Chem 333L Experiment 9 – Williamson Ether Synthesis Objectives 1. Synthesize 3-(2-methoxyphenoxy)-1,2-propanediol (guaifenesin) from guaiacol and 3-chloro-1,2-propediol through a Williamson Ether Synthesis. 2. Extract natural product from Mucinex simultaneously and compare IR and melting point data Theory 1. General A Williamson Ether Synthesis is a nucleophilic substitution reaction where an organic oxide anion reacts with an alkyl halide to form a new carbon-oxygen bond. In this SN2 reaction, the lone pair on the oxide anion displaces the halide from the alkyl halide group in a single step. Primary alkyl halides are preferable in this reaction because the steric hindrance of secondary and tertiary alkyl halides promotes a higher percentage of elimination (E2) product. 2. Synthetic vs. Natural Originally discovered as a natural product, Guiafensin has been used for a myriad of purposes. It can be acquired from a guiaic tree and was first used as a generic remedy. However due to recent demand for its use as a cough expectorant, a more efficient synthesis was developed for pharmaceutical purposes. In the course of our experiment we will look at the tablet form and the synthesized form to determine the differences. From this we will be able to determine which is more pure: the natural or the synthesized form. 3. Choice of Solvent Solvent choice is a crucial step in this experiment as with all substitution type reactions. The ether synthesis that we are performing involved the use of a phenoxide which is a strong base and a good nucleophile. However, because it is such a strong base, we must pick a solvent that is aprotic to eliminate any acid base chemistry that could occur. Acetonitrile fits this description and will be an ideal solvent for this experiment due to the fact that it is very polar and aprotic. 4. Phase Transfer Catalyst William Ether Synthesis is catalyzed by tetramethylammonium bromide, a phase transfer catalyst. A phase transfer is when an inorganic ion is moved from the aqueous phase of a solution to the organic phase of a solution, and any molecule that performs this transfer is referred to as a phase transfer catalyst. These types of catalysts are necessary in this experiment because, after the 4-ethylphenol is deprotonated, it exists as an oxide anion in the aqueous phase, but must be moved to the organic phase to react with the 1-iodopropane. Without the tetramethylammonium bromide, this reaction could not take place, since the reagents could not come into contact. MechanismProcedure 1. Add 3.55mL of Guaiacol/acetonitrile mixture followed by 1mL of 6.25M NaOH and a boiling stone to a 25mL round bottom flask. 2. Attach a condenser to the top of the round bottom flask and heat the mixture on a sand bath for 10 minutes with a Variac setting of 65. 3. During this time, obtain 0.50 mL of 3-chloro-1,2-propanediol mixed with 0.5mL of Acetonitrile in graduated cylinder. Also obtain a long Pasteur pipette. 4. When the round bottom flask begins to boil slowly, add the alkyl halide drop-wise into the refluxing column over the course of 5-7 minutes. 5. Allow mixture to heat for 45 minutes. Record any visible changes. 6. While mixture is refluxing, perform the following extraction of guaifensin from a tablet provided by your TA. a. Record the amount of active ingredient in the tablet you are using. b. Crush the tablet to a powder and add 5mL ethyl acetate and stir the suspension at room temp for 10 minutes. Heat slightly if needed to help dissolve the product. c. Remove any insoluble impurities by hot gravity filtration and save the filtrate. d. Add 10mL hexanes to the filtrate in 2-mL portions so that the white precipitant forms on standing for a few min. Cool the crystals and hexane mixture in an ice bath to complete crystallization. e. Collect the product by vacuum filtration and washed with 5mL cold hexanes. f. Calculate the percent of material recovered from the tablet vs. the reported amount. g. Record the melting point and IR of the sample. 7. When the 1 hour reflux has been completed, stop the reflux and transfer the round bottom flask to a Roto-Vap to remove the solvent. 8. When most of the solvent has been removed, add 3mL of deionized water. 9. Pour all the contents of the round bottom flask into a separatory funnel followed by 10 mL of ethyl acetate. Swirl and remove aqueous layer. 10. Wash aqueous layer again with 10mL of ethyl acetate Separate out the organic layer and combine the two organic layers into a 50mL Erlenmeyer flask 11. Add a micro-scoop of magnesium sulfate and allow excess water in sample to dry. 12. Evaporate the remaining solvent using the Roto-Vap until a pale yellow liquid remains. 13. Place the remaining liquid and magnetic stir bar into a 20mL scintillation vial bar and place into ice bath. 14. If crystals form, perform a suction filtration and allow your product to dry until next lab period. If no crystals, refrigerate vial until next lab period. 15. Obtain a crud melting point and crude mass. 16. Recrystallize using ethyl acetate and hexanes. 17. Obtain a pure melting point and mass. Calculate percent yield and percent difference. ApparatusReagent Table Name, Structure, MW (g/mol) Melting C Boiling C Density g/mL Properties Guaicol C7H8O2 124.14 27 205 1.129 Colorless aromatic compound. Light and air sensitive. 3-Chloro-1,2-Propanediol C3H7ClO2 -- 213 1.322 Light and air sensitive. Acrid smell. Emits toxic fumes of HCl when burning Sodium Hydroxide NaOH 39.99 318 1390 2.13 Corrosive material. Colorless, odorless solid. Ethyl Acetate C4H8O2 -83.6 77.1 0.8945 Colorless flammable liquid with a pleasant, fruity odor. Hexane C6H14 -95 69 .659 Colorless flammable liquid with mild gasoline-like odor. Magnesium sulfate MgSO4 120.36 1124 - 2.66 Hygroscopic. Drying agent, white powder. Guaifenesin C10H14O4 198.22 78-80 - - White solid with clay like consistency.Disposal • Wash excess aqueous solutions down to the drain with excess water. • Dispose of excess starting reagents and leftover product in the organic waste containers. • Dispose of soiled gloves, paper towels, and broken glass in the proper waste containers. References Chemistry 333L&334L: Microscale Experiments in Organic Chemistry Organic Chemistry 10th