g. (20 ml.) of acetic anhydride, 21 g. (20 ml.) of glacial acetic acid, and 01 g. of zinc dust (1). Boil the mixture gently for 30 minutes, and then pour the hot liquid in a thin stream into a 1 litre beaker containing 500 ml. of cold water whilst stirring continually. When cold (it is preferable to cool in ice), filter the crude product at the pump, wash with a little cold water, drain well and dry upon filter paper in the air. The yield of acetanilide, m.p. 113°, is 30 g. It may be recrystallised as in Method 1 affording 21 g. of pure acetanilide, m.p. 114°. 

Method 3. Fit up the apparatus shown in Fig. 7F, 45, 1 using a 250-ml. round-bottomed flask. Do not pass water through the glass jacket since the condenser will be employed only as an air condenser the empty filter flask is used merely as a trap to prevent the escape of vapours into 

Boil a mixture of 10 g. (10 ml.) of o-toluidine and 38 g. (35 ml.) of acetic anhydride in a 75 or 100 ml. Claisen flask fitted with a reflux condenser (Fig. Ill, 28,1, but with trap replaced by a calcium chloride or cotton wool guard tube) for 1 hour. Arrange the flask for distillation under reduced pressure (compare Fig. II, 20,1) and distil acetic acid and the excess of acetic anhydride pass over first, followed by the diacetyl derivative at 162-163°/20 mm. some mono-acetyl-o-toluidine (1-2 g.) remains in the flask. The yield of diacetyl-o-toluidine is 14-15 g. it is a colourless, somewhat unstable liquid, which slowly solidifies to yield crystals, m.p. 18°. 

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White crystals, m.p. 114" C. Manufactured by reacting aniline with excess ethanoic acid or ethanoic anhydride. Chief use is in the manufacture of dye intermediates such as p-nitro-acetanilide, p-nitroaniline and p-phenylene-diamine, in the manufacture of rubber, and as a peroxide stabilizer. 

On acetylation it gives acetanilide. Nitrated with some decomposition to a mixture of 2-and 4-nitroanilines. It is basic and gives water-soluble salts with mineral acids. Heating aniline sulphate at 190 C gives sulphanilic add. When heated with alkyl chlorides or aliphatic alcohols mono- and di-alkyl derivatives are obtained, e.g. dimethylaniline. Treatment with trichloroethylene gives phenylglycine. With glycerol and sulphuric acid (Skraup s reaction) quinoline is obtained, while quinaldine can be prepared by the reaction between aniline, paraldehyde and hydrochloric acid. 

CLOGP calculations on benzyl bromide and o-methyl acetanilide. 

Acetanilide (Semi-micro Scale) (1/40 of above scale). 

Hydrolysis of Acetanilide. Anilides in general, such as acetanilide and benzanilide (p. 245), may be hydrolysed by caustic alkalis or by acids. Alkaline hydrolysis, however, is usually very slow, and therefore... 

Place I g. of acetanilide and 10 ml. of the 70% sulphuric acid in a small flask fitted with a reflux water-condenser, and boil the mixture gently for 15 minutes, when the hot solution will smell perceptibly of... 

Acetanilide also undergoes ready bromination, with the formation of a mixture of o- and /(-bromoacetanilidc. The ortho compound is formed in only... 

Dissolve I g. of finely powdered acetanilide in 5 ml. of cold glacial acetic acid contained in a 25 ml. conical flask. Then in another small flask prepare a solution of 0 42 ml. (1 34 g.) of bromine (care ) in 6 ml. of glacial acetic acid, and add this solution slowly to the acetanilide solution, shaking the latter throughout the addition to ensure thorough mixing. Allow the final mixture to stand at room temperature for 15 minutes. Then... 

Required Acetanilide, 10 g. acetic acid, 10 ml. sulphuric acid, 20 ml. fuming nitric acid, 4 ml. 

Hydrolysis to p-Nitroaniline. For this purpose use 70 sulphuric acid, the usual reagent employed for the hydrolysis of anilides (p. 108). Add 5 g. of the recrystallised />-nitro-acetanilide to 30 ml. of 70%sulphuric acid, and boil the mixture gently under a reflux water-condenser for 20 minutes. Then pour the clear hot solution into about 150 ml. of cold water, and finally add an excess of sodium hydroxide solution until precipitation of the yellow p-nitroaniline is complete. Coo the mixture in ice-water if necessary, and then filter at the pump, wash well... 

Sulphanilamide, the simplest member of a large series of bacteriostatic drugs, can readily be prepared by the following reactions. Acetanilide, when treated v ith an excess of chlorosulphonic acid, gives p-acetaniidobenzencsulphonyl chloride (Reaction A), w hich readily reacts with ammonia to give p-acetamido-benzenesulphonamide (Reaction H). The acetamido-group in the latter... 

Hydrolysis of Benzanilide. For this hydrolysis, it is necessary to use 70% sulphuric acid (see Hydrolysis of Acetanilide, p. 108). Add I g. of benzanilide to 10 ml. of 70% sulphuric acid, and boil the mixture gently in a small flask under a reflux water-condenser for 30 minutes. Hydrolysis will now be complete, but much of the benzoic acid will have vaporised in the steam and then solidified in the conden-... 

The mixed bases are boiled with an acetic acid-acetic anhydride mixture to convert the aniline into acetanilide. The product is poured into water, when the acetanilide crystallises out while the quinoline remains in solution as quinoline acetate. The acetanilide is filtered off, and the filtrate made alkaline and steam-distilled. 

Ammonium acetate CH3COONH4 Acetamide CH CONHj Acetonitrile CH CN Phthalimide C,H,(CO),NU Acetanilide C H,NHCOCH,... 

Anilides, (a) To 1 ml. of aniline in a small conical flask add very slowly and carefully about i ml. of acetyl chloride. A vigorous reaction occurs and a solid mass is formed. Add just sufficient water (about 15 ml.) to dissolve the solid completely on boiling. On cooling, crystals of acetanilide separate out filter and determine the m.p. 

Acetanilide, benzanilide and their nuclear- and N-substituted derivatives. 

Physical Properties All colourless odourless crystalline solids. Acetanilide,CH3CONHCflH5,andbenzanilide,C,H6CONHCeH6 are both sparingly soluble in cold water, but acetanilide has the greater solubility in hot water. 

DETERMINATION OF MOLECULAR WEIGHT OF A GIVEN SUBSTANCE, e.g., ACETANILIDE, using the above Molecular Depression Constant of Camphor. 

Proceed precisely as in (2), but use pure powdered acetanilide instead of naphthalene. 

Vrocttd precisely as in the Determination of the Number of Hydroxyl Groups in Phenol, except that after weighing the flask A, run in about i ml. of pure aniline, and weigh again. Then continue exactly as before. The acetanilide which is formed usually remains in solution when the contents of the flask A are diluted with water for hydrolysis. 

Cool the flasks in cold water, and then titrate the contents of each with /i/.t a()H solution, using phenolphthalein as an indicator. Shake the contents of the flask A repeatedly during the titration in order to keep the fine crystals of acetanilide dispersed in the aqueous solution. 

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