Exp 6 Williamson Ether Synthesis

WILLIAMSON ETHER SYNTHESIS of NEROLIN

This experiment has been adapted from Miller, J., Neuzil, E. Modern Experimental Organic Chemistry, D.C. Heath and Co.: Lexington, MA 1982, pp228-231 and has undergone microwave enhancement by Danielle Falcone, class of ’05 and R. Baar, M. R.; Falcone, D.; Gordon , C. J. Chem. Educ., 2010, 87, pp 84–86.

BACKGROUND:

Alkyl aryl ethers such as nerolin are useful as perfume additives. The product you are making is used in perfumes to impart the smell of orange blossoms. The class of alkyl aryl ethers that nerolin is in are used as both perfumes and as scent fixatives. Certain scents, particularly rose, lavender, or lemon, are so volatile that evaporation causes a product to lose its fragrance. A fixative agent (such as the one you are making) lowers the rate of loss of scent, making the product retain its fragrance for a longer time. One way to synthesize these types of compounds is through a Williamson ether synthesis, which is the reaction of an alcohol (usually deprotonated) with an organohalide. The reaction proceeds through a SN2 mechanism. The alcohol itself is not nucleophilic enough to undergo the reaction on its own so it needs to be deprotonated to make it a better nucleophile.

Nerolin will be synthesized by first deprotonating 2-naphthol with potassium hydroxide. The pKa of 2-naphthol is lower than that of an alcohol due to resonance stabilization of the conjugate base, so potassium hydroxide can completely deprotonate it. Iodoethane is then added and the reaction mixture will be heated in the microwave so the SN2 reaction can take place.

Microwave enhancement: The reaction is faster in the microwave than if the reaction was refluxed because in traditional thermal heating (Bunsen burners, Thermowells, or heating mantles), heat is first absorbed by the reaction vessel (metal pans or glass vessels) and then transferred to the solvent and dissolved reagents. Our Teflon microwave reaction vessels are “transparent” to microwave energy and so the energy passes through unchanged and is directly absorbed by the reaction mixture. Not only does microwave heating speed up the rate of this reaction, but it improves the yield as well which makes for an easier purification.

SAFETY NOTES: 1. The methanolic KOH solution is corrosive. Wear disposable plastic gloves when handling. Wash affected area with copious amounts of water. IMMEDIATELY CLEAN UP ANY SPILLS. 2. 2-Naphthol and iodoethane (ethyl iodide) are at least irritants and at the most toxic and readily absorbed through the skin. Wear gloves when handling and do not breathe vapors. 3. Methanol is poisonous. Do not drink it or breathe it. 4. Assembly of the microwave rxn vessel is critical. The cap must be tight.

EXPERIMENTAL PROCEDURE: Obtain a microwave reaction vessel with cap and stir bar from your TF. Preparation of Nerolin: Wearing gloves measure 0.5 g of 2-naphthol (MW: 144.17) directly into the microwave vessel containing a stirbar. Add 5 mL of methanolic KOH solution, which contains 200 mg of

KOH (MW= 56.11). Gently stir to completely dissolve the 2-naphthol. Move to the dispensing hood and add 0.30 mL of iodoethane (MW 155.97, d= 1.940) with a graduated pipette. Cap the reaction vessel (make sure to have both white Teflon plug and cap) and tighten the cap with the wrench. Label the top of your reaction vessel with your name on a piece tape. Make sure not to cover the hole on the top of the vessel. Your TF will microwave your reaction for 10 minutes at 130 °C at 1200 W power setting. At the end of the heating period, recover your reaction vessel from the microwave turntable and let the reaction mixture cool. Spot a solution of the 2-naphthol standard (you can do this while your reaction is in the microwave to save time) and spot your reaction mixture on a TLC plate (see TLC plate below).

Work-Up Add 5 mL of H2O to your reaction mixture and transfer to a falcon tube. Add 5 mL of diethyl and shake well. Collect the top organic layer with a Pasteur pipette and repeat this step 2 more times. Each time collect the top layer and combine the organic fractions. Add the diethyl ether fractions to a large falcon tube and add 10 mL of 2 M NaOH in water. Shake well and discard the bottom layer. Repeat one more time and remove the bottom layer. Add 10 mL of saturated NaCl solution in water to the falcon tube and shake. Collect the top organic layer. Dry the solution by adding Na2SO4 (~0.5 g). Filter the suspension through a small pipette with cotton in it and collect the filtrate. Rinse the Na2SO4with 2 mL of diethyl ether and collect. Evaporate the diethyl ether away by blowing air on the sample until a solid is obtained. Record the mass of your product obtained. TLC Dissolve a small amount of your product in acetone and spot it on your TLC plate from before. Run your TLC plate in 4:1 hexane:ethylacetate, which has been provided. Record your TLC plate in your notebook and calculate the RF of your product and 2-naphthol for your postlab.

Analysis Obtain a mass of your purified product, TLC, IR, GC/MS (1 mg of product dissolved in 1.5 mL of hexane) and NMR (CDCl3).

TLC plate

Postlab Questions

1) What should be the difference in the IR for 2-naphthol and your product?

2) Why do you have to extract the reaction with 2 M NaOH in water?

3) What would be the major difference between the NMR of the starting material and the product?

4) Why do you need to add base (KOH) to the reaction?

Prelab: Purpose, reaction scheme, mechanism and procedure. Postlab: Report = Yield calculations: including determining the limiting reagent. Discussion section: You should describe how you know you made the desired product and its purity by TLC, IR, 1H NMR, GC/MS. Make sure to include the RF of the product and starting material from the TLC. Answer the postlab questions. Make sure to attach a copy of your IR, NMR and GC/MS to your report. Assign peaks for both the IR and NMR directly on the spectrum. IR: Assign C-H and C-O stretches. NMR: Assign aromatic peaks (you don’t have to assign them

individually) and both peaks that correspond to the ethyl group. (Identity which peak corresponds to which Hs on the ethyl group).