Laboratory Experiment 3_ Salicylates (1)

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Kibria 1 Laboratory Experiment 3: Salicylates Rafia Kibra Partner: Daania Teaching Assistant: Jamie Rice Date: November 1st, 2023

Kibria 2 Table of Contents: Introduction ………………………………………….. 3-6 Experimental ………………………………………… 7-10 Results and Calculations …………………………….. 11-15 Discussion …………………………………………… 16-17 Conclusion ………………………………….………… 18 References …………………………………..……….. 19-20 Appendices ……..……………………………………. 21-22

Kibria 3 Introduction In the realm of pharmaceutical chemistry, the synthesis of medicinal compounds stands as the foundation of scientific and industrial advancement. This is shown by the synthesis of Acetylsalicylic acid (ASA), more commonly recognized as aspirin, which is an enduring and vital analgesic medication used very commonly by people for reducing fevers and relieving pain. The historical significance of the development of Acetylsalicylic acid is extremely significant as it was an accidental discovery by scientist Felix Hoffman, and as the years have progressed, this compound has evolved into one of the most widely utilized and respected drugs. Although, before these drugs were discovered, medicinal treatments were treated by plants that contained the salicylic acid which belongs to the family of the salicylates. The salicylic acid must go through preparation by undergoing an esterification reaction because “it cannot be easily ingested”(1). In this reaction, the salicylic acid reacts with an acetic anhydride causing the the hydroxyl group (which causes the main issue) to convert into an ester and having the byproduct of acetic acid to form and therefore alternating the chemical properties to amplify its stability and solubility, but most importantly its ingestion (2) . The primary objective of this laboratory experiment was to produce acetylsalicylic acid through multistep synthesis reactions while practicing the significant techniques often used in organic chemistry laboratories, and more specifically in this experiment, which was completed over the course of three weeks. Figure 1: Overall breakdown of the formation of Acetylsalicylic Acid.

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Kibria 4 In the first week, methyl salicylate was broken down using aqueous sodium hydroxide producing disodium salicylate and byproducts like water and methanol. This compound was then diluted with sulphuric acid and the product of it was salicylic acid. Figure 2: Chemical equations that describe the reaction that takes place. The second phase of this experiment revolves around the synthesis of acetylsalicylic acid (ASA). This transformation is achieved through an acid-catalyzed reaction involving the phenolic hydroxyl (OH) group of salicylic acid and the acetylating agent, acetic anhydride, which ultimately yields the acetylsalicylic acid along with acetic acid. The phenol group within salicylic acid acts as a nucleophile instigating a substitution reaction at one of the carbonyl groups of the acetic anhydride. The overall chemical equation for this week's reaction is given below: Figure 3: Acid-catalyzed reaction for the synthesis of Acetylsalicylic acid.

Kibria 5 The final week of this experimentation involved the analysis and purification of the crude compounds produced in the earlier two weeks. This was done by techniques such as melting point analysis, thin layer chromatography and infrared spectroscopy.Various techniques play a fundamental role in the processes of chemical analysis and purification as these techniques encompass a range of critical aspects. Firstly, the determination of the melting point range, which signifies the temperature span at which a solid undergoes the transition to a liquid state, which is achieved with the aid of a specialized melting point apparatus. This apparatus not only heats the sample but also provides the means to observe and record the melting point range. Furthermore, infrared spectroscopy stands as a pivotal tool in chemical analysis, with its primary function being the measurement of energy absorbance. This technique delves into the molecular structure by observing atomic vibrations, with the wavenumber serving as a crucial indicator of absorbed energy's wavelength and is done with the use of a spectrophotometer. A purification method that follows the dissolution of a substance in a hot solvent is known as recrystallization where subsequent filtration and cooling result in the formation of crystals.This step involves vacuum filtration, employing a Buchner funnel and vacuum suction to expedite the process. Furthermore, refluxing, a frequently employed technique in organic chemistry laboratories, entails the consistent heating of a solution to prevent solvent evaporation. Similarly, distillation involves the conversion of a liquid into vapor which is condensed back into liquid form. Lastly, Thin Layer Chromatography (TLC) serves as an invaluable tool for the separation of compounds, particularly analgesics. A TLC plate coated in silica acts as the medium for the movement of the compound, driven by capillary action. This process entails applying a small sample to the plate, submerging it in a solvent, and conducting the analysis under fluorescent light in a darkened

Kibria 6 environment. These techniques collectively empower chemists and researchers, facilitating the synthesis, purification, and analysis of chemical compounds within the laboratory setting.

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Kibria 7 Experimental: Week 1: Hydrolysis of methyl salicylate Experiment A - Saponification of Methyl Salicylic 5g of methyl salicylate was added to 50mL of 20% NaOH solution in a 250mL flask. A reflux. A condenser was attached to the flask and the flask was heated for around 20 minutes. The mixture was allowed to cool to room temperature and then transferred to a 600mL beaker. 275mL of sulphuric acid was added to the mixture until the blue litmus paper turned pink. Solution was cooled in an ice bath and solid crystals were collected using vacuum filtration. Mixture was poured through a Buchner funnel which separated the crystals from the liquid. Experiment B - Purification of Salicylic acid The crude salicylic acid was added to water and boiled. The solution was allowed to cool until crystals formed. Beaker was placed in an ice bath. Vacuum filtration was used once again to collect the crystals of salicylic acid. Crystals were then stored until week Week 2: Synthesis of Acetylsalicylic acid Experiment A - Weigh the salicylic acid Required weighing of the salicylic acid produced in week 1 was performed and its melting point was by the melting point apparatus. Experiment B - Synthesis of Aspirin A warm bath was prepared by heating 100 mL of water in a 400 mL beaker at 45- 50°C, making sure boiling chips were added. Using a top loading balance, 3g of salicylic acid was

Kibria 8 weighed and added to a 100 mL beaker, where then 5mL of acetic anhydride was added as well along with 5 drops of sulphuric acid. This Mixture was warmed in a warm water bath and stirred continuously and this solution was allowed to cool to room temperature. Acetylsalicylic acid crystals started to form. Once crystals started to forms and the crystallization was complete, 50mL of ice cold water was added and the crystals were separated using vacuum filtration. Crude acetylsalicylic acid was weighed. Experiment C - Recrystallization 20 mL was used to dissolve the crystals in a 250 mL beaker until the aspirin was fully dissolved. Once it was, the volume added was recorded and this was allowed to cool and transferred to an ice bath. The crystals are then vacuum filtered and transferred to a weighted 50 mL beaker and handed to the TA. Week 3: Analysis and purification of compounds Experiment A - Weigh the Acetylsalicylic acid The acetylsalicylic acid from week 2 was weighed and its melting point was taken using the melting point apparatus. The results were recorded in the lab notebook. Experiment B - Thin Layer Chromatography (TLC) In Part B of the procedure, a TLC plate was prepared by lightly inscribing it with a pencil, creating a start line about 2 cm from one end. Seven lanes were marked for standards, including pure methyl salicylate, salicylic acid, and acetylsalicylic acid, along with lanes for the crude and purified forms of salicylic acid and acetylsalicylic acid that were produced. Capillaries were used to spot the standards without moving the capillary from the station to prevent

Kibria 9 contamination. The capillary was dabbled gently on the plate's surface, ensuring minimal wetness with drying between dabs. After spotting, the plate was allowed to dry for 2-3 minutes before being placed in a solvent tank, ensuring no disturbance to the sample spots. The solvent front was traced with a pencil, and the plate was dried in a fume hood for 10 minutes. Visible spots were traced, and fluorescent spots were noted under UV light. Distances from the start line to the leading edge of each spot were measured, as well as the solvent's distance traveled. Observations regarding spot colors and purity were recorded. Data was entered on a data sheet, and a diagram of the TLC plate was included in the formal report, along with calculated retention factors (Rf). Part C: Chemical test. Ferric Chloride test In Part C, a ferric chloride test was conducted by labeling and adding methanolic ferric chloride solution to seven test tubes (#1-#7). Each tube was tested with different samples, including the four products (crude and purified salicylic acid and acetylsalicylic acid), pure methyl salicylate, salicylic acid, and acetylsalicylic acid. Any color changes were noted, and the test solutions were disposed of in a designated waste container. The test tubes were thoroughly cleaned after testing. Part D: Infrared Spectroscopy: In Part D, infrared spectroscopy was performed. The spectra of crude and purified salicylic acid and acetylsalicylic acid were obtained using a spectrometer, and peaks were

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Kibria 10 labeled. These spectra were included in the formal report, and reference spectra for reactants and products were used for comparison to confirm or deny their presence. A USB drive was required to save the data.

Kibria 11 Results: Table 1: Properties and results of crude and purified salicylic acid and acetylsalicylic acid Crude salicylic acid Pure salicylic acid Crude Acetylsalicylic acid Pure Acetylsalicylic acid Weight of amount collected (g): 7.5643 3.2343 6.5768 2.9118 Observed Melting point range ( C) ◦ - 156-159 - 131-134 Literature Melting point ( C) ◦ 159 138-140 Appearance White crystalline opaque powder Needle type crystals, white/grayish White crystalline powder White crystalline powder Percent yield (%) 57.24 55.73

Kibria 12 Table 2: Distance traveled on the TLC plate of solutes Salicylic acid Pure Salicylic acid Acetylsalicyli c acid Pure Acetylsalicyli c acid Pure Methyl Salicylate Distance traveled up on TLC plate (cm) 4.4 4.4 3.9 4.2 4.7 Distance solvent traveled (cm) 5.0 5.0 5.0 5.0 5.0 Refractive index values 0.88 0.88 0.78 0.84 0.94 SA - Salicylic Acid PASA - Pure Acetylsalicylic acid PSA - Pure Salicylic Acid ASA - Acetylsalicylic acid PMS - Pure methyl salicylic Figure 4: TLC plate of the compounds Sample Calculation 1: Percent Yield Experimental Yield Pure SA = 3.2343g Theoretical Yield Pure SA: 7.5643g 𝑃?????? 𝑌𝑖??? (%) = 𝑇ℎ?????𝑖?𝑎? ?𝑖??? − ?????𝑖????𝑎? ?𝑖??? 𝑇ℎ?????𝑖?𝑎? ?𝑖??? * 100

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Kibria 13 𝑃?????? 𝑌𝑖??? (%) = 7.5643−3.2343 7.5643 * 100 57.24% 𝑃?????? 𝑌𝑖??? (%) = Sample calculation 2: Retention factor for Pure Methyl salicylic acid 𝑅? = ?𝑖??𝑎??? ???? ??𝑎??𝑖?? ?𝑖?? ?? ?ℎ? ??𝑎?𝑖?? ???? (??) ?𝑖??𝑎??? ?ℎ? ???𝑣??? ??𝑎𝑣???? (??) 𝑅? = 4.7 5.0 𝑅? = 0. 94 The pure methyl salicylic acid had the highest retention factor and traveled the farthest. Table 3: Observation of Test Tubes samples and color Tube Number Compound Name Observation of Colour 1 Acetylsalicylic acid Dark yellow (Brown) 2 Pure Salicylic acid Dark Purple (Blackish) 3 Pure Acetylsalicylic acid Yellow 4 Salicylic acid Dark Purple (Blackish)

Kibria 14 Figure 5: % Transmittance vs Wavenumber graph that shows the infrared spectrum of pure Salicylic acid. Table 4 : The infrared spectrum analysis of Pure Salicylic Acid and the corresponding functional group of its wavenumber Functional Group Bond Type Literature Position of Wavenumber (Cm1) Position Wavenumber (Cm1) Alkene C-C C=C 1640 1654.938 Aldehyde C-H 2700 2534.5897 Alkane C 𝐻 3 -C - 𝐻 2 2930 2866.3228 Carboxylic Acid O-H C=O 3100 3239.0566

Kibria 15 Figure 6: % Transmittance vs Wavenumber graph that shows the infrared spectrum of pure Acetylsalicylic acid. Table 5 : The infrared spectrum analysis of Pure Acetylsalicylic Acid and the corresponding functional group of its wavenumber Functional Group Bond Type Literature Position of Wavenumber (Cm1) Position Wavenumber (Cm1) Alcohol C-O O-H 3350 3533.5163 Aldehyde C-H 2700 2892.4142 Aldehyde C-H 2700 1748.1214 Alkene C-C C=C 1670 - trans 1681.0294

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Kibria 16 Discussion In this comprehensive three-part experiment, various tests were conducted to assess the purity of the synthesized substances. The melting point determination revealed a narrow melting range of 156°C-159°C for purified salicylic acid and 131°C-134°C for purified acetylsalicylic acid, aligning closely with literature values and confirming their purity. By comparing the weights detailed in Table 1, it is clear to see that for both compounds (salicylic acid and acetylsalicylic acid), the crude compounds weighed significantly more than the pure compounds. This is to be expected as the crude compounds have slight impurities which contributes to the extra weight. Another reason that the crude weighs more is because some of the compound was lost in transfer of glassware between experiments and treatments which affected the yield. The percent yields for both compounds were not exceptionally high, falling in the 50s, they did surpass the 50% mark, indicating that at least half of the theoretical maximum yield was obtained. In chemistry, the yield represents the actual amount of product obtained in a reaction relative to the maximum theoretically attainable yield under ideal conditions, considering no side reactions or losses. Yields in the 50s typically suggest that the reaction may not have proceeded with high efficiency or that some losses occurred during the process. TLC analysis provided insights into the polarity of the compounds. Pure methyl salicylate exhibited the highest Rf value, indicating its greater polarity, as it traveled the farthest from the starting point on the TLC plate. In contrast, both pure and crude acetylsalicylic acids were closest to the starting point after plate development, suggesting weaker interactions with the plate's surface. The salicylic acids were located near the solvent line, indicating an intermediate polarity. The TLC plate (Figure 4) revealed multiple spots for pure forms of salicylic and acetylsalicylic acids, while the standards exhibited single spots. This observation suggested that impure compounds tend to produce

Kibria 17 multiple spots on a TLC plate, implying that some components of crude salicylic acid and acetylsalicylic acid did not separate effectively under the conditions of the 50:50 dichloromethane:ethanol solvent and silica gel. When ferric chloride was introduced to various solutions containing specific chemicals, distinct color changes were observed. Pure salicylic acid turned the solution purple/black, indicating the presence of a phenol group. In contrast, neither the crude nor pure acetylsalicylic acid samples displayed this color change, as acetylsalicylic acid lacks a phenol group. These outcomes were consistent with expectations. The final test conducted on these two compounds was infrared spectroscopy where it is clear to see that the pure acetylsalicylic acid has more drastic peaks. This can mean that there are more molecular bonding occurring in the acetylsalicylic acid than there are in salicylic acid. This makes sense when the molecular skeleton of both compounds are viewed as Acetylsalicylic acid has more intramolecular bonds than salicylic acid. Several potential sources of error were identified in the experiment. One possible error occurred during the hydrolysis of methyl salicylate, where rapid hydrolysis of acetic anhydride in the presence of water could lead to reactant loss if glassware was not thoroughly dried before use. The reduced product yield could be attributed to a potential issue in the vacuum filtration step, where improper wetting and clogged filter paper may have caused significant solvent loss and, consequently, reduced product formation. Additionally, exposure of acetic anhydride to the air without proper coverage may have resulted in product loss and a lower aspirin yield. Strict control over reaction conditions, temperature, and pressure is essential to prevent product loss. The transfer of chemicals, especially when scraping product from filter paper, may result in product loss and reduced overall yield.

Kibria 18 Conclusion In conclusion, this three-part experiment yielded valuable insights into the synthesis and analysis of acetylsalicylic acid (ASA) and salicylic acid. The results showed that both compounds exhibited relatively high purity, with their melting points closely matching literature values. Although the percent yields were in the 50s, indicating less than ideal efficiency, they surpassed the 50% mark, implying that at least half of the maximum theoretical yield was achieved. Thin layer chromatography (TLC) analysis provided information on the polarity of the compounds, with pure methyl salicylate being the most polar and acetylsalicylic acid being the least polar, and reflected on the retention factors the compounds possessed based on the distance of solvent and compound traveled on TLC plate, where methyl salicylate was found to have the highest. Furthermore, the ferric chloride test confirmed the presence of phenol groups in pure salicylic acid, while acetylsalicylic acid did not display this characteristic color change. Infrared spectroscopy on the other hand revealed marked differences in the molecular structures of pure salicylic acid and pure acetylsalicylic acid, with the latter demonstrating more complex intramolecular bonding. It is essential to acknowledge potential sources of error, such as reactant loss during hydrolysis, reduced product yield in vacuum filtration, and product loss due to improper handling of acetic anhydride. Overall, these results underscore the significance of precision and meticulous laboratory techniques in pharmaceutical chemistry experiments.

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Kibria 19 References (1) Viirre, Dr. R.; Johnson, Dr. A.; McFadden, Dr.; Denning, R. Organic Chemistry Laboratory Manual, CHY142 ; Department of Chemistry and Biology: Toronto Metropolitan University, 2023; pp. 20–27. (2) Acetylsalicylic Acid - an overview | ScienceDirect Topics . Sciencedirect.com. https://www.sciencedirect.com/topics/chemistry/acetylsalicylic-acid. (3) Acetylsalicylic acid (Aspirin ) - C9H8O4 - Formula, Structure, Properties, Preparation, Uses, Health risk and FAQs of Aspirin/ Acetylsalicylic ((C9H8O4) . BYJUS. https://byjus.com/chemistry/acetylsalicylic-acid/#Synthesis_of_Aspirin/Acetylsalicylic_acid. (4) Acetylsalicylic Acid Structure: Detailed Explanations - . lambdageeks.com. https://lambdageeks.com/acetylsalicylic-acid-structure/#:~:text=The%20addition%20of%20the% 20acetyl%20group%20to%20the (accessed 2023-11-02). (5) Synthesis and Characterization of Aspirin . Odinity. https://www.odinity.com/characterization-of-aspirin/. (6) Britannica. Distillation | Chemical Process. Encyclopædia Britannica ; 2019. (7)

Kibria 20 Study.com. https://study.com/learn/lesson/percent-yield-formula.html. (8) Ahmed, R. https://study.com/learn/lesson/retention-factor-chromatography-formula-overview.html . study.com. https://study.com/learn/lesson/retention-factor-chromatography-formula-overview.html. (9) Sandtorv, A. 2.4: TLC -ANALYSIS . Chemistry LibreTexts. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3A_How_to_be_a_Successf ul_Organic_Chemist_(Sandtorv)/02%3A_COMMON_ORGANIC_CHEMISTRY_LABORATO RY_TECHNIQUES/2.04%3A_TLC_-ANALYSIS. (10) What is the reaction of phenol with ferric chloride? – ShortInformer . short-informer.com. https://short-informer.com/what-is-the-reaction-of-phenol-with-ferric-chloride/#:~:text=Phenol% 20group%20reacts%20with%20ferric%20ion%20of%20ferric (accessed 2023-11-02). (11) Barich, A. Recrystallization . Chemistry LibreTexts. https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook_Maps/ Supplemental_Modules_(Physical_and_Theoretical_Chemistry)/Physical_Properties_of_Matter/ Solutions_and_Mixtures/Case_Studies/RECRYSTALLIZATION.

Kibria 21 Appendix 1) Calculation of Pure Acetylsalicylic acid Percent yield: 𝑃?????? 𝑌𝑖??? (%) = 𝑇ℎ?????𝑖?𝑎? ?𝑖??? − ?????𝑖????𝑎? ?𝑖??? 𝑇ℎ?????𝑖?𝑎? ?𝑖??? * 100 𝑃?????? 𝑌𝑖??? (%) = 6.5768−2.9118 6.5768 * 100 55.73% 𝑃?????? 𝑌𝑖??? (%) = 2) Retention factor Calculations: Pure Salicylic Acid 𝑅? = ?𝑖??𝑎??? ???? ??𝑎??𝑖?? ?𝑖?? ?? ?ℎ? ??𝑎?𝑖?? ???? (??) ?𝑖??𝑎??? ?ℎ? ???𝑣??? ??𝑎𝑣???? (??) 𝑅? = 4.4 5.0 𝑅? = 0. 88 Pure Acetylsalicylic Acid 𝑅? = ?𝑖??𝑎??? ???? ??𝑎??𝑖?? ?𝑖?? ?? ?ℎ? ??𝑎?𝑖?? ???? (??) ?𝑖??𝑎??? ?ℎ? ???𝑣??? ??𝑎𝑣???? (??) 𝑅? = 4.2 5.0 𝑅? = 0. 84

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Kibria 22 Salicylic Acid 𝑅? = ?𝑖??𝑎??? ???? ??𝑎??𝑖?? ?𝑖?? ?? ?ℎ? ??𝑎?𝑖?? ???? (??) ?𝑖??𝑎??? ?ℎ? ???𝑣??? ??𝑎𝑣???? (??) 𝑅? = 4.4 5.0 𝑅? = 0. 88 Acetylsalicylic Acid 𝑅? = ?𝑖??𝑎??? ???? ??𝑎??𝑖?? ?𝑖?? ?? ?ℎ? ??𝑎?𝑖?? ???? (??) ?𝑖??𝑎??? ?ℎ? ???𝑣??? ??𝑎𝑣???? (??) 𝑅? = 3.9 5.0 𝑅? = 0. 78

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