Just for fun!
What do aspirin and the Versailles treaty have in common? Aspirin and Heroin were once brand name products whose trademarks belonged to the German company Bayer. When Germany lost World War I, part of the Treaty of Versailles (1919) forced Bayer to give up the trademarks on the drugs. For more info, check out Wikipedia's article on aspirin.




Jokes
A chemist walks into a pharmacy and asks the pharmacist, "Do you have any acetylsalicylic acid?"
"You mean aspirin?" asked the pharmacist.
"That's it! I can never remember that word."

Q: What do dipoles say in passing?
A: Have you got a moment?

Q: Why did Carbon marry Hydrogen?
A: They bonded well from the minute they met.

Q: What do chemists call a benzene ring with iron atoms replacing the carbon atoms?
A: A ferrous wheel.

Laughing face image taken from Microsoft Office Clip Art.
Bayer advertisement taken from Wikipedia.

Synthesis of Aspirin

Goals

• Investigate the ability to synthesize and obtain sufficient yields of over-the-counter analgesics, such as, aspirin.
• Compare the bonding characteristics of certain molecules using VSEPR, computational models using semi-empirical calculations, and experimental data.

Background

Organic chemistry is heavily involved in the production of many everyday items, such as, plastics, petroleum, and pharmaceuticals.  Aspirin is the most commonly used drug in the United States, with more than 40 million pounds produced each year.  The chemical name for aspirin is Acetylsalicylic acid.  Aspirin is known to be an analgesic (pain reliever) and an antipyretic (fever reducer).  The multi-step synthesis of aspirin that you will be attempting is shown below (These structures are written in shorthand.  Every unlabeled vertex is a carbon, and hydrogens need to be added until each carbon has 4 bonds):

You will be performing several common organic synthetic techniques in creating aspirin.  In the first step, you will be performing a hydrolysis of methyl salicylate, otherwise known as, Oil of Wintergreen.  In the second step, you will be performing a condensation reaction to produce your final product, acetylsalicylic acid.  In each of these steps, certain pieces of each molecule are changing, while the core of the molecule remains unchanged.  These reaction sites are commonly referred to as functional groups.  Each functional group exhibits unique chemistry.  Methyl Salicylate is composed of an ester (RCOOR) (R indicates a carbon-containing group) and a phenol (C₆H₅OH).  In the presence of sodium hydroxide the hydrolysis of the ester takes precedence over any chemical change in the phenol.  Although the phenol is acidic and will react with the sodium hydroxide, once sulfuric acid is added, the phenol will reappear unchanged, while the ester becomes a new functional group known as a carboxylic acid (RCOOH).  In the presence of acetic anhydride, the carboxylic acid is less reactive than the phenol.  The phenol of salicylic acid is converted to the acetyl ester in the presence of acetic anhydride, therein; the common name of Acetylsalicylic acid is used for the final structure of aspirin.

Not only is the synthesis of aspirin a great demonstration of our ability to change functional groups on organic molecules, but the three organic molecules involved exhibit some unique chemical bonding principles.  Due to the different functional groups being synthesized, we will be able to use Infrared spectroscopy to confirm the synthesis of each new compound in our 2-step synthesis of aspirin.

Functional groups within molecules can be observed to have distinctive IR absorptions, similar to the gaseous compounds we observed in the Global Warming lab.  The IR absorptions can help us distinguish one type of bond from another.  Experimentally, you will be obtaining an infrared spectrum for each product you synthesize to help confirm the creation of each compound.  Table 1 gives the absorption values for certain bonds in the functional groups that you will be seeing in this lab.  A range of absorption values is given for each bond because the environment surrounding each bond can influence the final position in the IR spectrum.  At the end of this lab is an infrared spectrum with a complete analysis, in Table 2, of your starting material, Methyl Salicylate.  Every IR spectrum for this lab should include a complete analysis, similar to that shown for Methyl Salicylate.   Use Table 2 at the end of this lab to help track the changes seen from one compound’s IR spectrum to the next compound's IR spectrum.

Table 1: Principal IR Absorptions of Solids and Liquids for Certain Functional Groups
Click to open a printable version of this table

Functional Group Names & Example compounds	Absorption Ranges(cm-1) [Look for a single absorption in these regions, unless stated otherwise.]	Type of Vibration causing IR absorption
Alkanes:	3000-2800 (Note: The absorptions can be seen as several distinct peaks in this region.)	H-C-H  Asymmetric and Symmetric Stretch
	1500-1440	H-C-H Bend
Aromatic Rings:	3100-3000	C=C-H Asymmetric Stretch
	1600-1580	C-C=C Symmetric Stretch
	1500-1450	C-C=C Asymmetric Stretch
Phenols:	3600-3100 (Note: Phenols MUST have Aromatic Ring Absorptions too.)	Hydrogen-bonded O-H Stretch (This peak usually appears much broader than the other IR absorptions.)
Carboxylic Acids:	3400-2400 (This peak always covers the entire region with a VERY BROAD peak.)	Hydrogen-bonded O-H Stretch [Note: This peak can obscure other peaks in this region.]
	1730-1650	C=O Stretch
Esters:	1755-1650 (Note: Esters MUST have Alkane Absorptions too.)	C=O Stretch

Throughout this lab and the Computational Chemistry lab that follows, we hope to investigate the bonding characteristics of our three main organic molecules in the overall synthesis of aspirin.  We will do this using hand-held molecular model kits and HyperChem.  We will use IR spectroscopy and other experimental data to compare the various models we use to represent the bonding taking place in these molecules.

Equipment and Materials:

ATR-FTIR Spectrum One Spectrometer

For Step 1: Synthesis of Salicylic Acid

• Oil of Wintergreen (Methyl Salicylate) [C8H8O3], density = 1.174 g/mL
• 6M NaOH
• 9M H₂SO₄
• Hot Plate

For Step 2: Synthesis of Acetylsalicylic Acid

• Acetic Anhydride [C₄H₆O₃] in an automatic dispenser in the hood
• Conc. H₃PO₄ (85%)
• Watch Glass
• Microwave Oven

Figure 1 - Necessary glassware and Vacuum Filtration Setup

Preparation

Multi-Step Synthesis of Aspirin

Reading Assignment

• Description of experiment—see next page.
• Review Bonding—Zumdahl, Chapter 13 & 14.
• Review Stoichiometry & Percent Yield—Zumdahl, sec. 3.8, pp. 68-77.

Questions:

1. Draw the Lewis structure for Acetylsalicylic Acid (Aspirin) and add lone pair electrons where applicable. Predict the hybridization around each carbon atom in Acetylsalicylic Acid (Aspirin).
   
   
2. Indicate the direction of the predicted dipole moments for each bond labeled with a "?" in Methyl Salicylate and Salicylic Acid:
   
   Click to open a printable version of this table

   Methyl Salicylate		Salicylic Acid

   
   
3. Draw all the resonance structures for benzene.
   
   
4. For Step 1 of your experiment, there is a 1:1 stoichiometric ratio between Methyl Salicylate and Salicylic Acid. What is the theoretical yield, in grams, for the production of Salicylic Acid from Methyl Salicylate? Assume you start with 4.000 mL of Methyl Salicylate. Its density is listed in the Equipment and Materials section.
   
   
5. For Step 2 of your experiment, if you started with 1.40 grams of Salicylic Acid, how many grams of Aspirin could you produce?  (The balanced reaction shows a 1:1 stoichiometric ratio between Salicylic Acid and Aspirin.)

Experimental:

Click here for printable instructions

Work in pairs and wear gloves when handling the chemicals.

Step 1: Synthesis of Salicylic Acid from Oil of Wintergreen (Methyl Salicylate)
Transfer 4.0 mL of Oil of Wintergreen (Methyl Salicylate). [This is a quick way to measure Oil of Wintergreen. However, a better way to do this is to weigh the beaker before and after adding the Oil of Wintergreen. Then you know exactly how much transferred from the graduated cylinder. You would use your mass and the density of Methyl Salicylate to recalculate your exact theoretical yield for this reaction.] Add, with stirring, 40.0 mL of 6M NaOH. Heat with occasional stirring to a gentle boil, reduce the heating rate to avoid 'bumping', and continue boiling gently for 30 minutes. After 15 minutes of boiling, rinse down any undissolved solids with a small amount of distilled water. You may need to adjust the setting on the hot plate to maintain a 'gentle' boil.

Cool the beaker in an ice bath until it is completely cool, approximately 5 minutes (The bottom of the beaker will cool before the solution. When checking temperature, swirl liquid around a little bit before touching the bottom of the beaker.). While the solution is still on the ice bath, slowly add 50.0 mL of 9M H₂SO₄ while stirring continuously with a glass stirring rod. Let the reaction cool in the ice bath with occasional stirring for an additional 3 minutes. Isolate the product using a Buchner funnel and vacuum filtration. Leave the product under vacuum for 10-15 minutes to dry out your product. Weigh the dry solid in a watchglass or weighing boat before beginning of the next step. You will obtain an FTIR spectrum of your salicylic acid at the end of lab today.

Step 2: Synthesis of Acetylsalicylic Acid (Aspirin) from Salicylic Acid
Place 1.40g of your 'dry' salicylic acid product into a 150-mL beaker. Obtain the exact mass of salicylic acid used in your reaction and recalculate your theoretical yield. Save remaining salicylic acid product for analysis by FTIR.

Stir in 3.0 mL of Acetic Anhydride and 2-5 drops of Concentrated Phosphoric Acid (85% H₃PO₄). Mix thoroughly with a glass stirring rod and allow to sit at room temperature to cool. After approximately 2 minutes, cover the beaker with a watch glass and place the covered beaker into the microwave oven. Heat the beaker in the microwave oven on the "Low" setting for 5-7 minutes. Do not microwave more than one beaker at a time. Remove the beaker using paper towels to protect your fingers from the hot beaker and allow the beaker to sit at room temperature in the hood for approximately one minute. Then, add 2 mL of distilled water. Swirl the beaker and let it sit for approximately 5 minutes. To help precipitate your aspirin from the solution, add 15 mL of distilled water and stir continuously for approximately one minute. Add an additional 10 mL of distilled water while stirring and then put your beaker on ice for approximately 5 minutes to help induce recrystallization.

Collect your solid product in a vacuum filtration apparatus with a Buchner funnel. Rinse out the beaker with a small portion of cold distilled water and allow your final product to dry under vacuum for 10 – 15 minutes. Weigh the dry solid.

Take FTIR spectra of both your salicylic acid and aspirin products.

Disposal

• Pour all waste solutions into the containers provided.

Questions:

Click here for results worksheet. Please print on double-sided printer.

1. What was your percent yield in the synthesis of Salicylic Acid from Methyl Salicylate?
2. What was your percent yield for the synthesis of Acetylsalicylic Acid from Salicylic Acid?
3. What was your overall percent yield for the synthesis of Acetylsalicylic Acid (Aspirin) from Methyl Salicylate? (Note: Determine this by multiplying the individual yields in decimal form and then converting back to a percentage by multiplying the answer by 100.)
4. Discuss any errors that might have influenced the percent yields calculated above.
5. Do you see all the absorptions in the FT-IRs which are expected for your Salicylic Acid and Acetylsalicylic Acid? If not, please state which absorptions are present or missing or couldn't be seen/assigned for each product. Include all your FTIRs in your e-lab/notebook along with a completed Table 2.

Table 2: Analysis of FTIR Spectra from Aspirin Lab  [from 4000-1400cm^-1]
Click to open a printable version of this table

Compounds	Functional Groups	Bonds	Expected Absorption Ranges (in cm-1 from Table 1)	Experimental Absorptions (in cm-1)	Note functional group changes from previous compound's FTIR
	Alkane:	H-C-H Stretches	3000-2800	2956.01 (small peak)	Are all the functional groups still present?  Are new functional groups present? (N/A for methyl salicylate)
		H-C-H Bend	1500-1440	1439.25
	Aromatic:	C=C-H Asymmetric Stretch	3100-3000	3012.44 (small peak)
		C-C=C Symmetric Stretch	1600-1580	1585.02
		C-C=C Asymmetric Stretch	1500-1450	1485.13
	Phenol:	Hydrogen-bonded O-H Stretch (Note: Aromatic Ring Absorptions too)	3600-3100	3187.31 (broad, not a sharp peak)
	Ester:	C=O Stretch (Note: Alkane Absorptions too)	1755-1650	1673.80