Williamson Ether Synthesis

10 Lab Report Grading Rubric$ Williamson Ether Synthesis NAME COURSE-SECTION TA: Grading Rubric Calc ulation Experimental Procedure & Reaction Tables Introduction & Reaction Tables Performance Element Earned Excellent 5 pts: The introduction begins with a statement of the purpose of the lab undertaken and then presents a though, yet, concise, introduction to the chemical theory behind the lab, including a brief discussion of the mechanisms, analytical techniques, etc, At least one diagram supports the written word. 4 pts: Procedural details are written according to the examples provided with the correct format, including product name and reaction diagram. Math (mols, equivs, etc.) is correct. Procedure is original and authentic, and a diagram of the setup is included. Reaction tables are completed and correct. 5 pts: Calculations/equations are shown and explained. Good Fair Poor 4 pts: The report begins with a statement of purpose. The introduction may miss some of the relevant chemical theory or diagrams, or have a small amount of theory incorrect, but overall demonstrates proficient knowledge about the background material. Final conclusions and overall findings & adequately presented 3 pts: Minor errors in the format or calculations exist, but all required components are present including diagram, quantities, and stoichiometry. The procedure is original and authentic. Some mistakes are present in calculation of rxn table. 2-3 pts: Report may be missing a statement of purpose. Chemical theory background is minimal, contains substantive errors, or lacks application of the theory to the current lab undertaken. Final conclusions and overall findings may be missing, unclear, or lacking detail. 0-1 pt: The introduction does not connect the principles of the laboratory with the chemical theory. Very small amounts of material are presented, and very little original thought is shown. 2 pts: The experimental procedure contains several errors and/or resembles almost exactly the procedure provided by the text with no thought behind the actual procedure followed. One to two components may be missing. Rxn table is incorrect. 3 -2 pt: Some data spectra, tables, calculations, or equations are missing or grossly incorrect. 1 pt: Two or more required components are missing. The procedure is unclear or mimics the text. The procedure lacks or presents incorrect details such as mols, equiv, conc, etc. Details may be missing. 4 pts: Minor errors exist in titles, table presentation, or the description of acquisition method(s) Calculations are shown but have minor mistakes. 0-1 pts: Data section is incomplete. There are little to no spectra, tables, or calculations. Points Data Conclusion & Analysis Post - Lab 6 pts: The conclusion accurately restates the purpose of the lab and concisely indicates whether the purpose and goals were achieved. The data collected is explained and used to verify and prove the concluded outcome. Insightful explanations are offered for unexpected results/procedures. 5 pts: The author accurately restates the purpose of the lab. Data are used to solidly verify and prove conclusions, but with some minor errors in theory and analysis. Explanations for unexpected results are offered. 4 pts: The purpose and conclusions of the lab may or may not be correct, but the author of the report makes gross errors in analyzing the data to arrive at any of these conclusions. 3-1pts: Little to no connections between the data acquired and the conclusions of the lab are presented. Data explained contains little thought and depth. 0 if conclusion is copied from a different source Points are assigned (0-10 pts) Total Score (30 pts) à Lab Report 10 Williamson Ether Synthesis: Preparation of Phenacetin from Acetaminophen 28 July 2021 ! ! ! Williamson Ether Synthesis: Preparation of Phenacetin from Acetaminophen Introduction The purpose of this experiment is to synthesize phenacetin from acetaminophen using Williamson ether synthesis, purify by recrystallization and characterize by TLC, IR and melting point. Williamson ether synthesis is widely used to synthesize ethers due to its simplicity and broad applicability to multiple alcohol and alkyl halide precursors. This process proceeds in two steps: the first is the deprotonation of alcohol to form an alkoxide ion, followed by SN2 reaction where the alkoxide then acts as a nucleophile and the alkyl halide acts as an electrophile. See figure one for the mechanism of Williamson ether synthesis. Although this process may be commonly used, there are a few limitations. For instance, since alcohols are not very acidic, a strong base such as NaH, is required for deprotonation. On the other hand, phenols are more acidic than aliphatic alcohols and therefore a weaker base can be used for deprotonation. In addition, since Williamson ether synthesis proceeds via SN2 reaction, reactions with alkyl halides that are sterically hindered, such as tertiary compounds, will not be seen. SN2 reactions proceed fastest with methyl alkyl halides, then primary followed by secondary alkyl halides. Recall that for SN2 reactions, reactions happen faster in polar, aprotic solvents. For Williamson ether synthesis, the more sterically hindered the alkyl halide, the more likely an elimination reaction will occur as opposed to a substitution reaction. Overall, Williamson ether synthesis works best with methyl and primary alkyl halides. Acetaminophen (see figure two). is the active ingredient in one of the most common over-the-counter pain relievers and fever reducers known as Tylenol. Acetaminophen has been shown to work in at least two pathways. The first pathway involves production of prostanoids in which are involved in the inflammation responses from our bodies. The second pathway involves acetaminophen being metabolized into -acetyl- -benzoquinone imine (NAPQI) in order to act on cation channel receptors in the spinal cord that suppresses signal transduction, resulting in pain relief. Phenacetin is an older pain reliever that is metabolized into acetaminophen in the body to induce pain relief (see figure three). Phenacetin was banned in the 1980s for causing cancer and kidney disease. In this experiment a rotary evaporator, also called a “rotovap”, is used in which removes solvents from compounds that are solids at room temperature (see figure five). For this experiment, ethyl acetate and 2-butanone are removed the product using the rotovap. The rotovap works by creating a vacuum in which lowers the pressure above the liquid and decreases its boiling point, causing it to evaporate faster. The hot water bath is used to heat the liquid in order to bring the solution closer to the boiling point. Figure 1. Williamson ether synthesis mechanism. This image is from the UIC Organic Chemistry Lab Manual, pg. 163. Figure 2. This image is the molecular structure of acetaminophen. Figure 3. This image is the molecular structure of phenacetin. Equations Retention Factor: Percent Yield: % yield = Procedure Before beginning any experiment, laboratory safety such as goggles, gloves and appropriate lab attire are mandatory. To start, crushed acetaminophen is measured and added to a round bottom flask or “still pot” and dissolved using 2-butanone. Next, potassium carbonate and a boiling stone are added to the flask. Then, using a syringe, iodoethane is added to the flask and the flask is gently swirled intermittently to mix the contents. The flask is then clamped to a heating mantle and the reflux apparatus is assembled (see figure four). To do this a condenser is placed on top of the still pot, followed by the tubing for the water source and drainage. Once assembled, the water and heat are turned on to begin the reflux where the reaction is refluxed for one hour. Once the hour is up, the heat is removed to allow the flask to cool to room temperature. Once the flask has cooled, the water can be turned off, and the excess potassium carbonate is filtered by vacuum filtration. To do this ethyl acetate is measured using a pipette and added to the flask using a graduated cylinder and the flask is poured into the Buchner funnel to ensure all of the product is collected in the filtrate. Washing with ethyl acetate was repeated once more. Next, a TLC plate is taken of the filtrate. On the TLC plate, three spots are spotted using a capillary at the origin. Spot one is the acetaminophen, spot two is the co-spot and spot three is the reaction mixture. Once spotted, the TLC plate is placed in the eluting chamber, also known as the TLC chamber, to allow the solvent to elute up the plate. Once the solvent has is about one centimeter from the top of the plate, the plate is removed and the solvent line is marked. The plate is then dried using a heat gun to remove the excess solvent. The TLC plate is placed under UV light to identify spots and marked with a pencil to measure the distances traveled and calculate the Rf values. Other observations such as polarity between the starting material and the product are recorded. Next, the filtrate is transferred to a separatory funnel where it is washed with 5% sodium hydroxide (NaOH) to remove any excess acetaminophen. Once the 5% NaOH is added, the funnel is capped and shaken with intermittent venting to avoid pressure build-up. Once the layers have settled, they are separated by removing the aqueous (bottom) layer and leaving the organic (top) layer in the separatory funnel. The organic layer is then washed with water and the funnel is capped and again shaken with intermittent venting. Once the layers have settled, the aqueous (bottom) layer is removed and the organic (top) layer was also removed and transferred to a separate flask. The organic layer is then dried using sodium sulfate (Na2SO4) to removed water. The flask is swirled in between additions to mix the organic layer with Na2SO4. Sodium sulfate is added until there is no new clumping. The solution is then decanted into a stillpot where it is then attached to a rotary evaporator and held together using a Keck clip. See figure five for an image of the rotovap. The vacuum pump is then turned on and closed to create suction. The flask is spun to increase surface area for a faster rate of evaporation, and the water bath is turned on. By creating a vacuum, the atmospheric pressure is lowered with the water bath raising the vapor pressure in which allows the solvent to evaporate at a lower temperature. Once the solvent is removed, the vacuum pump is turned off and the air is allowed back into the system. Next, the spinning is stopped, and the flask is removed from the rotary evaporator. The phenacetin is then transferred to a conical flask. The crude phenacetin is then recrystallized in a small amount of hot ethanol. A minimal amount of hot ethanol is added until all of the phenacetin has completely dissolved. Once dissolved, the flask is cooled to room temperature and put on ice to induce recrystallization. The formed crystals are then vacuum filtered and dried to produce pure phenacetin. The recrystallized phenacetin is then analyzed using IR. A background scan is taken first in order to tare the system. Once the background scan is complete, a small amount of the recrystallized phenacetin is added to the ATR optical sampler and the hammer is lowered to press the solid down to minimize air gaps. The spectrum is taken, and the major peaks are analyzed. It is expected to see major peaks around 1720 cm-1 to represent C=O and another major peak of medium absorption around 3500 cm-1 to represent -NH stretch. Peaks to represent the aromatic ring should be seen around 1450-1650 cm-1. Finally, the melting point of the product, phenacetin is then measured in order to compare to the literature value. To do this, a small amount of the product is collected using a capillary and placed into the apparatus. The melting point range is recorded once the sample begins to melt and once the sample has completely melted. The measured melting point range is then compared to its literature melting point range. Finally, phenacetin can be characterized given the results of the TLC plate, IR and melting point range. Figure 4. The image above is an illustration of the reflux apparatus. This image is from the UIC Organic Chemistry Lab Manual, pg. 167. Figure 5. The image above is an illustration of the rotary evaporator or “Rotovap”. This image is from the lab textbook, Experimental Organic Chemistry: A Miniscale & Microscale Approach, 5 ed., pg. 92. Results Compound MW, g/mol d (g/mL) or M (mmol/mL) Rxn Weight or V (g or mL) mmol Equivalents acetaminophen 151.17 - 1.3 g 8.60 mmol 1.00 ethyl iodide (iodoethane) 155.97 1.94 g/mL 1.0 mL 12.4 mmol 1.44 K CO 138.21 - 2.5 g 18.1 mmol 2.10 2-Butanone 72.06 0.805 g/mL 15 mL 168 mmol 19.5 Compound MW, g/mol d (g/mL) or M (mmol/mL) Rxn Weight or V (g or mL) mmol Equivalents acetaminophen 151.17 - 1.64 g 10.8 mmol 1.00 ethyl iodide (iodoethane) 155.97 1.94 g/mL 1.25 mL 15.6 mmol 1.44 K CO 138.21 - 3.14 g 22.7 mmol 2.10 2-Butanone 72.06 0.805 g/mL 18.9 mL 211 mmol 19.5 Data Analysis Referencing figure eight, this shows the calculations to obtain the actual yield while given the percent yield of 78%. First, the theoretical yield was calculated to be 1.94g and with that, using the 78% yield, the actual yield was calculated to be 1.51g. Referencing figure nine, a TLC plate was done for this reaction to determine whether or not the reaction was complete. For a complete reaction, the TLC plate should contain one spot for line 1, two spots for line two, and one spot for line three. Line two represents the co-spot that contains both acetaminophen and the reaction mixture to allow for comparison between lines one and three. The calculated Rf value of spot one that contains pure acetaminophen was 0.26 and the calculated Rf value of spot three that contains the reaction mixture was 0.46. With these Rf values, it can be said that acetaminophen is more polar than phenacetin given its lower retention factor. For IR analysis, the peaks that were expected of both acetaminophen and phenacetin are all present in the IR and NMR spectrums shown in figures ten and eleven. For the IR spectrum of acetaminophen (figure ten), five major peaks are present: -NH (3300cm-1), -OH (3180cm-1), C=O (1660cm-1), arene (1570-1450cm-1), and C-O (1250cm-1). For the IR spectrum of phenacetin (figure eleven), four major peaks are present: -NH (3300cm-1), -OH (3180cm-1), C=O (1670cm-1), arene (1570-1490cm-1), and C-O (1250cm-1). Key differences between the two IR spectrums can be seen around 3000cm-1: acetaminophen contains -NH and -OH peaks in this region, whereas phenacetin is missing the -OH peak and only has the -NH peak. This is one way to tell using IR that we no longer have acetaminophen. Similarities and differences can also be seen in the 1H NMR spectrum. Acetaminophen has five 1H signals and phenacetin has six 1H signals. Both NMR spectrums have two signals that account for the 1,4 di-substituted arene, -NH and the methyl group that is a part of the amide. The acetaminophen NMR has a peak around 9.2ppm to account for the hydrogen that is a part of the alcohol group. The phenacetin NMR has a peak around 4ppm to account for the two hydrogens that are a part of the ether group and another peak that around 1.5ppm that represents the methyl group attached to the ether. The melting point obtained of the final product was measured to be 132-134°C. The literature value melting point of phenacetin is 133-136°C. With that, the measured melting point is slightly lower but still within the range of the literature value melting point of phenacetin. Upon comparison between the measured melting point and the literature value, it can be said that the final product produced, phenacetin, was pure. Conclusion The objective of this experiment was to synthesize phenacetin from acetaminophen using Williamson ether synthesis, purify by recrystallization and characterize by using TLC, IR/NMR and melting point. IR and NMR spectroscopy analysis was one way to determine whether or not the product was pure and did not contain acetaminophen. This was easily shown in the IR spectroscopy where phenacetin did not show a peak for an alcohol group present. As for melting point analysis, the product was within 1°C of the literature value, therefore, the product isolated can be characterized as a pure product. Overall, this experiment was successful at synthesizing phenacetin from acetaminophen. Post-Lab Questions 1. (1 pt) What is the purpose of adding 5% sodium hydroxide to the reaction during the workup? How one can tell that adding the NaOH served its purpose? 2. (2 pts) Looking at each reagent used during the synthesis and work-up, decide if the following substitutions could be made, and note why or why not they are appropriate: a. Sodium hydroxide for potassium carbonate: b. Propanol for 2-butanone: c. Ether for ethyl acetate: d. Water for 5% NaOH (aq): 3. (1 pt) Why does phenacetin remain in the organic layer during work-up, but acetaminophen is extracted to the aqueous layer? 4. (1 pt) If we tried the same reaction with iodoethane and potassium carbonate, but instead used cyclohexanol as the alcohol, would the reaction still proceed as expected? 5. (1 pt) If we tried the same reaction with acetaminophen and potassium carbonate, but instead used -butyl iodide as the alkyl halide, would the reaction still proceed as expected? If not, explain why. 6. (1 pt) Why could you not synthesize phenacetin via a Williamson ether synthesis using the following reagents? 7. (2 pts) What are the best starting materials to use to generate the following ethers? 8. (1 pt) Treatment of -butyl chloride with potassium tert-butoxide leads to no significant amounts of di( butyl) ether. What would you expect to be formed?