Salicylic acid, acetylations, acetic anhydride

Acetic anhydride is mainly used to make acetic esters and acetyl salicylic acid (aspirin). 

Various processes involve acetic acid or hydrocarbons as solvents for either acetylation or washing. Normal operation involves the recovery or recycle of acetic acid, any solvent, and the mother liquor. Other methods of preparing aspirin, which are not of commercial significance, involve acetyl chloride and salicylic acid, salicylic acid and acetic anhydride with sulfuric acid as the catalyst, reaction of salicylic acid and ketene, and the reaction of sodium salicylate with acetyl chloride or acetic anhydride. 

Acetic anhydride is often used to prepare acetate esters from alcohols and AT-substituted acetamides from amines. For example, aspirin (acetyl-salicylic acid) is prepared commercially by the acetylation of o-hydroxy-benzoic acid (salicylic acid) with acetic anhydride. Acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts, rather than the less nucleophilic -OH group. 

Aspirin, or acetyl salicylic acid, is synthesized by reacting salicylic acid with acetic anhydride ... 

CONVERSION OF ACID ANHYDRIDES INTO ESTERS Acetic anhydride is often used to prepare acetate esters from alcohols. For example, aspirin (acetyl-salicylic acid) is prepared commercially by the acetylation of o-hydroxy-benzoic acid (salicylic acid) with acetic anhydride. 

It should be emphasised that salicylic acid can be readily acetylated by Method 1, and that the above preparation of acetylsalicyclic acid is given solely as an illustration of Method 2. To employ Method 1, add 10 g. of salicylic acid to 20 ml. of a mixture of equal volumes of acetic anhydride and acetic acid, and boil gently under reflux for 30 minutes. Then pour into about 200 ml. of cold water in order to precipitate the acetylsalicylic acid (11 g.) and finally recrystallise as above. Method 2, however, gives the purer product. 

Acetylation. Boil i g. of salicylic acid with 4 ml. of an acetic anhydride-acetic acid mixture (equal volumes) under reflux for 10 minutes. Pour into water. Filter off the aspirin (p. 111), wash with water and recrystallise from aqueous acetic acid (1 1) m.p. l36 ... 

Phenols, unlike amines, cannot be acetylated satisfactorily in aqueous solution acetylation proceeds readily with acetic anhydride in the presence of a little concentrated sulphuric acid as catalyst. Salicylic acid (o-hydroxy-benzoic acid) upon acetylation yields acetylsalicylic acid or aspirin ... 

The filtrate from this first batch will comprise a solution of 180 to 270 kg of unprecipitated acetylsalicylic acid (1.0 to 1.5 mols), 510 kg of acetic anhydrice (5.0 mols), 600 kg of acetic acid (10.0 mols) (obtained as a by-product in the acetylation step) and 1,200 kg of the diluent toluene. Into this filtrate, at a temperature of 15° to 25°C, ketene gas is now passed through a sparger tube or diffuser plate, with good agitation, until a weight increase of 420.5 kg of ketene (10 mols) occurs. The reaction mixture wiil now contain 180-270 kg of unprecipitated acetylsalicylic acid (1.0-1.5 mols) and 1,532 kg of acetic anhydride (15 mols) in 1,200 kg of toluene. This mother liquor is recycled to the first step of the process for reaction with another batch of 1,382 kg of salicylic acid. On recirculating the mother liquor, the yield of pure acetylsalicylic acid is 1,780 to 1,795 kg per batch. 

Essentially, all methods of synthesis are variations of the reaction of acetylchloride, acetic anhydride or ketene11 with salicylic acid using a variety of catalysts such as pyridine12 or sulfuric acid13 and reaction conditions (c.f. 14). The preparation of aspirin labeled with a i4c iaj-,eie(j acetyl group has also been reported.15 Efforts to improve the commercial processes continue to the present day. 

Aspirin Aspirin, acetylsalicylic acid (3.2.2), is synthesized by the acetylation of salicylic acid (3.2.1) nsing acetic anhydride or acetyl chloride [60-63]. 

Esters of the phenolic hydroxyl are obtained easily by the Schotten-Baumann reaction. The reaction in many cases involves an acid chloride as the acylating agent. However, acylation is achieved more commonly by reaction with an acid anhydride. The single most important commercial reaction of this type is the acetylation of salicylic acid with acetic anhydride to produce acetylsalicylic acid [50-78-2] (aspirin). 

Manufacture. Aspirin [50-78-2] is manufactured by the acetylation of salicylic acid with acetic anhydride (eq. 9) (37,38). 

A number of 5//-l,4-benzodioxepin-ones and -diones have been prepared (72HC(26)319, p. 339). The reaction of the sodium salt of salicylic acid with 2-chloroethanol gave (269) (75BSF(2)277) and treatment of the methyl ester of 2-acetyl-6-chloro-3,5-dimethoxyphenoxyacetic acid with 3M hydrochloric acid gave (270). The dione (271) was prepared by heating 2-carboxy-5,6-dimethoxyphenoxyacetic acid in acetic anhydride and (272) was prepared from chloroacetylsalicylic acid. 

Salicylic acid [69-72-7] - [SALICYLIC ACID AND RELATED COMPOUNDS] pol 21) - [COSMETICS] pol 7) - pENTAL MATERIALS] pol 7) -acetic acid from acetylation of [ACETIC ACID AND DERIVATIVES - ACETIC ACID] pol 1) -acetylation of [ACETIC ACID AND DERIVATIVES - ANHYDRIDE] pol 1) -m antiacne products [COSMETICS] Pol 7) -as antidandruff agent [COSMETICS] Pol 7) -as dye primary pYES AND DYE INTERMEDIATES] pol 8) -as rubber chemical pUBBER CHEMICALS] pol 21) -synthesis of [MICROBIALTRANSFORMATIONS] pol 16) -use as disinfectants piSINFECTANTS AND ANTISEPTICS] pol 8) -m Whitfield s ointment [ANTIPARASITIC AGENTS - ANTIMYCOTICS] pol3)... 

By-product acetic acid is obtained chiefly from partial hydrolysis of cellulose acetate [9004-35-7 /. Lesser amounts are obtained through tke reaction of acetic anhydride and cellulose. Acetylation of salicylic acid [69-72-7] produces one mole of acetic acid per mole of product and the oxidation of ally alcohol using peracetic acid to yield glycerol furnishes by-product acid, but the net yield is low. 

The salicylic aldehyde is heated with sodium acetate and acetic anhydride when the above reaction takes place. The coumaric acid obtained as the sodium salt is then converted into its acetyl derivative. This goes over to the isomeric cis form and by the loss of sodium acetate yields the anhydride coumarin. 

Place 1 g of salicylic acid in each of four 13 x 100-mm test tubes and add to eachtube2 mL of acetic anhydride. To the first tube addO.2 gof anhydrous sodium acetate, note the time, stir with a thermometer, and record the time required for a 4°C rise in temperature. Replace the thermometer and continue to stir occasionally while starting the next acetylation. Obtain a clean thermometer, put it in the second tube, add 5 drops of pyridine, observe as before, and compare with the first results. To the third and fourth tubes add 5 drops of boron trifluoride etherate and 5 drops of concentrated sulfuric acid, respectively. What is the order of activity of the four catalysts as judged by the rates of the reactions ... 

Sulfuryl chloride and magnesium perchlorate have been suggested as acetylation catalysts for starch. Sulfur dioxide in acetic acid/ sulfur trioxide in acetic anhydride, and sulfonated fatty acid or sulfonated salicylic acid in a mixture of acetic anhydride and acetic acid have also been reported to acetylate starch. 

Acetylation. A comparative student experiment with salicylic acid and acetic anhydride demonstrates that common acetylation catalysts fall into the following order of relative effectiveness coned. H2SO4 > boron trifluoride etherate > pyridine > sodium acetate. Although it is a relatively weak catalyst, sodium acetate is completely nondestructive and can be employed in much larger than truly catalytic amounts. An example is the acetylation of furylcarbinol. A mixture of the reactants and solvent benzene was heated on the steam bath with stirring to prevent caking... 

Acetylation of salicylic acid with acetic anhydride yields aspirin. The crude produet may be recrystallized from benzene, mixture of acetie aeid and water (1 1) or various other non-aqueous solvents. 

Salicylic acid is a bifunctional compound, containing both a hydroxyl group and a carboxyl group. The hydroxyl group contains a free pair of electrons which would allow salicylic acid to act as a nucleophile upon a positive source. Such positive sources include the carbonyl carbons of methyl acetate, acetic anhydride, and acetyl chloride. The hydroxyl group would attack the carbonyl carbon of acetic anhydride in the presence of an acid catalyst to give acetylsalicylic acid (aspirin), one of our desired products. The mechanism is as follows ... 

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