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CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 1 of 9 Making Guaifenesin, the active ingredient in Mucinex® by Williamson Ether Synthesis Reference: Ryan Stiles and Andrew P. Dicks , Journal of Chemical Education , Vol. 80, No. 3, 2003, pp 313-315. Please note: This is a two-day lab. Be sure to check the lab schedule and the course module for specific details on meeting times and due dates. INTRODUCTION One of the most exciting and rewarding areas that organic chemistry plays a key role is the synthesis of organic compounds with medicinal properties. In research labs, organic chemists work hard to discover new medicines; in process labs, they work harder to find ways to produce known medicines more efficiently: with a higher yield, at a lower cost, or with a lower environmental impact. In this experiment, you’ll learn how to synthesize the over-the-counter cough remedy guaifenesin, known by its trade name Mucinex®. It’s an aromatic ether that acts as an expectorant, loosening and thinning bronchial secretions. The carbon atom marked with an asterisk is an asymmetric center. As you know already, when a molecule contains an asymmetric center (*) it can exist as two enantiomers. Guaifenesin exists as a pair of enantiomers: the (S)-(+) enantiomer and the (R)-( − ) enantiomer. The (S)-(+) enantiomer is believed to be significantly more biologically active than the (R)-( − ) enantiomer, although it is synthesized and sold as a racemic mixture. The synthesis of Guaifenesin (shown above) is a two-step process. First, the nucleophile is activated via an acid/base reaction. We can then utilize the Williamson ether synthesis method (an S N 2 reaction mechanism) as the key reaction step to generate the final product. O O OH OH * Guaifenesin O OH 2-methoxyphenol + OH O O + H 2 O 2-methoxyphenoxide O O Cl OH OH + O O OH OH * guaifenesin 2-methoxyphenoxide 3-chloro-1,2-propanediol

CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 2 of 9 Reflux Some reactions are slow at room temperature and must be heated to proceed at a reasonable rate. The reaction volume and temperature must be kept constant over the course of the reaction in order to avoid confounding variables that may affect the reaction’s outcome. By selecting an appropriate solvent and keeping the reaction mixture at a constant boil, the temperature of the reaction will remain at that solvent’s boiling point (recall that there is no temperature change during a phase change). If the reaction mixture is boiled for too long at the solvent’s boiling temperature, all of the solvent would eventually be vaporized. To prevent the solvent from being vaporized while it is boiled, a reflux condenser (cold water condenser/West condenser) is attached to the neck of the reaction flask. The cold water running through the condenser enables the vaporized solvent to cool down, re-condense, and return to the reaction flask. This process of boiling and condensing the solvent during a reaction is called “refluxing”. The apparatus used for reflux reactions is shown in the picture to the left. It is important to note that the heat output of the heating mantle must be controlled carefully to prevent the solvent vapor from traveling too far up the reflux condenser. The vapor condensation line should not pass more than halfway up the reflux condenser. When using this reaction apparatus, be sure to NEVER plug a heating mantle directly into an outlet! Plug the heating mantle into the Variac, then plug the Variac into the outlet on your hood. _______________________________________________________________ Pre-lab Questions (answer all four questions) 1. Identify the nucleophile and the electrophile in this reaction. Give structures. YKK GYYGIMKI OSGMKY

CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 3 of 9 2. Draw the curved arrow mechanism for the reaction between 2-methoxyphenoxide and 3-chloro-1,2-propanediol, in the guaifenesin synthesis. Be sure to clearly show the bimolecular transition state. 3. Why would NaOH specifically deprotonate 2-methoxyphenol to generate phenoxide while in a solution of ethanol? Couldn’t ethanol act as an acid too? Explain. 4. What is the purpose of refluxing the reaction? YKK GYYGIMKI KUW GQQ UWKQGG W[KYYOUSY GSI KOQQ OSY

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CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 4 of 9 Table of Physical Constants and Chemical Hazards: Compound name Molecular weight (g/mol) M.P. or B.P. ( o C) Amount required (g or mL) As stated in the procedure Density or Molarity Amount required (in moles) Chemical Hazards 2-methoxyphenol (Density) Sodium hydroxide (Molarity) 3-chloro-1,2- propanediol (Molarity) Guaifenesin Ethanol Ethyl acetate Diethyl ether Cite your references for the above information. (Not sure how to properly cite a reference? See the single-page document on “How to cite journals websites and books in your lab report” in Canvas module-2) :

CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 5 of 9 EXPERIMENTAL PROCEDURE Day I: Williamson Ether Synthesis ASSIGNMENT : Watch the Guaifenesin Synthesis video (Canvas Module, Start Here page) before coming to the lab. It guides you through the important techniques that you will be performing in the lab. Read the chapters on S N 2 reactions and Williamson Ether Synthesis from your textbook. 1. Bring a 50 mL round bottom flask, a yellow cap, and a cork ring to the reagent hood, measure 1 mL of 2- methoxyphenol using the syringe attached to the reagent bottle, and add it to your flask. 2. Measure 6 mL of 95% ethanol using your graduated cylinder and add it to the 50 mL round bottom flask. 3. Measure 2.0 mL of a 6.25M NaOH solution using the attached syringe and place it in a 10 mL Erlenmeyer flask then add it to the reaction mixture in the round bottom flask. 4. Add a boiling chip to the reaction flask, attach a reflux condenser, and heat the mixture to reflux, using a 50 mL heating mantle and a Variac. 5. Bring a clean 10 mL Erlenmeyer flask and obtain 2.0 mL of a 50:50 solution (5.98 M) of 3-chloro-1,2-propanediol in 95% ethanol, using the attached dispensing pipette. After 10 minutes of reflux, using your 1 mL syringe, add 1.8 mL of the 3-chloro-1,2- propanediol solution dropwise over 5 minutes through the top of the reflux condenser. 6. Continue refluxing for 30 minutes. 7. Turn off the Variac, unplug the Variac and the heating mantle. 8. Remove the reflux condenser and transfer the reaction mixture into a 125 mL Erlenmeyer flask. Evaporate ethanol with a stream of air (use the hot plate if needed. Be careful not to overheat the mixture). Store the reaction mixture securely in your private drawer until the next lab period. Amount of 2-methoxyphenol added: _______ Amount of Ethanol added: Amount of NaOH solution added: Amount of 3-chloro-1,2-propanediol added: Observations from the reaction: UGYGOSKI _KQQU] M[K ±S1 ²S1 ³S1 ³S1

CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 6 of 9 Day II: Workup and Analysis 9. Transfer the reaction mixture into a separatory funnel. 10. Rinse the Erlenmeyer flask with two 5 mL portions (no more than~10 mL total) of ethyl acetate and add it to the separatory funnel. 11. Rinse the Erlenmeyer flask with ~6 mL of sat. NaCl solution. Transfer it to the separatory funnel. Leave behind any solid in the flask. 12. Rinse the Erlenmeyer flask with 3 mL of water. Transfer it to the separatory funnel. Leave behind any solid in the flask. 13. Shake the separatory funnel to partition the product, Guaifenisen, into ethyl acetate, and by-products into sat. NaCl-water (aqueous layer). 14. Drain the aqueous layer into a beaker labeled aqueous , and drain the ethyl acetate into a beaker labeled organic . 15. Put the aqueous solution back into the separatory funnel and extract again with another fresh 10 mL of ethyl acetate. 16. Drain the water into the beaker labeled aqueous and drain the ethyl acetate into the beaker labeled organic . 17. Remove any residual water from the ethyl acetate layer in the beaker by adding a scoop full of magnesium sulfate. leave it in there for 10 minutes. 18. Vacuum filter the ethyl acetate solution into a beaker. Evaporate ethyl acetate using a warm water bath and a light stream of air. 19. A slightly yellow oil will remain in the flask. In order get the product to solidify, add ~10 mL of diethyl ether. Notes/observations: QKYY UWUI[IY YMGS K]UKIYKI KWUS OSOYOGQ GSU[SY

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CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 7 of 9 20. Collect the solid by vacuum filtration (or carefully decant the liquid without disturbing the solid). Let the solid air-dry in the hood. 21. Obtain the mass of the solid. 22. Obtain the melting point. Mass of solid: Melting Point observed: WASTE DISPOSAL : Organic liquid waste should be discarded in the “Halogenated” waste bottle. Aqueous waste should be discarded in the Aqueous Waste bottle. Discard the solids in the solid waste container. Please do not put filter papers or paper towels in the solid waste container. ANALYSIS Calculate the percent yield of the final product. Read the annexure on page 9, and refer to “Appendix II: Calculating Percent Yield” (Canvas Module) for instructions, and determine the percent yield. Be sure to show your calculations. Hint: find the limiting reagent first. If you used a pure liquid, you’ll need to use density to convert milliliters to grams. If you used a solution of a reagent, you’ll need to use the molarity of the solution to convert from milliliters of solution to moles of reagent. ´±µ²M KOQYKW ´³µµM YUMKYMKW ¶¶·¶¸I ¹´¹¸¶ M YKK GYYGIMKI OSGMKY

CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 8 of 9 Post-Lab Questions (Answer all) 1. What would be the reason to observe a wide melting point range or a deviated melting point from the literature value for the final product of this reaction? 2. A student only received a 60% yield from this reaction. Explain possible reasons for this low percent yield of the final product (other than spilling, transfer losses, or human error). 3. What additional technique could you use to purify the product? 4. If you wanted to make pure (S)-(+)-guaifenesin, what reagent would you need to use in place of one that was used in your synthesis? Draw the structure, including dashed and wedged bonds, showing the correct absolute configuration (R or S). /K YMK UGYKW[KI SKQYOSM UUOSY OY QU]KW UW G ]OIKW WGSMK YMGS YMK QOYKWGY[WK [GQ[K OY OY [KW_ QOQKQ_ YMGY OSU[WOYOKY GWK UWKYKSY OS YMK YGSUQK´ 9MK ]OIKW YMK WGSMK YMK SUWK OSU[WK YMK Y[GYYGSIK´ /IKGQQ_ ]K ]U[QI MKY G SGWWU] WGSMK ! ³ ) YU MG[K G KGOWQ_ U[WK KOSGQ YGSUQK´ 9USK UYMKW WKGYUSY UYMKW YMGS UWGIYOIGQ QUYYKY I[WOSM UU[WOSMºKOQYKWOSM GSI OSIUWWKIY SKGY[WOSM IU[QI GK YMGY OSIUSUQKYK WKGIYOUSY YUUQ UQGIK UW YOIK WKGIYOUSY YGQOSM UQGIK´ 9MKYK [S]GSYKI WKGIYOUSY IUSUKYK ]OYM YMK IKYOWKI WKGIYOUS´ =K IU[QI [YK SGS_ UYMKW YKIMSOW[KY OSIQ[IOSM» IMWUSGYUMWGUM_¼ Y[GQOSGYOUS¼ IOYYOQQGYOUS¼ GSI IW_YYGQQO_GYOUS´ YKK GYYGIMKI OSGMKY

CHEM246 Fundamentals of Organic Chemistry Laboratory Guaifenesin Synthesis Page 9 of 9 Annexure: How to calculate the percent yield of a reaction In organic synthesis, percent yield provides a measurement that indicates how successful a reaction has been. Therefore, it is important to know how to calculate it correctly. Assume you performed the following reaction in the lab: OCH 3 CH 3 OH H 2 SO 4 MW: 84.16 g/mol MW: 116.20 g/mol Density: 0.67 g/mL Density: 0.92 g/mL Amount used 1.50 mL Amount obtained: 0.96 g This is a typical acid-catalyzed addition of alcohol to an alkene. In this reaction, H 2 SO 4 is used as an acid catalyst, and methanol is used as the reactant + solvent, so it is in excess. Step 1: Find the limiting reagent The reactants of this reaction are 1-hexene, methanol, and H 2 SO 4 . The reaction mechanism tells you that H 2 SO 4 acts as a catalyst, and 1-hexene and methanol react in 1:1 molar ratio. However, methanol is also the solvent for this reaction, so it is in excess. Therefore, the amount of the final product that you obtain will depend on the amount of 1-hexene used in the reaction. Hence 1- hexene is your limiting reagent. From the data given above, you can calculate the number of moles of 1-hexene as shown below: Moles of 1-hexene = (0.67 g/mL x 1.50 mL) / 84.16 g/mol = 0.01 mol Please note: If methanol was not in excess, you will have to calculate the number of moles of methanol and compare it to the moles of 1-hexene to determine the limiting reagent (the reactant with the lowest number of moles is the limiting reagent). Step 2: Find the theoretical yield of the product The reaction mechanism tells you that for every mole of hexane consumed, one mole of 2- methoxy hexane (product) forms. So, 0.01 moles of 1-hexane, in theory, should generate 0.01 moles of the product. Therefore, you can calculate the theoretical yield of the product (2-methoxy hexane) as shown below. Theoretical yield of 2-methoxy hexane = 0.01 mol x 116.20 g/mol = 1.16 g Step 3: Calculate the percent yield The mass of the final product (2-methoxy hexane) obtained is 0.96 g (see the data below the chemical equation). So, the percent yield of this reaction is, Percent yield = (0.96 g / 1.16 g) x 100% = 82.75% Hope this clarifies how to calculate the percent yield. See “Appendix II: Calculating Percent Yield” for a more detailed explanation.

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