SYNTHESIS OF ACETYLSALICYLIC ACID AND QUANTITATIVE DETERMINATION USING BACKTITRATION

Victor Gregory Jude d.J. Garcia Institute of Chemistry, University of the Philippines, DIliman, Quezon City September 4, 2013 September 13, 2013 Abstract Acetylsalicylic acid (ASA) was synthesized from Salicylic Acid (SA) through esterification with Acetic Anhydride. This experiment aims to utilize the analytical technique of back-titration to evaluate the purity of the synthesized product. A sample of the synthesized ASA was reacted with a known excess of Sodium Hydroxide (NaOH), and the amount of unreacted was determined by titration with standardized Hydrochloric acid to determine the amount of reacted NaOH and, consequently, the amount of ASA in the sample. The results of the experiment show that the synthesized product was over-pure, which means that either the sample contains side-products and impurities, or that no ASA was synthesized at all. I. Introduction Acetylsalicylic acid, or better known as Aspirin, is a drug well-known for its analgesic, antipyretic and anti-inflammatory properties, an effect it shares with Salicylates (such as SA), but without the undesirable effects that often come with taking salicylates on its own. ASA is synthesized through the acid-catalyzed esterification of SA with Acetic Anhydride [1]. ASA, being an acid, can react with strong bases such as NaOH, and could thus be determined by titration. However, the endpoint between the reaction of ASA and NaOH can be difficult to determine. To circumvent this, a known excess of NaOH is added to react with all the ASA, and the unreacted NaOH is determined by titration with HCl, as the endpoint of this titration (using phenolphthalein as an indicator) is much easier to identify. From that, the amount of reacted NaOH can be determined, and likewise, the amount of ASA in the sample. This process is called a backtitration, and is useful in instances where the endpoint of the direct titration is much more difficult to determine [2]. This experiment aims to: (1) synthesize ASA from SA and (2) determine the purity of the synthesized product through back-titration and melting point determination and account for any errors that could have affected the experiment. II. Methodology 0.3564 grams of SA, 0.50 mL of Acetic Anhydride and three drops of concentrated Sulfuric acid was placed into a 100 mL round-bottom flask and swirled, and the solution flask was heated in a steam bath for fifteen minutes. After that, 0.5 mL of distilled water was added drop-wise, and the reaction was allowed to subside, after which, 3.5 mL of iced water was added all at once, and the flask swirled to mix the contents. The solution flask was then placed in an icebath to crystallize the synthesized product. The resulting suspension was filtered, washed with minimal ice-water, and the collected solid was allowed to dry. A small portion of the dried product was set aside and its melting point determined. A 0.050M working NaOH solution was prepared and standardized with 0.2002 grams Potassium Hydrogen Phthalate (KHP). A 0.100M HCl was prepared and standardized with 0.0998 grams Sodium Carbonate. In a 100 mL beaker, 0.1246 grams of the synthesized ASA was reacted with 4.4 mL 1.0M NaOH and simmered for 20 minutes and allowed to cool. The solution was transferred quantitatively to a 250 mL volumetric flask and diluted to the mark with boiled distilled water. A 50 mL aliquot was drawn and put into a 250 mL Erlenmeyer flask along with two drops of Phenolphthalein, and titrated with the standardized HCl solution to the end point. From the results, the purity of the synthesized ASA was calculated. 1

O O OH OH O CH3

O OH O H O HSO 4
-

III. Results and Discussion Salicylic acid reacts with Acetic Anhydride (Ac2O) in the presence of an acid catalyst in an esterification reaction to produce ASA and Acetic acid. An esterification is the reaction of a carboxylic acid or its derivatives and an alcohol to form an ester. In this case, Acetic Anhydride (activated by the acid catalyst) reacts with the OH group of the SA (which acts as the alcohol); the carboxyl group of SA remains untouched. The H of the OH group in SA is replaced by an Acetyl group from the Acetic Anhydride. Similarly, the reaction of ASA and AC2O is also an acetylation reaction, as it [3][4] introduces an Acetyl group to SA .
O O OH OH O O O CH3 H2SO4, H+ O CH3 O O OH

H3C

OH

H3C OH

CH3

O OH O O CH3 O

H3C OH

Fig.3: Synthesis of ASA mechanism A small amount of distilled water is added dropwise to decompose any excess Ac2O [4]. After allowing the reaction to finish, a volume of cold distilled water is added all at once to lower the temperature since ASA is insoluble in cold water, while all the other reactants are soluble [5]. The resulting solution is placed in an ice-bath until the final product, ASA, crystallizes. The inside of the flask could be scratched with a stirring rod to induce crystallization if it is not taking place. The crystallized product is dried and weighed. The synthesis produced 0.1733 grams of the product. A small portion of the product is used for melting point determination. It is found that the melting point of the synthesized product is within the range of 120-130oC. The theoretical melting point of ASA is 136oC. This implies that the synthesized ASA contains impurities, or the product contains no ASA at all [6]. The purity of the synthesized product is determined by back titration. NaOH reacts with ASA at a ratio of 2 moles NaOH for every mole of ASA. The strong base reacts quickly with the carboxylic acid group, but reacts slowly with the ester group of ASA, thus, ASA undergoes slow hydrolysis, and is thus unfavorable for direct titration [7]. To overcome this, a known excess of 1.0 M NaOH is added to the synthesized ASA. The mixture is simmered to speed up the hydrolysis. The mixture is then quantitatively transferred to a 250 mL volumetric flask and diluted to the mark. A 50 mL aliquot is taken and titrated with standardized HCl. The HCl reacts with the NaOH that didnt react with ASA. From that, the amount of reacted ASA can be determined, and consequently, after applying aliquot factors, the amount of ASA in the original sample. 4.4 mL of standardized 1M NaOH (actual concentration: 0.9491M) is reacted with 0.1246 grams of the synthesized product and simmered. The 50 mL 2

H3C

H3C OH

Fig.1: Reaction of ASA and Acetic Anhydride Without an acid catalyst, the reaction of Ac2O with SA is very slow. Sulfuric acid reacts with the Ac2O to make it more reactive toward SA. The Sulfuric acid breaks one C=O bond in Ac2O to give Carbon a partially positive charge, thus making it more reactive. The solution containing the Ac2O and SA is heated in a steam bath to further speed up the reaction.
O H3C O O CH3 O OH

HSO 4 H3C O CH3

HSO 4

Fig.2: Reaction of Ac2O with acid catalyst The remaining acetyl group takes the H from the OH group in SA to form Acetic acid. At the same time, the acetyl group activated by the acid catalyst bonds to the O in the OH group of SA. The conjugate base of the acid catalyst retakes the proton from the acetyl group to regenerate Sulfuric acid, and the C=O bond is reformed, resulting in the final product, ASA.

aliquot is titrated with standardized HCl (actual concentration: 0.098M). Five trials of this titration are done. The amount of unreacted NaOH is subtracted from the amount of the NaOH added to the ASA sample to get the amount of reacted NaOH and, consequently, the amount of ASA in the 50 mL aliquot. The ratio of the moles of ASA with the volume of the solution is the same for the original stock solution, or simply that there are five times as many moles ASA in the 250 mL stock than in the 50 mL aliquot. It is calculated that there 0.003 moles reacted NaOH in the 50 mL aliquot, which means that there are 0.016 moles reacted NaOH (around five times as much) in the 250 mL stock. Since NaOH reacts with ASA at 2:1, its calculated that there are 0.008 moles of ASA in the stock solution. Multiplying that by the formula weight (FW ASA = 180.157), it is found that there are 0.1458 grams of ASA in the original sample. It must be noted that the calculated mass of ASA is more than the mass of the starting product, translating to 117% purity. It must also be noted that it was already previously determined that the melting point of the synthesized product has a large range, and is far from the theoretical value. This already indicates that the synthesized product is riddled with impurities. Thus, it is possible that what was determined in backtitration was not ASA. In most instances, the most common impurity in the synthesis of ASA is the presence of unreacted SA. However, the melting point range is far from the theoretical melting point of SA (159oC), indicating that all the SA reacted to form the crude ASA. IV. Conclusions and Recommendations The experiment showed that back-titration is a useful analytical technique that can be used when direct titration is not feasible. However, due to the acquired over-purity, it is also concluded that ASA was not successfully synthesized, or that too many impurities were present in the synthesized sample. It would have been helpful if the synthesized product was recrystallized in order to lessen the amount of impurities in the product. The ASA was synthesized from previously synthesized SA, the purity of which was not completely ascertained. The impurities might have been minimized if the SA used for the synthesis was pure (such as commercially available/lab-grade SA).

References [1] Palleros, Daniel R.; Experimental Organic Chemistry; John Wiley and Sons, New York, 2000. [2] Kenkel, J.; Analytical Chemistry for Technicians, 3rd Edition; CRC Press, 2003.

[3] SIDS Initial Assessment Report, Geneva: UNEP; Acetic Anhydride; available online at http://www.inchem.org/documents/sids/sids/108247.p df (accessed September 16, 2013) [4] Periodic Table of Videos; Aspirin; available online at http://www.youtube.com/watch?v=amTAuK25P6c (accessed September 14, 2013) [5] Indiana University Southeast; Synthesis of Aspirin; available at http://homepages.ius.edu/DSPURLOC/c122/asp.htm (accessed September 15, 2013)

[6] California State University Stanislaus; The Synthesis of Aspirin; available online at http://wwwchem.csustan.edu/consumer/aspirincons/a spirincons.htm (accessed September 16, 2013) [7] University of Texas; Determination of Aspirin using Back-titration; available online at http://mccord.cm.utexas.edu/courses/fall2004/ch455/a spirin.pdf (accessed September 15, 2013)

Appendix Titration Raw Data Standardization of NaOH

Sample

Standardization of HCl
Weight (g) 0.0998 0.1 0.1 0.1 0.1002 Volum e (ml) 19.3 19 19.1 19.5 18.9

M HCl 0.09708707 0.09881766 0.09830029 0.09628387 0.09953919

Average 0.0980056

Sample 1 2 3 4 5

Weight 0.2002 0.2005 0.2006 0.2012 0.2084

Vol. 20.6 20.5 20.5 20.6 21.6

M NaOH 0.047350183 0.04765246 0.047676227 0.047586697 0.047007675

Average 0.047454648

1 2 3 4 5

ASA Backtitration (0.1246 g sample) mols unreacted NaOH in 50 mL aliquot 0.000499829

1 2 3 4 5 5.1

Sample

Volume HCl (ml)

mol reacted NaOH in 50 mL aliquot

mol reacted NaOH in 250mL stock

mol ASA in stock

g ASA 0.15105

0.000335373 0.001676866 0.000838433

0.00052923
5.4

0.000305971 0.001529857 0.000764929 0.137807 0.000325573 0.001627863 0.000813931 0.146635 0.000325573 0.001627863 0.000813931 0.146635 0.000325573 0.001627863 0.000813931 0.146635

0.000509629
5.2

0.000509629
5.2

0.000509629
5.2

Average g ASA = 0.145752632 grams %purity

Range

Relative Standard Deviation (in ppt)

Confidence Limits (95%) =