Preparation: Acetylation of primary amines is usually carried out with acetic anhydride, (CH3CO)2O, to form acetamides, CH3CONHR. For example, a substituted aniline can act as a nucleophile toward acetic anhydride in a nucleophilic acyl substitution. For acetic anhydride (McMurry: Fig. 21.7) only "half" of the anhydride appears in the acyl product while the other "half" forms a carboxylic acid.
Acetylation in multi-step organic synthesis is often a crucial reaction because it protects bare amino groups from undesired reactions, for example in the synthesis of 2-bromo-4-methyl-aniline, (McMurry: section 25.3). You are (or soon will be) studying reaction schemes involving this protection strategy. A similar scheme is also used to protect the amino groups during peptide synthesis. The protecting reagent in this case is often di-tert-butyl dicarbonate (BOC) that has the structure t-BuO(C=O)2O, (McMurry: section 27.11). As another example we see that in the synthesis of sulfanilamide, plain aniline would have reacted with chlorosulfonic acid as a base and not as a substrate in an electrophilic aromatic substitution reaction (p. 980, top).
In this experiment you will acetylate an unknown aminophenol (abbreviated HOC6H4NH2) and identify the product formed. Review the relevant sections of McMurry as outlined above to aid in your assignment.
Procedure:
Acetylation --Weigh out about 0.10 g of aminophenol and place it in a 3-mL conical vial.
Using a graduated pipet, add 0.300 mL of water and 0.11mL of acetic anhydride. Place a
spin vane in the conical vial, and attach an air condenser. Heat the reaction mixture in a
sand bath at about 115oC with gentle stirring. The conical vial should be
partially buried in the sand so that the vial is nearly at the bottom of the sand bath.
After the solid has dissolved, heat the mixture for an additional 10 minutes to complete
the reaction.
Remove the vial from the sand bath and allow it to cool. When the vial has cooled to the touch, detach the air condenser and remove the spin vane with clean forceps or a magnetic stirring bar. Rinse the spin vane with two to three drops of warm water. Allow the water to drop into the conical vial. Place the conical vial in a small beaker and cool to room temperature. If crystallization has not occurred, scratch the inside of vial with a glass stirring rod to initiate crystallization. Cool the mixture in an ice bath for 15-20 minutes and collect the crystals by vacuum filtration on a Hirsch funnel. Rinse the vial with about 1 mL of ice water and transfer this mixture to a Hirsch funnel. Wash the crystals on the funnel with two additional 0.5 ml portions of ice water. Dry the crystals for 5-10 minutes by allowing air to be drawn through them while they remain on the Hirsch funnel. Transfer the product to a watch glass and allow the crystals to dry in the air. It may take several hours for the crystals to dry completely, but you may go on to the next step before they are totally dry. Weigh the crude product and set aside a small sample for a melting point determination. Record the appearance of the crystals in your laboratory book.
Purification of the Product--Crystallize the crude product from a solvent mixture composed of 50% water and 50% methanol by volume. The crystallization is performed in a Craig tube (see Mayo, et. al. p. 135). The solubility of the product in this hot (nearly boiling) solvent is about 0.2 g/mL. To avoid adding too much solvent, add small portions (several drops) of hot solvent until the solid just completely dissolves in the boiling solvent. When the solid has dissolved, place the Craig tube in a 10-ml Erlenmeyer flask, insert the inner plug, and allow the solution to cool slowly.
When the mixture has cooled to room temperature, place the Craig tube in an ice-water bath for several minutes. If necessary induce crystallization. Place the Craig tube into a centrifuge tube. Place the assembly in a centrifuge. Balance the assembly with a centrifuge tube filled with water so that both tubes have the same mass. (Caution -- Do not use setting on the centrifuge greater than 5.) Turn on the centrifuge tube for several minutes. Collect the crystals on a watch glass and set them aside to air-dry. Very little time should be needed until they are dry.
Weigh the purified product and calculate the percentage yield (Reaction Table) based on the aminophenol and acetic anhydride used. Compare the color of the final product to that of the crude product. Identify your unknown using appropriate technique(s). Fully interpret your findings in the discussion section of your notebook.
Place your product into a plastic bag, seal it, and staple it to a page in your laboratory book.
Question:
1. What is the chemical structure of acetaminophen? What is the common use of this substance?
2. Write a mechanism for the formation of acetaminophen using the methodology of this experiment.
Reference:
"M&B": Morrison, R.T., and Boyd, R.N. Organic Chemistry, 6th ed.,
Prentice Hall: Englewood Cliffs, NJ, 1992
Revised by Shane Phillips on 1/22/98.