Painkillers - Planning Document - Project Scenario and Background -2

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Marymount University *

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Feb 20, 2024

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Synthesis and Analysis of Painkillers Scenario Your team has been employed by a drug development division of a start-up company that has decided to enter the arena of manufacturing over the counter (OTC) painkillers (also known as analgesics). Common ingredients for analgesics may include: Ibuprofen Aspirin Acetaminophen Caffeine The first and most commonly produced pain reliever was aspirin, and it is frequently featured in various formulations of analgesics. Although it is quite easy to synthesize, pharma start-ups like the one you’re employed at must balance the demand from consumers and hospitals, regulatory pressures, and profit margins to justify their investment. O OH OH O O O O O catalyst OH OH O O The start-up company has tasked your team with looking for a low-cost green alternative to satisfy EPA requirements and shareholders. Your team is going to explore ways to synthesize aspirin (as shown below) in order to achieve the highest yield, the greenest synthesis, and the most economical synthesis. After your team has optimized the synthesis of aspirin to satisfy the conditions above, your second task is a consultation with Ingham County Health Department. Patients have been

reporting to the emergency rooms in the greater mid-Michigan area after taking a generic OTC analgesic. Many analgesics have more than one active ingredient (or component). Each team member will be given a sample of the generic analgesic and asked to analyze it. You will need to report what the active ingredients are and quantify how much of each component is in the sample. These results will be used to trace the production issues. Tasks for successfully completing this project 1. Determine which catalyst is greenest and most economical to synthesize aspirin in high yield and provide confirmation of the purity. 2. Use three identification techniques to prove the isolated product from the synthesis is the intended product. 3. Compare the four different routes from a green chemistry perspective: efficiency, safety, waste prevention, cost, and greenness. 4. Analyze the sample of generic OTC analgesic using thin layer chromatography (TLC) to identify the active ingredients in the binary mixture. Special materials available for this project In addition to the necessary reagents, salicylic acid and acetic anhydride, your team will test the following catalysts: Catalysts Phosphoric acid Sulfuric acid Sodium acetate γ-valerolactone For your consultation with the Ingham County Health Department, a preliminary screening has indicated that the following components are the most likely active ingredients in the generic: Potential Components in the Generic OTC Analgesic Aspirin Acetaminophen

Caffeine Ibuprofen Acetanilide Safety notes: ● Be sure to consult the MSDS/SDS for any compound that you work with. ● Wear safety goggles, gloves, and appropriate clothing at all times in the laboratory. ● Dispose of waste in the labeled containers. Do not pour any waste down the drain unless you check with your instructor first. ● Use great care when transferring solutions of acids and bases. ● If you spill a strong acid or base on your clothes or skin, rinse with large amounts of water immediately and ask one of your team members to tell your TA. ● Salicylic acid is toxic and an irritant. Avoid contact with skin, eyes, and clothing. Avoid breathing the dust. ● Acetic anhydride is toxic, corrosive, and a lachrymator (causes tears). Wear gloves and use in the hood. Avoid contact. ● Sulfuric acid is corrosive and causes burns. Avoid contact. ● The aqueous filtrate from the crystallization step can be diluted with water and poured down the sink. Techniques you may need to learn or review Consider reviewing the following sections in the Lab Manual: ● Purification via recrystallization ● Isolation of crude product via vacuum filtration

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● Determination of purity ● Separation of components via Thin Layer Chromatography (TLC) ● Identification techniques ● Spectroscopy Concepts you may need to learn or review The following sections from the OCLUE (CEM 251/252) textbook may be helpful: ● Chapter 7: Nucleophilic Attack at the Carbonyl Carbon, especially the Esterification section (pages 135-136). ● Chapter 2: Spectroscopy, especially IR (pages 34-39) and 1 H-NMR (pages 46-49) Additional Background Your literature search has yielded this general procedure for the esterification reaction. Esterification - Catalyst: Phosphoric acid, Sulfuric acid, or γ-valerolactone Place 1.0 g salicylic acid and a stir bar in a small beaker, add 2 mL of acetic anhydride (with care in the hood) carefully while stirring the mixture. Add 5 drops of your chosen catalyst. After about 10 minutes place the beaker in a hot water bath so that any remaining solid dissolves and the reaction goes to completion. Pour the resulting solution onto about 20 mL of ice water, wait for crystallization, vacuum filter and dry. - Catalyst: sodium acetate Add 1g salicylic acid, 1.00 mL acetic anhydride, 0.3 g sodium acetate and a stir bar into an Erlenmeyer flask or a beaker (with watch glass on top). Stir the reaction at 55 °C for 50 minutes. Add 20 mL ice water into the reaction mixture. Perform vacuum filtration and dry the solid. Note: Do not copy and paste the procedures above directly to your notebook. Using Green Metrics and Tools In your course D2L page, there are links to Green Metrics and Tools. Use appropriate green chemistry metrics or principles to compare the efficiency, safety hazard, waste prevention, costs, and impact of different synthetic routes. Project Checklist These questions are not a graded assignment. However, you should use them (1) as a guide to determine if you have completed all of the required tasks and (2) to help you to be able to develop a good report. Part 1: Synthesis of aspirin

❏ Draw the structures of the catalysts and label the functional groups. For each catalyst, is this molecule acidic, basic, or neutral? ❏ I n your group, design an experimental protocol that will allow you to investigate which catalyst for the aspirin synthesis that (1) will produce the highest yield, (2) is the most economical (price reference is provided as a document), and (3) provides the greenest synthesis. Hint: refer to SDS information of all catalysts used. Protocols: Phosphoric Acid a. Catalyst: Phosphoric acid. Place 1.0 g salicylic acid and a stir bar in a small beaker, add 2 mL of acetic anhydride (with care in the hood) carefully while stirring the mixture. Add 5 drops of your chosen catalyst. After about 10 minutes place the beaker in a hot water bath so that any remaining solid dissolves and the reaction goes to completion. Pour the resulting solution onto about 20 mL of ice water, wait for crystallization, vacuum filter and dry. Sulfuric Acid b. Catalyst: Sulfuric acid. Place 1.0 g salicylic acid and a stir bar in a small beaker, add 2 mL of acetic anhydride (with care in the hood) carefully while stirring the mixture. Add 5 drops of your chosen catalyst. After about 10 minutes place the beaker in a hot water bath so that any remaining solid dissolves and the reaction goes to completion. Pour the resulting solution onto about 20 mL of ice water, wait for crystallization, vacuum filter and dry. γ-valerolactone c. Place 1.0 g salicylic acid and a stir bar in a small beaker, add 2 mL of acetic anhydride (with care in the hood) carefully while stirring the mixture. Add 5 drops of your chosen catalyst. After about 10 minutes place the beaker in a hot water bath so that any remaining solid dissolves and the reaction goes to completion.

Pour the resulting solution onto about 20 mL of ice water, wait for crystallization, vacuum filter and dry. sodium acetate d. Add 1g salicylic acid, 1.00 mL acetic anhydride, 0.3 g sodium acetate and a stir bar into an Erlenmeyer flask or a beaker (with watch glass on top). Stir the reaction at 55 °C for 50 minutes. Add 20 mL ice water into the reaction mixture. Perform vacuum filtration and dry the solid 2. Highest Yield Equation: a. Atom mass= mass of atoms in desired product/mass of atoms in product x100. 3. Most Economical: a. Compare the prices of each compound and determine upon analysis. 4. Greenest Synthesis: a. Use the 12 principles of green chemistry to determine the greenest catalyst for synthesis ❏ There are many ways to monitor the progress or completion. Propose a theoretical method. o Esterification reaction is exothermic. Student L plan to use a rise in temperature to monitor reaction progress. The rate of temperature change can be used to determine the fastest reaction. Would this work? Why or why not? This temperature change rate for the fastest reaction would not work in this case due to the catalysts introduced to the equation, rather the reaction progress and success can be measured after vacuum filtration when we find the mass of the product. ❏ How will you control the temperature (55 °C) for the esterification reaction using sodium acetate as catalyst? We can use a heat plate to 55 C and use a thermometer to constantly measure and control the temperature during esterification. ❏ How will you prepare ice water for recrystallization? Remember: the water you added in your solution must be DI water. Ice from ice machine is tap water. We will put a beaker filled with DI water into a larger beaker with the ice to lower the temperature of the ice water. ❏ How will you isolate your product after the reaction? How can addition of ice water assist with precipitation/crystallization? Will the aspirin product be a solid or liquid? We will use vacuum filtration to isolate the product after the reaction. The addition of ice water can help speed up the process of getting the crystals during recrystallization. The aspirin product will be a solid product. Which green metrics will you evaluate the various catalysts on? Atom economy, less hazardous syntheses, catalysis will be the most important to evaluate during this lab.

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What information will you need to record in order to calculate these? we will use the yield of product, price of the catalysts and environmental economy to evaluate the catalysts. Part 2: Recrystallization and purity testing of aspirin ❏ Draw the structure of aspirin. Label out the polar bonds. ❏ What solvent (solvent mixture) do you think it might be soluble in? Consult the green solvent guide in the lab manual to make your selections. ● I think aspirin would be soluble in the green solvent ‘ethanol’ or ‘DMSO’ due to aspirin’s polar nature. ❏ According to your online literature research, which solvent is most suitable for recrystallization of aspirin? ● According to my online literature research, ‘ethanol’ is most suitable for the recrystallization of aspirin. ❏ Describe three methods that you will use to prove that the product you isolated from the reaction is indeed the product you expected and not, for example, starting material. [Questions to think of] ❏ Calculate the percent yield and atom economy for each reaction. How will atom economy change using different catalysts? Percent atom economy=Mass of desired product/Total mass of product ×100. Different catalysts will increase the atom economy. ❏ Perform an economic analysis using the Cost Analysis Tool and the EcoScale rubric on each method. (Cost of each reagent was in a file on D2L Project 2 folder.) TLC and NMR are fairly expensive when it comes to the economic analysis of using these methods. Melting point is more cost-friendly but doesn’t provide the same reliable evidence as TLC and NMR. ❏ What recommendation would you make to the start-up company and justify that recommendation using the three metrics. ● Three methods we will use to prove that the product we isolated from the reaction is indeed the product we expected and not just starting material are

NMR in order to compare our spectra to spectra of aspirin found in literature, Thin Layer Chromatography (TLC) for identification, and melting point determination. Part 3: Analysis of multicomponent analgesics You will be given a sample which is a binary mixture of the analgesic from the Ingham County Health Department. You also have the pure standards of the potential components from the scenario (acetaminophen, caffeine, ibuprofen, acetanilide) and aspirin product that was purified in week 2. Perform a thin-layer chromatography (TLC) experiment to identify the unknown binary mixture. ❏ Using the standards of the pure analgesics provided, how will you identify what your mixture contains? We will identify what the mixture contains by using the thin-layer chromatography (TLC). This technique is used to separate the mixtures. The results we get from the TLC will be matched to the appropriate compounds to figure out the identity. ❏ Thin Layer Chromatography (TLC) techniques is widely used in organic synthesis for monitoring reaction completion and purity test. How does it work? ● Thin Layer Chromatography is a chromatography technique used to separate non-volatile mixtures based on differences in polarity between the mixture/compound and the chosen solvent. Polar compounds/mixtures have stronger interactions with the stationary phase and remain at the bottom of the TLC plate because they elute slower. Non-polar compounds/mixtures have less interaction with the stationary phase and go to the top of the TLC plate because they elute faster.