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L L AABB 212 1:: AA SPSPIIRRIINN AANNDD AA NANALLGGEESSIICCSS ::
S S YNYNTTHHEESSIISS && AA NNAALLYYSSIISS
P P UURRPPOOSSEE :: To synthesize aspirin from wintergreen or from salicylic acid.
To test the purity of aspirin by testing for the presence of phenols. To use thin-layer chromatography to identify substances in analgesics.
S S AAFFEETTYY CC OONNCCEERRNNSS ::
Always wear safety goggles. Acetic Anhydride and Acetic Acid are irritating to skin, eyes, and mucus membranes. If contacted, wash with soap and copious amounts of water.
A A SSPPIIRRIINN ::
History:
The bark of the willow tree was used by ancient Native Americans to counter fever and pain. Europeans learned of willow bark’s medicinal properties in 1763 when clergyman Edward Stone presented his findings to the Royal Society of London. Willow bark extract was found to be a powerful drug with analgesic (pain reliever), antipyretic (fever reducer), and anti- inflammatory (reduces swelling) properties. In 1838 organic chemists isolated the active ingredient and identified it as salicylic acid , named from salix , Latin for the willow tree.
Although an effective remedy, the use of salicylic acid was limited because it damaged mucous membranes of the mouth and esophagus, and caused hemorrhaging of the stomach lining. It was determined that the acidic phenol group could be responsible for the damaging effects so in 1893 German chemist Felix Hoffman, working for the firm of Bayer, synthesized an ester of salicylic acid, acetylsalicylic acid. Acetylsalicylic acid was marketed by Bayer under the trade name of aspirin. During World War I the U.S. Government seized Bayer’s assets and sold them and the Bayer name to Sterling Products which became Sterling Winthrop Inc.
Biological Effect:
Aspirin works to relieve fever and pain by inhibiting the formation of prostaglandins , a class of 20-carbon acids that form at the site of an injury and are responsible for causing the inflammation and pain.
Aspirin works as a blood thinner by also inhibiting the formation of thromboxins which aid in the production of blood clots.
Aspirin should not be given to children who have influenza or chicken pox because of the risk of the rare but often fatal Reye’s Syndrome. Children suffering from these diseases should be given a nonaspirin pain reliever such as acetaminophen. Unless directed by a physician, aspirin should not be taken during the last 3 months of pregnancy.
Preparation and Reactivity:
Aspirin is easily prepared in the laboratory by esterification of salicylic acid with acetic acid.
Acetic Acid
Salicylic acid (^) Acetylsalicylic acid (Aspirin)
Water
C
O
OH
OH C
O
O C
O
OH
CH 3
H
O
C H
O
HO CH 3
Esterification
Hydrolysis
H+
Preparation of aspirin by treatment of salicylic acid with acetic anhydride, however, is much faster than traditional esterification so is more practical for us to do in a limited laboratory time.
Acetic Acid
Salicylic acid (138 g/mol)
Acetylsalicylic acid= Aspirn (180 g/mol)
Acetic Anhydride
C
O
OH
OH C
O
O C
O
OH
CH 3
CH 3
C
O
C
CH 3
O O
CH 3
C
OH
O
Like salicylic acid, aspirin is an analgesic, antipyretic, and anti-inflammatory; but it is much less irritating to the stomach. Aspirin does cause slight gastrointestinal bleeding that can, over time, cause iron deficiency or gastric ulcers. These complications can be avoided with enteric-coated aspirin, which does not dissolve until reaching the small intestine. The basic conditions in the small intestine hydrolyze the acetylsalicylic acid to salicylic acid, which is absorbed into the bloodstream.
In commercial aspirin tablets about 325 mg (5 grains) of aspirin is bound together with inert materials called binders, whose function is to hold the tablet together. Some manufactures apply a micro-coating of hydroxypropyl methylcellulose to prevent the tablet from dissolving in the mouth but permit it to dissolve in the stomach. Sometimes buffers are added to combat stomach irritation.
Aspirin may be reconverted into salicylic acid in either of two ways; hydrolysis in an acidic solution which is the reversing of the equilibrium esterification to make it, or by hydrolysis with base (called saponification).
If aspirin is stored over a long period of time, especially under moist conditions, the hydrolysis reaction takes place, and the characteristic odor of vinegar (acetic acid) is easily detected. Generally, "old" aspirin tablets contain traces of acetic acid and salicylic acid.
T T (^) HHIINN -L-L AYAYEERR CC (^) HHRROOMMAATTOOGGRRAAPPHHYY :: Thin-layer chromatography (TLC) is a technique used to separate substances in a mixture. A TLC plate is typically a sheet of plastic, coated with a thin layer of a solid adsorbent such as silica gel. Small amounts of known and unknown substances are placed as small spots at one end of the TLC plate. Then the end of the plate with the spots is placed in a solvent contained in a developing chamber.
The solid silica layer on the TLC plate is called the stationary phase. The solvent or the mobile phase slowly moves up the silica layer on the TLC plate carrying the substances in the spot with it. The more soluble a substance is in the solvent, the higher the solvent will carry it up the plate. A substance that adheres strongly to the stationary silica gel moves only a short distance with the solvent. Thus, differences in the substances determine the distances they travel up the plate.
As the solvent front nears the top of the TLC plate, the plate is removed, marked, and dried. Then the substances are visualized. If they have colors, they can be seen directly. In this experiment, they are colorless. Be cause the silica material on the plate contains a fluorescent compound, ultraviolet light (254 nm) from a UV lamp can be used to visualize the substances. Compounds with aromatic rings will absorb the UV light and appear as dark spots on the plate.
A value called the Rf value can be calculated for each substance on a plate. The Rf is the distance that a substance moves on the plate divided by the distance the solvent moves. An unknown substance is identified if its Rf value matches the Rf value of one of the known substances used on the plate.
In this experiment of will use TLC to determine the Rf values for several known analgesics and to determine the purity of Aspirin product that you have made.
P P ROROCCEEDDUURREESS ::
ACTIONS :
I. SYNTHESIS OF A SPIRIN:
A. PREPARATION:
- In the fume hood prepare a boiling water bath by heating about 150 mLs of water in a 400 mL beaker over a hot plate.
- Carefully mass 2.00g^1 of salicylic acid and put it into a 125 mL Erlenmeyer flask.
- Under the fume hood 2 carefully add 5 mL of acetic anhydride 3 to the flask of salicylic acid and swirl or stir to mix.
- Slowly add 10 drops of 85% phosphoric acid, (H 3 PO 4 ) to the salicylic acid and acetic anhydride and mix well.
- Place the flask and its contents in the boiling water bath under the hood and stir until all the solid dissolves.
- Let react over steam bath for about 10 minutes. Then remove the flask from the hot water and let it cool to room temperature.
- Cautiously^4 add 20 drops of deionized water to the cool mixture.^5
- When the reaction is complete and the flask is room temperature, add another 50 mL of ice water directly to the reaction flask and then cool the mixture by placing the flask in an ice bath for about 10 minutes. Crystals of aspirin should form. 6
B. C OLLECTION OF ASPIRIN CRYSTALS
- Set up a Buchner or Hirsh funnel apparatus and moisten the filter paper.
- Turn on the water aspirator and pour the aspirin product onto the filter paper in the funnel. 7
- Use a spatula to transfer any aspirin crystals left in the flask to the funnel and rinse the inside of the flask into the funnel with a 10 mL portion of ice cold water. 8
- Spread the aspirin crystals out on the filter paper in the Buchner funnel and continue to draw air through the funnel to help dry the crystals. 9
- Turn off the water aspirator and use a spatula to lift and transfer the filter paper with the aspirin residue on it to a watch glass. Allow the crystals to air dry. 10
NOTES :
(^1) The measurement does not need to be exactly 2.00g, however, you do need to know exactly how much you do have. Report whatever mass you obtain to the accuracy of your balance so that you can most correctly determine the percent yield of your product when you are done. (^2) Acetic anhydride is irritating to the nose and sinus. Handle carefully. (^3) Acetic anhydride is used in excess so the salicylic acid is the limiting reagent. (^4) Keep your face away from the top of the flask: The acetic acid vapors that are produced are irritating. (^5) The water is stopping the reaction by hydrolyzing any unused acetic anhydride into acetic acid. (^6) If no crystals appear, gently scratch the insides of the flask with a stirring rod. (^7) The aspirin product will be the residue that remains on the filter paper. (^8) The 10 mLs of ice water can be used a little at a time to make several small rinses. Several small rinses will be more effective at transferring product that one large rinse. (^9) This helps to partially dry the crystals. (^10) You may need to let your crystals dry in your drawer until the next lab period to get an accurate weight for yield calculations and an accurate melting point in Part IIE.
- When the solvent has evaporated from the TLC plate, observe it under UV light. 19 Circle each spot and draw a picture of the spots on your report sheet.
- Measure the distance from the origin to the solvent front and measure the distance from the origin to the center of each spot. Calculate the Rf value for each spot and record them next to each spot on your report sheet.
- Determine and label the identity of each spot^19 on the report sheet and formulate conclusions as to the purity of your prepared aspirin and as to the make up of extra strength Excedrin.
- Place used chromatography solvent in the organic waste solvent container.
B. P H:
- Obtain 5 test tubes (any size) and label them A, B, C, D, & E.
- Into tube A place 3 mL of 0.15% Salicylic acid solution. Into tubes B, C, D, and E, place about 3 mL of deionized water.^20
- Into tubes B, C, D, and E, add a few crystals (the amount on the tip of a spatula) of the indicated solids: Tubes B; add Commercial Aspirin (crushed). Tube C; add Buffered Aspirin (crushed). Tube D; add Aspirin product you prepared in Part I. Tube E; add Acetylsalicylic acid. Mix each well 21
- Stir each mixture A through E and touch the wet stirring rod to a piece of pH indicator paper. Compare the color of the wet paper to the chart on the container and record the pH.
- From your results make some conclusions as to potential throat, esophagus or stomach irritation.
- Use the same samples A through E for the test for phenols.
C. TEST FOR PHENOLS:
- To each of the sample tubes A through E add 5 drops of 0.1 M ferric chloride (FeCl 3 ) solution. Mix well. Record your observations.^221
- From your data make some conclusions as to the composition of your prepared aspirin as well as the other samples.
- Conclude whether the Aspirin you made in Part I would be considered pure by USP standards. 23
(^19) Compounds containing an aromatic ring will appear dark under the UV light. Those without an aromatic ring will not appear at all. Salicylic Acid show fluorescent blue under UV light. (^20) The measurement does not need to be exact. You can determine 3 mls for the first tube with a graduated cylinder and then eyeball the height of water in each of the other tubes to match. (^21) Mixing can be done by tapping the sides of the test tubes, by stirring with a glass rod, or by stoppering and shaking. (^22) Any free salicylic acid either unreacted during synthesis or resulting from hydrolysis of aspirin, reacts with the Fe +3^ ion to give a purple color. More salicylic acid in the sample results in a deeper color. A purple color resulting from addition of Fe+3^ to aspirin or acetylsalicylic acid indicates that the product is either impure or that decomposition has taken place. (^23) The maximum salicylic acid allowed in commercially prepared aspirin products is 0.15%. If the sample test has a lighter color than a 0.15% standard, the sample would be considered pure by United States Pharmacopeia (USP) standards. If the sample is darker, it is impure and not considered safe for ingestion. However, no matter what the results of the test, your laboratory- prepared aspirin must not be ingested!
D. I DENTIFICATION OF COMMERCIAL BINDER :
- Place a small amount (the amount on the tip of a spatula) of solid crushed commercial aspirin tablet in a test tube. Add a drop of dissolved Iodine (I 2 in KI solution). Record your observations.
- Make any conclusions as to the identity of the binder used in the commercial tablet.^24
E. MELTING POINT:
- If a melting point apparatus is available, determine the melting point of your dry aspirin product prepared in Part I. Compare the melting point of your aspirin with the known melting points of aspirin^25 and of salicylic acid 26.
- From your melting point data make some conclusions as to the identity and purity of your prepared aspirin.
(^24) Hint: Refer back to the carbohydrate chapter of your text.
(^25) Aspirn melts at 135 oC.
(^26) Salicylic acid melts at 157-159 oC.
L L ABAB 212 1:: AA SPSPIIRRIINN && AA (^) NNAALLGGEESSIICCSS (^) :: NN AMAMEE (^) ______________________________________
RR (^) EEPPOORRTT :: PP AARRTTNNEERR __________________DD ATATEE (^) ______
I. SYNTHESIS OF A SPIRIN:
STARTING R EAGENT Salicylic Acid
PRODUCT Acetylsalicylic Acid
Molar Mass
Grams (Actual grams used)^ (Theoretical yield: grams expected: Show calculations)
Moles (Actual Moles used: Show calculations)^ (Theoretical moles expected:)
Yield, grams (Actual experimental yield)
Percent Yield (% yield: Show calculations)
Error Analysis:
Are your experimental results as expected or are there discrepancies? Explain
II. A NALYSIS :
A. Chromatography: Draw and label each spot.
Summary & Conclusions:
Identity of Excedrin Components from Product Label :
Identity of Excedrin Components from TLC:
Error Analysis: (how does this compare to expected?)
Purity of prepared Aspirin from TLC
A B C D E F Error Analysis: (how does this compare to expected?)
L L ABAB 212 1:: AA SPSPIIRRIINN && AA (^) NNAALLGGEESSIICCSS (^) :: NN AMAMEE (^) __________________________
RR (^) EELLAATTEEDD EE XEXERRCCIISSEESS :: DD ATATEE (^) ____________________________
1.___ An antipyretic serves to A. relieve pain. B. reduce fever. C. reduce swelling D. all of these
2.___ An analgesic serves to A. relieve pain. B. reduce fever. C. reduce swelling D. all of these
3.___ The bark of the willow tree contains? A. Aspirin B. Prostaglandins C. Salicylic Acid D. More than one of these.
4.___ Which functional group of salicylic acid is thought to most irritate the stomach? A. phenol B. carboxylic acid C. ester D. aromatic ring
5.___ Aspirin works as a pain reliever by inhibiting the formation of A. thromboxins B. anhydrides C. prostaglandins D. endorphins
6.___ What quantity of aspirin is contained in most over-the-counter adult aspirin products? A. 1 g B. 325 mg C. 225 mg D. varies widely
7.___ The presence of salicylic acid in an aspirin tablet indicates A. the aspirin is fresh. C. the aspirin contains large quantities of binder. B. the aspirin is old D. the aspirin contains small quantities of binder.
- In most fatal cases of aspirin poisoning, the dosage has been greater than 20 grams. How many aspirin tablets are necessary to supply 20 grams of aspirin? Show your work and circle your answer.
- You are stranded on an island but find a source of wintergreen oil. You have a headache. Use structures to show the reactions you could use to turn wintergreen (methyl salicylate) into aspirin.
R R EFEFEERREENNCCEE SS EEAARRCCHH ::
- Look up Aspirin in the Physician’s Desk Reference (PDR) and list any side effects of concern.
