Post Lab #5 - I earned an A in this lab class. PDF

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I earned an A in this lab class....

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Experiment #5: Synthesis of Acetylsalicylic Acid (Aspirin) Name :Danielle Curtis Lab Partners: Virginia Van Grod and Yefrain Munoz TA: Katrinah Tirado

Introduction/Background Aspirin, which is also known as acetylsalicylic acid, is a medication commonly used to treat mild to moderate pain, fever and inflammation.1 This is due to its analgesic, antipyretic and anti-inflammatory properties.2 Moreover, the use of aspirin also results in a decrease in platelet aggregation, thus making it suitable for the treatment of arterial and venous thrombosis.1 Aspirin is synthesized by reacting salicylic acid with an excess of acetic anhydride in the presence of a catalyst, such as a small amount of a strong acid like the H3PO4 used in this experiment.2 Besides being an aromatic compound, aspirin contains 2 additional functional groups that contribute to its properties: a carboxylic acid group and an ester group.3 As a result of these functional groups, aspirin belongs to a class of organic compounds called phenol esters.3 Phenol esters are characterized by a benzene ring with a hydroxyl group and an ester group as its substituents.3 An ester group is a functional group in organic chemistry that is very important and can be synthesized using different methods. Esters can be prepared by reacting an alcohol with a carboxylic acid, acid anhydride or acid chloride.2 Each method requires certain reaction conditions in order to proceed. When preparing an ester by reacting an alcohol with a carboxylic acid, the reaction is heated and takes place in the presence of an acid catalyst.4 However, it is important to note that this method will not work with phenols because the reaction rate is so slow.4 An example of synthesizing an ester from an alcohol and a carboxylic acid is the reaction of ethanoic acid and ethanol in the presence of heat and concentrated sulfuric acid.4 When preparing an ester by reacting an acid with an acid anhydride, the reaction is typically heated to speed up the reaction.4 It is important to note that phenols can be used in this reaction, but it must

react with sodium hydroxide first to form the more reactive phenoxide ion.4 An example of synthesizing an ester from an alcohol and an acid anhydride is the reaction of salicylic acid with acetic anydride in the presence of H3PO4 to form acetylsalicylic acid, the reaction that takes place in this experiment.2 Finally, when preparing an ester by reacting an alcohol with an acid chloride, the reaction typically takes place at colder temperatures because the reaction is quite vigorous.4 Moreover, it also does not require a catalyst as the acid chloride and alcohol react instantly with each other.4 An example of synthesizing an ester from an alcohol and an acid chloride is the reaction of ethanol with ethanoyl chloride to form ethyl ethanoate and hydrogen chloride.4 The purpose of this experiment was to prepare acetylsalicylic acid, or aspirin, via a Fisher esterification. In order to establish that the ester product had been synthesized, melting point was determined and IR, 1H NMR and 13C NMR spectra were obtained. Collecting these spectras of the final product helps in determining whether aspirin was synthesized because the unique peaks on each spectra allow the structure of the final product to be elucidated. If the final product is in fact aspirin, the IR spectra will have 6 important peaks. A peak at 1725 cm-1 representing the C=O in –COOH, a peak at 1740 cm-1 representing the C=O in –OCOCH3, a peak at 1200 cm-1 representing the O-C in –OCOCH3, a peak at 3050 cm-1 representing the C-H on the benzene and a peak at 1600 cm-1 representing the C=C in the benzene. On the 1 HNMR spectra there should also be 6 signals. One signal at about 10-12 ppm will represent the proton on the –COOH, one signal at about 2-2.5 ppm will represent the proton on the –OCOCH3, where as the rest of the signals will represent the unique protons on the benzene ring at around 7-8 ppm. Finally, on the 13C NMR spectra there should be 9 signals. Two signals should fall in the 170 ppm range, representing the C=O. Six signals should fall in the 110-170 ppm range, representing the C on the benzene ring. Finally, one signal should fall in the 8-35 ppm range, representing the

R-CH3 group. Identifying all of these signals on their respective spectras will confirm whether or not aspirin was the product that was produced.

Acetic Anhydride

Salicylic Acid

Intermediate

Acetylsalicylic Acid

Figure 1: Mechanism for Synthesis of Acetylsalicylic Acid

salicylic acid

salicylic acid

Figure 2: Mechanism for Possible Side Reaction

salicylic acid dimmer

water

Experimental Section:

0.14 g of salicylic acid, a boiling chip, a drop of 85% H3PO4 and 0.3 mL of acetic anhydride were added to a conical vial. A drop of this mixture was placed on a TLC plate. The reactants were mixed thoroughly and then the vial was placed over a steam bath at 90˚C.

The mixture was decanted into a Hirsch funnel and the product underwent vacuum filtration. The excess crystals in the vial was transferred to the Hirsh funnel by being washed with cold water over the funnel. The mixture continued to be vacuum filtered until dry.

The product was weighed and percent yield was determined. The melting point was determined, a 1H NMR and IR were obtained for the product.

The vial was held over the steam bath for a total of 10 minutes. A drop of the mixture was placed on the TLC plate. The TLC plate was placed in a TLC chamber containing a 1:1 mixture of EtOAc:Hexane. After the solvent reached the solvent line, the TLC plate was removed from the chamber, allowed to dry and placed in an iodine chamber.

0.2 mL of water was cautiously added to the reaction mixture in the vial. After the bubbling subsided, an additional 0.3 mL of water was added to the vial and the vial was allowed to cool to room temperature. To initiate crystallization of the product, the inside of the vial was scratched with a glassstirring rod. The vial was allowed to cool in an ice bath for 10 minutes until crystallization was complete.

* Note that an IR was not obtained for this groups particular product because the product was destroyed before it could be taken* Chemicals Used: Name of Chemical IUPAC Name Formula Molar Mass Melting Point Boiling Point Density Safety

Salicylic Acid 2-hydroxybenzoic acid C7H6O3 138.121 g/mol 159C 211C 1.44 g/cm3 > Acute/delayed skin irritant

Acetic Anhydride Ethanoic anhydride C4H6O3 102.09 g/mol -73.1C 140C 1.08 g/cm3 > Acute/delayed irritant

> Irritant if inhaled/ingested > Combustible at high temperatures

> Corrosive to skin > Skin permeator > Flammable

Chemical Structure

Table 1: Table of Chemicals – Reactants Name of Chemical IUPAC Name Formula Molar Mass Melting Point Boiling Point Density Safety

Phosphoric Acid Phosphoric acid H3PO4 97.994 g/mol 42.35C 158C 1.88 g/cm3 > Acute/delayed irritant > Skin permeator > Corrosive to skin/eyes

Acetylsalicylic Acid 2-acetoxybenzoic acid C9H8O4 180.157 g/mol 135C 140C 1.40 g/cm3 > Acute/delayed irritant > Corrosive to skin > Skin permeator > Combustible at high temperatures

Chemical Structure

Table 2: Table of Chemicals – Reagent and Product Results: Appearance of Product Color of Product Melting Point Mass of Crystals Percentage Yield Rf Values

Crystals appeared white, fine and flakey White crystals 130˚C 0.1 g 54.6% Reactant = 0.8; Product = 0.75

The reaction proceeded relatively quickly Overall Reaction Rate (Easiness) Table 3: Data Collected from the Product Synthesized

Figure 3: 1 H NMR Spectra of Final Product

Figure 4: IR Spectra of Final Product

Figure 5: 13 C NMR of Commercial Aspirin

CALCULATIONS:

0.3 mLC4H6O3 x 1.08 g/mLC4H6O3 x 1 molC4H6O3 x 1 molC9H8O4 = 0.0032 mol C9H8O4 1 mL C4H6O3 102.09 g/mol C4H6O3 1 mol C4H6O3

0.14 gC7H6O3 x 1 molC7H6O3 x 1 mol C9H8O4 = 0.001 mol C9H8O4 138.12 g/mol C7H6O3 1 mol C7H6O3 *Therefore, C7H6O3 is the limiting reagent Calculation 1: Determining the Limiting Reagent

0.14 gC7H6O3 x 1 molC7H6O3

x

1 mol C9H8O4 x 180.157 g/mol C9H8O4 = 0.183 gC9H8O4

138.12 g/mol C7H6O3

1 mol C7H6O3

1 mol C9H8O4

Calculation 2: Determining Theoretical Yield

% Yield = Actual Yield x 100% = 0.1 g C9H8O4 x 100% = 54.6% Theoretical Yield 0.183 g C9H8O4 Calculation 3: Determining % Yield

Rf = Distance Moved by Mixture Spot . Distance from Mixture Spot to Solvent Front Reactant (Salicylic acid, Acetic Anhydride, H3PO4) Rf = 3.2 cm = 0.8 4.0 cm Acetylsalicylic Acid Rf = 3.0 cm = 0. 75 4.0 cm Calculation 4: Determining the Rf for the Starting Reactants and the Product

Discussion: To confirm that the correct product was obtained, the percent yield was determined and an IR and 1H NMR spectra were obtained. At the end of the experiment, the product was weighed and found to be 0.1 g. The limiting reagent of the reaction, salicylic acid, was used to calculate the theoretical yield of the reaction, which was found to be 0.183 g. Based on this information, the percent yield for this project was found to be 54.4%, which is a relatively poor yield. There are many reasons that can explain why the percent yield for this project was so low. For example, some of the final product may have been lost due to human error; such as when transferring the product to the Hirsh funnel, some of the product may have remained in the vial

or on the boiling stone. Another reason for a poor percent yield is because of the possibility of side reactions. In this experiment, one side reaction that could have occurred was the interaction of salicylic acid with salicylic acid, leading to a salicylic acid dimer. This would have occurred if there was not enough excess acetic anhydride in the mixture for the salicylic acid to react with completely. The melting point of the reaction was determined to be 130˚C. The literature states that the melting point for acetylsalicylic acid is 135˚C. Although the determined melting point is similar to the literature value, it is 5˚C lower. This could indicate that the final product is impure or that the final product obtained is not acetylsalicylic acid. Upon analyzing the calculated Rf values, it can be ascertained that the reaction did not proceed completely and that acetylsalicylic acid, or aspirin, was not the final product. This is known because the initial Rf for the mixture of salicylic acid and acetic anhydride was 0.80. Where as, after the reaction was complete, the Rf was 0.75. Polar compounds typically produce smaller Rf values than nonpolar substances. Both salicylic acid and acetylsalicylic acid are somewhat polar because of the –OH groups. However, salicylic acid has one more polar group than acetylsalicylic acid, an extra –OH group, thus making it more polar and hindering it from traveling as far up the TLC plate as acetylsalicylic acid would. Therefore, salicylic acid should have had a smaller Rf value than acetylsalicylic acid. However, the actual Rf values obtained for this experiment do not support this theory, thus leading to the conclusion that aspirin was not actually produced or that the product was contaminated. When analyzing the IR spectra, there should have been 6 peaks. A peak at 1725 cm-1 representing the C=O in –COOH, a peak at 1740 cm-1 representing the C=O in –OCOCH3, a peak at 1200 cm-1 representing the O-C in –OCOCH3, a peak at 3050 cm-1 representing the C-H

on the benzene and a peak at 1600 cm-1 representing the C=C in the benzene. However, it is apparent that there are no distinct peaks on the IR spectra collected from the product. Therefore, it is logical to conclude that the product was contaminated or the reaction was not completed and the final product obtained was not acetylsalicylic acid. The 1H NMR spectra can also be used to indicate whether acetylsalicylic acid is formed. One signal at about 11 ppm would represent the proton on the –COOH, where as the rest of the signals would represent the unique protons on the benzene ring at around 7-8 ppm. There would also be a signal at around 2-2.5 ppm, indicative of the proton on the –OCOCH3. The 1H NMR spectra for this product showed a signal at around 12 ppm, a signal at 2 ppm and 4 signals at around 7-8 ppm, indicative of an acetylsalicylic acid product. However, the spectra displayed an extra signal in the 7-8 ppm range. This data suggests that the final product could possibly be contaminated or that the final product is not in fact acetylsalicylic acid. The data collected from both TLC and IR spectra combined can be used to help determine whether or not the product prepared is aspirin. However, TLC is often used throughout the experiment to compare the starting reactants to the final product to determine whether the reaction has completed. Where as, IR can only be conducted at the end of the experiment because the final product must be used to obtain the spectra. The presence or absence of important functional groups will prove whether or not the product obtained was the correct product. Overall, this reaction was not efficient because, based on the data obtained, the expected final product was not obtained.

Question #1:

6

5

7

4

All 4 signals will fall between 7-8 ppm because they are aromatic protons. Both proton 4 and 7 will be doublet of doublets because of their adjacent neighbors. However, 4 will appear more downfield because it is more deshielded by the electron-withdrawing group beside it. Both protons 5 and 6 will be triplet of doublets because of the influence of their adjacent neighboring protons. However, proton 6 will appear more downfield because it is more deshielded than proton 5.

Question #2: The NMR spectra would include the peaks for both salicylic acid and acetylsalicylic acid. The NMR would display peaks between 7-8 ppm from the aromatic protons, a peak at around 2 ppm from the protons located on the –OCOCH3 as well as a peak at around 11 ppm from the – COOH. However, the salicylic acid would also cause a peak to appear between 4 – 7 ppm from the alcohol group on the aromatic ring, but slightly downfield since the election-withdrawing group beside it deshields it. It would cause an additional peak to occur at around 11 ppm from the –COOH as well as additional peaks to occur in the 7-8 ppm range from the aromatic protons.

Conclusion: The goal of this experiment was to prepare an ester by reacting acetic anhydride with salicylic acid to produce acetylsalicylic acid. The data collected throughout this experiment indicates that acetylsalicylic acid was produced, but it was contaminated. It can be seen that the appropriate peaks are visible in the H NMR spectra. However, there is one additional peak in the 7-8 ppm range that is not accounted for in the structure of acetylsalicylic acid. Therefore, this suggests that there was a contaminant in the final product. Moreover, the IR spectra did not show any of the characteristic peaks of acetylsalicylic acid, which could also indicate the presence of a contaminant. Finally, the Rf values determined for this experiment do not correspond with the expected trend of the Rf values for salicylic acid and acetylsalicylic acid. The Rf value for salicylic acid should have been smaller than that of acetylsalicylic acid. However, in reality it was not. The melting point can be used to confirm the theory that the acetylsalicylic acid was impure. Although the determined melting point was somewhat similar to the literature value, it was 5˚C lower. This is indicative of an impurity in the final product sample.

The skills learned throughout this experiment are important because esterification reactions have many real world applications. Moreover, ester products are chemical compounds used throughout many industries. For example, one of the most controversial esters used throughout various industries is methyl paraben.5 This ester compound is used in cosmetics, toothpastes, hair care products, moisturizers and deodorants because of the distinctive smell it generates.5 Moreover, it is also used as a food preservative and helps to protect pharmaceuticals against fungal decay.5 It is a controversial ester compound because recent research has started to shed a light on its potential health concerns, particularly its connection to cancer, causing it to be banned in countries like Japan and Sweden.5 Overall, this lab did not accomplish what it set out to do because the product synthesized was not pure acetylsalicylic acid. However, many new skills were learned throughout this experiment that are important because they have many practical applications.

References: [1] Aspirin. National Center for Biotechnology Information. PubChem Compound Database. U.S. National Library of Medicine. Accessed Feb. 22, 2018 [2] Wildegirma, S. Experimental Organic Chemistry Lab Manual; University of South Florida: Tampa, FL, 2016; P. 92-95 [3] Aspirin. Drug Details. Accessed Feb. 22, 2018 [4] Libretexts. (2017, March 19) Preparation of Esters. Chemistry LibreTexts. Libretexts. Accessed Feb. 22, 2018 [5] Foundation, C. K.-12. Functions and Applications of Esters. CK-12 Foundation. Accessed Feb. 22, 2018...