Acetylation of a Hydroxyl Group: Acetylsalicylic Acid (Aspirin) from Salicylic Acid
Introduction
An acetyl group is a methyl group bonded to a carbonyl group. It is a special case of an acyl group, which is any R group bonded to a carbonyl group. Figure 1 shows the structures of several acyl groups, including the acetyl group.
Figure 1. Acyl groups.
The name of an acyl group is derived from the corresponding carboxylic acid. The acetyl group is found in acetic acid. The name acetyl is derived from acetic by changing the ic in acetic to yl in acetyl. Both acetic and acetyl are common names. Likewise, the IUPAC name ethanoic acid is changed to ethanoyl by changing the ic in ethanoic to yl in ethanoyl. Figure 2 shows the relationships between the name and structure of the acid and the acyl group.
Figure 2. Common and IUPAC nomenclature.
Acyl groups are found in carboxylic acids and acid derivatives. Acid halides get their names from the acyl group. Figure 3 shows the structures and names of some common acyl chlorides.
Figure 3. Acyl chlorides.
Acid anhydrides or simply anhydrides are acid derivatives that contain two acyl group joined by an oxygen atom. When carboxylic acids are pyrolyzed (i.e., heated strongly), they produce acid anhydrides by a condensation reaction (overall loss of water from two molecules). Figure 4 shows the equation for the reaction that produces acetic anhydride from acetic acid.
Figure 4. Acetic anhydride from acetic acid.
The name of an anhydride is the name of the acid from which it is derived followed by anhydride. For example, acetic anhydride is the anhydride from acetic acid, and propanoic anhydride is the anhydride from propanoic acid.
When an acyl group is transferred from one chemical species to another, the reaction is referred to as an acylation reaction. The Friedel-Crafts acylation reaction is an example of such a reaction applied to arenes.
Acid halides and anhydrides are useful as reagents for transferring an acyl group to a heteroatom in another organic compound. The groups shown in black in Figures 3 and 4 are acyl groups that can be transferred in acylation reactions. Later, we shall consider the acylation of a nitrogen atom of an amine. Now, we shall consider the acylation of an oxygen atom in a hydroxyl group found in either an alcohol or phenol. Figure 5 shows the structures of alcohols and phenols. A phenol contains a hydroxyl group directly bonded to an arene ring such as benzene. An alcohol contains a hydroxyl group bonded to a non-aromatic carbon atom, normally an sp3-hybridized carbon atom.
Figure 5. Phenols and alcohols.
The acylation of a hydroxyl group of either a phenol or an alcohol may be accomplished by the use of either an acid halide (Figure 3) or an acid anhydride (Figure 4). Figure 6 shows examples of acylation reactions in which the acyl group is the acetyl group. Such reactions are called acetylation reactions. These reactions involve the transfer of an acetyl acyl group to an oxygen atom (i.e., the substitution of an acetyl group for an H atom bonded to oxygen). When alcohols or phenols are acylated, the products are esters, which are derivatives of carboxylic acids. When alcohols or phenols are acylated with acetyl chloride or acetic anhydride, the ester is an acetate ester, because the acid from which the ester is derived is acetic acid. Thus, the use of acetic anhydride or acetyl chloride is a good way to convert an alcohol or phenol to an acetate ester.
Figure 6. Acetylation reactions.
Mechanism of Acetylation
Figure 7 shows the mechanism for the acetylation of ethanol by acetyl chloride.
Figure 7. Mechanism of acetylation of an alcohol with acetyl chloride.
In Step 1, a pair of non-bonded electrons from the alcohol oxygen atom forms a bond with the carbonyl group of the acid chloride. In Step 2, the proton moves from one oxygen atom to the other, changing the di-ion into an uncharged molecule. Note, the combination of Steps 1 and 2 is an addition reaction that you might predict for a carbonyl group. The product of Step 2 is a hemiacetal (i.e., a carbon is bonded to two oxygen atoms; one oxygen atom is in a hydroxyl group and the other is an ether). The hemiacetal reforms the carbonyl group in Step 3 with the loss of the chloride ion. The intermediate product of Step 3 is deprotonated by the chloride ion to produce the acetate ester and hydrogen chloride.
The mechanism of an acetylation by acetic anhydride is very similar to the mechanism shown in Figure 6. The difference is that the leaving group is the acetate ion instead of the chloride ion, and the byproduct of the overall reaction is acetic acid instead of hydrochloric acid. The product is acetylated (i.e., it now has an acetyl group that it did not have before), and the product is an acetate ester.
The Experimental Reaction
Salicylic acid is o-hydroxybenzoic acid; it is a phenol and a carboxylic acid because it contains a hydroxyl group bonded to an arene and a carboxyl group. The hydroxyl group can be acylated by acetic anhydride to convert the hydroxyl group into an acetate ester. The acid group remains unchanged. Thus, salicylic acid becomes acetylsalicylic acid. Figure 8 shows the equation for the reaction you will perform in the lab. Acetylsalicylic acid is also known by the common name of aspirin.
Figure 8. Acetylation of salicylic acid.
Procedure
1. Prepare a hot-water bath by adding about 50-mL tap water to a 100-mL beaker and warm the beaker to about 90 oC on a hot plate.
2. Weigh 0.14-g salicylic acid on a creased weighing paper, record the exact mass in your lab notebook, and transfer the solid into a small test tube.
3. Add one drop of 85% phosphoric acid (H3PO4) and six drops of acetic anhydride to the test tube containing the salicylic acid.
4. Thoroughly mix the contents of the test tube and add a tiny boiling chip to the test tube.
5. Immerse the test tube in the hot-water bath at about 90 oC for five minutes.
6. Remove the test tube from the hot-water bath and carefully add 10 drops of water to hydrolyze any un-reacted acetic anhydride to water-soluble acetic acid.
The hydrolysis reaction is an exothermic reaction.
7. Allow the test tube to cool to room temperature and then place it in an ice-water bath and leave it there until crystallization of acetylsalicylic acid is complete (i.e., you do not observe the formation of new crystals).
8. Collect the crystals on a Hirsh funnel.
9. Weigh the dry crystals and show them to the instructor who will tell you what to do next.
10. Clean and return all equipment to their storage locations. Check the balance area. Turn off all balances and return any chemicals to their original locations.
Questions O-Acylation
Student last name_________________________, First name_______________________
1. Write a general equation for the preparation of an acid anhydride from a carboxylic acid.
2. Write an equation for the hydrolysis of acetic anhydride.
3. Write an equation for the reaction between p-chlorophenol and acetyl chloride.
4. Write an equation for the reaction between benzyl alcohol and acetic anhydride.
5. Draw the structures of each of the following groups: isobutyl group, butyl group, t-butyl group, and sec-butyl group.
6. When a member of either the alcohol or phenol family of compounds is acylated, what family of organic compounds is formed? ________________
7. Write an equation for the preparation of phenyl acetate, starting with phenol.
8. Write an equation for the acetylation of ethanol and name the products.
9. Why must acetyl chloride and acetic anhydride be stored in a water-free environment?
10. Show the mechanism for the acetylation of salicylic acid with acetic anhydride.
6
Lab 6