ORG1 Syntheses of Acetaminophen and Aspirin

Transcription

1 RG1 Syntheses of Acetaminophen and Aspirin Estimated Time Required: 60 minutes Introduction Ethanoylation (better known as acetylation) is the introduction of an acetyl functional group onto a suitable nucleophile. As a common moiety in many syntheses, acetyls can be used as a protecting group, intermediate, or may be part of a final target (Figure 1b), a) H b) H H H Figure 1. a) acetyl protected glucose. b) the C and D rings of Taxol, a natural product and cancer therapeutic. H Acetylation can proceed by both acid and base catalyzed pathways as seen below (Scheme 1). The left pathway below shows the use of a non-nucleophilic base to deprotonate the oxygen of phenol. Acetic anhydride then undergoes a nucleophilic attack by the phenolic anion, forming a tetrahedral intermediate before the acetate anion is eliminated. This results in formation of the phenyl acetate product. The pathway on the right demonstrates the acid catalyzed acetylation pathway. First, protonation of acetic anhydride activates the carbonyl carbon for a nucleophilic attack by phenol. Following formation of a tetrahedral intermediate, proton transfer causes elimination of acetic acid, while subsequent deprotonation forms the phenyl acetate product. B H H + H H tetrahedral intermediate tetrahedral intermediate H H H + transfer H + H H H H Scheme 1. Base (left) and acid (right) catalyzed acetylation of phenol with acetic anhydride. In this experiment, acetic anhydride is used to acetylate different starting materials resulting in two common analgesic compounds, acetaminophen (Tylenol) and acetylsalicylic acid (aspirin). Microwave heating allows these reactions to be performed in only minutes while maintaining good yields.

2 Experimental Draw reaction scheme below: Reagent CAS MW (g/mol) Density (g/ml) Equivalents mmol Amount 4-aminophenol 2.75 acetic anhydride 2.89 water 0.55 M Note: The concentration of the solution with respect to the limiting reagent is given under the mmol column for water. Product CAS MW (g/mol) mmol Theo. Yield N-(4-hydroxyphenyl)acetamide 2.75 Required equipment: Discover microwave synthesizer 10-mL glass microwave reaction vessel small stir bar microwave vessel cap 25-mL Erlenmeyer flask ice bath glass stirring rod vacuum filtration assembly Procedure: 1) Weigh g of 4-aminophenol and place it into a 10-mL microwave reaction vessel with stir bar. 2) Add 5.00 ml of deionized water to the reaction vial, washing down any 4-aminophenol stuck to the sides of the vessel. 3) To this solution, add ml of acetic anhydride and seal the vessel with a cap. 4) Place the sealed vessel into the microwave cavity and heat the reaction mixture using a standard method to 110 C with 300 W for a one-minute hold time. 5) After the reaction is complete, transfer the solution to a small flask then place it in an ice bath until crystals form. Scratch the sides of the flask to promote crystallization, allowing it to sit in an ice bath for at least 15 minutes after crystals form. 6) Vacuum filter the resultant crystals and wash them with cold water. Let the crystals dry thoroughly before recording the mass of acetaminophen product. Calculate the percent yield of product and perform a melting point (lit: C) analysis to confirm purity; NMR (DMS-d 6 ) and IR analysis can be performed, if available.

3 Experimental Draw reaction scheme below: Reagent CAS MW (g/mol) Density (g/ml) Equivalents mmol Amount 2-hydroxybenzoic acid 3.62 acetic anhydride 5.43 Product CAS MW (g/mol) mmol Theo. Yield 2-acetoxybenzoic acid 3.62 Required equipment: Discover microwave synthesizer 10-mL glass microwave reaction vessel small stir bar microwave vessel cap 25-mL Erlenmeyer flask ice bath glass stirring rod vacuum filtration assembly Procedure: 1) Weigh g of salicylic acid and place it into a 10-mL microwave reaction vessel with stir bar. 2) Add 1.00 ml of acetic anhydride to the reaction vial and seal the vessel with a cap. 3) Place the sealed vessel into the microwave cavity and heat the reaction mixture using a standard two-stage method to 80 C for 10 seconds and 130 C for a one minute hold time using 200W of power. 4) After the reaction is complete, transfer the solution to a small flask and dilute it with 2 ml of ice water. Transfer the flask to an ice bath and scratch the sides of the beaker to promote crystallization, allowing it to sit in an ice bath for at least 15 minutes after crystals form. 5) Vacuum filter the resultant white aspirin crystals washing with cold water. 6) Recrystallize the aspirin from hot deionized water, adding a few drops of ethanol if the aspirin product does not go into solution. Collect the recrystallized aspirin by vacuum filtration, allowing the crystals to dry over vacuum before recording the mass. Calculate the percent yield of product and perform a melting point (lit: C) analysis to confirm purity; NMR (CDCl 3 ) and IR analysis can be performed, if available. Qualitative analysis for salicylic acid: In a test tube, dissolve a few crystals of your final product in some ethanol. Add a couple of drops of aqueous 1% iron(iii) chloride solution (or a few grains of iron(iii) chloride hexahydrate) to your sample

4 and note the color of the solution. Add a few grains of salicylic acid to the same test tube and note any changes to the color of the solution. Results and Discussion 1) In the above experiment, why does acetylation NT take place at the positions indicated? Explain. NH 2 H H H 2) The following NMR spectra show the acetaminophen product and an unwanted by-product. What is the byproduct and how did it form?

5 Acetaminophen X : parts per million : 1 H By-product X : parts per million : 1 H

6 3) Water is not used in the acetylation of salicylic acid. Why not? Conclusions 1) How would you make the compound below? NH 2 2) What would you do to prevent the formation of the by-product in 2) above?