Synthesis of aspirin without acetic anhydride

Chemicals needed

Acetyl chloride  F C     R 11-14-34    S 9-16-26-45

Methyl tert-butyl ether (MTBE)  F Xi   R 11-36/37/38    S 9-16-26-29-33-36

2-Picolin (α-) Xn    R 10-20/21/22-36/37    S 26-36

Salicylic acid Xn    R 22-36/38    S 22

Sulphuric acid 96 %  C    R 35   S (1/2)-26-30-45

Instead of 2-Picolin one can use pyridine or other methylpyridines. If one uses these purely as solvents, then these substances are often interchangeable, this must, however, be verified in the individual case.

Information concerning dangerous substances

O-Acetylsalicylic acid Xn   R 23/24/25-36/37/38    S 22-26-45-36/37/39

Aspirin is therefore harmful to one's health, according to the Aldrich cataloge even toxic (T)!

Equipment needed

• 25 ml round-bottomed flask
• calcium chloride drying tube (filled witg calcium chloride)
• 50 ml round-bottomed flask
• 100 ml beaker
• glass rod
• 100 ml seperating funnel
• distilling link with a Liebig condensor or corresponding invididual parts or a rotary evaporator
• hot plate with oil or water bath
• funnel and filter paper

Test procedure

• One should provide for ventilation or still better work with an exhaust hood. Especially the vapors of acetyl chloride and picolin are very harmful to your health and exceptionally unpleasant! Safety goggles!
• With a slight external warming one dissolves in a 25 ml round-bottomed flask 1.00 g of salicylic acid(7.2 mmol) into 4-5 ml of 2-Picolin. The clear, yellow solution which is thereby obtained, is if required, allowed to cool off and is then carefully drop for drop mixed with 1.0 ml (d=1.104; MW=78.50 g/mol; about 1.1 g; 14.0 mmol) of acetyl chloride (if any acetyl chloride is spilled it is best to wipe it up with ethanol - with water acetyl chloride reacts rather violently), whereby an intense warming occurs (approximately up to 50 - 60°C). One then puts on a calcium chloride drying tube and lets the reactive mixture stand for at least 1 - 1 1/2 hours.
• The reactive mixture is then poured into approximately 40 ml of distilled water, whereby a nearly colorless solution results, merely a somewhat oily liquid is left behind. Subsequently at least 3 ml of concentrated sulphuric acid is added while stirring(caution!). As a result of mild heating a clear, practically colorless solution is produced.
• After the cooling of the solution two different processing approaches were tried out:
  1. Salting out of the product
  2. Extraction of the product with MTBE
• a) About 1/20 of the solution was mixed with twice the volume of a concentrated NaCl solution (NaCl : H₂O - ca. 1 : 3 - m : m). After a certain latency period pretty crystals slowly formed themselves. Neither yield nor purity were investigated, however, this appears to be a viable approach.
• b) The rest of the solution was shaken up twice with 10 ml MTBE respectively and the combined organic phases were vaporized in a distillation apparatus. This left behind a clear, almost colorless oil, which only in cooling crystallized into a brownish-white crystalline mass. Through recrystallization with distilled water (about 40 mL) quite pretty crystals in a voluminous mass were obtained (let it cool undisturbed!). This was then by washing with a little distilled water filtered out (it would probably have been better to have siphoned it off). Even after drying in free air it still appeared to be markedly fluffy (very low bulk density). Yield 0.73 g (4.0 mmol; based on 19/20 * 1.00 g = 0.95 g salicylic acid: 59 % d. Th.). Melting point: (will be added shortly) (Kofler heating bank).
• Yield calculation: MW(salicylic acid) = 138.12 g/mol; MW (O-acetylsalicylic acid) = 180.16 g/mol.

Disposal

• The watery phases can be disposed of as halogen-free organic waste. Likewise with the evaporated MTBE, or else recycle.The product itself one can either save or dispose of as halogen-free organic waste.
• I cannot recommend that this so derived aspirin be used in self-experiments, particulary as one can easily get this in pharmaceutical quality at any pharmacy!

Elucidation

For the synthesis of acetylsalicylic acid from salicylic, acid acetic anhydride is usually used as an acetylating agent.The increased reactivity of acetyl chloride is basically not needed here. Due to problems in the acquisition of acetic anhydride it is at a minimum of interest to hobby chemists. Picolin serves on the one hand as a solvent, on the other, however, it serves to bind the released hydrogen chloride:

o-C₆H₄(OH)COOH  + CH₃COCl + 2-(CH₃)C₅H₄N  -->  o-C₆H₄(OCOCH₃) + 2-(CH₃)C₅H₄N . HCl

salicylic acid + acetyl chloride + 2-picolin ---> O-acetylsalicylic acid + 2-picolin hydrogen chloride

Photos

Voluminous crystallization of acetylsalicylic acid

Literature

The synthesis was thought of rather spontaneously, still I will at some point try to find a useful reference in the literature.