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Synthesis of Aspirin

Introduction
Why do chemists make new compounds? One fundamental reason is curiosity, driven by a hunch that a new substance, or series of substances, may yield a rich source of interesting results. Another is chance, coupled with astute observation, where an experiment that went wrong was actually more signicant than the expected results. And compounds are synthesized because they are urgently needed; the industrial and pharmaceutical elds have created signicant chemical compounds in their respective elds. Many modern drug discoveries are the result of a designed synthesis starting from a known natural product. Aspirin1 (C9 H8 O4 , molar mass 180.16) has been used for medicinal purposes for years. This organic compound can be synthesized from salicylic acid2 (C7 H6 O3 , molar mass 138.12) and acetic anhydride (C4 H6 O3 , molar mass 102.09, density 1.082 g mL1 ) by equation 1.
CO2H O O C O CH3 CO2H O H3C C OH

+
OH H3C

H3PO4

+
O O C CH3

(1)

salicylic acid

acetic anhydride

aspirin

acetic acid

1 Listed in newer handbooks as benzoic acid, 2-(acetyloxy)- and in older handbooks as benzoic acid, 2-hydroxy-, acetate or as salicylic acid acetate. It may also be called acetylsalicylic acid in various references. This last name is historically signicant, although now it is not consistent with modern organic nomenclature. 2 Listed in handbooks as benzoic acid, 2-hydroxy-.

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Synthesis of Aspirin

Lab Notebook Preparation


Prepare in advance your lab notebook by writing a (a) lab summary, (b) chemical equation for the synthesis of aspirin, (c) compound table (name of substance, formula weight, melting point for solids/boiling point for liquids), and (d) experimental procedure. You will have to record your mass measurements, observations, product solubility and melting point. You may only use your hand-written procedure in your lab notebook to complete this experiment in lab; the lab manual may not be used.

Experimental Procedure
This experiment is completed over two weeks. During the rst lab period you will synthesize aspirin, recrystallize it and let it air-dry in your lab drawer until the second week. During the second lab period you determine the actual yield, melting point and solubility of aspirin. Obtain a digital thermometer for use during this experiment. Safety Precautions The safety precautions of the reagents used in this experiment are listed below. C4 H6 O3 , acetic anhydride, liquid. Concentrated weak acid. Hydrolyzes in water to form acetic acid. Wash exposed skin or eyes with cold water. Do not ingest. C2 H5 OH, ethyl alcohol, liquid. Flammable solvent. Relatively safe to handle. Do not ingest. C7 H6 O3 , salicylic acid, solid. Relatively safe to handle. Can be irritating if inhaled. Wash exposed skin or eyes with cold water. Do not ingest. H3 PO4 , phosphoric acid, liquid. Concentrated acid. Wash exposed skin or eyes immediately with cold water. Do not ingest. The following safety guidelines must be followed when completing this experiment. Wear safety goggles, a lab apron, and protective gloves. Mel-temps become very hot when taking a melting point of a solid, especially that part of this device which holds the thermometer/thermocouple and melting point capillary. Exercise care when working with a Mel-temp. Ceramic hot plates become very hot when heating reaction mixtures. Do not touch the surface of a hot plate until it has cooled for 10-15 minutes.

Synthesis of Aspirin Any broken glassware should be cleaned up by your TA. Used melting point capillaries must be discarded in the broken glass box.

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Waste disposal - Any liquids/solutions or solid/liquid mixtures generated by this experiment can be discarded down the drain with copious amounts of cold water. Your solid product will be submitted to your TA and evaluated for purity.

Preparing Ice Water Put a 500-mL distilled water bottle (at least half-full) in an ice bath at the beginning of the lab period. This will be used later to induce crystallization and rinse the product. Preparing the Reaction Mixture Prepare a hot water bath by putting a 250-mL beaker with 150-200 mL of water on a hot plate in a fume hood (do not use a Bunsen burner as a source of heat). Heat the water temperature to the range of 90100 C. This water bath is used to heat the reaction mixture. Clean and dry a 25150 mm (large) test tube. Carefully insert the 25150 mm test tube into your 250-mL Erlenmeyer ask, and record the mass (0.001 g) of both test tube and ask. Transfer (do not weigh) about 3 g of salicylic acid into the 25150 mm test tube at the reagent station (a sample has been provided by your TA). Put the large test tube containing the salicylic acid in the 250-mL Erlenmeyer ask and record the combined mass. Subtract the mass of the test tube/ask and record the mass (accurate to 0.001g) of salicylic acid.

Figure 1: Aspirin Reaction Mixture

Have your teaching assistant add 6.00 mL of acetic anhydride directly to the test tube containing the salicylic acid. Add 5 drops of 85% H3 PO4 (which acts as a catalyst) to the reaction mixture. Gently swirl the test tube to mix these reagents.

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Synthesis of Aspirin

While working in the hood put the test tube containing the reaction mixture in the hot water bath and swirl the test tube (by hand) until all reactants have dissolved. After the reactants have dissolved heat the solution for 5-10 minutes. When the solution is nished heating for 5-10 minutes add 3 mL of distilled water (room temperature) dropwise to the reaction mixture while it is still in the water bath. This added water will react with the excess acetic anhydride; do not add the water too quickly or the reaction mixture may spatter. Crystallization Remove the test tube from the water bath and slowly add in small portions 40 mL of ice-cold distilled water to the reaction mixture (some product may form at this time). Cool the reaction mixture to room temperature and, if necessary, gently stir the mixture to induce crystallization. Finally put the mixture in an ice bath for 10 minutes to complete crystallization.

Figure 2: Vacuum Filtration Apparatus

Synthesis of Aspirin Collecting the Product

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Clamp your side-arm ask to the metal lattice at the back of the hood. Put both #2 and #3 rubber lter adapters (see gure 2) on the stem of the Buchner funnel, and seat the funnel in the neck of the side-arm ask (the adapters form a seal between the stem of the funnel and the neck of the ask). Use vacuum tubing to connect the side-arm ask to the vacuum pump in your hood. Put a piece of 5.5 cm lter paper in the funnel, have your TA show you how to turn on the vacuum pump, and wet the entire paper with a small amount of ice-cold distilled water (this ensures that the paper is properly seated in the funnel). Check your rubber policeman (probably attached to your glass stirring rod). If the policeman is old (cracked, sti, or small pieces ake o upon bending) replace it immediately! Using an old policeman in the next step will contaminate your aspirin product! Immediately transfer the product from the test tube to the lter paper using a rubber policeman attached to a stirring rod (a small amount of ice-cold distilled water can be used to facilitate this transfer). Rinse the product with two 10-mL portions of ice-cold distilled water while it is on the lter paper, then let it air dry after the nal rinsing (on the paper with vacuum pump turned on) for 5-10 minutes. Transfer your crude product from the funnel into a weight boat. Recrystallization The crude product will be recrystallized using a mixed-solvent system. This technique typically uses two solvents, where the product is soluble in one solvent but not the other. Aspirin is much more soluble in ethyl alcohol than in water. This procedure rst dissolves the aspirin in hot ethyl alcohol; hot water is then added until the rst appearance of solid product, then the system is allowed to cool in an ice bath to allow formation of crystals of aspirin. Prepare a hot water bath in a hood by putting 300-400 mL of deionized water into your 600-mL beaker and setting it on a hot plate. Turn on the hot plate (about 75% maximum setting). The glassware containing either solvents or crude product must be clean to ensure that the crystals that form are not contaminated. Put about 75 mL of distilled water in a 250-mL beaker and set the beaker on the hot plate. Put about 5 mL of ethyl alcohol in a 10-mL graduated cylinder. Transfer your crude product into a clean 125-mL Erlenmeyer ask and put the ask in the water bath. When the temperature of the water bath reaches 70 C reduce the hot plate setting to about 25% maximum. Initially add 2 mL of ethyl alcohol in 0.5-mL increments to the crude aspirin and vigorously stir the mixture with a

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Synthesis of Aspirin

stirring rod after each addition while keeping the ask in the hot water bath. If needed continue adding ethyl alcohol in 0.5-mL aliquots at 45-60 second intervals with stirring until all of the crude aspirin dissolves. The minimum amount of ethyl alcohol should be used; otherwise, reduced yield will result. If too much alcohol is added you will not obtain any product; 5 mL of alcohol is a typical maximum volume. After the aspirin has completely dissolved in the alcohol add hot distilled water in 2-3 mL increments until the rst appearance of aspirin (usually a white, cloudy appearance). Usually 15-20 mL of water is enough; do not add more than 50 mL. Put the 125-mL ask containing the product in an ice bath and allow it to remain undisturbed until the temperature reaches 5 C. Collect the recrystallized product by vacuum ltration then rinse it with two 10-mL portions of ice-cold distilled water while it is on the lter paper, allowing it air dry after the nal rinsing (on the paper with vacuum pump turned on) for 5-10 minutes. Transfer your product into a clean, dry weigh boat and put it in your lab drawer until the next lab period. Characterizing the Product After the product has dried for one week you will complete the following. When you are nished put any remaining aspirin into the container provided. 1. Per cent yield - Weigh the mass of the product and calculate the per cent yield for the reaction. 2. Product purity - Submit a sample of your aspirin, prepared according to your TAs instructions, to determine product purity. 3. Solubility - Determine the solubility of aspirin in water, 6 M HCl, 6 M NaOH and ethyl alcohol. Put a small amount of aspirin (tip of a spatula) in a 16150 mm test tube, add 1 mL (25 drops) of each solvent and stir vigorously for 1 minute using a glass stirring rod. Keep all four tests then record your observations. Categorize the solubility in each solvent as s for soluble, sls for slightly soluble or i for insoluble. 4. Melting point - Record a literature or web site melting point of aspirin. Then record your aspirins melting point range using a Mel-Temp apparatus (instructions given below). The melting point of your sample and two others can be determined simultaneously. Discard your used melting point capillary in a glass disposal box.

Synthesis of Aspirin Melting Point Determination

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The instructions for packing a melting point capillary and operating a Mel-Temp device are given on p. 48 in the Techniques section of the lab manual. A digital thermometer is used with the Mel-Temp to eliminate lacerations and exposure to mercury resulting from breakage of traditional glass thermometers. You only need to put a very small sample of aspirin in the melting point capillary as shown in the accompanying gure. This is needed to ensure a small melting point range, which should increase the accuracy of the melting point. Each Mel-Temp apparatus can accommodate three solid samples at one time, so the melting points of three samples can be determined simultaneously. When you are nished determining the melting point of your aspirin give the used capillary to your TA for appropriate disposal.

solid sample

CAUTION: Please turn o the Mel-Temp when you are nished! Skin burns can occur from Mel-Temps that have not been turned o. Percent Yield The percent (%) yield is determined as follows: %yield = actual yield of product 100 theoretical yield of product
!

The actual yield of product is the weight of dry aspirin. The theoretical yield is the weight of aspirin obtained when all the limiting reagent reacts to form the product. We also assume that none of the product is lost in the subsequent ltration and recrystallization procedures for theoretical yield. The limiting reagent must be determined from between the amounts of the reactants salicyclic acid and acetic anhydride used in the experiment. To determine the limiting reagent, calculate the mol/C value for each reactant, where mol is the experimental number of moles and C is the coecient from the balanced reaction (p. 135). The reactant whose mol/C value is smaller is the limiting reagent.

142 Heat of Reaction

Synthesis of Aspirin

Table 1 lists the standard heats of formation H f and free energy G f for the substances used to prepare aspirin in Equation (1).

Table 1: Standard Heats of Formation Substance salicylic acid acetic anhydride aspirin acetic acid molar mass 138.12 102.09 180.16 60.05 density 1.44 1.08 1.049 H f -478.86 -760.45 -671.58 -434.88 G f -378.06 -637.94 -526.6 -377.95

Thermodynamic data in kJ mol1 calculated using CS ChemBioDraw Ultra, version 12.0.3; CambridgeSoft Corporation: Cambridge, MA, 2010. Determine the standard heat of reaction H r for equation (1), where the standard heat for a reaction is calculated as follows: H r =
X

n H f (products)

where n represents the number of moles of a given substance in the reaction. The standard heat of reaction H r is based on using one mole of both reactants (and producing one mole of products) at standard conditions for this synthesis. When you completed the experiment in lab you used much less than one mole of reactants, so any change in heat q for this reaction (which is not completed at standard conditions) will be much less. Use your number of moles of limiting reagent for this reaction to determine the heat of reaction q for the synthesis of aspirin in this experiment. The change in free energy G r for a chemical reaction is calculated as follows: G r =
X

n H f (reactants)

(2)

n G f (products)

The equilibrium constant is related to the free energy as follows: G r = RT ln K (4)

n G f (reactants)

(3)

Calculate the equilibrium constant from the standard reaction free energy for equation 1 at 25 C. Use R = 8.3145 JK1 mol1 with temperature in kelvins.

Synthesis of Aspirin

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Lab Writeup
Each student will turn in an individual writeup for this experiment in accordance with the Academic Code of Honor3 and it should contain the following. A copy (top, original) of your lab notebook including the lab summary, balanced chemical equation, compound table and procedure. Record the actual yield of your aspirin. Solubility (s, sls or i) of aspirin in each solvent. Observed melting point range of recrystallized aspirin. Comparison with literature value (source identied). Percent yield calculation - moles of salicylic acid and acetic anhydride used in the reaction, identication of the limiting reagent, calculation of theoretical yield.
Energy calculations - Include calculations for H r , G r and K for reaction 1. Show your work as well as your nal answer for these calculations.

The Academic Code of Honor. http://honorcode.nd.edu (accessed August 2012).

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Synthesis of Aspirin

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