(04:141) Experiment #4

Synthesis of Acetaminophen and Analysis of Some Common

Analgesics

Background

In this experiment, p-acetamidophenol (acetaminophen) will be prepared from p-

aminophenol by reaction with acetic anhydride. Note that p-aminophenol is a bifunctional

compound, containing both a phenol and an amine, and that both of these groups can participate

to form either an ester or an amide. Under these conditions, however, only the amide is isolated.

Once prepared, the synthetic p-aminophenol will be analyzed qualitatively by TLC. The

product will be compared with commercial acetaminophen and a series of other analgesics, and

this information will be used to determine the active component(s) of several unknowns.

Acetaminophen

p-Aminophenol

NH2

O O

OHO

CH3

H3C

Procedure

A. Synthesis of Acetaminophen

Place 2.1 g p-aminophenol (Caution: avoid contact, it’s a sensitizer) and 35 mL water in a

125-mL Erlenmeyer flask. Add concentrated hydrochloric acid dropwise with frequent swirling

until the p-aminophenol dissolves completely. (Caution: Do not add too much conc. HCl.

Why?) Add a spatula tip-ful of decolorizing charcoal to the solution, swirl the solution in a hot

water bath for a few minutes, and remove the charcoal by gravity filtration. Use a FLUTED filter

paper (Zubrick p. 136).

Prepare a solution for use as a buffer by dissolving 2.5 g sodium acetate in 7.5 mL of

water and clarify the solution by gravity filtration. Use a FLUTED filter paper (Zubrick p. 136).

Transfer the filtered p-aminophenol hydrochloride solution to a 125-mL Erlenmeyer flask

and warm in a hot water bath for a few minutes. Add the sodium acetate solution in one portion.

Immediately add 2 mL of acetic anhydride while swirling the solution on the hot water bath. Stir

with a magnetic stir bar in the hot water bath for 10 minutes to ensure reaction.

Cool the reaction mixture by immersing the flask in an ice-water bath, and stir the mixture

with the magnetic stir bar (on a cool stir plate) until crude acetaminophen crystallizes. Allow the

flask to sit in the ice bath for about 20 minutes. Once crystallization is complete, collect the

crude product by vacuum filtration using a Hirsch or a Büchner funnel. Using 1 mL or less ice

cold water, wash the remaining solids out of the flask. After filtration is complete, dry your

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Synthesis of Acetaminophen and Analysis of Some Common

Analgesics

Background

In this experiment, p-acetamidophenol (acetaminophen) will be prepared from p- aminophenol by reaction with acetic anhydride. Note that p-aminophenol is a bifunctional compound, containing both a phenol and an amine, and that both of these groups can participate to form either an ester or an amide. Under these conditions, however, only the amide is isolated. Once prepared, the synthetic p-aminophenol will be analyzed qualitatively by TLC. The product will be compared with commercial acetaminophen and a series of other analgesics, and this information will be used to determine the active component(s) of several unknowns. p-Aminophenol Acetaminophen

NH 2 HO O O O HO NH O CH 3 H 3 C CH 3

Procedure

A. Synthesis of Acetaminophen Place 2.1 g p-aminophenol (Caution: avoid contact, it’s a sensitizer) and 35 mL water in a 125-mL Erlenmeyer flask. Add concentrated hydrochloric acid dropwise with frequent swirling until the p-aminophenol dissolves completely. (Caution: Do not add too much conc. HCl. Why?) Add a spatula tip-ful of decolorizing charcoal to the solution, swirl the solution in a hot water bath for a few minutes, and remove the charcoal by gravity filtration. Use a FLUTED filter paper (Zubrick p. 136). Prepare a solution for use as a buffer by dissolving 2.5 g sodium acetate in 7.5 mL of water and clarify the solution by gravity filtration. Use a FLUTED filter paper (Zubrick p. 136). Transfer the filtered p-aminophenol hydrochloride solution to a 125-mL Erlenmeyer flask and warm in a hot water bath for a few minutes. Add the sodium acetate solution in one portion. Immediately add 2 mL of acetic anhydride while swirling the solution on the hot water bath. Stir with a magnetic stir bar in the hot water bath for 10 minutes to ensure reaction. Cool the reaction mixture by immersing the flask in an ice-water bath, and stir the mixture with the magnetic stir bar (on a cool stir plate) until crude acetaminophen crystallizes. Allow the flask to sit in the ice bath for about 20 minutes. Once crystallization is complete, collect the crude product by vacuum filtration using a Hirsch or a Büchner funnel. Using 1 mL or less ice cold water, wash the remaining solids out of the flask. After filtration is complete, dry your

crystals by continuing to apply a vacuum and gently scraping them with a spatula. Record the weight of your crude product, and its melting point. B. Recrystallization of Acetaminophen Add about 0.5 g of your crude product to a large test tube. Be sure you have enough left over (at least 5-10 crystals) for use later in TLC analysis. Add boiling water drop wise to your product while heating it in the hot water bath. Swirl the tube often to help dissolve the solid. Too much solvent will markedly reduce your recovery of acetaminophen. Once your solid has dissolved, allow the solution to cool slowly to room temperature. Do not shake or stir the test tube while crystals are forming. Do not touch it to a cool surface (like the lab bench). When crystallization is complete at room temperature, cool the mixture further in an ice bath. Collect the product by vacuum filtration using your Buchner funnel, and wash the collected crystals over vacuum with ~0.5 mL ice cold water. Record the weight of your recrystallized product, and obtain a melting point and an IR (use mineral oil; be sure you have a mineral oil standard). Save a few crystals of recrystallized product for TLC, and prepare an NMR sample. C. TLC Analysis of Analgesic Drugs

TLC Analysis of Active Ingredients In separate test tubes, dissolve approximately 10 mg (exact weights are unimportant) of the following compounds in 1 mL dichloromethane: your crude acetaminophen, your recrystallized acetaminophen, p-aminophenol, aspirin, and caffeine. Run a TLC of the crude acetaminophen, recrystallized acetaminophen, and p-aminophenol using ethyl acetate (EtOAc) to develop the plate. Allow sufficient time for the solvent to evaporate, then visualize the plate first using UV light, then in an I 2 chamber (note the order). Circle the spots with a pencil, using a solid line for the UV visualization and a dashed line for the I 2. Record this information in your notebook. Identify the spots observed, and calculate their Rf values. Run a TLC of your recrystallized acetaminophen, aspirin, caffeine, and a reference sample (available in the lab) containing all three of these compounds. Elute with EtOAc, then repeat using CH 2 Cl 2 as the eluting solvent. Visualize the plates as before, being sure to record your observations. Note the effect of eluant polarity on Rf, as well as any variation in the shapes of the spots (i.e., tailing, elongation, etc.).
Evaluation of Commercial Analgesics and Unknowns Obtain two of the commercial analgesics available in the laboratory. Transfer the powders into separate small test tube and dissolve it in about 2 mL of CH 3 OH. You may need to heat the tube slightly in warm water. Since these tablets usually contain inert ingredients such as starch binders and inorganic buffering agents, not all of your tablet will dissolve. Allow the sample to cool and settle before running your TLC. Run a TLC of your reference solution (from

Name: Section: ID #: Date: Acetaminophen:

Crude Acetaminophen (g): _______ 4) Amount Recovered (g):
% Yield (crude): 5) Percent Recovery:
Amount Recrystallized (g): 6) Purified Percent Yield: TLC of Analgesics: Rf value(s) TLC plate drawing: p-aminophenol crude acetaminophen recrystallized acetaminophen Rf value(s) EtOAc CH 2 Cl 2 aspirin acetaminophen caffeine reference sample Rf value(s) Active Ingredient(s) Identity Tylenol: ___________________ ________________________ n/a Excedrin: ___________________ ________________________ n/a Unknown A: _________ Unknown B: _________

Experiment 4: Synthesis of Acetaminophen and Analysis of Some Common Analgesics, Lab Reports of Organic Chemistry

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Synthesis of Acetaminophen and Analysis of Some Common

Analgesics

Background

Procedure