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Esterification reaction: the synthesis and purification of 2-
Acetoxybenzoic acid and subsequent analysis of the pure
product (acetylsalicylic acid ) via Thin-Layer Chromatography.
Andra C. Postu Department of Chemistry, American University, Washington, D.C. 20016 Date of Publication: February 25, 2014 ABSTRACT: acid, the prodrug and active ingredient in Aspirin. Salicylic acid is made less acidic by converting its An esterification reaction was performed in order to convert salicylic acid to acetylsalicylic alcohol functional group into an ester so that it is less damaging to the digestive system in the human body. The purpose of the experiment is to synthesize, isolate, and purify 2-acetoxybenzoic acid and analyze determine if pure aspirin was synthesized. The amount of crude aspirin synthesized was 3.029 grams salicylic acid, crude product, and acetylsalicylic acid via Thin-Layer Chromatography to and the amount of pure aspirin synthesized was 2.169. The theoretical yield was 2.520 grams. Thus, there was a percent error of 13.93 % and percent yield of 86.07%. TLC analysis showed that acetylsalicylic had a higher R acid was more polar because of its extra polar functional group and did not travel as far. Thus, puref value than salicylic acid (.800 vs. .315 Rf value, respectively). The salicylic aspirin was synthesized.
INTRODUCTION 2-Acetoxybenzoic acid, more commonly known as Aspirin, is a white, crystalline substance most commonly known for its pain-relieving qualities1,2. Acetylsalicylic acid (active ingredient of Aspirin) is an acetyl derivative of salicylic acid and the prodrug of the active metabolite, salicylic acid.^2 Aspirin is a salicylate drug because it is an ester of salicylic acid. It is commonly known for its pain relieving properties. However, it does not only serve as an analgesic but also as an antipyretic, anti-inflammatory, and antiplatelet medication^2. The main metabolite of acetylsalicylic acid, salicylic acid, is an essential part of the human metabolism^3. Salicylic acid is an integral part of pain management and was often used by ancient cultures, such as the Native Americans, who extracted the chemical from willow tree bark^3. This fundamental compound can cause stomach irritation and is bitter tasting, so a milder prodrug called acetylsalicylic acid was synthesized in 1893 by the German chemist Felix Hoffmann who worked for Bayer2,3,4. Acetylsalicylic acid is a type of drug that is formulated deliberately so that it will deteriorate in the body into the active drug^5. This prodrug was developed because it is much less abrasive when delivered to the body and is much more easily absorbed^6. The active drug, salicylic acid, is the active metabolite because it is the form of the drug after the body has
processed it. Edward Stone of Oxford University discovered salicylic acid in 1763 from the bark of willow tree4,5,6. Aspirin works by suppressing the synthesis of prostaglandins and thromboxanes in the human body3,4,5. Prostaglandins function as local hormones produced in the body that aid in the transmission of pain signals, regulate the hypothalamic thermostat, and inflammation^2. Thromboxanes are involved in the aggregation of platelets that form blood clots. It does this by the irreversible inactivation of prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase 2, an enzyme that is needed in the synthesis of prostaglandin and thromboxane.^5 Aspirin serves as the acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the prostaglandin-endoperoxide synthase enzyme. The ability of aspirin to diminish inflammation is due to its inhibition of the synthesis of prostaglandins. Aspirin alters the oxygenase activity of prostaglandin synthetase by moving the acetyl group to a terminal amine group^4. Though aspirin has numerous benefits, there are several adverse affects as well. It is particularly damaging to the stomach lining and there is an increased risk of gastrointestinal bleeding3,5. The risk of stomach bleeding increases with use of drugs such as warfarin and alcohol^6. Large doses can cause a ringing in the ears, or tinnitus. Some people may have allergy- like symptoms including hives and swelling because of a possible salicylate intolerance^1. Aspirin can cause swelling of skin tissues (angioedema), increase risk of Reye’s syndrome and can cause hyperkalemia1,2,3. Although most commonly known for its anti-inflammatory properties and pain-reducing qualities, acetylsalicylic acid is also an effective fever-reducer and has been to shown to prevent the progression of existing cardiovascular issues such as heart attacks or strokes in low does on a long term basis. Aspirin’s antiplatelet effects come from its ability to inhibit the synthesis of thromboxane, which otherwise bind platelets together in areas where vessel damage has occurred 4. These platelets can clot together and become harmful otherwise. It also controls fevers through a similar mechanism (prostaglandin system) and the inhibition of PTGS that is not reversible^5. Thin Layer Chromatography (TLC) is a chromatography technique that is used to separate mixtures that are non-volatile such as salicylic acid, acetylsalicylic acid, and the crude
more. The vacuum filtration apparatus was left on for several minutes to aid in the drying of the solid product before it was weighed and recorded^3. Purification About 5 mg of crude acetylsalicylic acid were set aside for TLC analysis. The remaining crude aspirin was added to a 125 mL Erlenmeyer flask. About 60 mL of hot ethanol/water solvent was added slowly to the crude aspirin in a warm water bath. Once the crystals dissolved, the flask was covered and left to cool to room temperature before it was placed in an ice bath for 10 minutes to fully crystallize. Then, the crystals were placed into a vacuum filter where they were subsequently rinsed with two 3 mL portions of cold deionized water and one 2 mL portion of cold ethanol^3. TLC Analysis A developing chamber was made by using a 400 mL beaker and watch glass. 10 mL of 9:1 mixture of ethyl acetate and methylene chloride respectively was placed inside the beaker with a 110 mm filter paper in order to saturate the chamber with solvent vapors. The solvent was left to travel to the top of the filter paper before the silica gel coated TLC plate was placed inside of the beaker. 3 mg of each salicylic acid, crude product, and recrystallized product was place inside three separate small beakers and dissolved with 6 drops of TLC solvent. A different pipette was then used for each of the three samples to lightly spot the TLC plate at the light pencil hash mark about ½ inch from the bottom of the plate. The plate was left to develop until the solvent front was about ½ inch away from the top of the TLC plate. The plate was then removed from the developing chamber and the solvent front was promptly marked. The plate was left to dry before it was examined under UV light^3.
RESULTS
Figure 1: Structure of Salicylic Acid, Acetic anhydride, and Acetyl salicylic acid
The structures of salicylic acid, acetic anhydride, and acetylsalicylic acid are pictured above with their functional groups clearly visible in red. Mass= Density x Volume Mass (g) acetic anhydride used= (1.08 g/mL) x (5.00 mL) (Eq.1) Mass (g) acetic anhydride= 5.40 g Mass of aspirin synthesized (g)= (Mass of aspirin and filter paper) – (Mass of filter paper) Mass of aspirin synthesized (g)= (3.159 g)-(.1300 g) (Eq.2) Mass of aspirin synthesized (g)= 3. Mass of purified aspirin product (g)= (Mass of purified aspirin and filter paper)- (mass of filter paper) Mass of purified aspirin product (g)= (2.299 g)- (.1300 g) (Eq.3) Mass of purified aspirin product (g)=2. Table 1: Synthesis of Aspirin Data
Salicylic Acid
Acetic anhydride
Acetylsalicylic acid
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Mass of salicylic acid used (g) 2. Volume of acetic anhydride used (mL) 5. Mass of acetic anhydride used (1.08 g/mL) used (g) 5. Mass of aspirin and filter paper (g) 3.
Pictured above is the TLC plate with salicylic acid, crude product, and final purified produce under UV light, respectively. The final product (acetylsalicylic acid) traveled the furthest up the TLC plate. The salicylic acid travelled the smallest distance.
R Rff Value= (distance from start to center of substance/distance from start to solvent front)Value= (2.0 cm/6.35 cm) (Eq. 7) Rf Value=. Table 3: Rf Values of Salicylic Acid, Crude Product, and Final Product from TLC Analysis
The salicylic acid travelled the smallest distance with and Rf value of .315. Crude acetylsalicylic acid had an Rf value of .480. The purified acetylsalicylic acid product traveled the furthest up the TLC plate with an Rf value of .800.
DISCUSSION The esterification reaction is a term for a general reaction in which two reactants, an alcohol and an acid, form an ester in the final product^2. This reaction can be used to synthesize aspirin from salicylic acid. These types of reactions are typically reversible, so most esterification reactions are equilibrium reactions. Le Chatelier’s principle is a pillar of modern chemistry that states that any change imposed on a system that is in equilibrium will cause the system to adjust to a new equilibrium in order to counteract the change^2. The reaction is slow in pure acetic anhydride, therefore phosphoric acid was used as a catalyst for the reaction because it is a strong acid^2. According to Le Chatelier’s principle, an excess amount of acetic anhydride
Salicylic Acid Rf value. Crude Acetylsalicylic Acid Rf value. Pure Acetylsalicylic Acid Rf value.
would force the equilibrium towards the desired product, acetylsalicylic acid. This mechanism would cause the reaction to favor the product side (aspirin and acetic acid).The solution was also heated in order to accelerate the approach to equilibrium2,3. Salicylic acid contains two acidic functional groups, a carboxylic acid and an a phenol group^2. The alcohol group (more specifically, the phenol group) in the salicylic acid participates in the reaction because it undergoes esterification and forms an acetylated ester. The human acid is acidic, but the acidity of salicylic acid is great and can thus be very damaging to the digestive system. It can cause gastric and intestinal bleeding as well as stomach ulcers to form. The acidy is to harsh on the lining of the stomach, so “covering up” or removing one of the acidic portions of salicylic acid and leaving the carboxylic acid part with an acetyl group makes it much less damaging to the body and makes absorption much easier^2. It is for this reason that acetylsalicylic acid is the active ingredient in Aspirin and serves as the prodrug. Aspirin works by irreversibly inhibiting cyclooxygenase 2 (COX-2) also known as PTGS and prevents the synthesis prostaglandins and thromboxane, which are involved in damage repair in tissues via inflammation, clotting, pain signaling, and temperature regulation5,6. The overall mechanism of reaction that is taking place in the synthesis of aspirin is much more complex than one would guess. Basically, an esterification reaction such as the synthesis of aspirin occurs when a carboxylic acid and an alcohol combine in a reaction to produce an ester. A molecule of water splits off and the remaining carboxylic acid and alcohol form the ester in its place. In the reaction, the phenoxide ion (OH on the ring) is stabilized by the electron withdrawing carbonyl group on the salicylic acid, making it a very stable nucleophile. The carbonyl carbon of the acetic anhydride is makes it an excellent electrophile because the leaving group or acetate ion is stabilized by the acidic conditions provided by the phosphoric acid catalyst. Firstly, protonation of acetic anhydride make it an even better electrophile. It takes a proton from phosphoric acid, leaving it with a negative charge. The nucleophile, salicylic acid attacks the carbonyl carbon on acetic anhydride and bonds. A bond forms between the carbonyl carbon of acetic anhydride and the oxygen (partial positive charge) from the –OH group of salicylic acid form a bond. Phosphoric acid deprotonates the intermediate and removes the hydrogen atoms that is bonded to the oxygen with the partial positive charge. This forms a tetrahedral intermediate and phosphoric acid is thus regenerated. An acetate anion is present and removes the hydrogen attached to oxygen on the intermediate. The removal of this hydrogen gives rise to an ester, and thus the product acetylsalicylic acid. Acetic acid is also formed. Phosphoric acid is essential in this reaction because it acts as a catalyst that (combined with heat) helps the reaction occur in a decent amount of time. It is a liquid acid and thus does not contain a large amount of water that would otherwise affect the yield of the reaction. It also has a strong conjugate base, which is important because this is a reversible reaction. The reaction was placed in a hot water bath and heated to 70-80 °C to help the reaction occur at a faster rate because adding heat to a system increases the energy present and particles move and collide at a faster rate. Otherwise, the reaction would take too far to long to react and the equilibrium would not favor the product side (aspirin and acetic acid). After heating the reaction, distilled water was added to help with recrystallization and to decompose any remaining acetic anhydride because it strongly reacts with water. There is remaining acetic anhydride because salicylic acid is the limiting reagent and acetic anhydride is present in excess. It is important to consider that
CONCLUSION
A total of 2.169 grams of pure aspirin was synthesize out of a possible yield of 2. grams. Thus, there was a 13.93 % error and 86.07% product yield. TLC analysis further confirmed these results due to the observation that aspirin had a higher Rf value that salicylic acid (.800 vs. .315, respectively), thus demonstrating that the one of polar functional groups had been converted to an ester. This makes aspirin less acidic and therefore less damaging to the digestive system of the human body. In the future, special care should be given to the washing of the crystals with cold distilled water to maximize yield. Also, a stronger acid catalyst such sulfuric acid could be used to further increase the rate of reaction.
Mechanism 1: phosphoric acid, and acetic anhydride Reaction between salicylic acid,
Mechanism 2 : Reaction of Water and byproducts
REFERENCES
(1) Pehlic, E.; Nuhanovic, M.; Sapcanin, A.; Banjanin…, B. Characterization of acetylsalicylic acid with thin-layer chromatography and hot--stage microscopy depending to solvent system. 2012. (2) Klein, D. Organic Chemistry: 2nd^ ed.;Wiley:Hoboken, 2013. (3) Williamson, K and Katherine Masters. Macroscale and Microscale Organic Experiments, 6th ed.; Brooks/Cole, 2011. (4)Rainsford, K. History and development of the salicylates. Aspirin and Related Drugs 2004 , 1–
(5)Olmsted, J. A. Synthesis of Aspirin: A General Chemistry Experiment. Journal of Chemical Education 1998 , 75.
(6)Truelove, J.; Hussain, A.; Kostenbauder, H. Synthesis of 1-O-(2’-acetoxy)benzoyl-alpha-D-2- deoxyglucopyranose, a novel aspirin prodrug. Journal of pharmaceutical sciences 1980 , 69 , 231–
Andra Postu Organic Chemistry Lab II Lab Partner: Michael Bible February 19, 2014
